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Iodine: The Next Vitamin D ? Part II
Iodine: the Next Vitamin D?
by Lara Pizzorno, MDiv, MA, LMT and Chris Meletis, ND
Part II: Not Just for Thyroid
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.
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 (T4) 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 (T4), which constitutes ~90% of the thyroid hormone secreted from the gland, and triiodothyronine (T3), which accounts for the remaining 10%. Combining two molecules of DIT produces T4; combining one molecule of MIT and one particle of DIT produces T3.9 Iodine accounts for 65% of the molecular weight of T4 and 59% of the molecular weight of T3.10,11
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 T3 and T4, 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 T3 to T4, 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 T4 and T3, 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. T4, which has a half-life of about one week and serves as a reservoir for conversion to the more active hormone, T3, whose half-life is only 1 day.1
Conversion of T4 to T3 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 T4, is the form primarily produced in breast tissue during pregnancy and lactation. DI3 inactivates T3 producing reverse T3, and, to a lesser extent, prevents T4 from being activated. Deiodinase activity has been identified not only in the liver (which contains ~30% of the extra-thyroidal T4), but also in the breast, kidney, in human skeletal muscle, and in the brain, where DI2 plays a crucial role in deiodinating T4 to T3.12,13,2
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 pdf version of 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 T4; DIT + MIT produce T3. 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. T3 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. T3 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 T4 to T3 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 T3 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 T3's effects are mediated by nuclear receptors, but T4 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 (T3) and thyroxine (T4). 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 T4.27
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 T3 only 46% that of controls, and 20-60% lower serum levels of T3 and T4. In human studies, TSH signals were significantly increased, hepatic thyroxine-5'-deiodinase activity reduced, and serum T3 and T4 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 T4 to the far more active T3.79 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 T3 can remain unchanged or increase, and serum T4 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, T4 and T3.7
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.
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by Lara Pizzorno, MDiv, MA, LMT and Chris Meletis, ND
Part II: Not Just for Thyroid
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.
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 (T4) 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 (T4), which constitutes ~90% of the thyroid hormone secreted from the gland, and triiodothyronine (T3), which accounts for the remaining 10%. Combining two molecules of DIT produces T4; combining one molecule of MIT and one particle of DIT produces T3.9 Iodine accounts for 65% of the molecular weight of T4 and 59% of the molecular weight of T3.10,11
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 T3 and T4, 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 T3 to T4, 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 T4 and T3, 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. T4, which has a half-life of about one week and serves as a reservoir for conversion to the more active hormone, T3, whose half-life is only 1 day.1
Conversion of T4 to T3 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 T4, is the form primarily produced in breast tissue during pregnancy and lactation. DI3 inactivates T3 producing reverse T3, and, to a lesser extent, prevents T4 from being activated. Deiodinase activity has been identified not only in the liver (which contains ~30% of the extra-thyroidal T4), but also in the breast, kidney, in human skeletal muscle, and in the brain, where DI2 plays a crucial role in deiodinating T4 to T3.12,13,2
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 pdf version of 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 T4; DIT + MIT produce T3. 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. T3 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. T3 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 T4 to T3 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 T3 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 T3's effects are mediated by nuclear receptors, but T4 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 (T3) and thyroxine (T4). 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 T4.27
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 T3 only 46% that of controls, and 20-60% lower serum levels of T3 and T4. In human studies, TSH signals were significantly increased, hepatic thyroxine-5'-deiodinase activity reduced, and serum T3 and T4 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 T4 to the far more active T3.79 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 T3 can remain unchanged or increase, and serum T4 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, T4 and T3.7
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.
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Abstract
Iodine - The Next Vitamin D ?
Iodine: the Next Vitamin D?
by Lara Pizzorno, MDiv, MA, LMT
Part I: Americans at High Risk for Iodine Insufficiency (*Note Link to Part II Here)
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 RDI, although capable of preventing rickets, has been proven inadequate for this pro-hormone's numerous other functions in the body, the iodine RDI 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 fetal brain development or optimal health in adults. 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.
Introduction
Iodine deficiency, defined as urinary iodine excretion <100 1 ="/-" mg =" typical">10 mg/L, the federal maximum contaminant level. Two million families are estimated to drink water from private wells that fail to meet the federal drinking-water standard for nitrate. In urban areas, municipal wastewater-treatment discharges on surrounding farmland aggravate the problem.36 Hypertrophy of the thyroid gland has been noted at nitrate levels exceeding 50 mg/L. School children living in a community in Slovakia, where drinking-water wells contained high nitrate levels (>50 mg/L), were found to have enlarged thyroid glands and signs of subclinical thyroid disorder (thyroid hypoechogenicity37 [low intensity echoes] by ultrasound [seen in Hashimoto's thyroiditis and Graves disease], increased TSH levels, positive thyroperoxidase antibodies).38
Dietary thiocyanate also inhibits iodine uptake by the NIS. Brassica family vegetables contain compounds that can be converted to thiocyanates in the gut; however, cooking reduces the thiocyanate (and nitrate) content of vegetables, plus only about 50% of the thiocyanate produced in the gut is bioavailable. Cigarette smoking, however, is a significant source of thiocyanate in the body. Recent studies in the U.S. have found that thiocyanate concentrations in the breast milk of smokers were fourfold higher than those of non-smokers, and iodine content in the breast milk of smoking mothers was twofold reduced, likely due to the thiocyanate's competitive inhibition for NIS in the mammary gland. Thiocyanate has a half-life of approximately 6 days, compared to 8 and 5 hours for perchlorate and nitrate respectively.35
Lastly, research suggests a synergistic effect of perchlorate with thiocyanate resulting in significantly more damage to thyroid function than either compound alone in iodine-deficient individuals. Data from the 2001-2002 NHANES revealed that in women with urinary iodine levels <100 mcg/L, the association between perchlorate and decreased T4 was 66% greater than in non-smokers. These results suggest that thiocyanate in cigarette smoke interacts with perchlorate at commonly occurring perchlorate exposures to negatively impact thyroid function to a much greater degree in individuals with urinary iodine levels <100 mcg/L.39 Little or no data are available on the daily-required dose of dietary iodine to withstand inhibition of NIS iodine—uptake by perchlorate, nitrate and thiocyanate present in American's drinking water, food and exposure to cigarette smoke.35
Conclusion
The combination of changes in food production and American dietary habits have significantly decreased iodine consumption in the U.S. The majority of Americans may not even be meeting RDI recommendations for iodine, which given our unremitting, widespread, and increasing exposure to a variety of iodine uptake inhibitors, are likely insufficient for the promotion of optimal brain development or adult thyroid function.
