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 WHO, the Danish Investigation on Iodine Intake and Thyroid Disease (DanThyr) was established to monitor the effect on thyroid health and diseases. 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.

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.

UNLABELLED: Autoantibodies against the thyroid gland with thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) as the most common can often be demonstrated in serum. The effect of public iodization programmes on antibody prevalence is uncertain. AIM: To measure the concentrations of thyroid autoantibodies in the Danish population before and after mandatory iodization of salt. METHODS: Two identical cross-sectional population studies were performed before (Cohort 1 (C1), year 1997-1998, n = 4649, median urinary iodine 61 µg/l) and 4-5 years after (Cohort 2 (C2), year 2004-2005, n = 3570, median urinary iodine 101 µg/l) mandatory iodine fortification of salt was implemented in Denmark. Blood tests were analysed for TPO-Ab and Tg-Ab using sensitive assays. RESULTS: Antibodies were more frequent in C2 than in C1: TPO-Ab > 30 U/ml, C1 vs C2: 14·3 vs 23·8% (P < 0·001) and Tg-Ab > 20 U/ml, C1 vs C2: 13·7 vs 19·9% (P < 0·001). The C2 vs C1 effect was confirmed in multivariate regression models (C1 reference): TPO-Ab: OR (95% CI): 1·80 (1·59-2·04) and Tg-Ab: 1·49 (1·31-1·69). The increase in the frequency of thyroid antibodies was most pronounced in young women and especially observed at low concentrations of antibodies. CONCLUSION: The prevalence of both TPO-Ab and Tg-Ab was higher 4-5 years after a cautious iodine fortification of salt was introduced in Denmark. The increase was most pronounced in young women and in the low concentrations of antibody. Further studies are needed to evaluate the long-term effects of increased iodine intake on thyroid autoimmunity in the population.

Estimation of iodine intake from various urinary iodine measurements in population studies.

BACKGROUND: Iodine intake is often measured by a surrogate measure, namely urine iodine excretion as almost all ingested iodine is excreted in the urine. However, the methods for urine collection and the reporting of the results vary. These methods, and their advantages and disadvantages, are considered in this article. SUMMARY: There are two main ways in which urine can be collected for iodine measurement. The first is the collection of urine over a period, usually 24 hours. The second is the collection of a spot urinary sample. Urinary iodine values can be expressed as the content or concentration and reported without modification or as a function of creatinine in the same sample. The 24-hour urine for iodine measurement is often considered as the "reference standard" for giving a precise estimate of the individual iodine excretion and thereby iodine intake. As 24-hour collections are difficult to perform for large number of persons, single spot urinary samples are preferable to the 24-hour urinary collections in population studies. The iodine concentration in urine depends on the intake of both iodine and fluid. This, and the fact that there is a considerable variability in the daily iodine intake, makes the iodine measurement in spot urine samples unreliable for evaluating individuals for iodine deficiency, though they can be used to screen for exposure to large amounts of iodine from sources such as amiodarone and certain radiographic contrast agents. In populations of at least 500 subjects, the median value of spot urinary iodine concentration is a reliable measure of the iodine intake in the population as there is a leveling out of the day-to-day variation in iodine intake and urinary volume. Expressing the urinary iodide concentration as a function of urinary creatinine is useful in correcting for the influence of fluid intake. When doing so, it is recommended to adjust for the age- and sex-specific creatinine excretion in the given population. CONCLUSION: In studies of iodine intake, the correct choice of the method for collecting urine and the format for expressing the results of urine iodine measurement is essential to avoid misinterpretation of data on the iodine status of a population or individuals.

Serum selenium and selenoprotein P status in adult Danes - 8-year followup.

Selenium is an essential micronutrient important to human health. The main objective of this study is to describe serum selenium and selenoprotein P status in two samples of the Danish population. In addition, the influence of various factors potentially associated with selenium status was investigated. Blood samples from a total of 817 randomly selected subjects from two cities in Denmark were analyzed. Half of the samples were collected in 1997-1998 and the other half in 2004-2005. Samples from women aged 18-22, 40-45 and 60-65 years, and men aged 60-65 years were selected for this study. All subjects had filled in a food frequency questionnaire (FFQ) and a questionnaire with information about smoking habits, alcohol consumption and exercise habits. Mean serum selenium level was 98.7+/-19.8microg/L and median selenoprotein P level was 2.72 (2.18-3.49)mg/L. Serum selenium and selenoprotein P increased with age, and selenoprotein P was higher in men than in women. Serum selenium levels decreased by 5% on average from 1997-98 to 2004-05 (P<0.001), whereas selenoprotein P level increased (P<0.001). The intake of fish correlated weakly with serum selenium level (r=0.14, P<0.001) but not with selenoprotein P level. Smoking status, alcohol intake, exercise habits, BMI and medicine use did not influence selenium status. It is concluded that selenium status in this Danish population is at an acceptable level. No major groups with regard to age, sex or lifestyle factors could be identified as being in risk for selenium deficiency.

