Toxic Adenoma and Multinodular Toxic Goiter

  • Massimo TonaccheraEmail author
  • Dagmar Führer
Reference work entry
Part of the Endocrinology book series (ENDOCR)


Toxic thyroid adenoma (TA) is a well-encapsulated homogeneous neoplasia secreting thyroid hormones in the absence of a TSH stimulus, in an otherwise normal gland. The diagnosis involves the ability to take up iodide autonomously and the decreased or suppressed uptake in the rest ofthe thyroid, as demonstrated by scintigraphy. Toxic multinodular goiter (TMNG) encompasses a spectrum of pathologies ranging from a single hyperfunctioning nodule within an enlarged thyroid gland, which has additional normal or nonfunctioning nodules, to multiple hyperfunctiong nodules.Toxic adenoma is more common in women, and can occur at any age, being more frequent between the ages of 30 and 60 years, while TMNG tends to occur at older age. The prevalence of TA and TMNG as a cause of thyrotoxicosis varies throughout the world, and higher prevalences are observed in areas with mild to moderate iodine deficiency. Both TA and TMNG are characterized by the presence of autonomous tissues. TA are monoclonal benign encapsulated tumors that grow, metabolize iodide and secrete thyroid hormones independently of TSH control. The metabolism in autonomous adenomas is characterized mainly by a greatly increased iodine accumulation and consequently by a high iodination rate. Activating TSHR mutations and with lower frequencies Gs-alpha mutations are the main causes of TA or in hyperfunctioning nodules within TMNGs. Furthermore, a recent study has identified a second hit mutation in enhancer of zeste homolog 1 (EZH1) in TA. A significant proportion of patients with TA or TMNG develops thyrotoxicosis, and this is directly related to the duration the goiter has been present. Typically, the thyrotoxicosis comes about insidiously, hence the patient is often unaware of the symptoms. This is particularly seen in the elderly. The symptoms of thyrotoxicosis are those observed with other causes of thyroid hormone excess. The diagnosis of TA and TMNG is based on clinical examination, thyroid function tests, thyroid ultrasound and scintiscanning. Due to the underlying molecular defect, there is no spontaneous resolution of TA and TMNG. Hence ablative treatment is generally indicated, once thyroid autonomy is diagnosed with subclinical or overt hyperthyroidism. The two most widely used ablation modalities are thyroid surgery and radioiodine. Both options, their advantages and potential risks should be openly discussed with the patient and the final decision will be based on patient characteristics (age, the severity of hyperthyroidism, goitre size and extent of nodular thyroid disease, concomitant non-thyroid illness), patient’s preferences, possibly costs and and also logistics.


Toxic adenoma Toxic multinodular goiter Goiter TSH receptor mutations Cell proliferation Hyperthyroidism 131-I therapy Surgical treatment Antithyroid drugs 


  1. Abrahamsen B, Jorgensen H, Laulund AS, et al. Low serum thyrotropinlevel and duration of suppression as a predictor of major osteporotic fractures – the OPENTHYRO register cohort. J Bone Miner Res. 2014;29:2040–50.CrossRefPubMedGoogle Scholar
  2. Aghini-Lombardi F, Antonangeli L, Martino E, et al. The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano survey. J Clin Endocrinol Metab. 1999;84:561–8.PubMedPubMedCentralGoogle Scholar
  3. Aghini-Lombardi F, Fiore E, Tonacchera M, et al. The effect of voluntary iodine prophylaxis in a small rural community: the Pescopagano survey 15 years later. J Clin Endocrinol Metab. 2013;98(3):1031–9.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Agretti P, Segni M, De Marco G, et al. Prevalence of activating thyrotropin receptor and Gsα gene mutations in paediatric thyroid toxic adenomas: a multicentric Italian study. Clin Endocrinol. 2013;79(5):747–9.Google Scholar
