The Danish investigation on iodine intake and thyroid disease (DanThyr): history and implications.

Due to mild-to-moderate iodine deficiency in Denmark, health authorities initiated a voluntary iodine fortification (IF) program in 1998, which became mandatory in 2000. In line with recommendations from the World Health Organization, the Danish investigation on iodine intake and thyroid disease (DanThyr) was established to monitor the effect on thyroid health and disease. The program involved different study designs and followed two Danish sub-populations in the years before IF and up till 20 years after. Results showed that the IF was successfully implemented and increased the level of iodine intake from mild-moderate iodine deficiency to low adequacy. The level of thyroglobulin and thyroid volume decreased following IF, and there was an indication of fewer thyroid nodules. The incidence of hyperthyroidism increased transiently following IF but subsequently decreased below the pre-fortification level. Conversely, thyroid-stimulating hormone levels and the prevalence of thyroid autoimmunity increased along with an increase in the incidence of hypothyroidism. These trends were mirrored in the trends in treatments for thyroid disease. Most differences in thyroid health and disease between regions with different iodine intake levels before IF attenuated. This review illustrates the importance of a monitoring program to detect both beneficial and adverse effects and exemplifies how a monitoring program can be conducted when a nationwide health promotion program - as IF - is initiated.

Serum thyroglobulin as a biomarker of iodine deficiency in adult populations.

OBJECTIVE: To clarify which factors may influence the serum Tg level in an adult population and how this may affect Tg as a biomarker of iodine deficiency (ID). DESIGN AND METHODS: Two identical cross-sectional studies were performed before (C1a: 1997-98, n = 4649) and after (C2: 2004-05, n = 3570) the Danish mandatory iodine fortification (IF) of salt (2000). Additionally, a follow-up study of C1a was performed after IF (C1b: 2008-10, n = 2465). The studies took place in two regions with mild (Copenhagen) and moderate (Aalborg) ID before IF. Serum Tg was measured by immunoradiometric method and investigated as outcome variable in multivariate models. RESULTS: Multiple factors were associated with serum Tg. Some were directly related to iodine intake (cohort, urinary iodine concentration (UIC) level and region), and some were likely mediators of iodine intake effects on Tg (thyroid nodularity, thyroid size and autonomy with low TSH). Others were caused by Tg assay interference (Tg-Ab positivity), aggravation of ID (childbirths and smoking) or TSH stimulation of the thyroid. Estimated 24-h urinary iodine excretion was a more sensitive predictor of Tg than UIC. Iodine supplement users had low median Tg values compared with nonusers both before and after IF. CONCLUSIONS: Multiple factors should be taken into consideration when evaluating Tg as a marker of ID in adult populations, and the Tg results may depend on the assay used. Still, Tg is a sensitive marker of ID. We suggest including a reference population with known sufficient iodine intake when Tg is used to evaluate ID.

Can Elastography Predict Growth of Incidental Thyroid Nodules? A Pilot Two-Year Follow-Up Study.

The objective of this study was to examine the ultrasonography (US) and ultrasound elastography (USE) features of thyroid incidentalomas in a population exposed to iodine deficiency and to investigate whether baseline elasticity scores (ES) predicted changes in thyroid nodule US characteristics. We conducted a two-year follow-up pilot study of thyroid incidentalomas by US and USE. One sonographer performed the US and USE examination on the same apparatus at baseline and at follow-up. We evaluated 83 incidental thyroid nodules detected in a population study. The follow-up period saw no change in median thyroid nodule diameter (p = 0.18) or in the prevalence of thyroid nodule US characteristics (hypoechoic: p = 0.05; solid nodule: p = 1.00; microcalcifications: p = 0.55). Individual changes in thyroid nodule diameter (>20%) were seen in 23% (11% had decreased, and 12% had increased in diameter). Changes in ES were frequently observed; 37% changed from ES A + B to ES C + D, and 27% changed from ES C + D to ES A + B. In a multivariate logistic regression model, we found no association between baseline ES and individual changes in nodule size. In an area with mild iodine deficiency and a high prevalence of thyroid nodules, thyroid USE performed on thyroid incidentalomas did not predict individual changes in thyroid nodule size.

