Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

11E.Iodine Deficiency

François M. Delange

John T. Dunn*

*Deceased.

Iodine is a trace element present in the human body in minute amounts (15 to 25 mg), almost exclusively in the thyroid gland (1). It is an essential component of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3), comprising 65% and 59% of their respective weights. Thyroid hormones, in turn, regulate metabolic processes in most cells, and play a determining role in the process of early growth and development of most organs, especially the brain (2). In humans, most of the growth and development of the brain occur during fetal life and the first 2 to 3 postnatal years (3). Consequently, iodine deficiency, if severe enough to affect thyroid hormone synthesis during this critical period, will result in hypothyroidism and brain damage. The clinical consequence will be irreversible mental retardation (4).

The daily dietary intake of iodine recommended by the World Health Organization/International Council for Control of Iodine Deficiency Disorders/United Nations Emergency Children's Fund (WHO/ICCIDD/UNICEF) is 90 µg for age 0 to 59 months, 120 µg for age 6 to 12 years, 150 µg for adolescents and adults, and 200 µg during pregnancy and lactation (5). Fairly similar recommendations have been made by the Food and Nutrition Board of the U.S. National Academy of Sciences, but higher for pregnancy (220 µg) and lactation (290 µg). A recent summary of these and other national and international guidelines has been published (6)

When these physiologic requirements of iodine are not met in a given population, a series of functional and developmental consequences occur (Table 11E.1), including thyroid function abnormalities and, when iodine deficiency is severe, endemic goiter and cretinism (7,8), decreased fertility rate, and increased perinatal death and infant mortality (9). These complications, which hinder the development of the affected populations, are grouped under the general heading of iodine deficiency disorders (IDD) (10).

TABLE 11E.1. SPECTRUM OF IODINE DEFICIENCY DISORERS


Fetus

  Spontaneous abortions

  Stillibirths

  Congenital anomalies

  Increased perinatal and infant mortallity

  Endemic cretinism

Neonate

  Goiter

  Overt or subclinical hypothyroidism

  Cretinism

Infant/Child/Adolescent

  Goiter

  Subclinical or overt hypothyroidism

  Mental renardation

  Retarded physical development

  Increased susceptibility of the thyroid gland to nuclear radiation

Adult

  Goiter and its complications

  Hypothyroidism

  Endemic mental retardation

  Decreased fertility

  Spontaneous hyperthyoidism in the elderly

  Increased susceptibility of the thyroid to nuclear radiation


From Hetzel BS. Iodine deficiency disorders (IDD) and their eradication. Lancet 1983:ii:1126; Stanbury JB, Ermans AE, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998;8:83; and Laurberg P, Nohr SB, Pedersen KM, et al. Thyroid disorders in mild iodine deficiency. Thyroid 2000;10:951, with permission.

Broad geographic areas exist where the population's daily intake of iodine is below the recommended dietary allowance, and the population is affected by IDD (7,8,11). These areas frequently are mountainous because the soils lowest in iodine are those that were covered longest by quaternary glaciers. When these glaciers melted, most of the iodine leached out of the ground beneath (12). The most important goitrous areas in the world today include the Himalayas and the Andes, but iodine deficiency also occurs in lowlands far from the oceans, such as in the central parts of Africa, central Asia, and central and eastern Europe.

In 1999, IDD represented a significant public health problem for 2.225 billion people (38% of the world population) in 130 countries (Table 11E.2), and 740 million had a goiter (11). In 1994, 43 million were believed to be mentally handicapped as a result of iodine deficiency (13), which, therefore, is the most prevalent preventable cause of impaired intellectual development in the world. WHO and ICCIDD keep databases on the current global status of iodine nutrition, by country (13a,13b). In a recent tabulation 50% of the world's population were thought to live in countries with iodine deficiency (14). The true extent is not fully known, however, because many countries have inadequate monitoring systems.

TABLE 11E.2. POPULATIONS AFFECTED BY IODINE DEFICIENCY AND BY GOITER AS OF 1999


WHO Region

Population, Million

Population Affected by Iodine Deficiency, Million (%)

Population Affected by Goiter, Million (%)


Africa

612

295 (48.2)

124 (20.3)

Americas

788

196 (24.9)

39 (4.9)

Eastern Mediterranean

473

348 (73.6)

152 (32.7)

Europe

869

275 (31.6)

130 (15.0)

Southeast Asia

1,477

599 (40.6)

172 (11.6)

Western Pacific

1,639

513 (31.3)

124 (7.6)

Total

5, 858

2, 225 (38.4)

741 (12.6)


From WHO/UNICEF/ICCIDD. Progress towards the elimination of iodine deficiency disorders (IDD). Geneva: World Health Organization; 1999. Publication WHO/NHD/99.4, modified with permission.

From WHO/UNICEF/ICCIDD. Progress towards the elimination of iodine deficiency disorders(IDD). Geneva: World Health Organization;1999. Publication WHO/NHD/99.4, modified with permission.

Although the disorders that result from iodine deficiency are preventable by appropriate iodine delivery, they continue to occur because of various socioeconomic, cultural, and political limitations to adequate iodine supplementation (11).

The objective of this chapter is to review present knowledge about the thyroid disorders induced by iodine deficiency. Endemic cretinism and mental retardation are discussed in Chapter 49. As indicated in Table 3, three different degrees of severity of IDD have been considered: mild, moderate, and severe. Although the basic mechanisms of adaptation to iodine deficiency are similar among them, this discussion separates severe IDD complicated by cretinism, as seen typically in remote areas of developing countries, and mild to moderate IDD, as seen typically in Europe. Special emphasis is placed on the pediatric aspects of adaptation to iodine deficiency: neonates and young infants are the most important targets of iodine deficiency because it causes irreversible brain damage and mental retardation from thyroid failure during fetal and early postnatal life (see Chapter 49). Extensive reviews are available on endemic goiter, the disorders induced by iodine deficiency and its treatment (7,8,15,16,17,18,19,20,21,22), including its pediatric aspects (23,24).

TABLE 11E.3. CLASSIFICATION OF GOITER ENDEMIAS BY SEVERITY


Variables

Target Population

Mild Iodine Deficiency

Moderate Iodine Deficiency

Severe Iodine Deficiency


Median urinary iodine, µg/L

SAC

50–99.0

20–49.0

≥20.0

Prevalence of goiter, %(Grade>0)

SAC

5.0–19.9

20.0–29.9

≥30.0

Frequency of thyroid volume >97th percentile by ultra sound, %

SAC

5.0–19.9

20.0–29.9

≥30.0

Frequency of serum TSH >5m U/L whole blood, %

Newborns

3.0–19.9

20.0–39.9

≥40.0


SAC, school-aged children; Tsk, thyrotropin.

Adapted from WHO/UNICEF/ICCIDD. Assessment of the iodine deficiency disorders and monitoring their elimination. Geneva: World Health Organization; 2001. Publication WHO/NHD/01.1; and WHO/ UNICEF/ICCIDD. Indicators for assessing iodine deficiency disorders and their control through salt iodization. Geneva: World Health Organization; 1994. Publication WHO/NUT/94.6, with permission.

SEVERE IODINE DEFICIENCY DISORDERS

Epidemiology

The following definitions were proposed by WHO/UNICEF/ICCIDD for public health studies conducted in the field (5).

Goiter

A thyroid gland each of whose lobes has a volume greater than the terminal phalanx of the thumb of the person examined will be considered goitrous. Under this condition the thyroid is enlarged by a factor of at least 4 to 5.

The following simplified classification of goiter by palpation has been proposed:

Grade 0: No palpable or visible goiter.

Grade 1: A goiter that is palpable but not visible when the neck is in the normal position (i.e., the thyroid is not visibly enlarged). Nodules in a thyroid that is otherwise not enlarged fall into this category.

Grade 2: A swelling in the neck that is clearly visible when the neck is in a normal position and is consistent with an enlarged thyroid when the neck is palpated.

This clinical classification is still appropriate for field surveys in remote areas where no other methods are available. However, the use of transportable ultrasonographic equipment in field studies has shown that the clinical assessment of thyroid size is imprecise for small goiters, especially in young children. In these circumstances, misclassification between grades 0 and 1 can be as high as 40% (13,25,26,27), and, consequently, the goiter rate can be incorrect. Therefore, measurement of thyroid volume by ultrasonography is highly recommended (5), especially in endemic areas where the visible goiter rate is low. Results of ultrasonography from a study population should be compared with normative data. Values proposed by WHO/ICCIDD (28) on the basis of data collected in Europe (29) were overestimated by some 30% (30), but reliable new values have recently been obtained by an international team applying standardized methodology in six study areas on five continents with long-standing iodine sufficiency (31).

Endemic Goiter

An area is arbitrarily defined as an endemic goiter area if more than 5% of the children aged 6 to 12 years have a goiter. The figure 5% was chosen because a higher prevalence usually implies an environmental factor, while a prevalence of less than 5% is common even when all known environmental risk factors are absent.

Goiter endemics should be described not only by the frequency of goiter but also by the severity of iodine deficiency. Table 11E.3 shows recommendations for classification of goiter endemias based on public health surveys.

The present definitions are deliberately less severe and elaborate than those used in clinical endocrinology, to avoid overestimation of severity and to facilitate comparison of results obtained in different parts of the world by health workers who are not necessarily endocrinologists.

In epidemiologic surveys, the most rigorous method for evaluating the prevalence of goiter is to examine the entire population in a likely area. This is often difficult to organize, especially in urban areas. Many surveys are limited, therefore, to particular age groups, most typically children in school (11).

Goiter prevalence is critically influenced by age and sex (Fig. 11E.1). In severe endemias, goiter appears very early. Its prevalence increases sharply and peaks during puberty and child-bearing years. From the age of 10 years onward, the prevalence is higher in girls than in boys. In both sexes, it decreases during adulthood, but more sharply in men than in women.

FIGURE 11E.1. Pattern of goiter prevalence in relation to age and sex in the inhabitants of Idjwi Island endemic goiter area, Democratic Republic of Congo. (From Delange F. Endemic goitre and thyroid function in Central Africa. Monographs in pediatrics. Basel: S. Karger AG, 1974:1, modified with permission.)

Etiology

Iodine Deficiency

Low dietary iodine intake is the main factor responsible for the development of endemic goiter (5,7,8,18,19,20,21,22,32,33). When iodine supplementation is introduced in an endemic area, the goiter incidence always declines markedly. The long-term persistence of a significant goiter prevalence in spite of correction of iodine deficiency suggests the additional role of a naturally occurring goitrogen (34).

Goiter develops in iodine-deficient environments among populations that consume locally grown foods. The iodine content of most foodstuffs is low; the highest being found in sea fish and shellfish and, to a lesser extent, in milk, eggs, and meat, depending on the diet of the livestock and poultry (35). Fruits and vegetables usually have a very low iodine content. The iodine content of foodstuffs varies greatly, depending on country, season, and method of cooking. The iodine content of drinking water is too low to serve as a consistent contributor.

A rigorous assessment of food iodine content is extremely difficult, for methodological reasons. Iodine balance studies have shown that adults are in equilibrium with their iodine environment and that the fecal excretion of iodine is usually negligible (5 µg/day) (35). Therefore, most estimates of dietary iodine intake are based on measurements of iodine excretion in urine. In nonendemic areas, the daily urinary excretion of iodine is at least 100 µg (5). In endemic areas it is usually much lower and varies from 75 to 3 µg/day (see reviews in references 6,7,18,19,20,21,22,33). Complete 24-hour collection of urine is often difficult in field investigations. An alternative procedure is measuring the ratio between the concentrations of iodine and creatinine in casual urine samples (36,37) or even the concentration of iodine alone, provided that the observation covers at least 50 to 100 randomly selected samples (5,38).

The etiologic role of iodine deficiency in endemic goiter also has been confirmed by an enormous amount of experimental work in animals (39,40). In several regions, it has been possible to demonstrate geographic superimpostion of human endemic goiter and enzootic goiter (33,39,41).

The correction of iodine deficiency usually is followed by the disappearance of endemic goiter (see treatment and prophylaxis).

Other Goitrogenic Factors

Iodine deficiency is not the sole cause of endemic goiter. Indeed, the disease has been found in regions where there is no iodine deficiency (42,43) or even where iodine excess is present (44,45,46). Conversely, some other regions with extremely severe iodine deficiency are free of endemic goiter (34,47,48,49). These data strongly suggest that goitrogenic factors in the diet or environment, other than iodine deficiency, can play a critical role in the etiology of the disease (34,50,51,52,53,54,55). Table 11E.4 summarizes data from goiter endemias where such environmental goitrogenic factors have been demonstrated.

TABLE 11E.4. GOITER ENDEMIAS ATTRIBUTED TO GOITROGENS IN FOOD AND TO CHEMICAL AND BACERIAL POLLUTION OF THE WATER-EXPOSURE PATHWAY


Locality

Source

Vehicle

Active Ingredient


Europe

    Finland

Grass, weeds

Milk

L-5-Vinyl-2-thiooxazolidone (goitrin)

  England (Sheffield area)

Grass

Milk

(?)

  Spain (Navarro)

Grass

Milk

Thiocyanate

  Spain (Availa)

Walnuts

 (?)

  Ex-Czecoslovakia (Bohemia-Moravia)

Grass (Brassicae)

Milk

Goitrin

  Ex-Yugoslavia (Krk island)

Grass (Brassiae)

Milk

Goitrin

  Greece

Escherichia coli

Water

Throid antibodies (?)

North America

   West Virginia

Escherichia coli

Water

(?)

  Eastern Kentucky

Coals and gramnegative bacteria

Water

Phenolic and phtalate ester derivatives (?)

South America

   Colombia

Shales and coals, humic substances, and gram-negative bacteria

Water

Resorcinol, phtalate ester derivatives, and disulfides

  Venezuela

Various rocks and soils

Water

Lithium

  Chile

Pinon nuts

(?)

