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

49.Endemic Cretinism

François M. Delange

Many people with severe endemic goiter have irreversible impairment of intellectual and physical development. These abnormalities are extremely polymorphous and have been grouped under the general heading of endemic cretinism. The prevalence of the disorders may reach 5% to 15% of the population. It is by far the most serious complication of endemic goiter and represents a veritable scourge, both medically and socially (1,2,3).

Despite recent experimental data, the etiopathogenesis of endemic cretinism remains only partly understood (see later sections Etiology and Pathogenesis), and information on its pathology is scanty (4,5,6). For these reasons, the diagnosis of the condition is still mostly descriptive.

This chapter summarizes the present knowledge on the epidemiology and clinical manifestations, laboratory data, etiology, pathogenesis, therapy, and prevention of endemic cretinism. A comprehensive bibliography, including the historical aspects, is available in more extensive reviews on the topic (1,2,3,4,5,6,7,8,9,10,11).

EPIDEMIOLOGY, CLINICAL MANIFESTATIONS, AND LABORATORY DATA

In 1986, a study group of the Pan American Health Organization (PAHO) formulated the following definition of endemic cretinism (12):

The condition of endemic cretinism is defined by three major features:

A. Epidemiology. It is associated with endemic goiter and severe iodine deficiency.

B. Clinical manifestations. These comprise mental deficiency, together with either:

1. A predominant neurological syndrome including defects of hearing and speech and characteristic disorders of stance 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 syndromes will occur.

C. Prevention. In areas where adequate correction of iodine deficiency has been achieved, endemic cretinism has been prevented.

The clinical manifestations of endemic cretinism summarized in the PAHO definition correspond to the two extreme types of endemic cretinism initially defined in the pioneering work of McCarrison in 1908 (13) in the Himalayas and subsequently reported in the studies of endemic goiter and cretinism conducted in other parts of the world, for example, New Guinea (14,15) and the Democratic Republic of Congo (DRC, formerly Zaire) (16,17,18,19,20,21,22,23). The first type is marked by neurologic disorders (neurologic cretinism) and the second by symptoms of severe thyroid insufficiency (myxedematous cretinism).

Figure 49.1 shows the typical picture of neurologic cretinism as seen in New Guinea (14,15): the cretins in this endemia are extremely mentally retarded, and most of them are reduced to a vegetative existence. Almost all are deaf-mutes and have the following neurologic defects: (a) impaired voluntary motor activity, usually involving the pyramidal track, chiefly affecting the lower limbs, with hypertonia, clonus, and plantar cutaneous reflexes in extension—extrapyramidal signs are occasional; (b) spastic or ataxic gait—in the severest cases, walking or even standing is impossible; and (c) strabismus.

FIGURE 49.1. A 14-year-old boy with neurologic endemic cretinism, Mulia Valley, Western New Guinea. The boy has severe mental retardation, deaf-mutism, spastic diplegia, and strabismus. There are no clinical signs of hypothyroidism. Serum protein bound iodine (PBI) 1.7 µg/dL. (Photograph courtesy of Professor A. Querido, Leiden, The Netherlands.)

The prevalence of goiter in these cretins is as high as in the noncretin population of the area, and they are clinically euthyroid. Thyroid function is usually normal (14,15), but subclinical hypothyroidism with high basal serum thyrotropin (TSH) or exaggerated TSH response to thyrotropin-releasing hormone (TRH) may occur (24,25).

Figure 49.2 shows the typical picture of myxedematous endemic cretinism as most typically seen in the DRC (3,7,16,17,18,19,20,21,22,23). These cretins have less mental retardation than the neurologic cretins; they are often capable of performing simple manual tasks. All have major symptoms of long-standing hypothyroidism: dwarfism, myxedema, dry skin, sparseness of hair and nails, retarded sexual development, and retarded maturation of body proportions and of naso-orbital configuration. The initial reports from the DRC indicated that myxedematous cretins occasionally had neurologic signs, including spasticity of the lower limbs, jerky movements, Babinski's sign, and shifting gait (18,23).