In adults, iodine is necessary not only for the production of thyroid hormones, but has recently been recognized to play a protective role against fibrocystic breast disease and breast cancer. A relationship has also been suggested between iodine deficiency and a number of other health issues including other cancers, obesity, attention deficit hyperactivity disorder (ADHD), psychiatric disorders, and fibromyalgia.
Part II of this article will suggest revising the RDIs to levels that consider these factors and are based on our recently developed understanding of iodine's varied roles in the body and the relationship of iodine insufficiency to the above mentioned pathologies. Available options in laboratory assessments of iodine levels, preferential forms of iodine supplementation, and cofactors necessary for optimal iodine utilization will also be discussed.
Read Part II: Iodine: the Next Vitamin D? Not Just for Thyroid
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Pearce EN, Pino S, He X, et al. Sources of dietary iodine: bread, cows' milk, and infant formula in the Boston area. J Clin Endocrinol Metab. 2004 Jul;89(7):3421-4.
Abstract
Keller KL, Kirzner J, Pietrobelli A, et al. Increased sweetened beverage intake is associated with reduced milk and calcium intake in 3- to 7-year-old children at multi-item laboratory lunches. J Am Diet Assoc. 2009 Mar;109(3):497-501.
Abstract
Rampersaud GC, Bailey LB, Kauwell GP. National survey beverage consumption data for children and adolescents indicate the need to encourage a shift toward more nutritive beverages. J Am Diet Assoc. 2003 Jan;103(1):97-100.
Abstract
Bleich SN, Wang YC, Wang Y, et al. Increasing consumption of sugar-sweetened beverages among US adults: 1988-1994 to 1999-2004. Am J Clin Nutr. 2009 Jan;89(1):372-81.
Abstract
Stasiak M, Lewiński A, Karbownik-Lewińska M. Relationship between toxic effects of potassium bromate and endocrine glands.] Endokrynol Pol. 2009;60(1):40-50.
Abstract
World Health Organization Monograph. Potassium bromate. IARC Monogr Eval Carcinog Risks Hum. 1999;73:481-96.
Abstract
Kurokawa Y, Maekawa A, Takahashi M, Hayashi Y. Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen. Environ Health Perspect. 1990 Jul;87:309-35.
Abstract
van Netten C, Hoption Cann SA, Morley DR, van Netten JP. Elemental and radioactive analysis of commercially available seaweed. Sci Total Environ. 2000 Jun 8;255(1-3):169-75.
Abstract
MacArtain P, Gill CI, Brooks M, et al. Nutritional value of edible seaweeds. Nutr Rev. 2007 Dec;65(12 Pt 1):535-43. PMID: 18236692
Abstract
Interagency Board for Nutrition Monitoring and Related Research. Third Report on Nutrition Monitoring in the United States. Executive Summary; 1995; p.ES-10
Link
American Medical Association. AMA calls for measures to reduce sodium intake in U.S. diet; 2006; http://www.ama-assn.org/ama/pub/category/16461.html
Northwestern University Nutrition Fact Sheet, Iodine: http://www.feinberg.northwestern.edu/nutrition/factsheets/iodine.html
Link
Ebbin R. Americans' Dining-Out Habits, Restaurants USA, National Restaurant Association, November 2000
Link
Shake Your Salt Habit, http://www.americanheart.org
Link
Sevenier G. The Proof of the Pudding, April 14, 2006
Link
Soldin OP, Braverman LE, Lamm SH 2001 Perchlorate clinical pharmacology and human health: a review. 2001 Aug;23(4):316-31.
Abstract
Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amiodarone on the thyroid. Endocr Rev. 2001 Apr;22(2):240-54.
Abstract
Wolff J Perchlorate and the thyroid gland. Pharmacol Rev. 1998 Mar;50(1):89-105.
Abstract
Lawrence JE, Lamm SH, Pino S, et al. The effect of short-term low-dose perchlorate on various aspects of thyroid function. 1: Thyroid. 2000 Aug;10(8):659-63.
Abstract
Dohán O, De la Vieja A, Paroder V, et al. The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance. Endocr Rev. 2003 Feb;24(1):48-77.
Abstract
Sanchez CA, Krieger RI, Khandaker N, et al. Accumulation and perchlorate exposure potential of lettuce produced in the Lower Colorado River region. J Agric Food Chem. 2005 Jun 29;53(13):5479-86.
Abstract
Sanchez CA, Crump KS, Krieger RI, et al. Perchlorate and nitrate in leafy vegetables of North America. Environ Sci Technol. 2005 Dec 15;39(24):9391-7.
Abstract
Sanchez CA, Krieger RI, Khandaker NR, et al. Potential perchlorate exposure from Citrus sp. irrigated with contaminated water. Anal Chim Acta 2006 May 10;567(1):33-38.
Abstract
Blount BC, Pirkle JL, Osterloh JD, et al. Urinary perchlorate and thyroid hormone levels in adolescent and adult men and women living in the United States. Environ Health Perspect. 2006 Dec;114(12):1865-71.
Abstract
Snyder SA, Pleus RC, Vanderford BJ, Holady JC. Perchlorate and chlorate in dietary supplements and flavor enhancing ingredients. Anal Chim Acta 2006 May 10;567(1):26-32.
