THYROIDVolume 4, Number 1, 1994Mary Ann Liebert, Inc., Publishers

The Disorders Induced by Iodine Deficiency

F. DELANGE

ABSTRACT

This paper reviews present knowledge on the etiology, pathophysiology, complications, prevention, and therapy ofthe disorders induced by iodine deficiency. The recommended dietary allowances of iodine are 100 pg/day for adultsand adolescents, 60-100 p-g/day for children aged 1 to 10 years, and 35-40 pg/day in infants aged less than 1 year.When the physiological requirements of iodine are not met in a given population, a series of functional anddevelopmental abnormalities occur including thyroid function abnormalities and, when iodine deficiency is severe,endemic goiter and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death, andinfant mortality. These complications, which constitute a hindrance to the development of the affected populations,are grouped under the general heading of iodine deficiency disorders (IDD). At least one billion people are at risk ofIDD. Iodine deficiency, therefore, constitutes one of the most common preventable causes of mental deficiency in theworld today. Most of the affected populations live in montainous areas in preindustrialized countries, but 50 to 100million people are still at risk in Europe. The most important target groups to the effects of iodine deficiency from a

public health point ofview are pregnant mothers, fetuses, neonates, and young infants because the main complicationof IDD, i.e., brain damage resulting in irreversible mental retardation, is the consequence of thyroid failure occurringduring pregnancy, fetal, and early postnatal life. The main cause of endemic goiter and cretinism is an insufficientdietary supply of iodine. The additional role of naturally occurring goitrogens has been documented in the case ofcertain foods (milk, cassava, millet, nuts) and bacterial and chemical water polluants. The mechanism by which thethyroid gland adapts to an insufficient iodine supply is to increase the trapping of iodide as well as the subsequent stepsof the intrathyroidal metabolism of iodine leading to preferential synthesis and secretion of triiodotyronine (T3). Theyare triggered and maintained by increased secretion of TSH, which is ultimately responsible for the development ofgoiter. The acceleration of the main steps of iodine kinetics and the degree of hyperstimulation by TSH are much moremarked in the pédiatrie age groups, including neonates, than in adults, and the development of goiter appears as anunfavorable side effect in the process of adaptation to iodine deficiency during growth. The most serious complicationof iodine deficiency is endemic cretinism, a syndrome characterized by irreversible mental retardation together witheither a predominant neurological syndrome or predominant hypothyroidism, or a combination of both syndromes.The prophylactic action of iodine on the incidence ofboth types of cretinism demonstrates the fundamental etiologicalrole of iodine deficiency. The possible additional roles of thyroid growth-blocking immunoglobulins and of seleniumdeficiency have been suggested. The pathogenic roles of maternal and fetal hypothyroidism or a combination of bothas well as of hypothyroidism present during the postnatal period are clearly established, but the relative importanceof the three mechanisms in the pathogenesis of the various clinical manifestations of endemic cretinism is not entirelyclearly established. A particularly important issue established both in severe and moderate conditions of iodinedeficiency is that obvious neurointellectual deficits due to the deficiency are also frequently observed in individualswho do not present any of the other signs ofendemic cretinism. The status of iodine nutrition was recently reevaluatedin all European countries, including those in the Eastern part of the continent. Iodine deficiency is presently undercontrol in only 5 countries (Austria, Finland, Norway, Sweden, and Switzerland). All other countries are still affectedto varying degrees, especially in the southern and central parts of the continent. The public health consequences ofiodine deficiency in Europe are an elevated thyroidal uptake of radioiodine that aggravates the risk of thyroid cancerin case of a nuclear accident, the occasional presence of neurointellectual deficits in schoolchildren, elevated

Department of Pediatrics, Hospital Saint-Pierre, University of Brussels, 1000 Brussels, Belgium.

107

108 DELANGE

frequencies of transient primary hypothyroidism and of transient hyperthyrotropinemia in young infants. Neonatalscreening for congenital hypothyroidism using serum TSH as primary screening test appears as a particularlysensitive index of the effects of iodine deficiency at a population level and as a monitoring tool in the evaluation of theeffects of iodine prophylaxis. Although theoretically entirely preventable, IDD still prevail in the world because ofvarious socioeconómica!, cultural, and political limitations to adequate programs of iodine supplementation,especially in Europe. Prevention of iodine deficiency in Western countries is most efficiently achieved by programs ofsalt iodization at the level of one part of iodide to 10,000-50,000 parts salt, depending on the degree of the deficiencyand on salt intake. Iodized salt should be made available not only for household salt but also in industrial foodproduction including cheese and bread as well as for animal consumption. As a matter of fact, milk appears as themain source of iodine in many industrialized countries. In preindustrialized countries where food fortification withiodine is impossible to organize, prophylaxis and therapy of IDD can be achieved extremely efficiently by theadministration of large quantities of iodine (20-960 mg) in the form of slowly resórbanle iodized oil administered byintramuscular injections or orally. This approach not only corrected thyroid function on a long-term basis withprogressive disappearance of goiter but also prevented the occurrence of endemic cretinism and endemic mentalretardation.

INTRODUCTION

IODINE IS A TRACE ELEMENT present in the human body inminute amounts (15-20 mg, i.e., 0.02 x 10"3% of body

weight). Iodine is an essential substrate for synthesis of thyroidhormones. Thyroxine is approximately 60% iodine by weightand the daily requirement of iodine is at least equal to the amountof hormonal iodine degraded and unrecovered daily by thethyroid gland. In adolescents and adults, this amount is 50-100p-g/day. Consequently, the classical recommended dietary al-lowance (167) of iodine is 100 u.g/day for adolescents and adults(150 p-g/day in pregnant and lactating women). It is 60-100P-g/day for children aged 1-10 years, 40 p-g/day for infants aged6-12 months, and 35 p-g/day for infants 6 months of age or

younger, which represents about 8 u-g/kg/day, 5 p-g/dL/milk and 7p-g/100 kcal. However, a réévaluation of the iodine requirementsin young infants based on iodine balance studies showed that, atleast in conditions of marginally low iodine intake as observed inEurope, the recommended dietary allowance should be increasedto 90 p-g/for infants aged less than 1 year (47).

When the physiological requirements of iodine are not met ina given population, a series of functional and developmentalabnormalities occur (Table 1), including thyroid function abnor-malities and, when iodine deficiency is severe, endemic goiterand cretinism, endemic mental retardation, decreased fertilityrate, increased perinatal death, and infant mortality. Thesecomplications, which constitute a hindrance to the developmentof the affected population, are grouped under the generalheading of iodine deficiency disorders (IDD) (112, 113).

Broad geographic areas exist in which the population dailyintake of iodine is below the recommended dietary allowanceand in which the population is affected by IDD (116, 182).These areas usually are mountainous because the soils lowest iniodine are those that were covered longest by the quaternaryglaciers. When these glaciers melted, most of the iodine leachedout of the ground beneath (124). The most important goitrousareas in the world today include the Himalayas and the Andes.Iodine deficiency also occurs in lowlands far from the oceanssuch as the central part of Africa or, to a lesser extent, of Europe.

The data available in 1987 (116), probably underestimated,indicated that at least 800 million people were at high risk ofdeveloping IDD, including approximately 190 million withgoiter and 3.2 million with endemic cretinism. Recent figuresfrom Europe should probably increase this number by another50-100 million (65, 68, 105, 168). Iodine deficiency disorderstherefore constitute a major public health issue and constituteone of the most common preventable cause of mental deficiencyin the world today (113). Although theoretically entirely pre-ventable, these disorders still prevail because of various socio-economical, cultural, and political limitations to adequate pro-grams of iodine supplementation (188).

Table 1. The Spectrum of Iodine DeficiencyDisorders (IDD)°

Fetus

Neonate

Infant-childAdolescent

Adult

AbortionsStillbirthsIncreased perinatal and infant mortalityEndemic cretinism

NeurologicalMental deficiencyDeafmutismSpastic diplegiaSquint

MyxedematousMental deficiencyHypothyroidismDwarfism

GoiterOvert or subclinical hypothyroidismGoiterJuvenile hypothyroidismImpaired mental and physical developmentGoiter and its complicationsHypothyroidismEndemic mental retardationDecreased fertility rate

"Adapted from Hetze! (112,113).

DISORDERS INDUCED BY IODINE DEFICIENCY 109

Table 2. Classification of Goiter Endemias by Severity0

VariablesTarget

population Mild IDD Moderate IDD Severe IDD

Prevalence of goiter (%) (Grade > 0) SAC 5.0-19.9 20-29.9Frequency of thyroid volume > 97th centile by SAC 5.0-9.9 10-19.9

ultrasound (%)Median urinary iodine level (p-g/dL) SAC 5.0-9.9 2.0-4.9Median breast milk, iodine level (p-g/dL) Lactating 3.5-5.0 2.0-3.5

women day 5Median urinary iodine level (p-g/dL) Newboms 3.5-5.0 1.5-3.0Frequency of TSH > 5 mU/L whole blood (%) Newborns 3.0-19.9 20.0-39.9Median Tg (ng/mL) C/A 10.0-19.9 20.0-39.9

5=30.05=20.0

<2.0<2.0

<1.53=40>40

"IDD, iodine deficiency disorders; SAC, school-aged children; C/A, children and adults; Tg, thyroglobulin. Adapted from a WHO/UNICEF/ICCIDDconsultation on IDD indicators, WHO Geneva, November 1992, unpublished, with permission; Delange et al. (63), Delange and Bürgi (65), and Dunn andVan Der Haar (80).