FIGURE 49.2. Myxedematous endemic cretinism in children in Ubangi, northwestern DRC. On the left, a clinically euthyroid 6-year-old girl with a height of 105 cm (50th percentile for age for the local population). On the right, a 17-year-old girl with a height of 100 cm, severe mental retardation, myxedema, markedly delayed puberty, flat and broad nose, hypoplastic mandibule, dry and scaly skin, dry and brittle hair, and prominent abdomen. Pseudomuscular hypertrophy, muscular weakness, flat feet, and genu valgum are present; no deaf-mutism. The thyroid gland was not palpable. Har serum concentration of thyrotropin was 288 µU/mL, thyroxine 0.1 µldl (1.29), and triiodothyronine 10 ngldl (0.154 nM).

The prevalence of goiter in the myxedematous cretins is much lower than in the noncretin population. Many have palpable thyroid tissue, although thyroid scintigrams show small amounts of thyroid tissue located in normal position (18,23), precluding thyroid dysgenesis (agenesis, ectopic thyroid) as the cause of hypothyroidism.

The clinical diagnosis of hypothyroidism in myxedematous cretins is confirmed by a biochemical picture of thyroid failure with almost undetectable serum concentrations of thyroxine (T4) and triiodothyronine (T3) and extremely elevated serum levels of TSH (Table 49.1). The iodine pool of the thyroid is drastically reduced with a particularly fast turnover rate of iodine, as indicated by elevated serum radiolabeled protein bound iodine (PB131I). The diagnosis of severe and long-standing hypothyroidism is further confirmed by a very important retardation in bone maturation and epiphyseal dysgenesis, indicating hypothyroidism of perinatal onset, and by characteristic changes in the electrocardiogram (23).

TABLE 49.1. THYROID FUNCTION TESTS AND CLINICAL AND RADIOLOGIC DATA IN HYPOTHYROID ENDEMIC CRETINS IN DRC, CHINA, AND INDONESIA


 Hypothyroid Endemic Cretins


Variables

Belgian Controls
(n = 12–255)

Noncretin Iodine-Deficient Adults (DRC)
(n = 30–358)

DRC Idjwi-Ubangi
(n = 6–120)

China Qinghai
(n = 25)

Indonesia Bandung
(n = 3)


Thyroid function tests

  Serum concentration of

    T4 (nM)

104.2 ± 1.3

63.1 ± 2.6

6.4 ± 0.1

53.9 ± 7.1

     FT4 (pM)

8.4 ± 1.3

 

 11.2

    T3 (nM)

2.21 ± 0.05

2.55 ± 0.04

0.70 ± 0.05

2.1 ± 0.2

     TSH (µU/mL)

1.7 ± 0.1

18.6 ± 2.1

303 ± 20

123.8 ± 23.0

40.1

    Protein bound 131I (% dose/liter)

0.06 ± 0.01

0.17 ± 0.02

1.09 ± 0.18

      24-hour 131I thyroid uptake (% dose)

46.4 ± 1.1

65.2 ± 0.9

28.3 ± 2.6

 Thyroid organic iodine pool (mg)

15.8 ± 3.5

1.60 ± 0.3

0.01–0.1

 Clinical and radiologic data

  Age (yr)

  

16.8

31.6

33.3

  Clinical myxedema (%)

 

 

100

54

   Height (cm)

 103

131

144

  Bone maturation (yr)

 2.8

26.2

   Epiphyseal dysgenesis

 +++

±

±

  Mental development vs. euthyroid cretins

 Higher

Equal

Equal


DRC, Democratic Republic of Congo
Values recorded as mean ± SEM.
Data from references 18, 20, 44, 48, 114, 116, and 125.

The review of the world literature on endemic cretinism up to the late 1970s indicated that the frequency distribution of the two extreme types of endemic cretinism varied markedly from one endemic area to another. In most of them, the neurologic type predominated, while in others, especially in DRC, myxedematous endemic cretinism was most frequently encountered. The reasons for these geographical variations in the epidemiologic pattern of endemic cretinism were unknown. It was also agreed that, between the two extreme types of cretinism, there were mixed forms characterized by dominant neurologic disorders or dominant hypothyroidism in the same individual (8,14,15,16,17,18,19,20,21,22,23,26,27,28,29,30,31,32,33,34,35,36).