  Brazil

Palm tree fruit (Babassu)

 Phenolic derivatives (?)

Africa

   Nigeria

Cassva

 Thionamide-like goitrogen

  Zaire

Cassava

 Cyanogenic glucoside (llinamarin→thiocnate)

  Sudan

Millet

Flavonoids and thiocyanate

Asia

   Lebanon

Onions, garlic

 (?)

  Japan

Seaweeds

 Iodide and polyhydroxyphenols (?)

  Malaysia

Cassava

 Linamarin→thiocyanate

  China

Seaweeds

Iodide

Oceania

   Tasmania

Grass, weeds

 Isothiocyanate (cheilorine)


?, active ingredient not known.

Data from Gaitan E. Environmental goitrogenesis. Boca Raton: CRC Press, 1989:1–250; and Delange F, Ermans AM. Endemic goiter and cretinism. Naturally occurring goitrogens. Pharmacol Ther 1976;1:57–93.

Natural goitrogens were first found in vegetables of the genus Brassica (53) (of the Cruciferae family) that cause goiter in animals. Their antithyroid action is related to the presence of thioglucosides, which, after digestion, release thiocyanate and isothiocyanate (52,56,57). A particular thioglucoside, goitrin (L-5-vinyl-2 thiooxazolidone), is present in certain Cruciferae growing as weeds in pastures in Finland and Tasmania (42,57). Goitrin has potent thionamide-like properties (52). It can probably reach humans by ingestion of milk (53,58).

Another important group of naturally occurring goitrogens is the cyanoglucosides, which have been found in several staples (cassava, maize, bamboo shoots, sweet potatoes, lima beans) (47,35,54,57). After ingestion, they release cyanide, which is detoxified by conversion to thiocyanate, a powerful goitrogenic agent that acts acutely by inhibiting thyroid iodide transport and, at higher doses, competes with iodide in the organification process (59,60,61).

Cassava (manioc), one of the basic foodstuffs in tropical areas, has definite goitrogenic properties in rats (59,62). Its role in the etiology of endemic goiter, in association with iodine deficiency, has been clearly demonstrated in Africa (50,51,63,64), and confirmed in Malaysia (65) and Brazil (66). The chronic consumption of poorly detoxified cassava in these areas induces a marked increase in the serum concentration of thiocyanate which, in association with iodine deficiency, impairs thyroid function, characterized by low serum T4 and high thyrotropin (TSH) concentrations, and produces goiter (64). Improved detoxification of cassava results in normalization of serum thiocyanate and of thyroid function (67).

The determining factor in the goitrogenic action of cassava is the balance between the dietary supplies of iodine and of thiocyanate. Goiter develops when the urinary iodine/thiocyanate ratio, used as an index of this balance, decreases below a critical threshold of about 3 µg iodine per mg thiocyanate (51). This can occur when thiocyanate is excessive in overt iodine deficiency, or even with an almost normal iodine supply when the thiocyanate overload is very high (68). Experimentally, acute thiocyanate overload inhibits thyroidal uptake of iodine-131 (131I), but chronic administration of cassava or of small doses of thiocyanate in iodine-deficient rats does not decrease thyroidal uptake of 131I in spite of high concentrations of thiocyanate. A marked inhibition of thyroidal iodide uptake may be detected, however, in the same animals if iodine organification is blocked by propylthiouracil (59). These findings agree with previous observations that a moderate increase in the thiocyanate concentration markedly accelerates the exit rate of iodide from the gland but does not affect unidirectional iodide clearance (69). These observations account both for the clinical observation of a very high thyroidal uptake of radioiodine in iodine-deficient subjects with abnormally high serum thiocyanate levels and for the fact that iodine supplementation completely reverses the goitrogenic effect of cassava.

Pathophysiology: Adaptation of Thyroid Function to Iodine Deficiency

Endemic goiter is a disease of adaptation that develops in response to dietary iodine deficiency. This classic concept was established in 1954 by Stanbury and colleagues (70) and has been confirmed since by an enormous number of clinical and experimental observations (6,7,17,18,19,20,21,22,23,33,71).

When iodine intake is abnormally low, adequate secretion of thyroid hormones may still be achieved by marked modifications of thyroid activity. This adaptation includes stimulation of the trapping mechanism as well as of the subsequent steps in the intrathyroidal metabolism of iodine, leading to preferential synthesis and secretion of T3. These responses are triggered and maintained by increased secretion of TSH. The morphologic consequence of prolonged TSH stimulation is the development of goiter, making it appear to be the mechanism of adaptation to iodine deficiency (70). However, large goiters may no longer be considered adaptive in view of their decreased ability to synthesize thyroid hormones (72).

Increased Stimulation by Thyrotropin

High serum TSH levels have been reported often, but not systematically, in humans with chronic iodine deficiency (73,74,75,76,77). Moreover, within a given area, striking and large variations in serum TSH levels occur in adults independently of the presence or absence of goiter (73,74,76). The lack of systematic correlation between goiter and TSH levels suggests that differences in the duration of high TSH levels and in thyroid responsiveness to TSH, as well as other factors (e.g., growth hormone, epidermal growth and fibroblast factors, insulin, cortisone, cyclic GMP, or other intrathyroidal mechanisms) may determine whether goiter develops (78).

Increase in Iodide Trapping

The fundamental mechanism by which the thyroid gland adapts to an insufficient iodine supply is to increase the trapping of iodide. This results in the accumulation within the gland of a larger percentage of the ingested exogenous iodide and a more efficient reuse of iodide released by the thyroid or generated by the degradation of thyroid hormones (70,79). The increased iodide trapping is the result of both TSH stimulation and TSH-independent stimulation of iodide trapping by the thyroid sodium-iodide symporter (80).

For any adequate adjustment of iodide supply to the thyroid, iodide trapping must fulfill two conditions. First, it must reduce the amount of iodine excreted in the urine to that of iodine intake, this condition being required to preserve preexisting iodine stores. Second, it must ensure the accumulation in the thyroid of definite amounts of iodide per day (about 100 µg). This latter parameter is extremely important because it quantitatively controls all further steps of intrathyroidal iodine metabolism, including the secretion rate of the thyroid hormones. Two examples of adjustment of iodide trapping are shown in Fig. 11E.1, the first for a presumably normal subject (iodine supply: 100 µg/day) and the second for a goitrous subject living in an endemic area (iodine supply: 20 µg/day) (81). In the normal subject, renewal of the extrathyroidal iodide compartment is 200 µg/day, half of which originates from iodine intake (In) and the other half from peripheral degradation of the thyroid hormones. Thyroid iodide clearance (Clt) is adjusted to 30 mL/min and thus equals renal iodide clearance (Clr). The fraction of the iodide compartment taken up by the thyroid gland (IU) is given by the following equation: IU = IClt /(IClt + IClr). The amount of iodide taken up by the gland (A) and excreted in urine (E) per day are thus, respectively, IU and I (1–U). In a normal subject: U = 30/(30 + 30) = 0.5, and A and E are both 100 µg/day (200 µg × 0.5). In a patient with goiter, renewal of the extrathyroidal iodide compartment is only 120 µg/day, reflecting the reduction of iodide intake (20 µg/day). Thyroid clearance is adjusted to 155 mL/min, and the resulting value of U is 155/(155 + 30) = 0.83, A being equal to 120 µg × 0.83 = 100 µg and E = 120 µg × 0.17 = 20 µg.

Thus, despite a drastic reduction in the iodide supply, renal iodide excretion does not exceed iodine intake, and adequate amounts of iodine accumulate in the gland. It is obvious that this oversimplified scheme accounts neither for the qualitative changes of thyroid secretion nor for the iodide spillage observed in endemic goiter (82). The fraction of extrathyroidal iodide taken up by the gland thus appears as the main determining factor for the distribution of both exogenous and endogenous iodide. The U fraction does not, however, give a reliable estimate of the true modification of the trapping mechanism. As shown in Figure 11E.2, the adaptation from a normal iodine supply to a poor one enhances the value of U from 50% to 87%, that is by a factor of 1.7. This situation is achieved only by a tremendous augmentation of thyroid clearance, which increases from 30 to 155 mL/min, an increase by a factor of 5.7.

FIGURE 11E.2. Kinetics of iodide in a normal subject (left) and in a goitrous subject living in an iodine-deficient area (right). Respective iodine intakes (In) are 100 µg/day and 20 µg/day. The three iodine compartments are intrathyroid iodine (t); hormonal (“bound”) extrathyroid iodine (b); and extrathyroid iodide (ei). Transfer rates of iodine are expressed in µg/day; ei, renewal of extrathyroid iodide originating from intake and from hormonal degradation (D)A, accumulation rate within the thyroid; S, secretion rate; E, urinary excretion rate. 131iodine thyroid uptake (U) is the fraction of 131I tracer accumulated in the thyroid and 1-U, the fraction of 131I excreted in urine. Thyroid and renal clearances of iodide are expressed in mL/min. The schema is based on the three-compartment model of iodine metabolism proposed by Riggs. (From Riggs DS. Quantitative aspects of iodine metabolism in man. Pharmacol Rev 1952;4:284, with permission.)

For practical purposes, U is given with a good approximation by the 131I thyroidal uptake. Absolute iodine uptake (A) is generally estimated from the daily renal excretion of iodide (E) according to the formula: A = EU /(1-U). This equation is based on the assumption that the distribution of extrathyroidal stable iodide during 24 hours is the same as the distribution of a single tracer dose of 131I (70). The ratio between thyroidal accumulation and renal excretion is the same for 127I and 131I; therefore, the equation from which the formula mentioned earlier is derived: A/E = U (1-U).

Increased thyroidal uptake of 131I and reduction of urinary iodine excretion are the main markers of a goiter endemia caused by iodine deficiency. A clear-cut inverse relationship between both parameters was demonstrated in 1954 (70), has been confirmed in a large number of goiter endemias (33), and is further illustrated in Fig. 11E.3. It indicates that as soon as the iodine supply decreases below the physiological requirement of 100 µg per day in adults, the thyroid uptake of radioiodine increases, indicating an accelerated clearance rate of iodide by the thyroid.

Under these conditions, in spite of a decrease in the serum concentration of iodide, the absolute uptake of iodide by the thyroid remains normal (79) and its organic iodine content remains within the limits of normal (i.e., 15 to 25 mg), as long as the iodine intake remains above a threshold of about 50 µg/day. Below this critical level, in spite of a further increase of thyroid clearance, the absolute uptake of iodide diminishes and the iodine content of the thyroid decreases. Goiter, the visible consequence of iodine deficiency, starts to develop only when the iodine intake is still lower, although for low iodine intake, the prevalence of goiter markedly varies from one area to another (83,84,85).

Because of the relationship between thyroidal uptake and urinary iodine excretion, it has been suggested that the estimation of urinary 127I excretion, and therefore of the iodine intake, could be directly deduced, with considerable accuracy, from the value of the 131I thyroidal uptake (86).

Modifications of Intrathyroidal Iodine Metabolism

Under experimental conditions, increased TSH stimulation induced by iodine deficiency provokes a marked acceleration of all steps of intrathyroidal iodine metabolism, with a consequently faster turnover of this compartment and an increase in its heterogeneity (87). A similar pattern is observed in endemic goiter, but only in a restricted number of subjects, generally children and adolescents (88). In most goitrous subjects, 131I distribution reveals a slow-release pattern: plasma protein-bound 131I is as low as in subjects with normal thyroid uptake living in nongoitrous areas, and the biologic half-life of thyroidal 131I is long. These observations would suggest that in these highly stimulated glands, intrathyroidal iodine would turn over at a subnormal rate. A possible explanation for this finding (87) is that the glands with apparently slow secretion could have access to a large endogenous source of stable iodine not in equilibrium with the compartment labeled by the exogenous tracer. This unlabeled iodine could dilute the tracer and render the fast turnover undetectable by isotope studies.

Studies in rats show that thyroid hyperplasia induced by iodine deficiency is associated with an altered pattern of tracer iodine distribution in the gland, characterized by an increase in poorly iodinated compounds, monoiodotyrosine (MIT) and T3, and a decrease in diiodotyrosine (DIT) and T4 (87,89). Fig. 11E.4 indicates that the increases in the MIT/DIT and T3/T4 ratios are closely related to the degree of iodine depletion of the gland. Table 11E.5 confirms these findings by showing that the iodine depleted glands of iodine-deficient rats have a dramatic reduction of T4 and a markedly increased T3/T4 ratio.

FIGURE 11E.4. Relationship between monoiodotyrosine (MIT)*/diiodotyrosine (DIT)* and triiodothyronine (T3)*/thyroxine (T4)* ratios in the hydrolysates of rat thyroids and corresponding concentrations of 127I in the thyroid tissue. Each point corresponds to the mean value of five animals. Rats were fed a low iodine diet for 15 to 20 days with, in some groups, an iodine supplement of 5 µg/day. *, radioactive compound. (From Delange F, Ermans AM. Iodine deficiency. In: Braverman LE, Utiger RD, eds. The thyroid: A fundamental and clinical text. Philadelphia: JB Lippincott Co, 1991:368, with permission.)

TABLE 11E.5. WEIGHT, IODINE CONTENT, AND IODOAMINO ACID DISTRIBUTION IN THE THYROID AND IN THE SERUM OF NORMAL AND IODINE-DEFICIENT ADULT RATS


 Mean±SD


Variables

Normal Rats (n = 12)

Iodine-Deficient Rats (n = 10)


Thyroid

    Weight (mg/100 g)

4.1±0.7

12.0±3.0

   Iodine content (ng/mg thyroid wt)

880.0±180.0

21.0±30.0

   MIT*/DIT*ratio

0.42±0.07

2.00±0.30

   T3*/T4* ratio

0.12±0.01

1.80±0.90

   T3/T4 ratio (M)

0.12±0.03

1.01±0.90

Serum

    T4(µg/dL)

4.2±0.6

< 0.5

   T3(µg/dL)

44.0±;9.0

43.0±6.0


DIT, diiodotyrosine; MIT, monoiodotyrosine; T3, triiodothyronine; T4, thyroxine; 125I-labeled.