Abstract
Baier-Anderson C, Blount BC, Lakind JS, et al. Estimates of exposures to perchlorate from consumption of human milk, dairy milk and water, and comparison to current reference dose. J Toxicol Environ Health A. 2006 Feb;69(3-4):319-30.
Abstract
Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004 Jan 14;291(2):228-38.
Abstract
De Groef B, Decallonne BR, Van der Geyten S, et al. Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Eur J Endocrinol. 2006 Jul;155(1):17-25.
Abstract
Greer FR, Shannon M; American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Committee on Environmental Health. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics. 2005 Sep;116(3):784-6.
Abstract
Blum M. Ultrasonography of the thyroid, Chapter 6c at Thyroid Disease Manager, http://www.thyroidmanager.org
Link
Tajtakova M, Semanova Z, Tomkova Z, et al. Increased thyroid volume and frequency of thyroid disorders signs in schoolchildren from nitrate polluted area. Chemosphere 2006 62 559–564.
Abstract
Steinmaus C, Miller MD, Howd R. Impact of smoking and thiocyanate on perchlorate and thyroid hormone associations in the 2001-2002 national health and nutrition examination survey. Environ Health Perspect. 2007 Sep;115(9):1333-8.
Abstract
by Lara Pizzorno, MDiv, MA, LMT
Part I: Americans at High Risk for Iodine Insufficiency (*Note Link to Part II Here)
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 RDI, although capable of preventing rickets, has been proven inadequate for this pro-hormone's numerous other functions in the body, the iodine RDI 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 fetal brain development or optimal health in adults. 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.
Introduction
Iodine deficiency, defined as urinary iodine excretion <100 1 ="/-" mg =" typical">10 mg/L, the federal maximum contaminant level. Two million families are estimated to drink water from private wells that fail to meet the federal drinking-water standard for nitrate. In urban areas, municipal wastewater-treatment discharges on surrounding farmland aggravate the problem.36 Hypertrophy of the thyroid gland has been noted at nitrate levels exceeding 50 mg/L. School children living in a community in Slovakia, where drinking-water wells contained high nitrate levels (>50 mg/L), were found to have enlarged thyroid glands and signs of subclinical thyroid disorder (thyroid hypoechogenicity37 [low intensity echoes] by ultrasound [seen in Hashimoto's thyroiditis and Graves disease], increased TSH levels, positive thyroperoxidase antibodies).38
Dietary thiocyanate also inhibits iodine uptake by the NIS. Brassica family vegetables contain compounds that can be converted to thiocyanates in the gut; however, cooking reduces the thiocyanate (and nitrate) content of vegetables, plus only about 50% of the thiocyanate produced in the gut is bioavailable. Cigarette smoking, however, is a significant source of thiocyanate in the body. Recent studies in the U.S. have found that thiocyanate concentrations in the breast milk of smokers were fourfold higher than those of non-smokers, and iodine content in the breast milk of smoking mothers was twofold reduced, likely due to the thiocyanate's competitive inhibition for NIS in the mammary gland. Thiocyanate has a half-life of approximately 6 days, compared to 8 and 5 hours for perchlorate and nitrate respectively.35
Lastly, research suggests a synergistic effect of perchlorate with thiocyanate resulting in significantly more damage to thyroid function than either compound alone in iodine-deficient individuals. Data from the 2001-2002 NHANES revealed that in women with urinary iodine levels <100 mcg/L, the association between perchlorate and decreased T4 was 66% greater than in non-smokers. These results suggest that thiocyanate in cigarette smoke interacts with perchlorate at commonly occurring perchlorate exposures to negatively impact thyroid function to a much greater degree in individuals with urinary iodine levels <100 mcg/L.39 Little or no data are available on the daily-required dose of dietary iodine to withstand inhibition of NIS iodine—uptake by perchlorate, nitrate and thiocyanate present in American's drinking water, food and exposure to cigarette smoke.35
Conclusion
The combination of changes in food production and American dietary habits have significantly decreased iodine consumption in the U.S. The majority of Americans may not even be meeting RDI recommendations for iodine, which given our unremitting, widespread, and increasing exposure to a variety of iodine uptake inhibitors, are likely insufficient for the promotion of optimal brain development or adult thyroid function.
In adults, iodine is necessary not only for the production of thyroid hormones, but has recently been recognized to play a protective role against fibrocystic breast disease and breast cancer. A relationship has also been suggested between iodine deficiency and a number of other health issues including other cancers, obesity, attention deficit hyperactivity disorder (ADHD), psychiatric disorders, and fibromyalgia.
Part II of this article will suggest revising the RDIs to levels that consider these factors and are based on our recently developed understanding of iodine's varied roles in the body and the relationship of iodine insufficiency to the above mentioned pathologies. Available options in laboratory assessments of iodine levels, preferential forms of iodine supplementation, and cofactors necessary for optimal iodine utilization will also be discussed.
Read Part II: Iodine: the Next Vitamin D? Not Just for Thyroid
References
Patrick L. Iodine: deficiency and therapeutic considerations. Altern Med Rev. 2008 Jun;13(2):116-27.
Abstract
Vitti P, Rago T, Aghini-Lombardi F, et al. Iodine deficiency disorders in Europe. Public Health Nutr. 2001 Apr;4(2B):529-35.
Abstract
Hollowell JG, Staehling NW, Hannon WH, et al. 1998 Iodine nutrition in the United States: trends and public health implications: iodine excretion data from the National Health and Nutrition Surveys I and III (1971–1974 and 1988–1994). J Clin Endocrinol Metab. 1998 Oct;83(10):3401-8.
Abstract
Caldwell KL, Jones R, Hollowell JG. Urinary iodine concentration: United States National Health And Nutrition Examination Survey 2001-2002. Thyroid. 2005 Jul;15(7):692-9.