Parity and 11-Year Serum Thyrotropin and Thyroid Autoantibody Change: A Longitudinal Population-Based Study.

BACKGROUND: A role for female reproductive factors in the pathogenesis of thyroid autoimmunity has been suggested. This study investigated the prospective association between parity, abortion, use of oral contraceptive pill (OCP), and use of hormone replacement therapy (HRT), and 11-year change in serum thyrotropin (TSH), as well as change in thyroid peroxidase autoantibody (TPOAb) status. METHODS: A random sample of 4649 people aged 18-65 years participated in a population-based study in the period 1997-1998. In the study presented here, 1749 non-pregnant women with no history of thyroid disease were included who participated in the 11-year follow-up examination in the period 2008-2010. Gynecological exposures were reported in a self-administered questionnaire at baseline and follow-up. TSH and TPOAb were measured at baseline and follow-up. Increased TPOAb status during follow-up was defined as a TPOAb below the assay cutoff (<30 kIU/L) at baseline and a TPOAb ≥30 kIU/L at follow-up. Multiple linear regression models were used, adjusted for age, smoking status, and urinary iodine excretion. RESULTS: An inverse association was found between the number of years on HRT and the risk (odds ratio) of increased TPOAb status during follow-up (0.735 [confidence interval 0.558-0.968], p = 0.03). However, this association was not statistically significant when applying the Bonferroni adjusted significance level. The remaining reproductive factors showed no statistically significant association with risk of increased TPOAb during follow-up. Furthermore, parity, abortions, use of OCP, HRT use, age at menarche, and being pre- or postmenopausal were not significantly associated with 11-year TSH change. CONCLUSIONS: No statistically significant association was found between the studied female reproductive measures and 11-year risk of TSH or TPO change. A possible protective role for HRT in the etiology of thyroid autoimmunity, however, deserves further research.

Serum thyroglobulin before and after iodization of salt: an 11-year DanThyr follow-up study.

OBJECTIVE: Our objective was to investigate individual serum thyroglobulin (Tg) changes in relation to iodine fortification (IF) and to clarify possible predictors of these changes. DESIGN: We performed a longitudinal population-based study (DanThyr) in two regions with different iodine intake at baseline: Aalborg (moderate iodine deficiency (ID)) and Copenhagen (mild ID). Participants were examined at baseline (1997) before the mandatory IF of salt (2000) and again at follow-up (2008) after IF. METHODS: We examined 2465 adults and a total of 1417 participants with no previous thyroid disease and without Tg-autoantibodies were included in the analyses. Serum Tg was measured by immunoradiometric method. We registered participants with a daily intake of iodine from supplements in addition to IF. RESULTS: Overall, the follow-up period saw no change in median Tg in Copenhagen (9.1/9.1 µg/l, P=0.67) while Tg decreased significantly in Aalborg (11.4/9.0 µg/l, P<0.001). Regional differences were evident before IF (Copenhagen/Aalborg, 9.1/11.4 µg/l, P<0.001), whereas no differences existed after IF (9.1/9.0 µg/l, P=1.00). Living in Aalborg (P<0.001) and not using iodine supplements at baseline (P=0.001) predicted a decrease in Tg whereas baseline thyroid enlargement (P=0.02) and multinodularity (P=0.01) were associated with an individual increase in Tg during follow-up. CONCLUSIONS: After IF we observed a decrease in median Tg in Aalborg and the previously observed regional differences between Aalborg and Copenhagen had levelled out. Likewise, living in Aalborg was a strong predictor of an individual decrease in serum Tg. Thus, even small differences in iodine intake at baseline were very important for the individual response to IF.

