Abstract

Despite the widely held assumption that Americans are iodine-sufficient due to the availability of iodized salt, the U.S. population is actually at high risk for iodine insufficiency. Iodine intake has been decreasing in the U.S. since the early 70s as a result of changes in Americans’ food and dietary habits, including the facts that iodized salt is infrequently used in restaurant and processed foods, and iodized salt sold for home use may provide far less than the amount of iodine listed on the container’s label. The widespread dispersal of perchlorate, nitrate and thiocyanate (competitive inhibitors of iodide uptake) in the environment blocks absorption of the little iodine Americans do consume, further compounding the problem.

In adults, iodine is necessary not only for the production of thyroid hormones, thus affecting systemic metabolism, but is now recognized to play a protective role against fibrocystic breast disease and breast cancer. In addition, a relationship has been hypothesized between iodine deficiency and a number of other health issues including other malignancies, obesity, attention deficit hyperactivity disorder (ADHD), psychiatric disorders, and fibromyalgia.

Analogous to the case of vitamin D, a nutrient for which the 400 IU DRI, although capable of preventing rickets, has been proven inadequate for this pro-hormone’s numerous other functions in the body, the iodine DRI for adults of 150 mcg/day (220 mcg/day for pregnant women), while sufficient to prevent goiter (and cretinism), is inadequate for the promotion of optimal health in adults or optimal fetal brain development. Intake of 3-6 mg/day, an amount commonly consumed in Japan without increased incidence of autoimmune thyroiditis or hypothyroidism, may be necessary to support not only thyroid hormone production, but iodine’s important antioxidant functions in the breast and other tissues in which this trace mineral is concentrated.

Part I of this article discusses the numerous factors that place Americans at high risk for iodine insufficiency. Part II reviews iodine’s roles in the body, the relationship of iodine insufficiency to the above mentioned pathologies, available options in laboratory assessments of iodine levels, optimal intake, preferential forms of supplementation, and cofactors necessary for optimal iodine utilization.

Part II: Not Just for Thyroid

Introduction

Metabolism and Physiological Effects

A trace mineral increasingly recognized as essential for a number of physiologic functions, iodine belongs to the halogen family of elements, a group of highly reactive nonmetals that includes fluorine, chlorine and bromine. Iodine is concentrated by certain seaweeds, but is the least abundant halogen in the Earth’s crust. Although the iodine content of soils varies, most has been leached out since primordial times when much more of the Earth’s surface was covered by seas.1

The second halogen to be identified (after chlorine), iodine was discovered by Bernard Courtois in Paris in 1811, but it took nearly 100 years before its key role in thyroid function was recognized. It was 1927 when Sir Charles Harrington first reported that the major part of the thyroxine (T 4 ) molecule (65.3% by weight) was made up of iodine.2

While iodine’s importance for thyroid function as a primary constituent of thyroid hormones and its use as a topical antibacterial agent3 4 5 have long been recognized, only recently has attention been given to this trace mineral’s other roles, which include antioxidant and anticancer activity (discussed below).

Usually ingested in the form of an iodate or iodide compound (I¯, inorganic sodium and potassium salts, see Glossary), iodine is also naturally present in seaweeds (e.g., dulse, wakame, kombu) in the form of inorganic diatomic iodine (molecular iodine or I2) and organic monoatomic iodine (C¯I). Iodine is rapidly absorbed into the circulation and actively concentrated within thyroid follicles to 20-40 times its concentration in the blood, a reflection of its critical role in the production of thyroid hormones. Only about 30% of the body’s iodine is sequestered in thyroid tissue and hormones; however, the body also concentrates iodide in the salivary glands, breast tissue, gastric mucosa, and choroid plexus, among other sites, indicating that this trace mineral plays vital roles in areas other than the thyroid gland.6

As noted in Part I of this review, iodine’s concentration at these sites is so critical to physiological function that the body possesses a specific mechanism, the sodium/iodide transporter—a.k.a. the sodium/iodide symporter (NIS) –able to transport iodide from the blood into the thyroid gland and other tissues across a concentration gradient as high as 50-fold.7 NIS activity is upregulated by the binding of TSH to receptors on the follicular cells. Inside the follicular thyroid cell, iodide is carried, by a process called iodide efflux, through the apical membrane to the follicular lumen by pendrin, an anion transporter predominantly expressed in the thyroid, kidney and inner ear. (Mutations in the pendrin gene are associated with hypothyroidism and Pendred syndrome, the most common recessive syndromic form of congenital deafness.)8 I2 is transported by facilitated diffusion.

Within the thyroid’s follicular cells (where the glycoprotein, thyroglobulin, is synthesized), iodide is catalyzed by thyroid peroxidase (TPO) using H2O2, and bound to tyrosine residues in the thyroglobulin molecule to form mono- or diiodotyrosine (MIT or DIT), which in turn combine to produce the thyroid hormones, primarily thyroxine (T 4 ), which constitutes ~90% of the thyroid hormone secreted from the gland, and triiodothyronine (T 3 ), which accounts for the remaining 10%. Combining two molecules of DIT produces T 4 ; combining one molecule of MIT and one particle of DIT produces T 3 .{ref9 Iodine accounts for 65% of the molecular weight of T 4 and 59% of the molecular weight of T 3 .10 11