Abstract
Caldwell KL, Miller GA, Wang RY, et al,. Iodine status of the U.S. population, National Health and Nutrition Examination Survey 2003-2004. Thyroid. 2008 Nov;18(11):1207-14.
Abstract
Pearce EN, Leung AM, Blount BC, et al. Breast milk iodine and perchlorate concentrations in lactating Boston-area women. J Clin Endocrinol Metab 2007;92:1673-1677.
Abstract
Dasgupta PK, Liu Y, Dyke JV. Iodine nutrition: iodine content of iodized salt in the United States. Environ Sci Technol. 2008 Feb 15;42(4):1315-23.
Abstract
Pearce EN, Pino S, He X, et al. Sources of dietary iodine: bread, cows' milk, and infant formula in the Boston area. J Clin Endocrinol Metab. 2004 Jul;89(7):3421-4.
Abstract
Keller KL, Kirzner J, Pietrobelli A, et al. Increased sweetened beverage intake is associated with reduced milk and calcium intake in 3- to 7-year-old children at multi-item laboratory lunches. J Am Diet Assoc. 2009 Mar;109(3):497-501.
Abstract
Rampersaud GC, Bailey LB, Kauwell GP. National survey beverage consumption data for children and adolescents indicate the need to encourage a shift toward more nutritive beverages. J Am Diet Assoc. 2003 Jan;103(1):97-100.
Abstract
Bleich SN, Wang YC, Wang Y, et al. Increasing consumption of sugar-sweetened beverages among US adults: 1988-1994 to 1999-2004. Am J Clin Nutr. 2009 Jan;89(1):372-81.
Abstract
Stasiak M, Lewiński A, Karbownik-Lewińska M. Relationship between toxic effects of potassium bromate and endocrine glands.] Endokrynol Pol. 2009;60(1):40-50.
Abstract
World Health Organization Monograph. Potassium bromate. IARC Monogr Eval Carcinog Risks Hum. 1999;73:481-96.
Abstract
Kurokawa Y, Maekawa A, Takahashi M, Hayashi Y. Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen. Environ Health Perspect. 1990 Jul;87:309-35.
Abstract
van Netten C, Hoption Cann SA, Morley DR, van Netten JP. Elemental and radioactive analysis of commercially available seaweed. Sci Total Environ. 2000 Jun 8;255(1-3):169-75.
Abstract
MacArtain P, Gill CI, Brooks M, et al. Nutritional value of edible seaweeds. Nutr Rev. 2007 Dec;65(12 Pt 1):535-43. PMID: 18236692
Abstract
Interagency Board for Nutrition Monitoring and Related Research. Third Report on Nutrition Monitoring in the United States. Executive Summary; 1995; p.ES-10
Link
American Medical Association. AMA calls for measures to reduce sodium intake in U.S. diet; 2006; http://www.ama-assn.org/ama/pub/category/16461.html
Northwestern University Nutrition Fact Sheet, Iodine: http://www.feinberg.northwestern.edu/nutrition/factsheets/iodine.html
Link
Ebbin R. Americans' Dining-Out Habits, Restaurants USA, National Restaurant Association, November 2000
Link
Shake Your Salt Habit, http://www.americanheart.org
Link
Sevenier G. The Proof of the Pudding, April 14, 2006
Link
Soldin OP, Braverman LE, Lamm SH 2001 Perchlorate clinical pharmacology and human health: a review. 2001 Aug;23(4):316-31.
Abstract
Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amiodarone on the thyroid. Endocr Rev. 2001 Apr;22(2):240-54.
Abstract
Wolff J Perchlorate and the thyroid gland. Pharmacol Rev. 1998 Mar;50(1):89-105.
Abstract
Lawrence JE, Lamm SH, Pino S, et al. The effect of short-term low-dose perchlorate on various aspects of thyroid function. 1: Thyroid. 2000 Aug;10(8):659-63.
Abstract
Dohán O, De la Vieja A, Paroder V, et al. The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance. Endocr Rev. 2003 Feb;24(1):48-77.
Abstract
Sanchez CA, Krieger RI, Khandaker N, et al. Accumulation and perchlorate exposure potential of lettuce produced in the Lower Colorado River region. J Agric Food Chem. 2005 Jun 29;53(13):5479-86.
Abstract
Sanchez CA, Crump KS, Krieger RI, et al. Perchlorate and nitrate in leafy vegetables of North America. Environ Sci Technol. 2005 Dec 15;39(24):9391-7.
Abstract
Sanchez CA, Krieger RI, Khandaker NR, et al. Potential perchlorate exposure from Citrus sp. irrigated with contaminated water. Anal Chim Acta 2006 May 10;567(1):33-38.
Abstract
Blount BC, Pirkle JL, Osterloh JD, et al. Urinary perchlorate and thyroid hormone levels in adolescent and adult men and women living in the United States. Environ Health Perspect. 2006 Dec;114(12):1865-71.
Abstract
Snyder SA, Pleus RC, Vanderford BJ, Holady JC. Perchlorate and chlorate in dietary supplements and flavor enhancing ingredients. Anal Chim Acta 2006 May 10;567(1):26-32.
Abstract
Baier-Anderson C, Blount BC, Lakind JS, et al. Estimates of exposures to perchlorate from consumption of human milk, dairy milk and water, and comparison to current reference dose. J Toxicol Environ Health A. 2006 Feb;69(3-4):319-30.
Abstract
Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004 Jan 14;291(2):228-38.
Abstract
De Groef B, Decallonne BR, Van der Geyten S, et al. Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Eur J Endocrinol. 2006 Jul;155(1):17-25.
Abstract
Greer FR, Shannon M; American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Committee on Environmental Health. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics. 2005 Sep;116(3):784-6.
Abstract
Blum M. Ultrasonography of the thyroid, Chapter 6c at Thyroid Disease Manager, http://www.thyroidmanager.org
Link
Tajtakova M, Semanova Z, Tomkova Z, et al. Increased thyroid volume and frequency of thyroid disorders signs in schoolchildren from nitrate polluted area. Chemosphere 2006 62 559–564.