This paper reviews present knowledge on the disordersinduced by iodine deficiency. As indicated in Table 2, threedifferent degrees of severity of IDD have been considered.Although the basic mechanisms of adaptation to iodine defi-ciency are similar in the three degrees, we will considerseparately the problem of severe IDD complicated by cretinismas seen typically in remote areas in preindustrialized countriesand mild or moderate IDD as seen typically in Europe. In thethree degrees of severity of IDD, special attention will bedevoted to the prenatal period and the pédiatrie age groups as

they constitute the most important target groups regarding themain complication of iodine deficiency, i.e., brain damage andmental retardation (71, 114). Extensive review papers withexhaustive bibliographies are available on endemic goiter andthe other disorders induced by iodine deficiency, including theirpédiatrie aspects (16, 39,40,42,45, 53, 67, 71, 79, 113, 116,143, 180-183).

Stage III: very large goiter that can be recognized at aconsiderable distance (Fig. 1).

The total goiter rate is the prevalences of stages I, II, and III;the visible goiter rate is the prevalence of stages II and III.

This classification can be simplified into stages 0, no goiter; I,palpable but not visible goiter, and II, visible goiter when theneck is in a normal position (WHO/UNICEF/ICCIDD consulta-tion on IDD indicators, unpublished).

These clinical classifications are appropriate for field surveysin remote areas where no other methods are available. However,

SEVERE IODINE DEFICIENCY DISORDERS:ENDEMIC GOITER AND CRETINISM

EpidemiologyThe following definitions were proposed by the Pan Ameri-

can Health Organization (PAHO) for public health studiesconducted in the field (62):

Goiter. A thyroid gland with lateral lobes that have a volumegreater than the terminal phalanges of the thumbs of the personexamined is considered goitrous. In these conditions the thyroidis enlarged by a factor of 4-5.

Type ofgoiter. The following stages classify goiter accordingto the size of the thyroid gland:

Stage 0: no goiter.Stage la: goiter detectable only by palpation and not visible

when the neck is fully extended.Stage lb: goiter palpable and visible only when the neck is

fully extended; this stage also includes nodular glands,even if not goitrous.

Stage II: goiter visible with the neck in normal position;palpation is not needed for diagnosis. FIG. 1. Stage III nodular goiter in Nepal.

110 DELANGE

the availability and the use of transportable ultrasonographicequipment in field studies have shown that in such studies theclinical assessment of thyroid size is imprecise for small goiters,especially in children (104). In these conditions, the distinctionbetween absence of goiter (stage 0) and the presence of smallgoiter (stage I) is difficult and, consequently, the overallprevalence of goiter can be incorrect. Therefore, the frequencydistribution of thyroid volume measured by ultrasonography ishighly recommended (106), especially in endemic areas wherethe visible goiter rate is low.

Endemic goiter. According to PAHO (62), an area is arbi-trarily defined as endemic with respect to goiter if more than10% of the children aged 6 to 12 years are found to be goitrous.The figure 10% was chosen because a higher prevalence usuallyimplies an environmental factor, while a prevalence of severalpercent is common even when all known environmental factorsare controlled.

A WHO/UNICEF/ICCIDD consultation on IDD indicatorsrecently proposed to decrease the threshold of prevalence ofgoiter from 10 to 5% (unpublished).

In epidemiologic surveys, the most rigorous methods forevaluating the prevalence of goiter consists of examination ofthe entire population of a likely area. This is occasionallydifficult to organize, especially in urban areas. Many surveysare limited, therefore, to particular age groups, most typically tochildren in school (187). The prevalence of goiter is criticallyinfluenced by age and sex with a maximal frequency in femalesduring puberty and child bearing age (Fig. 2).

maleso—o females

0 10 20 30 40 50 60 70Age(years)

FIG. 2. Changes of the prevalence of goiter as a function of ageand sex in severe endemic goiter (Idjwi Island, Zaire). FromDelange and Ermans (67), with permission.

The most serious areas of endemic goiter and cretinism arelocated in remote areas with a self-subsistence economy systemin the Himalayas and the Andes and in the Central part of theAfrican continent. An accurate description of the status ofiodine nutrition and goiter in Africa, Latin America, Asia,Oceania, and Europe is presently available (68, 113,116, 182)as a result of the combined efforts of national authorities in allcountries in the world, the International Council for Control ofIodine Deficiency Disorders (ICCIDD), the United NationsChildren's Fund (UNICEF), and the World Health Organization(WHO).

EtiologyAn insufficient dietary supply of iodine is the main cause of

endemic goiter and cretinism. Its role has been demonstrated bynumerous epidemiological, clinical, and experimental data re-

ported in details elsewhere (7, 53, 67, 113).Measurement of iodine in food is technically difficult and

tedious (123). Adults are in equilibrium with their iodineenvironment and the fecal excretion of iodine is usually consid-ered as negligible (137). Therefore, most estimates of thedietary supply of iodine are based on the measurements of theexcretion of iodine in urines. Complete 24-h collection of urinesis often difficult to achieve in field investigations. An alternativeprocedure is the measurement of the ratio between the concen-trations of iodine and creatinine in casual urine samples (119) oreven just the concentration of iodine, provided that the observa-tion covers at least 50 to 100 randomly selected urine samples inone given population sample (11).

Goitrogenic factors in the diet or environment other thaniodine deficiency can play a role in the etiology of IDD. The roleof these substances had to be considered as endemic goiter hasbeen found in regions with no iodine deficiency (30, 36, 154)and, conversely, as endemic goiter can be absent in areas withsevere iodine deficiency (28, 48, 170). The role of thesegoitrogenic factors has been extensively reviewed elsewhere(53,67, 95,129, 162, 198). Natural goitrogens were first foundin vegetables of the genus Brassica (the Cruciferae family),which possess goitrogenic properties in animals (162). Theirantithyroid action is related to the presence of thioglucosides,which, after digestion, release thiocyanate and isothiocyanate(87, 99, 129). Another important group of naturally goitrogensis the cyanoglucosides, which have been found in several staples(cassava, maize, bamboo shoots, sweet potatoes, lima beans)(59,87, 198). After ingestion, these glucosides release cyanide,which is detoxified by conversion to thiocyanate, a powerfulgoitrogenic agent that acutely acts by inhibiting thyroid iodidetransport and, at higher doses, competes with iodide in theorganification process (86,206,207). Cassava (manioc in French,Yuca in Spanish), is one of the basic foodstuffs in tropical areas.Its role in the etiology of endemic goiter, in association withiodine deficiency, has been clearly demonstrated in Africa (10,43,49,59,86) and confirmed in Malaysia (136). The determin-ing factor involved in the goitrogenic action of cassava is thebalance between the dietary supplies of iodine and thiocyanate(59). Goiter develops when the urinary iodine/thiocyanate ratio,used as index of this balance, decreases below a criticalthreshold of about 3 p-g iodine per mg thiocyanate. This canoccur when thiocyanate is elevated in the presence of overt

DISORDERS INDUCED BY IODINE DEFICIENCY 111

iodine deficiency or even in the presence of an almost normaliodine supply when thiocyanate overload is excessive (56).

Other aspects of environmental goitrogenesis are reviewedand discussed in depth in the classical textbook of Gai tan (95),which contains an exhaustive bibliography on the topic: inaddition to milk and cassava, other foodstuffs are involved in theetiology of endemic goiter. The role of millet was demonstratedin Sudan. The goitrogens appear to be C-glycosylflavones andthiocyanate. The nut of Araucaria (Pinon) has been suspected tohave a role in the pathogenesis of endemic goiter in an Indianreservation in Chile. The role of a palm-tree fruit was suspectedin Brazil. The goitrogen involved is a potent inhibitor of thyroidperoxidase. An excess intake of iodine, arbitrarily defined as 2mg or more per day, inhibits the proteolysis and release ofthyroid hormones and eventually produces "iodide goiter." Theendemic coast goiter described in Japan and China is caused notonly by the high quantity of iodine contained in seaweeds butalso by phloroglucinol and other polyhydroxyphenols containedin large quantities in the seaweeds and which are potentantithyroid compounds.

Bacterial and chemical pollution of water supplies also play arole: lithium containing water in Venezuela, microorganismscontaining water supplies in Greece and in Richmond County,Virginia. The classical studies of Gaitan and colleagues (95) inColombia and Eastern Kentucky demonstrated the role of waterpolluants (resorcinol, phalate ester derivatives, and disulfides)originating from shales and coals, humic substances, and gram-negative bacteria.

Pathophysiology: Adaptation of thyroid functionto iodine deficiency

In adults. Endemic goiter is an adaptative disease that devel-ops in response to an insufficient supply ofdietary iodine. Thisclassic concept was established in 1954 by Stanbury andcolleagues (180) and has been confirmed since by an enormousamount of clinical and experimental observations (7, 53, 116,143, 183).

When iodine intake is abnormally low, adequate secretion ofthyroid hormones may still be achieved by marked modifica-tions of thyroid activity. These adaptative processes includestimulation of the trapping mechanism as well as of the subse-quent steps of the intrathyroidal metabolism of iodine, leadingto preferential synthesis and secretion of triiodothyronine (T3).They are triggered and maintained by increased secretion ofTSH.

