Epidemiology

The prevalence of iodine deficiency is mainly based on data from urinary iodine levels in school children, which generally reflects the status of the entire population⁽¹¹⁾. However, some authors found major differences in the nutritional profile of children and adults, suggesting that the outcome of the earlier studies might not present an accurate picture of iodine deficiency in the whole population⁽Reference Moreno-Reyes, Carpentier and Macours⁶⁾. The total prevalence of goitre is not sufficiently sensitive to recent changes in iodine intake. In 2007, the WHO reported that nearly 2 billion individuals worldwide (36·5 % of school-age population and 35·3 % of the general population) had insufficient iodine intake, including one-third of all school-age children. Until recently there was no system for monitoring iodine deficiency. Unlike the USA, where >90 % of the households use iodised salt, European countries are characterised by a high degree of iodine deficiency ( ± 60 %). Implementation of structured iodine supplementation programmes led to a turnaround in 2003, with a decline in the proportion of school-going children at risk⁽³⁾. Presently, the prevalence of goitre globally is 15·8 %, with the highest frequency in the Eastern Mediterranean (37·3 %) and the lowest in the USA (4·7 %)⁽Reference Andersson, Takkouche and Egli¹²⁾. The interpretation of the WHO data should be done with caution. Representative (sub)national studies covering 60 % of the global population can underestimate or overestimate the extent of iodine deficiency. Extrapolation of a population indicator (the median urinary iodine content) to define the number of affected individuals is also not so accurate⁽³⁾. Finally, there are insufficient data available to estimate the prevalence of this health problem in pregnant women⁽Reference de Benoist, McLean, Andersson, Preedy, Burrow and Watson¹³⁾.

Polymorphism

Although iodine supplementation will aid significantly in ameliorating thyroid problems, evolutionary pressure should also be taken into account. Strong selective pressures in the past have shaped our ability to detect anti-thyroid compounds and to avoid them⁽Reference Sandell and Breslin¹⁴⁾. Food preferences are influenced by a number of factors such as personal experiences, cultural adaptations and perceived health benefits. Based on the response to bitter-tasting compounds such as phenylthiocarbamide (PTC) or 6-n-propylthiouracil, individuals can be classified as supertasters (30 % of the world's population), tasters (50 % of the world's population) or non-tasters (20 % of the world's population)⁽Reference Forrai and Bánkövi^15–Reference Facchini, Abbati and Campagnoni²¹⁾. The prevalence of taste insensitivity to PTC and 6-n-propylthiouracil varies in human populations: Indians: 40 %, Caucasians: 30 %, Chinese: 6–23 % and West Africans: 3 %⁽Reference Tepper^22–Reference Guo and Reed²³⁾. Bitter substances bind to approximately thirty human taste receptors type 2, residing on the surface of the taste cells within the taste buds of the tongue. Those receptors belong to the heptahelical or G protein-coupled receptor (GPCR) family, characterised by the presence of seven transmembrane helices and the interaction with intracellular G proteins⁽Reference Adler, Hoon and Mueller^24–Reference Chandrashekar, Hoon and Ryba²⁶⁾. Activation of the G protein-coupled receptor signalling pathways leads to bitter perception⁽Reference Behrens and Meyerhof²⁷⁾. Polymorphisms of the TAS2R38 gene (located in a small region on chromosome 7q) account for 55–85 % of the variance in PTC sensitivity, which is almost completely explained by amino acid substitutions at position 49 (alanine or proline), 262 (valine or alanine) and 296 (isoleucine or valine)⁽Reference Kim, Jorgenson and Coon²⁸⁾. This gives rise to two major haplotypes (proline–alanine–valine (the taster variant) and alanine–valine–isoleucine (the nontaster variant)) and three less common variants, which are either rare (alanine–alanine–valine and proline–valine–isoleucine) or limited to specific populations (alanine–alanine–isoleucine in sub-Saharan Africans)⁽Reference Wooding, Kim and Bamshad²⁹⁾. Subjects, homozygous for the proline–alanine–valine haplotype are most sensitive to the taste of PTC or 6-n-propylthiouracil; those who are homozygous for the alanine–valine–isoleucine haplotype are least sensitive while individuals who carry a copy of both haplotypes (proline–alanine–valine/alanine–valine–isoleucine) have an intermediate sensitivity⁽Reference Bufe, Breslin and Kuhn^30–Reference Duffy, Davidson and Kidd³¹⁾.

