Iodine deficiency, other trace elements, and goitrogenic factors in the etiopathogeny of iodine deficiency disorders (IDD)

�9 1992 by The Humana Press, Inc. All rights of any nature, whatsoever, reserved. 0163-4984/92/3201-3--0229 $03.00

Iodine Deficiency, Other Trace Elements, and Goitrogenic Factors in the

Etiopathogeny of lodine Deficiency Disorders (IDD)

C. H. THILLY,"" J. B. VANDERPAS, 1 N. BEBE, 2 K. NTAMBUE, 3

B. CONTEMPRE, 1 B. SWENNEN, 1 R. MORENO-REYES, 1

P. BOURDOUX, 1 AND F. DELANGE 1

'Cemubac University of Brussels; 2School of Public Health of Kinshasa, Zaire; and 3Bureau National TDCI

Kinshasa/Gombe, Zaire

Received January 31, 1991; Accepted May t4, 1991

ABSTRACT

Severe goiter, cretinism, and the other iodine deficiency disorders (IDD) have their main cause in the lack of availability of iodine from the soil linked to a severe limitation of food exchanges. Apart from the degrees of severity of the iodine deficiency, the frequencies and symptomatologies of cretinism and the other IDD are influenced by other goitrogenic factors and trace elements. Thiocyanate overload originating from consumption of poorly detoxified cassava is such that this goitrogenic factor aggravates a relative or a severe iodine deficiency. Very recently, a severe selenium deficiency has also been associated with IDD in the human population, whereas in animals, it has been proven to play a role in thyroid function either through a thyroidal or extrathyroidal mechanism. The former involves oxidative damages mediated by free radicals, whereas the latter implies an inhibition of the deiodinase responsible for the utilization of T4 into T3. One concludes that:

*Author to whom all correspondence and reprint requests should be addressed.

Biological Trace Element Research 229 rot 32, 1992

230 Thilly et al.

1. Goiter has a multifactorial origin; 2. IDD are an important public health problem; and 3. IDD are a good model to study the effects of other trace

elements whose actions in many human metabolisms have been somewhat underestimated.

Index Entries: Iodine deficiency disorders; goitrogenic factor; trace elements; selenium deficiency; thiocyanate overload; free radical; deiodinase; hypothyroidism.

INTRODGCTION

The main cause of endemic goiter is a problem of biochemistry of soil--the lack of availability of iodine, which when it is associated with a limitation of food exchanges produces a severe nutritional iodine deficiency. The main complication of severe iodine deficiency has been classically described as the typical cases of marked cretinism. Further- more, cretinoid subjects presenting only some of the symptoms of the most florid cases have always been observed (1). However, recently, the importance of a whole spectrum of iodine deficiency disorders (IDD), such as low birthweight, high perinatal mortality, endemic cognitive disorders, and motor or intellectual subnormality, has been reassessed, and these disorders are now considered to be the main public health consequences of iodine deficiency (2,3).

Frequency of cretinism and other IDD varies according to the levels of severity of the iodine deficiency. It is, for instance, well known that cretinism is only observed when the iodine intake is <40 or even <20 p~g/d. However, goiter frequencies and the relative frequencies of the different types of cretinism and other IDD in different endemias are also related to other goitrogenic factors, such as goitrin, flavonoids, or thiocyanate overload (4).

The aim of the present article is first to assess the public health dimension and the most likely consequences of different degrees of severity of iodine deficiency. The persistence of mild to moderate iodine deficiency in Europe will be discussed. A second aim is to further review, as an example of complementary goitrogenic factors, the role of thiocyanate overload and selenium deficiency in the severe goiter endemia of Ubangui in the North of the Republic of Zaire (5).

MATERIALS AND METHODS

Three main sets of data will be introduced and discussed. First there will be the results from studies undertaken in the extremely severe goiter endemia of Ubangui in the North of Zaire. A second set of data will be taken from European studies already published, including original re-

Biological Trace Element Research Vol. 32, 1992

Trace Elements in Endemic Goiter 231

sults relating to the maintenance in Europe of some degree of iodine deficiency. Finally, other relevant data will be discussed in order to present both an original contribution and a review, including the epidemiological and public health dimension of iodine deficiency disorders.

