Synonyms

We usually speak of iodine or Iodine (in English ), but in food it usually occurs in a loaded form and is called Iodide or Iodine (in English).

Introduction

There is little or no interest in iodine within the health care sector. In general it is assumed that we get enough iodine, mainly through the use of salt to which iodine has been added (JoZo). The government does recognise the importance of iodine and mentions it among the 10 most important micronutrients considered by RIVM and the Health Council of the Netherlands as described in the RIVM report of 2008 (1). However, recent research shows that part of the population does not take in enough iodine. Reducing salt intake, as currently proposed internationally, can also lead to insufficient iodine intake (2).

All the iodine that the body needs must come from the diet. Food of the land naturally (in most regions of the world) contains little to very little iodine, because the soil contains little iodine. The sea contains small amounts of iodine and some animals and plants that live in the sea are able to absorb and concentrate relatively large amounts of iodine: algae, seaweed (kelp), lobster, cod, shrimp, sardine, tuna. In addition, small amounts of iodine can be found in dairy products (milk products) and eggs; the human mammary gland is also able to concentrate iodine and excrete it in the milk.

Iodine was detected in seaweed in 1811 by Bernard Courtois. David Marine demonstrated in a study between 1917 and 1922 that a dose of 200 µg of sodium iodide per day for 10 days at 6-month intervals for 2.5 years could prevent goitre in over 2000 American schoolgirls (3). This was the basis for adding 100mg of iodine per kg table salt (JoZo).

Iodine is especially important in the body as a component of thyroid hormones. These are needed for the growth and development of organs (including the brain) for the regulation of protein, fat and carbohydrate metabolism as well as heat regulation of the body. 

For a long time, the amount of thyroid hormone (T4) and the thyroid stimulant hormone (TSH) in the blood has been used as a measure for iodine deficiency. In case of prolonged severe iodine deficiency, the thyroid gland can no longer produce sufficient iodine-containing thyroxine: iodine deficiency is then induced hypothyroidism. This almost no longer occurs in the Netherlands, after a government decision in 1942 made it compulsory to add iodine-enriched salt to bread, the bread salt. Since 2009, bakers are no longer allowed to use bread salt, but had to switch to baker's salt, which contains approximately 30 % less iodine. Salt with ratios up to max 65 mg/kg is used in bakery products and ratios up to max 25 mg/kg in other industrially prepared foods (2).

However, there are clear indications that iodine has more functions in the body than just for the production of thyroid hormone. In case of long-term mild or moderate iodine deficiency, there are also complaints and diseases that are not related to thyroid function. Iodine intake is not sufficient for everyone. This is due to the reduced content of iodine in baker's salt, but also because of the reduced use of salt and the use of other types of salt (e.g. sea salt) where there is (almost) no iodine and because of lower consumption of bread. The WHO has drawn up criteria for a healthy iodine status based on excretion of iodine in urine (4).
 
In the years following the introduction of iodine in the salt and addition to bread, there were publications of an increase in the number of cases of (temporary) thyrotoxicosis immediately after the start of the iodine supplement in areas where there was a long-term deficiency of iodine and a high incidence of goitre (5). Unfortunately, this has revived the idea of iodine intoxication.

Function in the body

Iodine and thyroid hormone

In the thyroid gland, for the production of thyroid hormone, the following processes take place, see figure 1. It starts with the absorption of iodide from the blood stream via an iodine pump (NIS) in the walls of the follicular cells. This iodide is passed on to the lumen of the follicle via transport proteins such as pendrin and anocamin-1 (ANO-1). 

In the endoplasmic reticulum of the follicular cells, the protein thyreoglobulin is produced, which will serve as a store of iodine and a foundation for the construction of thyroid hormone. In order to bind iodide to an organic substance (this is called organification) it is necessary to oxidize the iodide to free iodide (I0) using the enzyme thyroperoxidase (TPO). This also requires hydrogen peroxide (H2O2), produced by thyroid NADPH-Oxidase (NOX). Free iodide is highly reactive and is linked to tyrosyl groups, originating from the amino acid tyrosine, bound to the thyroglobulin.