Increased stimulation by TSH. Elevated serum TSH levelshave been reported repeatedly but not systematically in humanswith chronic iodine deficiency (22, 27, 50, 90, 110, 111, 153).Moreover, within a given area, striking and large variations inserum TSH levels are observed in adults independently of thepresence or absence of goiter (27, 50, 153). Differences in theduration of elevated TSH levels or in thyroid responsiveness aswell as other factors, including thyroid autoregulation indepen-dent of TSH, may determine whether goiter develops (17, 77,82, 184). Experimental studies indicate that growth hormone,perhaps through IGF, as an intermediate, induces thyroidgrowth. Human chorionic gonadotropin at high concentrationsactivates the cAMP cascade, and consequently proliferation, inFRTL-5 cells and human thyroid cells. Several growth factors

have been shown to be mitogenic for thyrocytes: epidermalgrowth factor (EGF), fibroblast growth factor (FGF), andinsulin like growth factor 1 (IGF,) (77). However, the role ofthese growth factors in the pathogenesis ofendemic goiter is notdemonstrated. Similarly, the possible role of thyroid autoimmu-nity in the goitrogenesis in endemic goiter remains largelyunknown.

Increase in iodide trapping. The fundamental mechanism bywhich the thyroid gland adapts to an insufficient iodine supply isto increase the trapping of iodide. This results in the accumula-tion within the gland of a larger percentage of the ingestedexogenous iodide and a more efficient reuse of iodide directlyreleased by the thyroid or generated by the degradation ofthyroid hormones (180, 183, 204). The increased iodide trap-ping is the result of both TSH-independent augmentation ofmembrane iodide trapping and TSH stimulation of the iodidepump (17, 77, 184).

Increased thyroidal uptake of 13II and reduction of urinaryiodine excretion are the markers of a goiter endemia caused byiodine deficiency. A clearcut inverse relationship between bothparameters was demonstrated in 1954 (180), has been con-firmed in a large number of goiter endemias (7), and is furtherillustrated in Figure 3. This figure indicates that as soon as theiodine supply decreases below the physiological requirement of100 p-g iodine/day in adults, there is an increase in the thyroidaluptake of radioiodine, indicating an increase in the clearancerate of iodide by the thyroid.

In these conditions, in spite of a decrease in the serumconcentration of iodide, the absolute uptake of iodide by thethyroid remains normal and the organic iodine content of the

PREVALENCE Of GOITER (%>

i|¿.

i M

THYROID«. ORGANIC IODINE Imgl

24-H ""| THYROIDAL UPTAKE! %Do*el

0 20 40 60 80 100 120 140 160 180 200 300 500 700 900URINARV EXCRETION OF IODINE Uig/dayl

FIG. 3. Relationship between the daily urinary excretion ofiodine and the prevalence of goiter, the hormonal iodine content ofthe thyroid (thyroidal exchangeable organic iodine pool, deter-mined by kinetic studies), and the 24-h thyroidal uptake of radioio-dine. From Delange and Ermans (67), with permission.

112 DELANGE

thyroid remains within the limits of normal (i.e., 10-20 mg) as

long as the iodine intake remains above a threshold of about 50u.g/day. Below this critical level of iodine intake, in spite of afurther increase of thyroid clearance, the absolute uptake ofiodide diminishes and the iodine content of the thyroid de-creases. Goiter, the visible consequence of iodine deficiency bypublic health standards starts to develop usually when the iodineintake is still lower.

Modifications of intrathyroid iodine metabolism and alter-ations of circulating thyroid hormones. Studies in the rat showthat thyroid hyperplasia induced by iodine deficiency is associ-ated with an altered pattern of tracer iodine distribution in thegland characterized by increased poorly iodinated compounds,monoiodotyrosine (MIT) and triiodothyronine (T3), and a de-crease in diiodotyrosine (DIT) and thyroxine (T4) (2, 82, 127,183). These severely iodine-deficient animals have a low serumconcentration of T4 and a high serum concentration of T3 (2).Similarly, the pattern of circulating thyroid hormones in clini-cally euthyroid adults in areas of severe iodine deficiency (Table3) is characterized by low serum T4, elevated TSH, and normalor supranormal T3 (27, 50, 51, 111, 120, 153, 156). Themechanisms responsible for this pattern are unclear but mayinclude thyroidal secretion of T4 and T3 in the proportion inwhich they exist within the gland (2, 82, 127), preferentialsecretion of T3 ( 101 ) or increased peripheral conversion of T4 toT3. The shift to increased T3 secretion and increased serum

T3/T4 ratios play an important role in the adaptation to iodinedeficiency, since T3 possesses about four times the metabolicpotency of T4 but requires only 75% as much iodine forsynthesis (101). Thyroidal uptake of radioiodine is elevated, the

thyroid organic iodine exchangeable pool is low, and themarkedly accelerated turnover rate of this pool is evidenced byan elevated apparent hormonal secretion rate and an elevatedserum protein bound I31I.

In severe endemic goiter, there is an inverse relationshipbetween serum T4 and TSH but this correlation is not found forserum T3, which is the most active thyroid hormone (82). Thisparadoxical finding is explained by the fact that the direct effectof T4 on TSH suppression results from intrapituitary T4 to T3conversion and the subsequent binding of T3 to the nucleus ofthe thyrotropes; in other tissues, the largest part of intracellularT3 originates from circulating T3 (130, 131). These findingsaccount 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 isdepressed. In less severe goiter endemias, serum T4 and T3levels are only slightly modified or even remain normal. In theseconditions, basal TSH is slightly increased and the TSH re-

sponse to intravenous injection of thyrotropin-releasing hor-mone is often exaggerated, indicating an increase in TSHpituitary reserves (145), a condition often reported as subclini-cal hypothyroidism (89).

Morphologic changes. Diffuse enlargement of the thyroid isfound in severe endemic goiter only in young subjects. At thisstage, parenchyma is abundant, follicular epithelium is highwith papillary infolding, and colloid is rare. A later stage is theformation of small nodules that dissect the entire thyroid tissueby formation of nodules of very different size and consistency.At this time, histologically, the major part of the gland isoccupied by extremely distended vesicles with a flattened

Table 3. Comparison of Epidemiological and Biochemical Data Exploring Thyroid Function"

Zaire

VariablesBrussels

Euthyroid adults Euthyroid adultsMyxedematous

cretins

Daily urinary excretion of iodine (pig/day)Prevalence of goiter (%)Serum concentration of

T4 (p-g/dL)

T3 (ng/dL)TSH (p-U/mL)Protein-bound'311 24 h (% dose/L)

Thyroidal uptake of ,3II 24 h (% dose)

Thyroidal exchangeable organic iodine pool (mg)

"Apparent" hormonal secretion rate (%/day)

51.2 ± 5.8(38)

3

8.1 ±0.1(125)

144 ± 3(124)

1.7 ± 1.1(255)

0.06 ± 0.01(27)

46.4 ±1.1(255)

15.8 ±3.5(12)

0.39 ± 0.04(12)

15.5 ± 1.3(243)76.8

4.9 ± 0.2(358)

166 ± 3(299)

18.6 ± 2.1(365)

0.17 ±0.02(105)

65.2 ± 0.9(167)

1.6 ±0.2(30)

1.92 ±0.12(24)

0.5 ± 0.01(120)

46± 3(109)

302 ± 20(122)

1.09 ±0.18(19)

28.3 ± 2.6(6)

0.01-0. \b(8)

"In Brussels, Belgium and in the Idjwi Island and Ubangi endemic goiter areas, Zaire. Results given as mean ± SEM or range. (* ) The number of patientsis given in parentheses. The differences between the three groups are highly significant (p < 0.0001) for all variables. Adapted from Ermans et al. (84),Dumont et al. (76), Camus et al. (24), Delange et al. (52), Delange et al. (58).

DISORDERS INDUCED BY IODINE DEFICIENCY 113

epithelium filled with colloid. A few patches of thyroid folli-cles, on the contrary, show a typical pattern of stimulation ( 143,183, 184).

In the pédiatrie age groups. Sequential development of themechanisms of adaptation to iodine deficiency during growth.The metabolic pattern observed in adults in severe endemicgoiter represents the final stage of an adjustment process, whichis critically influenced by age: a study on the time course as a

function of age from 3 to 22 years of the changes in thyroidfunction in goitrous and nongoitrous inhabitants of the IdjwiIsland endemic goiter area in Zaire (39,40) (Fig. 4) showed thatthyroidal uptake of radioiodine reached its maximum value inthe earliest years of life and then declined progressively untiladulthood. Uptake was systematically higher in goitrous than innongoitrous patients. The thyroid exchangeable hormonal io-dine pool was about 0.5 mg iodine in young infants; it increasedprogressively with age but reached only 2.5 mg in adults, whichis 4 to 10 times lower than in adults in nonendemic areas.

Conversely, the renewal rate of intrathyroidal radioactive iodine(apparent secretion rate, K'4) decreased drastically with age.

This study demonstrates that the acceleration of the mainsteps of iodine kinetics is much more marked in childhood andadolescence than in adulthood and progressively decreasesduring growth. Similar studies conducted in the area of IdjwiIsland with a similar degree of iodine deficiency but withoutgoiter showed that in this area, (a) radioiodine uptake also was

increased but to a lesser extent, (b) iodine stores in the thyroidwere much lower, and (c) the plasma PBI was higher. Thesedata suggest that goiter is by no means the optimal mechanism ofadaptation to environmental goitrogens but constitutes a ratherunfavorable side-effect of such a mechanism.