It was then thought that neurologic and myxedematous endemic cretinism, in fact, constituted the extreme aspects of a continuous spectrum of developmental abnormalities, between which there were numerous intermediate forms (7,8,37). A similar variability in the geographic pattern of endemic cretinism has been reported from China: neurologic cretinism has been found in almost all the cretin endemias of China; the myxedematous type was less frequent and was found principally in the northwestern part of the country (38,39,40).

The results of subsequent detailed studies of cretinism in Ecuador (41,42,43), China (44,45,46,47), Indonesia (48), and Thailand (49,50) vigorously challenged the concept of a continuous spectrum of developmental abnormalities in endemic cretinism between two extreme types, myxedematous and neurologic. The main reason is that in their studies in China and Indonesia, the Australian researchers reported an identical pattern of intensity of neurologic, intellectual, and audiometric deficits in all cretins examined, regardless of type (myxedematous or neurologic) and current thyroid function (44,48). The neurologic aspects of both euthyroid and hypothyroid cretins are polymorphous and vary widely from one subject to another: in the 139 subjects they investigated in China and Indonesia, Halpern and colleagues (48) reported significant pyramidal dysfunction in a proximal distribution and exaggeration of the tendon reflexes, more commonly encountered in the lower limbs than in the upper. The posture is typical, with hips and knees flexed and the trunk tilted forward. The gait is broad based and knock-kneed. The arms are held with the shoulders abducted and the elbows flexed. These signs indicate extrapyramidal features. All the cretins have severe intellectual impairment, with a mean IQ of about 29. About half the patients have impaired hearing, and nearly one third have a squint. Musculoskeletal abnormalities are common and predominantly involve the weight-bearing joints, with excessive laxity of the hips, feet, and ankles. There are no signs of cerebellar dysfunction.

Subsequently, Rajatanavin and colleagues (49) reported a similar frequency of low intelligence, defects in visual perceptive neuromanual ability, sensorineural hearing loss, and neurologic defects in 57 neurologic, 19 myxedematous, and 36 mixed cretins in northern Thailand.

In another study conducted in China, in an attempt to better define the underlying pathology in the nervous system causing the functional deficits and to determine the developmental timing of the critical neurologic events, Delong and colleagues (47) identified five patterns of neurologic involvement in these cretins:

1. “Typical” pattern, with hearing and speech deficit, proximal spastic rigid motor disorder, and mental retardation

2. “Thalamic” posturing, with undermost limbs extended and uppermost limbs flexed, together with severe mental retardation, marked microcephaly, inability to sit, stand, or walk, and primitive facial reflexes including a marked sucking or rooting reflex elicited by bringing an object into the visual field near the face

3. An autistic pattern, with severe mental deficiency aggravated by deaf-mutism and an almost total disregard of their surroundings and absence of purposeful activity

4. A cerebellar pattern, with marked abnormalities in standing, walking, and sitting, hypotonic truncal tone, tremor, and dysmetria that are typical of cerebellar dysfunction

5. A hypotonic pattern, with marked truncal hypotonia and delayed sitting, standing, and walking

The hypothesis was proposed that the typical pattern may represent an insult occurring principally during the second trimester of pregnancy; that the severe thalamic form may represent a longer period of insult; that deafness results from a cochlear lesion occurring during the first and second trimesters; that the cerebellar form may result from a postnatal insult; and that the autistic form may depend on a severe insult to the cerebral cortex as well as the hippocampus, both pre- and postnatally (47,51).

In contrast to the exhaustive clinical descriptions of the nervous system defects in cretins and the diversity and severity of these deficits, information on brain pathology is scanty and does not elucidate entirely the anatomic locations of the injury: computed tomographic (CT) scans of cretins from Ecuador showed widespread atrophy that included the cerebral cortex and subcortical structures of the brainstem, with corresponding enlargement of the basal cisternae, the lateral ventricles, and the sulci over the surface of the cerebral cortex (52). Basal ganglia calcifications and cerebral atrophy were occasionally observed by Halpern et al (48), but there was no correlation between the CT scan abnormalities and the clinical signs. Magnetic resonance imaging in three cretins from China appeared remarkably normal (47).

