The Role of Iodine Deficiency and Subsequent Repletion in Autoimmune Thyroid Disease and Thyroid Cancer
Robyn Murphy, BSc, ND
Caroline Turek, HBSc, MD
Leigh Arseneau, HBSc, ND


Iodine excess
Thyroid autoimmunity
Thyroid cancer


Iodine is an essential trace mineral that is necessary for thyroid hormone production. With the prevalence of iodine deficiency worldwide, universal salt iodization programs were successfully implemented to reduce the incidence of iodine deficiency disorders; however, unexpected increases in the prevalence of thyroid autoimmunity occurred, and iodine excess was implicated as the causative factor. Despite these observations, epidemiological studies are inconsistent, and the etiology of autoimmune thyroid disease remains undefined. A review of observational and in vitro studies revealed that iodine alone is not responsible for thyroid autoimmunity. Experimental models used to explain iodine excess as the culprit in thyroid autoimmunity fail to induce thyroid autoantibodies unless iodine is in the presence of excess inflammatory cytokines (interferon [IFN]-γ) and hydrogen peroxide (H2O2). Within iodine-deficient populations, regulatory mechanisms to limit oxidative stress and excess iodine are lost. Thyroid-stimulating hormone persistently activates the sodium-iodide symporter, while iodine concentrations fail to achieve levels high enough to produce iodolactones, which are responsible for modulating NADPH oxidase and H2O2 production. Subsequently, the thyroid becomes susceptible to oxidative stress as iodine is reintroduced. Oxidation of thyroid peroxidase and thyroglobulin initiate the release of inflammatory cytokines (IFN-γ) and lymphocytic infiltration, which induce autoantibody production and thyroid autoimmunity. Population studies revealed that iodine administration even below the recommended dietary allowance alters thyroid autoimmunity. Despite increases in thyroid antibodies, these changes are found to be transient. Interestingly, reports of iodine in combination with other nutrients and standardized botanical extracts have been used successfully to restore thyroid function. On the basis of our review of the literature, it is apparent that a loss of regulatory mechanisms due to preexisting iodine deficiency followed by iodine repletion, as opposed to iodine excess, is a causal factor in the development of thyroid autoimmunity.