  5. Als C, Listewnik M, Roesler H, et al. Immunogenic and non-immunogenic hyperthyroidism. Recent trends in prealpine Switzerland and in coastal Poland. Nuklearmedizin. 1995;34:92–7.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Andersen SL, Olsen J, Laurberg P. Antithyroid drug side effects in the population and in pregnancy. J Clin Endocrinol Metab. 2016;101(4):1606–14.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bähre M, Hilgers R, Lindemann C, et al. Thyroid autonomy: sensitive detection in vivo and estimation of its functional relevance using quantified high-resolution scintigraphy. Acta Endocrinol. 1988;117(2):145–53.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Baltisberger BL, Minder CE, Burgi H. Decrease of incidence of toxic nodular goiter in a region of Switzerland after full correction of mild iodine deficiency. Eur J Endocrinol. 1995;132:546–51.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Belfiore A, Sava L, Runello F, et al. Solitary autonomously functioning thyroid nodules and iodine deficiency. J Clin Endocrinol Metab. 1985;56:283–7.CrossRefGoogle Scholar
  10. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29(1):76–131.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bonnema SJ, Hegedus L. Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome. Endocr Rev. 2012;33:1–61.CrossRefGoogle Scholar
  12. Bonnema SJ, Bertelsen H, Mortensen J, et al. The feasibility of high dose iodine 131-I treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function. J Clin Endocrinol Metab. 1999;84:3636–41.PubMedPubMedCentralGoogle Scholar
  13. Bourdoux P, Ermans AM, Mukalay WA, et al. Iodine induced thyrotoxicosis in Kivu Zaire. Lancet. 1996;347:552–3.PubMedCrossRefPubMedCentralGoogle Scholar
  14. Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab. 2016;101(6):2273–83.PubMedCrossRefPubMedCentralGoogle Scholar
  15. Brandt F, Green A, Hegedus L, et al. A critical review and meta-analysis of the association between overt hyperthyroidism and mortality. Eur J Endocrinol. 2011;165:491–7.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Brandt F, Almind D, Christensen K, et al. Excess mortality in hyperthyroidism: the influence of preexisting comorbidity and genetic confounding: a Danish nationwide register-based cohort study of twins and singletons. J Clin Endocrinol Metab. 2012;97:4123–9.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Brandt F, Thvilum M, Almind D. Morbidity before and after the diagnosis of hyperthyroidism: a nation-wide register-based study. PLoS One. 2013a;8:e66711.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Brandt F, Thvilum M, Almind D. Hyperthyroidism and psychiatric morbidity: evidence from a Danish nation-wide register study. Eur J Endocrinol. 2013b;170:341–8.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Brunetti A, Chiefari E, Filetti S, et al. The 3′-5′ cyclic adenosine monophosphate response element binding protein (CREB) is functionally reduced in human toxic thyroid adenomas. Endocrinology. 2000;141:722–30.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Calebiro D, Grassi ES, Eszlinger M, et al. Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. J Clin Invest. 2016;126(9):3383–8.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Carle A, Pedersen IB, Knudsen N, et al. Epidemiology of subtypes of hyperthyroidism in Denmark: a population-based study. Eur J Endocrinol. 2011;164:801–9.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Ceccarelli C, Bencivelli W, Vitti P, et al. Outcome of radioiodine-131 therapy in hyperfunctioning thyroid nodules: a 20 years’ retrospective study. Clin Endocrinol. 2005;62(3):331–5.CrossRefGoogle Scholar
  23. Cirocchi R, Trastulli S, Randolph J, et al. Total versus subtotal thyroidectomy for multinodular non toxic goitre in adults. Cochrane Database Syst Rev. 2015;8:CD013070.Google Scholar
  24. Corvilain B, Dumont JE, Vassart G Toxic adenoma and toxic multinodular goiter. In: the Thyroid eds Braverman LE, Utiger RD Werner and Ingbar’s. Philadelphia: Lippincott-Ravn, 2000; 564–572.Google Scholar
  25. Deleu S, Allory Y, Radulescu A, et al. Characterization of autonomous thyroid adenoma: metabolism, gene expression, and pathology. Thyroid. 2000;10:131–40.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Dremier S, Coppee F, Delange F, et al. Thyroid autonomy; mechanism and clinical effects. J Clin Endocrinol Metab. 1996;81:4187–93.PubMedPubMedCentralGoogle Scholar