In addition to its essential involvement in thyroid hormone production, iodine also affects the release of thyroid hormone, which is regulated in two ways: (1) through thyroid releasing hormone (TRH) which stimulates the pituitary gland to secrete thyroid stimulating hormone (TSH), which in turn stimulates the thyroid to release T 3 and T 4 , and (2) via autoregulation activated in response to the concentration of iodine in the thyroid (a.k.a. the Wolff-Chaikoff effect, see Glossary). Iodine’s rate of uptake into the follicle, the ratio of T 3 to T 4 , and their release into the circulation are all affected by the concentration of iodine in the thyroid, such that an increase in iodine intake results in a decrease in its organification (see Glossary) in the follicles, thus preventing excessive hormone production and release, and maintaining stability in hormone secretion despite possibly wide variation in iodine intake.1 7

In an iodine-replete adult, approximately 15-20 mg of iodine (30% of the body’s iodine stores) is concentrated in the thyroid; the remaining 70% (~44 mg) is found in a variety of extra-thyroidal tissues, including the breast, eye, gastric mucosa, cervix and salivary glands.11 When the thyroid is stimulated to release its hormones, thyroglobulin is degraded, releasing T 4 and T 3 , which, upon entering the circulation, are rapidly bound to transport hormones (~70% to thyroxine binding globulin; the remaining 30% to other proteins, e.g., transthyretinm, albumin and lipoproteins) and delivered to peripheral tissues. Any iodide freed in the degradation of thyroglobulin is for the most part recycled, and the iodinated tyrosine reused for hormone production. T 4 , which has a half-life of about one week and serves as a reservoir for conversion to the more active hormone, T 3 , whose half-life is only 1 day.1

Conversion of T 4 to T 3 via deiodination occurs primarily in target organs and is catalyzed by iodothyronine deiodinase (a.k.a. iodide peroxidase) type 2 (DI2).There are two other iodothyronine deiodinases, DI1 and DI3, but all three are selenium-dependent enzymes. DI1, a kinetic enzyme that both activates and inactivates T 4 , is the form primarily produced in breast tissue during pregnancy and lactation. DI3 inactivates T 3 producing reverse T 3 , and, to a lesser extent, prevents T 4 from being activated. Deiodinase activity has been identified not only in the liver (which contains ~30% of the extra-thyroidal T 4 ), but also in the breast, kidney, in human skeletal muscle, and in the brain, where DI2 plays a crucial role in deiodinating T 4 to T 3 .12 13 2

Approximately 90% of iodine is eventually excreted in the urine. According to the International Council for the Control of Iodine Disorders, WHO and UNICEF, borderline iodine deficiency is indicated by average daily excretion rates of 100 mcg/L per day. As noted in Part I of this review, the World Health Organization has determined 50-99 mcg/L indicates mild deficiency, 20-49 mcg/L indicates moderate deficiency, and less than 20 mcg/L indicates severe deficiency.14

For comparison, median urinary iodine excretion in the U.S. population was 145 µg/L during the years 1988 through 1994, which was a significant decrease from the 321 µg/L found in a similar survey two decades prior.10 Among the Japanese, urinary iodine excretion in euthyroid Japanese subjects has been reported to be as high as 9.3 mg per day, and mean urinary iodine levels are approximately twice those reported in the U.S, NHANES 2001-2002 data.11 15

Click here for a PDF version of the chart.

Chart Notes: Normal process: Thyroid hormone levels drop. TSH binds to receptors on the follicular cells, stimulates NIS activity and also ensures H202 will be available as a substrate by inducing NADPH oxidase, which oxidizes NADPH to NADP, liberating superoxide radicals (O2¯), which are then converted to the less potent free radical, H202, by SOD, a selenium-dependent enzyme. NIS transports Iodide (I¯) into the follicular cell where it is catalyzed by heme-dependent TPO using H202 to form I2, which then binds to tyrosine residues in thyroglobulin to form MIT and DIT. DIT+ DIT then produce T 4 ; DIT + MIT produce T 3 . H202 that is not used up in this process is neutralized by selenium-dependent glutathione peroxidase. Iodine deficiency / Selenium deficiency / Iron deficiency: Low iodine stores result in low levels of thyroid hormones, which activates TSH. H202 is produced, but no iodide arrives. If selenium is also insufficient, O2¯, a more potent ROS than H202, is formed and is not converted to H202. If iron is deficient, TPO will not be available to catalyze iodide, so H202 will remain to cause damage to the follicular cell. Iodine repletion: the Wolff-Chaikoff effect will prevent excessive organification of iodide; however, during the formation of thyroid hormones, some ROS will be generated in excess of those used to produce I2, and will cause damage if not reduced by glutathione peroxidase.

Iodine’s Effects on Physiological Function

Through its essential inclusion in thyroid hormones, iodine has long been recognized to impact virtually every cell in the body, affecting a wide range of metabolic functions, including basal metabolic rate; protein, fat and carbohydrate metabolism; protein synthesis, and brain development.

Effects on Adult Brain Function

Recently, proper thyroid hormone signaling has been shown to be essential not only for fetal and neonatal brain development, but adult brain function. T 3 is concentrated in the locus coeruleus, a nucleus in the brain stem that is the principal site for synthesis of norepinephrine and is involved in physiological responses to stress. T 3 is also found in the junctions between synapses and regulates the amounts and activity of serotonin, norepinephrine, and gamma-aminobutyric acid (GABA) in the brain. Hence, iodine insufficiency (and/or selenium deficiency since the deiodinases that convert T 4 to T 3 are selenium-dependent) is hypothesized to be a contributing factor in the pathogenesis of a wide range of mental disturbances, from autism to ADHD to post-traumatic stress disorder to depression.2

Recent studies have noted a relationship between subclinical hypothyroidism and decrements in mood and working memory16, anxiety, psychoses, depression, and dementia (impaired short-term memory, slowed information processing speed, reduced efficiency in executive functions, and poor learning), particularly in women and the elderly.17 18 19 20

