Geraldo Medeiros-Neto and Meyer Knobel

Iodine Supply

Iodine is found in relative abundance in marine plants and animals, in the thyroid gland of vertebrates, in deposits of organic origin, in certain natural mineral water, in sedimentary phosphate rock, and in association with certain mineral deposits. Most of the iodine ingested by humans comes from food of animal and plant origin. This iodine, in turn, is derived from the soil. Only a relatively small fraction is derived from drinking water. A most important factor in the depletion of iodine has been glaciation, which removes old soil and scrapes bare the virgin rocks, which have iodine concentrations far lower than those of the covering soil. This situation is found in regions that remained longest under Quaternary glaciers and lost their iodine when the ice thawed.⁵

Optimal Iodine Intake

Iodine is an essential component of the thyroid hormones thyroxine (T₄) and triiodothyronine (T₃) and contributes 65% and 59% of their respective molecular weights. To meet the demand for adequate hormone, the thyroid has developed an elaborate mechanism for concentrating iodine from the circulation and converting it into hormone, which it then stores and releases into the circulation as needed. The recommended intake of iodine is at least 90 µg/day for children aged 0 to 5 years, 120 µg/day for children aged 6 to 10 years, 150 µg/day for adolescents older than 12 years and adults, and 250 µg/day for pregnant or lactating women.1,6 About 90% of iodine is eventually excreted in urine. The median urinary iodine concentration in casual samples, expressed as micrograms per liter or deciliter, is currently the most practical biochemical laboratory marker of community iodine nutrition.⁷ Recommendations by the International Council for the Control of Iodine Deficiency Disorders, the World Health Organization, and the United Nations International Children’s Emergency Fund set 100 µg/L as the minimal urinary iodine concentration for iodine sufficiency.⁶ Daily iodine intake for population estimates can be extrapolated from urinary iodine concentration using estimates of mean 24-hour urine volume and assuming an average iodine bioavailability of 92% using the formula: urinary iodine (µg/L) × 0.0235 × body weight (kg) = daily iodine intake.^8,9 This figure roughly corresponds to a daily intake of 150 µg iodine. A report on iodine nutrition in the United States indicated adequate iodine intake for the overall U.S. population,¹⁰ but the median concentration decreased more than 50% between 1971 and 1974 (320 ± 6.0 µg/L) and 1988 and 1994 (145 ± 3.0 µg/L). Low urinary iodine concentrations (50 µg/L) were found in 11.7% of the 1988-1994 population, a 4.5-fold increase over the proportion in the 1971-1974 study. Possible reasons for this decline included changes in national food consumption patterns (lower salt intake) and food industry practices. A more recent evaluation found a median urine iodine of 153 µg/L (men) and 124 µg/L (women) and did not vary with increasing age, indicating that the U.S. adult population is iodine sufficient.¹¹

Prevalence

It is much easier to list the iodine-sufficient countries than those with different degrees of iodine deficiency. In the beginning of the 1990s, it was estimated that 29% of the global population lived in areas of iodine deficiency. Historically, the occurrence of thyroid disease in Europe has been dominated by iodine deficiency with some geographical variation. Severe iodine deficiency with endemic cretinism and goiter in the major part of the population was primarily found in the Alps and in other mountainous regions, but milder forms of iodine deficiency were present in regions of nearly every European country. As reviewed previously by Delange,²⁰ iodine deficiency has been eradicated in some European countries for many years, but other countries have lagged behind, especially in prevention of mild to moderate iodine deficiency. Owing to keen efforts by dedicated, hard-working people, the situation has improved in recent years. The number of European countries affected by iodine deficiency is steadily decreasing, and the efforts and results in the fight to prevent and control iodine deficiency have markedly progressed. During the 10 years between 1994 and 2004, the number of European countries which were considered iodine sufficient went from only 5 to 21.²¹

In 2007, WHO estimated that nearly 2 billion individuals had an insufficient intake of iodine, including a third of all school-aged children (Table 17-2).²² The lowest prevalence of iodine deficiency is in the Americas (10.6%), where the proportion of households consuming iodized salt is the highest in the world (about 90%). The highest prevalence of iodine deficiency is in Europe (52%), where the household coverage with iodized salt is the lowest (about 25%), and many countries have weak or nonexistent control programs for iodine-deficiency disorders.

Iodine deficiency remains a public health problem in 47 countries (Fig. 17-1). However, progress has been made since 2003; 12 countries have progressed to optimum iodine status, and the percentage of school-aged children at risk of iodine deficiency has decreased by 5%.⁵ However, iodine intake is more than adequate or even excessive in 34 countries, increased from 27 in 2003. In Australia and the United States, two countries that were previously iodine sufficient, iodine intake is falling. Australia is now mildly iodine deficient, and in the United States, the median urinary iodine is 145 µg/L, as mentioned, which is still adequate but half the median value of 311 µg/L noted in 1970. These changes emphasize the importance of regular monitoring of iodine status in countries to detect both low and excessive intakes of iodine.