Age-related modifications of TSH regulation. By studyingthe time course as a function of age of the serum concentrationsof TSH, T4 and T3 in clinically euthyroid patients in severe

endemic goiter in the Ubangi area in Zaire (40), it was shown

U6 C/.dO4»)

AGE (YEARS)

FIG. 4. Changes with age of the 6-h thyroidal uptake of radioio-dine (U6), the thyroidal exchangeable organic iodine pool (QG),and the apparent hormonal secretion rate by the thyroid (K'4) ingoitrous (G+) and nongoitrous (Go) inhabitants of the Idjwi Islandendemic goiter area, Zaire. Values recorded as mean ± SEM. Thenumber of patients is shown in parentheses. Adapted from Delangeand Ermans (67), with permission.

(Fig. 5) that, unexpectedly, the highest values of serum TSHwere observed in the youngest infant in spite of the fact that theyalso had the highest serum T4 values. Consequently, for a givenvalue of T4, the level of TSH was roughly twice as high in the 4to 15 year age group as in the 16 to 20 year age group. Thesevariations of the TSH7T4 ratio as a function of age are poorlyunderstood: they could reflect the increase in the iodine storeswithin the thyroid as a function of age. They also could beexplained by modifications with age of the turnover rate of T4(138) and/or by modifications in thyroid gland sensitivity toTSH including progressive development of thyroid tissue auton-omy (4).

Thyroid function in early life. One of the major achievementsof recent years is the results obtained by pilot studies on

systematic screening for congenital hypothyroidism in the new-

born in iodine-deficient areas. The studies have shown that, insuch areas, the alterations of thyroid function in neonates aremuch more frequent and severe than in adults.

The most extreme situation has been reported from Zaire (54,58, 186) (Table 4 and Fig. 6) where thyroid failure in neonatesresults from the combined action of iodine deficiency andthiocyanate overload during fetal life. In this area (Fig. 6), cordserum TSH and T4 in unselected newborns showed an importantvariability between individuals and were frequently distinctlyoutside the normal range. Eleven percent of the newborns hadboth a cord serum TSH above 100 p-U/ml and a cord serum T4

14

12

10

8

6

4

2

T4 (pg/dl )BRUSSELS

-« UBANGI

"'"t°..•» T _-4o-K?<839)

.. %',-tfi''' -••'"3I'¿-. ¿Ç~~ï*r.f

i T5H(LiU/ml)50TT ÎII'll \A40

30

20

10

0.

*k+-..,

I-1-1-1-1-1-

0 2 4 6 8 10 15rlrt (399)

(813)

20 40 60 80

AGE (YEARS)FIG. 5. Changes with age of the serum concentrations of T4 andTSH in the Ubangi endemic goiter area, Zaire (o) and in Brussels(•). Values recorded as mean ± SEM. The number of patients isshown in parentheses. Adapted from Delange and Ermans (67),with permission.

114 DELANGE

Table 4. Comparison of Biochemical Findings in Mothers at Delivery and Newborns"

Brussels, Belgium Ubangi area, Zaire

Variables Mothers at delivery Newborns (cord) Mothers at delivery Newborns (cord)

Urinary concentration of I (p-g/day)SCN (mg/dL)

Serum concentration of T4 (u.g/dL)T3 (ng/dL)TSH (p-U/mL)SCN (mg/dL)

4.4 ± 0.3(119)

1.03 ±0.05(120)

12.7 ± 0.3(112)

182 ±5(109)

3.6 ±0.2(111)

0.35 ± 0.03(111)

11.4 ±0.2(204)

50 ± 1(202)

8.2 ± 0.4(201)

0.27 ± 0.01(200)

1.8 ± 0.09(130)

1.41 ±0.09(128)

8.0 ± 0.5(117)

196 ±6(118)

14.0 ± 2.4(120)

0.76 ± 0.03(170)

7.4 ± 0.4(83)

96 ±7(84)

70.7 ± 13.1(83)

0.66 ± 0.04(131)

"In Brussels, Belgium and in the Ubangi endemic goiter area, Zaire. Results are given as mean ± SEM. The number of patients is shown in parentheses.The differences for each variable between Brussels and Ubangi are highly significant (p < 0.0001). Modified from Delange et al. (58).

below 3 p-g/dL, indicating severe congenital hypothyroidismaccording to the criteria used in western countries, where theincidence of the condition is only 0.025% (57). A similarfrequency of biochemical hypothyroidism has been found in thesame area in young infants (38), indicating that the situationfound in neonates was not due to a nonspecific factor such as thestress ofdelivery. The picture of congenital hypothyroidism was

only transient in some infants but remained unchanged in others(40). The abnormalities of neonatal thyroid function were

prevented by correcting iodine deficiency in mothers before or

during pregnancy (186, 191) (Fig. 6).

In-204) <n.1S«) (n*35)

BRUSSELS UBANGIUNTREATED BOOED Ol TREATED

MOTHERSIn -204) (B-1S6) (n-35)

FIG. 6. Comparison of the frequency distributions of the serumconcentrations of TSH and T4 in cord blood in Brussels and innewborns in the Ubangi endemic goiter area in Zaire bom tountreated mothers or to mothers treated with a single injection ofiodized oil during pregnancy. The values within the intervalmean ± 2 SD in Brussels are not given as individual symbols but as

percentages of the total number of cases. The number of newbornsis shown in parentheses. The dotted lines correspond to the valuesconsidered as suggestive (hypo?) or characteristic (hypo) of perma-nent sporadic congenital hypothyroidism in the neonatal thyroidscreening program in Brussels. From Delange and Ermans (67),with permission.

A similar prevalence of congenital hypothyroidism in severeendemic goiter has been reported from the Himalayas in North-ern India, Nepal, and Bhutan (121). Alterations of thyroidfunction in neonates have been subsequently reported fromother less severe endemic areas, even when thyroid function inadults was barely or even not modified ( 172). The alterations arecharacterized by a shift of the frequency distributions of neona-tal TSH and T4 toward elevated and low values, respectively.

ComplicationsIn addition to the mechanical complications of goiter and the

increased mortality rate due to thyroid cancer in endemic goiter,principally due to the late diagnosis of the condition in a

population where thyroid enlargement and nodules are the rule(109, 169, 202), the main complication of endemic goiter isbrain damage due to a lack of thyroid hormone at the cellularlevel during the critical period of brain development.

Endemic cretinism and endemic mental retardation. In se-

vere endemic goiter, an abnormally high number of patientsexhibit irreversible anomalies of intellectual and physical devel-opment. These anomalies are extremely polymorphous andhave been grouped under the general heading of endemiccretinism. The prevalence of the disease may attain 5 to 15% ofthe population. It is by far the most serious complication ofendemic goiter and represents a veritable scourge, both medi-cally and socially (41, 45, 113, 158, 183).

The etiopathogenesis of endemic cretinism is only partlyunderstood and information on its pathology is scanty (73, 122).For these reasons, the diagnosis of endemic cretinism is onlydescriptive and is made on epidemiological grounds. In 1986, a

study group of the Pan American Health Organization (PAHO)formulated the following definition of endemic cretinism (62):

The condition of endemic cretinism is defined by threemajor features:

A. Epidemiology. It is associated with endemic goiterand severe iodine deficiency.

DISORDERS INDUCED BY IODINE DEFICIENCY 115

B. Clinical features. These comprise mental defi-ciency, together with either:

1 ) A predominant neurological syndrome including de-fects of hearing and speech and characteristic disorders ofstance and gait of varying degree; or

2) Predominant hypothyroidism and stunted growth.Although in some regions, one of the two types may

predominate, in other areas a mixture of the two syndromeswill occur.

C. Prevention. In areas in which iodine deficiency hasbeen adequately corrected, endemic cretinism has beenprevented.

Epidemiology, clinical features and laboratory data. Theclinical features of endemic cretinism summarized in the PAHOdefinition correspond to the two extreme types of endemiccretinism clearly defined from the pioneer work of McCarrisonin 1908 (144) and repeatedly reported in subsequent epidemio-lógica! and clinical descriptions of endemic cretinism: the firsttype is marked by dominant neurological disorders (neurologi-cal cretinism) and the second by signs of severe thyroid insuffi-ciency (myxedematous cretinism).

