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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

Department of Internal Medicine I (P.V., N.K., H.P.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; Department of Endocrinology (A.C., P.L., I.B.P.), Aalborg Hospital, University of Aarhus, 9000 Aalborg, Denmark; Department of Nutrition (L.B.R.), Danish Institute for Food and Veterinary Research, 2860 Søborg, Denmark; Danish Heart Association (L.O.), 1127 Copenhagen, Denmark; and Research Centre for Prevention and Health (P.V., N.K., T.J.), 2600 Glostrup, Denmark

Address all correspondence and requests for reprints to: Pernille Vejbjerg, Department of Internal Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark. E-mail: pervej01{at}glostruphosp.kbhamt.dk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Objective: We aimed to evaluate prospectively the effect of 4 yr of mandatory iodization of salt (13 ppm iodine) on thyroid volume in two regional areas with respectively mild and moderate iodine deficiency.

Methods: Two separate cross-sectional studies were performed before (n = 4649) and after (n = 3570) the iodization in year 2000 in two areas with mild and moderate iodine deficiency. Women aged 18–22, 25–30, 40–45, and 60–65 yr and men aged 60–65 yr were examined. Thyroid ultrasonography was performed.

Results: A lower median thyroid volume was seen in all age groups after iodization. The largest relative decline was found among the younger females from the area with previous, moderate iodine deficiency. Only a minor decrease was seen among the youngest participants in the area with previous, mild iodine deficiency. After iodization, there were no regional differences in median thyroid volume in the age groups younger than 45 yr. When adjusted for confounders, a lower mean volume was seen among those with multiple nodules in both areas and in the group with diffuse structure in the area with moderate iodine deficiency. Before the iodization, 17.6% of the total cross-section had thyroid enlargement; after the iodization, 10.9% of the cross-section had thyroid enlargement.

Conclusion: In this prospective study, we demonstrated a lower thyroid volume in all age groups after iodization of salt. The decline was largest in the area with former, moderate iodine deficiency. The equal volumes in the regions among the younger age groups indicate approximation to an optimal iodine intake.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
WORLDWIDE, IODIZATION PROGRAMS have been initiated to prevent iodine deficiency disorders. Iodization of salt is considered the appropriate method for iodine fortification in prosperous countries (1); however, careful monitoring is essential because excessive iodine intake can also be disadvantageous and even small differences in iodine intake have proven to be decisive for the prevalence of endemic goiter and other iodine-related thyroid diseases (2, 3, 4, 5, 6).

One study has followed the initiation of a population-based iodine program in an area with severe iodine deficiency (7) showing a significant reduction in median thyroid volume in children 2 yr after the introduction of iodized salt, whereas a 1-yr study focusing on thyroid autoimmunity did not find a significant reduction in thyroid volume (8). Most previous studies, however, evaluated distribution of disease patterns before or after a modification of iodization level (9, 10).

In Denmark, iodization of salt was prohibited from 1982 until 1998, when an optional iodization of salt was initialized. This led to only a limited use of iodized salt, so from year 2000 iodization of all household salt and salt used in the bread industry was made mandatory to a level of 13 ppm iodine. Calculations based on the Danish national dietary survey showed that this fortification should increase median iodine intake to 150 µg/d. The design of our study with two cross-sectional studies, one before and one 4 yr after the iodization of salt, in two areas in Denmark with respectively mild and moderate iodine deficiency (11), enables us to prospectively investigate the consequences of iodization on a population level.

	Subjects and Methods

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Cross-sectional study before iodization of salt

The first study (1997–1998) was carried out before the iodization of salt in two regions suspected to be respectively mildly (the northern part of Copenhagen, eastern Denmark) and moderately (Aalborg, western Denmark) iodine deficient (12, 13). All procedures (e.g. invitation procedure, questionnaires, and examination) were similar to the procedures used in the current study carried out after the iodization of salt. For the preiodization study, 9274 persons were invited and 4649 (50.1%) participated. The study is described in detail elsewhere (4).