Thyroglobulin as a marker of iodine nutrition status in the general population.

OBJECTIVE: The iodine status of a population is traditionally evaluated by either urinary iodine (UI) excretion or by some measure of thyroid volume and the prevalence of goitre. In this prospective study of a mandatory iodization programme, we aimed to evaluate serum thyroglobulin (Tg) as a marker of iodine status in the population. METHODS: Two identical cross-sectional studies were performed before (1997-1998, n=4649) and after (2004-2005, n=3570) the initiation of the Danish iodization programme in two areas with mild and moderate iodine deficiency. Serum Tg was measured from blood samples. Thyroid volume was measured by ultrasonography. RESULTS: Before iodization, the median serum Tg was considerably higher in moderate than in mild iodine deficiency. Iodization led to a lower serum Tg in all examined age groups. The marked pre-iodization difference in Tg level between the regions was eliminated. The prevalence of Tg above the suggested reference limit (40 microg/l) decreased from 11.3 to 3.7% (P<0.0001). Using bootstrapping, we demonstrated a higher efficacy of Tg than of thyroid volume to show a difference between pre- and post-iodization values. CONCLUSION: We found serum Tg to be a suitable marker of iodine nutrition status in the population. The results may suggest that the Danish iodization programme has led to a sufficient iodine intake, even if the median UI excretion is still marginally low according to WHO criteria.

Lower prevalence of mild hyperthyroidism related to a higher iodine intake in the population: prospective study of a mandatory iodization programme.

OBJECTIVE: Marked differences in pattern of thyroid dysfunction are seen in populations with different iodine intakes. We evaluated the influence of a higher iodine intake on thyroid hormone levels and the prevalence of thyroid dysfunction in the Danish population. DESIGN: Two cross-sectional studies matched on a group level according to sex and age. PARTICIPANTS: In all, 8219 individuals were examined before (n = 4649) or after (n = 3570) the introduction of a mandatory iodization programme in 2000 in two regions with established mild and moderate iodine deficiency. Serum TSH, fT(4) and fT(3 )were measured. An ultrasonography of the thyroid was performed. RESULTS: We found a higher median serum TSH after the introduction of mandatory iodization of salt: 1.51 mU/l (10-90th percentiles: 0.72-3.00) vs. 1.30 mU/l (10-90th percentiles: 0.59-2.66) before iodization. The difference was found in both regions and across age groups. There was a lower prevalence of mild hyperthyroidism and a tendency towards a lower prevalence of overt hyperthyroidism. The prevalence of mild hypothyroidism increased, most pronounced among young women after iodization. Conversely, there was a lower prevalence of undiagnosed overt hypothyroidism. However, when currently treated participants were included, the prevalence of hypothyroidism increased after iodization in the area with formerly mild iodine deficiency. CONCLUSION: A change in pattern of thyroid dysfunction was seen in relation to mandatory iodization of salt. There was no rise in the prevalence of hyperthyroidism and the prevalence of mild hyperthyroidism was halved. Conversely, prevalence of hypothyroidism increased.

The impact of smoking on thyroid volume and function in relation to a shift towards iodine sufficiency.

The aim of the study was to investigate whether the influence of smoking on thyroid volume and function changes in relation to a higher iodine intake in the population. The study comprised a total of 8,219 individuals each examined in one of two separate cross-sectional studies performed before (n = 4,649) and after (n = 3,570) a mandatory iodization of salt in year 2000 in two areas with established mild and moderate iodine deficiency. Participants answered questionnaires regarding life style factors and a thyroid ultrasonography was performed. Blood samples were analysed for serum thyroid stimulating hormone, free thyroxin and free tri-iodothyronine. All procedures used were similar in the two cross-sectional studies. The overall difference in thyroid volume between heavy smokers and non-smokers across the age groups was reduced after iodization of salt from 24% (19-29%) to 12% (6-18%). After the iodization the odds ratio for having thyroid enlargement was still increased for smokers (OR: 1.9 (CI: 1.5-2.6)) compared to non-smokers. The aetiological fraction of thyroid enlargement due to smoking was 39.3% before the iodization and 24.2% after the iodization. Like before iodization smokers had a lower mean thyroid stimulating hormone and a higher free thyroxin in serum than non-smokers. Conclusively, in areas approaching iodine sufficiency a decline in the impact of smoking on thyroid volume was seen. The effect of smoking on hormonal level was unchanged after the iodization. Thus the effect of smoking on thyroid volume seems to be dependent on iodine intake, whereas the effect on function seems mainly to depend on other factors.

Iodine intake before and after mandatory iodization in Denmark: results from the Danish Investigation of Iodine Intake and Thyroid Diseases (DanThyr) study.