More precisely, data from Ubangui Zaire will first include results from a prospective controlled trial, including placebo cases to assess if an intramuscular injection of iodized oil containing a supraphysiological dose of iodine given to pregnant women during pregnancy will be beneficial or deleterious to the fetus. Secondly, results from an experi- ment in which two groups of adolescent girls received either a meal of cassava or a control meal of rice will be presented. Results will consist of the urinary excretion of stable and radioactive iodine (after the oral administration of a tracer dose of 131I) during the 6 h following the meal (6). Finally, an epidemiological study in which, as a first step, the thyroid and selenium status was determined in three areas affected with severe, intermediate, or absence of goiter will be presented. In a second step, a selenium supplementation trial was undertaken in 23 school children by giving them 50 ~g of selenium as selenomethionine. At the end of the study, all school children received iodized oil (5). Data from Europe will include results obtained in 1975 of a collaborative study aimed at deter- mining the average 24-h radioiodine thyroidal uptake as an index of the iodine intake in various European medical centers. The subjects are patients undergoing thyroidal investigation in these centers whose status has been considered normal after the exploration. Another set of data are adapted from a collaborative study undertaken 10 yr later by the Euro- pean Thyroid Association (ETA) and the European Society for Pediatric Endocrinology (ESPE) on the regional variations of iodine nutrition and its consequence on screening for congenital hypothyroidism (7).

RESULTS

IDD are typically problems of whole populations, and many preven- tive interventions, such as iodated salt, iodized fortified water, baby foods, or intramuscular and oral administration of iodized oil, are now available with different and complementary medical or public health indications. It has thus become more important to classify the different goiter endemias according to their three degrees of severity, i.e., severe, moderate, and mild goiter endemias. However, the criteria and signifi- cances in terms of the health dimension of these three categories are not yet completely defined or understood (3).

From Severe to Moderate Iodine Deticiency

Severe iodine deficiency is generally defined by a high prevalence of goiter (above 30 or 50% of the total population), the presence of cretinism (prevalence above 1% and as high as 10%), and a median urinary iodine

Biological Trace Element Research Vot. 32, 1992

232 Thilly et al.

level below 25 lag of iodine/L of urine. A large spectrum of IDD is expected in such endemia.

The endemia of Ubangui is a good example of such extremely severe endemia. Total goiter frequency in that area is above 50% for several million inhabitants, and Fig. 1 illustrates the main complication, i.e., endemic cretinism. As shown in this figure, there are in each village groups of 20-40 myxedematous cretin and cretinoid subjects affected with mental deficiency, neurological and hypothyroidal symptoms, severe dwarfism or stunted growth, and so forth. They represent a true population scourge impairing social and economic development.

The origin of these disorders has been mainly attributed to long- standing hypothyroidism during a critical period of thyroid adaptation, i.e., fetal and early postnatal lives. Indeed at birth, no cases or as much as 15% of neonatal hypothyroid neonates were observed, respectively, in a controlled trial of mothers whose iodine deficiency has been or not been corrected at midpregnancy. Other differences were also present in children of untreated compared to those born of iodized-oil-treated mothers: mean birthweight 2634 ___ 52 (n = 98) vs 2837 + 55 (n = 112) (P < 0.01), infant mortality 228 vs 137% (P < 0.05), developmental quotient 104 + 3 vs 115 + 2 (P < 0.05). Figure 2 illustrates that, for all weight groups, the infantile mortality rate is higher in the untreated compared to the treated group. The difference is significant between the groups of all treated and untreated children (P < 0.05) as well as between the groups of children with birthweights between 2.0-3.5 kg (P < 0.01). In view of the serious disorders described in Ubangui as well as in other severe endemias, such as in Ecuador (8) or China (9), a new recognition of the whole spectrum of iodine deficiency disorders (IDD) linked to severe endemias has been reached. Some works have also suggested that moderate goiter through subclinical hypothyroidism during the critical period of brain maturation around birth and during childhood may lead to suboptimal psychomotor development (9,10). However, adequately controlled studies are scarce in this domain, and the question is not entirely solved today.