The organization takes place in the lumen (inner space) of the thyroid follicle. Conjugation of two tyrosyl groups leads to the formation of mono-, di-, tri- and tetraiodithyronine. These molecules contain 1, 2, 3 and 4 iodine atoms respectively. Subsequently, the "loaded" thyroglobulin is reabsorbed by the follicular cell, within which the tetraiodithyronine (= thyroxine or T4) and trijoodthyronine (= T3) are released by degradation (proteolysis) of the thyroglobulin and finally excreted in the bloodstream.  Monoiodine tyronine is referred to as MIT, dijoodthyronine as DIT, the thyroglobulin bound MIT and DIT forms a storage of iodine and a stock of precursors of thyroid hormones, so that they can be produced faster if necessary.  See also the chapters on pathophysiology and antioxidant activity.

The thyroid gland makes about 90% T4 and 10% T3. Most of T3 is made from T4 in other body cells (mainly liver). T3 is the most important biologically active thyroid hormone. An excess of T3 and T4 is converted into the inactive forms rT3 and T2 with the help of selenium-containing enzymes, the dejodinases (DIO). T3 regulates the energy metabolism and ensures normal growth and development. A shortage of thyroid hormone during pregnancy causes serious developmental disorders of the fetus. The amount of thyroid hormone in the body is therefore strictly regulated, with the thyroid stimulating hormone (TSH) playing an important guiding role. Prolonged serious deficiency of iodine causes a greatly enlarged thyroid gland called goitre or crop.

Iodine as antioxidant

Iodine also plays a role as an antioxidant in the regulation of oxidative processes in the body. From an evolutionary point of view, iodine is a very long-standing and important antioxidant mechanism (6,7). It is precisely in the organs of the body where the NOXs mentioned above are active that they have an active transport mechanism for iodine. These organs are characterized by the presence of secretory epithelial cells such as in (endocrine) glands and in protective epithelial tissue: thyroid, ovary, prostate, salivary glands, pituitary, pancreas, testes, mammary gland, adrenal and stomach, intestine and lung. These are various transport proteins with high affinity for iodine, chloride, bicarbonate and other anions: CFTR, Pendrin and Anoctamin-1 (ANO1). By regulating these transporters, more or less mucin proteins (in mucus, saliva and other secretions) with antimicrobial action can be excreted. Especially the very recently discovered ANO1 (8) has high affinity and permeability for iodine and plays a very important role in the luminal iodide transport in the thyroid gland (9), but probably also in other tissues with ANO1 activity. The transported iodide (and possibly trijodide) in these glands and in the protective mucous layers of the stomach, intestine and lungs can capture the formed radicals and H2O2 as antioxidant. Of course, no thyroxin is formed, as in the thyroid gland, but iodized proteins.

Recently it has been demonstrated that inflammation in the intestine (Crohn's disease) and in the lungs in case of viral infection with RSV virus (respiratory syncytial virus) is very high NOXs activity and H2O2 production (10) . In 3-week old lambs, infected with RSV virus, lung damage was greatly reduced after administration of sodium iodide (NaI). In the lungs, lactoperoxidase (LPO) appears to cooperate with DUOX by reacting peroxide with iodide (if sufficiently present) under formation of hypoiodic acid: H2O2 + I- <--> HOI.  Hypoiodic acid is known to have very strong antiviral, antibacterial and antifungal properties. It has been shown that the combination of iodine (I2) dissolved in iodide (I-) solution in the form of e.g. Lugol is even more effective (7). Lugol has long been used as a disinfectant liquid. In addition, I2 (molecular iodine) may have antiproliferative action (inhibition of unwanted cell growth), plays a role in cell differentiation (natural maturation to the final function) and helps with the absorption of iodide in various organs (7). Molecular iodine and iodide dissolved in water in the form of trijodide can occur both as an oxidizer and as a reductor:
I2(aq) + I- <--> I3-
I3- + 2e- <--> 3I-

Iodine and cancer

As briefly pointed out in the introduction, the mammary gland is also able to concentrate iodine for the benefit of the infant. Iodine deficiency can also lead to hyperplasia of breast tissue and fibrocystic mastopahtia (11). There are indications from population studies of Japanese versus Americans that a higher intake of iodine in Japan is associated with a lower frequency of breast cancer (12,13).