Iodine deficiency is still common in some European countries. In Denmark an iodine fortification programme was introduced in 1998 and a monitoring programme was established prior to iodization. This study reports the change in urinary iodine excretion caused by fortification and investigates determinants of iodine intake after fortification. Iodine excretion in casual urine samples was assessed in 4649 subjects in 1997-8 and in 3570 comparable subjects in 2004-5 in women 18-22, 25-30, 40-45 and 60-65 years of age and in men 60-65 years of age living in Aalborg (western part of Denmark) or Copenhagen (eastern part of Denmark). These areas had moderate and mild iodine deficiency, respectively, before iodine fortification. All subjects filled in a FFQ and a questionnaire regarding lifestyle factors. Iodine excretion, expressed as the estimated 24 h urinary iodine excretion and as urinary iodine concentration, increased significantly in all age and sex groups. However, the iodine intake was still below the recommended in the youngest age groups in both cities and in women 40-45 years of age living in Aalborg. Intake of milk and salt had strong significant direct associations with iodine excretion (P < 0.001). It is concluded that although the median iodine intake in the whole study population is at the recommended level, some groups still have an intake below the recommended. It is important to have a moderate milk intake to obtain a sufficient iodine intake in Denmark.

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.

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.

The association between hypoechogenicity or irregular echo pattern at thyroid ultrasonography and thyroid function in the general population.

OBJECTIVE: Patients with overt hypothyroidism show decreased echogenicity of the thyroid at ultrasonography (US). The aim of this study was to investigate the association between echogenicity of the thyroid/irregular echo pattern, and thyroid function in the general population, i.e. subjects without overt thyroid disease. DESIGN: A cross-sectional investigation of 4649 randomly selected adult subjects. METHODS: Blood samples were analysed for serum TSH, thyroid hormones and thyroid autoantibodies. US of the thyroid was performed. RESULTS: Participants with decreased echogenicity (n=379) had a higher mean TSH (1.65 mU/l) compared with subjects with normal echogenicity (1.21 mU/l, P<0.0001). The association was stronger in subjects with markedly decreased echogenicity (4.20 mU/l, P<0.0001). A similar association was seen when the subjects were divided into subgroups according to the level of TSH; more subjects with high levels of TSH had decreased echogenicity (P<0.0001). Likewise, more subjects with high levels of TSH had an irregular echo pattern (P<0.0001). Subjects with decreased echogenicity had a higher risk of having thyroid autoantibodies than subjects without decreased echogenicity (P<0.0001). This association was stronger when echogenicity was markedly decreased. CONCLUSIONS: We demonstrated an association between hypoechogenicity at thyroid US and higher levels of serum TSH even in subjects without overt thyroid disease, suggesting decreased echogenicity as an early sign of thyroid dysfunction. Irregular echo pattern, whether accompanied by hypoechogenicity or not, was another possible marker of thyroid failure. This indicates a possible use of thyroid US in detecting early and subclinical thyroid dysfunction.

The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives.

OBJECTIVE: Denmark was an area of iodine deficiency, and mandatory iodine fortification of table salt and salt in bread (13 p.p.m. iodine) was initiated in 2000/2001. The Danish investigation on iodine intake and thyroid disease (DanThyr) is the monitoring of the iodine fortification program. DESIGN AND METHODS: DanThyr consists of three main parts: a study of population cohorts initialized before (n=4649) and after (n=3570) iodization of salt, a prospective identification of incident cases of overt hyper- and hypothyroidism in a population of around 550,000 people since 1997, and compilation of data from the national registers on the use of thyroid medication, thyroid surgery, and radioiodine therapy. Studies were carried-out in parallel in subcohorts living in areas with differences in iodine content of ground water. RESULTS: The study showed profound effects of even small differences in iodine intake level on the prevalence of goiter, nodules, and thyroid dysfunction. Mild and moderate iodine deficiency was associated with a decrease in serum TSH with age. Other environmental factors were also important for goiter development (increase in risk, smoking and pregnancy; decrease in risk, oral contraception and alcohol consumption), and the individual risk depended on the genetic background. Environmental factors had only a minor influence on the prevalence of thyroid autoantibodies in the population. There were more cases of overt hypothyroidism in mild than in moderate iodine deficiency caused by a 53% higher incidence of spontaneous (presumably autoimmune) hypothyroidism. On the other hand, there were 49% more cases of overt hyperthyroidism in the area with moderate iodine deficiency. The cautious iodine fortification program, aiming at an average increase in iodine intake of 50 mug/day has been associated with a 50% increase in incidence of hyperthyroidism in the area with the most severe iodine deficiency. The incidence is expected to decrease in the future, but there may be more cases of Graves' hyperthyroidism in young people. CONCLUSION: A number of environmental factors influence the epidemiology of thyroid disorders, and even relatively small abnormalities and differences in the level of iodine intake of a population have profound effects on the occurrence of thyroid abnormalities. Monitoring and adjustment of iodine intake in the population is an important part of preventive medicine.