Figure 7 illustrates the picture of neurologic cretinism as seen

in Nepal: the endemic cretins are extremely mentally retardedand most of them are reduced to a vegetative existence. Almostall are deaf mutes and are afflicted with the following neurolog-ical defects: (a) impaired voluntary motor activity, usuallyinvolving paresis or paralysis of pyramidal origin, chiefly in thelower limbs, with hypertonia, clonus, and plantar cutaneousreflexes in extension. Extrapyramidal signs are occasional, (b)

FIG. 7. Neurological endemic cretinism. Nepal. Clinically eu-

thyroid 41-year-old man. Normal height. Severe mental retarda-tion, deafmutism, spastic diplegia with hyperreflexia, clonus andBabinski sign. Stage II goiter.

spastic or ataxic gait. In the severest cases, walking or even

standing is impossible, and (c) strabismus.Subsequent detailed clinical studies in Ecuador (69, 70, 93)

and China (12, 107, 108, 133, 174, 203) emphasized theimpariment of the extrapyramidal tract in neurological endemiccretinism. In these areas, the pattern of neurological deficitincluded proximal spasticity and rigidity involving the lowerextremities more than the upper, with increased knee jerks andadductor jerks. By contrast, increased reflexes or spasticitywere usually absent or mild in the lower extremities withBabinski sign only in 20% of the cretins. According to DeLong(70), this clinical picture suggests dysfunction of the basalglanglia, especially putamen and globus pallidus, thus of theextrapyramidal tract, rather than dysfunction of the pyramidaltract with spastic diplegia. Unfortunately, recent accurate dataon brain pathology in neurological cretinism are missing.Computerized tomographic scans of cretins from Ecuador dem-onstrated widespread atrophy including the cerebral cortex andsubcortical structures and the brainstem, with correspondingenlargement of the basal cisterns, the lateral ventricles, and thesulci over the surface of the cerebral cortex (165).

The prevalence of goiter in neurological cretins is as high as

the noncretin population of the area and they are clinicallyeuthyroid. Thyroid function is usually normal (12, 23, 29, 171,177) but can indicate subclinical hypothyroidism with elevatedbasal TSH or exaggerated TSH response to TRH (173, 209).

Figure 8 show the clinical aspects of the myxedematous type

FIG. 8. Myxedematous endemic cretinism. Ubangi, Zaire. Onthe left a euthyroid 21-year-old man with a height of 162 cm. On theright, a 15-year-old female cretin with a height of 88 cm. Dwarfism.Severe myxedema and puffy features. No puberty. Immaturenasoorbital configuration with flat and broad nose, hypoplasticmandibule, dry and scaly skin, dry and brittle hair, prominentabdomen. Severe mental retardation. No deafmutism. Unpalpablethyroid gland. From Delange (46), with permission.

116 DELANGE

of endemic cretinism as the most typically seen in Zaire (5, 39,52, 75, 76, 197). These cretins show less mental retardationthan the neurological cretins; they are often capable of perform-ing simple manual tasks. All exhibit major clinical symptoms oflong-standing hypothyroidism: dwarfism, myxedema, dry skin,sparseness of hair and nails, retarded sexual development, andretarded maturation of body proportions and of nasoorbitalconfiguration. Myxedematous cretins in Zaire occasionallyexhibit neurological signs including spasticity of the lowerlimbs, jerky movements and Babinski sign, shifting gait, asobserved in long-standing unrecognized sporadic congenitalhypothyroidism (175).

The prevalence of goiter in the myxedematous cretins is muchlower than in the noncretin population. Many of them havenonpalpable thyroid tissue although thyroid scintigrams showsmall residues of thyroid tissue located in normal position (39,52), precluding thyroid dysgenesis (agenesis, ectopic thyroid)as the cause of hypothyroidism.

Table 3 shows that in these cretins, the clinical diagnosis ofhypothyroidism is confirmed by a characteristic biochemicalpicture of thyroid failure with almost undetectable serum con-centrations of T4 and T3 and extremely elevated serum TSH.The iodine pool of the thyroid is drastically reduced with a

particularly fast turnover rate of iodine as indicated by elevatedserum PB1311. The diagnosis of severe and long-standing hy-pothyroidism is further confirmed by a very important retarda-tion in bone maturation and epiphyseal dysgenesis indicatinghypothyroidism of perinatal onset, and by characteristicchanges in the electrocardiogram (39).

The frequency distribution of the two extreme types ofendemic cretinism markedly varies from one endemia to an-other. In most, the neurological type predominates while in

others, especially in Zaire, myxedematous endemic cretinism ismost frequently encountered (see pathogenesis).

Finally, it is widely agreed that between the two extremetypes of cretinism, there are a number of mixed forms charac-terized by dominant neurological disorders or dominant hy-pothyroidism in the same individual (37, 118, 126, 133, 177,203, 209). Some authors have suggested that deafness may bethe only manifestation of cretinism in certain patients (118).

Table 5 summarizes the data available in the literature on theneuromotor and intellectual development in noncretinous indi-viduals in areas with severe endemic goiter and cretinism. Thesame tests, optimally with no, or as little as possible, "culturalbias" were administered to two groups of noncretinous individ-uals living in the same environmental conditions except for thegoitrogenic factors; a test group was exposed to these factorswhile in a control group, exposure was prevented by iodineprophylaxis, or these factors had never been present.

Table 5 indicates that in severe endemic goiter, neuromotorand intellectual deficits are also frequently observed in individ-uals who do not present any of the other signs of endemiccretinism.

Thus, endemic cretinism constitutes only the extreme expres-sion of a spectrum of abnormalities in physical and intellectualdevelopment and in the functional capacities of the thyroidgland observed in the inhabitants of severe endemic goiter areas.

Etiology. Iodine deficiency. Iodine deficiency is fundamen-tal in the etiology ofendemic cretinism. This conclusion rests on

(a) the correlation between the degree of iodine deficiency andthe frequency of cretinism (158, 164), (b) the prophylacticaction of iodine on the incidence of cretinism (41, 54, 115, 117,158, 164, 166, 185, 186, 191), and (c) the emergence ofcretinism in previously unaffected populations as a consequence

Table 5. Intellectual, Cognitive, and Neurological Deficits in Noncretin Individuals in Severe Endemic Goiter0

Regions Tests Findings Authors

Ecuador

Bolivia

Chile

Papula-New Guinea

ZaireJava

China

India

Goodenough Draw-a-ManStanford-BinetGesellLeiterBender-GestaltStanford-BinetBender-GestaltWechslerBender Kopitz

Brunet-LezineLocally adapted "culture free"

intelligence testsWechslerCatellRavenOzeretsky

GriffithsHiskey-NebraskaBhatiaBender-Gestalt

Low DQ, IQ and visual-motorperformances

Low IQ and visual-motorperformances

LowIQ

Motor performancesLow motor skillLow DQLow IQLow perceptual and neuromotor

abilities

Low IQ-relationship between IQand nerve deafness andabnormal neurological signs

LowIQ

Fierro-Benitez et al. (92)Ramirez et al. (166)Dodge et al. (74)Trowbridge (194)Greene (100)Bautista et al. (6)

Muzzo et al. (151)

Connolly et al. (31)Pharoah et al. (159)Thilly et al. (190)Bleichrodt et al. (9)

Boyages et al. (13)Ma et al. (134)

Kochupillai et al. (121)

"Adapted from Delange (45), with permission.

DISORDERS INDUCED BY IODINE DEFICIENCY 117

of iodine deficiency of recent onset, as observed in the Jimivalley in New Guinea after replacement of natural rock salt richin iodine with low iodine industrial salt (157).

Finally, iodine deficiency during gestation in animals resultsin thyroid deficiency in the offspring. All the models usedmimic the myxedematous type of cretinism; none was able to

reproduce the neurological type (113, 163, 176).Naturally occurring goitrogens. Thiocyante overload result-

ing from chronic consumption of poorly processed cassava

plays an additional role in the etiology of myxedematouscretinism (86). This role has been suggested from the observa-tion that people in areas with severe but uniform iodine defi-ciency exhibit cretinism only when a certain critical threshold inthe dietary supply of SCN is reached (59). The action of SCN isentirely due to an aggravation of iodine deficiency resulting infetal hypothyroidism. SCN freely crosses the placenta (18) andits concentration in cord blood is three times higher in Ubangithan in Brussels (58) (Table 4). The role played by this SCNoverload in the impairment of thyroid function of the newborn isstrongly suggested by the observation that, in severely iodine-deficient pregnant women, elevated urinary SCN values are

accompanied by a further increase of TSH and decrease of T4levels in cord serum (58). The antithyroid action of SCN in thenewborn probably results from the fact that this ion interfereswith the trapping of iodide by the placenta and by the neonatalthyroid gland. These two factors probably critically reduce thebuildup of iodine stores within the thyroid gland during fetal andearly postnatal life.

This mechanism is consistent with the very low iodine contentof the thyroid gland reported in the myxedematous cretins (76).Thiocyante overload aggravating the effect of iodine deficiencyalso explains the postnatal occurrence of juvenile hypothy-roidism developing after weaning (148, 195).

Thyroid autoimmunity. Boyages et al. (14) showed thatpurified IgG fractions of serum from patients with myxedema-tous endemic cretinism inhibited thyrotropin-induced DNAsynthesis and, consequently, thyroid growth, in guinea pigthyroid segments in a sensitive cytochemical assay. On thecontrary, no growth-blocking effect was observed with IgGsfrom euthyroid subjects or neurological cretins from the samearea. It was concluded that the IgGs identified specifically inmyxedematous cretinism were responsible for the condition byinhibiting thyroid growth. These IgGs, often called thyroidgrowth blocking immunoglobulins (TGBI), are similar to theones found by the same authors in sporadic congenital hypothy-roidism (14). The antigenic stimulus is unknown as well as thetiming of appearance in action of these IgGs in the course ofpregnancy, fetal or postnatal life.

Serum TGBI were also identified using the FRTL5 system incretins in Brazil with atrophie thyroids (147).

However, TGBI could not be found in sporadic congenitalhypothyroidism by other authors (19, 26) and, consequently,the possible role of thyroid autoimmunity in the etiology ofendemic cretinism remains controversial.

