Both insufficient and excessive iodine intake may lead to disease in an individual, and the epidemiology of thyroid disorders depends on the iodine intake level of the population (1). Historically, the occurrence of thyroid disease in Europe has been dominated by iodine deficiency with some geographical variation. Severe iodine deficiency with endemic cretinism and goitre in the major part of the population was primarily found in the Alps and in other mountainous regions, but milder forms of iodine deficiency were present in regions of nearly every European country (2). As reviewed previously by Delange (3), iodine deficiency has been eradicated in some European countries for many years, but other countries have lagged behind, especially in prevention of mild to moderate iodine deficiency. Fortunately, and due to keen efforts by dedicated, hard-working people, the situation has improved in recent years. The number of European countries affected by iodine deficiency is steadily decreasing (4). However, continued focus on the necessity to monitor and adjust the iodine intake of European populations is necessary.

Challenges in the field of iodine intake

Thyroid disease may occasionally cause permanent impairment of health and undiagnosed and untreated thyroid function abnormalities in pregnant women may permanently harm fetal brain development leading to mental deficits(5). Even small aberrations in thyroid function at the population level may change the occurrence of overweight (6,7) and blood pressure abnormalities (8,9). Thus, thyroid disorders should be prevented if possible. Without going into the complicated discussion on interaction between genes and environment, the three factors most important for the occurrence of thyroid abnormalities are: 1) The level of iodine intake 2) The genetic background 3) Tobacco smoking. How should iodine intake be modified to prevent thyroid disorders? The primary concern is always to avoid iodine deficiency as this may most seriously affect the health of a population. However, the level of iodine intake should optimally be increased in a way that will not cause unnecessary disease from excessive iodine intake.

Optimal iodine intake to prevent brain damage

It is a balance to discuss optimization of iodine intake and avoidance of excessive iodine intake without bringing iodization programs into discredit, which may lead to reoccurrence of iodine deficiency, and thereby worsen the situation. As illustrated in fig. 1, the risks from iodine deficiency are much higher than those from a higher than necessary iodine intake. The most severe complication from low iodine intake is developmental brain damage, which is well documented in severe iodine deficiency (10).

The damage is caused by an iodine deficiency induced decrease in thyroid hormone production in the pregnant woman and/or the fetus/neonate, that may also lead to stillbirth and other pregnancy complications. The iodine intake level in a population at which this may occur may depend on individual genetic factors as well as on deficiency of other nutrients (11) and on intake of goitrogens that may hamper iodine utilization of the maternal and fetal thyroid, and iodine transport into the mother’s milk (12). Moreover, in a population there is a certain spread in iodine intake between individuals with some people having intake considerably below average, and the iodine needs of every single pregnant woman should be covered. In a group of men living in a moderately iodine deficient area, we found that thyroid function at the individual level varied in parallel with the iodine intake of the person when average urinary iodine excretion over one year was below 50 µg per day (13).
In pregnancy iodine needs are higher than normal (5), but the extra needs may to some degree be covered by thyroidal iodine stores if the woman lives in an area with sufficient iodine intake. Corresponding to this, signs of impaired thyroid function in pregnant women have been observed in small studies when iodine intake was only mildly to moderately deficient (14,15). Thus, to cover the increased needs of iodine during pregnancy the population should be iodine sufficient with a median urinary iodine concentration above 100 µg/L. As an additional measure in countries with a low normal iodine intake, iodine should be part of the vitamin + mineral supplements taken by many European women during pregnancy (16). Table 1 lists a number of abnormalities that may be less common after an increase in iodine intake of a population. The evidence for such a beneficial effect according to the authors’ opinion (‘confidence’) is indicated, ranging from possibly true to established. The outcome in a given population would depend on the levels of iodine intake before and after. As indicated, the evidence for less disease when iodine deficiency is eradicated is in general good.
Some disorders may become more common after an increase in iodine intake as discussed below, although the evidence is less firm (table 1), and the overall burden of disease will be lower (fig. 1).

Optimal iodine intake to prevent development of goitre and thyroid autonomy

Iodine intake below the recommended level leads to a dose dependent increase in the incidence and prevalence of goitre and thyroid autonomy in a population. In severe iodine deficiency the highest prevalence of goitre is seen in young adults (17), but in areas of mild to moderate iodine deficiency goitre and autonomous thyroid nodules develops with age (18). The DanThyr study which is the monitoring of the Danish iodine program (19) showed that even relatively small differences in population iodine intake of around 30 µg per day were associated with considerable differences in the risk of goitre (18) and hyperthyroidism caused by thyroid autonomy (20). Moreover, a moderate increase in iodine intake of 50-60 µg per day has led to a clear reduction in thyroid size in the Danish population after a few years (21). The DanThyr study has confirmed that the lower limit of sufficient iodine intake of a population set by the WHO (median urinary iodine concentration 100 µg/L) corresponds to the limit below which the risk of goitre and thyroid nodules may increase in a European population.
The cause for development of the multifocal thyroid abnormalities characteristically found in many elderly people when iodine intake is below recommended has not been fully elucidated (22). One candidate is H₂O₂ generated in the thyroid as part of the thyroid hormone synthesis process (23). As recently reviewed (24) thyroid cells generate large amounts of H₂O₂ and this process is up-regulated when iodine intake is low as part of thyroidal iodine-auto-regulation, similar to many other processes involved in iodine utilization. Genetics and tobacco smoking are two other factors important for development of simple goitre (25). As both may act via partial impairment of thyroid iodine utilization, a sufficient iodine intake in a population is a most effective measure to prevent goitre and hyperthyroidism caused by thyroid autonomy. The importance of abnormalities caused by mild to moderate iodine deficiency at the population level is considerable. In a population study of 68 year old people living in Randers, Denmark (with mild to moderate iodine deficiency) before the Danish iodization program, 8 % of the women had undergone thyroid surgery for non-toxic goitre, 4 % had a clinically significant goitre and one out of 30 had undiagnosed overt hyperthyroidism caused by thyroid autonomy (26). The economic consequences of mild to moderate iodine deficiency are considerable (27).