Recent reports on goiter and iodine deficiency in Europe²⁰ have indicated, however, that goiter persists in adults (but is seldom seen in children) in Bulgaria, Czechoslovakia, the Netherlands, Belgium, and Switzerland.²¹ According to a relatively recent study, the iodine status of the Swiss population is currently adequate.²³ Substantial areas of high goiter prevalence persist in Austria, Hungary, Romania, Poland, the constituent countries of the former Yugoslavia (Slovenia, Croatia, Bosnia and Herzegovina, Macedonia, Serbia, Montenegro), and western Russia. In other countries (southwestern Germany, Greece, Italy, Portugal, Spain, and Turkey), iodine prophylaxis is not mandatory, and goiter and even endemic cretinism continue to be major problems, either nationally or regionally (goiter prevalence rates of 18% to 22%).

Iodine deficiency has been a public health problem in most Latin American countries. Iodine status has been reassessed over the last 15 years, and programs have been implemented for the control of IDD. Great progress has been made, particularly in the aggressive push for iodized salt use. But problems remain, such as weak governmental support and lack of effective monitoring of salt iodization in some countries, threatening the effective and sustained elimination of IDD in the region. Data on the present situation, however, are incomplete because regular monitoring is carried out in only a few countries. Moreover, different methods were used to measure iodine in urine and salt, and goiter was evaluated only by palpation. Using the ThyroMobil model, which has proven to be a convenient and efficient model for standardized and rapid evaluation for urinary iodine and goiter prevalence in Europe, 163 sites in 13 countries were visited to assess randomly selected schoolchildren of both genders, 6 to 12 years of age. The median urinary iodine concentration (8208 samples) varied from 72 to 540 µg/L. The Guatemala median was below the recommended range of 100 to 200 µg/L; Bolivia, Nicaragua, El Salvador, Mexico, and Argentina were at 100 to 200 µg/L; and Peru, Honduras, Paraguay, Venezuela, Brazil, Ecuador, and Chile were higher than 200 µg/L, including three (Brazil, Ecuador, Chile) greater than 300 µg/L. Urinary iodine concentration correlated with the iodine content of salt in all countries. Median values of thyroid volume were within the normal range for age in all countries, but the goiter prevalence varied markedly from 3.1% in Bolivia to 25.0% in Nicaragua because of scatter.24,25

In the sub-Himalayan area of Pakistan, the overall prevalence of goiter is 39.7%, and endemic cretinism is common.²⁶ In India, despite intensive efforts to promote iodized salt, only about half the population is covered, and coverage is especially poor in low socioeconomic populations. Iodized salt is unavailable in many rural markets, or salt sold as iodized is poorly or incompletely iodized or both.²⁷ The Himalayas of India, Nepal, Bhutan, and southern China, as well as the mountains extending into northern Burma, Thailand, Laos, and Vietnam, have long been known as goitrous areas.

It is estimated that 30 million Chinese have goiter, and possibly 200,000 suffer from the consequences of endemic cretinism.²⁸ Accordingly, new cases of cretinism have been recently detected in isolated regions of Western China.²⁹ An intensive program of salt iodination and administration of iodized oil (orally and intramuscularly), however, has reduced the prevalence of goiter and iodine deficiency in China. A 1995 national survey among children aged 8 to 12 years showed a total goiter rate of 20.4%. A 1997 national survey of children in the same age group reported a total goiter rate of 10.9% and a median urinary iodine level of 300.2 µg/L. According to the surveillance results of 2002, the coverage of iodized salt had reached 95.2%, and the coverage of qualified iodized salt had reached 88.8%. With the implementation of the new standards for edible salt, the quality of iodized salt improved, and in 2002, the median urinary iodine among children 8 to 10 years of age was 241.2 µg/L. Furthermore, the study confirmed that the goiter rate among children in the 8-to-10 age group was continuing to decline over time, from 20.4% in 1995 down to 5.8% by 2002, so IDD can presently be considered as extensively eliminated in this country³⁰ The Philippines and Indonesia are severely iodine deficient.³¹ Worse conditions persist in the remote regions of African countries.³² In sub-Saharan Africa, 64% of households use iodized salt, but coverage varies widely from country to country.³³ In countries such as Sudan, Mauritania, Guinea-Bissau, and the Gambia, coverage is less than 10%, whereas in Burundi, Kenya, Nigeria, Tunisia, Uganda, and Zimbabwe, it is more than 90%. Further, iodine status varies from iodine deficiency in countries such as Ethiopia, Sierra Leone, and Angola to iodine excess in Democratic Republic of the Congo, Uganda, and Kenya.^34,35 However, many countries have outstanding programs—Nigeria, for example, which has been recognized as the first African country to successfully eliminate iodine deficiency.³⁶ In South Africa, coverage of adequately iodized household salt (i.e., iodized at >15 mg/kg) was 62.4% of households 2 years after the introduction of compulsory iodization at a level of 40 to 60 mg/kg. A total of 7.3% of households used noniodized agricultural salt and salt obtained directly from producers. The iodine concentration in salt was lower in rural areas than in urban and periurban areas. The consequences of using underiodized or noniodized salt were most likely to be experienced in the country’s three northern provinces, among people in the low socioeconomic categories, and in rural households³⁷ (Fig. 17-2).