Thyroid hormones control several genes in the CNS and are essential for differentiation of somatotrophs (which produce growth hormone) and pituitary lactotrophs (which produce prolactin). A number of thyroid hormone signaling pathways in the hypothalamus are thought to be involved in the adaptation of the thyroid axis, not only to hypo- and hyperthyroidism, but also to inflammation, the stress response, and critical illness (a pattern of decreased pituitary-thyroid function, sometimes referred to as low T 3 syndrome, is known to accompany life-threatening trauma, major surgery and severe illness). Regardless of the challenge, insufficient thyroid hormone leads to defects in hypothalamus-pituitary-thyroid-periphery-feedback regulation.21 22

Other recently published research indicates that thyroid hormones modify genetic expression via their action on nuclear receptors within the large family of receptors that also bind vitamins A and D, and steroids. Most of T 3 ‘s effects are mediated by nuclear receptors, but T 4 itself, and its iodinated metabolites, have also been found to exert direct biological effects in the brain.23 24 25 26 21

Iodine’s Antioxidant Actions

For centuries, iodine rich brines or seaweeds have been used as thalassotherapy or balneotherapy (see Glossary) in health spas, treatments that have been repeatedly shown to produce beneficial effects in cardiac and respiratory disease, thyroid function, arteriosclerosis, diabetes mellitus and eye diseases.27 Iodine’s antioxidant effects provide one underlying mechanism for these positive clinical results. I¯ itself exerts significant antioxidant effects; NaI levels as low as 15 μM produce equivalent antioxidant effects to those seen with ascorbic acid at levels of 50 μM.28

Iodine’s antioxidant effects are a byproduct of the redox reactions that occur during the formation of thyroid hormones, when iodide (I¯) is organified (oxidized) to become iodine (I2).27 The first step in iodide’s (I¯) organification to iodine (I2) is accomplished when I¯ is oxidized by thyroid peroxidase (TPO) using hydrogen peroxide (H202). By reducing H202, iodide becomes I2, and binds to tyrosine residues in the thyroglobulin molecule, forming the mono- and diiodotyrosines that are the precursors of triiodothyronine (T 3 ) and thyroxine (T 4 ). Since this process decreases available H202, less remains for damaging oxidative activity; thus iodide serves, in effect, as an antioxidant.

Substrate H202 for iodide’s organification is provided in the thyroid by TSH-mediated induction of the thyroid oxidases (ThOX1 and ThOX2), which oxidize NADPH to NADP, liberating superoxide radicals (O2¯), which are then converted to the less potent free radical, H202 by superoxide dismutase (a selenium dependent enzyme). H202 that is not utilized for the organification of iodide is, in individuals with adequate selenium, removed by antioxidant enzymes, principally those of the selenium-dependent glutathione peroxidase (GPx) family.27

This is why iodine deficiency, which triggers increased stimulation by TSH resulting in excessive H202 production within the thyroid’s follicular cells with little substrate iodide to be oxidized, results in damage to the thyroid. Selenium deficiency exacerbates the risk of oxidative stress since it causes a deficit in the glutathione peroxidases that would normally convert H202 to H2O. Thus, the combination of iodine and selenium deficiencies greatly increases oxidative damage to DNA in thyroid follicular cells and risk for thyroid malignancies. At higher levels of intake, iodide also acts as an antioxidant by a related mechanism—reducing the sensitivity of the thyroid gland to TSH, thus diminishing production of both H202 and T 4 .27

Yet another way in which iodine exerts antioxidant effects is through the formation of iodolipids, which are produced when iodine reacts with double bonds on lipids, rendering them less accessible to reactive oxygen species (ROS). This antioxidant effect of iodine provides significant protection in the thyroid where arachidonic acid, a fat that contains four double bonds and is highly susceptible to oxidation, plays a role in intracellular signaling. Iodolipid formation may also play a protective role against lipid peroxidation in other areas of the body that concentrate iodine. Of clinical note, lack of iodolipid formation contributes to the pathological outcomes of hypothyroidism, which results in reduced oxidative metabolism and markedly increased lipid and lipoprotein levels.27

Beyond Thyroid: The Iodine Link to Breast Health

Beyond its thyroid-hormone mediated effects, iodine is required for the normal growth and development of breast tissue, and acts an antioxidant and antiproliferative agent protecting the integrity of the mammary gland. The high level of iodine intake by Japanese women, noted in Part I, has been associated with a low incidence of both benign and cancerous breast disease in this population.11 29 In contrast, evidence linking iodine deficiency with an elevated risk of breast, endometrial, and ovarian cancer has been hypothesized since 1976, when it was noted that low dietary iodine intake could result in increased gonadotrophin stimulation, producing a hyperestrogenic state (increased production of estrone and estradiol, and a lower ratio of estriol to estrone + estradiol) that could increase the risk of these cancers.30 Furthermore, estradiol has been shown to increase cell proliferation and down-regulate NIS expression and iodide uptake in vitro.31

In support of this hypothesis, in vitro evidence that iodine inhibits cancer promotion through modulation of the estrogen pathway was published in 2008. Researchers looked at the effect of Lugol’s iodine solution (5% I2, 10% KI) on gene expression in the estrogen responsive MCF-7 breast cancer cell line. Twenty-nine genes were up-regulated, and 14 genes were down-regulated in response to iodine treatment, including several involved in hormone metabolism as well as others involved in the regulation of cell cycle progression, growth and differentiation.32

An association between breast cancer and thyroid disease was found in a recent study of 26 breast cancer patients (aged 30-85 years) and 22 age-matched controls. Incidence of thyroid disease was much higher in patients than controls (58% vs. 18%, respectively). Subclinical hyperthyroidism was the most frequent disorder in patients (31%), although hypothyroidism (8%) and positive anti-TPO antibodies (19%) were also seen. The conclusion drawn by the researchers was that subclinical hyperthyroidism was the only statistically significant thyroid alteration found in this breast cancer population. What they failed to mention, except as an afterthought, was that all of the women with breast cancer, but none the healthy controls, came from an area endemic for low iodine intake.33 It is not surprising that iodine deficiency results in thyroid dysfunction, nor, given iodine’s antioxidant, estrogen modulating and gene regulating effects, that a deficiency of this trace mineral increases risk for breast cancer.