Abstract
Steinmaus C, Miller MD, Howd R. Impact of smoking and thiocyanate on perchlorate and thyroid hormone associations in the 2001-2002 national health and nutrition examination survey. Environ Health Perspect. 2007 Sep;115(9):1333-8.
Abstract
Thursday, 14 May 2009
BioLargo Launches Products
SOURCE: BioLargo, Inc.
May 13, 2009 06:26 ET
BioLargo Launches Odor-No-More(TM)
Products Helping Reduce Greenhouse Gas Emissions
Co-Designed by Hall of Fame Thoroughbred
Trainer Jack Van Berg
IRVINE, CA--(Marketwire - May 13, 2009) - BioLargo, Inc. (
Legendary Hall of Fame Thoroughbred trainer Mr. Jack Van Berg commented "My paddock smells cleaner and we remove less soiled bedding when cleaning the stalls. In my 50+ years in the industry, training legendary horses and winning the biggest races, I have not seen any product that can out perform the Odor-No-More™ products."
Master Farrier and Reined Cow Horse trainer for 30+ years Rocky Waldt states, "I tested them extensively, recommend them to my customers, and use them throughout my own facility. My fly population is down significantly and I believe the products will be very beneficial to the long-term hoof health of my animals."
"Our test customers and experts urged us to bring these products to market because they work so well and fill a void in the marketplace", says BioLargo VP of Operations and Product Manager Joe Provenzano.
BioLargo's President, Dennis Calvert states, "This is a great example of how our BioLargo technology makes products better. We believe these products will continue to enhance our technology licensing efforts with global leaders in major industries."
About BioLargo, Inc.
BioLargo's business strategy is to harness and deliver Nature's Best Solution™ -- free iodine -- in a safe, efficient, environmentally sensitive and cost-effective manner. The centerpiece of BioLargo's technology is CupriDyne™ which works by combining micro-nutrient salts with water from any source to deliver "free iodine" on demand, in controlled dosages, in order to balance efficacy of performance with concerns about toxicity. BioLargo's technology has potential commercial applications within global industries, including but not limited to agriculture, animal health, beach and soil environmental uses, consumer products, food processing, medical, and water industries. BioLargo's strategic partner Ioteq IP Pty Ltd. was named a "Top 50 Water Company for the 21st Century" by the Artemis Project; BioLargo markets their iodine based water disinfection technology, the Isan® system. The Company's website is www.BioLargo.com.
Safe Harbor Statement
The statements contained herein, which are not historical, are forward-looking statements that are subject to risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements, including, but not limited to, the company's filings and future filings with the Securities and Exchange Commission, including those set forth in the company's Annual Report on Form 10-K for the year ended December 31, 2008.
Saturday, 25 April 2009
University of Hawaii Beach Study Results
PROJECT TITLE:Evaluation of CupriDyneTM to Mitigate Microbial Contamination of Beach Sand: Phase One (Laboratory Based Study)
PRINCIPAL INVESTIGATOR:Dr. Roger Fujioka, Water Resources Research Center, University of Hawaii at Manoa (UH)
FUNDING AGENCY:
BioLargo, Inc.2603 Main Street, Suite 1155 Irvine, CA 92614
Tuesday, 21 April 2009
Iodine For Health Article - Dr. Miller
LInk to Article Here
There is growing evidence that Americans would have better health and a lower incidence of cancer and fibrocystic disease of the breast if they consumed more iodine. A decrease in iodine intake coupled with an increased consumption of competing halogens, fluoride and bromide, has created an epidemic of iodine deficiency in America.
People in the U.S. consume an average 240 micrograms (µg) of iodine a day. In contrast, people in Japan consume more than 12 milligrams (mg) of iodine a day (12,000 µg), a 50-fold greater amount. They eat seaweed, which include brown algae (kelp), red algae (nori sheets, with sushi), and green algae (chlorella). Compared to terrestrial plants, which contain only trace amounts of iodine (0.001 mg/gm), these marine plants have high concentrations of this nutrient (0.5–8.0 mg/gm). When studied in 1964, Japanese seaweed consumption was found to be 4.5 grams (gm) a day and that eaten had a measured iodine concentration of 3.1 mg/gm of seaweed (= 13.8 mg of iodine). According to public health officials, mainland Japanese now consume 14.5 gm of seaweed a day (= 45 mg of iodine, if its iodine content, not measured, remains unchanged). Researchers have determined that residents on the coast of Hokkaido eat a quantity of seaweed sufficient to provide a daily iodine intake of 200 mg a day. Saltwater fish and shellfish contain iodine, but one would have to eat 15–25 pounds of fish to get 12 mg of iodine.
Health comparisons between the two countries are disturbing. The incidence of breast cancer in the U.S. is the highest in the world, and in Japan, until recently, the lowest. Japanese women who emigrate from Japan or adopt a Western style diet have a higher rate of breast cancer compared with those that consume seaweed. Life expectancy in the U.S. is 77.85 years, 48th in 226 countries surveyed. It is 81.25 years in Japan, the highest of all industrialized countries and only slightly behind the five leaders – Andorra, Macau, San Marino, Singapore, and Hong Kong. The infant mortality rate in Japan is the lowest in the world, 3.5 deaths under age one per 1,000 live births, half the infant mortality rate in the United States.
Today 1 in 7 American women (almost 15 percent) will develop breast cancer during their lifetime. Thirty years ago, when iodine consumption was twice as high as it is now (480 µg a day) 1 in 20 women developed breast cancer. Iodine was used as a dough conditioner in making bread, and each slice of bread contained 0.14 mg of iodine. In 1980, bread makers started using bromide as a conditioner instead, which competes with iodine for absorption into the thyroid gland and other tissues in the body. Iodine was also more widely used in the dairy industry 30 years ago than it is now.
