Iodine is an essential element to human health. Globally, a large percentage of the world’s population is affected by iodine deficiency disorders. Iodine-rich diets and iodinization of salt around the world has reduced the prevalence of endemic goiters. In the United States, as well as around the world, the most vulnerable populations to the consequences of iodine deficiency are pregnant women and children. Maintaining adequate iodine status while avoiding acute exposure to large doses of iodine may be the most effective means of lessening iodine-related diseases.
In 1811, Bernard Courtois serendipitously discovered iodine while extracting saltpeter (ammonium nitrate) from seaweed to produce gunpowder for Napoleon’s army.1 He mistakenly added excess sulfuric acid, which caused a violet-colored vapor to exude and recrystalize. Iodine derives its name from the Greek word iodes, which means violet. Elemental iodine is by far the heaviest of the required human elements known, with an atomic mass of 127. It is essential for normal development and metabolism in all animals, including humans. Collectively, all adverse health effects emerging from iodine deficiency are currently called iodine deficiency disorders” (IDD). The World Health Organization (WHO) estimates that roughly 2 billion people suffer from, or are at risk for, IDD.2 The most severe consequences of IDD take place during growth and development and include spontaneous abortion, increased infant mortality, cretinism, and cognitive defects.3,4 The cognitive effects are so widespread, the WHO has designated iodine deficiency the most preventable cause of mental retardation in the world.5
In adults, the effects of iodine deficiency are much more insidious and can take years to decades for symptoms to manifest. By far the most prevalent consequence of iodine deficiency in adolescence and adulthood is development of a goiter. This is referred to as “endemic goiter” when it occurs in greater than 10% of any geographical area. If iodine deficiency is severe enough, then there is inadequate iodine available to synthesize thyroid hormones and hypothyroidism ensues. While this is the No. 1 cause of hypothyroidism globally, in areas like the United States where overt iodine deficiency is less common, autoimmune hypothyroidism is the most prevalent cause of hypothyroidism.
Iodine refers to the diatomic molecule I2. Iodide refers to the elemental form I-, which is often complexed with a cation to form a salt, such as potassium iodide (KI). Iodine (I2) is not very soluble in water. However, when I2 is combined with an iodide salt, such as KI, it becomes soluble. This is due to the formation of triiodide ions in solution, I3-. Triiodides are found in Lugol’s solution, which is 5 grams of iodine and 10 grams of potassium iodide brought to a total 100 ml solution with distilled water. Iodine is the form that is used as an antiseptic and antimicrobial. Tincture of iodine is, not surprisingly, iodine in alcohol. It is important to note that distinctions between the words “iodide” and “iodine” are not strictly adhered to in the medical literature. This leads to confusion in assessing the clinical use and the toxicity of the 2 compounds.
Absorption and Metabolism of Iodine
Iodine is readily absorbed via the entire length of the intestinal tract with an estimated bioavailability of 92%.6 Iodine is absorbed via passive diffusion, while iodide is absorbed via a transport protein called the sodium iodide symporter (NIS) in the gastric mucosa.7 There is no condition known that results in gastrointestinal malabsorption, even in those with malabsorption syndromes such as celiac disease.
Some absorption of iodine through the skin appears to take place, although the vast majority of what is applied evaporates before being absorbed.8 Tincture of iodine painted directly on the thyroid appears to reduce the ensuing uptake of the radiotracer I131 at 24 hours, implying that some of the topical iodine does reach the thyroid tissue.9 Of note, in this same study, tincture of iodine was much less efficient than a single, oral bolus dose of 130 mg of KI in reducing absorption of I131.
Elimination of iodine is primarily through the kidneys. Lesser, variable amounts are also excreted in feces, sweat, saliva, and breast milk. The proportions of iodine excreted by different routes are variable between and within individual subjects.10
Iodine deficiency during pregnancy can have repercussions on both the mother and the fetus. Because there is normally an increase in thyroxine production during pregnancy, marginal iodine status in the mother can become outright deficiency during pregnancy.11 This iodine deficiency can lead to increased stimulation of the thyroid, hypothyroxinemia, and goiter formation. While the interplay of the maternal and fetal hypothalamus pituitary axis is intricate,12 ultimately the impaired neurological development of the fetus is due to inadequate amounts of circulating thyroxine.13 If the hypothyroxinemia is severe enough, cretinism may result.