Molecular Iodine, the Preferred Form in Breast Tissue

Despite reports of the enhanced expression of NIS in human breast cancer tissue, I2 may be the preferred form of iodine supplementation for the prevention and treatment of breast cancer since non-lactating breast tissue is known to be peroxidase-poor and thus is less capable of iodide organification. The use of I2 bypasses the need for NIS involvement and peroxidase activity. Not surprisingly, the mammary gland more effectively captures and concentrates I2 than the thyroid, and more I2 is concentrated in breast than thyroid tissue.34 35

In vitro studies have found that I2 inhibits proliferation and induces apoptosis in some human breast cancer cell lines by causing loss of selective permeability of the mitochondrial membrane, which leads to the release of apoptogenic proteins normally confined to mitochondrial intermembrane space. Supplementation with I2 has been shown to suppress the development and size of both benign and cancerous neoplasias.34 35

As noted above in the discussion of iodine’s antioxidant effects, iodine is also used to produce iodolipids with antioxidant and antiproliferative effects in extra-thyroidal tissues as well as in the thyroid gland. Iodolactones may provide yet another protective mechanism in the breast and other extra-thyroidal tissues since the antiproliferative effects of I2 supplementation are accompanied by a significant reduction in cellular lipoperoxidation.36 37

I2 has also recently been shown to induce formation of an iodolactone derived from arachidonic acid, 6-iodolactone (6-IL), which activates cellular pathways involved in cell cycle arrest and apoptosis. Mammary cancer cells are known to contain high concentrations of arachidonic acid, which may help explain why I2 selectively exerts apoptotic effects at lower concentrations only in mammary tumor cells and not in normal mammary tissue.38

Of clinical note, potassium iodine, the form used in iodized salt, does not have these effects.

Iodine Protective Against Fibrocystic Breast Disease

Benign, fibrocystic breast disease has also been shown to be associated with iodine deficiency. In rat studies, blocking iodine uptake with perchlorate caused histologic changes indicative of fibrocystic breast disease, as well as precancerous lesions in the mammary tissue, with much greater deleterious changes in older animals.39 40 Double the risk of fibrocystic breast disease was found among those women with increased blood levels of TSH and a decline in thyroid function in a recent study of 90 women ranging in age from 23 – 50.41

In a series of three clinical trials, researchers looked at the effect of different forms of iodine-supplementation in women diagnosed with fibrocystic breast disease. In Study 1, an uncontrolled trial in which 233 volunteers received sodium iodide for 2 years, and 588 received protein-bound iodide for 5 years, 70% of the women treated with sodium iodide and 40% of patients treated with protein-bound iodide experienced clinical improvement; however, the rate of side effects (e.g., bad breath, increased salivation, rhinitis, skin eruption) was high.

In Study 2, a prospective, control, crossover study, 1,365 women received I2 (0.8 mg/kg), including 145 patients who were switched over from treatment with protein-bound iodide in Study 1; 74% of these cross-over patients experienced clinical improvement, as did 72% of those receiving I2 initially.

In Study 3, a prospective, control, double-blind study in which I2 was compared to placebo, 65% of those in the treatment group and 33% in the placebo group experienced improvement.42 Given that, as noted above, non-lactating breast tissue is peroxidase-poor and less capable of iodide organification, these results add further support for the use of I2 as the preferred form of supplemental iodine for breast tissue.

I2 supplementation has also been shown to ease mastalgia. Supplementation with 3 or 6 mg/day of molecular iodine significantly decreased pain reported by patients, as well as physicians’ assessments of pain, tenderness, and nodularity in benign breast disease, with a dose of 6 mg/day providing significant reduction of pain in more than 50% of patients.43

Iodine—A Protective Role against Cancer?

As noted above, iodine is engaged in a variety of antioxidant activities and has also been shown to induce apoptosis in human breast cancer cells, but not in normal cells, via a mitochondrial-mediated pathway. The data suggests a role for iodine in the prevention and treatment of cancer since, in iodine-deficient individuals, these protective processes are highly likely to be impaired, increasing oxidative damage to DNA, lessening apoptosis, and eventually promoting the development of malignancies.34 31

In rats, chronic dietary iodine deficiency results in thyroid follicular adenomas within 12 months and follicular carcinomas within 18 months. An increased risk of thyroid cancer has been reported in humans with goiter and those living in iodine-deficient areas of the world.44

Thyroid cancer incidence increased 2.4 fold from 1973 – 2002.45 It has become one of the ten leading cancer types in females. Accounting for 22,590 new cases per year in the United States; thyroid cancer is more frequent than ovarian, urinary bladder or pancreatic cancer. Researchers analyzing the trend in rising thyroid cancer incidence in the U.S., during the period from 1980-2005, concluded that medical surveillance and more sensitive diagnostic procedures cannot account for the observed increases in thyroid cancer and suggest other possible explanations should be explored.46 Given that iodine intake has dropped significantly in the U.S. during this same time period, iodine insufficiency seems to be worth considering as a likely contributing factor. Particularly in light of the fact that 4–6% of American adults are goitrous despite what has been considered “adequate” iodine intake.47