On the basis of the observations in China, Indonesia, and Thailand, the concept was proposed that all cretins, including the so-called myxedematous form, belong to the neurologic type (44,48,50). The reason for the discrepancy between this concept and the concept of a spectrum with two extreme types is unclear. One possible explanation could be an underevaluation or misinterpretation of the neurologic signs in myxedematous cretins in DRC by the different Belgian and African teams (43) which investigated the Uele, Idjwi Island, and Ubangi areas during the past 40 years (16,17,18,19,20,21,22,23). If so, the same mistakes were also made by the team from Washington, which again investigated the Uele area and obtained exactly the same epidemiologic findings (53). It has to be recognized that at least some of the neurologic signs found in the myxedematous cretins of the DRC, including flat feet, knock knees, hyperreflexia, ataxia, strabismus, nystagmus, and hearing defects, have been occasionally reported in the past in unrecognized and consequently untreated children with sporadic congenital hypothyroidism (54,55).

Another possible explanation of the difference between the two concepts could be that the term “myxedematous cretinism” has been applied in China and Indonesia to patients with predominantly neurologic cretinism and postnatally acquired hypothyroidism with moderate biochemical impairment of thyroid function, similar to that found in neurologic cretinism in other parts of the world and in noncretin, severely iodine-deficient adults (Table 49.1). In fact, the degree of hypothyroidism reported in the hypothyroid cretins in China and Indonesia is much milder than the hypothyroidism observed in Africa. The difference in severity is reflected by the results obtained for the biochemical tests and could explain why the retardation in height and especially in bone maturation is much less marked in hypothyroid cretins in China than in the DRC, where hypothyroidism is of perinatal onset. Only half of the myxedematous cretins in China are clinically myxedematous, while, by definition, all of them are in DRC.

The most probable explanation for the discrepancy between the two concepts, however, is that, although severe iodine deficiency is the main cause of all types of cretinism, additional causes, varying from place to place, may modulate the clinical expression of the disorder (see later sections Etiology and Pathogenesis).

ENDEMIC MENTAL RETARDATION IN SEVERE ENDEMIC GOITER

The statement that “feeble mindedness, a part of cretinism, arises distinctly in areas of endemic goiter” (56) has been rather difficult to confirm on an objective basis, particularly because of major technical limitations in the assessment of intelligence in preindustrialized societies (6,57).

Table 49.2 summarizes data available in the literature on the neuromotor and intellectual development in noncretinous people in areas with severe endemic goiter and cretinism. The same tests (optimally with no “cultural bias” or as little as possible) were administered to two groups of noncretinous subjects living in the same environmental conditions except for the goitrogenic factors: a test group was exposed to these factors, while in a control group, exposure was prevented by iodine prophylaxis, or these factors had never been present. In the test groups, neuromotor and intellectual deficits were frequently observed in subjects who did not have any of the other signs of endemic cretinism.

TABLE 49.2. INTELLECTUAL, COGNITIVE, AND NEUROLOGIC DEFICITS IN NONCRETINS IN SEVERE ENDEMIC GOITER REGIONS


Regions

Tests

Findings

References


Ecuador

Goodenough Draw-a-man
Stanford-Binet
Gesell
Leiter
Bender-Gestalt

Low DQ, IQ, and visual-motor performances

57,123
126,127,128

Bolivia

Stanford-Binet
Bender-Gestalt

Low IQ and visual-motor performances

129

Chile

Wechsler
Bender Kopitz

Low IQ

130

Papua-New Guinea

Motor performances

Low motor skill

96,131,132

DRC (Zaire)

Brunet-Lezine

Low DQ

133

Java-Spain

Locally adapted “culture-free” intelligence tests
Wechsler
Catell
Raven
Ozeretsky

Low IQ
Low perceptual and neuromotor abilities

134

China

Griffith
Hiskey-Nebraska

Low IQ—Relationship between IQ and nerve deafness and abnormal neurologic signs

48,135,136

India

Bhatia
Malin
Bender-Gestalt
Verbal, pictorial learning tasks
Test of motivation

Low IQ

Low rates of hearing
Low motivation

137,138

Iran

Bender-Gestalt
Raven

Low IQ

139


Thus, endemic cretinism only constitutes the extreme expression of a spectrum of abnormalities in physical and intellectual development and in the functional capacities of the thyroid gland in the inhabitants of severe endemic goiter areas.