Sun X, Shan Z, Teng W. Effects of increased iodine intake on thyroid disorders. Endocrinol Metab (Seoul). 2014; 29:240–7.
Chung HR. Iodine and thyroid function. Ann. Pediatr Endocrinol Metab. 2014; 19:8–12.
Fiore E, Tonacchera M, Vitti P. Influence of iodization programmes on the epidemiology of nodular goitre. Best Pract Res Clin Endocrinol Metab. 2014; 28:577–88.
Zimmermann MB, Boelaert K. Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol. 2015; 3:286–95.
Caturegli P, Kimura H, Rocchi R, Rose NR. Autoimmune thyroid diseases. Curr Opin Rheumatol. 2007; 19:44–8.
Saranac L, Zivanovic S, Bjelakovic B, et al. Why is the thyroid so prone to autoimmune disease? Horm Res Paediatr. 2011; 75:157–65.
Duntas LH. Environmental factors and autoimmune thyroiditis. Nat Clin Pract Endocrinol Metab. 2008; 4:454–60.
Papanastasiou L, Vatalas IA, Koutras DA, Mastorakos G. Thyroid autoimmunity in the current iodine environment. Thyroid. 2007; 17:729–39.
Reinhardt W, Luster M, Rudorff KH, et al. Effect of small doses of iodine on thyroid function in patients with Hashimoto’s thyroiditis residing in an area of mild iodine deficiency. Eur J Endocrinol. 1998; 139:23–8.
Yang F, Shan Z, Teng X, et al. Chronic iodine excess does not increase the incidence of hyperthyroidism: a prospective community-based epidemiological survey in China. Eur J Endocrinol. 2007; 156:403–8.
Zaletel K, Gaberšček S. Hashimoto’s thyroiditis: from genes to the disease. Curr Genomics. 2011; 12;576–88.
Drutel A, Archambeaud F, Caron P. Selenium and the thyroid gland: more good news for clinicians. Clin Endocrinol (Oxf). 2013; 78:155–64.
Chazenbalk GD, Valsecchi RM, Krawiec L, et al. Thyroid autoregulation: inhibitory effects of iodinated derivatives of arachidonic acid on iodine metabolism. Prostaglandins. 1998; 36:163–72.
Dugrillon A. Iodolactones and iodoaldehydes – mediators of iodine in thyroid autoregulation. Exp Clin Endocrinol Diabetes. 1996; 104(Suppl 4):41–5.
Brownstein D. AIT: a holistic approach. Presented at: 2016 Restorative Medicine Conference; January 29–31, 2016; Toronto, ON, Canada.
Flechas J. Autoimmune thyroiditis and iodine therapy. J Restor Med. 2013; 2:54–9.
Gärtner R, Rank P, Ander B. The role of iodine and δ-iodolactone in growth and apoptosis of malignant thyroid epithelial cells and breast cancer cells. Hormones (Athens). 2010; 9:60–6.
Thomasz L, Oglio R, Randi AS, et al. Biochemical changes during goiter induction by methylmercaptoimidazol and inhibition by δ-iodolactone in rat. Thyroid. 2010; 20:1003–13.
Pisarev MA, Krawiec L, Juvenal GJ, et al. Studies on the goiter inhibiting action of iodolactones. Eur J Pharmacol. 1994; 258:33–7.
Langer R, Burzler C, Bechtner G, Gärtner R. Influence of iodide and iodolactones on thyroid apoptosis: evidence that apoptosis induced by iodide is mediated by iodolactones in intact porcine thyroid follicles. Exp Clin Endocrinol Diabetes. 2003; 111:325–9.
Friedman M. Thyroid autoimmune disease. J Restor Med. 2013; 2:70–81.
Miranda DMC, Massom JN, Catarino RM, et al. Impact of nutritional iodine optimization on rates of thyroid hypoechogenicity and autoimmune thyroiditis: a cross-sectional, comparative study. Thyroid. 2015; 25:118–24.
Kostic I, Toffoletto B, Fontanini E, et al. Influence of iodide excess and interferon-γ on human primary thyroid cell proliferation, thyroglobulin secretion, and intracellular adhesion molecule-1 and human leukocyte antigen-DR expression. Thyroid. 2009; 19:283–91.
Bagnasco M, Caretto A, Olive D, et al. Expression of intercellular adhesion molecule-1 (ICAM-1) on thyroid epithelial cells in Hashimoto’s thyroiditis but not in Graves’ disease or papillary thyroid cancer. Clin Exp Immunol. 1991; 83:309–13.
Roebuck KA, Finnegan A. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukoc Biol 1999; 66:876–88.
Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med. 1996; 335:99–107.
Cui SL, Yu J, Shoujun L. Iodine intake increases IP-10 expression in the serum and thyroids of rats with experimental autoimmune thyroiditis. Int J Endocrinol. 2014; 2014:581069.
Abraham GE. The safe and effective implementation of orthoiodosupplementation in medical practice. Original Internist. 2004; 11:17–36.
Vanderpump MPJ. The epidemiology of thyroid disease. Br Med Bull. 2011; 99:39–51.
Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in the United States: trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971–1974 and 1988–1994). J Clin Endocrinol Metab. 1998; 83:3401–8.
Leung AM, Pearce EN, Braverman LE. Sufficient iodine intake during pregnancy: just do it. Thyroid. 2013; 23:7–8.
Luo Y, Kawashima A, Ishido Y, et al. Iodine excess as an environmental risk factor for autoimmune thyroid disease. Int J Mol Sci. 2014; 15:12895–912.
Rasooly L, Burek CL, Rose NR. Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. Clin Immunol Immunopathol. 1996; 81:287–92.
Braley-Mullen H, Sharp GC, Medling B, Tang H. Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J Autoimmun. 1999; 12:157–65.
Bürgi H. Iodine excess. Best Pract Res Clin Endocrinol Metab. 2010; 24:107–15.
Zimmermann MB, Galetti V. Iodine intake as a risk factor for thyroid cancer: a comprehensive review of animal and human studies. Thyroid Res. 2015; 8:8.
Krejbjerg A, Brilli L, Pikelis A, et al. Thyroid malignancy markers on sonography are common in patients with benign thyroid disease and previous iodine deficiency. J Ultrasound Med. 2015; 34:309–16.
Gérard AC, Humblet K, Wilvers C, et al. Iodine-deficiency-induced long lasting angiogenic reaction in thyroid cancers occurs via a vascular endothelial growth factor–hypoxia inducible factor-1–dependent, but not a reactive oxygen species–dependent, pathway. Thyroid. 2012; 22:699–708.
Qureshi IA, Khabaz MN, Baig M, et al. Histopathological findings in goiter: a review of 624 thyroidectomies. Neuro Endocrinol Lett. 2015; 36:48–52.
Carvalho Santos JE, Kalk WJ, Freitas M, et al. Iodine deficiency and thyroid nodular pathology – epidemiological and cancer characteristics in different populations: Portugal and South Africa. BMC Res Notes. 2015; 8:284.
Rösner H, Torremante P, Möller W, Gärtner R. Antiproliferative/cytotoxic activity of molecular iodine and iodolactones in various human carcinoma cell lines: no interfering with EGF-signaling, but evidence for apoptosis. Exp Clin Endocrinol Diabetes. 2010; 118:410–9.
Pedersen IB, Knudsen N, Carlé A, et al. A cautious iodization programme bringing iodine intake to a low recommended level is associated with an increase in the prevalence of thyroid autoantibodies in the population: increase in TPO-Ab and Tg-Ab after iodization. Clin Endocrinol (Oxf). 2011; 75: 120–126.
Zimmermann MB, Moretti D, Chaouki N, Torresani T. Introduction of iodized salt to severely iodine-deficient children does not provoke thyroid autoimmunity: a one-year prospective trial in northern Morocco. Thyroid. 2003; 13:199–203.

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