  27. Dremier S, Pohl V, Poteet-Smith C, et al. Activation of cyclic AMP-dependent kinase is required but may not be sufficient to mimic cyclic AMP-dependent DNA synthesis and thyroglobulin expression in dog thyroid cells. Mol Cell Biol. 1997;17:6717–26.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Dumont JE, Lamy F, Roger P, et al. Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors. Physiol Rev. 1992;72:667–97.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Duprez L, Hermans J, Van Sande J, et al. Two autonomous nodules of a patient with multinodular goiter harbor different activating mutations of the thyrotropin receptor gene. J Clin Endocrinol Metab. 1997;82:306–8.PubMedPubMedCentralGoogle Scholar
  30. Elte JW, Bussemaker JK, Haak A. The natural history of euthyroid multinodular goiter. Postgrad Med J. 1990;66:186–90.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Ermans AM, Camus M. Modifications of thyroid function induced by chronic administration of iodide in the presence of “autonomous” thyroid tissue. Acta Endocrinol. 1972;70(3):463–75.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Fast S, Bonnema SJ, Hegedus L. The majority of Danish non-toxic goitre patients are ineligible for levothyroixine suppressive therapy. Clin Endocrinol. 2008;69:653–8.CrossRefGoogle Scholar
  33. Fuhrer D, Holzapfel HP, Wonerow P, et al. Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab. 1997;82:3885–91.PubMedPubMedCentralGoogle Scholar
  34. Fuhrer D, Kubisch C, Scheibler U, et al. The extracellular thyrotropin receptor domain is not a major candidate für mutations in toxic thyroid nodules. Thyroid. 1998;8:997–1001.PubMedCrossRefPubMedCentralGoogle Scholar
  35. Fuhrer D, Warner J, Sequeira M, et al. Novel TSHR germline mutation (Met463val) masquerading as Graves’ disease in a large Welsh kindred with hyperthyroidism. Thyroid. 2000;10:1035–41.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Fuhrer D, Lewis MD, Alkhafaji F, et al. Biological activity of activating thyroid-stimulating hormone receptor mutants depends on the cellular context. Endocrinology. 2003;144(9):4018–30.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Gabriel EM, Bergert ER, Grant CS, Van Heerden JA, Thompson GB, Morris JC. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodulkar goiter. J Clin Endocrinol Metab. 1999;84:3328–3335.Google Scholar
  38. Georgopoulos NA, Sykiotis GP, Sgourou A, et al. Autonomously functioning thyroid nodules in a former iodine deficient area commonly harbor gain-of-function mutations in the thyreotropin signaling pathway. Eur J Endocrinol. 2003;149:287–92.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Gharib H, Hegedus L, Pacella CM, et al. Clinical review: nonsurgical, image-guided, minimally invasive therapy for thyroid nodules. J Clin Endocrinol Metab. 2013;98:3949–7.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Gozu HI, Bircan R, Krohn K, et al. Similar prevalence of somatic TSH receptor and Gs alpha mutations in toxic thyroid nodules in geographical regions with different iodine supply in Turkey. Eur J Endocrinol. 2006;155:535–45.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Gozu HI, Lublinghoff J, Bircan R, et al. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010;322(1–2):125–34.PubMedCrossRefPubMedCentralGoogle Scholar
  42. Hamburger JI. The autonomously functioning thyropid nodule: Goetsch’s disease. Endocr Rev. 1987;8:439–450.PubMedCrossRefPubMedCentralGoogle Scholar
  43. Ha EJ, Baek JH, Kim KW, et al. Comparative efficacy of radiofrequency and laser ablation for the treatment of benign thyroid nodules: systematic review including traditional pooling and bayesian network meta-analysis. J Clin Endocrinol Metab. 2015;100:1903–11.PubMedCrossRefPubMedCentralGoogle Scholar
  44. Havgaard Kjaer R, Andersen MS, Hansen D. Increasing incidence of juvenile thyrotoxicosis in Denmark: a nationwide study, 1998–2012. Horm Res Paediatr. 2015;84:102–7.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Hegedus K, Nygaard B, Hansen JMI. Routine thyroxine treatment to hinder postoperative recurence of nontoxic goiter justified. J Clin Endocrinol Metab. 1999;84:756–60.PubMedPubMedCentralGoogle Scholar
