Langenbeck's Archives of Surgery

, 396:1127 | Cite as

Molecular pathogenesis of nodular goiter

  • Ralf PaschkeEmail author
Review Article



Familial clustering of goiters mostly with an autosomal dominant pattern of inheritance has repeatedly been reported. Moreover, other environmental and etiologic factors are likely to be involved in the development of euthyroid goiter. Therefore, a multifactorial etiology based on complex interactions of both genetic predisposition and the individuals’ environment is likely.


The line of events from early thyroid hyperplasia to multinodular goiter argues for the predominant neoplastic (i.e., originating from a single mutated cell) character of nodular structures. Etiologically, relevant somatic mutations are known in two thirds of papillary and follicular thyroid carcinomas and hot thyroid nodules. In contrast, the somatic mutations relevant for benign cold or benign isocaptant thyroid nodules which constitute the majority of thyroid nodules are unknown.


The nodular process is triggered by the oxidative nature of thyroid hormone synthesis or additional oxidative stress caused by iodine deficiency or smoking. If the antioxidant defense is not effective, this oxidative stress will cause DNA damage followed by an increase of the spontaneous mutation rate which is a substrate for tumorogenesis.


Therefore, the hallmark of thyroid physiology—H2O2 production during hormone synthesis—is very likely the ultimate cause for the frequent mutagenesis in the thyroid gland. Because iodine deficiency increases the oxidative burden, DNA damage and mutagenesis could provide the basis for the frequent nodular transformation of endemic goiters.


Goiter Multinodular Molecular etiology Genetic predisposition 



R.P. was funded by DFG, Thyssen Stiftung, Krebshilfe, and Wilhelm Sander Stiftung.