ETIOLOGY

Iodine Deficiency

Iodine deficiency is fundamental in the etiology of endemic cretinism. This conclusion rests on (a) the correlation between the degree of iodine deficiency and the frequency of cretinism (3,8,11); (b) the prophylactic action of iodine on the incidence of cretinism (see later section Prevention); and (c) the emergence of cretinism in previously unaffected populations as a consequence of iodine deficiency of recent onset, as observed in the Jimi valley in New Guinea after replacement of natural rock salt rich in iodine with low-iodine industrial salt (58) (see section Iodine Deficiency in Chapter 11).

In addition, iodine deficiency during gestation in animals results in thyroid deficiency in the offspring. All the models used mimic the myxedematous type of cretinism; none was able to reproduce the neurologic type (59,60,61).

Naturally Occurring Goitrogens

The additional role played by naturally occurring goitrogens in the etiology of endemic cretinism has been established for a cyanogenic glucoside (linamarin) present in cassava, a staple food in many tropical areas (19,20). Linamarin yields cyanide on hydrolysis. This is metabolized to thiocyanate (SCN), which is well known for its goitrogenic effects. The role of SCN in the etiology of endemic cretinism in Africa has been proposed from the observation that people in areas with severe but uniform iodine deficiency had cretinism only when a certain critical threshold in the dietary intake of SCN is reached (62). It has been shown experimentally in the rat that SCN affects the development of the central nervous system during fetal life (20). The action of SCN is entirely due to an aggravation of iodine deficiency resulting in fetal hypothyroidism.

Thyroid Autoimmunity

Boyages and colleagues (63) reported that purified immunoglobulin G (IgG) fractions of serum from patients with myxedematous endemic cretinism inhibited TSH-induced DNA synthesis and, consequently, growth of guinea pig thyroid segments in a sensitive cytochemical assay. By contrast, no growth-blocking effect was observed with IgGs from euthyroid subjects or neurologic cretins from the same area. These IgGs, often called thyroid growth-blocking immunoglobulins (TGBIs), are similar to those found by the same researchers in sporadic congenital hypothyroidism (64). The antigenic stimulus is unknown, as is the timing of appearance of these IgG fractions during pregnancy and fetal or postnatal life. Serum TGBIs were also detected using rat thyroid FRTL-5 cells in cretins in Brazil with atrophic thyroids (65). However, TGBI could not be found in sporadic congenital hypothyroidism or myxedematous endemic cretinism in Peru and Italy by other researchers (66,67,68); consequently, the possible role of thyroid autoimmunity in the etiology of endemic cretinism remains controversial.

Trace Elements

One question about the etiology of both myxedematous and neurologic endemic cretinism concerns the role of combined iodine and selenium deficiencies (69,70,71,72,73). In the DRC, myxedematous cretinism is found only in severe iodine-deficient areas that are also deficient in selenium (69,73) (Table 49.3). Selenium is present in high concentrations (0.72 µg/g) in the normal thyroid (74). It is present in glutathione peroxidase (GPX) and superoxide dismutase, the enzymes of the thyroid responsible for the detoxification of toxic derivates of oxygen (H2O2 and perhaps O2-) (75). It is also present in both iodothyronine 5′-deiodinases responsible for the conversion of T4 to T3 (76).

TABLE 49.3. COMPARISON BETWEEN AN AREA WITH SEVERE DEFICIENCIES IN IODINE AND SELENIUM AND OVERLOAD IN THIOCYANATE (UBANGI, NORTHERN DRC) AND CONTROL OF AREAS (BRUSSELS OR KIKWIT, DRC)


 Controls


Variables

(Brussels, Kikwit)
(n = 38–204)

Ubangi
(n = 140–243)


Prevalence of goiter (%)

3

76.8

Prevalence of cretinism (%)

0

4.7

Urinary concentration of

    Iodine (µg/dL)

5.3 ± 0.7

2.3 ± 0.1

  SCN (mg/dL)

0.60 ± 0.07

1.82 ± 0.10

Serum concentration of

 

