Graves’ disease (GD) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism and occurs at all ages but especially in women of reproductive age. Graves’ hyperthyroidism is caused by autoantibodies to the thyroid-stimulating hormone receptor (TSHR) that act as agonists and induce excessive thyroid hormone secretion, releasing the thyroid gland from pituitary control. TSHR autoantibodies also underlie Graves’ orbitopathy (GO) and pretibial myxoedema. Additionally, the pathophysiology of GO (and likely pretibial myxoedema) involves the synergism of insulin-like growth factor 1 receptor (IGF1R) with TSHR autoantibodies, causing retro-orbital tissue expansion and inflammation. Although the aetiology of GD remains unknown, evidence indicates a strong genetic component combined with random potential environmental insults in an immunologically susceptible individual. The treatment of GD has not changed substantially for many years and remains a choice between antithyroid drugs, radioiodine or surgery. However, antithyroid drug use can cause drug-induced embryopathy in pregnancy, radioiodine therapy can exacerbate GO and surgery can result in hypoparathyroidism or laryngeal nerve damage. Therefore, future studies should focus on improved drug management, and a number of important advances are on the horizon.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Incidence and treatment outcomes of Graves’ disease in Thailand: a single-center retrospective observational study
Thyroid Research Open Access 19 December 2022
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $79.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
McLeod, D. S. & Cooper, D. S. The incidence and prevalence of thyroid autoimmunity. Endocrine 42, 252–265 (2012).
Taylor, P. N. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat. Rev. Endocrinol. 14, 301–316 (2018).
Adams, D. D. & Purves, H. D. Abnormal responses in the assay of thyrotropin. Proc. Univ. Otago Med. Sch. 34, 11–12 (1956). This is the first short report describing TSHR antibodies as long-acting thyroid stimulators. The author later injected serum from patients with GD into himself and his colleagues to show the presence of stimulating activity.
Perros, P. et al. Graves’ orbitopathy as a rare disease in Europe: a European Group on Graves’ Orbitopathy (EUGOGO) position statement. Orphanet J. Rare Dis. 12, 72 (2017).
Fatourechi, V. Thyroid dermopathy and acropachy. Best Pract. Res. Clin. Endocrinol. Metab. 26, 553–565 (2012).
Koren, S. et al. A 2017 survey of the clinical practice patterns in the management of relapsing Graves disease. Endocr. Pract. 25, 55–61 (2019).
Carle, A. et al. High age predicts low referral of hyperthyroid patients to specialized hospital departments: evidence for referral bias. Thyroid 23, 1518–1524 (2013).
Smith, T. J. & Hegedus, L. Graves’ disease. N. Engl. J. Med. 375, 1552–1565 (2016).
Laurberg, P. et al. Iodine intake as a determinant of thyroid disorders in populations. Best Pract. Res. Clin. Endocrinol. Metab. 24, 13–27 (2010).
Pedersen, I. B. et al. Surveyance of disease frequency in a population by linkage to diagnostic laboratory databases. A system for monitoring the incidences of hyper- and hypothyroidism as part of the Danish iodine supplementation program. Comput. Methods Prog. Biomed. 67, 209–216 (2002).
Carle, A. et al. Epidemiology of subtypes of hyperthyroidism in Denmark: a population-based study. Eur. J. Endocrinol. 164, 801–809 (2011).
Laurberg, P., Pedersen, K. M., Vestergaard, H. & Sigurdsson, G. High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves’ disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. J. Intern. Med. 229, 415–420 (1991).
Petersen, M. et al. Changes in subtypes of overt thyrotoxicosis and hypothyroidism following iodine fortification. Clin. Endocrinol. 91, 652–659 (2019).
Cerqueira, C. et al. Association of iodine fortification with incident use of antithyroid medication–a Danish nationwide study. J. Clin. Endocrinol. Metab. 94, 2400–2405 (2009).
Yang, F. et al. Chronic iodine excess does not increase the incidence of hyperthyroidism: a prospective community-based epidemiological survey in China. Eur. J. Endocrinol. 156, 403–408 (2007).
Yang, F. et al. Epidemiological survey on the relationship between different iodine intakes and the prevalence of hyperthyroidism. Eur. J. Endocrinol. 146, 613–618 (2002).
Lee, H. J., Li, C. W., Hammerstad, S. S., Stefan, M. & Tomer, Y. Immunogenetics of autoimmune thyroid diseases: a comprehensive review. J. Autoimmun. 64, 82–90 (2015).
Brix, T. H., Kyvik, K. O., Christensen, K. & Hegedus, L. Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts. J. Clin. Endocrinol. Metab. 86, 930–934 (2001). This paper describes the classic use of twins to explore the genetic contribution to GD.
Vos, X. G., Smit, N., Endert, E., Tijssen, J. G. & Wiersinga, W. M. Variation in phenotypic appearance of Graves’ disease: effect of genetic anticipation and duration of complaints. Eur. J. Endocrinol. 161, 113–118 (2009).
McLeod, D. S., Caturegli, P., Cooper, D. S., Matos, P. G. & Hutfless, S. Variation in rates of autoimmune thyroid disease by race/ethnicity in US military personnel. JAMA 311, 1563–1565 (2014).
McLeod, D. S., Cooper, D. S., Ladenson, P. W., Whiteman, D. C. & Jordan, S. J. Race/ethnicity and the prevalence of thyrotoxicosis in young Americans. Thyroid 25, 621–628 (2015).
Hiromatsu, Y., Eguchi, H., Tani, J., Kasaoka, M. & Teshima, Y. Graves’ ophthalmopathy: epidemiology and natural history. Intern. Med. 53, 353–360 (2014).
Wong, Y. et al. A British Ophthalmological Surveillance Unit (BOSU) study into dysthyroid optic neuropathy in the United Kingdom. Eye 32, 1555–1562 (2018).
Villanueva, R., Greenberg, D. A., Davies, T. F. & Tomer, Y. Sibling recurrence risk in autoimmune thyroid disease. Thyroid 13, 761–764 (2003).
Yin, X. et al. mRNA-Seq reveals novel molecular mechanisms and a robust fingerprint in Graves’ disease. J. Clin. Endocrinol. Metab. 99, E2076–E2083 (2014).
Brix, T. H., Christensen, K., Holm, N. V., Harvald, B. & Hegedus, L. A population-based study of Graves’ disease in Danish twins. Clin. Endocrinol. 48, 397–400 (1998).
Farid, N. R. & Bear, J. C. The human major histocompatibility complex and endocrine disease. Endocr. Rev. 2, 50–86 (1981). This is the first major review of the association between HLA and autoimmune thyroid disease.
Roman, S. H., Greenberg, D., Rubinstein, P., Wallenstein, S. & Davies, T. F. Genetics of autoimmune thyroid disease: lack of evidence for linkage to HLA within families. J. Clin. Endocrinol. Metab. 74, 496–503 (1992).