Cross-sectional study after iodization of salt

For the current cross-sectional study, subjects were invited from the same two regions in Denmark, now known to have been mildly iodine deficient and moderately iodine deficient before iodization, with median urinary iodine of respectively 61 and 45 µg/liter in the first study excluding subjects taking vitamin tablets containing iodine (4). The crude median values in the two regions were 68 and 53 µg/liter, respectively. From these areas, all women born in Denmark aged 18–22, 25–30, 40–45, and 60–65 yr and men born in Denmark aged 60–65 yr who did not participate in the previous study were drawn from the civil registration system (n = 37,963), a register where all persons living in Denmark are registered by an exclusive 10-digit number. The groups were largely chosen to represent women before childbearing age, in the childbearing age, and after the childbearing age (pre- and postmenopausal). To reflect the female population, pregnant women were included. For comparison between the genders, a group of men was included corresponding to the group of postmenopausal women. The persons were given random numbers within each sex and age group and were subsequently invited in order of the random numbers. The goal was to reach 350 participants in each sex and age group in each region, and the number of invitations was regulated throughout the study to attain this. The participation rate was 46.6%, highest in the area with previous moderate iodine deficiency (Table 1).

The study was carried out by two teams, each comprising a physician and a sonographer, and in Aalborg additionally a laboratory technician.

The participant answered questionnaires regarding previous thyroid disease, lifestyle (i.e. smoking, eating, and drinking habits), socioeconomic factors, and medication. In case of doubt, the questionnaires were amplified in a subsequent interview.

An ultrasonography was performed using a Sonoline Versa Pro 7.5 MHz 70 mm linear transducer (Siemens, Munich, Germany), effective length 62 mm. Thyroid volume was calculated as maximal length*width*depth*/6 of each lobe. Thyroid enlargement was defined as a thyroid volume greater than 18 ml for women and 25 ml for men, which corresponds to the mean + 3 SD values in iodine-sufficient populations (14). Records were made on distinct nodules larger than 5 mm. In the event of more than three nodules in a lobe, only the three largest were registered. The structure of the gland was classified as diffuse (no registered nodules), solitary nodule (one thyroid nodule), or multinodular (more than one thyroid nodule). The two sonographers previously performed the ultrasonographies in the corresponding study carried out before the iodization of salt using the same apparatus. Their comparability was studied and described (15). Before the current study, a confirmatory interobservational study was performed showing continued good correlation (r = 0.95) between the observers in determination of thyroid size. In judging the left lobe, there was a tendency toward larger volume judged by the observer from the area with mild iodine deficiency. This tendency reached significance in the latest interobservational study, but has been of similar size throughout the whole study period.

Nonfasting spot urinary samples were collected during the time interval from 0800–1800 h and analyzed for iodine concentration for 3554 subjects. The urine samples were digested by alkaline ashing and analyzed by the Ce⁴⁺/As³⁺ method for iodine contents as previously described (16, 17). The median iodine excretion in the combined cross-section was 101 µg/liter. It was 108 µg/liter in Copenhagen and 93 µg/liter in Aalborg, making the areas iodine sufficient and mildly iodine deficient according to criteria outlined by the World Health Organization (18). After exclusion of subjects taking individual iodine supplementation, the figures were 99 and 86 µg/liter, respectively. This corresponds to an increase in median values of 38 and 41 µg/liter compared with values before iodization of salt. The study was approved by the regional Ethics Committee, and all participants gave written informed consent.

Statistics

Data processing was conducted using SAS 9.1 statistical software (SAS Institute Inc., Cary, NC). The desired number of participants was established by a power calculation to be able to demonstrate a potential decrease in thyroid size of 1 ml in the young adults after the iodization of salt ( = 0.05, ß = 0.20). Nonparametric tests (Mann-Whitney U/Wilcoxon test) were used to compare thyroid volume before and after iodization of salt and in between the regions, because the distribution of volumes was skewed toward higher values. Comparisons between frequencies were done using ² test or Fisher’s test. In regression models, possible confounding by region, sex, age, lifestyle (tobacco, alcohol, iodine supplementation, and oral contraceptives), familial disposition (at least one first-degree relative with thyroid disease), educational level, parity, and body surface area [0.0235 x height (cm)^0.42246 x weight (kg)^0.51456] (19) were considered. A reparameterization of cohort and region of inhabitancy was done because of interaction between the two. Because of skewness, thyroid volume was logarithmically transformed for analyses in regression models.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Thyroid volume