 

  Selenium (ng/mL)

201.9 ± 5.23

27.1 ± 1.9

  RBC-GPX (U/g Hb)

15.0 ± 0.8

3.3 ± 0.3

Cord serum concentration of

    TSH (µU/mL)

8.2 ± 0.4

70.7 ± 13.1

  T4 (nM/L)

146.7 ± 2.6

95.2 ± 5.1

  T3 (nM/L)

0.57 ± 0.01

1.47 ± 0.10


Epidemiologic data, variables exploring the nutritional status in iodine, SCN, and selenium (including RBC-GPX) and variables exploring thyroid function in cord blood. Values recorded as mean ± SEM. All the differences between the two groups are highly significant (p < .01 to p < .001).
RBC-GPX, red blood cell–glutathione peroxidase; SCN, thiocyanate; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.
Data from references 69, 71, and 99.

The following scheme has been proposed to explain the frequency of myxedematous cretinism and the relative rarity of neurologic cretinism in areas such as the DRC where both iodine and selenium are deficient (69,70,71,72) (Fig. 49.3): iodine deficiency results in hyperstimulation of the thyroid by TSH and consequently in increased production of H2O2 within the cells. Selenium deficiency results in GPX deficiency and consequently in accumulation of H2O2. Excess H2O2 could induce thyroid cell destruction and thyroid fibrosis, resulting in myxedematous cretinism. The recent observation that the necrotizing effect of a high dose of iodide on the thyroid cells is much greater in selenium-deficient than in selenium-supplemented rats is consistent with this hypothesis, suggesting that the selenium-deficient thyroid gland is more sensitive to oxidative stress (77). The necrotizing effect is aggravated in the presence of SCN overload (78).

FIGURE 49.3. Effects of selenium deficiency on thyroid function and thyroxine metabolism in the presence of severe iodine deficiency. GPX, glutathione peroxidase. (From Contempré B, Many MC, Vanderpas J et al. Interaction between two trace elements: selenium and iodine. Implications of both deficiencies. In: Stanbury JB, ed. The damaged brain and iodine deficiency. New York: Cognizant Communication, 1994:133, with permission.)

On the other hand, in pregnant women deficiency of the selenoenzyme iodothyronine 5′-deiodinase induced by selenium deficiency causes decreased catabolism of T4 to T3 and thus increased availability of maternal T4 for the fetus and its brain. Indeed, despite a similar degree of iodine deficiency, serum T4levels are higher in selenium-deficient pregnant women in the DRC than in pregnant women in New Guinea (51). This mechanism could prevent the development of neurologic cretinism. Combined iodine and selenium deficiencies together with SCN overload due to the chronic consumption of cassava could thus explain the large predominance of the myxedematous type of endemic cretinism, rather than the neurologic type, in the DRC.

PATHOGENESIS

Endemic cretinism results from an insufficient supply of thyroid hormone to the developing brain. The physiologic role of thyroid hormones is to ensure the timed coordination of different developmental events through specific effects on the rate of cell differentiation and gene expression (79). Thyroid hormone action is exerted through the binding of T3 to nuclear receptors, which regulate the expression of specific genes in different brain regions following a precise development schedule (79). During the fetal and early postnatal life, T3 bound to nuclear receptors is entirely dependent on its local production from T4 via type 2 deiodinase (D2) (80) (see Chapter 74).

Maternal and Fetal Hypothyroxinemia before Onset of Fetal Thyroid Function

Despite the independence of maternal and fetal hypothalamus–pituitary–thyroid feedback mechanisms (81), maternal thyroid hormone is involved in the development and thyroid hormone economy of the fetus.

In rats, thyroid hormones are found in embryonic and fetal tissues before the onset of fetal thyroid function, which occurs at day 18 (82). The hormones are thus of maternal origin. Their concentrations remain fairly constant until day 18, when the fetal thyroid secretion begins (83). After day 18, the fetal thyroidal T4 and T3 pools as well as the circulating T4 level increase steadily (84). At term, 17.5% of the fetal extrathyroidal T4 is still of maternal origin (85).