Barbesino, G., Tomer, Y., Concepcion, E. S., Davies, T. F. & Greenberg, D. Linkage analysis of candidate genes in autoimmune thyroid disease:1. Selected immunoregulatory genes. International Consortium for the Genetics of Autoimmune Thyroid Disease. J. Clin. Endocrinol. Metab. 83, 1580–1584 (1998).
Ban, Y. et al. Analysis of immune regulatory genes in familial and sporadic Graves’ disease. J. Clin. Endocrinol. Metab. 89, 4562–4568 (2004).
Hodge, S. E. et al. Possible interaction between HLA-DRβ1 and thyroglobulin variants in Graves’ disease. Thyroid 16, 351–355 (2006).
Qian, W. et al. Association between TSHR gene polymorphism and the risk of Graves’ disease: a meta-analysis. J. Biomed. Res. 30, 466–475 (2016).
Marin-Sanchez, A. et al. Regulation of TSHR expression in the thyroid and thymus may contribute to TSHR tolerance failure in Graves’ disease patients via two distinct mechanisms. Front. Immunol. 10, 1695 (2019).
Stefan, M. et al. Genetic-epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity. Proc. Natl Acad. Sci. USA 111, 12562–12567 (2014).
Villanueva, R. et al. Limited genetic susceptibility to severe Graves’ ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. Thyroid 10, 791–798 (2000).
Yin, X., Latif, R., Bahn, R. & Davies, T. F. Genetic profiling in Graves’ disease: further evidence for lack of a distinct genetic contribution to Graves’ ophthalmopathy. Thyroid 22, 730–736 (2012).
Ban, Y. et al. The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts. J. Autoimmun. 28, 201–207 (2007).
Yuan, F. F. et al. Genetic study of early-onset Graves’ disease in the Chinese Han population. Clin. Genet. 93, 103–110 (2018).
Heiberg, B. T. et al. High frequency of skewed X chromosome inactivation in females with autoimmune thyroid disease. A possible explanation for the female predisposition to thyroid autoimmunity. J. Clin. Endocrinol. Metab. 90, 5949–5953 (2005).
Brix, T. H. et al. High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J. Clin. Endocrinol. Metab. 90, 5949–5953 (2005).
Yin, X., Latif, R., Tomer, Y. & Davies, T. F. Thyroid epigenetics: X chromosome inactivation in patients with autoimmune thyroid disease. Ann. N. Y. Acad. Sci. 1110, 193–200 (2007).
Santiwatana, S. et al. Skewed X chromosome inactivation in girls and female adolescents with autoimmune thyroid disease. Clin. Endocrinol. 89, 863–869 (2018).
Andersen, S. L., Olsen, J., Carle, A. & Laurberg, P. Hyperthyroidism incidence fluctuates widely in and around pregnancy and is at variance with some other autoimmune diseases: a Danish population-based study. J. Clin. Endocrinol. Metab. 100, 1164–1171 (2015).
Amino, N. et al. Aggravation of thyrotoxicosis in early pregnancy and after delivery in Graves’ disease. J. Clin. Endocrinol. Metab. 55, 108–112 (1982). This study demonstrated that the surge in human chorionic gonadotropin in early pregnancy can worsen GD.
Benhaim Rochester, D. & Davies, T. F. Increased risk of Graves’ disease after pregnancy. Thyroid 15, 1287–1290 (2005).
Jansson, R. et al. The postpartum period constitutes an important risk for the development of clinical Graves’ disease in young women. Acta Endocrinol. 116, 321–325 (1987).
Rotondi, M. et al. The post partum period and the onset of Graves’ disease: an overestimated risk factor. Eur. J. Endocrinol. 159, 161–165 (2008).
Tada, H. et al. Prevalence of postpartum onset of disease within patients with Graves’ disease of child-bearing age. Endocr. J. 41, 325–327 (1994).
Mintziori, G., Kita, M., Duntas, L. & Goulis, D. G. Consequences of hyperthyroidism in male and female fertility: pathophysiology and current management. J. Endocrinol. Invest. 39, 849–853 (2016).
Andersen, S. L., Olsen, J. & Laurberg, P. Maternal thyroid disease in the Danish National Birth Cohort: prevalence and risk factors. Eur. J. Endocrinol. 174, 203–212 (2016).
Cooper, D. S. & Laurberg, P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol. 1, 238–249 (2013).
La Rocca, C., Carbone, F., Longobardi, S. & Matarese, G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol. Lett. 162, 41–48 (2014).
Stagnaro-Green, A. et al. A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. J. Clin. Endocrinol. Metab. 74, 645–653 (1992).
Sharif, K. et al. The role of stress in the mosaic of autoimmunity: an overlooked association. Autoimmun. Rev. 17, 967–983 (2018).
Falgarone, G., Heshmati, H. M., Cohen, R. & Reach, G. Mechanisms in endocrinology. Role of emotional stress in the pathophysiology of Graves’ disease. Eur. J. Endocrinol. 168, R13–R18 (2013).
Sakkas, E. G. et al. Associations of maternal oestradiol, cortisol, and TGF-beta1 plasma concentrations with thyroid autoantibodies during pregnancy and postpartum. Clin. Endocrinol. 89, 789–797 (2018).
Wickham, S. & Carr, D. J. Molecular mimicry versus bystander activation: herpetic stromal keratitis. Autoimmunity 37, 393–397 (2004).
Srinivasappa, J. et al. Molecular mimicry: frequency of reactivity of monoclonal antiviral antibodies with normal tissues. J. Virol. 57, 397–401 (1986).
Hargreaves, C. E. et al. Yersinia enterocolitica provides the link between thyroid-stimulating antibodies and their germline counterparts in Graves’ disease. J. Immunol. 190, 5373–5381 (2013).
Menconi, F., Hasham, A. & Tomer, Y. Environmental triggers of thyroiditis: hepatitis C and interferon-alpha. J. Endocrinol. Invest. 34, 78–84 (2011).
Faustino, L. C. et al. Interferon-alpha triggers autoimmune thyroid diseases via lysosomal-dependent degradation of thyroglobulin. J. Clin. Endocrinol. Metab. 103, 3678–3687 (2018).
Bartalena, L., Bogazzi, F. & Martino, E. Amiodarone-induced thyrotoxicosis: a difficult diagnostic and therapeutic challenge. Clin. Endocrinol. 56, 23–24 (2002).
Basaria, S. & Cooper, D. S. Amiodarone and the thyroid. Am. J. Med. 118, 706–714 (2005).
Vitale, M. et al. Iodide excess induces apoptosis in thyroid cells through a p53-independent mechanism involving oxidative stress. Endocrinology 141, 598–605 (2000).
DeGroot, L. Effects of irradiation on the thyroid gland. Adolesc. Endocrinol. 22, 607 (1993).