Risks from an increase in population iodine intake

The major concern when iodine intake has been abruptly increased from insufficient to high has been a transient surge of hyperthyroidism, as reviewed by Stanbury et al (28). Iodization programs in Europe as elsewhere should be carefully planned and executed. However, as illustrated in fig. 1, a higher iodine intake level may also be associated with a more permanent increase in the occurrence of some thyroid abnormalities.
The three abnormalities which will be discussed are primary hypothyroidism, Graves’ disease and diffuse goitre. In a comparative study of elderly people living in Iceland (with high iodine intake) and Jutland, Denmark (with moderate iodine deficiency) the prevalence of subclinical hypothyroidism was much higher in Iceland than in Denmark (26). Similar findings have been reported when comparing people with low and high iodine intake in Hungary (29), people with sufficient and high iodine intake in China (30,31) and people with different degrees of excess iodine intake in Japan (32). In the DanThyr register of overt hypo- and hyperthyroidism (19) we found a considerably higher incidence rate of overt hypothyroidism in an area with mild (Copenhagen, Sealand) compared to an area with moderate (Aalborg, Jutland) iodine deficiency (20). The difference was caused by 50 % more cases of spontaneous autoimmune hypothyroidism in the area with the highest iodine intake level (33). After increasing the iodine intake of the Danish population with around 60 µg/day to a low normal level, a small increase in the incidence of overt hypothyroidism has been observed (34).
The exact dose/response curve for this association between higher iodine intake and more hypothyroidism is at present unknown. There are large differences between the occurrence of hypothyroidism between populations, part of which may be genetically determined. In Scotland, hypothyroidism is as common in young women in fertile age as it is in 80 year old women in Denmark (35). It is beyond the scope of this article to discus in detail the possible mechanism involved in the association between higher iodine intake and more hypothyroidism. Iodine has a series of inhibitory effects on thyroidal processes involved in hormone synthesis and secretion. Some people seem to be less able to escape from these inhibitory effects (36) which may be more prevalent if the thyroid is affected by autoimmunity.
In our comparative study of overt hyperthyroidism in Iceland and Jutland, Denmark (37) the life-time risk of Graves’ disease was not much different between the two populations, but on average the disease developed 15-20 years earlier in the population in Iceland. This may suggest a genetic predisposition with a higher risk of overt disease if the iodine intake is higher. Such a mechanism is supported by studies showing risk of reoccurrence of hyperthyroidism with higher iodine intake in people who are in remission after a previous episode of Graves’ disease (38,39).
A higher frequency of diffuse goitre with excessive iodine intake has been observed in school-age children both in the USA (40) and in China (30).

Ways to achieve and maintain optimal iodine intake in European populations

Iodine intake depends on the dietary habits and the iodine content of the individual food items. Fig. 2 illustrates the relative contribution of different sources to iodine intake in the DanThyr population study before the Danish iodization program (41).

Iodine in dairy products contributed nearly half of the average iodine intake. The lactating mammary gland concentrates iodide from blood by way of an iodine transporter identical to thyroidal NIS, and iodine content of dairy milk depends on the contents of iodine and of NIS inhibitors in cow feed (42). Because dairy products are so important for iodine intake in many populations iodine feeding of dairy cows should be monitored and regulated.
In the DanThyr cohort the second most important source of iodine was beverages (fig. 2). The iodine content of fresh water varies depending on the aquifer (43), and regional differences in iodine intake may be caused by different sources of water (44). It is relatively easy to identify areas with high iodine content of water. In such areas individual intake of iodine supplements should probably be avoided.
In many European areas with low iodine content of natural food, an iodization program has to be running. This is normally done by salt iodization. Because both low and high iodine intake may lead to more disease than seen with optimal iodine intake, attempts should be made to create programs that keep the spread of iodine intake between individuals relatively narrow. This is illustrated in figure 3A.

Iodization of all salt used by households and the food industry will distribute iodine quite even in the population and increase the iodine intake without marked changes in the dispersion of individual iodine intake. However, such iodization is often difficult to achieve because of political and commercial concerns. In Denmark, household salt and salt used for commercial bread production is mandatorily iodized (19). Bread is a stable dietary component in Denmark, and this type of iodization gives nearly as good a distribution of iodine as universal salt iodization.
If, on the other hand, iodide is added to only a minor part of food the amount of iodide added has to be considerably higher to give the same increase in medium iodine intake of the population. After such a program the dispersion of iodine intake between individuals may be much higher depending on dietary habits (fig. 3B). For the same average increase in iodine intake some people will still be iodine deficient and others will have en excessive intake (compare fig. 3A and 3B). To avoid iodine deficiency in part of the population after such a program, it will be necessary to increase the iodization level further, and more people will have excessive iodine intake (see fig. 3C).

Conclusion
Eradication of iodine deficiency has always the highest priority. The situation in Europe has improved in recent years.
Optimal prevention of thyroid disease by modification of iodine intake in the population is achieved by keeping iodine intake in individuals within a relatively narrow interval around the recommended level. To run an optimal iodization program it is necessary to have information on dietary habits in the population, and on iodine contents of different food items. Iodine used for enrichment of food should be well distributed in different food items, e. g. by universal or nearly universal iodization of salt. Optimal methods may differ between European countries depending on dietary habits.