/Vlild or Moderate lodine Deficiency in Europe

With regard to the persistence of mild to moderate iodine deficiency and its medical and economical consequences, the different countries of Europe are an exemplary case of the situation in the industrialized countries. Indeed, some of these countries, such as Great Britain, have never had a significant iodine deficiency problem, whereas a few others, such as Switzerland, Finland, the Netherlands, or East Germany, have implemented very effective and cheap iodized salt prophylactic programs. However, many others have failed to introduce such public health measures (1I).

Table 1 presents the 24-h thyroidal radioiodine uptake from various European centers. A large variability, resulting from different iodine



Fig. 1. Group of adult myxedematous cretins and cretinoids from one village of Ubangui.

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intake, is observed among the countries, and it is also present among the different centers inside each country. Indeed, many pockets of moderate or even severe goiter still affect populat ion groups of u n k n o w n sizes in Europe today. This is, for instance, the situation in some areas of Greece, Spain, and Sicily, and it has also been demonstra ted in France. In the southern part of West Germany, different studies demonstrate the persistence of a severe iodine deficiency with the consequence that 1% of the neonates born in this area present at birth a delay in bone maturation as well as transient hypothyroxinemia. He idemann and Stubbe (12) determined for instance that the mean serum thyroxine in these neonates was

Biological Trace Element Research VoL 32, 1992

234 Thiily et aL

Table 1 Mean, Mode and Median of 24-H Radioactive Thyroidal Uptake

in 45 Medical Centers from 7 European Countries

Number of Number 24 h I thyroidal uptake Country subjects of centers Mean _+ SEM Mode Median

Switzerland 162 2 32.6 + 0.8 28 32 Netherlands 411 3 39.9 -+ 0.5 40 37 France 938 8 40.9 + 0.6 38 38 Italy 1510 10 42.2 _+ 0.4 40 37 Belgium 1232 14 47.0 _+ 0.5 44 46 Luxembourg 69 1 52.3 +-_ 1.5 55 53 Germany 1055 7 59.6 + 0.5 62 60 Total 5377 45 46.2 _+ 0.2 40 42

6.3 ~g/dL compared to 16.6 for the other newborns. Furthermore, this transient hypothyroxinemia corrects itself with iodine treatment in a few days.

Very recently in a large study of pregnant women, Glinoer et al. (13) suggested that, linked to the supplementary demand that pregnancy imposes upon iodine stores and to the persistent borderline iodine deficiency still prevalent today in Belgium, the thyroid status of pregnant women, although still in the normal range, were in fact suboptimal. They demonstrated that the iodine status of these pregnant women degrada- ted itself in the course of pregnancy and lactation.

With regard to the critical period of thyroid adaptation around birth, hypothyroxinemia may be linked either to internal factors, i.e., absence of the thyroid gland by agenesia or ectopia in 1 out of every 3000--4000 births, or to external factors, such as moderate or severe iodine deficiency. In the first case, the hypothyroidism is permanent, and in order to avoid brain damage, a systematic screening of newborns followed by thyroid hormone replacement therapy is now organized in all industrialized countries. In the second case, the hypothyroidism is often only transient around birth, and the long-term consequence of such an episode on brain and bone maturation is not clear. However, it is much more frequent than permanent neonatal hypothyroidism, so that during screening for permanent congenital hypothyroidism, the recall rate is very much inflated with false positive cases linked to this iodine deficiency.

Table 2 presents, from a collaborative work by Delange et al. (7), the mean urinary iodine concentration for four towns in Europe, together with the recall rate at screening and the percentage of newborns that will be diagnosed later as affected with permanent congenital hypothyroidism in contrast to those only affected with a transient episode of hypothyroidism. In Stockholm, where the iodine intake is satisfactory, the recall rate of newborns is low (0.07% of the screened children, which is approx 1 out of every 1400 newborns), and among those recalled children, 60% are true permanent cases of congenital hypothyroidism. By

B~ological Trace Element Research Vol. 32, 1992


Table 2 Urinary Iodine, Percentage of Newborns Recalled for Abnormally Low Thyroid Hormones During Screening for Congenital Hypothyroidism

and Percentage of Those Recalled Affected by True Permanent Congenital Hypothyroidism

Towns

Median Recall rate, % Permanent urinary I, of newborns hypothyroidism,

p.g/dL screened % of rec. child.