  46. Hegedus L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: current status and future perspectives. Endocr Rev. 2003;24:102–32.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Holm LE, Lundell G, Israelsson A, et al. Incidence of hypothyroidism occurring long after iodine-131-I therapy for hyperthyroidism. J Nucl Med. 1982;23(2):103–7.PubMedPubMedCentralGoogle Scholar
  48. Holzapfel HP, Fuhrer D, Wonerow P, et al. Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiter. J Clin Endocrinol Metab. 1997;82:4229–33.PubMedPubMedCentralGoogle Scholar
  49. Kopp P, van Sande J, Parma J, Duprez L, Gerber H, Joss E, Jameson JL, Dumont JE, Vassart G. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med. 1995;332(3):150–4.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Kopp P, Muirhead S, Jourdain N, et al. Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281→isoleucine) in the extracellular domain of the thyrotropin receptor. J Clin Invest. 1997;100(6):1634–9.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Kraemer S, Rothe K, Pfaeffle R, et al. Activating TSH-receptor mutation (Met453Thr) as a cause of adenomatous non-autoimmune hyperthyroidism in a 3-year-old boy. J Pediatr Endocrinol Metab. 2009;22(3):269–74.PubMedCrossRefPubMedCentralGoogle Scholar
  52. Krause K, Boisnard A, Ihling C, et al. Comparative proteomic analysis to dissect differences in signal transduction in activating TSH receptor mutations in the thyroid. Int J Biochem Cell Biol. 2012;44(2):290–301.PubMedCrossRefPubMedCentralGoogle Scholar
  53. Krohn K, Führer D, Holzapfel HP, et al. Clonal origin of toxic thyroid nodules with constitutively activating thyrotropin receptor mutations. J Clin Endocrinol Metab. 1998;83(1):130–4.PubMedPubMedCentralGoogle Scholar
  54. Krohn K, Wohlgemuth S, Gerber H, et al. Hot microscopic areas of iodine deficient euthyroid goiters contain constitutively activating TSH receptor mutations. J Pathol. 2000;192:37–42.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Krohn K, Führer D, Bayer Y, et al. Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev. 2005;26(4):504–24.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Krohn K, Maier J, Paschke R. Mechansims of disease: hydrogene peroxide, DNA damage and mutagenesis in the development of thyroid tumours. Nat Clin Pract Endocrinol Metab. 2007;3:713–20.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Lauberg P, Pedersen KM, Vestergard H, et al. High incidence of multinodular toxic goiter 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. 1991;229:415–20.CrossRefGoogle Scholar
  58. Lauberg P, Pedersen KM, Hreidarsson A, et al. Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab. 1998;83:765–9.CrossRefGoogle Scholar
  59. Laurberg P, Jorgensen T, Perrild H, et al. The Danish investigation on iodine intake and thyroid disease, DanThyr: status and Perspectives. Eur J Endocrinol. 2006;155:219–28.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Lavard L, Ranlov I, Perrild H, et al. Incidence of juvenile thyrotoxicosis in Denmark, 1982–1988. A nation-wide study. Eur J Endocrinol. 1994;130:563–8.CrossRefGoogle Scholar
  61. Ledent C, Dumont JE, Vassart G, et al. Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism. EMBO J. 1992;11:537–42.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Lillevang-Johansen M, Abrahamsen B, Jørgensen HL, Brix TH, Hegedüs L. Excess mortality in treated and untreated hyperthyroidism is related to cumulative periods of low serum TSH. J Clin Endocrinol Metab. 2017;102:2301. (epub).PubMedPubMedCentralCrossRefGoogle Scholar
  63. Ly S, Frates MC, Benson CB, et al. Features and outcome of autonomous thyroid nodules in children: 31 consecutive patients seen at a single center. J Clin Endocrinol Metab. 2016;101(10):3856–62.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Meller J, Siefker U, Hamann A, et al. Incidence of radioiodine induced Graves’ disease in patients with multinodular toxic goiter. Exp Clin Endocrinol Diabetes. 2006;114(5):235–9.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Monzani F, Caraccio N, Goletti O, et al. Five-year follow-up of percutaneous ethanol injection for the treatment of hyperfunctioning thyroid nodules: a study of 117 patients. Clin Endocrinol. 1997;46:9–15.CrossRefGoogle Scholar