Thyroid malignancy markers on sonography are common in patients with benign thyroid disease and previous iodine deficiency.

OBJECTIVES: The purpose of this study was to evaluate the characteristics of benign thyroid nodules on sonography and ultrasound elastography in a population exposed to iodine deficiency. METHODS: We conducted a prospective systematic evaluation of preoperative thyroid sonography and elastography in patients assigned for surgical excision of benign thyroid nodules. Two experienced sonographers performed all sonographic and elastographic examinations. Thyroid nodules were evaluated by 7 generally accepted sonographic malignancy risk markers and assigned an elasticity score on elastography. The final diagnosis of a benign thyroid nodule was based on histopathologic analysis of resected thyroid gland tissue. RESULTS: We evaluated 232 thyroid nodules in 105 patients (86 women and 19 men). In total, 57% of the examined nodules had 1 or 2 malignancy risk markers present, and 24% did not have any markers present. A solid nodule larger than 15 mm was the most common malignancy risk marker observed (63%), followed by low elasticity (33%), microcalcifications (26%), and hypoechogenicity (15%). In an analysis stratified according to the number of nodules (solitary versus multiple), low elasticity was described more frequently in solitary nodules (61.9% versus 30.4%; P= .004). A large nodular volume was a predictor (P < .05) of microcalcifications and intranodular vascularization, whereas an absent halo sign and a solid nodule were found less frequently in nodules with larger volumes. CONCLUSIONS: Our results show that routine preoperative malignancy risk evaluation of presumably benign thyroid nodules is of little value when performed on patients exposed to iodine deficiency.

Iodine status in Danish pregnant and breastfeeding women including studies of some challenges in urinary iodine status evaluation.

Denmark was previously iodine deficient with regional differences. Moderate iodine deficiency appeared in West Denmark and mild iodine deficiency in East Denmark and also Danish pregnant and breastfeeding women suffered from iodine deficiency. The Danish mandatory iodine fortification of salt was introduced in the year 2000 and has increased iodine intake in the Danish population. However, median urinary iodine concentration in the general population and in pregnant and breastfeeding women is still below the level recommended, corresponding to mild iodine deficiency. Certain characteristics may challenge the evaluation of urinary iodine status in pregnancy and during breastfeeding. This review also addresses methodological challenges related to spot urine sampling conditions and the use of iodine supplement and discusses the use of non-pregnant population groups as a proxy for iodine intake in pregnant women.

Challenges in the evaluation of urinary iodine status in pregnancy: the importance of iodine supplement intake and time of sampling.

OBJECTIVES: Median urinary iodine concentration (UIC) is the recommended method to evaluate iodine status in pregnancy, but several factors may challenge the interpretation of the results. We evaluated UIC in pregnant women according to (1) sampling in the hospital versus at home, (2) time of the most recent iodine supplement intake prior to sampling, and (3) members of their household. STUDY DESIGN: Danish cross-sectional study in the year 2012. Pregnant women (n = 158), their male partners (n = 157) and children (n = 51) provided a questionnaire with detailed information on iodine supplement intake and a spot urine sample obtained in the hospital and/or at home for measurement of UIC and urinary creatinine concentration. RESULTS: In the pregnant women providing a urine sample both in the hospital and at home (n = 66), individual UIC (p = 0.002) and urinary creatinine concentration (p = 0.042), but not estimated 24-hour urinary iodine excretion (p = 0.79), were higher when sampling was at home. Median UIC was dependent on the time of the most recent iodine supplement intake prior to sampling [same day (n = 79): 150 µg/l (95% CI 131-181 µg/l), the day before (n = 51): 105 µg/l (78-131 µg/l), several days ago/non-user (n = 28): 70 µg/l (56-94 µg/l), p < 0.001]. The pattern was similar in the male partners. Apart from a more frequent iodine supplement intake in pregnancy (87.3% vs. partners 15.9%), no systematic differences were observed in urinary measurements between the pregnant women and their partners. CONCLUSIONS: Time of spot urine sampling and time span from iodine supplement intake to spot urine sampling should be considered when evaluating urinary iodine status in pregnancy.