Huysmans, D. et al. Autoimmune hyperthyroidism occurring late after radioiodine treatment for volume reduction of large multinodular goiters. Thyroid 7, 535–539 (1997).
McGregor, A. M. et al. A prospective study of the effects of radio-iodine therapy on thyroid-stimulating antibody synthesis in Grave’s disease [proceedings]. J. Endocrinol. 81, 114P–115P (1979).
Laurberg, P. et al. TSH-receptor autoimmunity in Graves’ disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur. J. Endocrinol. 158, 69–75 (2008). This is an important study showing that TSHR autoantibodies disappear most rapidly after surgery and quite quickly with antithyroid drugs but take a long time to fall after radioiodine therapy.
Bartalena, L. et al. An update on medical management of Graves’ ophthalmopathy. J. Endocrinol. Invest. 28, 469–478 (2005).
Weetman, A. P. Graves’ disease following immune reconstitution or immunomodulatory treatment: should we manage it any differently? Clin. Endocrinol. 80, 629–632 (2014).
de Filette, J., Andreescu, C. E., Cools, F., Bravenboer, B. & Velkeniers, B. A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors. Hormone Metab. Res. 51, 145–156 (2019).
de Oliveira, G. L. V., Leite, A. Z., Higuchi, B. S., Gonzaga, M. I. & Mariano, V. S. Intestinal dysbiosis and probiotic applications in autoimmune diseases. Immunology 152, 1–12 (2017).
Ishaq, H. M. et al. Molecular alteration analysis of human gut microbial composition in Graves’ disease patients. Int. J. Biol. Sci. 14, 1558–1570 (2018).
Yang, M. et al. Alteration of the intestinal flora may participate in the development of Graves’ disease: a study conducted among the Han population in southwest China. Endocr. Connect. 8, 822–828 (2019).
Shi, T. T. et al. Alterations in the intestinal microbiota of patients with severe and active Graves’ orbitopathy: a cross-sectional study. J. Endocrinol. Invest. 42, 967–978 (2019).
INDIGO Project. http://www.indigo-iapp.eu/publishable-summary/.
Masetti, G. et al. Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease. Microbiome 6, 97 (2018).
Moshkelgosha, S. et al. Gut microbiome in BALB/c and C57BL/6J mice undergoing experimental thyroid autoimmunity associate with differences in immunological responses and thyroid function. Hormone Metab. Res. 50, 932–941 (2018).
Lauritano, E. C. et al. Association between hypothyroidism and small intestinal bacterial overgrowth. J. Clin. Endocrinol. Metab. 92, 4180–4184 (2007).
Paschke, R. et al. Regional stimulation of thyroid epithelial cells in Graves’ disease by lymphocytic aggregates and plasma cells. Acta Endocrinol. 125, 459–465 (1991).
Morshed, S. A., Ma, R., Latif, R. & Davies, T. F. Cleavage region thyrotropin receptor antibodies influence thyroid cell survival in vivo. Thyroid 29, 993–1002 (2019).
Arnold, B., Schonrich, G. & Hammerling, G. J. Multiple levels of peripheral tolerance. Immunol. Today 14, 12–14 (1993).
Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281–294 (2017).
Arata, N., Ando, T., Unger, P. & Davies, T. F. By-stander activation in autoimmune thyroiditis: studies on experimental autoimmune thyroiditis in the GFP+ fluorescent mouse. Clin. Immunol. 121, 108–117 (2006).
Mirakian, R., HAMMOND, L. J. & Bottazzo, G. F. Pathogenesis of thyroid autoimmunity: the Bottazzo-Feldmann hypothesis. Immunol. Today 19, 97–98 (1998).
Piccinini, L. A., Goldsmith, N. K., Schachter, B. S. & Davies, T. F. Localization of HLA-DR alpha-chain messenger ribonucleic acid in normal and autoimmune human thyroid using in situ hybridization. J. Clin. Endocrinol. Metab. 66, 1307–1315 (1988).
Pujol-Borrell, R. et al. Inappropriate major histocompatibility complex class II expression by thyroid follicular cells in thyroid autoimmune disease and by pancreatic beta cells in type I diabetes. Mol. Biol. Med. 3, 159–165 (1986). This paper is an early summary by the investigators who first showed HLA class II antigen expression on thyroid cells as an important clue to aetiology.
Mao, C. et al. Impairment of regulatory capacity of CD4+CD25+ regulatory T cells mediated by dendritic cell polarization and hyperthyroidism in Graves’ disease. J. Immunol. 186, 4734–4743 (2011).
Pan, D., Shin, Y. H., Gopalakrishnan, G., Hennessey, J. & De Groot, L. J. Regulatory T cells in Graves’ disease. Clin. Endocrinol. 71, 587–593 (2009).
Schwartz, R. H. T cell anergy. Sci. Am. 269, 62–63 (1993).
ElTanbouly, M. A. et al. VISTA is a checkpoint regulator for naive T cell quiescence and peripheral tolerance. Science 367, eaay0524 (2020).
Rapoport, B., Chazenbalk, G. D., Jaume, J. C. & McLachlan, S. M. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr. Rev. 19, 673–716 (1998).
Sanders, J., Miguel, R. N., Furmaniak, J. & Smith, B. R. TSH receptor monoclonal antibodies with agonist, antagonist, and inverse agonist activities. Methods Enzymol. 485, 393–420 (2010).
Galofre, J. C. & Davies, T. F. Autoimmune thyroid disease in pregnancy: a review. J. Womens Health 18, 1847–1856 (2009).
Furmaniak, J. et al. Photoaffinity labelling of the TSH receptor on FRTL5 cells. FEBS Lett. 215, 316–322 (1987).
Couet, J. et al. Cell surface protein disulfide-isomerase is involved in the shedding of human thyrotropin receptor ectodomain. Biochemistry 35, 14800–14805 (1996).
Chen, C. R. et al. The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim. J. Clin. Invest. 111, 1897–1904 (2003).
Nagayama, Y., Wadsworth, H. L., Russo, D., Chazenbalk, G. D. & Rapoport, B. Binding domains of stimulatory and inhibitory thyrotropin (TSH) receptor autoantibodies determined with chimeric TSH-lutropin/chorionic gonadotropin receptors. J. Clin. Invest. 88, 336–340 (1991).
Chazenbalk, G. D. et al. Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor. J. Clin. Invest. 110, 209–217 (2002). This paper describes the extracellular component of TSHR as the most immunogenic form, stimulating its use as an efficient mouse immunization model of hyperthyroidism from TSHR autoantibodies.
Latif, R., Morshed, S. A., Zaidi, M. & Davies, T. F. The thyroid-stimulating hormone receptor: impact of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on multimerization, cleavage, and signaling. Endocrinol. Metab. Clin. North. Am. 38, 319–341 (2009).