  66. Müller K, Krohn K, Eszlinger M, et al. Effect of iodine on early stage thyroid autonomy. Genomics. 2011;97(2):94–100.PubMedCrossRefPubMedCentralGoogle Scholar
  67. Nogueira CR, Kopp P, Arseven OK, et al. Thyreotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil. Thyroid. 1999;11:1063–8.CrossRefGoogle Scholar
  68. Nygaard B, Knudsen J, Hegedus L, et al. Thyrotropin receptor antibodies and Graves’ disease, a side effect of 131-I treatment in patients with non-toxic goiter. J Clin Endocrinol Metab. 1997;82:2926–30.PubMedPubMedCentralGoogle Scholar
  69. Nygaard B, Hegedüs L, Ulriksen P, et al. Radioiodine therapy for multinodular toxic goiter. Arch Intern Med. 1999a;28(12):1364–8.CrossRefGoogle Scholar
  70. Nygaard B, Hegedus L, Nielsen KG, et al. Long-term effect of radioactive iodine on thyroid function and size in patients with solitary autonomously functioning toxic thyroid nodules. Clin Endocrinol. 1999b;50:197–202.CrossRefGoogle Scholar
  71. Palos-Paz F, Perez-Guerra O, Cameselle Teijero J, et al. Prevalence of mutations in TSHR, GNAS, PRKAR1A, and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine deficient area in NW Spain. Eur J Endocrinol. 2008;159:623–31.PubMedCrossRefPubMedCentralGoogle Scholar
  72. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature. 1993;365:649–51.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Parma J, Van Sande J, Swillens S, et al. Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3′,5′-monophosphate and inositolphosphate-Ca++ cascades. Mol Endocrinol. 1995;9:725–33.PubMedPubMedCentralGoogle Scholar
  74. Parma J, Duprez L, Van Sande J, et al. Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenoma. J Clin Endocrinol Metab. 1997;82:2695–701.PubMedPubMedCentralGoogle Scholar
  75. Paschke R, Tonacchera M, Van Sande J, et al. Identification and functional characterization of two new somatic mutations causing constitutive activation of the TSH receptor in hyperfunctioning autonomous adenomas of the thyroid. J Clin Endocrinol Metab. 1994;79:1785–9.PubMedPubMedCentralGoogle Scholar
  76. Pedersen IB, Knudsen N, Perrild H, et al. TSH receptor antibody measurement for differentiation of hyperthyroidism into Graves’ disease and multinodular toxic goiter: a comparison of two competitive binding assays. Clin Endocrinol. 2001;55:381–90.CrossRefGoogle Scholar
  77. Porcellini A, Ciullo I, Laviola L, et al. Novel mutations of thyrotropin receptor gene in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab. 1994;79:657–61.PubMedPubMedCentralGoogle Scholar
  78. Porterfield JR Jr, Thompson GB, Farley DR, et al. Evidence-based management of toxic multinodular goiter (Plummer’s disease). World J Surg. 2008; 32:1278–84.PubMedCrossRefPubMedCentralGoogle Scholar
  79. Reinwein D, Benker G, Konig MP, et al. The different types of hyperthyroidism in Europe. Results of a prospective survay of 924 patients. J Endocrinol Investig. 1988;11:193–200.CrossRefGoogle Scholar
  80. Reinwein D, Benker G, Lazarus JH, et al. A prospective randomized trial of antithyroid drug dose in Graves’ disease therapy. European Multicenter Study Group on antithyroid drug treatment. J Clin Endocrinol Metab. 1993;76(6):1516–21.PubMedPubMedCentralGoogle Scholar
  81. Reschini E, Ferrari C, Castellani M, et al. The trapping-only nodules of the thyroid gland: prevalence study. Thyroid. 2006;16(8):757–62.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Roger PP, van Staveren WC, Coulonval K, et al. Signal transduction in the human thyrocyte and its perversion in thyroid tumors. Mol Cell Endocrinol. 2010;321(1):3–19.PubMedCrossRefPubMedCentralGoogle Scholar
  83. Ross DS, Burch HB, Cooper DS, et al. American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343–421.CrossRefPubMedGoogle Scholar
  84. Russo D, Arturi F, Suarez HG, et al. Thyrotropin receptor gene alterations in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab. 1996;81:1548–51.PubMedPubMedCentralGoogle Scholar
  85. Scholz GH, Hagemann E, Arkenau C, et al. Is there a place for thyroidectomy in older patients with thyrotoxic storm and cardiorespiratory failure? Thyroid. 2003;13:933–40.PubMedCrossRefPubMedCentralGoogle Scholar