As PTC-related substances show anti-thyroid activity, a significant excess of non-tasters with non-toxic goitre has been reported in communities with endemic goitre⁽Reference Harris and Kalmus^16, Reference Kitchin, Howel-Envas and Clarke^20, Reference Facchini, Abbati and Campagnoni^21, Reference Greene³²⁾. Ingestion of glucosinolates in plants inhibits thyroid peroxidase activity and blocks active transport of iodide into the thyroid, resulting in both retarded sexual maturation and mental retardation in low iodine regions⁽Reference Green, Werner and Ingbar^33–Reference Clements and Wishart³⁵⁾. After iodine supplementation, the described association is no longer observed. It has been suggested that PTC polymorphism is conserved in human beings as a protective mechanism against the overconsumption of dietary goitrogens⁽Reference Greene³²⁾.

Detection methods for iodine deficiency

Four complementary indicators are available for determining iodine status: urinary iodine concentration (UI), thyroid size, serum thyroid-stimulating hormone (TSH) and thyroglobulin (Tg). UI is a sensitive biochemical marker of recent iodine intake (d)⁽Reference Nicola, Basquin and Portulano³⁶⁾. A simple spot urine sample collected from a representative sample is sufficient to measure iodine output (μg/l). Although the median UI gives no direct information on the thyroid function, a low value is an indication of an increased risk for thyroid problems⁽Reference Zimmermann³⁷⁾. Iodine excretion may vary on a daily basis, intra-/inter-individually and among different population groups⁽Reference Andersen, Karmisholt and Pedersen³⁸⁾. The thyroid size is primarily determined by inspection and palpation (grade 0–2). Despite the advantages (non-invasive and quick to implement), the reliability of this method is limited by high inter- and intra-observer variations. An additional ultrasound of the thyroid, taking into account the international reference ranges for a normal thyroid size in iodine-sufficient children, is recommended. Changes in goitre development reflect long-term iodine nutrition (months to years)⁽Reference Zimmermann, Hess and Molinari³⁹⁾. Serum TSH is dependent on serum concentration of the circulating thyroid hormone. Although slightly elevated levels are observed in iodine-deficient populations, the majority of school children and adults present normal TSH concentrations. The increase in the number of neonates with moderately elevated TSH concentrations (>5 mIU/l in whole blood) is proportional to the degree of iodine deficiency⁽Reference Zimmermann^{37, 40–}Reference Zimmermann, Burgi and Hurrell⁴²⁾. Serum Tg concentrations are increased in thyroid hyperplasia and after TSH stimulation. There is a good correlation with the degree of iodine deficiency, measured by UI. Moreover, Tg is also a better indicator for iodine repletion (weeks to months) compared with TSH or T₄⁽Reference Knudsen, Bülow and Jørgensen⁴³⁾. As the widespread use of TSH and Tg in the determination and monitoring of iodine deficiency at the population level is still very limited, these data were not included in the WHO database on iodine deficiency⁽⁴⁰⁾.

Iodine fortification and supplementation

The universal iodisation of salt (both for human and animal consumption) is considered as the most appropriate strategy to address the problem of iodine deficiency. Its success has many reasons. Salt is used by almost everyone and its intake is even throughout the year. In most countries, the production and import of salt are carried by a limited number of people. The implementation of a universal salt iodisation is a larger, but still a worthy challenge in areas with many small salt producers. Moreover, it is a simple and cost-effective method, with no change in colour and taste of the salt. The amount of iodine added to salt can easily be monitored⁽Reference Zimmermann^37, Reference Horton and Miloff⁴⁴⁾.

The WHO recommends a daily iodine intake of 90 μg for infants (0–59 months), 120 μg for school-age children (6–12 years), 150 μg for adolescents and adults and 200 μg for pregnant and lactating women. Fortification of iodine to salt can occur in the form of potassium iodide (KI) or iodate. Depending on the local salt intake, 20–40 mg iodine/kg salt is added following the guidelines of the WHO/UNICEF/International Council for the Control of Iodine Deficiency Disorders⁽³⁾. Environmental factors, such as the consumption of goitrogens and a shortage of trace elements in the diet (Se and Fe), may prevent an optimal response to administered iodine⁽Reference Köhrle^45, Reference Zimmermann, Adou and Torresani⁴⁶⁾.

Alternatives to universal salt iodisation have been described. Bread, water, irrigation water, milk and cattle feed are vehicles for iodised salt⁽Reference Cao, Jiang and Kareem^47–Reference Seal, Doyle and Burgess⁵¹⁾. Iodised oil, obtained by esterification of unsaturated fatty acids in seed or vegetable oils, can be given daily or annually in a peroral or intramuscular administration^(3, Reference Benmiloud, Chaouki and Gutkeunst^52, Reference Untoro, Schultink and West⁵³⁾. The dose is 200–400 mg iodine/year and is primarily intended for young or pregnant women and children⁽³⁾. The administration of iodine in the form of KI (30 mg/month or 8 mg/2 weeks) or potassium iodate drops/tablets is another option⁽Reference Todd and Dunn⁵⁴⁾. Antiseptics (Lugol solution) are also iodine preparations⁽Reference Zimmermann³⁷⁾.