Another indication of iodine’s anti-cancer effects is that iodide uptake is diminished in thyroid cancer compared with normal thyroid tissue, despite the fact that expression of the NIS receptor is increased in malignant cells. When thyroid cancer undergoes total loss of differentiation, and the prognosis is clearly worse, no iodide uptake is observed. In vitro studies have found that the activation of key oncogenes in malignant transformation and tumor progression in thyroid cancer (the BRAF, RAS and RET genes) causes a decrease in NIS mRNA levels among other thyroid-specific genes. Not only does BRAF decrease NIS protein expression, but this oncogene also impairs NIS targeting to the follicular membrane both in vitro and in vivo, a finding consistent with the association between BRAF mutation and the fact that in a high frequency of thyroid cancer recurrences, the gland’s ability to concentrate iodide has been wholly lost. Researchers have therefore begun to look into treating thyroid cancer by re-inducing endogenous NIS expression, and therefore iodine uptake. Retinoic acid, a vitamin A derivative that plays a central role in differentiation and cell growth and is known to have tumor-inhibitory effects, has been partially effective in inducing NIS mRNA in thyroid cancer cell lines.31 48 49 50

Thyroid function impacts many organs, including the prostate. A recent prospective analysis of iodine status and prostate cancer risk using data from the NHANES I Epidemiologic Follow-up Study found that men with low urinary iodine had a 1.33 increased age-adjusted risk for prostate cancer. In men with diagnosed thyroid disease, risk was increased 2.34, and a history >10 years of thyroid disease was associated with a 3.38 elevated risk of prostate cancer. Study authors concluded that thyroid disease and/or factors contributing to thyroid disease [e.g., iodine and/or selenium insufficiency] may be risk factors for prostate carcinogenesis.51

Gastric Disease on the Rise—Iodine Correlation?

Given iodine’s antioxidant actions and the fact that the gastric mucosa is one of the areas in which the body concentrates iodine, it is not surprising that iodine deficiency has been linked to an increased risk of gastric carcinoma. One study demonstrated an increased prevalence of gastric cancer and an increased risk of atrophic gastritis in areas with a greater-than-average prevalence of iodine-deficiency related goiter. The researchers also reported that competitive inhibitors of iodine transport by NIS, such as nitrates and thiocyanate, increased the risk of gastric cancer.52 53

In a Chinese cohort of 29,584 adults, self-reported goiter was significantly associated with upper gastrointestinal cancer, specifically, a 2.04 increased risk of gastric non cardia adenocarcinoma, and a 1.45 increased risk for gastric cardia adenocarcinoma (see Glossary).54

Another study found a significant correlation between decreased mean urinary iodine levels and prevalence of stomach cancer, as well as a greater frequency of severe iodine deficiency in patients with stomach cancer (49%) than in controls (19.1%).55 There is also evidence for lower levels of iodine in cancerous gastric tissue than in surrounding normal tissue.56

Iodine Safety Issues

Iodine, per se, is not the Cause of Autoimmune Thyroiditis

Any suggestion of iodine intake at levels above the DRI is always met with concerns about higher levels of iodine causing autoimmune thyroiditis.

Autoimmune thyroiditis, a.k.a, Hashimoto’s thyroidits, is characterized by infiltration of the thyroid gland by inflammatory cells and production of autoantibodies to thyroid-specific antigens, thyroglobulin and thyroperoxidase. Autoimmune thyroiditis accompanies and is considered a main cause of hypothyroidisim since it results in destruction and eventual fibrous replacement of thyroid follicle cells.57

Although excess iodine intake has been singled out as the cause of autoimmune thyroiditis, current research clearly shows that this condition is multifactorial in etiology. Deficiencies of other key nutrients, genetic susceptibility, and exposure to environmental pollutants are all contributing factors. Iodine repletion without at least one of these other factors, is insufficient to cause autoimmune thyroiditis.

It is well recognized that increased iodine intake results in increased iodination of thyroglobulin, which, since this process also results in increased production of H202, increases thyroglobulin’s antigenic potential. In addition, since H2O2 is one of the compounds known to stimulate the intracellular adhesion molecule-1 (ICAM-1) promoter to increase transcription of the ICAM-1 gene, increased iodine intake (which can result in increased levels of unquenched H2O2) can also upregulate expression of ICAM-1. Iodine therefore has significant potential for harm; however, for this potential to be actualized, at least one or more of a number of other contributing factors must be present. These include selenium deficiency, iron deficiency, and/or exposure to environmental pollutants.58

Selenium deficiency: Selenium deficiency is widespread. Not only have the selenium contents of surface soils been depleted by erosion and glacial washout, similar to iodine, but the use of nitrate fertilizers (which typically do not replace trace minerals such as selenium in the soil, but do produce perchlorate, an iodide uptake inhibitor), compounds the problem.59

Selenium is a necessary component of both superoxide dismutase and glutathione peroxidase, key enzymes for the iodination of iodide and for the neutralization of excess ROS produced during this process, including H2O2 and O2¯. As noted earlier, generation of H202 is the rate limiting step in thyroid hormone synthesis and is regulated by TSH. Thus, the combination of iodine and selenium deficiency, which results in higher levels of TSH and greatly diminished levels of glutathione peroxidase, most severely increases susceptibility of thyroid tissue to free radical damage, upregulated expression of ICAM-1, and activation of antibodies to thyroid peroxidase (TPO) and thyroglobulin.