Cretinism is the phenotypic result of a hypothyroid state through gestation and early development and can be due to iodine deficiency or congenital defects in thyroid gland formation. Cretinism is marked by mental retardation, goiter, dwarfism, and soft bones. Cretinism may also include spastic muscles, lack of coordination, and deaf-mutism.14 Less severe hypothyroxinemia can result in cognitive impairments without cretinism. Studies suggest that people living in areas of severe iodine deficiency have intelligent quotients (IQs) up to 13.5 points lower than people in comparable areas with adequate iodine.15
Iodine deficiency can induce a goiter at any age from newborn to adult. It is essential to note that goiter formation precedes overt hypothyroidism; as such, it is not indicative of, nor synonymous with, a hypothyroid state. Goiters have been mentioned in medical texts since 2700 BC.16 Chinese physicians documented that goiters could be reversed by ingesting burnt seaweed powder and eventually by orally ingesting animal thyroid tissue. These treatments for goiter, documented as early as 1600 BC, may be the earliest medical treatment still in use.17
Table 1: Human Requirements for Iodine (Institute of Medicine, 2001)22
Dietary Sources of Iodine
The densest source of iodine in foods is seaweeds, or sea vegetables. These have been dietary staples in coastal areas throughout the world. Iodine content of most types of seaweed used for consumption is a few hundred micrograms of iodine per gram (dry weight). In one study of commercially sold seaweed products, iodine levels varied considerably from 16 mcg/gram in nori (Porphyra tenera) to as high as 8,100 mcg/gram in a kelp (Laminaria digitata) supplement.18 While it is assumed most people can benefit by including traditional dietary sources of iodine such as nori, kombu, wakame, or dulse to their diets, this study suggests those taking more concentrated forms such as kelp supplements may exceed the upper safe limit of iodine set by the Institute of Medicine. There is one case report on apparent iodine-induced thyrotoxicosis from consumption of a kelp-containing tea.19
There is potential then, for Americans to be high salt consumers who are simultaneously too low in iodine.
Iodized salt is the main dietary source of iodine in the industrialized world. In 1922, Switzerland was the first country to adopt the use of adding potassium iodide to salt. The United States soon followed suit. Today, Europe has iodized salt with potassium iodide, while the United States allows fortification with either potassium or copper iodide.20 Since the early 1920s, parts of Europe as well as the United States began fortifying table salt with potassium iodide. In the United States, salt used in food processing and restaurants is generally not iodized to prevent cumulative toxicity. Interestingly, most salt in the modern American diet now comes from restaurants and pre-made grocery items, which use non-iodized salt. There is potential then, for Americans to be high salt consumers who are simultaneously too low in iodine.