Latif, R., Michalek, K. & Davies, T. F. Subunit interactions influence TSHR multimerization. Mol. Endocrinol. 24, 2009–2018 (2010).
Latif, R., Michalek, K., Morshed, S. A. & Davies, T. F. A tyrosine residue on the TSH receptor stabilizes multimer formation. PLoS One 5, e9449 (2010).
Allen, M. D., Neumann, S. & Gershengorn, M. C. Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling. FASEB J. 25, 3687–3694 (2011).
Ando, T., Latif, R. & Davies, T. F. Antibody-induced modulation of TSH receptor post-translational processing. J. Endocrinol. 195, 179–186 (2007).
Rapoport, B., Aliesky, H. A., Chen, C. R. & McLachlan, S. M. Evidence that TSH receptor A-subunit multimers, not monomers, drive antibody affinity maturation in Graves’ disease. J. Clin. Endocrinol. Metab. 100, E871–E875 (2015).
Krieger, C. C. et al. TSH/IGF-1 receptor cross talk in Graves’ ophthalmopathy pathogenesis. J. Clin. Endocrinol. Metab. 101, 2340–2347 (2016).
Adams, D. D. & Kennedy, T. H. Evidence to suggest that LATS protector stimulates the human thyroid gland. J. Clin. Endocrinol. Metab. 33, 47–51 (1971).
Morris, J. C. et al. Identification of epitopes and affinity purification of thyroid stimulating auto-antibodies using synthetic human TSH receptor peptides. Autoimmunity 17, 287–299 (1994).
Tahara, K. et al. Epitopes for thyroid stimulating and blocking autoantibodies on the extracellular domain of the human thyrotropin receptor. Thyroid 7, 867–877 (1997).
Ando, T. et al. A monoclonal thyroid-stimulating antibody. J. Clin. Invest. 110, 1667–1674 (2002). This paper describes the first monoclonal TSHR antibody, raised in a hamster, with stimulating activity.
Sanders, J. et al. Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid 17, 395–410 (2007). This paper shows the first crystal structure of most of the TSHR extracellular sequence stabilized by a TSHR autoantibody.
McLachlan, S. M. & Rapoport, B. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid 23, 14–24 (2013).
Sanders, P. et al. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J. Mol. Endocrinol. 46, 81–99 (2011).
Jiang, X. et al. Evidence for follicle-stimulating hormone receptor as a functional trimer. J. Biol. Chem. 289, 14273–14282 (2014).
Kleinau, G. & Krause, G. Thyrotropin and homologous glycoprotein hormone receptors: structural and functional aspects of extracellular signaling mechanisms. Endocr. Rev. 30, 133–151 (2009).
Morshed, S. A., Ando, T., Latif, R. & Davies, T. F. Neutral antibodies to the TSH receptor are present in Graves’ disease and regulate selective signaling cascades. Endocrinology 151, 5537–5549 (2010).
Sun, S. et al. Antigenic “Hot-Spots” on the TSH receptor hinge region. Front. Endocrinol. 9, 765 (2018).
Allgeier, A., Laugwitz, K. L., Van Sande, J., Schultz, G. & Dumont, J. E. Multiple G-protein coupling of the dog thyrotropin receptor. Mol. Cell Endocrinol. 127, 81–90 (1997).
Frenzel, R., Voigt, C. & Paschke, R. The human thyrotropin receptor is predominantly internalized by β-arrestin 2. Endocrinology 147, 3114–3122 (2006).
Boutin, A., Eliseeva, E., Gershengorn, M. C. & Neumann, S. β-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation. FASEB J. 28, 3446–3455 (2014).
Morshed, S. A., Ma, R., Latif, R. & Davies, T. F. Biased signaling by thyroid-stimulating hormone receptor-specific antibodies determines thyrocyte survival in autoimmunity. Sci. Signal. 11, eaah4120 (2018).
Bahn, R. S. Current insights into the pathogenesis of Graves’ ophthalmopathy. Horm. Metab. Res. 47, 773–778 (2015).
Kumar, S., Nadeem, S., Stan, M. N., Coenen, M. & Bahn, R. S. A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves’ ophthalmopathy. J. Mol. Endocrinol. 46, 155–163 (2011).
Kahaly, G. J., Wuster, C., Olivo, P. D. & Diana, T. High titers of thyrotropin receptor antibodies are associated with orbitopathy in patients with Graves disease. J. Clin. Endocrinol. Metab. 104, 2561–2568 (2019).
Weightman, D. R., Perros, P., Sherif, I. H. & Kendall-Taylor, P. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 16, 251–257 (1993).
Smith, T. J. et al. Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy. Thyroid 18, 983–988 (2008).
Smith, T. J. et al. Teprotumumab for thyroid-associated ophthalmopathy. N. Engl. J. Med. 376, 1748–1761 (2017). This paper is a clinical trial report showing the first highly successful use of an IGF1R-blocking monoclonal antibody in the treatment of moderate to severe GO.
Prabhakar, B. S., Bahn, R. S. & Smith, T. J. Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr. Rev. 24, 802–835 (2003).
Douglas, R. S. et al. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J. Clin. Endocrinol. Metab. 95, 430–438 (2009).
Boelaert, K., Torlinska, B., Holder, R. L. & Franklyn, J. A. Older subjects with hyperthyroidism present with a paucity of symptoms and signs: a large cross-sectional study. J. Clin. Endocrinol. Metab. 95, 2715–2726 (2010).
Bell, L., Hunter, A. L., Kyriacou, A., Mukherjee, A. & Syed, A. A. Clinical diagnosis of Graves’ or non-Graves’ hyperthyroidism compared to TSH receptor antibody test. Endocr. Connect. 7, 504–510 (2018).
Tozzoli, R., Bagnasco, M., Giavarina, D. & Bizzaro, N. TSH receptor autoantibody immunoassay in patients with Graves’ disease: improvement of diagnostic accuracy over different generations of methods. Systematic review and meta-analysis. Autoimmun. Rev. 12, 107–113 (2012).
Ross, D. S. et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26, 1343–1421 (2016). This paper describes the current guidelines for the treatment of GD from the American Thyroid Association.
McKee, A. & Peyerl, F. TSI assay utilization: impact on costs of Graves’ hyperthyroidism diagnosis. Am. J. Manag. Care 18, e1–e14 (2012).
Struja, T. et al. Comparison of five TSH-receptor antibody assays in Graves’ disease: results from an observational pilot study. BMC Endocr. Disord. 19, 38 (2019).
Fujimoto, Y., Oka, A., Omoto, R. & Hirose, M. Ultrasound scanning of the thyroid gland as a new diagnostic approach. Ultrasonics 5, 177–180 (1967).
Blum, M., Weiss, B. & Hernberg, J. Evaluation of thyroid nodules by A-mode echography. Radiology 101, 651–656 (1971).
Ahn, H. S., Kim, H. J. & Welch, H. G. Korea’s thyroid-cancer “epidemic” – screening and overdiagnosis. N. Engl. J. Med. 371, 1765–1767 (2014).