Results are calculated from the percentages of 125I found in each iodocompund in thyroid hydrolysates 24 hours after injection of 125I. From Abrams GM, Larsen PR.Triidothyronine and thyroxine in the serum and thyroid glands of iodine-deficient rats. J Clin Invest 1973;52:2522, with permission.

Corresponding information about human endemic goiter is more limited. In them, the amount of iodine is markedly reduced and the MIT/DIT ratio is increased. There is also, as in sporadic goiter, an increased DIT/T4 ratio, suggesting reduced efficiency of the coupling reaction (87).

The main features of intrathyroidal metabolism in endemic goiter appear to be as follows (71,72,87): because of a large thyroidal iodine pool that is not in equilibrium with the compartment labeled by the exogenous tracer, iodination of the large amounts of thyroglobulin (Tg) accumulated within the colloid remains low. The subsequent abnormal configuration of Tg is responsible for reduced efficiency of iodothyronine synthesis. Only a small fraction of the large iodine stores is, therefore, actually moving along the normal pathway of hormone synthesis and secretion, while a considerable percentage seems to be wasted, accounting for the tremendous morphological, functional and biochemical heterogeneity of endemic goiter. These different metabolic anomalies are particularly evident in large colloid goiters, which, therefore, represent maladaptation to iodine deficiency (72).

Thyrotropin Stimulation and Alterations in Circulating Thyroid Hormones

Clinically, euthyroid adults in areas of severe iodine deficiency have a low serum T4, high TSH, and normal or high T3 (73,74,76,77,90,91,92) (Table 11E.6). The mechanisms responsible for this pattern are unclear but may include thyroidal secretion of T4 and T3 in the same ratio they have within the gland (87,89,93,94,95), preferential secretion of T3 (96) or increased peripheral conversion of T4 to T3. The shift to increased T3 secretion and serum T3/T4 ratios may play an important role in the adaptation to iodine deficiency, since T3 has about 4 times the metabolic potency of T4 but requires only 75% as much iodine for synthesis (96). It is only under conditions of extreme thyroid failure, as are found in myxedematous endemic cretinism (see Chapter 49), that both serum T4 and T3 are low and serum TSH is dramatically elevated. In less severe goiter endemias, serum T4 and T3 levels are only slightly abnormal or remain normal. Under these conditions, basal TSH and TSH response to the intravenous injection of thyrotropin-releasing hormone (TRH) are often exaggerated, indicating an increase in pituitary TSH reserve (97), a condition often reported as subclinical hypothyroidism (98). This condition represents mild thyroid failure and should be treated (99).

TABLE 11E.6. COMPARISON OF EPIDEMIOLOGIC AND BIOCHEMICAL DATAA EXPLORING THYROID FUNCTION AND ENDEMIC GOITER IN BRUSSELS, DELGIUM, AND THE IDJWI ISLAND AND UBANGI AREAS OF THE DEMOCRATIC REPUBLIC OF CONGO


 Means ± SE (n)

 Variables

Belgium

Congo


Daily urinary excretion of iodine (µg/d)

51.2 ± 5.8 (38)

15.5 ± 1.3 (243)

Prevalence of goiter (%)

3

77

Serum concentration of:

     T4(µg/dL)

8.1 ± 0.1 (125)

4.9 ± 0.2 (358)

    T3(µg/dL)

144 ± 3 (124)

166 ± 3 (299)

    TSH (µU/mL)

1.7 ± 1.1 (255)

18.6 ± 2.1 (365)

    PB131l 24h (%dose/L)

0.06 ± 0.01 (27)

0.17 ± 0.02 (105)

Thyroidal uptake of 131l 24h (%dose)

46.4 ± 1.1 (255)

65.2 ± 0.9 (167)

Thyroidal organic iodine exchangeable pool (mg)

15.8 ± 3.5 (12)

1.6 ± 0.2 (30)


PB, protein-bound; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.

The differences between the two groups are highly significant (p < 0.0001) for all variables.

Adapted from from Delange F. Adaptation to iodine deficiency during growth: etiopathogenesis of endemic goiter and cretinism. In: Delange F, Fisher D, Malvaux P, eds. Pediatric thyroidology. Basel: S. Karger AG, 1985:295; Delange F, Iteke FB, Ermans AM. Nutritional factors involved in the goitrogenic action of cassava. Ottawa: International Development Research Centre, 1982:1; Ermans AM, Kinthaert J, Delcroix C, et al. Metabolism of intrathyroidal iodine in nomal men. J Clin Endocrinol Metab 1968;28:169; Dumont JE, Ermans AM, Bastenie PA. Thyroidal function in a goiter endemic. IV. Hypothyroidism and endemic cretinism. J Clin Endocrinol Metab 1963;23:325; and Camus M, Ermans AM, Bastenie PA. Alterations of iodine metabolism in asymptomatic thyroiditis. Metabolism 1968;17:1064.

In severe endemic goiter, an inverse relation exists between serum T4 and TSH, but not for serum T3, which is the most active thyroid hormone (87). This paradoxical finding is explained, in part, by the fact that the direct effect of T4 on TSH suppression results from intrapituitary T4 to T3 conversion and the subsequent binding of T3 to the nucleus of the thyrotrophs, while, in other tissues, the largest part of intracellular T3 originates from serum T3 (100). These findings account for the observation in endemic goiter that normal serum T3 levels enable a patient to maintain an overall euthyroid status, but pituitary stimulation persists as long as the serum T4 level is low.

In endemic goiter, the serum concentration of thyroxine-binding globulin (TBG) is normal unless its synthesis is decreased by the concomitant presence of protein malnutrition (101). The serum concentration of Tg is markedly elevated (102,103,104,105,106). Serum Tg correlates with serum TSH and is not higher in goitrous than in nongoitrous subjects. Finally, the incidence of positive anti-Tg and antimicrosomal antibodies (anti-TP0) is very low (102,107,108,109), but may increase after iodine prophylaxis (107) (see also section below on side effects of iodine supplementation).

Morphologic Changes

Morphologic changes in patients with endemic goiter are mainly nodular enlargement of the thyroid gland with striking macroscopic and microscopic heterogeneity (110,111). Diffuse enlargement is rarely found in severe endemic goiter and then only in young subjects. At this stage, the characteristic hyperplastic picture induced experimentally by iodine deficiency may be observed: parenchyma is abundant, follicular epithelium is high with papillary infolding, and colloid is decreased. A later stage is the formation of small nodules of different size and consistency throughout the entire thyroid gland. At this time, histologically, the major part of the gland has extremely distended vesicles with a flattened epithelium filled with colloid, but a few thyroid follicles show a typical pattern of stimulation.

CLINICAL ASPECTS AND DIAGNOSIS

The symptoms of endemic goiter do not differ from those found in nontoxic sporadic goiter; the differential diagnosis is established mainly by epidemiologic criteria. In individual patients, all types of thyroid enlargement may be observed, from the small, solitary thyroid nodule without any appreciable hyperplasia of the rest of the gland, to a huge multinodular goiter. Complications are those described for sporadic goiter (see Chapter 69). The most common are deviation and compression of the trachea, venous distension, the development of a collateral venous circulation on the chest, and thyroid hormone insufficiency. Hypothyroidism is often difficult to demonstrate on clinical grounds or from biologic data, because, as mentioned earlier, the serum T4 concentration is often low, the TSH concentration high, and the 131I thyroid uptake high (>50% at 24 hours) in clinically euthyroid subjects living in goitrous areas. Scintigraphy of the thyroid reveals the marked heterogeneity of the goiters and often cold or hot nodules.

The presence of hard thyroid nodules may suggest the diagnosis of thyroid cancer. An increase in the absolute number of thyroid cancers in endemic goiter remains controversial (112,113,114); however, the mortality rate from thyroid cancer may be higher because enlarged thyroids are already frequent in the population and may delay concern about individual nodules.

PEDIATRIC ASPECTS OF ADAPTATION TO IODINE DEFICIENCY

Sequential Development of the Mechanisms of Adaptation to Iodine Deficiency during Growth

Pathogenesis of Endemic Goiter

The view that endemic goiter constitutes the most efficient mechanism of adaptation to iodine deficiency is based, with a few exceptions (47,115,116,117,118), on information obtained from adults. Therefore, in an attempt to define the metabolic history of endemic goiter, a study was conducted (23,32) on how thyroid function changed with age, from 3 to 22 years, in goitrous and nongoitrous inhabitants of the Idjwi Island endemic goiter area in the Democratic Republic of Congo (Fig. 11E.5). Thyroidal uptake of radioiodine reached its maximum value in the earliest years of life and then declined progressively until adulthood. Uptake was higher in goitrous than in nongoitrous subjects. The thyroid exchangeable hormonal iodine pool increased progressively with age. The value was about 0.5 mg iodine in young infants; it increased progressively with age but reached only 2.5 mg in adults, which is 4 to 10 times lower than in adults in nonendemic areas. Conversely, the renewal rate of intrathyroidal radioactive iodine (apparent secretion rate, K′4) was extremely high in infancy and decreased with age.

FIGURE 11E.5. Changes with age of the 6-hour thyroidal uptake of radioiodine (U6), the thyroidal iodine exchangeable hormonal pool (Qg), the apparent secretion rate of radioiodine by the thyroid (K′4) and the serum concentration of protein-bound iodine (PBI) in goitrous (G+) and nongoitrous (Go)inhabitants of the Idjwi Island endemic goiter area, Democratic Republic of Congo. Values recorded as mean±SE. The number of patients is shown in parentheses. (From Delange F. Adaptation to iodine deficiency during growth: etiopathogenesis of endemic goiter and cretinism. In: Delange F, Fisher D, Malvaux P, eds. Pediatric thyroidology. Basel: S. Karger AG, 1985:295; and Delange F. Endemic goitre and thyroid function in Central Africa. Monographs in pediatrics. Basel: S. Karger AG, 1974:1, with permission.)

This study demonstrates that the acceleration in the main steps of iodine kinetics is more marked in childhood and adolescence than in adulthood, and that it progressively decreases during growth. Subjects from another part of Idjwi Island, with a similar degree of iodine deficiency but no goiter (32), showed that (a) the radioiodine thyroidal uptake also was increased but to a lesser extent, (b) the iodine stores in the thyroid were much lower, and (c) the plasma protein-bound iodine was higher. These data suggest that goiter is by no means the optimal mechanism of adaptation to iodine deficiency, confirming the view that goiter represents, rather, maladaptation to iodine deficiency (72).

AGE-RELATED MODIFICATIONS OF THYROTROPIN REGULATION

In clinically euthyroid subjects residing in a severe endemic goiter area in the Ubangi region of the Democratic Republic of Congo, the youngest infants unexpectedly had the highest values of serum TSH, although they also had the highest T4 values (Fig. 11E.6) (119). For a given value of T4, the TSH level was about twice as high in the 4- to 15-year-old group as in the 16- to 20-year-old group (Fig. 11E.7). These variations in the serum TSH/T4 ratio as a function of age are poorly understood and could reflect the increase in thyroidal iodine with age. They also could be explained by changes with age in the T4 turnover rate (120) or by changes in thyroid gland sensitivity to TSH, including progressive development of thyroid autonomy (121).

FIGURE 11E.6. Changes with age of the serum concentrations of thyroxine, triiodothyronine, thyrotropin, and thiocyanate (SCN) in the Ubangi endemic goiter area, Democratic Republic of Congo (O), and in Brussels (). Values recorded as mean±SE. The number of patients is shown in parentheses. (From Delange F. Adaptation to iodine deficiency during growth: etiopathogenesis of endemic goiter and cretinism. In: Delange F, Fisher D, Malvaux P, eds. Pediatric thyroidology. Basel: S. Karger AG, 1985:295, with permission.)

FIGURE 11E.7. Computed correlation curves between thyrotropin (TSH) and thyroxine (T4) serum concentrations in 840 inhabitants of the Ubangi endemic goiter area (Democratic Republic of Congo). The curves are derived from the linear inverse correlations (p < 0.001) between log TSH and T4 in four age groups (younger than 15 year, 16 to 25 years, 26 to 35 years, and older than 35 years). (From Bourdoux P, Ermans AM. Factors influencing the levels of circulating T4, T3 and TSH in human beings submitted to severe ioding deficiency. Ann Endorinol (Paris) 1981;42:40:40A, with permission.)

Thyroid Function in Early Life

Results from systematic screening for congenital hypothyroidism in the neonates in iodine-deficient areas have provided much useful information (24). In such areas, the alterations of thyroid function in neonates are much more frequent and severe than in adults. A large number of neonates and young infants have the biochemical features of thyroid failure that are found in western countries only in permanent sporadic congenital hypothyroidism.

The most extreme situation has been reported from the Democratic Republic of Congo (122,123,124), where thyroid failure in neonates results from the combined action of iodine deficiency and thiocyanate overload during late fetal life (see Chapter 49). In this area (Fig. 11E.8), cord serum TSH and T4 levels in unselected newborns were frequently outside the normal range. Eleven percent of the neonates had both a cord serum TSH above 100 µU/mL and a cord serum T4 below 3.1 µg/dL (40 nmol/L), indicating severe congenital hypothyroidism according to the criteria used in western countries, where the incidence of the condition is only 0.025%. A similar frequency of biochemical hypothyroidism has been found in the same area in young infants (125), indicating that the findings in neonates were not due to nonspecific factors, such as the stress of delivery. The picture of congenital hypothyroidism was only transient in some infants but remained unchanged in others (23).