Trace elements. One quite stimulating new concept in theetiology of both myxedematous and neurologic endemic cretin-ism is the role of combined iodine and selenium deficiencies;selenium is present in high concentrations (0.72 p-g/g) in thenormal thyroid ( 1 ). It is present in glutathione peroxidase (GPX)and Superoxide dismutase (35). It is also present in the type I

5'-deiodinase (8). The following scheme has been proposed toexplain the frequency of myxedematous cretinism and therelative rarity of neurologic cretinism in areas such as Zairewhere both iodine and selenium are deficient (103, 197): iodinedeficiency results in hyperstimulation of the thyroid by TSH andconsequently in increased production of H202 within the cells.Selenium deficiency results in GPX deficit and consequently inaccumulation of H202. Excess ofH202 could induce thyroid celldestruction, and finally thyroid fibrosis resulting in myxedema-tous cretinism (33, 35). The recent observation of thyroid cellnecrosis in severely selenium- and iodine-deficient rats submit-ted to acute iodide overload (34) is consistent with this hypoth-esis. On the other hand, deficiency in the selenoenzyme 5'-deiodinase in pregnant mothers induced by selenium deficiencycauses decreased catabolism of T4 to T3 and thus increasedavailability of T4 for the fetus and its brain. This mechanismcould prevent the development ofneurologic cretinism, which isdue to fetal hypothyroxinemia during early gestation. Combinediodine and selenium deficiencies in Zaire could thus explain thelarge predominance of the myxedematous type of endemiccretinism, rather than the neurological type, as seen typically inthis area.

Pathogenesis. Fetal and maternal hypothyroidism or a com-bination of both has been proposed as a pathogenic mechanism.

Fetal hypothyroidism. Several observations clearly demon-strate that myxedematous endemic cretinism results from severe

thyroid failure occurring during fetal or early postnatal life.Chinese data have indicated that hypothyroidismn is present inhuman fetuses from the fourth month of gestation in regions ofsevere iodine deficiency and myxedematous endemic cretinism(132). Thyroid failure at birth due to iodine deficiency has beenevidenced in several endemic areas with myxedematous en-demic cretinism such as Zaire (54, 58, 186), India (121),Algeria (25), and even in some parts of Europe such as Sicily(172). In addition, about 10% of infants aged less than 12months in Ubangi, Zaire are clinically hypothyroid, and nearlyhalf have a marked delay in bone maturation, which is directlycorrelated to serum TSH and inversely correlated to serum T4(54). The presence of epiphyseal dysgenesis in X-ray studies ofthe knees of some adult myxedematous endemic cretins in Zairewith clinical, biochemical, and radiologie signs of long-stand-ing hypothyroidism suggests that hypothyroidism was presentbefore or around birth (3, 205); this provides indirect evidenceof perinatal hypothyroidism. Also the direct correlations ob-served in these cretins between mental retardation and bothheight retardation and retardation in bone maturation indicatethat hypothyroidism present in early life would account for themental deficiency of the dwarfs (75, 126).

In some young infants in the Ubangi area in Zaire, thebiochemical signs of thyroid failure disappeared spontaneouslywithin 6 to 10 weeks (38). The hypothesis has been proposedthat permanent thyroid failure from birth results in myxedema-tous endemic cretinism, while transient hypothyroxinemia oc-

curring during the critical period of brain development could atleast partly explain the endemic mental retardation observed innoncretin individuals in this population (40).

In contrast to the situation reported for myxedematous en-

demic cretinism, there is no evidence that fetal hypothyroidismis involved in the pathogenesis of neurological endemic cretin-ism; there is no evidence of hypothyroidism in the newborn in

118 DELANGE

areas where neurological cretinism predominates (42, 146, 179).Conversely, there is no clinical picture similar to that of neurolog-ical endemic cretinism in sporadic thyroid agenesis, which resultsin the most severe degree of fetal hypothyroidism (3, 81).

However, the well-documented preventive action of correc-tion of iodine deficiency in pregnant mothers on the incidence ofendemic cretinism indicates that maternal thyroid function playsa role in the pathogenesis of endemic cretinism.

Maternal hypothyroidism. Maternal hypothyroxinemia israre in nonendemic areas. It can result in impaired neurointel-lectual development in the offspring (122, 139). In contrast,maternal hypothyroxinemia is extremely frequent in endemicareas (58, 159, 179). It is associated with increased mortalityand morbidity in offspring ( 159, 189) and increased incidence ofhypothyroidism in neonates (186). In addition, data collected inrats showed that maternal hypothyroxinemia due to iodinedeficiency results in lack of thyroid hormones in fetal tissuesduring early pregnancy, even before the onset of fetal thyroidfunction, and also later on during fetal development (88, 149,150, 208). These data indicate that in rats, there is a substantialtransfer of thyroid hormones from mother to fetus during earlygestation, which plays a role in fetal development, especially ofthe brain. In contrast, the rate of transfer of thyroid hormonesacross the placenta in humans is largely unknown. The classicalconcept that there is no or only minimal transfer (18, 94) hasbeen recently challenged by the observation that infants bornwithout any thyroid (thyroid agenesis) or with nonfunctioningthyroids (dyshormonogenesis) still have detectable serum concen-trations of thyroid hormones at birth (cord blood), which rapidlydecrease thereafter (64,201). For these reasons, the consequencesof maternal hypothyroxinemia and iodine deficiency for fetaldevelopment in humans are still largely unknown.

In an attempt to present a unifying hypothesis for the etio-pathogenesis of endemic cretinism, and based on very carefuland extensive studies of endemic cretinism as seen in China andIndonesia (16, 69, 70, 107, 108), it has been proposed that theclinical picture of endemic cretinism results from the product oftwo pathophysiological events, both resulting from iodine defi-ciency: the first event is maternal or/and fetal hypothyroidism. Itoccurs in all cretins and results in the neurological features of thedisorder. The second event is postnatal hypothyroidism. Thisevent does not occur in all cretins and is determined by the thyroidgland's functional capacity of the individual. Postnatal hypothy-roidism is responsible for growth, mental and sexual retardation,and for the myxedematous appearance of the cretins.

The hypothesis is attractive and is probably satisfying forexplaining the situation as seen in China and Java, but, in theopinion of the author, cannot be considered as universal. As amatter of fact, as indicated earlier, maternal or/and fetal hy-pothyroidism are much more severe and frequent in areas in theworld where the myxedematous component of cretinism pre-dominates than in areas where the neurological componentpredominates, and not the reverse.

Therapy. There is no specific therapy of neurological en-demic cretinism. These patients need rehabilitation like patientswith cerebral palsy in Western countries.

Thyroid function can be improved by iodine supplementationin myxedematous cretins aged less than 4 years but not in olderdefectives, indicating that in this type of cretinism, the atrophiethyroid progressively loses its functional capacity (15, 196). As

in unrecognized sporadic congenital hypothyroidism, substitu-tive therapy with 1-thyroxine will restore euthyroidism but willnot correct the neuropsychointellectual sequelae.

Figure 9 shows that injections of iodized oil during pregnancyin Zaire will prevent hypothyroidism not only at birth but untilthe age of 2-3 years.

The fact that in some children, hypothyroidism starts after theage of 3 years is consistent with the observation of Goslings etal. (102) that hypothyroid patients in severe endemic goiter arenot necessarily affected by severe and irreversible mentalretardation and of Boyages et al. (12) that cretins with thyroidfailure may have only moderate retardation in height and bonematuration.

Treatment and prophylaxis of iodine deficiency disorders

Prolonged administration of iodide or of thyroid hormoneshas been found highly effective in reducing the size of the goiter.Surgical treatment is often justified in large goiters with pressuresymptoms. Nevertheless, such types of treatment administeredat an individual level are, in practice, impossible to apply to a

general population in view of the epidemiologic size of theproblem and the general lack of adequate medical infrastructurein the most severely affected populations. The single logicalmedical attitude is the introduction of iodine prophylaxis.

For almost 50 years, iodized salt has been used as the simplestmost effective way of providing extra iodine in the diet (72,140,142, 181). Iodine is most often added in the form of potassiumiodide, but iodate is prefered in humid regions owing to itsgreater stability. The first large scale successful campaign to

242016

_12

5 8S 6

ff 4

21

0

242016

-. 12

I 8'en* 6? 4-

21

0

UNTREATED :

v • .••...„•- -r

TREATED !

'• •:' V.

05 1 2 3 4 5 6 7AGE(YEARS)

FIG. 9. Changes with age of the serum concentrations of thyrox-ine in infants bom to untreated mothers (upper panel) or to motherstreated with a single injection of iodized oil during pregnancy.Ubangi endemic goiter area, Zaire. The shaded areas correspond tothe normal range for Belgian controls. The figures in the circlesindicate the number of clinically euthyroid subjects in each agegroup, the stars correspond to subjects with clinical signs ofhypothyroidism. From Thilly et al. (188), with permission.