Now iodized table salt is the chief source of iodine in a Western diet. But 45 percent of American households buy salt without iodine, which grocery stores also sell. And over the last three decades people who do use iodized table salt have decreased their consumption of it by 65 percent. Furthermore, the much higher concentrations of chloride in salt (NaCl) inhibits absorption of its sister halogen iodine (the intestines absorb only 10 percent of the iodine present in iodized table salt). As a result, 15 percent of the U.S. adult female population suffers from moderate to severe iodine deficiency, which health authorities define as a urinary iodine concentration less than 50 µg /L. Women with goiters (a visible, noncancerous enlargement of the thyroid gland) owing to iodine deficiency have been found to have a three times greater incidence of breast cancer. A high intake of iodine is associated with a low incidence breast cancer, and a low intake with a high incidence of breast cancer.
Animal studies show that iodine prevents breast cancer, arguing for a causal association in these epidemiological findings. The carcinogens nitrosmethylurea and DMBA cause breast cancer in more than 70 percent of female rats. Those given iodine, especially in its molecular form as I2, have a statistically significant decrease in incidence of cancer. Other evidence adding biologic plausibility to the hypothesis that iodine prevents breast cancer includes the finding that the ductal cells in the breast, the ones most likely to become cancerous, are equipped with an iodine pump (the sodium iodine symporter, the same one that the thyroid gland has) to soak up this element.
Similar findings apply to fibrocystic disease of the breast. The incidence of fibrocystic breast disease in American women was 3 percent in the 1920s. Today, 90 percent of women have this disorder, manifested by epithelial hyperplasia, apocrine gland metaplasia, fluid-filled cysts, and fibrosis. Six million American women with fibrocystic disease have moderate to severe breast pain and tenderness that lasts more than 6 days during the menstrual cycle.
In animal studies, female rats fed an iodine-free diet develop fibrocystic changes in their breasts, and iodine in its elemental form (I2) cures it.
Russian researchers first showed, in 1966, that iodine effectively relieves signs and symptoms of fibrocystic breast disease. Vishniakova and Murav’eva treated 167 women suffering from fibrocystic disease with 50 mg KI during the intermenstrual period and obtained a beneficial healing effect in 71 percent (it is reference 49 here).
Then Ghent and coworkers, in a study published in the Canadian Journal of Surgery in 1993, likewise found that iodine relieves signs and symptoms of fibrocystic breast disease in 70 percent of their patients. This report is a composite of three clinical studies, two case series done in Canada in 696 women treated with various types of iodine, and one in Seattle. The Seattle study, done at the Virginia Mason Clinic, is a randomized, double-blind, placebo-controlled trial of 56 women designed to compare 3–5 mg of elemental iodine (I2) to a placebo (an aqueous mixture of brown vegetable dye with quinine). Investigators followed the women for six months and tracked subjective and objective changes in their fibrocystic disease.
A statistical analysis of the Seattle study (enlarged to include 92 women) was done, which shows that iodine has a highly statistically significant beneficial effect on fibrocystic disease (P < 0.001). Iodine reduced breast tenderness, nodularity, fibrosis, turgidity, and number of macroscysts, the five parameters in a total breast examination score that a physician blinded to what treatment the woman was taking, iodine or placebo, measured. This 36-page report, now available online, was submitted to the Food and Drug Administration (FDA) in 1995 seeking its approval to carry out a larger randomized controlled clinical trial on iodine for treating fibrocystic breast disease. It declined to approve the study, telling its lead investigator, Dr. Donald Low, "iodine is a natural substance, not a drug." But the FDA has now decided to approve a similar trial sponsored by Symbollon Pharmaceuticals. This company is enrolling 175 women in a phase III trial, registered on clinicaltrials.gov. (Any women with fibrocystic disease reading this who might be interested in participating in this study should call its sponsor, Jack Kessler, Ph.D., at 508-620-7676, Ext. 201.)
Most physicians and surgeons view iodine from a narrow perspective. It is an antiseptic that disinfects drinking water and prevents surgical wound infections, and the thyroid gland needs it to make thyroid hormones – and that’s it. (When painted on the skin prior to surgery, tincture of iodine kills 90 percent of bacteria present within 90 seconds.) The thyroid gland needs iodine to synthesize thyroxine (T4) and triiodothyronine (T3), hormones that regulate metabolism and steer growth and development. T4 contains four iodine atoms combined with 27 other atoms of carbon, hydrogen, oxygen, and nitrogen, but owing to its large size accounts for 65 percent of the molecule’s weight. (T3 has three iodine atoms.) The thyroid needs only a trace amount of iodine, 70 µg a day, to produce the requisite amount of T4 and T3. For that reason thyroidologists say that iodine is best taken just in microgram amounts. They consider consuming more than 1 to 2 mg of iodine a day to be excessive and potentially harmful.
Expert opinion on iodine is now the purview of thyroidologists. Mainstream physicians and surgeons accept their thyroid-only view of iodine and either ignore or discount studies that show iodine in larger amounts provides extrathyroidal benefits, particularly for women’s breasts. Thus a leading textbook on breast disease, Bland and Copeland’s The Breast: Comprehensive Management of Benign and Malignant Disorders (2003), fails to mention iodine anywhere in its 1,766 pages.
Iodine has an important and little understood history. This relatively scarce element has played a pivotal role in the formation of our planet’s atmosphere and in the evolution of life. For more than two billion years there was no oxygen in the atmosphere until a new kind of bacteria, cyanobacteria (blue-green algae), began producing oxygen as a byproduct of photosynthesis. Cyanobacteria also developed an affinity for iodine. The most likely reason is that these organisms used iodine as an antioxidant to protect themselves against the free radicals that oxygen breeds (superoxide anion, hydrogen peroxide, and hydroxyl radical). Studying kelp, researchers have shown how iodine does this and have found that kelp will absorb increased amounts of iodine when placed under oxidative stress. Other researchers have shown that iodine increases the antioxidant status of human serum similar to that of vitamin C.