Median thyroid volume was lower in all age groups after iodine fortification compared with before (Table 2). The largest absolute difference, 2.6 ml, was found among the elderly men in the area with previous, moderate iodine deficiency, and the largest relative difference was found among the younger females from the area with previous, moderate iodine deficiency. Only a minor decrease, 0.4 ml, was seen among the youngest participants in the area with previous, mild iodine deficiency (P = 0.051). After the iodization, there were no regional differences in median thyroid volume in the age groups younger than 45 yr old. The distribution of thyroid volumes shifted toward lower values, and the range narrowed in both regions (Table 2).

View larger version (38K): [in this window] [in a new window]   FIG. 1. Crude median thyroid volume before and after iodization of salt according to thyroid structure [solitary nodule, diffuse (no nodules > 5 mm), or multinodular] in two regions of Denmark with respectively mild and moderate iodine deficiency before iodization. Subjects treated for thyroid disease (n = 420) were excluded.

No difference was found, either in simple or in logistic regression models, in overall prevalence of solitary thyroid nodules larger than 10 mm (5.9 vs. 5.6%; P = 0.573) or multiple nodules (11.3 vs. 10.3%; P = 0.173) in the two cross-sections. The overall median size of registered solitary nodules was 9.0 mm before the iodization and 10.1 mm after the iodization (P = 0.04), and the median size of the largest of multiple nodules in an individual was 13.0 mm before iodization and 12.8 mm after iodization (P = 0.48). As expected, there was an increase in prevalence of nodules with increasing age. This was unchanged from before the iodization (4).

Data validation

In the present cross-sectional study there were no significant differences between participant and nonparticipant regarding prior thyroid dysfunction or thyroid surgery based on data from the National Patient Register, but the participants in Aalborg were more likely to have a known goiter diagnosis than the nonparticipants in Aalborg [odds ratio, 3.1 (95% CI, 1.6–6.0)]. This was not the case in Copenhagen [odds ratio, 1.2 (95% CI, 0.7–2.0)]. There were no differences between participants and responders to the short questionnaire in self-reported thyroid disease in any of the regions.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this prospective study of an adult population, we showed a lower median thyroid volume independent of sex and age and a decrease in prevalence of thyroid enlargement after 4 yr of mandatory iodization of salt in Denmark. We have no knowledge of similar prospective studies of adult populations related to the introduction of iodized salt. One other study used a prospective design studying children: Zimmermann et al. (7) examined school children in an area with severe iodine deficiency and found declining median thyroid volume, especially in the youngest children, during a 4-yr period of iodization of salt. Studies following changes in connection with altered regimes of iodization have shown varying results from no change in occurrence of palpable goiter among children 1 yr after a shift from optional to mandatory iodization (20) to normalization of goiter prevalence measured by ultrasonography among children 18 months after iodization in a small randomized study of different iodization regimes (21).

We found an effect in all investigated age groups with reduction in median thyroid volume after 4 yr of iodization, with normalization of thyroid volume in the younger age groups, but continued high rates of thyroid enlargement in subjects over 40 yr. This shows an effect of iodization of salt across life span but indicates that after long-standing exposure to iodine deficiency it may take years or even generations to normalize thyroid volumes in the population. The effect of iodization was most prominent and remained after adjustment for other risk factors among participants who had multinodular thyroid disease and among participants with diffuse structure from the area with the most pronounced previous iodine deficiency. Thus, the effect was primarily seen in subjects with clear signs of iodine deficiency. Additionally, we found a decrease in prevalence of large goiter (>50 ml). It could have been expected that the enlargement seen in multinodular glands was irreversible to a large extend, but this did not seem to be the case. A fall in the prevalence of large thyroids and multinodular thyroids could be explained by reduction in volume of already existing enlargements and/or by lower occurrence of new cases. However, the relative short period of time from mandatory iodization to the second investigation may suggest that the first option is most important, because the development of a multinodular goiter demands a relatively long time interval. The lower volume found after iodization is probably mainly caused by shrinkage of the perinodular tissue, because the prevalence of nodules was unchanged as was the median size of the nodules. There was a difference in effect of iodization of salt in the two regions: the largest volume reduction was seen in the area with moderate iodine deficiency, and only an insignificantly lower volume was seen among the youngest adults in the area with mild iodine deficiency, individuals who were teenagers when the iodization program was initiated.