DISORDERS INDUCED BY IODINE DEFICIENCY 119

Table 6. Administration of Iodized Oil in the Prevention of the Disorders Induced byIodine Deficiency0

Duration of effectOral (mg iodine)

Age groups 3 months 6 months 12 months

Intramuscular(mg iodine)

>1 year

Women of child bearing age 100-200 200-480 400-960(nonpregnant)

Pregnant women 50-100 100-300 300-480Infants-children

0-1 year 20-40 50-100 100-3001-5 years 40-100 100-300 300-4806-15 years 100-200 200-480 400-960

Males 16-45 years 100-200 200-480 400-960

480

240480480480

"From a WHO/UNICEF/ICCIDD consultation on IDD indicators, WHO Geneva November 1992, unpub-lished, with permission.

prevent endemic goiter by iodized salt was carried out in theUnited States in 1917 (141). Later epidemiologic surveysdemonstrated the successful result of this program (143). Theeffectiveness of the method was later confirmed by a number ofsimilar campaigns in Switzerland, India, Mexico, Guatemala,Greece, Argentina, Switzerland, Austria, and Finland (188).These brought not only a dramatic reduction of the prevalence ofgoiter but also progressive disappearance of endemic cretinism(117, 160, 166, 191).

The recommended levels of iodine supplementation varywidely. In the United States, one part iodide is added to 10,000parts salt. In other countries, the ratio is one in 100,000. A saltconsumption of 5 g/day being presumed, extra iodine supplywould vary therefore from 500 p-g to 50 p-g/day. A reasonablerecommendation is one part in 20,000 to 50,000 (72, 80).

Iodide has been used as a supplement in bread alone inHolland and in Tasmania, but wide variations in the amount ofbread consumption make this a less than satisfactory technique(181). Iodination of water has been successfully used in someareas with adequate water supply and control of iodination ofwater (135, 178).

However, in many developing countries with severe prob-lems of endemic goiter, iodination of salt, bread, or water failedto prevent or eradicate the disease because various socioeco-nomic, climatic, or geographic conditions made systematiciodine supplementation difficult or even impossible, includingareas where iodized salt does not reach the endemic areas or inareas where house salt is not available (72, 142, 188).

In such conditions, prophylaxis and therapy can be achievedextremely effectively by the administration of large quantities ofiodine in the form of slowly resorbable iodized oil administeredby intramuscular injections or orally (72, 80, 116, 161). Themethod is cheap and can be easily implemented through localhealth services using existing facilities or by small teams. Themethod appears as most convenient for ioslated communitiesbeyond the reach of commercial chañéis.

In light of investigations completed in various countries byinjection of iodized oil (72, 80, 116, 182), it appears necessaryto inject the entire population from 0 to 45 years for females and0 to 20 years for males. This sex distinction is not, however,

always applied for psychological reasons (188). The long-termeffectiveness and safety of this procedure are now extensivelydocumented for at least 7 years in adults and 2-3 years in youngchildren (Fig. 9).

The recommended doses of iodine administered as iodized oilare shown in Table 6. Smaller doses of oral iodized oil are,however, equally effective at least for 1 year (193).

The principal complication of iodine prophylaxis is theoccurrence of thyrotoxicosis (142). This complication was firstnoticed in the early days after the introduction of iodidesupplementation. An increased incidence of thyrotoxicosis was

observed in Tasmania following bread iodination in 1966 or/andfollowing contamination of dairy products by iodine containingdisinfectants (iodophores). The complication was most evidentin the older age groups (32). It was attributed to the presence ofautonomous nodules often observed in these subjects. Patientswith thyrotoxicosis were occasionally reported after administra-tion of iodized oil in Ecuador, Peru and Argentina but not inNew Guinea and Zaire ( 181 ). In all reports the disease was mildand easily managed. The question may arise whether thisdevelopment of thyrotoxicosis is to be considered as a compli-cation of iodine prophylaxis or an ineluctable consequence ofthe normalization of the iodine intake. Even in nongoitrousareas, it has been shown that the shift from a low normal iodineintake (100 p.g/day) to a high normal one (500 p-g/day) mayinduce clear-cut thyrotoxicosis in euthyroid subjects with an

autonomous thyroid nodule (85).The large amount of information now available from all over

the world clearly establishes that the occurrence of thyrotoxico-sis is exceptional and does not put in question the enormousbenefit that follows the introduction of iodine prophylaxis inendemic goiter regions.

MILD TO MODERATE IODINE DEFICIENCY:THE SITUATION IN EUROPE

EpidemiologyEndemic goiter, occasionally complicated by endemic cretin-

ism, has been reported in Europe up to the turn of the twentieth

120 DELANGE

Table 7. Comparison of the Results Obtained in European Countries or Regions for Urinary Iodine Excretion inAdults, for the Iodine Content of Breastmilk and of Urine of Infants on Day 5 of Life"

Country or region

Urinary excretion ofiodine in adults

(P-g/day)

Iodine concentration (\LgldL)

CityBreast milk

(mean ± SEM)Urine infants

day 5 (median)The NetherlandsFinlandSwedenSicily (nonendemic area)SwitzerlandSpainFrance

BelgiumItalyGermany

NorthSouth

Sicily (endemic area)

88-140238-27091-140

113126-141

8955-126

5137

35201622

RotterdamHelsinkiStockholmCataniaZürichMadridParisLilleBrusselsRome

BerlinFreiburglenaSan Angelo

9.3 (60)

7.7 ± 0.9 (69)8.2 ± 0.5 (68)

9.5 ± 0.6 (91)

2.5 (41)1.2 ±0.1 (55)2.7 ± 0.3 (59)

16.2 (64)11.2(39)11.0(52)7.1 (14)6.2 (62)

5.8 (82)

4.7(114)

2.8 (87)12(41)0.8 (54)

"The number of determinations is shown in parentheses. Adapted from Delange et al. (63).

century, especially from remote, isolated, mountainous areas inthe central part of the continent including Switzerland, Austria,and northern Italy (122, 125, 128). The problem of IDD hasbeen entirely eradicated in Switzerland due to the implementa-tion and monitoring of a program of salt iodization (20).Probably because of the impact of this remarkable program onthe medical world, IDD seems to have been considered no

longer as a significant public health problem in Europe.However, réévaluation of the problem in the late 1980s under

the sponsorship of the European Thyroid Association clearlyindicated that with the exception of most of the Scandinaviancountries, Austria, and Switzerland, most of the Europeancountries or at least certain areas of these countries were stillaffected, especially in the Southern part of the continent (105,168). Shortly thereafter, it was shown that changes in the iodinesupplies in the adult populations were accompanied by parallelchanges in the iodine content of breastmilk and of urines ofneonates (65) (Table 7). These surveys also revealed a lack ofinformation on IDD in countries of the Eastern part of thecontinent.

Based on this information and as a result of recent changes inthe political situation in Europe, the status of iodine nutritionwas recently reevaluated in all European countries, including inthe Eastern part of the continent (68). The results are summa-rized in Figure 10.

Iodine deficiency is presently under control in only fivecountries, namely Austria, Finland, Norway, Sweden, andSwitzerland. Iodine deficiency is marginal or present mainly in"microfoci" (pockets of goiter or even of cretinism) in Belgium,the former Czechoslovakia, Denmark, France, Hungary, Ire-land, Portugal, and the United Kingdom. IDD have recurredafter transitory resolution in Croatia, the Netherlands, andpossibly some Eastern European countries. Finally, iodinedeficiency persists and ranges from moderate to severe in all theother European countries, namely Bulgaria, the Commonwealth

of Independent States (CIS), Germany, Greece, Italy, Poland,Romania, Spain, and also Turkey. In some of these countries,such as Bulgaria and Romania, the prevalence of goiter in

FIG. 10. Updated evaluation of iodine intake in Europe (p-g/day).Range of the values observed during regional or national surveys.The figures correspond to the measurement of the daily urinaryexcretion of iodine or to the extrapolation to 1 L of urine per daywhen the results were expressed as iodine concentrations or iodine/creatinine ratios. N, Norway; S, Sweden; SF, Finland; DK, Den-mark; IRL, Ireland; UK, United Kingdom; B, Belgium; NL, TheNetherlands; G, Germany; PL, Poland; CS, Former Czechoslova-kia; CIS, The Commonwealth of Independent States; F, France;CH, Switzerland; A, Austria; H, Hungary; Ro, Romania; P,Portugal; E, Spain; I, Italy; CRO, Croatia; Y, Yugoslavia; BG,Bulgaria; GR, Greece, AL, Albania; TR, Turkey. Compiled fromDelange et al. (68).

DISORDERS INDUCED BY IODINE DEFICIENCY 121

Table 8. Values of 24 Thyroidal Uptake of Radioiodinein Euthyroid Subjects"

CountryNo. ofcenters

No. ofsubjects

24 h l3'¡ thyroidaluptake (% dose)

SwitzerlandThe NetherlandsFranceItalyBelgiumGermany

238

10147

162411938

151012321055

32.6 ± 0.839.9 ± 0.540.9 ± 0.642.2 ± 0.447.0 ± 0.559.6 ± 0.5

" Subjects are from six European countries listed according to decreasingdietary intake of iodine (see also Fig. 10). Results are given asmean ± SEM. From Thilly et al. (192), with permission.

schoolchildren varies from 16 to 81% and the median urinaryiodine concentrations can be as low as 2 p-g/dL, i.e., as low as inthe most severely affected areas in the center of the Africancontinent.

Public health consequencesIn adults. The frequency of simple goiter is elevated in many

countries and the cost of therapy of thyroid problems in the adultpopulation is enormous (155). As shown in Table 8, thyroidaluptake of radioiodine varies markedly from one Europeancountry to another and is inversely related to the iodine intake.Elevated thyroidal uptake due to iodine deficiency aggravatesthe risk of thyroid irradiation and development of thyroid cancerin case of a nuclear accident (44). The best prophylaxis ofnuclear hazards in case of radioiodine fallout is to increase thebasal intake of iodine of the population (83).