Many regions of the world have been known to have low soil iodine and high prevalence of goiters. These regions are usually high mountainous areas, such as the Himalayas, the Andes, or the Alps or lake beds such as the Ganges River or Great Lakes regions. Goiters in these regions were especially common when nearly all food was locally grown. This is because the amount of iodine found in plants varies with the concentration of iodine in the soil. Plants grown in iodine-replete soil average 1 mg iodine per kg of dry weight, while those grown in iodine-deficient soil may have levels as low as 0.01 mg/kg.21
It appears people in regions with poor soil selenium levels in addition to low iodine levels may be especially vulnerable to the adverse effects of iodine deficiency on thyroid function. Selenium is a cofactor for type 1 deiodinase, which converts T4 to T3. It is also critical for formation of glutathione peroxidase, which protects the thyroid from oxidative stress.22,23
In addition to plants, other sources of iodine in the diet include ocean-derived seafood, dairy products, and some bread products. Dairy products can vary 10-fold in their iodine content. The source of iodine in dairy products is either supplemental iodine given to the cattle or povidone iodine used to sanitize the cow's teats during the milking process. Both of these sources of exposure are highly variable. While the use of iodine in baked goods is not as common as it once was, a 2004 a study done in the Boston area still found iodine in commercially available breads, with the concentration varying from 10–300 mcg per slice.24
Table 2: Sources of Iodine in Food25
Iodine Status in the United States
Iodine fortification of salt, which began in 1924 in the United States has proved an effective means of eliminating goiter development. In 1928, 4 years after iodine fortification of salt, the rate of goiters in Michigan schools reduced from 40% to 10%. A few years later the rate was down to 1.4%.26
Currently, the vast majority of Americans consume enough iodine to avoid gross iodine deficiency. However, iodine consumption in the United States swooned during the late 1980s. According to the National Health and Nutrition Examination Surveys (NHANES), median urinary iodine in the general US population plummeted 50% between NHANES I (1971–1974) and NHANES III (1988–1994). The number of women with median urinary iodine values indicating moderate to severe deficiency (≤50 ug/L) went from 1% to 7%. It is speculated that the low-salt diet popular at the time may have played some role in the dramatic decrease. When the NHANES was done in 2003-2004, the general trend showed a reversal, but 37.2% of pregnant women still had levels below the lower limit recommended for normal fetal development by the WHO (100 ug/L). In a recent NHANES (2005–2006) subgroups of women, including nonpregnant, nonlactating women between 40–44; pregnant women in their teens, 20s, and 40s; and women who do not drink dairy all were at higher risk of iodine deficiency.27,28
Iodine and the Thyroid Gland
The adult body is estimated to contain 15–20 mg of iodine, with 30% in the thyroid gland and thyroid hormones and the remaining 70% dispersed throughout other tissues. Physiologically, iodine’s best-defined function is as an essential component of thyroid hormones. Thyroxine (T4) and triiodothyronine (T3) are composed of approximately 65 and 59 percent iodine by weight, respectively.29 All mammals depend on thyroid hormones for regulation of enzymatic activity and protein synthesis, and every metabolically active cell in the body requires it.
Major effects of thyroid hormones:30
- Regulation of basal metabolic rate
- Regulation of macronutrient metabolism
- Regulation on ion transport/muscle contraction
- Regulation of development, growth, and sexual maturation
Histologically, the lobes of the thyroid are divided into lobules, which contain numerous follicles. Follicles are made of simple epithelium (follicular cells) encompassing a colloid center. Capillaries, lymph vessels, and sympathetic nerves create an intricate network of plexuses around these follicles. As the name implies, parafollicular cells, which produce calcitonin, are also outside of the follicles.
Iodide is taken into follicular cells by a sodium-iodide symporter (NIS) in the basal membrane, in which I- and Na+ are transported into the cytosol via the sodium gradient. This sodium gradient is maintained by sodium/potassium ATP pumps in the basal membrane. Of note, NIS can also transport other anions such as bromide, cyanate, and perchlorate, all of which can result in a reduced influx of iodide.31 Once the iodide is inside the follicular cell, it diffuses through the cell to its apical membrane and enters the colloid via pendrin, a transport protein. After entering the colloid, iodide is oxidized via thyroid peroxidase (TPO), which allows it to bind with tyrosyl residues on thyroglobulin precursor proteins. This iodination forms monoiodotyrosine (MIT or T1) and diiodotyrosine (DIT or T2). T1 and T2 then couple to form either tetraiodothyronine, (thyroxine or T4) or triiodothyronine (T3). Iodinated thyroglobulin is taken back into the follicular cells in droplets via pinocytosis. These droplets are broken down by lysosomes and proteolytic enzymes, freeing the T3, T4, and T2 from the thyroglobulin and releasing them back through the basal membrane of the epithelial cell and into surrounding capillaries.32