These findings indicate approximation to an optimal iodine intake in Denmark judged by thyroid volumes, which are now resembling thyroid volumes in areas considered iodine replete, e.g. Amsterdam, The Netherlands (mean thyroid volume, 10.7 ml among 20 to 70 yr olds) (22) and Sweden (median thyroid volume, 11.5 ml among adolescents, 14.3 ml among 60 to 65 yr olds) (23). An important question is whether such an increase in iodine intake is associated with an increase in the occurrence of other thyroid disorders than goiter. Data from the DanThyr-register shows a significant increase in the incidence of hyperthyroidism, not only as expected among the older individuals with multinodular goiter but also among the young individuals (24). Therefore, continued surveillance of the iodine program is essential.

The rate of attendance was only 46.6%, which introduces a possible selection bias. We have, however, self-reported information regarding previous thyroid disease on further 26.9% and data from the National Patient Register regarding previous thyroid diagnosis and/or operations on all invited subjects. These data show an overrepresentation of previous goiter diagnosis among the participants in Jutland compared with nonparticipants, possibly causing an overestimation of goiter prevalence in this region. No differences in prevalence of self-reported thyroid disease were found between participants and responders to the short questionnaire in either region. Prior thyroid goiter diagnosis (in registers and self-reported) was generally more common among participants than among nonparticipants in the first cross-section (4). This indicates that participants in the second cross-section are "healthier" than participants in the previous cross-section. This could cause an overestimation of the difference in thyroid volume and thyroid enlargement between the two cross-sections. However, participants known to have been treated for thyroid disease were excluded from the analyses, and only a few diagnosed with thyroid enlargement during the study were aware of this beforehand, making selection bias less likely. The difference between the regions in previous goiter diagnosis based on data from the National Patient Register in the second cross-section could cause an overestimation of median thyroid volume in the area with previous moderate iodine deficiency, and the actual difference in volume between the regions after the iodization might be even smaller than reported.

The strength of the study is the planned prospective design with investigation of similar age-stratified populations before and after the iodization of salt with standardized procedures between the regions and between the two compared cross-sectional studies. The two ultrasonographers performed the ultrasonographies in both studies, and their interobservational relationship was investigated before the first study (15) and was continuously checked during the study periods. All procedures in the second study were uniform with those in the first study, enabling us to make direct comparisons of thyroid volumes and prevalence of thyroid enlargement before and after the iodization.

Conclusively, with a prospective design and standardized procedures, we demonstrated approximation to an optimal iodine intake in Denmark, with normalization of thyroid size among the young individuals and reduction in prevalence of thyroid enlargement, 4 yr after mandatory iodization of salt. Continued monitoring of the iodization program is crucial in defining the appropriate level of iodization.

	Acknowledgments

 
We express our thanks to Ingelise Leegaard and René Fiege, who carefully performed the ultrasonographies.

	Footnotes

 
This work was supported by Musikforlæggerne Agnes og Knut Mørks Foundation, H:S’s Research Foundation, Tømmerhandler Vilhelm Bang Foundation, and North Jutland County Research Foundation.

Disclosure Statement: P.V., N.K., H.P., A.C., P.L., I.B.P., L.O., and T.J. have nothing to declare. L.B.R received lecture fees from the Danish Meat Association and Arla Foods.

First Published Online January 30, 2007

Abbreviation: CI, Confidence interval.

Received November 28, 2006.

Accepted January 22, 2007.

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