Thyroid function is usually normal in adults in Europe. Incontrast, it is frequently altered in pregnant women. Duringpregnancy, the thyroid is submitted to a triple challenge result-ing in thyroid hyperstimulation by TSH, which can potentiallyinduce thyroid disorders (98): there is an increase in the serumconcentration of thyroxin binding globulin (TBG) under theinfluence of the estrogens accompanied by a desaturation of thebinding protein; there is increased stimulation, at least duringearly pregnancy, by the human chorionic gonadotrophin (hCG),and, finally, there is an increased loss of iodine in the urine. It

has been shown that, at least in conditions of borderline iodineintake as seen in Belgium (50-70 p-g/day), pregnancy is accom-

panied by a progressive decrease of serum-free T4 and conse-

quently by an increase of serum TSH. This state of chronic TSHhyperstimulation results in the development of goiter in about10% of the pregnant women and in a progressive increase in theserum concentration of thyroglobulin. Goiter can persist afterpregnancy in an important number of women (98). Pregnancy,especially in conditions of borderline iodine intake, at leastpartly explains the higher frequency of thyroid problems inwomen than in men.

In adolescents and children. Euthyroid pubertal goiter isespecially frequent in adolescents and occasionally requiressubstitutive therapy by T4 or iodide. Iodine metabolism isaccelerated during this period of life (138).

A very important issue is the demonstration that even inEurope today, clinically euthyroid schoolchildren born andliving in an iodine-deficient environment exhibit subtle or evenovert neuropsychointellectual deficits as compared to controlsliving in the same ethnic, demographic, nutritional, and socio-economic system, except that they are not submitted to iodinedeficiency (Table 9). These deficits are of the same nature,although less marked, than those found in schoolchildren inareas with severe iodine deficiency and endemic mental retarda-tion. These deficits could result, as demonstrated in severeendemic goiter, from thyroid failure occurring during fetal or

early postnatal life, i.e., during the critical period of braindevelopment.

In neonates. The most important and frequent alterations ofthyroid function due to iodine deficiency in Europe occur inneonates and young infants:

1. The frequency of transient primary hypothyroidism is almost8 times higher in Europe than in North America (21). Asshown in Figure 11, this syndrome is characterized bypostnatally acquired severe primary hypothyroidism lastingfor a few weeks and requiring substitutive therapy (55). Therisk of transient hypothyroidism in the neonates increaseswith the degree of prematurity (60). The specific role playedby iodine deficiency in the etiology of this type of hypothy-roidism is demonstrated by the disappearance of neonataltransient thyroid failure in Belgian preterms since they were

systematically supplemented with 30 p-g potassium iodide/day.

Table 9. Neuropsychointellectual Deficits in Infants and Schoolchildren in Conditions of Mild to moderate IodineDeficiency in Europe

Regions Tests Findings Authors

Spain

ItalySicily

Tuscany

Tuscany

Locally adaptedBayleyMcCarthyCattell

Bender-Gestalt

WechslerRavenWiseReaction time

Lower psychomotor and mental developmentthan controls

Low preceptual integrative motor abilityNeuromuscular and neurosensorial abnormalitiesLow verbal IQ, perception, motor, and attentive

functionsLower velocity of motor response to visual

stimuli

Bleichrodt et al. (9)

Vermiglio et al. (199)

Fenzi et al. (91)

Vitti et al. (200)

122 DELANGE

TSHtyjU/ml)

10 15 20 30 40AGE(OAVS)

50 55 100 150

FIG. 11. Time course of the serum concentrations of TSH, totalT4 and T3 in 11 infants with transient primary hypothyroidism.Values recorded as mean ± SEM. SCR, screening; DIAG, diagno-sis. From Delange et al. (60), with permission.

As shown in Figure 12, there is an inverse relationshipbetween the urinary iodine concentration in newborn popu-lations in Europe used as an index of their state of iodinenutrition and the frequency of serum TSH above 50 p-U/ml atday 5, at the time of screening for congenital hypothy-roidism, i.e., in the recall rate under suspicion of congenitalhypothyroidism. Neonatal thyroid screening appears as a

particularly sensitive index of the presence and action ofgoitrogenic substances in the environment (61) and can be

used as a monitoring tool in the evaluation of the effects ofiodine prophylaxis at a population level (152).

The reasons for the particular sensitivity of the newborn,especially of the preterm infant, to the effects of iodine defi-ciency are shown in Figure 13 and Table 10. In an area such as

Belgium, with a borderline iodine intake, the iodine content ofthe fetal thyroid is extremely low and increases progressivelywith gestational age (Fig. 13). Table 10 shows that this contentfound in full-term infants is related to the iodine intake of thepopulation and thus probably of the mother during gestation.The iodine content of the thyroid in full-term infants is almost300 p-g in Canada; it is only 82 p-g in Belgium where the iodineintake is borderline and is as low as 43 p-g in Germany where theiodine intake is severely insufficient. In these conditions, theturnover rate of intrathyroidal iodine is markedly acceleratedand, therefore, thyroid failure is more likely to occur. Theseneonatal data contrast with adult data that have shown that theiodine stores ofthe thyroid are not affected by iodine deficiencyunless there is an extreme degree of deficiency (Fig. 3).

Prevention and therapy of IDD in EuropeIt is hard to understand and impossible to admit that iodine

deficiency, the most common preventable cause of mentaldeficiency in the world to day (113), is still so prevalent inEurope. The most probable cause of the phenomenon is theinsufficient awareness of the problem by the health authorities,including the medical and paramedical world, and by the public.The consequence is the absence of programs of health educationfocusing on the use of sea products, milk, and iodized salt andthe absence, except in some countries such as the Scandinaviancountries, Switzerland, and Austria, of efficient and well-controlled and monitored programs of iodized salt. As a matterof fact, iodized salt is available in many European countries.However, it has been reported that the iodination of householdsalt alone can raise urinary iodine excretion far below expecta-tion (65). This apparent failure of programs of salt iodizationcan result from the fact that, even in Europe today, many of theiodized salt analyses were grossly inadequate with respect totheir iodine content (65). It also could result from a grossoverestimation of household salt consumption, as the actual

^

OB H

06 n

5 6 7 8 9 10 II

URINARY IODINE CONC ( ug/dl )

FIG. 12. Relationship between the urinary iodine concentrationand the recall rate at the time of screening for congenital hypothy-roidism in newborn populations in Europe. Each points results fromthe analysis of 50 to 200 urine samples and from 200,000 to 300,000screening tests. From Delange and Ermans (67), with permission.

100-j50

10 o\5 0

GESTATIONAL AGE (WEEKS)

FIG. 13. Changes in the iodine content of fetal thyroid as afunction of gestational age in Brussels (Belgium).

DISORDERS INDUCED BY IODINE DEFICIENCY 123

Table 10. Relationship between the Iodine Content of Urines in Adults and Neonates"

Neonates

Iodine concentrationin urines Thyroids

Adults --Urinary excretion Values below Iodine Estimated turnover

Cities of iodine (\Lglday) Median (\¡.gldL) 5 \¡-gldL (%) Weight (g) content (\Lg) rate0 (%/day)Toronto Canada 600-800 14.8(81) 11.9 1.00 ± 0.12 (13) 292 ± 47 17Brussels Belgium 51 4.8(196)*** 53.2 0.76 ± 0.25 (4) 81 ± 9** 62Leipzig Germany 16 1.6(70)*** 97.2 3.27 ± 0.39 (10)** 43 ± 6** 125

"Relationship used as an index of iodine supply and thyroid weight, iodine content, and estimated turnover rate of thyroidal iodine (*based on a

requirement of IT4of 50 |xg/day) in neonates in three areas in Europe with markedly different iodine intake. Results given as mean ± SEM. The number ofpatients is shown in parentheses. Levels of significance as compared to Toronto **p < 0.01, ***p < 0.001. Adapted from Delange et al. (66) and fromDelange and Ermans (67), with permission.

ingestion of household salt measured by the lithium markertechnique indicates that it is only about 15% of the total saltintake. Therefore, iodized salt should be made available notonly for household salt but also industrial food productionincluding cheese and bread as well as for animal consumption.As a matter of fact, milk appears as the main source of iodine inmany industrialized countries (78).

Because of the obvious effects of iodine deficiency in Europeon the main target groups including pregnant women, fetuses,neonates, and young infants and before the introduction ofgeneralized programs of fortification of food including iodizedsalt, pregnant and lactating women and young infants should besupplemented with iodine. In addition, the iodine content offormula milk should be increased in Europe above the classicalrecommendation of 5 p-g/dL milk. The present recommenda-tion, endorsed by the European Thyroid Association (ETA) andthe International Council for the Control of Iodine DeficiencyDisorders (ICCIDD), is 10 p-g/dL for full-term and 20 p-g/dL forpreterm infants (47).

ACKNOWLEDGMENTS

Parts of this article are adapted, with permission, fromDelange (45) and Delange and Ermans (67).

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Address reprint requests to:F. Delange, M.D.

Department of PediatricsHôpital Saint-Pierre

322, rue Haute1000 Brussels, Belgium

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