Iodine repletion coupled with selenium deficiency sets up a situation in which H202 production increases while the balancing factors for its neutralization, selenium-dependent enzymes, are largely absent. Thus programs that rely on iodized salt to restore iodine levels without consideration of selenium sufficiency can promote increased ROS generation, which, particularly in genetically susceptible individuals, may result in enhanced expression of intracellular adhesion molecule-1 (ICAM-1) on thyroidal follicular cells, infiltrating mononuclear cells, and enhanced cytokine production.60

In addition to serving as a co-factor for glutathione peroxidase and superoxide dismutase, selenium is an integral component of the thioredoxins, which are key players in a major cellular redox system that maintains cysteine residues in numerous proteins (including glutathione), in the reduced state, thus greatly reducing inflammation. Smoking has been clearly demonstrated to increase risk of thyroiditis. Cigarette smoking increases thiocyanate concentrations to levels that inhibit iodide transport. Plus, selenium concentrations in blood have been found to be significantly lower (and blood cadmium levels significantly higher) in smokers than in nonsmokers, indicating poorly controlled ROS and inflammation. Thioredoxin, which has been shown to inhibit the harmful effects of tobacco smoking in the lungs, is also produced in the thyroid gland—if selenium is present.61 62 63 64 58

Recent clinical studies have documented the suppressive effect of selenium treatment on serum anti-thyroid peroxidase concentrations in patients with Hashimoto’s thyroiditis} 65 and a number of studies conducted in areas with different iodine and selenium exposures have shown that co-administration of selenium with levothyroxine markedly reduces anti-TPO antibody levels in patients with severe autoimmune thyroiditis, all of which suggests that the problem is not iodine, but the production of thyroid hormone without sufficient selenium for redox control.66 67 68 69 70

Environmental Pollutants: Pollution from car emissions and heavy industry (including particulate emissions of such metals as lead and cadmium, solvents such as benzene and dioxane, as well as polychlorinated biphenyls) increases oxidative stress, increasing need for selenium-dependent antioxidant enzymes. Polychlorinated biphenyls have been shown to interfere with iodide transport.71 Substantially increased prevalence of anti-TPO antibodies is seen in populations living in areas heavily polluted with polychlorinated biphenyls, and the frequency of various signs of autoimmune thyroiditis (e.g., hypoechogenicity on ultrasound images, increased levels of TSH and the presence of anti- TPO antibodies), has been positively correlated with polychlorinated biphenyl levels.58

Genetic susceptibility: Although the molecular mechanisms through which they induce thyroid autoimmunity have yet to be understood, a number of polymorphic genes strongly associated with significantly increased risk for autoimmune thyroiditis have been identified, some of which increase susceptibility to autoimmunity in general (e.g., the human leukocyte antigen gene [HLA], the cytotoxic T lymphocyte antigen-4 gene[CTLA-4], the tumor necrosis factor gene [TNF]), and others thought to be specific to autoimmune thyroid disorders (e.g., the TSH receptor gene [TSHR], and thyroglobulin gene [Tg]).72 73 74 Exposure to environmental pollutants combined with insufficient intake of co-factors necessary for normal thyroid metabolism exacerbates the potential for dysfunction significantly increasing risk of autoimmune thyroiditis in genetically susceptible individuals.58 59

Iron—Another Trace Mineral Necessary for Normal Thyroid Hormone Metabolism

The initial steps of thyroid hormone synthesis are catalyzed by heme-dependent TPO. TPO activity is significantly reduced in iron deficiency anemia.59

Extensive data from animal studies indicates that iron deficiency, with or without anemia, impairs thyroid metabolism, resulting in blunted TSH responses, lowered hepatic thyroxine- 5′-deiodinase activity, hepatic production of T 3 only 46% that of controls, and 20-60% lower serum levels of T 3 and T 4 . In human studies, TSH signals were significantly increased, hepatic thyroxine-5′-deiodinase activity reduced, and serum T 3 and T 4 levels significantly decreased in individuals with moderate-to-severe Fe deficiency.59

A series of clinical trials conducted in North and West Africa, in areas of endemic goiter with a high prevalence of iron deficiency anemia, have shown that iron supplementation so significantly improves the efficacy of iodine phrophylaxis that study authors have proposed dual fortification of salt with iodine and iron.59

In summary, to claim that iodine per se is the cause of autoimmune thyroiditis and/or hypothyroidism is a gross oversimplification with the potential to cause significant public harm.

Iodine—Time to Consider Changing U.S. Recommendations for Daily Intake?

Although the U.S. Institute of Medicine limit for the tolerable upper intake level for iodine in adults is 1,100 mcg/day, dietary iodine intake in Asia is much higher. High iodine-containing seaweeds are frequently consumed and well tolerated by millions of people in Japan, Korea, and coastal China. In Japan, where seaweed intake averages ~ 4–7 grams/day (with some estimates as high as 10 gram/day), average dietary iodine intake was recently estimated to be 1.2 mg/day.75 However, a study of 4,138 apparently healthy, euthyroid Japanese men and women found a mean urinary iodine excretion of 5,100 mcg/day, which translates to a daily intake of 5,500 mcg (~5.5 mg) I/day, and yet other research has estimated daily Japanese iodine consumption ranges as high as 13,800 mcg/day.76 11

Regardless of which estimate of daily iodine intake among the Japanese we accept, their consumption of iodine is magnitudes higher than that in the U.S., where average daily consumption was estimated to be 167 mcg/day11, a number that recent studies suggest may be grossly overestimating actual intake, and certainly NIS uptake, of this trace mineral. Not only does the substantially higher intake of iodine among the Japanese appear to have no harmful effects in this population, but, on the contrary, incidence rates of autoimmune thyroiditis, hypothyroidism, benign and malignant breast disease, and prostate cancer are all dramatically lower among Japanese consuming an iodine-rich diet.76 77

Whether such high levels of iodine intake might cause problems in the U.S., particularly in susceptible individuals (e.g., those with autoimmune thyroiditis), has not yet been the subject of research. However, a number of recent studies suggest iodine intake ranging from 495 mcg/day to as high as 6 mg/day may be beneficial.