Barbesino, G. & Tomer, Y. Clinical review: clinical utility of TSH receptor antibodies. J. Clin. Endocrinol. Metab. 98, 2247–2255 (2013).
Saeed, P., Tavakoli Rad, S. & Bisschop, P. Dysthyroid optic neuropathy. Ophthalmic Plast. Reconstr. Surg. 34 (4S Suppl. 1), 60–67 (2018).
Dolman, P. J. & Rootman, J. VISA classification for Graves orbitopathy. Ophthalmic Plast. Reconstr. Surg. 22, 319–324 (2006).
Bartalena, L. et al. Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur. J. Endocrinol. 158, 273–285 (2008).
Perini, N., Santos, R. B., Romaldini, J. H. & Villagelin, D. Thyroid acropachy: a rare manifestation of Graves disease in joints. AACE Clin. Case Rep. 5, e369–e371 (2019).
Wilson, J. M. & Jungner, Y. G. Principles and practice of mass screening for disease [Spanish]. Bol. Oficina Sanit. Panam. 65, 281–393 (1968).
Dong, A. C. & Stagnaro-Green, A. Differences in diagnostic criteria mask the true prevalence of thyroid disease in pregnancy: a systematic review and meta-analysis. Thyroid 29, 278–289 (2019).
Kahaly, G. J. et al. 2018 European Thyroid Association guideline for the management of Graves’ hyperthyroidism. Eur. Thyroid. J. 7, 167–186 (2018).
Cooper, D. S. Antithyroid drugs. N. Engl. J. Med. 352, 905–917 (2005).
Van Dijke, C. P., Heydendael, R. J. & De Kleine, M. J. Methimazole, carbimazole, and congenital skin defects. Ann. Intern. Med. 106, 60–61 (1987).
Yang, J. et al. Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China. Thyroid 25, 278–283 (2015).
Andersen, S. L., Olsen, J. & Laurberg, P. Antithyroid drug side effects in the population and in pregnancy. J. Clin. Endocrinol. Metab. 101, 1606–1614 (2016).
Wang, M. T., Lee, W. J., Huang, T. Y., Chu, C. L. & Hsieh, C. H. Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study. Br. J. Clin. Pharmacol. 78, 619–629 (2014).
Watanabe, N. et al. Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves’ disease. J. Clin. Endocrinol. Metab. 97, E49–E53 (2012).
Nakamura, H., Miyauchi, A., Miyawaki, N. & Imagawa, J. Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J. Clin. Endocrinol. Metab. 98, 4776–4783 (2013).
Maugendre, D. et al. Antithyroid drugs and Graves’ disease – prospective randomized assessment of long-term treatment. Clin. Endocrinol. 50, 127–132 (1999).
Konishi, T. et al. Drug discontinuation after treatment with minimum maintenance dose of an antithyroid drug in Graves’ disease: a retrospective study on effects of treatment duration with minimum maintenance dose on lasting remission. Endocr. J. 58, 95–100 (2011).
Kaplowitz, P. B. & Vaidyanathan, P. Update on pediatric hyperthyroidism. Curr. Opin. Endocrinol. Diabetes Obes. 27, 70–76 (2020).
Franklyn, J. A. The management of hyperthyroidism. N. Engl. J. Med. 330, 1731–1738 (1994).
Alexander, E. K. & Larsen, P. R. High dose of 131I therapy for the treatment of hyperthyroidism caused by Graves’ disease. J. Clin. Endocrinol. Metab. 87, 1073–1077 (2002).
Franklyn, J. A., Sheppard, M. C. & Maisonneuve, P. Thyroid function and mortality in patients treated for hyperthyroidism. JAMA 294, 71–80 (2005).
Gronich, N., Lavi, I., Rennert, G. & Saliba, W. Cancer risk after radioactive iodine treatment for hyperthyroidism: a cohort study. Thyroid 30, 243–250 (2020).
Kuy, S., Roman, S. A., Desai, R. & Sosa, J. A. Outcomes following thyroid and parathyroid surgery in pregnant women. Arch. Surg. 144, 399–406 (2009).
Sosa, J. A. et al. The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann. Surg. 228, 320–330 (1998).
Stavrakis, A. I., Ituarte, P. H., Ko, C. Y. & Yeh, M. W. Surgeon volume as a predictor of outcomes in inpatient and outpatient endocrine surgery. Surgery 142, 887–899 (2007).
Adam, M. A. et al. Is there a minimum number of thyroidectomies a surgeon should perform to optimize patient outcomes? Ann. Surg. 265, 402–407 (2017).
Antakia, R., Edafe, O., Uttley, L. & Balasubramanian, S. P. Effectiveness of preventative and other surgical measures on hypocalcemia following bilateral thyroid surgery: a systematic review and meta-analysis. Thyroid 25, 95–106 (2015).
Geffner, D. L. & Hershman, J. M. Beta-adrenergic blockade for the treatment of hyperthyroidism. Am. J. Med. 93, 61–68 (1992).
Wiersinga, W. M. Combined thyroid eye clinic: the importance of a multidisciplinary health care in patients with Graves’ orbitopathy. Pediatr. Endocrinol. Rev. 7, 250–253 (2010).
Terwee, C. B. et al. Measuring disease activity to predict therapeutic outcome in Graves’ ophthalmopathy. Clin. Endocrinol. 62, 145–155 (2005).
Tooley, A. A., Godfrey, K. J. & Kazim, M. Evolution of thyroid eye disease decompression-dysthyroid optic neuropathy. Eye 33, 206–211 (2019).
Eckstein, A., Esser, J., Oeverhaus, M., Saeed, P. & Jellema, H. M. Surgical treatment of diplopia in Graves orbitopathy patients. Ophthalmic Plast. Reconstr. Surg. 34 (4S Suppl. 1), 75–84 (2018).
Clarke, L. & Eckstein, A. in Graves’ Orbitopathy: A Multidisciplinary Approach - Questions and Answers (eds Wiersinga W. M. & Kahaly G. J.) 247–259 (Karger, 2017).
Eckstein, A. et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br. J. Ophthalmol. 87, 773–776 (2003).
Rotondo Dottore, G. et al. Antioxidant actions of selenium in orbital fibroblasts: a basis for the effects of selenium in Graves’ orbitopathy. Thyroid 27, 271–278 (2017).
Kahaly, G. J., Pitz, S., Hommel, G. & Dittmar, M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 90, 5234–5240 (2005).
Bartalena, L. et al. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 97, 4454–4463 (2012).
Zhu, W. et al. A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 99, 1999–2007 (2014).
Hart, R. H., Kendall-Taylor, P., Crombie, A. & Perros, P. Early response to intravenous glucocorticoids for severe thyroid-associated ophthalmopathy predicts treatment outcome. J. Ocul. Pharmacol. Ther. 21, 328–336 (2005).