FIGURE 11E.8. Comparison of the distribution of the serum concentrations of thyrotropin (TSH) and thyroxine (T4) in cord blood in Brussels and in newborns in the Ubangi endemic goiter area in the Democratic Republic of Congo born to untreated mothers or to mothers treated with one single injection of iodized oil during pregnancy. The number of newborns is shown in parentheses. The dotted lines correspond to the values considered as suggestive (hypo?) or characteristic (hypo) of permanent sporadic congenital hypothyroidism in the neonatal thyroid screening program of Brussels. (From Delange F, Thilly C, Bourdoux P, et al. Influence of dietary goitrogens during pregnancy in humans on thyroid function of the newborn. In: Delange F, Iteke FB, Ermans AM, eds. Nutritional factors involved in the goitrogenic action of cassava. Ottawa: International Development Research Centre, 1982:40, modified with permission.)

The abnormalities of neonatal thyroid function were prevented by correcting iodine deficiency in mothers before or during pregnancy (123,126) (Fig. 11E.8). It has been suggested that permanent congenital hypothyroidism in severe iodine deficiency during the perinatal period causes myxedematous endemic cretinism and that transient hypothyroidism during the critical period of brain development is responsible for the endemic mental retardation frequently observed in clinically euthyroid children in severely affected areas (23) (see also Chapter 49).

A similar frequency of congenital hypothyroidism in association with severe endemic goiter has been reported from the Himalayas in northern India, Nepal, and Bhutan (127). Alterations of thyroid function in neonates have been subsequently reported from other less-severe endemic areas, even when thyroid function in adults was normal, and show a shift towards high serum TSH and lower T4 values (128).

MILD-TO-MODERATE IODINE DEFICIENCY DISORDERS: THE SITUATION IN EUROPE

Epidemiology

Endemic goiter, occasionally complicated by endemic cretinism, was often reported in Europe up to the turn of the 20th century, especially from remote, isolated, mountainous areas in its central parts, including Switzerland, Austria, northern Italy, Bulgaria, and Poland (129,130). The problem of IDD has been entirely eliminated in Switzerland due to the implementation and monitoring of a program of salt iodization (131). Probably because of this remarkable program's impact on the medical world, IDD have not been considered a significant public health problem in Europe during the last 5 decades.

However, reevaluation of the problem in the late 1980s, under the sponsorship of the European Thyroid Association, clearly indicated that, with the exception of some of the Scandinavian countries, Austria, and Switzerland, most European countries, or at least certain areas of them, were still iodine deficient, especially in the south (132). Shortly thereafter, it was shown that differences in iodine intake among the adult populations of several countries or areas were accompanied by parallel differences in the iodine content of breast milk and of urine in neonates (133,134) (Table 11E.7). The status of iodine nutrition was reevaluated in 1992 in western and central Europe (135). Iodine deficiency was controlled in only five countries, namely Austria, Finland, Norway, Sweden, and Switzerland.

TABLE 11E.7. COMPARISON OF THE RESULTS OBTAINED IN EUROPEAN COUNTRIES FOR URINARY IODINE EXCRETION IN ADULTS, IODINE CONTENT OF BREAST MILK, AND URINE OF INFANTS ON DAY 5 OF LIFE


 Iodine Concentration (µg/dL)


Country or Region (City)

Urinary Excretion of Iodine in Adults (µg/d)

Breast Milk (Mean ± SE)(n)

Urine from infants on Day 5 (Median)


The Netherlands (Rotterdam)

88–140

 

16.2 (64)

Finland (Helsinki)

238–270

 

11.2 (39)

Sweden (Stockholm)

91–140

9.3 (60)

11.0 (52)

Sicily (nonendemic area)

113

 

7.1 (14)

    (Catania)

 

 Switzerland (Zürich)

126–141

 

6.2 (62)

Spain (Madrid)

89

7.7 ± 0.9 (69)

 France (Paris)

55–126

8.2 ± 0.5 (68)

 

   (Lille)

  

5.8 (82)

Belgium (Brussels)

51

9.5 ± 0.6 (91)

4.8 (196)

Italy (Rome)

37

 

4.7 (114)

North Germany (Berlin)

35

 

2.8 (87)

South Germany (Freiburg)

20

2.5 (41)

1.2 (41)

    (lena)

16

1.2 ± 0.1 (55)

0.8 (54)

Sicily (endemic area)

22

2.7 ± 0.3 (59)

     (San Angelo)

 

 

 


Adapted from Delange F, Heidemann P, Bourdoux P, et al. Regional variations of iodine nutrition and thyroid function during the neonatal period in Europe. Biol Neonate 1986;49:322; and Delange F, Bürgi H. Iodine deficiency disorders in Europe. Bull World Health Organ 1989;67:317, with permission.

Programs aiming at the sustainable elimination of iodine deficiency were then reinforced or implemented in many European countries. A multicentre study conducted 5 years later in schoolchildren of 13 European countries, measuring thyroid volume by ultrasonography and urinary iodine, showed marked improvement in most (29).

Also, in 1997 the status of iodine nutrition was evaluated in the 26 countries of central and eastern Europe, the Commonwealth of Independent States, and the Baltic States (136). This study indicated mild to severe iodine deficiency in many countries and a dramatic return of the deficiency within 5 to 7 years after the interruption of iodized salt programs, for example, in Russia.

Finally, the data on IDD and their prevention in all European countries have been reviewed again (137,138,139,140). Evidence of a marked improvement in the status of iodine nutrition was clearly shown, especially in central Europe. However, at least 18 countries still have inadequate iodine nutrition.

Public Health Consequences

The state of mild to severe iodine deficiency persisting in many countries or regions has important consequences for public health, including the intellectual development of infants and children. As an example, Table 11E.8 summarizes the situation in Belgium, where the consequences of mild IDD on the main target groups, that is, pregnant and lactating women, neonates, and young infants, have been extensively investigated. A recent national survey of iodine nutrition in Belgium has shown marked improvement (141).

TABLE 11E.8. FUNCTIONAL CONSEQUENCES OF MILD IODINE DEFICIENCY IN BELGIUM


Age Groups

Recommended Iodine Intake (µg/day)a

Recommended Urinary Iodine Concentration (µg/L)

Actual Urinary Iodine Concentration (µg/L)

Functional Consequences


Pregnant and Lactating Women

200

200–300

< 100 in 90% of the cases

Increased thyroid stimulation; goiter Prevention of the anomalies by iodine supplementation

 Iodine content of brease milk: 98 ± 5µg/L (mean ± SE) (normal:140–180µg/L)

Adults

150

100–200

51–60

High thyroidal uptake of radioiodine increased risk of thyroid irradiation in case of nuclear accident

Adolescents

150

100–200

30–50

Goiter

Children (6–12 y)

120

100–200

55–80

Goiter

Infants (6–36 mo)

90

180–220

101

Risk for impaired intellectual development

Neonates

90

150

48–86

High cord serum TSH and Tg High serum TSH and risk of transient neonatal hypothyrodism


aPer World Health Organization/United Nations International Children's Emergency Fund/International Council for Control of Iodine Deficiency Disorders (WHO/UNICEF/ICCIDD. Assessment of the iodine deficiency disorders and monitoring their elimination. Geneva: World Health Organization; 2001. Publication WHO/NHD/01.1:1).

Adapted from Delange F. Iodine deficiency in Europe anno 2002. Thyroid International 2002;5:1, with permission.

More generally, the consequences of iodine deficiency in Europe can be summarized in the following sections.

Adults

The frequency of simple goiter is high in many countries and the cost of treating thyroid problems resulting from iodine deficiency in the adult population is enormous. For example, the diagnosis and treatment of goiter due to iodine deficiency in Germany cost an estimated US$1 billion per year (142), while prevention with iodized salt would cost only US$0.02 to $0.08 per person per year (143). Thyroidal uptake of radioiodine varies markedly from one European country to another and is inversely related to iodine intake (144). High thyroidal uptake due to iodine deficiency increases the risk of thyroid irradiation and development of thyroid cancer in case of a nuclear accident (145).

Thyroid function is usually normal in adults in Europe. In contrast, it is frequently altered in pregnant women. During pregnancy, three synergic effects stimulate the gland: direct stimulation by human chorionic gonadotropin, stimulation through the usual feedback mechanism via the increase in TBG and the lowering of free hormone concentrations, and additional loss of iodide through increased renal clearance and to the fetoplacental unit (146) (see Chapter 80). At least in conditions of borderline iodine intake, as seen in Belgium and southwestern France (146,147) (50 to 70 µg/day), pregnancy is accompanied by a progressive decrease of serum free T4 and consequently by an increase in serum TSH. This state of chronic TSH hyperstimulation causes goiter in about 10% of the pregnant women and progressively increases the serum Tg concentration (146,147). Goiter can persist after pregnancy in some women (148). Pregnancy, especially under conditions of borderline iodine intake, at least partly explains the higher frequency of thyroid problems in women than in men. Marginal iodine deficiency during pregnancy in Belgium causes even higher serum levels of TSH and Tg in neonates than in the mothers, and slight enlargement of the neonatal thyroid gland. The causal role of iodine deficiency in these changes is demonstrated by their prevention with iodine supplementation of the mothers during pregnancy (149) and their absence in iodine-replete areas of Europe, such as some parts of the Netherlands (150).

Adolescents and Children

Euthyroid goiter is especially frequent in adolescents and occasionally requires therapy with T4 and/or iodide.

Even in Europe, clinically euthyroid schoolchildren born and living in an iodine-deficient area have subtle or overt neuropsychointellectual deficits compared to iodine-sufficient children living in the same ethnic, demographic, nutritional and socioeconomic system (151,152,153,154,155) (Table 11E.9). These deficits are of the same nature, although less marked, as those found in schoolchildren in areas with severe iodine deficiency and endemic mental retardation. They could result, as demonstrated in severe endemic goiter, from transient thyroid failure occurring during fetal or early postnatal life, i.e., during the critical period of brain development (see Chapter 49 and 74).

TABLE 11E.9. NEUROPSYCHOINTELLECTUAL DEFICITS IN INFANTS AND SCHOOLCHILDREN IN CONDITIONS OF MILD TO MODERATE IODINE DEFICIENCY IN EUROPE


Regions

Tests

Findings

Reference no.


Spain

Locally adapted

Lower psychomotor and mental development than controls

151

Bayley, McCarthy, Cattell

 Italy
   Sicily

Bender-Gestalt

Low preceptual integrative motor ability

152

 Neuromuscular and neurosensorial abnormalities

Tuscany

Wechsler, Raven

Low verbal IQ, perception, motor, and attentive functions

153

Tuscany

Wechsler

Lower velocity of motor response to visual stimuli

154, 155

 Slower reaction time

 


Neonates

The most important and frequent alterations of thyroid function due to iodine deficiency in Europe occur in neonates and young infants.

The frequency of transient primary hypothyroidism is almost 8 times higher in Europe than in North America (156). The syndrome is characterized by postnatally acquired primary hypothyroidism lasting for a few weeks and requiring T4 therapy (157). The risk of transient hypothyroidism in the neonate increases with the degree of prematurity (158). The specific role of iodine deficiency in the etiology of this hypothyroidism was demonstrated by its disappearance in Belgian preterm infants after they were systematically supplemented with 30 µg of potassium iodide per day.

As shown in Fig. 11E.9, there is an inverse relationship between the urinary iodine concentration in newborn infants in Europe, used as an index of their status of iodine nutrition, and the frequency of serum TSH above 50 µU/mL at the time of screening for congenital hypothyroidism, that is, between iodine deficiency and the recall rate for suspected congenital hypothyroidism (19). Consequently, neonatal thyroid screening is a particularly sensitive indicator for the presence and action of environmental goitrogens, including iodine deficiency, and can be used as a monitoring tool in the evaluation of the effects of iodine prophylaxis on a population (159,160).

FIGURE 11E.9. Relationship between the urinary iodine concentration and the recall rate at the time of screening for congenital hypothyroidism in newborn populations in Europe. Each point results from the analysis of 50 to 200 urine samples and from 20,000 to 300,000 screening tests. (From Delange F. The disorders induced by iodine deficiency. Thyroid 1994; 4:107, with permission.)

The reason for the particular sensitivity of the newborn, especially of the preterm infant, to the effects of iodine deficiency appears from the data summarized in Table 11E.10. In Toronto, where the iodine intake is high, the iodine content of the thyroid in full-term infants is 300 µg.

TABLE 11E.10. RELATIONSHIP BETWEEN THE IODINE CONTENT OF URINE IN ADULTS AND NEONATES, USED AS AN INDEX OF IODINE SUPPLY, AND THYROID WEIGHT, THYROID IODINE CONTENT, AND ESTIMATED TURNOVER RATE OF THYROIDAL IODINE IN NEONATES


 

 

Neonates


 

Adults


Urine Iodine


Thyroid Gland


City

Urinary Excretion of Iodine (µg/d)

Median Iodine Concentration (µg/L)a,b

Values < 5µg/L (%)

Weight (g)a,b

Iodine Content (µg)a,b

Estimated Turnover Rate (%/d)c


Toronto

600–800

148 (81)

11.9

1.00 ± 0.12 (13)

292 ± 47

17

Brussels

51

48 (196)d

53.2

0.76 ± 0.25 (4)

81 ± 9e

62

Leipzig

16

16 (70)d

97.2

3.27 ± 0.39 (10)e

43 ± 6e

125


aThe number of patients is shown in parentheses.

bResults given as mean ± SE.

cBased on a requirement of thyroxine 50 µg/day.

dLevels of significance as compared to Toronto, Canada p < 0.001.

eLevels of significance as compared to Toronto, Canada p < 0.01.

From Delange F. Screening for congenital hypothyroidism used as an indicator of IDD control. Thyroid 1998;8:1185–1192, with permission.