Conflicts of interest



  1. 1.
    Hedinger C, Williams ED, Sobin LH (1989) The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 63:908–911PubMedCrossRefGoogle Scholar
  2. 2.
    Belfiore A, La Rosa GL, La Porta GA et al (1992) Cancer risk in patients with cold thyroid nodules: relevance of iodine intake, sex, age, and multinodularity. Am J Med 93:363–369PubMedCrossRefGoogle Scholar
  3. 3.
    Knudsen N, Perrild H, Christiansen E et al (2000) Thyroid structure and size and two-year follow-up of solitary cold thyroid nodules in an unselected population with borderline iodine deficiency. Eur J Endocrinol 142:224–230PubMedCrossRefGoogle Scholar
  4. 4.
    Chan JKC, Hirokawa M, Evans H, Williams ED, Osamura Y, Cady B, Sobrinho-Simoes M, Derwahl M, Paschke R, Belge G, Oriola J, Studer H, Eng C, Asa SL, Lloyd RV, Baloch Z, Ghossein R, Fagin JA (2004) Follicular adenoma. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds) WHO classification of tumours. Pathology and genetics of tumours of endocrine organs. IARC Press, Lyon, pp 98–103Google Scholar
  5. 5.
    Berghout A, Wiersinga WM, Smits NJ et al (1990) Interrelationships between age, thyroid volume, thyroid nodularity, and thyroid function in patients with sporadic nontoxic goiter. Am J Med 89:602–608PubMedCrossRefGoogle Scholar
  6. 6.
    Knudsen N, Laurberg P, Perrild H et al (2002) Risk factors for goiter and thyroid nodules. Thyroid 12:879–888PubMedCrossRefGoogle Scholar
  7. 7.
    Pisarikova B, Herzig I, Riha J (1996) Inorganic anions with a potential goitrogenic effect in drinking water supply for humans and animals. Vet Med (Praha) 41:33–39Google Scholar
  8. 8.
    Scanelli G (2002) Lithium thyrotoxicosis. Report of a case and review of the literature. Recenti Prog Med 93:100–103PubMedGoogle Scholar
  9. 9.
    Brix TH, Hansen PS, Kyvik KO et al (2000) Cigarette smoking and risk of clinically overt thyroid disease: a population-based twin case-control study. Arch Intern Med 160:661–666PubMedCrossRefGoogle Scholar
  10. 10.
    Brix TH, Kyvik KO, Hegedus L (1999) Major role of genes in the etiology of simple goiter in females: a population-based twin study. J Clin Endocrinol Metab 84:3071–3075PubMedCrossRefGoogle Scholar
  11. 11.
    Knudsen N, Bulow I, Laurberg P et al (2002) Parity is associated with increased thyroid volume solely among smokers in an area with moderate to mild iodine deficiency. Eur J Endocrinol 146:39–43PubMedCrossRefGoogle Scholar
  12. 12.
    Krohn K, Fuhrer D, Bayer Y et al (2005) Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev 26:504–524PubMedCrossRefGoogle Scholar
  13. 13.
    Hansen PS, Brix TH, Bennedbaek FN et al (2004) Genetic and environmental causes of individual differences in thyroid size: a study of healthy Danish twins. J Clin Endocrinol Metab 89:2071–2077PubMedCrossRefGoogle Scholar
  14. 14.
    Bayer Y, Neumann S, Meyer B et al (2004) Genome-wide linkage analysis reveals evidence for four new susceptibility loci for familial euthyroid goiter. J Clin Endocrinol Metab 89:4044–4052PubMedCrossRefGoogle Scholar
  15. 15.
    Bignell GR, Canzian F, Shayeghi M et al (1997) Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer. Am J Hum Genet 61:1123–1130PubMedCrossRefGoogle Scholar
  16. 16.
    Neumann S, Bayer Y, Reske A et al (2003) Further indications for genetic heterogeneity of euthyroid familial goiter. J Mol Med 81:736–745PubMedCrossRefGoogle Scholar
  17. 17.
    Brix TH, Hegedüs L (2000) Genetic and environmental factors in the aetiology of simple goitre. Ann Med 32:153–156PubMedCrossRefGoogle Scholar
  18. 18.
    Geerdsen JP, Hee P (1982) Nontoxic goitre. I. Surgical complications and longterm prognosis. Acta Chir Scand 148:221–224PubMedGoogle Scholar
  19. 19.
    Piraneo S, Vitri P, Galimberti A et al (1997) Ultrasonographic surveillance after surgery for euthyroid goitre in patients treated or not with thyroxine. Eur J Surg 163:21–26PubMedGoogle Scholar
  20. 20.
    Corral J, Martin C, Perez R et al (1993) Thyroglobulin gene point mutation associated with non-endemic simple goitre. Lancet 341:462–464PubMedCrossRefGoogle Scholar
  21. 21.
    Gonzalez-Sarmiento R, Corral J, Mories MT et al (2001) Monoallelic deletion in the 5' region of the thyroglobulin gene as a cause of sporadic nonendemic simple goiter. Thyroid 11:789–793PubMedCrossRefGoogle Scholar
  22. 22.
    Everett LA, Glaser B, Beck JC et al (1997) Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 17:411–422PubMedCrossRefGoogle Scholar