Stockholm 11.0 0.07 60.0 Rome 4.7 0.11 31.2 Brussels 4.8 0.21 15.2 South Germany '~ 1.2 0.89 3.4

"Heidelberg and Freiburg in Southern Germany.

contrast, in the Heidelberg-Freiburg area, where the iodine deficiency is severe, 0.89% of the children are recalled, which is 1 out of every 112 newborns, but among them only 3.4% proved themselves to be true congenital hypothyroid children, the others having only a transient episode. The situation in Rome or Brussels is intermediary. The percentage of true cases in these towns is between 15-30% of the children recalled, and this situation is still representative of many areas of Europe. The psychological and economic costs of elevated recall rate are high, and it would justify in itself iodized salt prophylaxis.

With regard to the economic cost of not preventing iodine deficiency disorders, Pfannenstiel, in 1985 (14), estimated this cost for West Ger- many, which was one of the countries of Europe still very much affected with iodine deficiency. This cost added up to 700 million German marks per year (approx 400 million dollars), whereas a rough estimation of the cost of iodizing all the alimentary salt would be on the order of 4 million dollars per year. Even if these estimates are not very precise, the benefit/ cost ratio will be definitely positive and in the order of 100 for this country.

Other Goitrogenic and Trace Element Factors

Apart from the different degrees of iodine deficiency, other goitrogenic factors play complementary roles in the etiopathogeny of IDD. Two of them are thiocyanate overload and selenium deficiency, as documented in the Ubangui endemia. A study of the goitrogenic role of chronic exposure to moderately elevated levels of thiocyanate originating from consumption of cassava has been made in Nigeria by Ekpechi (15). Among extensive studies undertaken in Ubangui (16), the role of thiocyanate overload in the development of late juvenile hypothyroidism has been studied by Vanderpas et al. (17). Table 3 compares three main parameters of thyroid function together with urinary iodine and thiocyanate concentrations for Ubangui children ages < 1 yr, 1-4, and 4-7 yr.


236 Thilly et aL

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The three parameters of serum thyroxine (T4) the main thyroid hormon from which triiodothyronine (T3) another active thyroid hormon is obtained (among others by deiodination of T4 in peripherical tissues) together with thyreostimulin, the pituitary hormon whose serum level is increased as a reaction to decreased serum T4 and/or T3. Compared to children of K 1 yr, those 4-7 yr old present a much lower mean serum thyroxine (4.8 + 4.2 vs 9.3 + 6.1 ~g/dL) and a higher mean serum TSH (24.3 +_ 9.6 vs 10.4 ___ 7.6 ~U/L) without significant changes in serum triiodothyronine. No change is observed for the urinary iodine concentration, which is very low, but the degradation of the thyroid status is accompanied by a progressive increase in urinary thiocyanate.

Figure 3A compares the evolution of the prevalence of goiter of serum thiocyanate, and urinary iodine for the same age period. Imme- diately after birth, the prevalence of goiter and serum thiocyanate is highly linked for thiocyanate to its placental transfer from the mothers. During the breast-feeding period, serum thiocyanate drops because thiocyanate concentration is low in human milk. Furthermore, between 3-12 mo of age, some of the children are still exclusively breast fed, whereas others are already partially or entirely weaned. The former have individual thiocyanate levels that are normal and significantly lower than those already weaned with cassava-based food. After 1 yr of age, the serum thiocyanate concentration increases to reach adult values about 4 x the normal average around 3 yr of age. For the same children, Fig. 3B presents, in a stereogram, the serum thyroxine both as a function of increasing urinary iodine deficiency and thiocyanate overload. Children with both goitrogenic factors have extremely low thyroxine with a mean of 2.1 ~g/dL.

In two groups of 11 adolescent girls from that endemia, Delange and Ermans (6) gave a meal of poorly detoxified cassava to one group and a control meal of rice to the other group. Stable and radioactive iodine during the 6 h following the meals were compared. For the stable iodine, the mean averages were 16.7 + 1.8 and 7.4 + 2.2 ~g/dL (P ~ 0.05) after the cassava and rice meal, respectively. For radioactive iodine, they were 9.4 + 1.7 and 5.8 ___ 1.1% of the dose (P > 0.05), respectively.