Iodine excretion has decreased in Denmark between 2004 and 2010--the importance of iodine content in milk.

Fortification with the essential trace element iodine is widespread worldwide. In the present study, results on iodine excretion and intake of iodine-rich foods from a cross-sectional study carried out in 2004-5, 4 to 5 years after the implementation of mandatory iodine fortification, were compared with data in a study carried out in 2008-10. The 2008-10 study was a follow-up of a cross-sectional study carried out before iodine fortification was implemented. Participants in the cross-sectional studies were randomly selected. Both studies were carried out in the cities of Aalborg and Copenhagen in Denmark. The median urinary iodine concentration decreased in women from 97 µg/l (n 2862) to 78 µg/l (n 2041) (P< 0.001). The decrease persisted after adjustment for age, city and education, and if expressed as estimated 24 h iodine excretion. The prevalence of users of iodine containing dietary supplements increased from 29.4 to 37.3 % (P< 0.001). The total fluid intake increased in women (P< 0.001), but the intake of other iodine-rich foods did not change. The median urinary iodine concentration did not change in men (114 µg/l (n 708) and 107 µg/l (n 424), respectively), while the total fluid intake decreased (P= 0.001). Iodine content was measured in milk sampled in 2000-1 and in 2013. The iodine content was lower in 2013 (12 (sd 3) µg/100 g) compared with that in 2000-1 (16 (sd 6) µg/100 g) (P< 0.001). In conclusion, iodine excretion in women has decreased below the recommended level. The reason might probably, at least partly, be a decreased content of iodine in milk.

Thyroid nodules in an 11-year DanThyr follow-up study.

CONTEXT: Limited longitudinal data are available on changes in the thyroid gland structure in a population and how this is influenced by iodine fortification (IF). OBJECTIVE: Our objective was to clarify how IF influenced thyroid gland structure in 2 regions with different iodine intake at baseline (Copenhagen, mild iodine deficiency [ID]; Aalborg, moderate ID). DESIGN AND SETTING: We conducted a longitudinal population-based study (DanThyr) where participants were examined before (1997) and after (2008) the Danish mandatory IF of salt (2000). PARTICIPANTS: We examined 2465 adults, and ultrasonography was performed by the same sonographers using the same equipment, after controlling performances. MAIN OUTCOME MEASURE: Change in thyroid gland structure was evaluated. RESULTS: The follow-up period saw an increased prevalence of multinodularity (9.8%-13.8 %, P < .001), especially in the previously moderate ID region of Aalborg (9.1%-15.4%, P < .001), whereas no change in prevalence was seen for solitary nodules (5.6%-5.1%, P = .34). In individual participants, changes in thyroid structure and disappearance of thyroid nodules during the 11 years was common with an overall normalization rate of 21.2 (95% confidence interval [CI] = 17.9-24.9) per 1000 person-years. Solitary nodules had a significantly higher normalization rate than multiple nodules (normalization rate ratio 0.47 [95% CI = 0.32-0.67]). A regional difference (Aalborg vs Copenhagen) was seen between normalization rates of multiple nodules (normalization rate ratio 0.29 [95% CI = 0.12-0.64]), but not for solitary nodules (normalization rate ratio 0.81 [95% CI = 0.53-1.21]). CONCLUSIONS: Changes in the thyroid gland structure with both appearance and disappearance of thyroid nodules are common after an iodization program.

Relapse following antithyroid drug therapy for Graves' hyperthyroidism.