Iodine also induces apoptosis, programmed cell death. This process is essential to growth and development (fingers form in the fetus by apoptosis of the tissue between them) and for destroying cells that represent a threat to the integrity of the organism, like cancer cells and cells infected with viruses. Human lung cancer cells with genes spliced into them that enhance iodine uptake and utilization undergo apoptosis and shrink when given iodine, both when grown in vitro outside the body and implanted in mice. Its anti-cancer function may well prove to be iodine’s most important extrathyroidal benefit.
Iodine has other extrathyroidal functions that require more study. It removes toxic chemicals – fluoride, bromide, lead, aluminum, mercury – and biological toxins, suppresses auto-immunity, strengthens the T-cell adaptive immune system, and protects against abnormal growth of bacteria in the stomach.
In addition to the thyroid and mammary glands, other tissues possess an iodine pump (the sodium/iodine symporter). Stomach mucosa, the salivary glands, and lactating mammary glands can concentrate iodine almost to the same degree as the thyroid gland (40-fold greater than its concentration in blood). Other tissues that have this pump include the ovaries; thymus gland, seat of the adaptive immune system; skin; choroid plexus in the brain, which makes cerebrospinal fluid; and joints, arteries and bone.
Today’s medical establishment is wary of iodine (as they are of most naturally occurring, nonpatentable, nonpharmaceutical agents). Thyroidologists cite the Wolff-Chaikoff effect and warn that TSH (thyroid stimulating hormone) blood levels can rise with an iodine intake of a milligram or more. The Wolff-Chaikoff effect, a temporary inhibition of thyroid hormone synthesis that supposedly occurs with increased iodine intake, is of no clinical significance. And an elevated TSH, when it occurs, is "subclinical." This means that no signs or symptoms of hypothyroidism accompany its rise. Some people taking milligram doses of iodine, usually more than 50 mg a day, develop mild swelling of the thyroid gland without symptoms. The vast majority of people, 98 to 99 percent, can take iodine in doses ranging from 10 to 200 mg a day without any clinically adverse affects on thyroid function. The prevalence of thyroid diseases in the 127 million people in Japan who consume high amounts of iodine is not much different than that in the U.S.
Everyone agrees that a lack of iodine in the diet causes a spectrum of disorders that includes, in increasing order of severity, goiter and hypothyroidism, mental retardation, and cretinism (severe mental retardation accompanied by physical deformities). Health authorities in the U.S. and Europe have agreed upon a Reference Daily Intake (RDI), formerly called the Recommended Dietary Allowance (RDA), for iodine designed to prevent these disorders, which the World Health Organization (WHO) estimates afflicts 30 percent of the world’s population. The RDI for iodine, first proposed in 1980, is 100–150 µg/day. Organizations advocating this amount include the American Medical Association, National Institutes of Health’s National Research Council, Institute of Medicine, United Nations Food and Agricultural Organization, WHO Expert Committee, and the European Union International Programme on Chemical Safety. These health authorities consider an RDI of 100–150 µg/day of iodine sufficient to meet the requirements of nearly all (97–98%) healthy individuals.
This consensus on iodine intake flies in the face of evidence justifying a higher amount. This evidence includes animal studies, in vitro studies on human cancer cell lines, clinical trials of iodine for fibrocystic breast disease, and epidemiological data. An intake of 150 µg/day of iodine will prevent goiters and the other recognized iodine deficiency disorders, but not breast disease. Prevention of breast disease requires higher doses of iodine. Indeed, a reasonable hypothesis is that, like goiters and cretinism, fibrocystic disease of the breast and breast cancer are iodine deficiency disorders (also uterine fibroids).
What Albert Guérard writes about new truths applies especially to iodine: "When you seek a new path to truth, you must expect to find it blocked by expert opinion." The reigning truth on iodine is that the thyroid gland is the only organ in the body that requires this micronutrient, and a daily intake considerably more than what the thyroid gland needs is potentially harmful. The new truth is that the rest of the body also needs iodine, in milligram, not microgram amounts. Tell that to a thyroidologist and her response will call to mind this admonition on new truths.
These are the four most common formulations of inorganic (nonradioactive) iodine, as iodide (I-), and with or without molecular iodine (I2): Potassium iodide (KI) tablets, in doses ranging from 0.23 to 130 mg; super saturated potassium iodide (SSKI), 19–50 mg of iodide per drop; Lugol’s solution, 6.3 mg of molecular iodine/iodide per drop; and Iodoral, each tablet containing 12.5 mg iodine/iodide. Both Lugol’s solution and Ioderal are one-third molecular iodine (5%) and two-thirds potassium iodide (10%). Studies done to date indicate that the best iodine supplement is one that includes molecular iodine (I2), which breast tissue prefers.
Iodine was used for a wide variety of ailments after its discovery in 1811 up until the mid-1900s, when thyroidologists warned that "excess" amounts of iodine might adversely affect thyroid function. It is effective in gram amounts for treating various dermatologic conditions, chronic lung disease, fungal infestations, tertiary syphilis, and even arteriosclerosis. The Nobel laureate Dr. Albert Szent Györgi (1893–1986), the physician who discovered vitamin C, writes: "When I was a medical student, iodine in the form of KI was the universal medicine. Nobody knew what it did, but it did something and did something good. We students used to sum up the situation in this little rhyme:
If ye don’t know where, what, and why Prescribe ye then K and I"
The standard dose of potassium iodide given was 1 gram, which contains 770 mg of iodine.
Regarding KI and other iodine salts (like sodium iodide), the venerated 11th edition of the Encyclopedia Britannica, published in 1911, states, "Their pharmacological action is as obscure as their effects in certain diseased conditions are consistently brilliant. Our ignorance of their mode of action is cloaked by the term deobstruent, which implies that they possess the power of driving out impurities from the blood and tissues. Most notably is this the case with the poisonous products of syphilis. In its tertiary stage – and also earlier – this disease yields in the most rapid and unmistakable fashion to iodides, so much so that the administration of these salts is at present the best means of determining whether, for instance, a cranial tumor be syphilitic or not."