  86. Smith TJ, Hegedus L. Graves’ disease. N Engl J Med. 2016;375:1552–65.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Sorensen JR, Hegedus L, Kruse-Andersen S, et al. The impact of goitre and its treatment on the trachea, airflow, oesophagus and swallowing function. A systematic review. Best Pract Res Clin Endocrinol Metab. 2014;28:1–14.CrossRefGoogle Scholar
  88. Stanbury JB, Ermans AS, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid. 1998;8:83–100.PubMedCrossRefPubMedCentralGoogle Scholar
  89. Studer H, Peter HJ, Gerber H. Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth. Endocr Rev. 1989;10:125–35.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Studer H, Gerber H, Zbaeren J, et al. Histomorphological and immunohistochemical evidence that human nodular goiters grow by episodic replication of multiple clusters of thyroid follicular cells. J Clin Endocrinol Metab. 1992;875:1151–8.Google Scholar
  91. Tagami T, Yambe Y, Tanaka T, et al. Short-term effects of beta-adrenergic antagonists and methimazole in new-onset thyrotoxicosis caused by Graves’ disease. Intern Med. 2012;51:2285–90.PubMedCrossRefPubMedCentralGoogle Scholar
  92. Takeshita A, Nagayama Y, Yokoyama N, et al. Rarity of oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in Japan. J Clin Endocrinol Metab. 1995;80:2607–10.PubMedPubMedCentralGoogle Scholar
  93. Tarantino L, Francica G, Sordelli I, et al. Percutaneous ethanol injection of hyperfunctioning thyroid nodules: long-term follow-up in 125 patients. AJR Am J Roentgenol. 2008;190(3):800–8.PubMedCrossRefPubMedCentralGoogle Scholar
  94. Tassi V, Di Cerbo A, Porcellini A, et al. Screening of thyrotropin receptor mutations by fine-needle aspiration biopsy in autonomous functioning thyroid nodules in multinodular goiters. Thyroid. 1999;4:353–7.CrossRefGoogle Scholar
  95. Thvilum M, Brandt F, Almind D, et al. Type and extent of somatic morbidity before and after the diagnosis of hypothyroidism. A nationwide register study. PLoS One. 2013;8:e75789.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Tonacchera M, Van Sande J, Parma J, et al. TSH receptor and disease. Clin Endocrinol. 1996;44:621–33.CrossRefGoogle Scholar
  97. Tonacchera M, Chiovato L, Pinchera A, et al. Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating somatic thyrotropin receptor mutations with solitary toxic adenoma. J Clin Endocrinol Metab. 1998a;83:492–8.PubMedPubMedCentralGoogle Scholar
  98. Tonacchera M, Vitti P, Agretti P, et al. Activating thyrotropin receptor mutations in histologically heterogeneous hyperfunctioning nodules of multinodular goiter. Thyroid. 1998b;7:559–64.CrossRefGoogle Scholar
  99. Tonacchera M, Vitti P, Agretti P, et al. Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms. J Clin Endocrinol Metab. 1999;84:4155–8.PubMedPubMedCentralGoogle Scholar
  100. Tonacchera M, Agretti P, Chiovato L, et al. Activating Thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter. J Clin Endocrinol Metab. 2000;85:2270–4.PubMedPubMedCentralGoogle Scholar
  101. Tonacchera M, Pinchera A, Vitti P. Assessment of nodular goiter. Best Pract Res Clin Endocrinol Metab. 2010;24(1):51–61.PubMedCrossRefPubMedCentralGoogle Scholar
  102. Van Sande J, Parma J, Tonacchera M, et al. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab. 1995;80:2577–85.PubMedPubMedCentralGoogle Scholar
  103. Viacava P, Bocci G, Tonacchera M, et al. Markers of cell proliferation, apoptosis, and angiogenesis in thyroid adenomas: a comparative immunohistochemical and genetic investigation of functioning and non-functioning nodules. Thyroid. 2007;17:191–7.PubMedCrossRefPubMedCentralGoogle Scholar
  104. Walter MA, Briel M, Crain MC, et al. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomized controlled trials. Br Med J. 2007;334:514.CrossRefGoogle Scholar
  105. Zingrillo M, Torlontano M, Ghiggi MR, et al. Radioiodine and percutaneous ethanol injection in the treatment of large toxic thyroid nodule: a long-term study. Thyroid. 2000;10:985–9.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical and Experimental Medicine, Endocrinology UnitUniversity Hospital of Pisa, University of PisaPisaItaly
  2. 2.Department of Endocrinology, Diabetes and MetabolismUniversity Hospital Essen, University Duisburg-EssenEssenGermany

Personalised recommendations