In iodine deficiency, the rat embryo is T4 deficient, and its brain is exposed to variable T3 deficiency not only because of its own impairment of T4 synthesis but also, and perhaps predominantly, because of maternal hypothyroxinemia and insufficient transfer of T4 from mother to fetus in early pregnancy, before the onset of fetal thyroid activity (86).

The key role of maternal T4 during early gestation on the brain development of the fetus is demonstrated by the observation that in the 40-day-old progeny of hypothyroxinemic iodine-deficient pregnant rats, there is a significant proportion of neurons that are aberrant or inappropriate locators with respect to their birthdate (87). This is the first direct evidence of an alteration in fetal brain histogenesis and cytoarchitecture that can be only related to early maternal hypothyroxinemia.

An additional cause of fetal hypothyroxinemia in iodine deficiency is that the fetal thyroid, contrasting with the maternal thyroid, is unable to increase its avidity for iodide, that is, its iodide clearance rate in case of decreased serum concentration of iodide (88), despite up-regulation of Na+/I- symporter expression in fetal thyroid and placenta during iodine deficiency (89). This will further decrease the iodine stores of the fetal thyroid and, consequently, T4synthesis.

A partial mechanism of adaptation to fetal hypothyroxinemia in rats is that, in these circumstances, there is an increase in fetal brain deiodinase type 2 activity that protects the fetal brain from T3 deficiency, even when euthyroidism is not maintained in other fetal tissues (90). In contrast, the transfer of maternal T3 does not protect the hypothyroid fetal brain from T3 deficiency.

In humans, T4 is present in coelomic fluid 6 weeks of gestational age (91). Nuclear T3 receptors are present in the brain of 10-week-old fetuses, and increase more than sixfold by 12 weeks and tenfold by 16 weeks (92), largely before the onset of fetal thyroid function, which occurs by 14 weeks of gestation. However, evaluation of fetal tissue exposure to maternal thyroid hormones up to midgestation indicated that first-trimester human fetal tissues are exposed to concentrations of T4 of at least one third of those in their euthyroid mothers (93). These findings further underline the critical role of maternal thyroxinemia on the timely sequence of brain development in the human fetus. Fetal plasma T4 is low although detectable up to the 14th week of gestation. After the onset of fetal thyroid function, T4 increases steadily, reaching adult values by 36 weeks (94). However, transfer of maternal T4 continues until birth, when it still represents 20% to 50% of cord serum T4 (95).

Maternal hypothyroxinemia is rare in nonendemic areas, but it can result in impaired neurointellectual development in the offspring (5,96,97,98). In contrast, maternal hypothyroxinemia is extremely frequent in endemic areas (99,100). It is associated with increased mortality and morbidity in offspring (101,102), and increased incidence of hypothyroidism in neonates (99,103).

A unifying concept has been proposed that the neurologic defects, present in all cretins, are due to maternal and fetal hypothyroxinemia (48,50). This would account for the picture of cretinism as found in China and Indonesia. In Africa, as indicated earlier, brain damage during early fetal life could be mitigated by concomitant selenium deficiency, which impairs peripheral conversion of T4 to T3 and consequently increases the availability of the prohormone T4 to the fetal brain.

Fetal and Neonatal Hypothyroidism after Onset of Fetal Thyroid Function

Even a moderate degree of iodine deficiency during pregnancy, as occurs in Western Europe, can be accompanied by indexes of hyperstimulation of the thyroid in the neonates, as indicated by high serum levels of TSH and thyroglobulin (Tg) and by a slight enlargement of the thyroid. These abnormalities are prevented by the daily administration of a physiologic dose of iodide to pregnant women throughout pregnancy (104).