In Brussels, with a borderline iodine intake, the iodine content of the thyroid is 81 µg, and in Leipzig, which was severely iodine deficient, the content is only 43 µg. The table also shows that the turnover rate of intrathyroidal iodine is markedly accelerated in iodine-deficient neonates; therefore, thyroid failure is more likely to occur. These neonatal data contrast with those from adults, in whom thyroidal iodine stores are not affected by iodine deficiency unless it is severe (Fig. 11E.3).

FIGURE 11E.3. Relationship between the daily urinary excretion of iodine and the prevalence of goiter, the hormonal iodine content of the thyroid (exchangeable organic iodine pool determined by kinetic studies), and thyroidal uptake of radioiodine. (From Schaefer AE. Status of salt iodization in PAHO member countries. In: Dunn JT, Medeiros-Neto GA, eds. Endemic goiter and cretinism: continuing threats to world health. Washington, DC; Pan American Health Organization (PAHO); 1974. Scientific No. 292:242; Delange F, Bourdoux P, Chanoine JP, et al. Physiopathology of iodine nutrition during pregnancy, lactation and early postnatal life. In: Berger H, ed. Vitamins and minerals in pregnancy and lactation. New York: Raven Press, 1988:205; and Tovar E, Maisterrena JA, Chavez A. Iodine nutrition levels of schoolchildren in rural Mexico. In: Stanbury JB, ed. Endemic goiter. Washington, D.C.: Pan American Health Organization (PAHO); 1969. Scientific No. 193: 411, with permission.)

TREATMENT AND PROPHYLAXIS OF IODINE DEFICIENCY DISORDERS

Prolonged administration of iodine or of thyroid hormones is highly effective in reducing the size of endemic goiters (161). Surgical treatment is often justified in large goiters with pressure symptoms. Nevertheless, such treatment is, in practice, impossible to apply to a general population in view of the extent of the problem and the general lack of adequate medical infrastructure in the most severely affected populations. The most logical approach is iodine prophylaxis. The public health features of iodine prophylaxis, including the planning and monitoring of prophylactic campaigns, the technical aspects of production and distribution of iodized salt, and the other methods of iodine delivery, as well as the cost-benefit evaluation of its effectiveness, are discussed in detail elsewhere (7,10,11,13,17,22,143,162,163,164,165,166).

For almost 80 years, iodized salt has been used as the simplest and most effective way of providing extra iodine in the diet (162,163). Iodine can be added in the form of potassium iodide, but potassium iodate is preferred in humid regions, owing to its greater stability. The recommended levels for salt iodization vary widely. In the early phases of the programs, these levels varied from 1.9 to 100 parts iodine per million (ppm) of salt (131,163). The latest recommendation by WHO/UNICEF/ICCIDD (166) is that, in order to provide 150 µg/day of iodine via iodized salt, and considering the average salt intake and the loss of iodine from production to household and in cooking, the iodine concentration in salt at the site of production should be in the range of 20 to 40 mg iodine (or 34 to 66 mg iodate) per kilo of salt. These levels should be adjusted to ensure a median urinary iodine concentration of 100 to 200 µg/L in the population (5,166).

The first successful large-scale campaigns to prevent endemic goiter by iodized salt were carried out in the United States in 1917 (167) and in Switzerland in 1922 (131, 168). Subsequent pilot surveys confirmed the benefits of salt iodization, especially in Central and South America (7). In 1990, the World Summit for Children adopted the goal, endorsed by WHO and UNICEF, of virtual elimination of IDD by the year 2000 (5,11). Major programs of salt iodization were implemented, including in the most populated and affected parts of the world such as China (400 million at risk) and India. At the beginning of the 1990s, iodized salt reached probably < 10% of consumers worldwide. In 1995, of 94 countries that were affected by IDD and had UNICEF programs, 58 had achieved the goal of iodization of 90% of all edible salt (169).

A world review of IDD control by iodized salt was performed by WHO/UNICEF/ICCIDD in late 1998 (Table 11) (11); 130 countries with IDD had laws on iodization of all salt for human and animal nutrition and for the food industry, a strategy called universal salt iodization (USI). However, implementation of the regulations was achieved in only 94 of these countries, with a coverage by USI of >50% of the population in 63 countries and between 10% and 50% in the other 31. Monitoring the quality of iodized salt was reported in 98 countries, but iodine nutrition was monitored in only 79 of them. A further need is the systematic implementation of reliable monitoring of iodized salt from the site of production to the consumer.

TABLE 11E.11. PROGRESS IN ELIMINATING IODINE DEFICIENCY DISORDERS (IDD) AS OF 1999


WHO Region

No. of Countries

No. With IDD Legislation

No. Monitoring Salt Quality

No. With Wide Access to Iodized Salt (%)

No. With Universal Salt Iodization (%)

Iodine Status Adequate (%)


Africa

46

44

34 (6)a

29

24

63

Americas

35

19

17

19

19

90

Southeast Asia

10

9

7 (1)

8

7

70

Eastern

22

17

14

14

10

66

    Mediterranean

  

Europe

51

32

20 (3)

17

13

27

Western Pacific

27

9

6 (2)

8

6

76

Total

191

130

98 (12)

95

79

68


aThe figures in parentheses refers to the number of additional countries that have legislation in draft form.

From WHO/UNICEF/ICCIDD. Progress towards the elimination of iodine deficiency disorders (IDD). Geneva: World Health Organization; 1999. Publication WHO/NHD/99.4, with permission.

Iodide has been used as a supplement in bread in the Netherlands and in Tasmania, but wide variations in consumption make this a less than satisfactory technique (170). Iodization of water has been successfully used in some areas with adequate water supply and control of the iodization process (169,170,171). Iodized irrigation water has been successfully used in China (174) and decreased the mortality rate (175).

In many developing countries with severe iodine deficiency, iodization of salt, bread, or water had initially failed to prevent or eradicate the disease because various socioeconomic, climactic, or geographic conditions made systematic iodine supplementation difficult or impossible (162). In such conditions, prophylaxis and therapy could be achieved urgently by the administration of large quantities of iodine in the form of slowly resorbable iodized vegetable oil given intramuscularly or orally (176,177,178). The method is inexpensive and can be easily implemented through local health services using existing facilities or by small teams. The long-term effectiveness and safety of this procedure, including during pregnancy, have been extensively documented for at least 7 years in adults and for 2 to 3 years in young children after intramuscular injection and for 1 year after oral administration (179,180).

A United Nations Special Session in 2002 moved its previous deadline for IDD elimination from 2000 to 2005 (181). As already recounted in this chapter, the progress in the past 15 years has been enormous, but about half the world's countries still have significant iodine deficiency, and use of adequately iodized salt has leveled off at about 70% of households. The resistant pockets are predictably in areas that are economically poorest and most isolated. In addition, some countries that achieved iodine sufficiency are now in danger of backsliding because of inadequate monitoring and lack of effective governmental infrastructure and education. International agencies and many national governments have been vigorous in pursuing the goal of iodine sufficiency through universal salt iodization, but changes in personnel and new priorities pose real threats to sustaining the effort. Past history, especially in Latin America where salt iodization was widely introduced over 40 years ago only to be later neglected, shows that deficiency will recur if not constantly confronted (182).

SIDE EFFECTS OF IODINE SUPPLEMENTATION

As discussed so far in this chapter, iodine deficiency is associated with the development of thyroid function abnormalities. Similarly, iodine excess, including the overcorrection of a previous state of iodine deficiency, can also impair thyroid function. The effect of iodine on the thyroid gland is complex, with a U-shaped relationship between iodine intake and risk of thyroid diseases, as both low and high iodine intake are associated with an increased risk. Normal adults can tolerate up to about 1,000 µg iodine per day without any side effects (6,183). However this upper limit of normal is much lower in a population previously exposed to iodine deficiency. The optimal level of iodine intake to prevent any thyroid disease may be a relatively narrow range around the recommended daily adult intake of 150 µg (5,184).

Iodide Goiter and Iodine-Induced Hypothyroidism

The prevalences of both goiter and subclinical hypothyroidism are increased when iodine intake is chronically high, as for example in coastal areas of Japan (44) and China (45) (due to chronic intake of seaweeds rich in iodine such as laminaria) or in eastern China (because of the high iodine content of water from shallow wells (46)). The mechanisms behind this impairment of thyroid function are probably both iodine enhancement of thyroid autoimmunity and reversible inhibition of thyroid function by excess iodine (Wolff-Chaikoff effect) in susceptible subjects (see next section of this chapter). However, this type of thyroid failure has not been observed after correction of iodine deficiency, including in neonates after the administration of huge doses of iodized oil to their mothers during pregnancy (180).

Iodine-Induced Thyrotoxicosis

Iodine-induced thyrotoxicosis is the main complication of iodine prophylaxis. It has been reported in almost all iodine supplementation programs (15). The most extensively investigated outbreak occurred in Tasmania in the late 1960s following iodine supplementation simultaneously by tablets of iodide, iodized bread, and the use of iodophors in the milk industry (185). The incidence of thyrotoxicosis increased from 24 per 100,000 in 1963 to 125 per 100,000 in 1967. It occurred most frequently in individuals over 40 years of age with multinodular goiters. The most severe manifestations were cardiovascular and were occasionally lethal. The epidemic lasted for some 10 to 12 years, after which the incidence of thyrotoxicosis was somewhat below that existing prior to the epidemic.

Concern about this problem was recently renewed by reports from Zimbabwe that the introduction of iodized salt had sharply increased the incidence of thyrotoxicosis, from 3 per 100,000 to 7 per 100,000 over 18 months (186). A high risk of IIH was also reported from eastern Congo following the introduction of iodized salt (187). A multicenter study conducted in seven African countries, including Zimbabwe and Congo (188), showed that in the last two countries thyrotoxicosis stemmed from the sudden introduction of poorly monitored and excessively iodized salt in populations that had been severely iodine deficient for very long periods. The conclusion of the study was that the risk is related to a rapid increment of iodine intake resulting in acute iodine overload. However, a high frequency of thyrotoxicosis was not reported in populations that could adjust their thyroid function and its regulation to a chronically high iodine intake.

Iodine-induced thyrotoxicosis following iodine supplementation cannot be entirely avoided, even when the supplementation uses only physiological amounts of iodine. In a well-controlled longitudinal study in Switzerland the incidence increased by 27% during the year after the iodine supply was increased from 90 µg/day to the recommended value of 150 µg/day (189). Similarly, the introduction of salt iodization in a Chinese region with borderline deficiency (median urinary iodine of 86 µg/L) resulted in a slight but significant increase in the incidence of thyrotoxicosis (190).

Contrasting with these different reports, thyrotoxicosis was not reported in Iran following a single intramuscular injection of 1 mL iodized oil containing 480 mg iodine to 3,420 subjects with simple goiter in an area with moderate iodine deficiency (mean urinary iodine 35.8 µg/L). Follow-up by clinical and laboratory evaluation every 3 months for 1 year, and every 6 months for the next 4 years, revealed a 0.6% incidence, occurring mostly during the first 5 months after the injection. This figure is close to the incidence of spontaneous thyrotoxicosis in this population (0.4) (191). Similarly, a clinical and biochemical 3-year survey of the effects of iodized oil injection found no case of iodine-induced thyrotoxicosis among 198 schoolchildren of Kiga, a village in a mountainous region of Iran, where the prevalence of visible goiter was 93% and the mean urinary iodine was 11.4 µg/g creatinine before intervention. Rather, serum T4 increased from 5.0 to 9.5 µg/dL, TSH decreased from 20.3 to 2.2 mU/L, and Tg from 132.0 to 23.0 ng/mL, and the goiter prevalence lessened substantially (192).

Similarly reassuring results were obtained from long-term biochemical monitoring after oral administration of iodized oil to severely iodine-deficient schoolchildren in Romania (109).

The mechanism for the development of iodine-induced thyrotoxicosis has now been identified (193): iodine deficiency increases thyrocyte proliferation and mutation rates, which, in turn, trigger the development of multifocal autonomous growth with scattered cell clones harboring activating mutations of the TSH receptor. Measurement of intrathyroidal iodine by X-ray fluorescence scanning showed that some nodules retain their capacity to store iodine; these can become autonomous and cause thyrotoxicosis after iodine supplementation (194).

Thus, iodine-induced thyrotoxicosis appears to be largely unavoidable in the early phase of iodine supplementation. It affects principally the elderly with longstanding autonomous nodules. The incidence of thyrotoxicosis reverts to normal or even below normal after 1 to 10 years of iodine supplementation.

Iodine-Induced Thyroiditis

Another possible effect of iodine supplementation is the aggravation or even the induction of autoimmune thyroiditis. Under experimental conditions, excessive iodine intake can precipitate spontaneous thyroiditis in genetically predisposed strains of beagles, rats, or chickens (reviewed in reference 195). The mechanism may be that high dietary iodine triggers thyroid autoimmune reactivity by increasing the immunogenicity of Tg or by inducing damage to the thyroid and its cells by free radicals.

Attention was drawn to the possibility of iodine-induced thyroiditis in humans when an increased frequency of Hashimoto's thyroiditis was seen in goiters removed surgically in the United States after the implementation of salt iodization (196). Later studies reported the development of thyroid autoantibodies after the introduction of iodized oil in Greece (107). More recently, Kahaly et al (197) described the development of thyroid autoantibodies in 6 of 31 patients with endemic goiter treated for 6 months with a supraphysiological dose of 500 µg potassium iodide (KI) per day. The development of lymphocytic infiltration in the thyroids was noted as well. Cross-sectional studies of populations in Italy (198), Great Britain (199), and more recently Denmark and Iceland (16), each with different iodine intakes, showed that the frequencies of thyroid autoantibodies and hypothyroidism are higher in iodine-replete than in iodine-deficient populations. Similarly, the frequencies of thyroid antibodies (200) and of thyroiditis (201) are higher in the United States than in Europe, where the iodine intake is lower.