PURPOSE OF REVIEW: In most patients with hyperthyroidism caused by Graves' disease, antithyroid drug (ATD) therapy is followed by a gradual amelioration of the autoimmune abnormality, but about half of the patients will experience relapse of hyperthyroidism when the ATDs are withdrawn after a standard 1 to 2 years of therapy. This is a major drawback of ATD therapy, and a major concern to patients. We review current knowledge on how to predict and possibly reduce the risk of such relapse. RECENT FINDINGS: Several patient and disease characteristics, as well as environmental factors and duration of ATD therapy, may influence the risk of relapse after ATD withdrawal. Depending on the presence of such factors, the risk of relapse after ATD withdrawal may vary from around 10 to 90%. Risk factors for relapse should be taken into account when choosing between therapeutic modalities in a patient with newly diagnosed disease, and also when discussing duration of ATD therapy. SUMMARY: Prolonged low-dose ATD therapy may be feasible in patients with high risk of relapse, such as children and patients with active Graves' orbitopathy, and in patients with previous relapse who prefer such therapy rather than surgery or radioiodine.

Epidemiology of nodular goitre. Influence of iodine intake.

More than one tenth of the world population is to some degree affected by goitre and most of these harbour nodules. The large differences in thyroid disease prevalence between populations may be caused by genetic and environmental factors. Among the latter, iodine deficiency seems by far to be the most important risk factor. Thus, nodular goitre is a condition predominantly seen in iodine deficient areas of the world. In the present review, we evaluated in detail autopsy and ultrasound studies of the thyroid gland. In autopsy studies, large thyroid volumes and high frequencies of goitres have been reported in countries affected by iodine deficiency. Many cross-sectional studies using thyroid ultrasound investigations have been performed world-wide and reported high thyroid volumes and goitre prevalences, and to some extent also high prevalences of thyroid nodules in iodine-deficient countries. Most of these goitres were classified as nodular goitres. On the other hand, few studies have shown that abundant iodine intake may lead to development of diffuse goitres, but world-wide this has been a minor problem compared with development of nodular goitres. In the past century we have observed a trend towards smaller thyroid glands, and hopefully less than 10% of the world population will experience goitre within a few decades.

Association between TSH-Receptor Autoimmunity, Hyperthyroidism, Goitre, and Orbitopathy in 208 Patients Included in the Remission Induction and Sustenance in Graves' Disease Study.

Background. Graves' disease may have a number of clinical manifestations with varying degrees of activity that may not always run in parallel. Objectives. To study associations between serum levels of TSH-receptor autoantibodies and the three main manifestations of Graves' disease (hyperthyroidism, goiter, and presence of orbitopathy) at the time of diagnosis of hyperthyroidism. Methods. We describe a cohort of 208 patients with newly diagnosed Graves' hyperthyroidism. Patients were enrolled in a multiphase study of antithyroid drug therapy of Graves' hyperthyroidism, entitled "Remission Induction and Sustenance in Graves' Disease (RISG)." Patients were systematically tested for degree of biochemical hyperthyroidism, enlarged thyroid volume by ultrasonography, and the presence of orbitopathy. Results. Positive correlations were found between the levels of TSH-receptor autoantibodies in serum and the three manifestations of Graves' disease: severeness of hyperthyroidism, presence of enlarged thyroid, and presence of orbitopathy, as well as between the different types of manifestations. Only around half of patients had enlarged thyroid gland at the time of diagnosis of hyperthyroidism, whereas 25-30% had orbitopathy. Conclusions. A positive but rather weak correlation was found between TSH-receptor antibodies in serum and the major clinical manifestation of Graves' disease. Only half of the patients had an enlarged thyroid gland at the time of diagnosis.

Thyroid function and body weight: a community-based longitudinal study.

