European Journal of Epidemiology

, Volume 26, Issue 8, pp 629–635 | Cite as

Doubling in the use of thyroid hormone replacement therapy in Denmark: association to iodization of salt?

  • Charlotte CerqueiraEmail author
  • Nils Knudsen
  • Lars Ovesen
  • Peter Laurberg
  • Hans Perrild
  • Lone Banke Rasmussen
  • Torben Jørgensen


Iodization of salt is an effective strategy to prevent iodine deficiency disorders. Recent studies, however, indicate that increasing the iodine intake in a population may give rise to an increased incidence of hypothyroidism, but the association has not been fully clarified. In Denmark, iodization of salt was initiated in 1998 because of mild-to-moderate iodine deficiency. The aim of this study was to evaluate the effect of the raised iodine intake on the nationwide incident use of thyroid hormone replacement therapy (levothyroxine) to treat hypothyroidism. Data on all use of levothyroxine was extracted from the Register of Medicinal Product Statistics during the period 1995–2009 and linked to other nationwide registers by use of the Danish identification number. Persons with previous thyroid surgery were excluded. In the studied period 71,565 incident users were identified. The incidence rate increased 75% in the moderately iodine deficient region (72.2 incident users/100,000 person-years in 1997 to 126.6 in 2008) and 87% in the mildly deficient region (86.9–162.9). When stratified by sex and age-group (00–39, 40–64, 65+) the largest relative increase was seen among women in the youngest age-group, where more than a doubling was seen. The mechanisms behind the increase may be a result of iodine-induced hypothyroidism, although a higher diagnostic activity with regard to thyroid dysfunction and intensified treatment of subclinical hypothyroidism may also play a role. Our findings stress the need for caution when initiating iodine fortification programs to keep the intake within the optimal range, and the need for continuous monitoring.


Fortification Hypothyroidism Iodine Pharmacoepidemiology Preventive medicine Thyroid hormone replacement therapy 



The Danish Investigation of Iodine Intake and Thyroid Diseases.


Anatomic therapeutical chemical.


Defined daily dose.


Iodine deficiency.


Confidence interval.



This study was part of The Danish Investigation on Iodine Intake and Thyroid Diseases (DanThyr), which is supported by grants from the Danish Medical Foundation, the 1991 Pharmacy Foundation, North Jutland County Research Foundation, Tømmerhandler Wilhelm Bangs Foundation, Copenhagen Hospital Corporation Research Foundation, The Danish Food Industry Agency, and the Danish Agency for Science Technology and Innovation (grant number 2101-06-0065).

Conflict of interest

The authors declare that no competing financial interests exist.