As assessed by measurements of urinary iodine, many countries have achieved the elimination of iodine deficiency—for example, Algeria, Kenya, Cameroon, Tanzania (Africa); Iran, Lebanon, Tunisia (Eastern Mediterranean); Bhutan, China, Indonesia, India, Thailand (Asia); Venezuela, Peru, Ecuador (Latin America); and Switzerland, Austria, Great Britain, Finland, Norway, Sweden, Poland, Macedonia, Croatia, the Czech Republic, Slovakia, and Bulgaria in Europe.⁵ However, in spite of the tremendous improvement of the implementation of programs of iodized salt, 35.2% of the general population in the world still had a urinary iodine below 100 µg per liter in 2003,²² and the percentage of the world population affected by goiter did not appreciably change between 1990 (12%)⁴⁰ and 1999 (13%).⁴¹

Etiology

Absolute and chronic iodine deficiency is the main cause of endemic goiter and allied disorders. It is entirely possible that in certain limited situations other etiologic factors such as genetic predisposition in highly inbred and isolated groups and the presence of effective goitrogens in unusual dietary situations (Table 17-3). The arguments supporting iodine deficiency as the cause of endemic goiter are: (1) an association between low iodine content in the food and water and the appearance of the disease in the population; (2) a reduction in goiter incidence that occurs when iodine is added to the diet; and (3) demonstration that the metabolism of iodine and thyroid changes in patients with endemic goiter are similar to those produced in animals subjected to a low-iodine diet.

Natural goitrogens (see Table 17-3) may be considered significant determinants of the prevalence of endemic goiter, either in iodine-deficient areas or in localities where iodine intake is abundant, as in the coal-rich Appalachian area of eastern Kentucky.⁴² Goitrogenic effects may be related to the consumption of certain foodstuffs (cassava, millet, babassu coconut, piñon, vegetables from the genus Brassica, and soybean).⁴⁴ The goitrogenic factor in cassava is related to the hydrocyanic acid liberated from the cyanogenetic glucoside (linamarin) and endogenously changed to thiocyanate, which competitively inhibits trapping and promotes the efflux of intrathyroidal iodine.⁴³ Pearl millet is one of the most important food crops in the semiarid tropics (large portions of Africa and Asia). Millet porridge is rich in C-glucosylflavones and also contains thiocyanate. Both are additive in their antithyroid effects. In Darfur province of western Sudan, the goiter prevalence in schoolchildren was linked to the level of consumption of millet.⁴⁴ Babassu coconut is largely consumed in northern Brazil, and studies have demonstrated the possible presence of flavonoids in the edible part of the nut.⁴⁵ Thus in areas where millet and babassu coconut are a major component of the diet, their ingestion may contribute to the genesis of goiter. Furthermore, flavonoids, besides being potent inhibitors of thyroid peroxidase, also interact with thyroid hormone at the peripheral level.⁴⁶ Turnips, like cabbage, cauliflower, and broccoli, contain glucosinolates whose metabolites compete with iodine for thyroidal uptake.⁴⁴ Soy-containing foods and dietary supplements are widely consumed for putative health benefits (e.g., cancer chemoprevention, beneficial effects on serum lipids associated with cardiovascular health, reduction of osteoporosis, relief of menopausal symptoms), but studies of soy isoflavones in experimental animals suggest possible adverse effects as well, like enhancement of reproductive organ cancer, modulation of endocrine function, and antithyroid effects (due to flavonoids which impair thyroid peroxidase activity).⁴⁷ Antithyroid effects may also be extended by increasing the loss of T₄ from the blood via bile into the gut and may cause goiter when iodine intake is limited.⁴⁸

Excess consumption of iodine-rich kelp (dry seaweed, 80 to 200 mg iodine per day) has caused sporadic and even endemic goiter in humans. In this case, goiter is common in some families and more frequent in girls at puberty, which suggests possible influences of additional genetic and hormonal factors. The organification of iodine and, consequently, the synthesis of T₄ and T₃ were lower than normal, and iodine-rich colloid goiter was observed in patients from the goiter-endemic coast of Hokkaido, Japan, after thyroidectomy.⁴⁹