Transport of iodide into thyroid follicular cells via NIS allows the thyroid to concentrate iodide by 20- to 50-fold above serum levels. NIS is also present in mammary tissue, the salivary glands, and the cervix, indicating an increase in concentration in those tissues.33 With the exception of iodine concentrated via lactating breast tissue, the physiological significance of iodine at the other sites is not well defined.34
In times of iodide excess, less iodide is transported into follicular cells of the thyroid. When iodide excess is severe or persistent, this reduction in iodide transport results in a decrease in thyroid hormone production within the gland. This effect is called the Wolff-Chaikoff effect, named after the first researchers to observe it in an animal model.35 The possible mechanisms for this reduction have been thought to be inhibition of thyroxin secretion, inhibition of oxidization of iodine within the thyroid, and/or inhibition of the iodination of tyrosine within the thyroid follicles. A recent study showed there are decreased levels of mRNA encoding NIS, suggesting downregulation of NIS expression.36 The Wolff-Chaikoff effect usually reverses in 2–3 weeks. This effect has been used therapeutically to suppress hyperthyroid states, although this treatment is no longer used with the advent of thioamide thyrotoxic drugs.37
Iodine Deficiency and Goiter Formation
Goiter is any enlargement of the thyroid gland. Iodine-deficiency goiter is also known as endemic goiter, simple goiter, or colloid goiter. When the body experiences an iodine deficiency (less than 100 mcg/day), it adapts by increasing secretion of thyroid-stimulating hormone (TSH). TSH stimulation leads to an increase in iodide transport into the thyroid via increased NIS expression.38 If the thyroid continues to have inadequate iodine for proper synthesis of T4 and T3, the colloid space enlarges, resulting in a diffuse enlargement of the gland. Underlying somatic mutations in thyroid hormone synthesis can be exacerbated by iodine deficiency, resulting in nodule formation as well.39
Substances that interfere with thyroid hormone synthesis are termed goitrogens, and their actions can be aggravated by concomitant iodine deficiency.40 Well-known goitrogenic foods include cruciferous vegetables such as broccoli, cauliflower, cabbage, and brussel sprouts, whose glucosinolate compounds compete with iodide uptake into the thyroid. Cyanogenic glucosides from foods such as cassava, lima beans, sorghum, and sweet potato are metabolized into thiocyanate, which also competes with iodide uptake at the NIS in the thyroid. Cooking renders the majority of the goitrogenic compounds inactive. Smoking tobacco is also goitrogenic.41 This is likely due to cyanide in the cigarettes, which is the metabolized to thiocyanate.42
Soy also contains flavonoids that can be goitrogenic. However, rather than affect iodine uptake, flavonoids impair oxidation of iodide within the colloid by thyroid peroxidase (TPO).43 This is of little concern in adults but has shown significant adverse affects in infants. Lastly, as mentioned above, bromide and perchlorate interfere with iodide uptake into the follicular cells of the thyroid, giving them goitrogenic potential.
Assessment of Iodine Status
Epidemiologically, the iodine status of various populations has been evaluated through urinary iodine (UI) testing, serum TSH, serum thyroglobulin, or assessing the size of the thyroid. The WHO now recommends UI as the most feasible and reliable means of monitoring iodine intake regionally. Since iodine is readily absorbed with an estimated bioavailability of 92%, low levels of UI in studied populations can be deduced and are a reliable indicator of inadequate dietary intake. Although UI is an adequate gauge of a population’s iodine status, it is not suitable for individual assessment, since there is considerable variation in UI measurements on repeat samples.44 However, assessment of an individual’s iodine intake can be estimated using three 24-hour urinary samples and a 92% bioavailability assumption (ie, UI (mcg/24-h)/0.92 = daily iodine intake).45
Some alternative practitioners have used 24-hour iodine/iodide challenge tests or skin iodine absorption tests to assess an individual’s iodine status. The 24-hour urinary challenge test requires the patient to ingest a bolus dose of iodine/iodide orally (usually 50 mg total), then collect a 24-hour urine sample. The premise of this test is based on two assumptions: 1) iodine-deficient tissue will take up the iodine, leaving low amounts of iodine excreted in the urine, and 2) nearly all the ingested iodine dose would be eliminated in 24 hours in a state of iodine repletion. There is little reason to assume this, as studies done in regional assessments of iodine status have suggested that urinary iodine output takes many months to change.46
The iodine skin test, which involves painting tincture of iodine or Lugol’s solution directly on the skin, is not a valid means of assessing iodine status. The vast majority of the iodine applied topically evaporates into the air.47 There is no evidence to support the assumption that the body is able to absorb greater amounts when there is a deficiency. While some of the iodine does get absorbed, it is a small fraction and is unlikely to have anything to do with physiological need for the element.