Thus, together with many other data, these results suggest that, at different levels of concentration, thiocyanate overload inhibits either the entry or the organification of iodine in the thyroid gland, so that in both cases there is an increased loss of iodine through the urine, thus aggravating a relative or severe iodine deficiency. Further experimental studies suggest that thiocyanate at these levels has no deleterious effect per se, but acts only by aggravating the iodine deficiency, so that iodine prophylaxis will prevent all the detrimental effects observed.

In three localities of Zaire affected with severe, moderate, and no goiter, respectively, Vanderpas et al. (5) studied the thyroid and selenium statuses. Figure 4 presents the individual and mean values of two parameters of selenium status (serum selenium and glutathione perox-


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Fig. 3. A: evolution with age of the prevalence of goiter, the serum thiocyanate, and the urinary iodine concentration. For the middle panel, the normal range (shaded area) and the thiocyanate values in children exclusively breast fed are also shown. B: Serum T4 in children of Ubangui 0-7 yr old, as a function of both increasing iodine deficiency and thiocyanate overload. Serum T4 values at the bottom of each column.


200

100

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SERUM SELENIUM (ng/ml)

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Fig. 4. Mean and individual values of two parameters of selenium status (serum selenium and red blood cell glutathion peroxidase) and of one parame- ter of iodine deficiency (urinary iodine) in three localities of Zaire affected with no goiter, moderate, or severe goiter, respectively.

idase measured in the red blood cells) together with urinary iodine concentration in these three areas. A progressive and important decrease is observed for all three parameters, and very low values are reached in the severely goitrous area, thus demonstrat ing both very severe iodine and selenium deficiencies in that area.

Biological Trace Element Research VoL 32, 1992

240 Thilly et aL

In view of the severity of the selenium deficiency in that severely goitrous area, a supplementation trial was undertaken in which 23 school children received 50 ~g/d of selenium as selenomethionine. With regard to selenium status immediately before and after 2 mo of selenium supplementation, the mean serum selenium values were 27 + 15 ng/mL and 74 + 22 (P < 0.001), respectively, and those of glutathion peroxidase in red blood cells were 3.0 + 1.9 U/g Hgb and 5.8 + 2.2 (P < 0.001). Thus, one observes extremely low selenium status before supplementation, and a total or partial significant correction of the selenium status after supplementation.

For the thyroid status, the classical pattern of compensated hypothyroidism was observed before selenium supplementation with a low mean serum thyroxine at 5.7 -+ 3.5 ~g/dL, a mean serum triiodothyronine at 134 -+ 31 ng/dL, and a mean serum TSH at 9.6 (7.0-13.1) ~U/mL. After 2 mo of selenomethionine supplementation, one observed a further decrease of serum thyroxine whose mean decreased to 3.8 + 1.8 (P < 0.001) together with a similar decrease in serum rT3 from 8.1 +_ 7.5 ng/dL before to 5.9 + 4.7 (P < 0.001) after supplementation. These decreases were not accompanied by any change in mean serum T3 or TSH, which were at 146 + 26 ng/dL and at 7.2 (5.6-9.3) ~U/mL after supplementation and not significantly different from their mean values before supplementation.

Table 4 presents the same parameters of thyroid function for the same children, but divided into two groups of 16 and 7 children classified according to their initial serum T4 being above or under 4 ~g/dL, respectively. It is observed that the decrease in serum T4 is restricted to the children with the normal serum T4 at the start and is not observed for those with the lowest serum T4. It is not accompanied either by any change in serum T3 or TSH. On the contrary, for the children with the lowest thyroid status at the start, a slight significant decrease in serum TSH is observed when an increase would have been expected in case of aggravated thyroid failure.

DISCUSSION

Severe goiter accompanied by a large spectrum of iodine deficiency disorders is a true population scourge impairing optimal socioeconomic development. The relative severity of the iodine deficiency in different areas is the major factor responsible for the size of the public health problem raised by this spectrum of disorders. Severe iodine deficiency is particularly damaging during the fetal and early postnatal lives, which are critical periods of thyroid adaptation as well as of brain, bone, and somatic maturation.