Acute massive iodine overload (daily consumption of at least 50 mg iodine daily) sharply increased thyroid peroxidase antibody values, serum TSH levels, and goiter prevalence, and all of these decreased after correcting iodine excess (202). However, although cross-sectional studies associated endemic goiter and the presence of thyroid autoantibodies, for example, in Sri Lanka (203), no large epidemiological, metabolic, or clinical surveys following iodine supplementation have uncovered significant iodine-induced thyroiditis with public health consequences (108, 109, 191).

Thyroid Cancer

In animals, the chronic stimulation of the thyroid by TSH can produce thyroid tumors (204). There is a tendency toward higher incidence rates of thyroid cancer in autopsy material from endemic goiter areas, although the relationship between thyroid cancer and endemic goiter has often been debated without agreement being reached on many aspects, including causal relationship (114,161,205).

Iodine supplementation is accompanied by a change in the epidemiological pattern of thyroid cancer, with an increased prevalence of occult papillary cancer at autopsy (206,207). However, the prognosis of thyroid cancer is improved following iodine supplementation, due to a shift toward more differentiated forms that are diagnosed at earlier stages. Careful monitoring in Switzerland following iodine supplementation showed that the incidence of thyroid cancer steadily decreased from 2 to 3 per 100,000 in 1950 to 1 to 2 per 100,000 in 1988, during a period when iodine intake increased and reached an optimal value (208). In another example, fine-needle thyroid biopsies of 3,572 patients in Poland, where iodine deficiency was progressively corrected between 1985 and 1999, found that the frequency of neoplastic lesions significantly decreased over the period and the ratio of papillary to follicular carcinomas increased, as did the frequency of cytologically diagnosed chronic thyroiditis (from 1.5% to 5.7) (209). Overall, correction of iodine deficiency appears to decrease the risk and morbidity of thyroid cancer.

In conclusion, the benefits of correcting iodine deficiency far outweigh its risks. Iodine-induced thyrotoxicosis and other adverse effects can be almost entirely avoided by adequate and sustained quality assurance and by monitoring of iodine supplementation, which should also confirm adequate iodine intake (182,195,210,211,212). The progress toward correction of iodine deficiency globally in the past decade is a public health success unprecedented for a noninfectious disease (11,213) and its sustainable elimination is within reach.

REFERENCES

1. Hays M. Estimation of total body iodine content in normal young men. Thyroid 2001;11:671–675.

2. Koibuchi N, Chin WW. Thyroid hormone action and brain development. Trends Endocrinol Metab 2000;4:123–128.

3. Dobbing J, Sands J. Quantitative growth and development of human brain. Arch Dis Child 1973;48:757–767.

4. DeLong GR, Robbins J, Condliffe PG. Iodine and the brain. New York: Plenum Press, 1989:1–379.

5. WHO/UNICEF/ICCIDD. Assessment of the iodine deficiency disorders and monitoring their elimination. Geneva: World Health Organization; 2001. Publication WHO/NHD/01.1:1–107.

6. Thomson CD. Dietary recommendations of iodine around the world. IDD Newsletter 2002;18:38–42.

7. Stanbury JB, Hetzel B. Endemic goiter and cretinism: iodine nutrition in health and disease. New York: John Wiley and Sons, 1980:1–606.

8. Hetzel BS, Dunn JT, Stanbury JB. The prevention and control of iodine deficiency disorders. Amsterdam: Elsevier Science, 1987: 1–354.

9. McMichael AJ, Potter JD, Hetzel BS. Iodine deficiency, thyroid function and reproductive failure. In: Stanbury JB, Hetzel BS eds. Endemic goiter and endemic cretinism: Iodine nutrition in health and disease. New York: John Wiley and Sons, 1980: 445–460.

10. Hetzel BS. Iodine deficiency disorders (IDD) and their eradication. Lancet 1983:ii:1126–1129.

11. WHO/UNICEF/ICCIDD. Progress towards the elimination of iodine deficiency disorders (IDD). Geneva: World Health Organization; 1999. Publication WHO/NHD/99.4:1–33.

12. Koutras DA, Matovinovic J, Vought R. The ecology of iodine. In: Stanbury JB, Hetzel BS eds. Endemic goiter and endemic cretinism. New York: John Wiley and Sons, 1980:185–195.

13. WHO/UNICEF/ICCIDD. Indicators for assessing iodine deficiency disorders and their control through salt iodization. Geneva: World Health Organization; 1994. Publication WHO/NUT/94.6:1–55.

13a. http://www3.who.int/whosis/menu.cfm?path=mn (accessed August 23, 2004).

13b. http://www.icccidd.org (access August 23, 2004),

14. ICCIDD. Global iodine nutrition. IDD Newsletter 2003;19: 24–25

15. Stanbury JB, Ermans AE, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998; 8:83–100.

16. Laurberg P, Nohr SB, Pedersen KM, et al. Thyroid disorders in mild iodine deficiency. Thyroid 2000;10:951–963.

17. Boyages SC, Halpern JP. Endemic cretinism: toward a unifying hypothesis. Thyroid 1993;3:59–69.

18. Delange F. The disorders induced by iodine deficiency. Thyroid 1994;4:107–128.

19. Hetzel BS, Pandav CS. S.O.S. for a billion: the conquest of iodine deficiency disorders, 2nd ed. Dehli: Oxford University Press, 1996:1–466.

20. Hollowell JG, Hannon WH. Teratogen update: Iodine deficiency, a community teratogen. Teratology 1997;55:389–405.

21. Semba RD. Iodine deficiency disorders. In: Semba RD, Bloem MW, eds. Nutrition and health in developing countries. Totowa, NJ: Humana Press, 2001:343–363.

22. Delange F, Hetzel B. The iodine deficiency disorders. [Thyroid Disease Manager Web site]. Available at: http://www.thyroidmanager.org. Accessed August 22, 2004.

23. Delange F. Adaptation to iodine deficiency during growth: etiopathogenesis of endemic goiter and cretinism. In: Delange F, Fisher D, Malvaux P, eds. Pediatric thyroidology. Basel: S. Karger AG, 1985:295–326.

24. Delange F. Iodine nutrition and congenital hypothyroidism. In: Delange F, Fisher DA, Glinoer D, eds. Research in congenital hypothyroidism. New York: Plenum Press, 1989:173–185.

25. Gutekunst R, Teichert HM. Requirements for goiter surveys and the determination of thyroid size. In: Delange F, Dunn JT, Glinoer D, eds. Iodine deficiency in Europe: a continuing concern. New York: Plenum Press, 1993:109–118.

26. Vitti P, Martino E, Aghini-Lombardi F, et al. Thyroid volume measurement by ultrasound in children as a tool for the assessment of mild iodine deficiency. J Clin Endocrinol Metab 1994; 79:600–603.

27. Zimmermann M, Saad A, Hess S, et al. Thyroid ultrasound compared with WHO 1960 and 1994 palpation criteria for determination of goiter prevalence in regions of mild and severe iodine deficiency. Eur J Endocrinol 2000;143:727–731.

28. WHO/ICCIDD. Recommended normative values for thyroid volume in children aged 6–15 years. Bull World Health Organ 1997;75:95–97.

29. Delange F, Benker G, Caron P, et al. Thyroid volume and urinary iodine in European schoolchildren: standardization of values for assessment of iodine deficiency. Eur J Endocrinol 1997; 136:180–187.

30. Zimmermann MB, Molinari L, Spehl M, et al. Towards a consensus on reference values for thyroid volume in iodine replete schoolchildren: results of a workshop on interobserver and interequipment variation in sonographic measurement of thyroid volume. Eur J Endocrinol 2001;144:213–220.

31. Zimmermann M, Hess S, Molinari L, et al. New reference values of thyroid volume by ultrasound in iodine-sufficient schoolchildren: a WHO/NHD Iodine Deficiency Study Group report. Am J Clin Nutr 2004;79:231.

32. Delange F. Endemic goitre and thyroid function in central Africa. Monographs in pediatrics. Basel: S. Karger AG, 1974:1–171.

33. Beckers C, Delange F. Etiology of endemic goiter. Iodine deficiency. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. New York: John Wiley and Sons, 1980:199–217.

34. Gaitan E. Environmental goitrogenesis. Boca Raton: CRC Press, 1989:1–250.

35. Koutras DA, Papapetrou PD, Yataganas X, et al. Dietary sources of iodine in areas with and without iodine-deficiency goiter. Am J Clin Nutr 1970;23:870–874.

36. Follis RH. Patterns of urinary iodine excretion in goitrous and nongoitrous areas. Am J Clin Nutr 1964;14:253–268.

37. Jolin T, Escobar del Rey F. Evaluation of iodine/creatinine ratios of casual samples as indices of daily urinary iodine output during field studies. J Clin Endocrinol 1965;25:540–542.

38. Bourdoux P, Thilly C, Delange F, et al. A new look at old concepts in laboratory evaluation of endemic goiter. In: Dunn JT, Pretell E, Daza C, Viteri FE, eds. Towards the eradication of endemic goiter, cretinism and iodine deficiency. Washington, DC: Pan American Health Organization (PAHO); 1986. Scientific No. 502:115–129.

39. Hetzel BS, Potter BJ, Dulberg EM. The iodine deficiency disorders: nature, pathogenesis and epidemiology. World Rev Nutr Diet 1990;62:59–119.

40. Pandav CS, Rao AR. Iodine deficiency disorders in livestock. Ecology and economics. New Delhi: Oxford University Press, 1997:1–288.

41. Orts S, Dustin P, Delange F. Goitrous enzootic in the wild rat with a geographical distribution similar to endemic human goitre. Acta Endocrinol (Copenh) 1971;66:193–200.

42. Clements FW, Wishart JW. A thyroid-blocking agent in the etiology of endemic goiter. Metabolism 1956;5:623–639.

43. Peltola P, Virtanen A. Effect of the prophylactic use of iodine on the thyroid of cattle in the endemic goitre in Finland. Ann Med Intern Fenn (Helsinki) 1954;43:209–215.

44. Suzuki H, Higuchi T, Sawa K, et al. “Endemic coast goitre” in Hokkaido, Japan. Acta Endocrinol (Copenh) 1965;50:161–176.

45. Ma T, Zhi-Heng Y, Ti-Zhang L, et al. High-iodide endemic goiter. Chin Med J (Engl) 1982;95:692–696.

46. Zhao J, Wang P, Shang L, et al. Endemic goiter associated with high iodine intake. Am J Public Health 2000;90:1633–1635.

47. Choufoer JC, Van Rhijn M, Kassenaar AAH, et al. Endemic goiter in western New Guinea: iodine metabolism in goitrous and non-goitrous subjects. J Clin Endocrinol Metab 1963;23: 1203–1217.

48. Delange F, Thilly C, Ermans AM. Iodine deficiency, a permissive condition in the development of endemic goiter. J Clin Endocrinol Metab 1968;28:114–116.

49. Roche M, Perinetti H, Barbeito A. Urinary excretion of stable iodine in a small group of isolated Venezuelan Indians. J Clin Endocrinol Metab 1961;21:1009–1012.

50. Ermans AM, Mbulamoko NM, Delange F, et al. Role of cassava in the etiology of endemic goitre and cretinism. Ottawa: International Development Research Centre, 1980:1–182.

51. Delange F, Iteke FB, Ermans AM. Nutritional factors involved in the goitrogenic action of cassava. Ottawa: International Development Research Centre, 1982:1–100.

52. Langer P, Greer MA. Antithyroid substances and naturally occurring goitrogens. Basel: S. Karger AG, 1977:1–178.

53. Podoba J, Langer P. Naturally occurring goitrogens and thyroid function. Bratislava: Publishing House of the Slovak Academy of Sciences, 1964:1–312.

54. Van Etten CH. Goitrogens. In: Liener IE, ed. Toxic constituents of plant foodstuffs. New York: Academic Press, 1969: 103–142.

55. Delange F, Ermans AM. Endemic goiter and cretinism. Naturally occurring goitrogens. Pharmacol Ther 1976;1:57–93.

56. Gmelin R, Virtanen AI. The enzymic formation of thiocyanate (SCN-) from a precursor(s) in Brassica species. Acta Chem Scand 1960;14:507–510.

57. Ermans AM, Bourdoux P. Antithyroid sulfurated compounds. In: Gaitan E, ed. Environmental goitrogenesis. Boca Raton, FL: CRC Press, 1989: 15–34.

58. Gibson HB, Howeler JF, Clements FW. Seasonal epidemics of endemic goitre in Tasmania. Med J Aust 1960;1:875–880.

59. Ermans AM, Kinthaert J, Van der Velden M, et al. Studies of the antithyroid effects of cassava and of thiocyanate in rats. In: Ermans AM, Mbulamoko NM, Delange F, Ahluwalia R, eds. Role of cassava in the etiology of endemic goitre and cretinism. Ottawa: International Development Research Centre, 1980:93–110.

60. Wolff J. Transport of iodide and other anions in the thyroid gland. Physiol Rev 1964;44:45–90.

61. Wollman SH. Inhibition by thiocyanate of accumulation of radioiodine by thyroid gland. Am J Physiol 1962;203:517–524.

62. Ekpechi OL. Pathogenesis of endemic goitre in eastern Nigeria. Br J Nutr 1967;21:537–545.

63. Delange F, Ermans AM. Role of a dietary goitrogen in the etiology of endemic goiter in Idjwi Island. Am J Clin Nutr 1971; 24:1354–1360.

64. Bourdoux P, Delange F, Gerard M, et al. Evidence that cassava ingestion increases thiocyanate formation: a possible etiology in endemic goiter. J Clin Endocrinol Metab 1978;216:613–621.

65. Maberly GF, Eastman CJ, Waite KV, et al. The role of cassava in endemic goitre in Sarawak, Malaysia. In: Ui N, Torizuka K, Nagataki S, Miayi K, eds. Current problems in thyroid research. Amsterdam: Excerpta Medica, 1983:341–344.