Recently, an interesting finding has been made that the iodine transporter ANO1 is highly expressed in thyroid adenoma, prostate hyperplasia and prostate carcinoma and pulmonary carcinoma (14,15) and in vitro tumor reduction occurs when ANO1 is inhibited (15). ANO1 consists of a group of transporters with a very high affinity for iodine, of which a number of isomers are regulated by the iodine concentration in blood (9,14). Possibly a role for iodine as regulator of ANO1 in tumor tissue and a key in the prevention of some of these cancers.

Other iodine compounds

Iodine can be incorporated into proteins (similar to the incorporation of iodine thyrosine into thyreoglobulin). The function of these proteins is not yet completely clear. Furthermore, iodide can be incorporated in unsaturated fatty acids (PUFAs), especially in the thyroid gland and breast tissue; so-called iodolipids. This results in δ-iodolactone compounds of arachidonic acid (AA) and eicosapentaenoic acid (EPA), which play a very important role in cell growth regulation of thyroid and breast tissue and possibly other tissues. Remarkably, the formation of these δ-iodolactone compounds with iodine is not made via active transport with NIS (iodide transport), but most probably via passive transport of molecular iodine (I2). Indeed, in vitro experiments showed that not iodide, but iodine (in the form of Lugol) is the main precursor for the formation of these δ-iodolactone compounds (16).

Pathophysiology

For the synthesis of thyroid hormones, iodine from the blood is absorbed into the thyroid cells by means of a specific transport protein: Sodium Iodide Symporter (NIS). This transporter is capable of supplying the thyroid gland cell with iodine when the iodine concentration in the blood is low. Only at prolonged very low iodine concentrations in the blood (corresponding to urine iodine concentration (UIC) of < 20 nmol/mmol, see table 1) a shortage of thyroid hormones T4 and T3 will occur; hypothyroidism. The thyroid gland will compensate for this by inducing enzymes and growing thyroid tissue, leading to head or goiter. This severe iodine deficiency induced hypothyroidism leads to severe growth and developmental disorder (with low IQ) in children; cretinism. This no longer occurs in the Netherlands.

In case of prolonged mild/moderate iodine deficiency, corresponding with a UIC between 20 and 100 nmol/mmol, a compensatory mechanism occurs. At low iodine concentrations, the thyroid gland is able to activate enzymes and transporters to still produce sufficient thyroid hormone with normal TSH and FT4 and FT3 values. But this continuous stimulation of the thyroid gland does have a price: there is an increased risk of autonomic thyroid hormone production and an increased risk of hyperthyroidism. In countries/regions where mild and moderate iodine deficiency is common, the prevalence of hyperthyroidism is higher than in countries with ample iodine intake. You can read more about this in a recent review article by Zimmerman (17). 

In organizing iodine, aggressive excipients such as hydrogen peroxide (contains oxygen radical) produced by NOX or superoxide dismutase (SOD) and oxidized iodide (iodine radical) are used. Disturbance of this balance can lead to overproduction of radicals and H2O2 resulting in oxidative damage including inflammation of the thyroid gland and damage to DNA resulting in possible cancer. In case of a chronic moderate iodine deficiency there will not immediately be a deficiency of T3 and T4, but there will be an imbalance in these radicals and peroxides. Low iodine intake increases SOD activity and the formation of H2O2. An excess of radicals is normally cleared away by selenium-containing substances (Se-x) and selenium-containing glutathione peroxidases (18). In other words, selenium deficiency is a risk factor for further thyroid damage. For an optimal nutrient balance for the thyroid gland, not only sufficient iodine, but also sufficient selenium and zinc and many types of antioxidants are needed, preferably from a healthy diet. 

Excessive iodine intake, corresponding to UIC > 500 nmol/mmol creature, again increases the risk of autoimmune thyroiditis resulting in hypothyroidism. This is seen in regions where iodine is naturally consumed through diet, such as Japan and Korea (19). The mechanism behind this has not yet been fully elucidated, but increased inflammatory activity may play a role. These inflammatory reactions cause thyroid cells to break down, after which the contents end up in the bloodstream. The enzyme TPO is then released and this is an enzyme against which the body quickly makes antibodies (anti-TPO). High anti-TPO titres are therefore an indication of thyroid inflammation (especially in Hashimoto's thyroiditis). From this it becomes clear that both a shortage of iodine and an excess of iodine are not healthy in the long run. Below more about the dosage and optimal target values.

Bromium, bromide and bromate are used in the food industry. These substances have an inhibiting effect on the iodine pump NIS and therefore on the absorption of iodine. It is therefore not inconceivable that this also plays a role in the development of thyroid disease.