Persistence of mild, moderate, or even severe goiter in some areas of Europe has as possible consequences a suboptimal development of chil-


Trace Elements in Endemic Goiter

Table 4 Serum T4, T3, and TSH Immediately Before and After 2 Mo

of Selenium Supplementation

241

Before Se After 2 m o Groups Thyr. par. supplem. SE supplem.

T4 > 4 a T4 (~g/dL) 7.4 + 0.7 4.4 +__ 0.4 b T3 (ng/dL) 126 + 7 134 _ 5 c TSH (p~U/mL) 5.2 + (4.0-6.7) 5.6 (4.0-7.7) c

T4 < 4 T4 (p~g/dL) 1.7 _+ 0.3 2.2 + 0.5 c T3 (ng/dL) 154 + 13 172 ___ 12 c TSH (p,U/mL) 39 (10-163) 13 (9-18) ~

aThe results are presented separately for the 16 (upper part) and the 7 (lower part) children who have had an initial serum T4 above or under 4 ~g/dL, respectively.

bp < 0.001. CNonsignificant. dp < 0.05.

dren linked to transient hypothyroidism, unacceptably high recall rates in screening for congenital hypothyroidism, persistent thyroid abnor- malities in women, and important diagnostic, therapeutic, and related costs. In view of the good feasibility and low cost of iodine salt prophylaxis programs in such industrialized countries, there is no excuse not to undertake this prophylaxis there immediately.

It has now been clearly demonstrated that other goitrogenic foods, such as cabbage, cassava, millet, and so on, or other contaminants, such as flavonoids, phenols, resorcinols, and so on, have a clear complementary deleterious effect either in maintaining some frequency of goiter in areas with sufficient iodine intake or, more seriously, in playing a key role in the et iopathogeny of goiter, cretinism, and other IDD. Thiocya- nate overload, although it probably has no toxic effect per se at relatively low level, is acting by increasing the iodine loss through the urine, thus aggravating a preexisting severe iodine deficiency. Furthermore, in some specific situations, such as the goiter endemia of Ubangui in Zaire, it plays a major role in the etiopathogeny of juvenile hypothyroidism, which is so prevalent in that endemia.

The very recent demonstrat ion that this area is also affected with a selenium deficiency whose level is only the second in severity after the Keshan area in China, where a cardiomyopathy has been linked to this deficiency, introduces a third factor whose mode of action is not yet known. Selenium deficiency in rats has been implicated in the inhibition of the prohormone thyroxine (T4) being deiodinated into the more active triiodothyronine (T3) (18). It has also been suggested that it has a facilitat- ing or damaging effect in the thyroid hormone synthesis by either increasing the availability of hydrogen peroxides needed for this synthesis or by creating oxidative damages linked to the excessive concentration of free radicals (19). Whatever the explanation, the data from Ubangui

Biological Trace Element Research Vot. 32, 1992

242 ?'hilly et at

clearly demonstrate for the first time that selenium deficiency and supplementation are a regulating factor of human thyroid metabolism in certain circumstances.

Thus, in conclusion, and in spite of the fact that iodine supplementation often eliminates most of the complications of iodine deficiency, goiter and the other IDD are diseases of polyfactorial origin. The public health dimension linked to this trace element deficiency is now increas- ingly recognized, and it is thus possible that this will also be the case for other trace elements whose roles in many human metabolisms have been probably very underestimated.

ACKNOWLEDGMENTS

The authors wish to thank Professors A. M. Ermans, H. L. Vis, J. Dumont, A. Diplock, A. Jaumotte, J. Pasteels, P. Salmon, E. Sand, Dr. Ngandu-Kabeya, Dr. J. Mahaut, Dr. Matundu, Dr. N. Kumu, Dr. K. Luvivila, Dr. K. Ntambue, M. Relecom, and J. P. Beernaerts for their generous support. This work was made possible through contract ULB/ FRSM no. 3.4535.90, contract Commission of European Community, Science, Research and development no. 130/2522, the Administration G6n6rale de Coop6ration au D6veloppement (AGCD), and The Bureau National de Lutte contre les Troubles Dhs ~ la Carence Iod6e, Kinshasa.

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Trace Elements in E n d e m i c Goiter 243

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Documents

Iodine deficiency, other trace elements, and goitrogenic factors in the etiopathogeny of iodine deficiency disorders (IDD)