Zang, S., Ponto, K. A. & Kahaly, G. J. Clinical review: intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J. Clin. Endocrinol. Metab. 96, 320–332 (2011).
Bartalena, L. et al. Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves’ orbitopathy? J. Endocrinol. Invest. 40, 547–553 (2017).
Curro, N. et al. Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid 24, 897–905 (2014).
Sisti, E. et al. Age and dose are major risk factors for liver damage associated with intravenous glucocorticoid pulse therapy for Graves’ orbitopathy. Thyroid 25, 846–850 (2015).
Kahaly, G. et al. Ciclosporin and prednisone v. prednisone in treatment of Graves’ ophthalmopathy: a controlled, randomized and prospective study. Eur. J. Clin. Invest. 16, 415–422 (1986).
Prummel, M. F. et al. Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N. Engl. J. Med. 321, 1353–1359 (1989).
Kahaly, G. J. et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol. 6, 287–298 (2018).
Rajendram, R. et al. Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2×2 factorial, double-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 6, 299–309 (2018).
Salvi, M. et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe graves’ orbitopathy: a randomized controlled study. J. Clin. Endocrinol. Metab. 100, 422–431 (2015).
Mitchell, A. L. et al. The effect of B cell depletion therapy on anti-TSH receptor antibodies and clinical outcome in glucocorticoid-refractory Graves’ orbitopathy. Clin. Endocrinol. 79, 437–442 (2013).
Stan, M. N. et al. Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 100, 432–441 (2015).
Perez-Moreiras, J. V. et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy: a randomized clinical trial. Am. J. Ophthalmol. 195, 181–190 (2018).
Mourits, M. P. et al. Radiotherapy for Graves’ orbitopathy: randomised placebo-controlled study. Lancet 355, 1505–1509 (2000).
Shams, P. N., Ma, R., Pickles, T., Rootman, J. & Dolman, P. J. Reduced risk of compressive optic neuropathy using orbital radiotherapy in patients with active thyroid eye disease. Am. J. Ophthalmol. 157, 1299–1305 (2014).
Marcocci, C. et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J. Clin. Endocrinol. Metab. 86, 3562–3567 (2001).
Oeverhaus, M. et al. Combination therapy of intravenous steroids and orbital irradiation is more effective than intravenous steroids alone in patients with Graves’ orbitopathy. Horm. Metab. Res. 49, 739–747 (2017).
Fatourechi, V. Pretibial myxedema: pathophysiology and treatment options. Am. J. Clin. Dermatol. 6, 295–309 (2005).
Alexander, E. K. et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 27, 315–389 (2017). This paper reports the American Thyroid Association consensus guidelines for the management of GD in pregnancy.
Lazarus, J. H. Pre-conception counselling in Graves’ disease. Eur. Thyroid. J. 1, 24–29 (2012).
Rotondi, M. et al. The effect of pregnancy on subsequent relapse from Graves’ disease after a successful course of antithyroid drug therapy. J. Clin. Endocrinol. Metab. 93, 3985–3988 (2008).
Casey, B. M. et al. Subclinical hyperthyroidism and pregnancy outcomes. Obstet. Gynecol. 107, 337–341 (2006).
Ochoa-Maya, M. R., Frates, M. C., Lee-Parritz, A. & Seely, E. W. Resolution of fetal goiter after discontinuation of propylthiouracil in a pregnant woman with Graves’ hyperthyroidism. Thyroid 9, 1111–1114 (1999).
Stagnaro-Green, A. et al. Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum. Thyroid 21, 1081–1125 (2011).
Samuels, S. L., Namoc, S. M. & Bauer, A. J. Neonatal thyrotoxicosis. Clin. Perinatol. 45, 31–40 (2018).
Wilson, I. B. & Cleary, P. D. Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA 273, 59–65 (1995).
Gerding, M. N. et al. Quality of life in patients with Graves’ ophthalmopathy is markedly decreased: measurement by the medical outcomes study instrument. Thyroid 7, 885–889 (1997).
Kahaly, G. J., Hardt, J., Petrak, F. & Egle, U. T. Psychosocial factors in subjects with thyroid-associated ophthalmopathy. Thyroid 12, 237–239 (2002).
Tehrani, M. et al. Disease-specific assessment of quality of life after decompression surgery for Graves’ ophthalmopathy. Eur. J. Ophthalmol. 14, 193–199 (2004).
Kahaly, G. J., Petrak, F., Hardt, J., Pitz, S. & Egle, U. T. Psychosocial morbidity of Graves’ orbitopathy. Clin. Endocrinol. 63, 395–402 (2005).
Watt, T. et al. Quality of life in patients with benign thyroid disorders. A review. Eur. J. Endocrinol. 154, 501–510 (2006).
Watt, T. et al. Which domains of thyroid-related quality of life are most relevant? Patients and clinicians provide complementary perspectives. Thyroid 17, 647–654 (2007).
Egle, U. T. et al. The relevance of physical and psychosocial factors for the quality of life in patients with thyroid-associated orbitopathy (TAO). Exp. Clin. Endocrinol. Diabetes 107, S168–S171 (1999).
Tehrani, M. et al. Disease-specific assessment of quality of life after decompression surgery for Graves ophthalmopathy. Eur. J. Ophthalmol. 14, 193–199 (2004).
Ponto, K. A. et al. Quality of life and occupational disability in endocrine orbitopathy. Dtsch. Arztebl Int. 106, 283–289 (2009).
Watt, T. et al. Validity and reliability of the novel thyroid-specific quality of life questionnaire, ThyPRO. Eur. J. Endocrinol. 162, 161–167 (2010).
Terwee, C. B., Gerding, M. N., Dekker, F. W., Prummel, M. F. & Wiersinga, W. M. Development of a disease specific quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL. Br. J. Ophthalmol. 82, 773–779 (1998).
Wong, C. K., Lang, B. H. & Lam, C. L. A systematic review of quality of thyroid-specific health-related quality-of-life instruments recommends ThyPRO for patients with benign thyroid diseases. J. Clin. Epidemiol. 78, 63–72 (2016).
Watt, T. et al. The thyroid-related quality of life measure ThyPRO has good responsiveness and ability to detect relevant treatment effects. J. Clin. Endocrinol. Metab. 99, 3708–3717 (2014).
Terwee, C. B. et al. Test-retest reliability of the GO-QOL: a disease-specific quality of life questionnaire for patients with Graves’ ophthalmopathy. J. Clin. Epidemiol. 52, 875–884 (1999).
McMillan, C., Bradley, C., Razvi, S. & Weaver, J. Psychometric evaluation of a new questionnaire measuring treatment satisfaction in hypothyroidism: the ThyTSQ. Value Health 9, 132–139 (2006).
Watt, T. et al. Improving a newly developed patient-reported outcome for thyroid patients, using cognitive interviewing. Qual. Life Res. 17, 1009–1017 (2008).