  1. 1.
    Hetzel BS, Dunn JT. The iodine deficiency disorders: their nature and prevention. Annu Rev Nutr. 1989;9:21–38.PubMedCrossRefGoogle Scholar
  2. 2.
    Knudsen N, Bulow I, Jorgensen T, Laurberg P, Ovesen L, Perrild H. Comparative study of thyroid function and types of thyroid dysfunction in two areas in Denmark with slightly different iodine status. Eur J Endocrinol. 2000;143(4):485–91.PubMedCrossRefGoogle Scholar
  3. 3.
    Laurberg P, Bulow PI, Knudsen N, Ovesen L, Andersen S. Environmental iodine intake affects the type of nonmalignant thyroid disease. Thyroid. 2001;11(5):457–69.PubMedCrossRefGoogle Scholar
  4. 4.
    Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med. 2006;354(26):2783–93.PubMedCrossRefGoogle Scholar
  5. 5.
    Tsatsoulis A, Johnson EO, Andricula M, Kalogera C, Svarna E, Spyroy P, et al. Thyroid autoimmunity is associated with higher urinary iodine concentrations in an iodine-deficient area of Northwestern Greece. Thyroid. 1999;9(3):279–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Szabolcs I, Podoba J, Feldkamp J, Dohan O, Farkas I, Sajgo M, et al. Comparative screening for thyroid disorders in old age in areas of iodine deficiency, long-term iodine prophylaxis and abundant iodine intake. Clin Endocrinol (Oxf). 1997;47(1):87–92.CrossRefGoogle Scholar
  7. 7.
    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(2):199–203.PubMedCrossRefGoogle Scholar
  8. 8.
    Benmiloud M, Chaouki ML, Gutekunst R, Teichert HM, Wood WG, Dunn JT. Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J Clin Endocrinol Metab. 1994;79(1):20–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Tajiri J, Higashi K, Morita M, Umeda T, Sato T. Studies of hypothyroidism in patients with high iodine intake. J Clin Endocrinol Metab. 1986;63(2):412–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Harach HR, Escalante DA, Day ES. Thyroid cancer and thyroiditis in Salta, Argentina: a 40-yr study in relation to iodine prophylaxis. Endocr Pathol. 2002;13(3):175–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Rose NR, Bonita R, Burek CL. Iodine: an environmental trigger of thyroiditis. Autoimmun Rev. 2002;1(1–2):97–103.PubMedCrossRefGoogle Scholar
  12. 12.
    Cerqueira C, Knudsen N, Ovesen L, Perrild H, Rasmussen LB, Laurberg P, et al. Association of iodine fortification with incident use of antithyroid medication–a Danish Nationwide study. J Clin Endocrinol Metab. 2009;94(7):2400–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Cerqueira C, Knudsen N, Ovesen L, Laurberg P, Perrild H, Rasmussen LB, et al. Nationwide trends in surgery and radioiodine treatment for benign thyroid disease during iodization of salt. Eur J Endocrinol. 2010;162(4):755–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Pedersen KM, Laurberg P, Nohr S, Jorgensen A, Andersen S. Iodine in drinking water varies by more than 100-fold in Denmark. Importance for iodine content of infant formulas. Eur J Endocrinol. 1999;140(5):400–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Rasmussen LB, Ovesen L, Bulow I, Jorgensen T, Knudsen N, Laurberg P, et al. Dietary iodine intake and urinary iodine excretion in a Danish population: effect of geography, supplements and food choice. Br J Nutr. 2002;87(1):61–9.PubMedCrossRefGoogle Scholar
  16. 16.
    World Health Organization, The United Nations Children′s Fund, International council for the control of iodine deficiency disorders. Assessment of iodine deficiency disorders and monitoring their elimination 3rd ed. Geneva. World Health Organization; 2008.Google Scholar
  17. 17.
    Pedersen KM, Nohr SB, Laurberg P. [Iodine intake in Denmark]. Ugeskr Laeger. 1997;159(15):2201–6.PubMedGoogle Scholar
  18. 18.
    Rasmussen LB, Carle A, Jorgensen T, Knudsen N, Laurberg P, Pedersen IB, et al. Iodine intake before and after mandatory iodization in Denmark: results from the Danish Investigation of Iodine Intake and Thyroid Diseases (DanThyr) study Br J Nutr. 2008;100(1):166–73.Google Scholar
  19. 19.
    Bulow PI, Knudsen N, Jorgensen T, Perrild H, Ovesen L, Laurberg P. Large differences in incidences of overt hyper- and hypothyroidism associated with a small difference in iodine intake: a prospective comparative register-based population survey. J Clin Endocrinol Metab. 2002;87(10):4462–9.CrossRefGoogle Scholar
  20. 20.
    Teng X, Shi X, Shan Z, Jin Y, Guan H, Li Y, et al. Safe range of iodine intake levels: a comparative study of thyroid diseases in three women population cohorts with slightly different iodine intake levels. Biol Trace Elem Res. 2008;121(1):23–30.PubMedCrossRefGoogle Scholar
  21. 21.
    Bülow Pedersen I, Knudsen N, Carle A, Vejbjerg P, Perrild H, Jorgensen T, et al. Even a cautious iodization program bringing iodine intake to a low recommended level is associated with an increase in the prevalence of TPO-Ab and Tg-Ab in the population. 14th International Thyroid Congress—800; 2010.Google Scholar
  22. 22.
    Pedersen IB, Laurberg P, Knudsen N, Jorgensen T, Perrild H, Ovesen L, et al. An increased incidence of overt hypothyroidism after iodine fortification of salt in Denmark: a prospective population study. J Clin Endocrinol Metab. 2007;92(8):3122–7.PubMedCrossRefGoogle Scholar
  23. 23.
    McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab. 2001;86(10):4585–90.PubMedCrossRefGoogle Scholar
  24. 24.
    Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American association of clinical endocrinologists, the American thyroid association, and the endocrine society. J Clin Endocrinol Metab. 2005;90(1):581–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med. 2000;132(4):270–8.PubMedGoogle Scholar
  26. 26.
    Canturk Z, Cetinarslan B, Tarkun I, Canturk NZ, Ozden M. Lipid profile and lipoprotein (a) as a risk factor for cardiovascular disease in women with subclinical hypothyroidism. Endocr Res. 2003;29(3):307–16.PubMedCrossRefGoogle Scholar
  27. 27.
    Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, et al. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Investig. 1993;71(5):367–71.PubMedGoogle Scholar
  28. 28.
    Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291(2):228–38.PubMedCrossRefGoogle Scholar
  29. 29.
    Chu JW, Crapo LM. The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab. 2001;86(10):4591–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Karmisholt JS, Laurberg P. [Subclinical hypothyroidism–a condition that must be treated?]. Ugeskr Laeger. 2006;168(37):3113–6.PubMedGoogle Scholar
  31. 31.
    Bonnema SJ, Bennedbaek FN, Wiersinga WM, Hegedus L. Management of the nontoxic multinodular goitre: a European questionnaire study. Clin Endocrinol (Oxf). 2000;53(1):5–12.CrossRefGoogle Scholar
  32. 32.
    Vejbjerg P, Knudsen N, Perrild H, Carle A, Laurberg P, Pedersen IB, et al. Effect of a mandatory iodization program on thyroid gland volume based on individuals’ age, gender, and preceding severity of dietary iodine deficiency: a prospective, population-based study. J Clin Endocrinol Metab. 2007;92(4):1397–401.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Charlotte Cerqueira
    • 1
    Email author
  • Nils Knudsen
    • 2
  • Lars Ovesen
    • 3
  • Peter Laurberg
    • 4
  • Hans Perrild
    • 2
  • Lone Banke Rasmussen
    • 5
  • Torben Jørgensen
    • 1
    • 6
  1. 1.Research Centre for Prevention and HealthGlostrup University HospitalGlostrupDenmark
  2. 2.Department of Endocrinology and GastroenterologyBispebjerg University HospitalCopenhagenDenmark
  3. 3.Department of GastroenterologySlagelse HospitalSlagelseDenmark
  4. 4.Department of Endocrinology, Aalborg HospitalAarhus University HospitalAalborgDenmark
  5. 5.Department of Nutrition, National Food InstituteTechnical University of DenmarkCopenhagenDenmark
  6. 6.Faculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations