Iodine Deficiency Disorders

Published on 03/04/2015 by admin

Filed under Endocrinology, Diabetes and Metabolism

Last modified 03/04/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 3720 times

Chapter 17

Iodine Deficiency Disorders

Iodine deficiency is the world’s most common endocrine problem, the easiest of the major nutritional deficiencies to correct, and the most preventable cause of mental retardation in many underdeveloped countries.1,2 Given these facts, it is remarkable that iodine deficiency continues to be a major public health problem. It is best known for causing endemic goiter, but its manifestations and consequences reach much deeper into human pathology (Table 17-1). Goiter, although frequently the most obvious feature, is much less important than the adverse effects of iodine deficiency on normal development, particularly normal development of the brain.3,4 To emphasize the more severe consequences, this health problem is now described as iodine deficiency disorders (IDD) instead of endemic goiter.

Table 17-1

Spectrum of Iodine Deficiency Disorders




Congenital anomalies

Increased perinatal mortality

Neurologic cretinism: mental deficiency, deaf-mutism, spastic diplegia, deafness

Myxedematous cretinism: dwarfism, mental deficiency, epiphyseal dysplasia

Psychomotor defects


Neonatal goiter

Neonatal hypothyroidism

Child and Adolescent

Goitrous juvenile hypothyroidism

Impaired mental function

Retarded physical development


Goiter with its complications


Impaired mental function

Iodine-induced hyperthyroidism

Spontaneous hyperthyroidism in the elderly

Adapted from Hetzel BS, Dunn JT, Stanbury JB (eds): The Prevention and Control of Iodine Deficiency Disorders. Amsterdam: Elsevier, 1987.

For many years, it has been recognized that a close and inverse relationship usually, if not always, exists between iodine in the soil and water and the appearance of endemic goiter and allied diseases. Nevertheless, it cannot be said as of this writing that the cause of iodine deficiency disorders has been completely determined in all cases, or even in any case, because nutritional, constitutional, genetic, or immunologic factors may be additive in the sum total of causes that lead to the appearance of these diseases. Therefore, iodine deficiency is a necessary cause, although it may not always be a sufficient cause. The role of iodine deficiency as the main etiologic factor in endemic goiter and cretinism has been extensively confirmed by the success of iodine prophylaxis programs in several countries, although iodine deficiency has persisted despite readily available means of supplementation, such as iodized salt and iodized oil.1

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

Iodine Nutrition During Pregnancy and Lactation

Iodine is particularly critical for pregnant women.6 During pregnancy, several physiologic changes take place in maternal thyroid economy which together lead to an increase in thyroid hormone production of approximately 50% above the preconception baseline hormone production. To achieve the necessary increment in thyroid hormone production, the iodine intake needs to be increased during early pregnancy.2 Also early in pregnancy, there is an increase in renal glomerular filtration leading to increased plasma iodide clearance. Women should have an adequate iodine intake, corresponding to 150 µg/day, to ensure that intrathyroidal iodine stores are replenished before they became pregnant. A recent guideline12 reached the consensus that iodine nutrition during pregnancy and breastfeeding should range between 200 and 300 µg/day, with an average of 250 µg/day. The prevalence of postpartum thyroiditis does not seem to be related to the iodine intake status of a population.13 Accordingly in a case-control study,14 there was a difference in iodine excretion in the immediate postpartum period between 73 women who developed postpartum thyroiditis and 135 women who did not. With regard to the effect of changes in iodine intake on the occurrence of postpartum thyroiditis, the data are conflicting. On the one hand, there are data indicating that increased iodine intake can influence the severity of thyroid dysfunction in postpartum thyroiditis. In Sweden, an iodine-sufficient area, 20 women who were thyroid peroxidase (TPO) positive in early pregnancy were treated with iodine (0.15 mg/d) for 40 weeks postpartum. In those women who developed thyroid dysfunction, thyroid-stimulating hormone (TSH) levels were higher, and T4 levels were lower, compared with the group who received no medication.15 On the other hand, in Denmark, in an area with mild to moderate iodine insufficiency, a placebo-controlled, randomized, double-blind trial was accomplished to verify the impact of iodine supplementation (0.15 mg/d) during pregnancy and the postpartum period in 72 TPO antibody–positive women.16,17 It was concluded that iodine supplementation did not induce or worsen postpartum thyroiditis.17

The most reasonable conclusion is that there is no proven further benefit in providing pregnant women with more than 300 µg/day. In most countries with a well-established salt iodination program, pregnancies are not at risk of having iodine deficiency. In case of situations in which ingestion of iodized salt should be restricted, preparations of potassium iodide may be used as oral supplements associated or not to multivitamin tablets. In areas with no iodide supplementation and difficult socioeconomic conditions, it is recommended to administer orally iodized oil as early in gestation as possible (400 mg of iodine given orally will cover thyroid needs for 1 year). The best single parameter to evaluate the adequacy of iodine nutrition is urine iodine, which should range between 150 and 250 µg/L. These values may vary during pregnancy,18 and iodine supplementation may be needed in late pregnancy. Accordingly, it was shown that prolonged iodized salt significantly improves maternal thyroid economy and reduces the risk of maternal thyroid insufficiency during gestation, probably because of nearly restoring intrathyroidal iodine stores.19

With regard to iodine nutrition during breastfeeding, thyroid hormone production and urinary iodine excretion return to normal, but iodine is efficiently concentrated by the mammary gland. Since breast milk provides approximately 100 µg/day of iodine to the infant, it is recommended that the breastfeeding mother should continue to take 250 µg per day of iodine.6


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.

Table 17-2

Proportion of Population and Number of Individuals in the General Population (All Age Groups) With Insufficient Iodine Intake*


*By WHO regions during the period between 1994 and 2006 and proportion of households using iodized salt.

Adapted from WHO/ICCIDD/UNICEF: Assessment of the Iodine Deficiency Disorders and Monitoring Their Elimination, 3rd edition. Geneva: WHO, 2007; and Zimmermann MB, Jooste PL, Pandav CS: Iodine-deficiency disorders. Lancet 372:1251–1262, 2008.

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


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.

Table 17-3

Natural Goitrogens Associated With Endemic Goiter

Goitrogens Agent Action
Millet, soy Flavonoids Impair thyroperoxidase activity
Cassava, sweet potato, sorghum Cyanogenic glucosides metabolized to thiocyanates Inhibit iodine thyroidal uptake
Babassu coconut, mandioca Flavonoids Inhibit thyroperoxidase
Cruciferous vegetables: cabbage, cauliflower, broccoli, turnips Glucosinolates Impair iodine thyroidal uptake
Seaweed (kelp) Iodine excess Inhibits release of thyroidal hormones
Malnutrition Vitamin A deficiency Increases TSH stimulation
  Iron deficiency Reduces heme-dependent thyroperoxidase thyroidal activity
  Selenium deficiency Accumulates peroxides and causes deiodinase deficiency; impairs thyroid hormone synthesis

Adapted from Zimmermann MB, Jooste PL, Pandav CS: Iodine-deficiency disorders, Lancet 372:1251–1262, 2008.

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.


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.

Table 17-5

Mechanisms Involved in the Adaptation to Iodine Deficiency

Increased thyroid clearance of plasma inorganic iodine

Hyperplasia of the thyroid and morphologic abnormalities

Changes in iodine stores and thyroglobulin synthesis

Modifications of the iodoamino acid content of the gland

Enrichment of thyroid secretion in T3

Enhanced peripheral conversion of T4 to T3 in some tissues

Increased thyroid-stimulating hormone production

T3, Triiodothyronine; T4, thyroxine.

Increase in Thyroid Clearance of Plasma Inorganic Iodine

An increase in thyroid clearance of plasma inorganic iodine is the fundamental adaptive mechanism by which the thyroid gland maintains a constant concentration of accumulated iodine in the presence of chronic iodine deficiency. A clear inverse relationship between the plasma inorganic iodine concentration and thyroid clearance was found by several authors. The relationship is such that the product of thyroid clearance and iodine concentration is constant within the observed range of serum iodine concentrations. This product represents absolute iodine uptake, which is the mass of iodine available to the gland per unit of time. Despite the elevated clearance, absolute iodine uptake tends to be lower in iodine-deficient areas, thus indicating that the compensatory mechanism is neither perfect nor complete. An inability to fully compensate for the low plasma inorganic iodine with an appropriate increase in thyroid clearance probably accounts for the fall in iodine concentration in endemic goiter. The increased iodine trapping reflects TSH stimulation, as well as an intrinsic autoregulatory mechanism dependent on the intrathyroidal iodine concentration.

Hyperplasia of The Thyroid

Although thyroid clearance may be increased without a demonstrable goiter, the anatomic accompaniment of functional activity is an increase in gland mass. Another interesting point is that iodine-concentrating ability is not uniformly distributed among follicular cells, even in normal glands. A certain level of TSH-dependent, autonomous iodine trapping is a feature of normal thyroid follicles, and the generation of new follicles from mother cells with an inherently high capacity for iodine trapping could well explain the heterogeneity in iodine metabolism among the follicles of glands affected by endemic goiter.64 Partial autonomy of iodine trapping could also account for the persistently high uptake after the administration of iodine supplements. Deficiency of cytosolic superoxide dismutase in endemic goitrous tissue has been claimed to cause more prolonged exposure to oxygen free radicals and contribute to the degenerative changes found in these tissues.65

As long as adaptation to iodine is effective, increased thyroid volume may be considered as a mechanism to store iodine during periods of increased supply to provide for less favorable periods. However, this adaptive mechanism has its limits.66 The capacity to synthesize thyroid hormones is not proportional to the increase of volume, and particularly in voluminous goiter, the thyroid function becomes insufficient.

Changes in Iodine Stores and Thyroglobulin Synthesis

A constant finding reported in endemic goiter is a drastic reduction in iodine concentration, expressed in iodine per gram of tissue. The amount of organic iodine in a thyroid affected by endemic goiter may range from 1.0 to 2.5 mg, in contrast with values of 10 mg obtained in normal control glands. Concomitantly, thyroid iodine turns over much faster, as shown by an increase in the rate of release of 131I from the gland. The presence of two compartments of organic iodine in an iodine-deficient gland has been postulated: a slow- and a fast-releasing compartment, with different sizes. The fast-release pattern is seen in children and adolescents with small, diffuse goiters and is associated with a rapid rise in plasma-bound 131I. Most adult goitrous patients have a slow-release pattern, with normal or low protein-bound 131I and a prolonged biological half-life of thyroid 131I. Such observations suggest that intrathyroidal iodine in these longstanding multinodular glands is turning over at a subnormal rate. Slow secretion of the tracer is apparently due to dilution in a large endogenous pool of stable iodine, largely as monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are present to an excessive degree in the poorly iodinated TG.

Modification of The Iodoamino Acid Content of The Gland

Experimental studies in the rat show that thyroid hyperplasia induced by iodine deficiency is associated with an altered pattern of iodine distribution within the gland.67 An increase in labeled MIT and a decrease in the concentration of DIT, as well as a progressive increase in the ratio of T3 to T4, are the main changes in the thyroid gland occurring during prolonged iodine deficiency and are directly related to the degree of iodine depletion of the gland. These alterations caused by iodine deficiency appear to be associated with a structural change in TG. Experimental studies have shown a greater degree of heterogeneity in the TG molecule. Its altered sedimentation peak, significantly lower than 19 S, indicates failure of TG maturation. In large human goiters, as the concentration of iodine is reduced, the MIT/DIT ratio increases, and the fraction of tracer found in the form of T4 and T3 is markedly reduced. Possibly, many of the iodotyrosyl groups do not have the spatial configuration that favors the normal coupling process, and therefore only a small fraction of the iodine accumulated is actually incorporated into the normal pathway of hormone synthesis and secretion. A significant amount of iodine seems to be wasted by incorporation into iodocompounds that are clearly different from TG, that are resistant to hydrolysis, and that have a very long half-life and low molecular weight. These iodocompounds are at least in part fragments of TG.