In countries with an iodised salt programme, attention must be paid to weaning infants, particularly to those not receiving iodine-containing infant formula milk. Infants are at high risk for iodine deficiency, because their requirements per kg body weight for iodine and thyroid hormone are much higher than at any other time in the life cycle⁽Reference Andersson, de Benoist and Delange^55, Reference Andersson, Aeberli and Wüst⁵⁶⁾. The iodine intake of breastfed infants relies solely on the iodine concentration of breast milk, which, in turn, reflects the mother's iodine status⁽Reference Mulrine, Skeaff and Ferguson⁸⁾. The highest concentration of iodine is found in colostrum with concentrations of 200–400 μg/l, decreasing to 50–150 μg/l in mature human milk⁽Reference Semba and Delange^57, Reference Leung, Pearce and Hamilton⁵⁸⁾. Pre-term infant formulas contain 20–170 μg iodine/l, which may be too low in particular situations to achieve the recommended intake of iodine⁽Reference Ares, Quero and Durán⁵⁹⁾.

Iodine dosage via the enteral or parenteral route is efficient, as oral iodine bioavailability is 90–95 %. However, parenteral solutions contain much less iodine than enteral formulas. In parenterally fed infants and children, with a daily recommended iodine dose of 1 μg/kg, this 50 % iodine intake deficit is corrected by the absorption of iodine through the skin from topical iodinated antiseptics and by the administration of iodine in other infusions⁽Reference Zimmermann and Crill^60, Reference Cicalese, Bruzzese and Guarino⁶¹⁾. In iodine-sufficient adults, with a daily iodine requirement of 70–150 μg, thyroidal iodine stores are often adequate to meet the needs of adult patients requiring total parenteral nutrition for less than 3 months⁽Reference Atkinson and Worthley⁶²⁾.

Besides iodised salt, which is the most important source of iodine worldwide, multiple dietary sources of iodine are of great importance for achieving a sufficient dietary iodine intake. Dietary sources of iodine vary with country and population⁽Reference Dahl, Meltzer, Preedy, Burrow and Watson⁶³⁾. The native iodine concentrations in most food groups are low. The most commonly consumed foods provide 3–80 μg/serving⁽Reference Zimmermann and Crill⁶⁰⁾. The highest content of this micronutrient is found in milk, eggs and products of marine origin (with higher mean iodine concentrations in lean fish species compared with fatty fish species). Milk and dairy derivates contain relatively high amounts of iodine. A seasonal variation of iodine concentration in milk is reported with a significantly higher iodine content of milk in the winter season, compared with the summer season. This finding can be explained by the use of cow fodder fortified with iodine during winter. The average iodine content within the same season is comparable for different types of milk⁽Reference Dahl, Meltzer, Preedy, Burrow and Watson⁶³⁾. In a group of pregnant women, a multivariate analysis showed that milk was the only variable influencing UI, including the use of iodised salt, iodine supplementation and different foods⁽Reference Mulrine, Skeaff and Ferguson⁸⁾. Moreover, in contrast to fish, eggs or iodised salt, a high correlation between UI, milk and dairy products intake was reported in Italian school children⁽Reference Girelli, Coin and Mian⁶⁴⁾. Eggs, and more specifically egg yolks, are another rich source of iodine. The content of iodine in eggs depends on the iodine concentration in hen fodder⁽Reference Shapira⁶⁵⁾. Recently, the value of fortified eggs as a unique nutritional supplement for peak brain development during pregnancy, nursing and infancy was demonstrated⁽Reference Alvarez-Pedrerol, Ribas-Fitó and García-Esteban⁶⁶⁾.

Seafood, including saltwater fish, shellfish, kelp, seaweed and seaweed products can provide a considerable amount of iodine. However, its contribution depends on the alimentary habits of the population⁽Reference Dahl, Meltzer, Preedy, Burrow and Watson⁶³⁾. Iodine inhalation may influence iodine status and may help explain why despite the absence of a regular source of dietary iodine intake such as iodised salt, coastal communities residing in seaweed-rich areas can maintain an adequate dietary iodine supply⁽Reference Smyth, Burns and Huang⁶⁷⁾.