  23. 23.
    Masmoudi S, Charfedine I, Hmani M et al (2000) Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation. Am J Med Genet 90:38–44PubMedCrossRefGoogle Scholar
  24. 24.
    Fujiwara H, Tatsumi K, Miki K et al (1998) Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect. J Clin Endocrinol Metab 83:2940–2943PubMedCrossRefGoogle Scholar
  25. 25.
    Matsuda A, Kosugi S (1997) A homozygous missense mutation of the sodium /iodide symporter gene causing iodide transport defect. J Clin Endocrinol Metab 82:3966–3971PubMedCrossRefGoogle Scholar
  26. 26.
    Neumann S, Willgerodt H, Ackermann F et al (1999) Linkage of familial euthyroid goiter to the multinodular goiter-1 locus and exclusion of the candidate genes thyroglobulin, thyroperoxidase, and Na+/I- symporter. J Clin Endocrinol Metab 84:3750–3756 [In Process Citation]PubMedCrossRefGoogle Scholar
  27. 27.
    Capon F, Tacconelli A, Giardina E et al (2000) Mapping a dominant form of multinodular goiter to chromosome Xp22. Am J Hum Genet 67:1004–1007PubMedCrossRefGoogle Scholar
  28. 28.
    Many MC, Denef JF, Hamudi S et al (1986) Effects of iodide and thyroxine on iodine-deficient mouse thyroid: a morphological and functional study. J Endocrinol 110:203–210PubMedCrossRefGoogle Scholar
  29. 29.
    Raspe E, Dumont JE (1995) Tonic modulation of dog thyrocyte H2O2 generation and I- uptake by thyrotropin through the cyclic adenosine 3',5'-monophosphate cascade. Endocrinology 136:965–973PubMedCrossRefGoogle Scholar
  30. 30.
    Krohn K, Wohlgemuth S, Gerber H et al (2000) Hot microscopic areas of iodine deficient euthyroid goiters contain constitutively activating TSH receptor mutations. J Pathol 192:37–42PubMedCrossRefGoogle Scholar
  31. 31.
    Abs R, Stevenaert A, Beckers A (1994) Autonomously functioning thyroid nodules in a patient with a thyrotropin-secreting pituitary adenoma: possible cause–effect relationship. Eur J Endocrinol 131:355–358PubMedCrossRefGoogle Scholar
  32. 32.
    Studer H, Huber G, Derwahl M et al (1989) The transformation of Basedow's struma into nodular goiter: a reason for recurrence of hyperthyroidism. Schweiz Med Wochenschr 119:203–208PubMedGoogle Scholar
  33. 33.
    Cheung NW, Boyages SC (1997) The thyroid gland in acromegaly: an ultrasonographic study. Clin Endocrinol (Oxf) 46:545–549CrossRefGoogle Scholar
  34. 34.
    Dumont JE, Ermans AM, Maenhaut C et al (1995) Large goitre as a maladaptation to iodine deficiency. Clin Endocrinol (Oxf) 43:1–10CrossRefGoogle Scholar
  35. 35.
    Maier J, Van SH, Van OC et al (2007) Iodine deficiency activates antioxidant genes and causes DNA damage in the thyroid gland of rats and mice. Biochim Biophys Acta 1773:990–999PubMedCrossRefGoogle Scholar
  36. 36.
    Gerard AC, Poncin S, Caetano B et al (2008) Iodine deficiency induces a thyroid stimulating hormone-independent early phase of microvascular reshaping in the thyroid. Am J Pathol 172:748–760PubMedCrossRefGoogle Scholar
  37. 37.
    Howie AF, Arthur JR, Nicol F et al (1998) Identification of a 57-kilodalton selenoprotein in human thyrocytes as thioredoxin reductase and evidence that its expression is regulated through the calcium-phosphoinositol signaling pathway. J Clin Endocrinol Metab 83:2052–2058PubMedCrossRefGoogle Scholar
  38. 38.
    Howie AF, Walker SW, Akesson B et al (1995) Thyroidal extracellular glutathione peroxidase: a potential regulator of thyroid-hormone synthesis. Biochem J 308:713–717PubMedGoogle Scholar
  39. 39.
    Demelash A, Karlsson JO, Nilsson M et al (2004) Selenium has a protective role in caspase-3-dependent apoptosis induced by H2O2 in primary cultured pig thyrocytes. Eur J Endocrinol 150:841–849PubMedCrossRefGoogle Scholar
  40. 40.
    Krohn K, Maier J, Paschke R (2007) Mechanisms of disease: hydrogen peroxide. DNA damage and mutagenesis in the development of thyroid tumors. Nat Clin Pract Endocrinol Metab 3:713–720PubMedCrossRefGoogle Scholar
  41. 41.
    Maier J, Van SH, Van OC et al (2006) Deoxyribonucleic acid damage and spontaneous mutagenesis in the thyroid gland of rats and mice. Endocrinology 147:3391–3397PubMedCrossRefGoogle Scholar
  42. 42.
    van Steeg H, Mullenders LH, Vijg J (2000) Mutagenesis and carcinogenesis in nucleotide excision repair-deficient XPA knock out mice. Mutat Res 450:167–180PubMedCrossRefGoogle Scholar
  43. 43.