Watt, T. et al. Establishing construct validity for the thyroid-specific patient reported outcome measure (ThyPRO): an initial examination. Qual. Life Res. 18, 483–496 (2009).
Aad, G. et al. Combined measurement of the Higgs Boson Mass in pp collisions at sqrt[s]=7 and 8 TeV with the ATLAS and CMS experiments. Phys. Rev. Lett. 114, 191803 (2015).
Terwee, C. B. et al. Interpretation and validity of changes in scores on the Graves’ ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clin. Endocrinol. 54, 391–398 (2001).
Ponto, K. A. et al. Quality of life in a German Graves orbitopathy population. Am. J. Ophthalmol. 152, 483–490.e1 (2011).
Marcocci, C. et al. Selenium and the course of mild Graves’ orbitopathy. N. Engl. J. Med. 364, 1920–1931 (2011).
Bartalena, L. et al. The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy guidelines for the management of Graves’ orbitopathy. Eur. Thyroid. J. 5, 9–26 (2016).
Wiersinga, W. & Kahaly, G. Graves’ Orbitopathy a Multidisciplinary Approach 3rd edn (Karger, 2017).
Terwee, C. et al. Long-term effects of Graves’ ophthalmopathy on health-related quality of life. Eur. J. Endocrinol. 146, 751–757 (2002).
Terwee, C. B. & Wiersinga, W. M. Graves’ quality of life. Ophthalmology 114, 1416–1417 (2007).
Rapoport, B., Aliesky, H. A., Banuelos, B., Chen, C. R. & McLachlan, S. M. A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor. J. Immunol. 194, 4154–4161 (2015). This paper reports the first mouse model to develop spontaneous autoimmune hyperthyroidism.
Furmaniak, J., Sanders, J. & Rees Smith, B. Blocking type TSH receptor antibodies. Autoimmun. Highlights 4, 11–26 (2013).
Marcinkowski, P. et al. A new highly thyrotropin receptor-selective small-molecule antagonist with potential for the treatment of Graves’ orbitopathy. Thyroid 29, 111–123 (2019).
Fassbender, J., Holthoff, H. P., Li, Z. & Ungerer, M. Therapeutic effects of short cyclic and combined epitope peptides in a long-term model of Graves’ disease and orbitopathy. Thyroid 29, 258–267 (2019).
Jansson, L., Vrolix, K., Jahraus, A., Martin, K. F. & Wraith, D. C. Immunotherapy with apitopes blocks the immune response to TSH receptor in HLA-DR transgenic mice. Endocrinology 159, 3446–3457 (2018).
Pearce, S. H. S. et al. Antigen-specific immunotherapy with thyrotropin receptor peptides in Graves’ hyperthyroidism: a phase I study. Thyroid 29, 1003–1011 (2019).
Paridaens, D., van den Bosch, W. A., van der Loos, T. L., Krenning, E. P. & van Hagen, P. M. The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye 19, 1286–1289 (2005).
Ayabe, R., Rootman, D. B., Hwang, C. J., Ben-Artzi, A. & Goldberg, R. Adalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye disease. Ophthalmic Plast. Reconstr. Surg. 30, 415–419 (2014).
Allison, A. C. Mechanisms of action of mycophenolate mofetil in preventing chronic rejection. Transpl. Proc. 34, 2863–2866 (2002).
Ye, X. et al. Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves’ orbitopathy. Clin. Endocrinol. 86, 247–255 (2017).
Perez-Moreiras, J. V., Alvarez-Lopez, A. & Gomez, E. C. Treatment of active corticosteroid-resistant Graves’ orbitopathy. Ophthalmic Plast. Reconstr. Surg. 30, 162–167 (2014).
Stan, M. N. & Salvi, M. Management of endocrine disease: rituximab therapy for Graves’ orbitopathy - lessons from randomized control trials. Eur. J. Endocrinol. 176, R101–R109 (2017).
Cordoba, F. et al. A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion. Am. J. Transpl. 15, 2825–2836 (2015).
Ristov, J. et al. Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody. Am. J. Transpl. 18, 2895–2904 (2018).
Kahaly, G. J. et al. A novel anti-Cd40 monoclonal antibody, iscalimab, for control of Graves’ hyperthyroidism - a proof-of-concept trial. J. Clin. Endocrinol. Metab. 105, dgz013 (2020).
Davies, T. F. & Latif, R. Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies. Expert. Opin. Ther. Targets 19, 835–847 (2015).
Gershengorn, M. C. & Neumann, S. Update in TSH receptor agonists and antagonists. J. Clin. Endocrinol. Metab. 97, 4287–4292 (2012).
Furszyfer, J., Kurland, L. T., McConahey, W. M. & Elveback, L. R. Graves’ disease in Olmsted county, Minnesota, 1935 through 1967. Mayo Clin. Proc. 45, 636–644 (1970).
Holm, I. A. et al. Smoking and other lifestyle factors and the risk of Graves’ hyperthyroidism. Arch. Intern. Med. 165, 1606–1611 (2005).
Phillips, D. I., Barker, D. J., Rees Smith, B., Didcote, S. & Morgan, D. The geographical distribution of thyrotoxicosis in England according to the presence or absence of TSH-receptor antibodies. Clin. Endocrinol. 23, 283–287 (1985).
Cox, S. P., Phillips, D. I. & Osmond, C. Does infection initiate Graves disease? A population based 10 year study. Autoimmunity 4, 43–49 (1989).
Vanderpump, M. P. et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin. Endocrinol. 43, 55–68 (1995). This paper is the follow-up to the classic epidemiological study of autoimmune thyroid disease in a defined community.
Mostbeck, A. et al. The incidence of hyperthyroidism in Austria from 1987 to 1995 before and after an increase in salt iodization in 1990. Eur. J. Nucl. Med. 25, 367–374 (1998).
Thjodleifsson, B. A study of Graves’ disease in Iceland. Acta Med. Scand. 198, 309–314 (1975).
Haraldsson, A., Gudmundsson, S. T., Larusson, G. & Sigurdsson, G. Thyrotoxicosis in Iceland 1980–1982. An epidemiological survey. Acta Med. Scand. 217, 253–258 (1985).
Berglund, J., Christensen, S. B. & Hallengren, B. Total and age-specific incidence of Graves’ thyrotoxicosis, toxic nodular goitre and solitary toxic adenoma in Malmo 1970–1974. J. Intern. Med. 227, 137–141 (1990).
Lundgren, E. & Borup Christensen, S. Decreasing incidence of thyrotoxicosis in an endemic goitre inland area of Sweden. Clin. Endocrinol. 33, 133–138 (1990).
Winsa, B. et al. Stressful life events and Graves’ disease. Lancet 338, 1475–1479 (1991).