This 19th and early 20th century medicine continues to be used in gram amounts in the 21st century by dermatologists. They treat inflammatory dermatoses, like nodular vasculitis and pyoderma gangrenosum (shown here), with SSKI, beginning with an iodine dose of 900 mg a day, followed by weekly increases up to 6 grams a day as tolerated. Fungal eruptions, like sporotrichosis, are treated initially in gram amounts with great success. These lesions can disappear within two weeks after treatment with iodine.
For many years physicians used potassium iodide in doses starting at 1.5 to 3 gm and up to more than 10 grams a day, on and off, to treat bronchial asthma and chronic obstructive pulmonary disease with good results and surprisingly few side effects.
There is a case report in the medical literature of a 54-year-old man who, thinking it was iced tea, drank a "home preparation" of SSKI in water that his aunt kept in the refrigerator for her rheumatism. Over a short period of time he consumed 600 ml of this solution, which contained 15 gm of iodide, an amount 100,000 times more than the RDI. He developed swelling of the face, neck, and mouth, had transient cardiac arrhythmias and made an uneventful recovery.
Dr. Guy Abraham, a former professor of obstetrics and gynecology at UCLA, mounted what he calls "The Iodine Project" in 1997 after he read the Ghent paper on iodine for fibrocystic disease. He had his company, Optimox Corp., make Iodoral, the tablet form of Lugol’s solution, and he engaged two family practice physicians, Dr. Jorge Flechas (in 2000) in North Carolina and Dr. David Brownstein (in 2003) in Michigan to carry out clinical studies with it.
The project’s hypothesis is that maintaining whole body sufficiency of iodine requires 12.5 mg a day, an amount similar to what the Japanese consume. The conventional view is that the body contains 25–50 mg of iodine, of which 70–80 percent resides in the thyroid gland. Dr. Abraham concluded that whole body sufficiency exists when a person excretes 90 percent of the iodine ingested. He devised an iodine-loading test where one takes 50 mg and measures the amount excreted in the urine over the next 24 hours. He found that the vast majority of people retain a substantial amount of the 50 mg dose. Many require 50 mg a day for several months before they will excrete 90 percent of it. His studies indicate that, given a sufficient amount, the body will retain much more iodine than originally thought, 1,500 mg, with only 3 percent of that amount held in the thyroid gland.
More than 4,000 patients in this project take iodine in daily doses ranging from 12.5 to 50 mg, and in those with diabetes, up to 100 mg a day. These investigators have found that iodine does indeed reverse fibrocystic disease; their diabetic patients require less insulin; hypothyroid patients, less thyroid medication; symptoms of fibromyalgia resolve, and patients with migraine headaches stop having them. To paraphrase Dr. Szent-Györgi, these investigators aren’t sure how iodine does it, but it does something good.
Thyroid function remains unchanged in 99 percent of patients. Untoward effects of iodine, allergies, swelling of the salivary glands and thyroid, and iodism, occur rarely, in less than 1 percent. Iodine removes the toxic halogens fluoride and bromide from the body. Iodism, an unpleasant brassy taste, runny nose, and acne-like skin lesions, is caused by the bromide that iodine extracts from the tissues. Symptoms subside on a lesser dose of iodine.
As these physicians point out, consuming iodine in milligram doses should, of course, be coupled with a complete nutritional program that includes adequate amounts of selenium, magnesium, and Omega-3 fatty acids. Done this way, an iodine intake 100 times the reference daily intake is "the simplest, safest, most effective and least expensive way to help solve the health care crisis crippling our nation," as the leader of The Iodine Project, Dr. Abraham, puts it.
People who take iodine in these amounts report that they have a greater sense of well-being, increased energy, and a lifting of brain fog. They feel warmer in cold environments, need somewhat less sleep, improved skin complexion, and have more regular bowel movements. These purported health benefits need to be studied more thoroughly, as do those with regard to fibrocystic breast disease and cancer.
Meanwhile, perhaps we should emulate the Japanese and substantially increase our iodine intake, if not with seaweed, then with two drops of Lugol’s Solution (or one Iodoral tablet) a day.
Recommended Reading:
Miller DW. Iodine in Health and Civil Defense. Presented at the 24th Annual Meeting of Doctors for Disaster Preparedness in Portland, Oregon, August 6, 2006. The text for this talk, with 68 references, can be found here, and the PowerPoint slides I used for it, here.
Abraham GE. The safe and effective implementation of orthoiodosupplementation in medical practice. The Original Internist 2004;11:17–36. Available online here. This is a good introduction to The Iodine Project. His other research studies are online here.
Flechas, JD. Orthoiodosupplementation in a primary care practice. The Original Internist 2005;12(2):89–96. Available online here.
Brownstein D. Clinical experience with inorganic, non-radioactive iodine/iodide. The Original Internist 2005;12(3):105–108. Available online here.
Derry D. Breast cancer and iodine: How to prevent and how to survive breast cancer. Victoria, B.C.: Trafford Publishing; 2002. The book is a bit disorganized, has references at the end of each chapter not cited in the text, and no index; but it is an eye-opener nonetheless.
Brownstein D. Iodine: why you need it why you can’t live without it. West Bloomfield, Michigan: Medical Alternatives Press; 2004. Well-written and referenced, with case histories.
Low DE, Ghent WR, Hill LD. Diatomic iodine treatment for fibrocystic disease: special report of efficacy and safety results. [Submitted to the FDA] 1995:1–38. Available online here. This study makes a strong case for iodine as the preferred treatment for fibrocystic disease.
August 14, 2006
Donald Miller (send him mail) is a cardiac surgeon and Professor of Surgery at the University of Washington in Seattle. He is a member of Doctors for Disaster Preparedness and writes articles on a variety of subjects for LewRockwell.com. His web site is www.donaldmiller.com
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