A study of the impact of seaweed consumption on thyroid function in American women found that iodine intake of 495 mcg/day, an amount significantly higher than current U.S. DRIs, causes no harm. In this randomized, placebo-controlled crossover trial, 25 healthy postmenopausal women (average age 58 years), 10 of whom had a history of early (Stage I or II) breast cancer but were disease-free at the time of the study, and 15 who had never been diagnosed with breast cancer, were randomized to receive either 6 weeks of supplemental iodine (in the form of 10 seaweed powder capsules providing a total of 475 mcg of iodine/day) or placebo (maltodextrose in 10 identical gelatin capsules).77

Since soy, a known goitrogen, is also commonly consumed in Japan, for 1 additional week, the women were also given high-isoflavone powder providing 141.3 mg of isoflavones and 67.5 g of protein/day in addition to seaweed or placebo capsules during the last week of each treatment arm.

Neither 7 weeks of seaweed nor 1 week of soy and seaweed supplementation affected thyroid end points. Seaweed supplementation was associated with a small increase in TSH, but values remained well within normal ranges. The women in this study, (who were already iodine-sufficient with well above average iodine intake for the United States since, during the control period at the beginning of the study, their mean UI was 266 mcg/day), excreted an average of 587 mcg of I/day while ingesting supplements providing 495 mcg of I/day.

As discussed earlier in this review, in the treatment of fibrocystic breast disease, Ghent, Eskin et al (1993), demonstrated the safety of therapeutic doses of molecular iodine (I2) of 3 to 6 mg/day over a period of 2-5 years,42 and a more recent (2004) trial evaluating the effects of varying dosages of I2 on fibrocystic breast disease (1.5, 3 or 6 mg/day) found that the 6 mg dose produced the best results: a 50% reduction in pain in 51.7% of women taking this dose with no adverse effects. No decreases in pain were seen in the groups receiving 1.5 mg or placebo.43

In an editorial in the June 2006 issue of the New England Journal of Medicine, Utiger discusses the evidence, world-wide, for risk of iodine-induced thyroid dysfunction. He concludes that while milligram or higher doses of iodine may cause hypothyroidism in people with damaged thyroid glands, excessive iodine intake for 5 years (defined as urinary iodine >300 mcg by Teng et al., in their investigation of iodine levels and thyroid dysfunction in people living in three regions in China) has only been associated with slightly increased cumulative 5 year incidence of subclinical hypothyroidism and autoimmune thyroiditis, both of which were not sustained in most people. Noting that, “Overall, the small risks of chronic iodine excess are outweighed by the substantial hazards of iodine insufficiency,” Utiger recommends that iodine intake be increased to at least 300 to 400 mcg daily.78

Supplement Recommendations

A reasonable clinical takeaway from all the data presented in this review overall is that iodine supplementation in amounts ranging from 400 mcg/day to as high as 1 mg/day is likely to be safe and of benefit to most individuals, even those at risk for autoimmune thyroiditis, providing that co-factors of iodine metabolism (e.g., selenium, iron) are not deficient.

Healthy individuals are remarkably tolerant to iodine intakes up to 1 mg per day, as the thyroid is capable of adjusting to a wide range of intakes to regulate the synthesis and release of thyroid hormones. However, in those with damaged thyroid glands, doses of iodine in the mg range may cause hypothyroidism because normal down-regulation of iodine transport is disrupted.59

Supplementation using I2 in dosages of 3-6 mg/day or higher may be of significant benefit to women with benign or malignant breast disease. With closely monitored physican care, therapeutic dosages ranging from12.5 to 50 mg/day or sometimes even higher, have been safely and effectively used.42

It should also be noted that intense exercise may increase daily iodine requirements; a study of male university students in Japan found high iodine losses in sweat induced by athletic training.76

In all individuals, the critical caveat accompanying iodine supplementation is that co-factors of iodine metabolism must also be present. While selenium, iron, and vitamin A play roles highlighted in current research, a number of other nutrients including zinc, copper, vitamin E, vitamin C and the B vitamins riboflavin (B2), niacin (B3) and pyridoxine (B6) are involved either in the manufacture of thyroid hormone or as cofactors of the deiodinases that convert T 4 to the far more active T 3 .79 Deficiencies of any of these nutrients can negatively impact the response to prophylactic iodine.59

Finally, thyroid function should be carefully monitored in any program of iodine prophylaxis.

Assessment of Iodine Status

Urinary iodine concentration (UI) is a sensitive indicator of recent iodine intake (days) since more than 90% of dietary iodine is excreted in the urine. UI can be expressed as a concentration (mg/L), in relationship to creatinine excretion (mg iodine/g creatinine), or as 24-hour excretion (mg/day). Single random urine sampling is the standard accepted method of measuring iodine body stores in population studies, but multiple spot urine measurements or 24-hour urine collection is recommended for individual measurements as these obviously provide more precise evaluation. As noted earlier, according to WHO standards, 50-99 mcg/L indicates mild deficiency, 20-49 mcg/L indicates moderate deficiency, and <20 mcg/L indicates severe deficiency.80

Thyroglobulin (Tg) may be preferable to UI since it is a much more convenient, simple blood test (Tg can also be assayed on dried blood spots taken by a finger prick), and provides a sensitive intermediate assessment (weeks to months) of iodine status. In iodine sufficiency, small amounts of Tg are secreted into the circulation, so serum Tg is normally <10 mcg/L.80

TSH. Either UI or Tg is preferable to TSH, which is unreliable because serum TSH values often remain within the normal range in older children and adults when iodine is deficient.80 Generally, a normal range for TSH for adults is between 0.4 and 5.0 uIU/mL (equivalent to mIU/L), but values vary slightly among labs. According to the U.S. National Academy of Clinical Biochemistry, the normal range for adults should be 0.4-2.5 uIU/mL since adults whose initial TSH level measures over 2.0 uIU/mL had “an increased odds ratio of developing hypothyroidism over the [following] 20 years.”