    Cardoso LC, Martins DC, Figueiredo MD et al (2001) Ca(2+)/nicotinamide adenine dinucleotide phosphate-dependent H(2)O(2) generation is inhibited by iodide in human thyroids. J Clin Endocrinol Metab 86:4339–4343PubMedCrossRefGoogle Scholar
  44. 44.
    Cooke MS, Evans MD, Dizdaroglu M et al (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214PubMedCrossRefGoogle Scholar
  45. 45.
    Poncin S, Gerard AC, Boucquey M et al (2008) Oxidative stress in the thyroid gland: from harmlessness to hazard depending on the iodine content. Endocrinology 149:424–433PubMedCrossRefGoogle Scholar
  46. 46.
    Parma J, Duprez L, Van Sande J et al (1993) Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365:649–651PubMedCrossRefGoogle Scholar
  47. 47.
    Führer D, Holzapfel HP, Wonerow P et al (1997) Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab 82:3885–3891PubMedCrossRefGoogle Scholar
  48. 48.
    Georgopoulos NA, Sykiotis GP, Sgourou A et al (2003) Autonomously functioning thyroid nodules in a former iodine-deficient area commonly harbor gain-of-function mutations in the thyrotropin signaling pathway. Eur J Endocrinol 149:287–292PubMedCrossRefGoogle Scholar
  49. 49.
    Gozu HI, Bircan R, Krohn K et al (2006) Similar prevalence of somatic TSH receptor and Gsalpha mutations in toxic thyroid nodules in geographical regions with different iodine supply in Turkey. Eur J Endocrinol 155:535–545PubMedCrossRefGoogle Scholar
  50. 50.
    Vassart G (2004) Activating mutations of the TSH receptor. Thyroid 14:86–87PubMedCrossRefGoogle Scholar
  51. 51.
    Krohn K, Paschke R (2001) Progress in understanding the etiology of thyroid autonomy. J Clin Endocrinol Metab 86:3336–3345PubMedCrossRefGoogle Scholar
  52. 52.
    Garcia-Delgado M, Gonzalez-Navarro CJ, Napal MC et al (1998) Higher sensitivity of denaturing gradient gel electrophoresis than sequencing in the detection of mutations in DNA from tumor samples. Biotechniques 24:72–74, 76PubMedGoogle Scholar
  53. 53.
    Trulzsch B, Krohn K, Wonerow P et al (1999) DGGE is more sensitive for the detection of somatic point mutations than direct sequencing. Biotechniques 27:266–268PubMedGoogle Scholar
  54. 54.
    Trülzsch B, Krohn K, Wonerow P et al (2001) Detection of thyroid-stimulating hormone receptor and Gsalpha mutations: in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis. J Mol Med 78:684–691PubMedCrossRefGoogle Scholar
  55. 55.
    Van Sande J, Parma J, Tonacchera M et al (1995) Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab 80:2577–2585PubMedCrossRefGoogle Scholar
  56. 56.
    Dugrillon A, Bechtner G, Uedelhoven WM et al (1990) Evidence that an iodolactone mediates the inhibitory effect of iodide on thyroid cell proliferation but not on adenosine 3',5'-monophosphate formation. Endocrinology 127:337–343PubMedCrossRefGoogle Scholar
  57. 57.
    Roger PP, Servais P, Dumont JE (1983) Stimulation by thyrotropin and cyclic AMP of the proliferation of quiescent canine thyroid cells cultured in a defined medium containing insulin. FEBS Lett 157:323–329PubMedCrossRefGoogle Scholar
  58. 58.
    Eggo MC, Bachrach LK, Burrow GN (1990) Interaction of TSH, insulin and insulin-like growth factors in regulating thyroid growth and function. Growth Factors 2:99–109PubMedCrossRefGoogle Scholar
  59. 59.
    Eszlinger M, Krohn K, Frenzel R et al (2004) Gene expression analysis reveals evidence for inactivation of the TGF-beta signaling cascade in autonomously functioning thyroid nodules. Oncogene 23:795–804PubMedCrossRefGoogle Scholar
  60. 60.
    Gärtner R, Schopohl D, Schaefer S et al (1997) Regulation of transforming growth factor beta 1 messenger ribonucleic acid expression in porcine thyroid follicles in vitro by growth factors, iodine, or delta-iodolactone. Thyroid 7:633–640PubMedCrossRefGoogle Scholar
  61. 61.
    Taton M, Lamy F, Roger PP et al (1993) General inhibition by transforming growth factor beta 1 of thyrotropin and cAMP responses in human thyroid cells in primary culture. Mol Cell Endocrinol 95:13–21PubMedCrossRefGoogle Scholar
  62. 62.
    Depoortere F, Pirson I, Bartek J et al (2000) Transforming growth factor beta(1) selectively inhibits the cyclic AMP-dependent proliferation of primary thyroid epithelial cells by preventing the association of cyclin D3-cdk4 with nuclear p27(kip1). Mol Biol Cell 11:1061–1076PubMedGoogle Scholar
  63. 63.
    Grubeck-Loebenstein B, Buchan G, Sadeghi R et al (1989) Transforming growth factor beta regulates thyroid growth. Role in the pathogenesis of nontoxic goiter. J Clin Invest 83:764–770PubMedCrossRefGoogle Scholar