Main Sources of Toxic Iodine Exposure
Exposure to iodine can result in an acute hyperthyroid state (thyrotoxicosis), stimulate latent autoimmune conditions (eg, Graves’ disease), or result in hypothyroidism.48 The hypothyroid state results from failure to escape from the Wolff-Chaikoff effect or from fibrotic damage due to iodine-induced thyrotoxicosis. Some of the adverse effects are limited in duration, while others can become lifelong consequences of iodine exposure.
Iodine as a contrast agent in medical imaging
Iodine-induced thyrotoxicosis is also called the Jod-Basedow phenomenon. It is most likely to be encountered when an individual is suddenly exposed to a large dose of iodine, such as radiocontrast iodine used in medical imaging.49
Amiodarone, a drug that is used for arrhythmias, contains 6–12.5 mg of iodide in a commonly used daily dose. It can induce thyrotoxicosis in up to 3% of patients and in 10% of those in iodine-deficient regions.50 Conversely, hypothyroidism with amiodarone can result from a failure to escape from the Wolff-Chaikoff effect or stimulation of latent TPO antibodies, particularly in iodine-deficient regions.51
Early research assessing iodide’s use for cystic fibrosis of the pancreas resulted in a high incidence of goiter development and hypothyroidism (47/55 children studied). There is some indication that children with cystic fibrosis may also be at particular risk of toxicity from iodine derivatives.52
Exposure secondary to iodine as a water-purifying agent
There have been case reports of iodine-containing water purification tablets inducing thyrotoxicosis and stimulating a latent autoimmune condition in travelers.53 One study of 102 Peace Corp volunteers in Niger, West Africa, showed goiter prevalence of 44%, with a high prevalence of elevated serum TSH and higher TPO antibodies. All of these parameters reversed with the discontinuation of iodine-containing water purification systems.54
There are also cases of Jod-Basedow effect from a sudden introduction of iodine in communities of iodine deficiency.55 There is some evidence that even in areas of mild iodine deficiency, salt fortification may raise incidence of hyperthyroidism, presumably through increasing latent autoimmunity.56
Of note, the majority of cases of iodine-induced hypothyroidism are in patients who have a history of thyroiditis or amiodarone-induced thyrotoxicosis.57,58,59
Non-thyroidal toxicities of iodine
Chronic iodine intake generally above 5,000 mcg daily can also cause non-thyroidal symptoms including a metallic taste in the mouth, increased salivation, gastrointestinal side effects, and acneiform skin lesions.60 Given the efficient renal clearance of iodine, non-thyroidal side effects tend to be limited to iodine ingestion and resolve with iodine removal. Other toxicities, particularly stimulation of latent autoantibodies or post-thyrotoxicosis damage, can cause lifelong disease. It is important to note that individuals with iodine deficiencies, even slight, and those with latent thyroid antibodies are especially susceptible to iodine toxicity.61
Table 3: Safe Upper Limit (Institute of Medicine)62
|Tolerable Upper Intake Levels for Iodine
|19 years and older
|Pregnant women 14–18 years
|Pregnant women 19 years and older
|Lactating women 14–18 years
|Lactating women 19 years and older
Proponents of Pharmacologic Iodine/Iodide
In the past decade, there has been a movement outside of conventional medicine that claims the accepted levels of iodine intake are far too low for optimal health. Guy Abraham, MD, the chief proponent of this hypothesis, claims that high doses of iodine/iodide (approximately 12.5–50 mg daily) are necessary for optimal function of the thyroid gland and other organ systems.63 This dose is found in Iodoral® (by Optimox Corp.), a high-dose tablet containing iodine/iodide (12.5mg/tablet). Abraham’s hypothesis is largely based on the use of high doses of iodine/iodide that were common practice up through the mid-20th century and empirical evidence from his clinic. Since the safe upper limit of iodine intake is established at 1.0 mg daily, this is a pharmacological dose in comparison. This has sparked considerable debate in the integrative medical community.64 While there are numerous reports on iodine’s toxic effects at high doses, Dr. Abraham points out that many of the reports are toxic effects of synthetic iodine compounds such as contrast agents and iodine-containing drugs such as amiodarone.65 Unfortunately, all of the modern information on the use of high-dose iodine/iodide is anecdotal, with the only case report published in non-peer reviewed newsletter. Since Abraham concedes that adverse reactions can occur at these high doses, and that these adverse effects are lessened when given with a comprehensive nutritional program, he fails to define the details of this program, what these events are, their prevalence, and who is at risk. In short, if the hypothesis is correct, then clinical trial data should be obtained so that the risks and benefits can be clearly, objectively delineated.