Nutrition and suppletion

Top 7 foods with high iodine content are: seaweed (100 - 3000 µg iodine / gram), cranberries (400 µg iodine/100 gram), cod (100 µg iodine/100 gram), yoghurt (90 µg iodine/150g), iodised salt (JoZo) (65 µg iodine / gram), potato with peel (60 µg iodine/100 gram), white beans (30 µg iodine/100 gram).

Before starting with iodine-rich nutrition or with iodine supplementation, it is recommended to maintain or restore selenium and zinc status and to pay ample attention to antioxidants in the diet. Especially in people who have had long-term mild/moderate deficiency of iodine, thyroid peroxidase (TPO) activity in thyroid cells is suppressed, while iodine transport proteins are overactive. There is a delicate balance between the formation of H2O2 under the influence of TPO (necessary for the production of thyroxin) and the elimination of excessive H2O2 by, among others, glutathione peroxidase (GPO). The activity of the latter enzyme strongly depends on its cofactor selenium. At the start of iodine treatment, TPO will be strongly induced, resulting in the formation of more T4 and T3 in a short period of time, but also an excess of H2O2. This gives a (temporary) inflammatory reaction in the thyroid gland, which can be (partly) reduced or prevented by supplementing selenium beforehand (26) and paying ample attention to the antioxidant status.

After a temporary increase of T4 and T3 (acute Wolff-Chaikoff effect), there is an immediate feedback via the pituitary gland due to less TSH production and therefore a reduced production of iodine transporters (escape of the Wolff-Chaikoff effect), causing the amount of iodine in the thyroid cell to normalize to a new level. This phenomenon has also been observed repeatedly in population studies shortly after adding iodide to salt in iodine-poor regions. Therefore, literature sometimes (wrongly) suggests that iodine supplementation is dangerous (5). Taking into account optimal dosage and toxic limits, this is not the case.

If the iodine intake cannot be met with a healthy diet, iodine supplementation may be necessary. From the above it is clear that with iodine supplementation it is important to supplement both molecular iodine (I2) and iodide (I-) as present in Lugol solution. However, due to the difficult dosage of Lugol solution (drops per day), concerns about overdose are certainly justified. This also applies to Iodoral tablet because of the very high iodine content in Iodoral (12 mg). Natural sources such as seaweed and other sea vegetables are preferred (see e.g. http://www.zeewierwijzer.nl). But also with seaweed caution is advised and there is a risk of overdose.

Although pregnant women have a higher need for iodine, supplementation during pregnancy should be done with great caution to avoid over-supply in the unborn child. Oversupply in this case leads to severe hypothyroidism in the child immediately after birth. A good iodine status before pregnancy is essential.

Contra-indications

Iodine supplementation should be discouraged, due to the risk of development of long-term iodine-induced thyroid disease, in people with increased risk factors:

1.    Underlying thyroid disease (Graves, Hashimoto thyrioiditis, subacute thyroiditis, postpartum thyroiditis, amiodarone induced thyroiditis, after haemithyroidectomy)
2.    Pregnant and breastfeeding women to prevent children from getting too high iodine intake through the placenta or milk
3.    Elderly people with subclinical hypothyroidism
4.    Patients with dialysis treatment
5.    Patients on medication: amiadorone, lithium

Interpretation

Although incidentally very low levels of iodine can be found in urine (< 20 nmo/mmol), there are no indications that this structurally leads to clinical hypothyroidism and goitre and growth retardation in children in the Netherlands. However, there is concern about brain development in babies and young children with chronically low iodine intake.

However, non-specific complaints and symptoms may be the result of prolonged mild-moderate iodine deficiency (excretion 20 - 100 nmol/mmol kreat) comparable to hypothyroidism and in some cases hyperthyroidism, even though TSH and FT4 in the blood are normal. 

An optimal iodine status should be sought, with iodine excretion in urine between 150 and 500 nmol/mmol creat.

Interaction with medication

Cordarone (amiadarone) is a medicine used in cardiac dysrhythmia. It contains many iodine atoms and is similar to T4. It can cause excessive hypothyroidism and hyperthyroidism (27).

Lithium inhibits iodine binding and inhibits the release of T4 from the thyroid gland and can cause hypothyroidism (28).