The mean iodine concentration in other foodstuffs (meat, meat products, bread, cereals, vegetables, potatoes, fruits, berries, fats and oils) is 2–3 μg/100 g, which is limited in comparison with the total iodine intake. The contribution of iodine from drinking-water is region dependent⁽Reference Dahl, Meltzer, Preedy, Burrow and Watson⁶³⁾. Iodine-containing compounds used in irrigation, fertilisers, livestock feed, dairy industry disinfectants and bakery dough conditioners influence iodine content in foods⁽Reference Zimmermann and Crill⁶⁰⁾.

Iodine supplementation by the independent administration of KI is preferable, as a lot of multivitamin preparations do not contain an adequate amount of iodide⁽Reference Smyth, Burns and Huang⁶⁷⁾. Recent studies in Spain have shown that only a minority of women used iodine supplements during their pregnancy, either as iodine or as multivitamin tablets containing 100–200 μg of iodine each. Although iodine supplementation alone was not effective, the combination of iodine supplements and a diet rich in milk reached an acceptable median UI. Pregnant women from an iodine-sufficient area could have a suboptimal iodine status without a diet rich in iodine or without supplementation with iodine-containing tablets⁽Reference Alvarez-Pedrerol, Ribas-Fitó and García-Esteban⁶⁶⁾. Apart from universal iodisation of salt, the use of iodine supplements as vitamin complexes or as KI tablets is recommended from the start of gestation or earlier in the case of planned pregnancy⁽Reference Marco, Vicente and Castro⁶⁸⁾.

Value and pitfalls

Abundance and toxicity (Table 1)

The thyroid gland is able to adapt to different doses of iodine to regulate the synthesis and release of thyroid hormones. A chronic intake of 30 mg up to 2 g iodine/d is tolerated by iodine-sufficient individuals. A persistent drop of serum T₄ and T₃ of 25 and 15 %, accompanied by a TSH rise of 2 mIU/l is observed. An excessive intake of iodine may increase the risk of autoimmune thyroiditis, hyperthyroidism (especially in a pre-existing multinodular goitre), (sub)clinical hypothyroidism (especially in a pre-existing Hashimoto's thyroiditis) and goitre⁽Reference Stanbury, Ermans and Bourdoux^92, Reference Vitale, Di Matola and D'Ascoli⁹³⁾.

Table 1 Classification according to the degree of iodine deficiency

One of the main side effects seen in multiple iodine supplementation programmes concerns iodine-induced hyperthyroidism⁽Reference Galofre, Fernandez-Calvet and Rios^94–Reference Krohn, Führer and Bayer⁹⁶⁾. The risk is elevated in an initial severe iodine deficiency, a subsequent (too) large increase in iodine intake, a mean urinary iodine level ≥ 300 μg/l and in smokers⁽Reference Sachs, Siegel and Horwitt^10, Reference Krohn, Führer and Bayer⁹⁶⁾. Especially, adults (>40 years) with a long-standing nodular goitre are at increased risk. Given that the symptoms of iodine-induced hyperthyroidism are not specific enough, this problem is frequently overlooked⁽Reference Corvilain, van Sande and Dumont⁹⁷⁾. Iodine-induced hyperthyroidism is almost always transient and the incidence falls over time (1–10 years after the introduction of the supplementation programme) back to its normal level⁽Reference Delange, de Benoist and Alnwick⁹⁸⁾. An excessive intake of iodine may induce a flare of Graves' disease, which is age independent⁽Reference Mostbeck, Galvan and Bauer⁹⁹⁾. Besides the effect on thyroid hormone synthesis, this is most probably due to the stimulation of the intra-thyroidal autoimmune process. However, autonomous nodules are not the only pathogenetic explanation for iodine-induced hyperthyroidism, as this phenomenon was also reported in entirely normal glands⁽Reference Bürgi¹⁰⁰⁾.