A clinical trial could also be designed to explore the validity of Abraham’s use of the 24-hour, post-Iodoral®, urinary iodine test. This test is not an accepted assessment of iodine status by any established entity and was developed by Abraham himself. For example, the test requires the assumption that nearly all 50 mg of the Iodoral ingested is absorbed completely. This fact, which is essential to the test’s interpretation of iodine status, has never been proven. The clinical utility of the test is questionable, and validating its accuracy in assessing iodine status would serve as a good starting point for practitioners interested in monitoring iodine status.
The arguments for or against the use of high-dose iodine/iodide are, to an extent, a moot point. Ultimately, the risks of high-dose iodine/iodide are real, whether common or rare. The benefits, however, are less well defined at least in modern medical literature. Without objective clinical data on the risk versus benefit of high-dose iodine/iodide, clinicians use such therapies with a better-defined risk to themselves than to their patients.
Other Medical Uses of Iodine
It should be noted that iodine has been manufactured in various forms throughout the 19th and 20th centuries for treatment of everything from goiter to syphilis. Today, its uses are limited to a few known medical applications.
Iodine’s antiseptic properties were quickly noticed after its identification in the 19th century. Specifically iodine, not iodide, has antiseptic properties. Tincture of iodine and Povidine-iodine (Betadine) are still widely used as topical antiseptics on the skin.
Another use of iodine today is as water purification. Water purification tablets containing iodide compounds are sold for use when traveling to areas with unsafe or unknown water purity. Backpackers drinking from streams and travelers to countries with questionable drinking water are advised to use such products.
KI, as super-saturated potassium iodide (SSKI) is recommended for fallout from nuclear disaster.66 [sup] A nuclear disaster can release radioactive iodine isotopes such as I137. SSKI has been shown to mitigate the toxic accumulation of I137 and lessen the ensuing risk of thyroid cancer. The dosage recommended by the CDC is 130 mg in a single dose for adults within the fallout area.
The use of iodine in breast health is also gaining evidence for use. The ideal form and dose of iodine is not established, but there is considerable evidence that iodine is a necessary element for mitigating fibrocystic disease and perhaps preventing breast cancer development.67,68,69,70
Complementary Nutrients to Iodine
Selenium is a cofactor for deiodinases, the enzymes used to convert thyroxine to the active triiodothyronine intracellularly. Therefore, selenium deficiency may exacerbate the hypothyroid state in areas of marginal iodine status.71 Deficiencies of vitamin A as well as iron have also been suggested to potentiate the adverse effects of iodine deficiency.72
In the context of discussions on diet and micronutrient intake, physicians should counsel patients on optimal iodine intake. Along with iodized salt, consuming a variety of fruits, vegetables, meats, seafoods, and grains can provide an adequate amount of iodine. Current recommendations for iodine intake include a safe upper limit of 1 mg total daily for adults. Deficiencies in the United States are rare, but iodine status is marginal in women in their 40s and pregnant women. In keeping with the recommendation of the American Thyroid Association, the recommended supplementation for pregnant and lactating women is 150 mcg/day.73