66. Gaitan E, Cooksey RC, Legan J, et al. Antithyroid effects in vivo and in vitro of babossu and manolioca: a staple food in goiter areas of Brazil. Eur J Endocrinol 1994;131:138–144.

67. Bourdoux P, Seghers P, Matufa M, et al. Cassava products: HCN content and detoxification processes. In: Delange F, Iteke FB, Ermans AM, eds. Nutritional factors involved in the goitrogenic action of cassava. Ottawa: International Development Research Centre, 1982:51–58.

68. Delange F, Vigneri R, Trimarchi F et al. Etiological factors of endemic goiter in north-eastern Sicily. J Endocrinol Invest 1978; 2:137–142.

69. Scranton JR, Nissen WM, Halmi NS. The kinetics of the inhibition of thyroidal iodine accumulation by thiocyanate: a reexamination. Endocrinology 1969;85:603–607.

70. Stanbury JB, Brownell GL, Riggs DS, et al. Endemic goiter. The adaptation of man to iodine deficiency. Cambridge, MA: Harvard University Press, 1954:1–209.

71. Studer H, Kohler H, B□rgi H. Iodine deficiency. In: Greer MA, Solomon DH, eds. Handbook of physiology. Section 7. Endocrinology. Washington, DC: American Physiological Society, 1974:303–328.

72. Dumont JE, Ermans AM, Maenhaut G, et al. Large goiter as a maladaptation to iodine deficiency. Clin Endocrinol (Oxf) 1995;43:1–10.

73. Chopra IJ, Sack J, Fisher DA. Circulating 3,3′,5′-triiodothyronine (reverse T3) in the human newborn. J Clin Invest 1975; 55:1137–1141.

74. Delange F, Hershman JM, Ermans AM. Relationship between the serum thyrotropin level, the prevalence of goiter and the pattern of iodine metabolism in Idjwi Island. J Clin Endocrinol Metab 1971;33:261–268.

75. Hennemann G, Djokomoeljanto R, Docter R, et al. The relationship between serum protein-bound iodine levels and urinary iodine excretion and serum thyrotropin concentrations in subjects from an endemic goitre area in central Java. Acta Endocrinol (Copenh) 1978;88:474–481.

76. Patel YC, Pharoah POD, Hornabrook RW, et al. Serum triiodothyronine, thyroxine and thyroid-stimulating hormone in endemic goiter: a comparison of goitrous and nongoitrous subjects in New Guinea. J Clin Endocrinol Metab 1973;37:783–789.

77. Pharoah POD, Lawton NF, Ellis SM, et al. The role of triiodothyronine (T3) in the maintenance of euthyroidism in endemic goitre. Clin Endocrinol (Oxf) 1973;2:193–199.

78. Dumont JE, Lamy F, Roger P, et al. Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors. Physiol Rev 1992;72:667–697.

79. Wayne EJ, Koutras DA, Alexander WD. Clinical aspects of iodine metabolism. Oxford: Blackwell Science, 1964:1–303.

80. Spitzweg C, Morris JC. The sodium iodide symporter: its pathophysiological and therapeutic implications. Clin Endocrinol (Oxf) 2002;57:559–574.

81. Riggs DS. Quantitative aspects of iodine metabolism in man. Pharmacol Rev 1952;4:284.

82. Ermans AM, Dumont JE, Bastenie PA. Thyroid function in a goitrous endemic. II. Nonhormonal iodine escape from the goitrous gland. J Clin Endocrinol Metab 1963;23:550–560.

83. Schaefer AE. Status of salt iodization in PAHO member countries. In: Dunn JT, Medeiros-Neto GA, eds. Endemic goiter and cretinism: continuing threats to world health. Washington, DC: Pan American Health Organization (PAHO); 1974. Scientific No. 292:242–250.

84. Delange F, Bourdoux P, Chanoine JP, et al. Physiopathology of iodine nutrition during pregnancy, lactation and early postnatal life. In: Berger H, ed.Vitamins and minerals in pregnancy and lactation. New York: Raven Press, 1988:205–213.

85. Tovar E, Maisterrena JA, Chavez A. Iodine nutrition levels of schoolchildren in rural Mexico. In: Stanbury JB, ed. Endemic goiter. Washington, D.C.: Pan American Health Organization (PAHO); 1969. Scientific No. 193:411–415.

86. Oddie TH, Fisher DA, McConahey WM, et al. Iodine intake in the United States: a reassessment. J Clin Endocrinol Metab 1970;30:659–665.

87. Ermans AM. Etiopathogenesis of endemic goiter. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. New York: John Wiley and Sons, 1980:287–301.

88. Ermans AM, Dumont J, Bastenie PA. Thyroid function in a goiter endemic. I. Impairment of hormone synthesis and secretion in the goitrous gland. J Clin Endocrinol Metab 1963;23: 539–549.

89. Abrams GM, Larsen PR. Triiodothyronine and thyroxine in the serum and thyroid glands of iodine-deficient rats. J Clin Invest 1973;52:2522–2531.

90. Delange F, Ermans AM. Iodine deficiency. In: Braverman LE, Utiger RD, eds. The thyroid: a fundamental and clinical text. Philadelphia: JB Lippincott Co, 1991:368–390.

91. Delange F, Camus M, Ermans AM. Circulating thyroid hormones in endemic goiter. J Clin Endocrinol Metab 1972;4: 891–895.

92. Kochupillai N, Karmakar MG, Weightman D, et al. Pituitary-thyroid axis in Himalayan endemic goitre. Lancet 1973;1: 1021–1024.

93. Ermans AM, Kinthaert J, Delcroix C, et al. Metabolism of intrathyroidal iodine in nomal men. J Clin Endocrinol Metab 1968;28:169–180.

94. Dumont JE, Ermans AM, Bastenie PA. Thyroidal function in a goiter endemic. IV. Hypothyroidism and endemic cretinism. J Clin Endocrinol Metab 1963;23:325–335.

95. Camus M, Ermans AM, Bastenie PA. Alterations of iodine metabolism in asymptomatic thyroiditis. Metabolism 1968;17: 1064–1072.

96. Greer MA, Grimm Y, Studer H. Qualitative changes in the secretion of thyroid hormones induced by iodine deficiency. Endocrinology 1968;83:1193–1198.

97. Medeiros-Neto GA, Imai Y, Kataoka K, et al. Thyroid function studies in endemic goiter and endemic cretinism. In: Robbins J, Braverman LE, eds. Thyroid research. Amsterdam: Excerpta Medica, 1976:497–500.

98. Evered DC, Ormston BJ, Smith PA, et al. Grades of hypothyroidism. BMJ 1973;i:657–662.

99. McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab 2001;86:4585–4590.

100. Silva JE, Dick TE, Larsen PR. The contribution of local tissue thyroxine monodeiodination to the nuclear 3,5,3′triiodothyronine in pituitary, liver and kidney of euthyroid rats. Endocrinology 1978;103:1196–1207.

101. Ingenbleek Y, Luypaert B, de Nayer P. Nutritional status and endemic goitre. Lancet 1980;i:388–392.

102. Van Herle AJ, Chopra IJ, Hershman JM, et al. Serum thyroglobulin in inhabitants of an endemic region of New Guinea. J Clin Endocrinol Metab 1976;43:512–516.

103. Pezzino V, Vigneri R, Squatrito S, et al. Increased serum thyroglobulin levels in patients with nontoxic goiter. J Clin Endocrinol Metab 1978;46:653–657.

104. Hershman JM, Due DT, Sharp B, et al. Endemic goiter in Vietnam. J Clin Endocrinol Metab 1983;57:243–249.

105. Fenzi GF, Ceccarelli C, Macchia E, et al. Reciprocal changes of serum thyroglobulin and TSH in residents of a moderate endemic goitre area. Clin Endocrinol (Oxf) 1985;23:115–122.

106. van den Briel T, West CE, Hautvast JGAJ, et al. Serum thyroglobulin and urinary iodine concentration are the most appropriate indicators of iodine status and thyroid function under conditions of increasing iodine supply. J Nutr 2001; 131:2701–2706.

107. Boukis MA, Koutras DA, Souvatzoglou A, et al. Thyroid hormone and immunological studies in endemic goiter. J Clin Endocr Metab 1983;57:859–862.

108. Azizi F, Navai L, Fattahi F. Goiter prevalence, urinary iodine excretion, thyroid function and anti-thyroid antibodies after 12 years of salt iodization in Shahriar, Iran. Int J Vitam Nutr Res 2002;72:291–295.

109. Simescu M, Varciu M, Nicolaescu E, et al. Iodized oil as a complement to iodized salt in schoolchildren in endemic goiter in Romania. Horm Res 2002;58:78–82.

110. Correa P. Pathology of endemic goiter. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. New York: John Wiley and Sons, 1980:303–332.

111. Studer H, Peter HJ, Gerber H. Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth. Endocr Rev 1989;10:125–135.

112. Wahner HW, Cuell C, Correa P, et al. Thyroid carcinoma in an endemic goiter area, Cali, Colombia. Am J Med 1966;40: 58–66.

113. Riccabona G. Thyroid cancer and endemic goiter. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. New York: John Wiley and Sons, 1980:333–350.

114. Harach HR, Escalante DA, Onativia A, et al. Thyroid carcinoma and thyroiditis in an endemic goitre region before and after iodine prophylaxis. Acta Endocrinol (Copenh) 1985;108: 55–60.

115. De Visscher M, Beckers C, Van Den Schrieck HG, et al. Endemic goiter in the Uele region (Reic of Congo). I. General aspects and functional studies. J Clin Endocrinol Metab 1961;21: 175–188.

116. Maisterrena JA, Tovar E, Cancino A, et al. Nutrition and endemic goiter in Mexico. J Clin Endocrinol Metab 1964;24: 166–172.

117. Wahner HW, Gaitan E. Thyroid function in adolescents from the goiter endemic of the Cauca Valley, Columbia. In: Stanbury JB, ed. Endemic goiter. Washington, DC: Pan American Health Organization (PAHO); 1969. Scientific No. 193:291–303.

118. Semiz S, Senol U, Bircan O, et al. Thyroid hormone profile in children with goiter in an endemic goiter area. J Pediatr Endocrinol Metab 2001;14:171–176.

119. Bourdoux P, Ermans AM. Factors influencing the levels of circulating T4, T3 and TSH in human beings submitted to severe iodine deficiency. Ann Endocrinol (Paris) 1981;42:40A.

120. Malvaux P. Thyroid function during the neonatal period, infancy and childhood. In: Delange F, Fisher DA, Malvaux P, eds. Pediatric thyroidology. Basel: S. Karger AG, 1985:33–43.

121. Bachtarzi H, Benmiloud M. TSH-regulation and goitrogenesis in severe iodine deficiency. Acta Endocrinol (Copenh) 1983;103: 21–27.

122. Delange F, Thilly C, Camus M, et al. Evidence for fetal hypothyroidism in severe endemic goiter. In: Robbins J, Braverman LE, eds. Thyroid research. Amsterdam: Excerpta Medica, 1976:493–496.

123. Thilly CH, Delange F, Lagasse R, et al. Fetal hypothyroidism and maternal thyroid status in severe endemic goiter. J Clin Endocrinol Metab 1978;47:354–360.

124. Delange F, Thilly C, Bourdoux P, et al. Influence of dietary goitrogens during pregnancy in humans on thyroid function of the newborn. In: Delange F, Iteke FB, Ermans AM, eds. Nutritional factors involved in the goitrogenic action of cassava. Ottawa: International Development Research Centre, 1982:40–50.

125. Courtois P, Delange F, Bourdoux P, et al. Significance of neonatal thyroid screening tests in severe endemic goiter. Ann Endocrinol (Paris) 1982;43:51A(abst).

126. Thilly CH, Vanderpas J, Bourdoux P, et al. Prevention of myxedematous cretinism with iodized oil during pregnancy. In: Ui N, Torizuka K, Nagataki S, Miyai K, eds. Current problems in thyroid research. Amsterdam: Excerpta Medica, 1983:386–389.

127. Kochupillai N, Pandav CS. Neonatal chemical hypothyroidism in iodine-deficient environments. In: Hetzel BS, Dunn JT, Stanbury JB, eds. The prevention and control of iodine deficiency disorders. Amsterdam: Elsevier Science, 1987:85–93.

128. Sava L, Delange F, Belfiore A, et al. Transient impairment of thyroid function in newborn from an area of endemic goiter. J Clin Endocrinol Metab 1984;59:90–95.

129. Merke F. History and iconography of endemic goitre and cretinism. Bern: Hans Huber, 1984:1–339.

130. Kŝ nig MP. Die Kongenitale Hypothyreose und der Endemische Kretinismus. Berlin: Springer-Verlag New York, 1968:1–175.

131. Bürgi H, Supersaxo Z, Selz B. Iodine deficiency diseases in Switzerland one hundred years after Theodor Kocher's survey: a historical review with some new goitre prevalence data. Acta Endocrinol (Copenh) 1990;123:577–590.

132. Gutekunst R, Scriba PC. Goiter and iodine deficiency in Europe: the European Thyroid Association report as updated in 1988. J Endocrinol Invest 1989;12:209–220.

133. Delange F, Heidemann P, Bourdoux P, et al. Regional variations of iodine nutrition and thyroid function during the neonatal period in Europe. Biol Neonate 1986;49:322–330.

134. Delange F, B□rgi H. Iodine deficiency disorders in Europe. Bull World Health Organ 1989;67:317–326.

135. Delange F, Dunn J, Glinoer D. Iodine deficiency in Europe. A continuing concern. New York: Plenum Press, 1993:1–491.

136. Delange F, Robertson A, McLoughney E, et al. Elimination of iodine deficiency disorders (IDD) in central and eastern Europe, the Commonwealth of Independent States, and the Baltic States. Geneva: World Health Organization; 1998. Publication WHO/Euro/NUT/98.1:1–168.