OBJECTIVE: Body weight and overt thyroid dysfunction are associated. Cross-sectional population-based studies have repeatedly found that thyroid hormone levels, even within the normal reference range, might be associated with body weight. However, for longitudinal data, the association is less clear. Thus, we tested the association between serum thyrotropin (TSH) and body weight in a community-based sample of adult persons followed for 11 years. METHODS: A random sample of 4,649 persons aged 18-65 years from a general population participated in the DanThyr study in 1997-8. We included 2,102 individuals who participated at 11-year follow-up, without current or former treatment for thyroid disease and with measurements of TSH and weight at both examinations. Multiple linear regression models were used, stratified by sex and adjusted for age, smoking status, and leisure time physical activity. RESULTS: Baseline TSH concentration was not associated with change in weight (women, P = 0.17; men, P = 0.72), and baseline body mass index (BMI) was not associated with change in TSH (women, P = 0.21; men, P = 0.85). Change in serum TSH and change in weight were significantly associated in both sexes. Weight increased by 0.3 kg (95% confidence interval [CI] 0.1, 0.4, P = 0.005) in women and 0.8 kg (95% CI 0.1, 1.4, P = 0.02) in men for every one unit TSH (mU/L) increase. CONCLUSIONS: TSH levels were not a determinant of future weight changes, and BMI was not a determinant for TSH changes, but an association between weight change and TSH change was present.

Iodine fortification may influence the age-related change in thyroid volume: a longitudinal population-based study (DanThyr).

OBJECTIVE: To assess the individuals' thyroid volume changes after the mandatory nationwide iodine fortification (IF) program in two Danish areas with different iodine intake at baseline (Copenhagen, mild iodine deficiency (ID) and Aalborg, moderate ID). DESIGN: A longitudinal population-based study (DanThyr). METHODS: We examined 2465 adults before (1997) and after (2008) the Danish IF of salt (2000). Ultrasonography was carried out by the same sonographers using the same equipment, after controlling performances. Participants treated for thyroid disease were excluded from analyses. RESULTS: Overall, median thyroid volume had increased in Copenhagen (11.8-12.2 ml, P=0.001) and decreased in Aalborg, although not significantly (13.3-13.1 ml, P=0.07) during the 11 years of follow-up. In both regions, there was an age-related trend in individual changes in thyroid volume from baseline to follow-up; thyroid volume increased in women <40 years of age and decreased in women >40 years of age. IN A MULTIVARIATE REGRESSION MODEL, HIGHER AGE AT ENTRY WAS A PREDICTOR (P0.05) FOR THYROID VOLUME DECREASE 20% DURING THE FOLLOW-UP PERIOD (WOMEN AGED 4045 YEARS: odds ratio (OR) 4.3 (95% CI, 2.2-8.2); women aged 60-65 years: 5.8 (2.9-11.6)) and individuals of higher age were also less likely to have an increase in thyroid volume (women aged 40-45 years: OR 0.2 (0.1-0.3); women aged 60-65: OR 0.3 (0.2-0.4)). CONCLUSIONS: Age-dependent differences in thyroid volume and enlargement had leveled out after the Danish iodization program. Thus, the previously observed increase in thyroid volume with age may have been caused by ID.

Mandatory iodine fortification of bread and salt increases iodine excretion in adults in Denmark - a 11-year follow-up study.

BACKGROUND & AIMS: Iodine fortification is widespread. Systematic monitoring of iodine fortification programs should be carried out to secure an optimal fortification level. Our aim was to investigate the effectiveness of the Danish iodine fortification program by comparing iodine excretion at baseline and at 11-year follow-up, and to study determinants for any change in iodine intake including dietary habits, education, life style factors and health parameters. METHODS: A follow-up study based on the Danish DanThyr cohort examined in 1997-1998 just before iodine fortification was introduced, and reexamined in 2008-2010. In total, 2465 (59.1%) adult participants were reexamined. RESULTS: Median (IQR) iodine concentration in urine had increased by 19 (-25-68) µg/L to 83 (47-133) µg/L. Estimated 24-h iodine excretion had increased by 36 (-21-95) µg/24-h to 134 (93-206), and calculated total iodine intake (diet plus supplements) had increased by 16 (-18-48) µg/day. Iodine excretion had increased significantly in all age and gender groups, but was still below the recommended amount at follow-up. The increase in iodine excretion was positively associated with changes in milk intake, with changes in the use of iodine supplements, and with bread intake at follow-up. Salt intake, education, self-rated health, smoking, alcohol intake and physical activity were not associated with the increase in iodine excretion. CONCLUSIONS: The strategy to combat iodine deficiency in Denmark seems to be working because the fortification led to increased urinary iodine excretion in (almost) all participants. However, the level of iodine fortification of salt is too low.