Generalized malnutrition (protein-calorie deprivation) has been recognized as an additive factor in the prevalence of endemic goiter in afflicted populations. On the basis of epidemiologic data recorded in 5- to 14-year-old South African children, it was recently shown that vitamin A supplements are effective in treating vitamin A deficiency in areas of mild ID. It also has an additional benefit: through suppression of the pituitary TSHβ gene, vitamin A supplements can decrease TSH thyroid hyperstimulation and thereby reduce the risk of goiter.⁵⁰ Vitamin A deficiency was also reported to impair thyroglobulin (TG) synthesis and thyroidal iodine uptake.⁵¹

Another stimulator of follicular cell growth that acts synergistically with endogenous TSH is the anti-GAL antibody.⁵² This human polyclonal antibody was found to mimic the in vitro TSH effects of stimulation of cyclic adenosine monophosphate synthesis, ¹²⁵I uptake, and cellular proliferation of cultured porcine thyrocytes. Anti-GAL antibodies were found to be higher in goitrous individuals and positively correlated with the size of goiter. Whether these antibodies contribute to the pathogenesis of the disease needs further clarification.

Besides iodine, several minerals and trace elements such as iron, selenium, and zinc are essential for normal thyroid hormone metabolism. Iron deficiency impairs thyroid hormone synthesis by reducing activity of heme-dependent thyroid peroxidase. Iron-deficiency anemia blunts and iron supplementation improves the efficacy of iodine supplementation.⁵³ In several regions of the world, people are exposed to inadequate selenium supply because the selenium content of surface soil has been depleted by erosion and glacial washout, similar to iodine. In spite of that, it was shown that selenium did not significantly influence thyroid volume in borderline iodine sufficiency, because the iodine status was most likely the more important determinant.⁵⁴

Zinc status also affects thyroid function. Research established a relationship between zinc deficiency and thyroid hormone levels. Zinc is required for the proper function of 1,5′-deiodinase, the enzyme required for the conversion of thyroxine to triiodothyronine.⁵⁵ In animal studies, severely zinc-deficient rats had flattened epithelial cells, colloid accumulation, and lower T₃ concentration; marked alterations of follicle cellular architecture, including signs of apoptosis, were found.⁵⁶ In a zinc deletion–repletion study carried out in humans, TSH, total T₄, and free T₄ tended to decrease during the depletion phase and returned to control levels after zinc repletion.⁵⁷

In addition to the aforementioned natural goitrogens, exposure to environmental chemicals may have deleterious thyroid-system effects in humans during development, especially in the nervous system, and also may adversely impact thyroid hormone metabolism (Table 17-4). The effects of some chemicals may be profound: the antithyroperoxidase (anti-TPO) activity of resorcinol is 26 times the activity of propylthiouracil. Many halogenated compounds compete with natural hormones for binding to protein carriers (transthyretin and to a lesser degree thyroxine-binding globulin), although the clinical consequences are unclear. Polychlorinated biphenyls (PCBs) may have a possible effect on thyroid hormone–regulated genes.⁵⁸ Disulfides from coal processes⁴⁴ and from sedimentary rock drained by water into deep wells are believed to be the cause of the incomplete reduction of endemic goiter after the use of iodized salt in Colombia.⁵⁹ Perchlorate is a competitive inhibitor of the sodium/iodine symporter, decreasing the active transport of iodine into the thyroid. There has been concern that naturally occurring perchlorate and industrial contamination of water supplies with perchlorate might pose a health hazard by inducing or aggravating underlying thyroid dysfunction. So far, available evidence has demonstrated that long-term, large but intermittent exposure to perchlorate does not adversely affect thyroid function, despite a lowering of the thyroid radioactive iodide uptake (RAIU).⁶⁰ Tobacco smoking is a major source of thiocyanate in humans, which inhibits the function of the iodide transporter in the lactating mammary gland. Smoking during the period of breastfeeding dose-dependently reduces breast milk iodine content to about half and, consequently, exposes the infant to increased risk of iodine deficiency.⁶¹ In brief, it seems that most goitrogens do not have a major clinical effect unless there is coexisting iodine deficiency.

Pathophysiology

Goiter was regarded as an obligatory response to prolonged and severe iodine deficiency, and an increase in thyroid iodine clearance was shown to be the basic mechanism of iodine conservation (for a review of iodine deficiency disorders, see ref. 63). Subsequently, a shift in thyroid hormone synthesis in favor of T₃ indicated an additional mechanism. These concepts have improved our understanding of how humans cope with low iodine intake, as well as the effects that both lack of iodine and adaptation mechanisms have on thyroid physiology. Thus, adaptation to iodine deficiency involves a number of biochemical and physiologic adjustments that ultimately result in maintenance of the intracellular concentration of T₃ within normal limits. These mechanisms are listed in Table 17-5.