  64. 64.
    Krohn K, Emmrich P, Ott N et al (1999) Increased thyroid epithelial cell proliferation in toxic thyroid nodules. Thyroid 9:241–246PubMedCrossRefGoogle Scholar
  65. 65.
    Derwahl M, Studer H (2001) Nodular goiter and goiter nodules: where iodine deficiency falls short of explaining the facts. Exp Clin Endocrinol Diabetes 109:250–260PubMedCrossRefGoogle Scholar
  66. 66.
    Studer H, Peter HJ, Gerber H (1989) Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth. Endocr Rev 10:125–135PubMedCrossRefGoogle Scholar
  67. 67.
    Krohn K, Reske A, Ackermann F et al (2001) Ras mutations are rare in solitary cold and toxic thyroid nodules. Clin Endocrinol 55:241–248CrossRefGoogle Scholar
  68. 68.
    Dohan O, Baloch Z, Banrevi Z et al (2001) Rapid communication: predominant intracellular overexpression of the Na(+)/I(−) symporter (NIS) in a large sampling of thyroid cancer cases. J Clin Endocrinol Metab 86:2697–2700PubMedCrossRefGoogle Scholar
  69. 69.
    Dohan O, De la Vieja A, Paroder V et al (2003) The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev 24:48–77PubMedCrossRefGoogle Scholar
  70. 70.
    Tonacchera M, Viacava P, Agretti P et al (2002) Benign nonfunctioning thyroid adenomas are characterized by a defective targeting to cell membrane or a reduced expression of the sodium iodide symporter protein. J Clin Endocrinol Metab 87:352–357PubMedCrossRefGoogle Scholar
  71. 71.
    Dunn JT, Dunn AD (2001) Update on intrathyroidal iodine metabolism. Thyroid 11:407–414PubMedCrossRefGoogle Scholar
  72. 72.
    Lazar V, Bidart JM, Caillou B et al (1999) Expression of the Na+/I- symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J Clin Endocrinol Metab 84:3228–3234PubMedCrossRefGoogle Scholar
  73. 73.
    Caillou B, Dupuy C, Lacroix L et al (2001) Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase (ThoX, LNOX, Duox) genes and proteins in human thyroid tissues. J Clin Endocrinol Metab 86:3351–3358PubMedCrossRefGoogle Scholar
  74. 74.
    De Vijlder JJ (2003) Primary congenital hypothyroidism: defects in iodine pathways. Eur J Endocrinol 149:247–256PubMedCrossRefGoogle Scholar
  75. 75.
    Pisarev MA, Krawiec L, Juvenal GJ et al (1994) Studies on the goiter inhibiting action of iodolactones. Eur J Pharmacol 258:33–37PubMedCrossRefGoogle Scholar
  76. 76.
    Krohn K, Paschke R (2001) Loss of heterozygocity at the thyroid peroxidase gene locus in solitary cold thyroid nodules. Thyroid 11:741–747PubMedCrossRefGoogle Scholar
  77. 77.
    Krohn K, Paschke R (2004) BRAF mutations are not an alternative explanation for the molecular etiology of ras-mutation negative cold thyroid nodules. Thyroid 14:359–361PubMedCrossRefGoogle Scholar
  78. 78.
    Xing M, Vasko V, Tallini G et al (2004) BRAF T1796A transversion mutation in various thyroid neoplasms. J Clin Endocrinol Metab 89:1365–1368PubMedCrossRefGoogle Scholar
  79. 79.
    Puxeddu E, Moretti S, Elisei R et al (2004) BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab 89:2414–2420PubMedCrossRefGoogle Scholar
  80. 80.
    Soares P, Trovisco V, Rocha AS et al (2003) BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22:4578–4580PubMedCrossRefGoogle Scholar
  81. 81.
    Eszlinger M, Krohn K, Berger K et al (2005) Gene expression analysis reveals evidence for increased expression of cell cycle-associated genes and Gq-protein-protein kinase C signaling in cold thyroid nodules. J Clin Endocrinol Metab 90:1163–1170PubMedCrossRefGoogle Scholar
  82. 82.
    Krohn K, Stricker I, Emmrich P et al (2003) Cold thyroid nodules show a marked increase of proliferation markers. Thyroid 13:569–576PubMedCrossRefGoogle Scholar
  83. 83.
    Bol S, Belge G, Thode B et al (1999) Structural abnormalities of chromosome 2 in benign thyroid tumors. Three new cases and review of the literature. Cancer Genet Cytogenet 114:75–77PubMedCrossRefGoogle Scholar
  84. 84.
    Rippe V, Drieschner N, Meiboom M et al (2003) Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene 22:6111–6114PubMedCrossRefGoogle Scholar
  85. 85.
    Ward LS, Brenta G, Medvedovic M et al (1998) Studies of allelic loss in thyroid tumors reveal major differences in chromosomal instability between papillary and follicular carcinomas. J Clin Endocrinol Metab 83:525–530PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department for Endocrinology and NephrologyUniversity of LeipzigLeipzigGermany

Personalised recommendations