137. Delange F. Iodine deficiency in Europe anno 2002. Thyroid International 2002;5:1–18.

138. Anonymous. West and central Europe assesses its iodine nutrition. IDD Newsletter 2002;18:51–55.

139. Vitti P, Delange F, Pinchera A, et al. Europe is iodine deficient. Lancet 2003;361.

140. Gerasimov G. IDD in eastern Europe and central Asia. IDD Newsletter 2002;18:33–37.

141. Delange F, Van Onderbergen A, Shabana W, et al. Silent iodine prophylaxis in western Europe only partly corrects iodine deficiency: the case of Belgium. Eur J Endocrinol 2000;143:189–196.

142. Kahaly GJ, Dietlein M. Cost estimation of thyroid disorders in Germany. Thyroid 2002;12:909–914.

143. Mannar V. The iodization of salt for the elimination of iodine deficiency disorders. In: Hetzel BS, Pandav CS, eds. S.O.S. for a billion: the conquest of iodine deficiency disorders. New Delhi: Oxford University Press, 1996: 98–118.

144. Thilly CH, Vanderpas JB, Bebe N, et al. Iodine deficiency, other trace elements and goitrogenic factors in the etiopathogeny of iodine deficiency disorders (IDD). Biol Trace Elem Res 1992;32:229–243.

145. Malone J, Unger J, Delange F, et al. Thyroid consequences of Chernobyl accident in the countries of the European Community. J Endocrinol Invest 1991;14:707–717.

146. Glinoer D. Maternal and fetal impact of chronic iodine deficiency. Clin Obstet Gynecol 1997;40:102–116.

147. Caron P, Hoff M, Bazzi S, et al. Urinary iodine excretion during normal pregnancy in healthy women living in the Southwest of France: correlation with maternal thyroid parameters. Thyroid 1997;7:749–754.

148. Glinoer D, Lemone M, Bourdoux P, et al. Partial reversibility during late postpartum of thyroid abnormalities associated with pregnancy. J Clin Endocrinol Metab 1992;74:453–457.

149. Glinoer D, De Nayer P, Delange F, et al. A randomized trial for the treatment of excessive thyroid stimulation in pregnancy: maternal and neonatal effects. J Clin Endocrinol Metab 1995; 80:258–269.

150. Berghout A, Endert E, Ross A, et al. Thyroid function and thyroid size in normal pregnant women living in an iodine replete area. Clin Endocrinol (Oxf) 1994;41:375–379.

151. Bleichrodt N, Escobar del Rey F, Morreale de Escobar G, et al. Iodine deficiency: implications for mental and psychomotor development in children. In: DeLong GR, Robbins J, Condliffe PG, eds. Iodine and the brain. New York: Plenum Press, 1989:269–287.

152. Vermiglio F, Sidoti M, Finocchiaro MD, et al. Defective neuromotor and cognitive ability in iodine-deficient schoolchildren of an endemic goiter region in Sicily. J Clin Endocrinol Metab 1990;70:379–384.

153. Fenzi GF, Giusti LF, Aghini-Lombardi F, et al. Neuropsychological assessment in schoolchildren from an area of moderate iodine deficiency. J Endocrinol Invest 1990;13:427–431.

154. Vitti P, Aghini-Lombardi F, Antonangeli L, et al. Mild iodine deficiency in fetal/neonatal life and neuropsychological performances. Acta Med Austriaca 1992;19:57–59.

155. Aghini-Lombardi F, Pinchera A, Antonangeli L, et al. Mild iodine deficiency during fetal/neonatal life and neuropsychological impairment in Tuscany. J Endocrinol Invest 1995; 18: 57–62.

156. Burrow GN, Dussault JH. Neonatal thyroid screening. New York: Raven Press, 1980:1–322.

157. Delange F, Dodion J, Wolter R, et al. Transient hypothyroidism in the newborn infant. J Pediatr 1978;92:974–976.

158. Delange F, Dalhem A, Bourdoux P, et al. Increased risk of primary hypothyroidism in preterm infants. J Pediatr 1984;105: 462–469.

159. Nordenberg D, Sullivan K, Maberly G, et al. Congenital hypothyroid screening programs and the sensitive thyrotropin assay: strategies for the surveillance of iodine deficiency disorders. In: Delange F, Dunn JT, Glinoer D, eds. Iodine deficiency in Europe. A continuing concern. New York: Plenum Press, 1993:211–218.

160. Delange F. Screening for congenital hypothyroidism used as an indicator of IDD control. Thyroid 1998;8:1185–1192.

161. Riccabona G. Treatment of the individual patient with endemic goiter. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. New York: John Wiley and Sons, 1980: 351–394.

162. Stanbury JB, Ermans AM, Hetzel BS, et al. Endemic goitre and cretinism: public health significance and prevention. WHO Chron 1974;28:220–228.

163. Demaeyer EM, Lowenstein FW, Thilly CH. The control of endemic goitre. Geneva: World Health Organization, 1979:1–86.

164. Mannar VMG, Dunn JT. Salt iodization for the elimination of iodine deficiency. MI/ICCIDD/UNICEF/WHO; 1995:1–126.

165. Sullivan KM, Houston R, Gorstein J, et al. Monitoring universal salt iodization programmes. Wageningen: PAMM/MI/ICCIDD; 1995:1–101.

166. WHO/UNICEF/ICCIDD. Recommended iodine levels in salt and guidelines for monitoring their adequacy and effectiveness. Geneva: World Health Organization; 1996. WHO/NUT/96.13: 1–9.

167. Marine D, Kimball OP. Prevention of simple goiter in man. Arch Intern Med 1920;25:661–672.

168. Bürgi H. Iodine deficiency in Switzerland. In: Delange F, Robertson A, McLoughney E, Gerasimov G, eds. Elimination of iodine deficiency disorders (IDD) in central and eastern Europe, the Commonwealth of Independent States, and the Baltic States. Geneva: World Health Organization, 1998:15–20.

169. UNICEF. The progress of nations. New York: United Nations Children's Fund; 1995:1–54.

170. Clements W, Gibson HB, Coy JF. Goiter prophylaxis by addition of potassium iodate to bread. Lancet 1970;1:489–501.

171. Maberly GF, Eastman CJ, Corcoran JM. Effect of iodination of a village water-supply on goitre size and thyroid function. Lancet 1981;2:1270–1272.

172. Squatrito S, Vigneri R, Runello F, et al. Prevention and treatment of endemic iodine-deficient goiter by iodination of a municipal water supply. J Clin Endocrinol Metab 1986;63:368–375.

173. Fisch A, Pichard E, Prazuck T, et al. A new approach to combatting iodine deficiency in developing countries: the controlled release of iodine in water by a silicone elastomer. Am J Public Health 1993;83:540–545.

174. Cao XY, Jian, XM, Kareem A, et al. Iodination of irrigation water as a method of supplying iodine to a severely iodine-deficient population in Xinjiang, China. Lancet 1994;344:107–110.

175. Delong GR, Leslie PW, Wang SH, et al. Effect on infant mortality of iodination of irrigation water in a severely iodine-deficient area of China. Lancet 1997;350:771–773.

176. Hetzel BS, Thilly CH, Fierro-Benitez R, et al. Iodized oil in the prevention of endemic goiter and cretinism. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. New York: John Wiley and Sons, 1980:513–532.

177. Dunn JT. Iodized oil in the treatment and prophylaxis of IDD. In: Hetzel BS, Dunn JT, Stanbury JB, eds. The prevention and control of iodine deficiency disorders. Amsterdam: Elsevier Science, 1987:127–134.

178. Dunn JT. The use of iodized oil and other alternatives for the elimination of iodine deficiency disorders. In: Hetzel BS, Pandav CS, eds. S.O.S. for a billion. The conquest of iodine deficiency disorders. New Delhi: Oxford University Press, 1996: 119–128.

179. Benmiloud M, Chaouki M., Gutekunst R, et al. Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J Clin Endocrinol Metab 1994;19: 20–24.

180. Delange F. Administration of iodized oil during pregnancy: a summary of the published evidence. Bull World Health Organ 1996;74:101–108.

181. ICCIDD. UN General Assembly pledges sustainable elimination of iodine deficiency disorders by 2005. IDD Newsletter 2002;18:17–19.

182. Dunn JT. Complacency: the most dangerous enemy in the war against iodine deficiency. Thyroid 2000;10:681–683.

183. WHO. Iodine and health. Eliminating iodine deficiency disorders safely through salt iodization. Geneva: World Health Organization; 1994:1–7.

184. Knudsen N, Bülow I, Jorgensen T, et al. Comparative study of thyroid function and types of thyroid dysfunction in two areas in Denmark with slightly different iodine status. Eur J Endocrinol 2000;143:485–491.

185. Connolly RJ, Vidor GI, Stewart JC. Increase in thyrotoxicosis in endemic goitre area after iodation of bread. Lancet 1970;i: 500–502.

186. Todd CH, Allain T, Gomo ZAR, et al. Increase in thyrotoxicosis associated with iodine supplements in Zimbabwe. Lancet 1995;346:1563–1564.

187. Bourdoux P, Ermans AM, Mukalay AMW, et al. Iodine induced thyrotoxicosis in Kivu, Zaire. Lancet 1996;347:552–553.

188. Delange F, de Benoist B, Alnwick D. Risks of iodine-induced hyperthyroidism following correction of iodine deficiency by iodized salt. Thyroid 1999;9:545–556.

189. Baltisberger BL, Minde CE, B□rgi H. Decrease of incidence of toxic nodular goiter in a region of Switzerland after full correction of mild iodine deficiency. Eur J Endocrinol 1995;132: 546–549.

190. Yan F, Teng W, Shan Z, et al. Epidemiological survey on the relationship between different iodine intakes and the prevalence of hyperthyroidism. Eur J Endocrinol 2002;146:613–618.

191. Azizi F, Daftarian N. Side-effects of iodized oil administration in patients with simple goiter. J Endocrinol Invest 2001;24: 72–77.

192. Mirmiran P, Kimiagar M, Azizi F. Three-years survey of effects of iodized oil injection in schoolchildren with iodine deficiency disorders. Exp Clin Endocrinol Diabetes 2002;110:393–397.

193. Dremier S, Coppée F, Delange F, et al. Thyroid autonomy: mechanism and clinical effects. J Clin Endocrinol Metab 1996; 81:4187–4193.

194. Jonckheer MH, Velkeniers B, Van Haelst L. Further characterization of iodine-induced hyperthyroidism based on the direct measurement of intrathyroidal iodine stores. Nucl Med Commun 1992;13:114–118.

195. Delange F, Lecomte P. Iodine supplementation: benefits outweigh risks. Drug Saf 2000;22:89–95.

196. McConahey WM, Keating FR, Beahr OH, et al. On the increasing occurrence of Hashimoto's thyroiditis. J Clin Endocrinol Metab 1962;22:542–544.

197. Kahaly GJ, Dienes HP, Beyer J, et al. Iodide induces thyroid autoimmunity in patients with endemic goiter: a randomised, double-blind, placebo-controlled trial. Eur J Endocrinol 1998; 139:290–297.

198. Aghini-Lombardi F, Antonangeli L, Martino E, et al. The spectrum of thyroid disorders in an iodine-deficient community: the Pescoporgano survey. J Clin Endocrinol Metab 1999;84: 561–566.

199. Vanderpump MPJ, Tunbridge WMG, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Wickham Survey. Clin Endocrinol (Oxf) 1995;43:55–68.

200. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988–1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489–499.

201. Braverman LE. Iodine and the thyroid: 33 years of study. Thyroid 1994;4:351–356.

202. Pearce EN, Gerber AR, Gootnick DB, et al. Effects of chronic iodine excess in a cohort of long-term American workers in West Africa. J Clin Endocrinol Metab 2002;87:5499–5502.

203. Premawardhana LDKE, Parkes AB, Smyth PPA, et al. Increased prevalence of thyroglobulin antibodies in Sri Lanka schoolgirls—is iodine the cause? Eur J Endocrinol 2000;143:185–188.

204. Money WL, Rawson RW. The experimental production of thyroid tumors in the rat exposed to prolonged treatment with thiouracil. Cancer 1950;3:321.

205. Pendergrast WJ, Milmore BK, Marcus SC. Thyroid cancer and thyrotoxicosis in the United States: their relation to endemic goiter. J Chronic Dis 1961;13:22–38.

206. Vigneri R, Pezzino V, Squatrito S, et al. Iodine deficiency and thyroid cancer. In: Delange F, Robertson A, McLoughney E, Gerasimov G, eds. Elimination of iodine deficiency disorders (IDD) in central and eastern Europe, the Commonwealth of Independent States, and the Baltic States. Geneva: World Health Organization; 1998.:67–72.

207. Williams ED. Dietary iodide and thyroid cancer. In: Hall R, Kŝbberling J, eds. Thyroid disorders associated with iodine deficiency and excess. New York: Raven Press, 1985: 201–207.

208. Levi F, Vecchia CL, Randriamiharisoa A. Cancer mortality in Switzerland, 1985–89. Soz Praventivmed 1991;36:112–126.

209. Slowinska-Klencka D, Klencki M, Sporny S, et al. Fine-needle aspiration biopsy of the thyroid in an area of endemic goitre: influence of restored sufficient iodine supplementation on the clinical significance of cytologic results. Eur J Endocrinol 2002; 146:19–26.

210. Braverman LE. Adequate iodine intake-the good far outweights the bad. Eur J Endocrinol 1998;139:14–15.

211. Delange F. Risks and benefits of iodine supplementation. Lancet 1998;351:923–924.

212. Delange F, Bürgi H, Chen ZP, et al. World status of monitoring of iodine deficiency disorders control programs. Thyroid 2002;12:915–924.

213. Delange F, de Benoist B, Pretell E, et al. Iodine deficiency in the world: where do we stand at the turn of the century. Thyroid 2001;11:437–447.