Berglund, J., Ericsson, U. B. & Hallengren, B. Increased incidence of thyrotoxicosis in Malmo during the years 1988–1990 as compared to the years 1970–1974. J. Intern. Med. 239, 57–62 (1996).
Abraham-Nordling, M. et al. Incidence of hyperthyroidism in Sweden. Eur. J. Endocrinol. 165, 899–905 (2011).
Baltisberger, B. L., Minder, C. E. & Burgi, H. Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency. Eur. J. Endocrinol. 132, 546–549 (1995).
Galofre, J. C., Fernandez-Calvet, L., Rios, M. & Garcia-Mayor, R. V. Increased incidence of thyrotoxicosis after iodine supplementation in an iodine sufficient area. J. Endocrinol. Invest. 17, 23–27 (1994).
Galofre, J. C. et al. Incidence of different forms of thyroid dysfunction and its degrees in an iodine sufficient area. Thyroidology 6, 49–54 (1994).
Paunkovic, N., Paunkovic, J., Pavlovic, O. & Paunovic, Z. The significant increase in incidence of Graves’ disease in eastern Serbia during the civil war in the former Yugoslavia (1992 to 1995). Thyroid 8, 37–41 (1998).
Brownlie, B. E. & Wells, J. E. The epidemiology of thyrotoxicosis in New Zealand: incidence and geographical distribution in north Canterbury, 1983–1985. Clin. Endocrinol. 33, 249–259 (1990).
Barbesino, G. Misdiagnosis of Graves’ disease with apparent severe hyperthyroidism in a patient taking biotin megadoses. Thyroid 26, 860–863 (2016).
Roos, J. C. P., Paulpandian, V. & Murthy, R. Serial TSH-receptor antibody levels to guide the management of thyroid eye disease: the impact of smoking, immunosuppression, radio-iodine, and thyroidectomy. Eye 33, 212–217 (2019).
Shine, B., Fells, P., Edwards, O. M. & Weetman, A. P. Association between Graves’ ophthalmopathy and smoking. Lancet 335, 1261–1263 (1990).
Bertelsen, J. B. & Hegedus, L. Cigarette smoking and the thyroid. Thyroid 4, 327–331 (1994).
Wiersinga, W. M. Smoking and thyroid. Clin. Endocrinol. 79, 145–151 (2013).
Rapoport, B., Alsabeh, R., Aftergood, D. & McLachlan, S. Elephantiasic pretibial myxedema: insight into (and a hypothesis regarding) the pathogenesis of the extrathyroidal manifestations of Graves’ disease. Thyroid 10, 685–692 (2000).
Sabini, E. et al. Occurrence of Graves’ orbitopathy and Graves’ hyperthyroidism after a trauma to the eye. Eur. Thyroid. J. 7, 51–54 (2018).
Dutton, J. J. Anatomic considerations in thyroid eye disease. Ophthalmic Plast. Reconstr. Surg. 34 (4S Suppl. 1), 7–12 (2018).
McLachlan, S. M., Nagayama, Y. & Rapoport, B. Insight into Graves’ hyperthyroidism from animal models. Endocr. Rev. 26, 800–832 (2005).
Nagayama, Y. et al. A novel murine model of Graves’ hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor. J. Immunol. 168, 2789–2794 (2002). This study describes the current classic approach to murine hyperthyroidism, that is, immunization with most of the TSHR ectodomain.
Kaneda, T. et al. An improved Graves’ disease model established by using in vivo electroporation exhibited long-term immunity to hyperthyroidism in BALB/c mice. Endocrinology 148, 2335–2344 (2007).
Holthoff, H. P. et al. Prolonged TSH receptor A subunit immunization of female mice leads to a long-term model of Graves’ disease, tachycardia, and cardiac hypertrophy. Endocrinology 156, 1577–1589 (2015).
Horie, I. et al. Distinct role of T helper type 17 immune response for Graves’ hyperthyroidism in mice with different genetic backgrounds. Autoimmunity 44, 159–165 (2011).
Nakahara, M. et al. Adoptive transfer of antithyrotropin receptor (TSHR) autoimmunity from TSHR knockout mice to athymic nude mice. Endocrinology 153, 2034–2042 (2012).
Zhao, S. X. et al. Orbital fibrosis in a mouse model of Graves’ disease induced by genetic immunization of thyrotropin receptor cDNA. J. Endocrinol. 210, 369–377 (2011).
Schluter, A. et al. Genetic immunization with mouse thyrotrophin hormone receptor plasmid breaks self-tolerance for a murine model of autoimmune thyroid disease and Graves’ orbitopathy. Clin. Exp. Immunol. 191, 255–267 (2018).
Milham, S. Scalp defects in infants of mothers treated for hyperthyroidism with methimazole or carbimazole during pregnancy. Teratology 32, 321 (1985). This paper describes methimazole embryopathy, a rare but unpleasant complication of the drug.
Clementi, M. et al. Methimazole embryopathy: delineation of the phenotype. Am. J. Med. Genet. 83, 43–46 (1999).
Bahn, R. S. et al. The role of propylthiouracil in the management of Graves’ disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 19, 673–674 (2009).
Cooper, D. S. & Rivkees, S. A. Putting propylthiouracil in perspective. J. Clin. Endocrinol. Metab. 94, 1881–1882 (2009).
Andersen, S. L., Olsen, J., Wu, C. S. & Laurberg, P. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J. Clin. Endocrinol. Metab. 98, 4373–4381 (2013).
Seo, G. H., Kim, T. H. & Chung, J. H. Antithyroid drugs and congenital malformations: a nationwide Korean cohort study. Ann. Intern. Med. 168, 405–413 (2018). This paper describes the potential for both propylthiouracil and methimazole to cause congenital defects.
T.F.D. acknowledges NIH funding for his research (grants DK069713, DK052464), the VA Merit Award program and the Segal Family Fund. A.K.E. acknowledges DFG funding for research (BE 3177/1-7, EC 3179/3, GRK 2098) and EU funding IAPP (GAN 612116) INDIGO.
The authors declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks D. Cooper, J. Orgiazzi, J. Lazarus, M. Salvi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Davies, T.F., Andersen, S., Latif, R. et al. Graves’ disease. Nat Rev Dis Primers 6, 52 (2020). https://doi.org/10.1038/s41572-020-0184-y
This article is cited by
Incidence and treatment outcomes of Graves’ disease in Thailand: a single-center retrospective observational study
Thyroid Research (2022)
Clinical value of functional thyrotropin receptor antibodies in Serbian patients with Graves’ orbitopathy
Journal of Endocrinological Investigation (2022)
Thyroid dysfunction following vaccination with COVID-19 vaccines: a basic review of the preliminary evidence
Journal of Endocrinological Investigation (2022)
Journal of Endocrinological Investigation (2022)
Autoimmune and inflammatory thyroid diseases following vaccination with SARS-CoV-2 vaccines: from etiopathogenesis to clinical management