Thyroid hormone concentrations are poor indicators of iodine status. In iodine-deficiency, serum T 3 can remain unchanged or increase, and serum T 4 usually decreases; however, these changes often remain within the normal range.80

Conclusion

Iodine deficiency is of concern not just in Europe and developing nations, but in the U.S. As with vitamin D and the omega-3 fatty acids, two other nutrients recently recognized as deficient in the Western diet, sub-clinical iodine deficiency may soon be found to be a significant contributing factor to declining health in the U.S. Sufficiency of not only iodine, but key co-factors in its metabolism, including selenium, iron and vitamin A, should be ensured in any protocol for healthy aging.

Read Part I: Iodine: the Next Vitamin D? Americans at High Risk for Iodine Insufficiency

Glossary

Balneotherapy: treatment of disease by bathing.

Gastric cardia adenocarcinoma: the gastric cardia is a small anatomical region in the proximal 2-3 cm of the stomach that is especially susceptible to overgrowth by tumors originating from adjacent mucosal sites. Tumors occurring in this region are referred to as gastric cardia adenocarcinomas, gastric tumors arising in the lower esophagus or body of the stomach are labeled noncardia adenocarcinomas. Interestingly, H. pylori is a strong risk factor for noncardia gastric cancer but is inversely associated with the risk of gastric cardia cancer.81

Iodate: a salt of iodic acid. Iodic acid contains iodine in the oxidation state +5, and is one of the most stable oxo-acids of the halogens in its pure state.

Iodide: A form in which iodine is stored as a single, negatively charged ion. It has recently been shown that iodide, as it is a reducing species that, through the activity of peroxidase enzymes, can detoxify reactive oxygen species such as hydrogen peroxide, functions as an antioxidant.82

Wolff-Chaikoff effect: Named after its discoverers, Wolff and Chaikoff, who reported in 1948 that organic binding of I¯ (i.e., I¯ organification) in the rat thyroid in vivo was blocked when I¯ plasma levels reached a critical high threshold. Since iodide organification resumed when plasma levels fell, Wolff and Chaikoff hypothesized this effect could be the mechanism by which administration of high iodine doses results in remission of Graves’ disease.83

In 1949, Wolff et al. reported that the maximum duration of the inhibitory effect of high concentrations of iodide on its organification was 50 hours in the presence of continued high plasma I¯ concentrations. However, as early as 2 days after onset of the acute effect, an escape or adaptation from the effect occurred, so that the level of organification of I¯ was restored and normal hormone biosynthesis resumed.

In 1963, Braverman and Ingbar investigated the mechanism underlying the escape from the acute Wolff-Chaikoff effect in rats. They found that the Wolff-Chaikoff effect and the ensuing escape constitute a highly specialized intrinsic autoregulatory system that protects the thyroid from the deleterious effects of I¯ overload, but, at the same time, ensures adequate I¯ uptake for hormone biosynthesis. The level of I¯ capable of inhibiting I¯ organification and concomitantly stopping thyroid hormone synthesis is determined by the ratio of organified to nonorganified intracellular I¯ content, which in turn depends on the previous iodine supply status of the individual.7

The mechanism underlying the inhibition of iodide organification by high levels of iodide remains poorly understood, although it has been hypothesized that it is mediated by iodolipids since these inhibit TSH-mediated adenylate cyclase activity.31

Organification: The term “organification” refers to the incorporation of iodide (I¯) into organic molecules, as opposed to non-incorporated, inorganic, or free I¯. Organification of iodide (I¯) occurs in a complex reaction in the thyroid follicular cell during which I¯ is oxidized by thyroid peroxidase (TPO, a heme-dependent enzyme) using H2O2 to form I2, which then binds to tyrosine residues in the thyroglobulin molecule to form the iodotyrosine residues, MIT and DIT that are the precursors of thyroid hormones, T 4 and T 3 .7

Thalassotherapy: treatment of disease with seawater.

Authors

Lara Pizzorno, MDiv, MA, LMT, a member of the American Medical Writers Association with 25+ years of experience writing for physicians and the public, is Managing Editor for Longevity Medicine Review as well as Senior Medical Editor for SaluGenecists, Inc. Recent publications include: contributing author to the Textbook of Functional Medicine, (IFM, 2006), a number of articles for Integrative Medicine: A Clinician’s Journal (Innovisions Communications, Inc., 2005 through present), and Textbook of Natural Medicine (Elsevier, 2005, e-dition through present); lead author of Natural Medicine Instructions for Patients (Elsevier, 2002); co-author of The Encyclopedia of Healing Foods (Scribner’s, 2005); and editor, The World’s Healthiest Foods Essential Guide for the healthiest way of eating (George Mateljan Foundation, 2006 through present).

Chris D. Meletis, N.D., is an international lecturer and author of over a dozen books. He seeks to empower health care professionals and the public with the latest scientific medical findings as it relates to optimizing true wellness. He has served as Dean and Chief Medical Officer at the National College of Natural Medicine and currently serves as the Executive Director of Healthy Aging, www.TheIHA.org, his personal website is www.DrMeletis.com.

References