Bülow Pedersen et al. ⁽Reference Bülow Pedersen, Laurberg and Knudsen¹⁰¹⁾ diagnosed new cases of hypothyroidism in addition to hyperthyroidism. Despite a careful introduction of iodised salt, the incidence of hypothyroidism slightly increased in areas with a previous moderate iodine deficiency. Even in subjects with normal thyroid function, high iodine intake can negatively affect thyroid hormone levels⁽Reference Hwang, Lee, Lee and Shin¹⁰²⁾. Investigation of the impact of iodine intake on thyroid diseases in China showed an increase in the prevalence of overt hypothyroidism, sub-clinical hypothyroidism and autoimmune thyroiditis with increasing iodine intake⁽Reference Teng, Shan and Teng¹⁰³⁾. In addition, the investigators showed in a recent paper that even a median UI of 200–300 μg/l might be related to a potential increased risk of developing sub-clinical hypothyroidism or autoimmune thyroiditis⁽Reference Teng, Shan and Chen¹⁰⁴⁾, which differs from the data published by the WHO (median UI>300 μg/l)⁽⁴⁰⁾. The exact mechanism by which chronic high iodine intake induces hypothyroidism remains unclear. Iodine-induced hypothyroidism usually resolves quickly after iodine withdrawal, but if the administration of iodide continues, overt or sub-clinical hypothyroidism will persist⁽Reference Markou, Georgopoulos and Kyriazopoulou¹⁰⁵⁾. Preventing iodine deficiency-induced hypothyroidism is important as it is an independent risk factor for CHD and can result in a poor neurodevelopmental outcome if present during pregnancy⁽Reference Hak, Pols and Visser^106, Reference Haddow, Palomaki and Allan¹⁰⁷⁾. A more than adequate iodine intake may be a risk factor for autoimmune thyroiditis in humans, which is reflected by the correlation between the prevalence of positive thyroid autoantibodies and the amount of iodine intake. The underlying mechanisms of this phenomenon induced by iodine intake are: (1) an increased immunogenicity of Tg, precipitating an autoimmune process at both the T and B-cell level; (2) a toxic effect on thyroid cells and (3) a direct stimulation of immune and immunity-related cells⁽Reference Teng, Shan and Chen¹⁰⁴⁾.

Acute iodine poisoning, which is uncommon as it usually occurs with doses of multiple grams, is associated with gastrointestinal discomfort (abdominal pain, nausea, vomiting and diarrhoea), cardiovascular symptoms, coma and cyanosis. An excessive intake of iodine may rarely cause iodermia, a dermatological condition comprising acneiform eruptions, an itchy rash and urticaria⁽Reference Pennington^108, Reference Parsad and Saini¹⁰⁹⁾. Iodine excess causes a temporary inhibition of thyroid hormone synthesis (the Wolff–Chaikoff effect), inhibits cell growth, induces apoptosis and affects cell morphology⁽Reference Vitale, Di Matola and D'Ascoli¹¹⁰⁾.

Although animal studies showed a significantly increased number of thyroid carcinomas after prolonged iodine deficiency, proof of a direct causative role for iodine deficiency remains elusive. A review of animal experiments, epidemiological and basic gene transfection studies showed a weak relationship between iodine intake and cancer⁽Reference Feldt-Rasmussen¹¹¹⁾. The overall incidence of differentiated thyroid carcinoma is generally not considered to be influenced by iodine intake of a population, whereas the distribution of the types of thyroid carcinoma (papillary:follicular carcinoma ratio) seems to be related to the intake of iodine. Papillary carcinoma is the predominant type of thyroid malignancy in non-endemic areas and shows an increasing incidence in goitrous regions after iodine prophylaxis. This could be related to the long-term effect of iodine supplementation and/or to other factors (e.g. radiation fallout, inclusion of papillary microcarcinomas, better access to medical care, etc.)⁽Reference Lind, Langsteger and Molnar^112–Reference Rubén Harach, Preedy, Burrow and Watson¹¹⁴⁾. Iodine-deficient regions have a tendency to show higher rates of undifferentiated (anaplastic) carcinomas before iodine prophylaxis, compared with post-prophylaxis periods and regions with high dietary iodine intake⁽Reference Rubén Harach, Preedy, Burrow and Watson¹¹⁴⁾.

In the treatment and follow-up of well-differentiated thyroid cancer, a temporary low-iodine diet (LID) is generally recommended before high-dose radioactive iodine (¹³¹I) ablation therapy or radioactive iodine scanning. The stringency and the duration of restriction about the time of therapy are debatable⁽Reference Sawka, Ibrahim-Zada and Galacgac¹¹⁵⁾. The American Thyroid Association recommends an LID defined by an intake of < 50 μg/d for 1–2 weeks before ¹³¹I ablation⁽Reference Cooper, Doherty and Haugen¹¹⁶⁾; the British Thyroid Association recommends an LID for 2 weeks before ¹³¹I ablation or therapy⁽¹¹⁷⁾; the European Thyroid Cancer Taskforce recommends an LID for 3 weeks before ¹³¹I administration⁽Reference Pacini, Schlumberger and Dralle¹¹⁸⁾ and the American Association of Clinical Endocrinologists recommends consumption of an LID for 2–4 weeks before radioiodine scanning, with no specific recommendations on stringency or diet before ¹³¹I treatment. It is currently not known whether an LID may result in improved long-term outcomes in thyroid cancer⁽Reference Sawka, Ibrahim-Zada and Galacgac¹¹⁵⁾.