Iodine deficiency in Danish pregnant women.

INTRODUCTION: Maternal iodine requirements increase during pregnancy. Studies performed before the introduction of mandatory iodine fortification of salt in Denmark in 2000 showed that pregnant women with no intake of iodine-containing supplements were moderately iodine-deficient and showed signs of thyroidal stress. We investigated the intake of iodine-containing supplements and urinary iodine excretion in Danish pregnant women after the introduction of iodine fortification of salt. MATERIAL AND METHODS: We conducted a cross-sectional study between June and August 2012 in an area of Denmark where iodine deficiency had previously been moderate. Pregnant women coming to Aalborg University Hospital for obstetric ultrasound were recruited consecutively. Participants filled in a questionnaire and handed in a spot urine sample for measurement of iodine and creatinine. RESULTS: Among the pregnant women included (n = 245) 84.1% reported an intake of iodine-containing supplements, and compared with those not taking iodine supplements the median urinary iodine concentration was significantly higher in this group: 109 g/l (25th-75th percentile: 66-191 µg/l). On the other hand, the median urinary iodine concentration was considerably below the recommended level, even for the non-pregnant state in pregnant women with no iodine supplement intake: 68 µg/l (35-93 µg/l), p < 0.001. CONCLUSION: The majority of pregnant women took iodine-containing supplements, but the subgroup of non-users was still iodine-deficient after the introduction of iodine fortification of salt. Iodine supplement intake during pregnancy in Denmark should be officially recommended. FUNDING: The study was supported by a grant from Musikforlæggerne Agnes og Knut Mørks Fond and from Speciallæge Heinrich Kopps Legat. TRIAL REGISTRATION: not relevant.

Predictors of change in serum TSH after iodine fortification: an 11-year follow-up to the DanThyr study.

CONTEXT: Few data are available on the effect of iodine fortification on thyroid function development in a population. OBJECTIVE: Our objective was to evaluate changes in thyroid function after iodine fortification in a population and to identify predictors for changes in serum TSH. DESIGN AND SETTING: A longitudinal population-based study of the DanThyr C1 cohort examined at baseline (1997-1998) and reexamined 11 yr later (2008-2010). The mandatory program for iodization of salt was initiated in 2000. PARTICIPANTS: A total of 2203 individuals, with no previous thyroid disease, living in two areas with different levels of iodine intake, with measurement of TSH and participation in follow-up examination were included in the analysis. MAIN OUTCOME MEASURE: Change in serum TSH was evaluated. RESULTS: During the 11-yr follow-up, mean TSH increased significantly from 1.27 mU/liter [95% confidence interval (CI) = 1.23-1.30] to 1.38 mU/liter (CI = 1.34-1.43) (P < 0.001). The most pronounced increase was observed in the area with the highest iodine intake [1.30 mU/liter (CI = 1.25-1.35) to 1.49 mU/liter (CI = 1.43-1.55), P < 0.001], whereas the increase was not significant in the low-iodine-intake area [1.24 (CI = 1.19-1.29) to 1.28 (CI = 1.23-1.34), P = 0.06)]. Change in TSH was positively associated with the presence of thyroid peroxidase antibody at baseline (P < 0.001) and negatively associated with baseline thyroid enlargement (P < 0.001) and multiple nodules (P < 0.001). CONCLUSIONS: Even small differences in the level of iodine intake between otherwise comparable populations are associated with considerable differences in TSH change at the 11-yr follow-up. Multinodular goiter predicted a less pronounced TSH increase during follow-up, which may be explained by iodine-dependent activity of autonomous nodules.