As noted above, the myxedematous endemic cretinism results from severe thyroid failure occurring during late fetal or early postnatal life: data from China have shown hypothyroxinemia and retardation in brain growth in human fetuses from the sixth month of gestation in regions of severe iodine deficiency and myxedematous endemic cretinism (105). Thyroid failure at birth due to iodine deficiency occurs in several endemic areas with myxedematous endemic cretinism, such as the DRC (99,103), India (106), Algeria (107), and even some parts of Europe such as Sicily (108). The most dramatic picture of neonatal hypothyroidism has been reported from DRC, where the frequency of myxedematous endemic cretinism is the highest: in this area, about 10% of unselected newborns and infants 1 to 24 months of age have both serum TSH above 100 µU/mL and T4 levels below 3.1 µg/dL (40 nM) (99,103), a biochemical picture characteristic of congenital hypothyroidism in Western countries (109,110). About 10% of infants under 12 months of age are clinically hypothyroid, and nearly half have a marked delay in bone maturation, which is directly correlated with serum TSH and inversely correlated with serum T4 (99,103). Finally, correction of iodine deficiency in pregnant women by injections of iodized oil results in a complete normalization of the biochemical and radiologic indexes of hypothyroidism in newborns and infants (103,111).

The presence of epiphyseal dysgenesis in x-ray studies of the knees (Fig. 49.4B) of some adult myxedematous endemic cretins with clinical, biochemical, and radiologic signs of long-standing hypothyroidism suggests that hypothyroidism was present before or around birth (112). Also, the direct correlations observed in these cretins between mental retardation and both height retardation and retardation in bone maturation indicate that hypothyroidism present in early life would account for their mental deficiency (17).

FIGURE 49.4. Clinical appearance (A) and knee x-ray (B) of a 17-year-old myxedematous cretin of Idjwi Island, DRC, with a height of 87.5 cm (56% of normal for the local population) and a serum protein bound iodine (PBI) of 1.0 µg/dL. Bone maturation is estimated at 2 to 5 years. The x-ray film shows failure of modeling, and tibial and femoral epiphyseal dysgenesis. The immaturity of the naso-orbital configuration, the mandibular hypoplasia, and the epiphyseal dysgenesis indicate hypothyroidism of pre- or perinatal onset.

In some infants in the Ubangi area in DRC, the biochemical signs of thyroid failure disappeared spontaneously within 6 to 10 weeks of life (113). The hypothesis has been proposed that permanent thyroid failure from birth results in myxedematous endemic cretinism, whereas transient hypothyroxinemia occurring during the critical period of brain development explains the endemic mental retardation in this population (114).

The cause of fetal hypothyroidism in the DRC is most likely the combined action of iodine deficiency and SCN overload. The latter results from the chronic consumption of cassava, which aggravates the effects of iodine deficiency (19,20). SCN freely crosses the placenta (115), and its concentration in cord blood is three times higher in Ubangi than in Brussels (99). The importance of this SCN overload in the impairment of thyroid function of the newborn is strongly suggested by the observation that, in severely iodine-deficient pregnant women, high urinary SCN values are associated with very high serum TSH and very low cord serum T4 levels (99). The hypersensitivity of the newborn to the antithyroid action of SCN probably results from the fact that this ion interferes with the trapping of iodide by both the placenta and the thyroid gland of the newborn. These two factors probably critically reduce the buildup of iodine stores within the thyroid gland during fetal and early postnatal life. This mechanism is consistent with the low iodine content of the thyroid gland reported in myxedematous cretins (116) (Table 49.1).

As discussed earlier, selenium deficiency could further aggravate thyroid failure during the late fetal and neonatal periods by damaging the hyperstimulated gland through the accumulation of H2O2 derivatives. This process, called exhaustion atrophy, would explain the usual absence of goiter in the myxedematous cretins in the DRC.

In addition, iodine deficiency can induce thyroid failure at any time, including after brain development, resulting in infantile hypothyroidism without the irreversible brain damage characteristic of cretinism (28,117,118).

This unifying view of the pathogenesis of endemic cretinism would account for the differences in the epidemiologic and clinical aspects of cretinism seen around the world. Iodine deficiency is a prerequisite. When present during early gestation before onset of fetal thyroid function, it would account for the neurologic aspects of cretinism via maternal and fetal hypothyroxinemia. Selenium deficiency could mitigate the neurologic picture by increasing the availability of the prohormone T4 to the developing brain. It also could induce irreversible damage of the thyroid. Severe iodine and selenium deficiencies aggravated by SCN overload present during late pregnancy, after the onset of active fetal thyroid function, would account for the myxedematous component of cretinism.

It thus appears that the particular situation reported in the DRC with less neurologic damage and severe thyroid failure could be explained by a combination of severe iodine and selenium deficiencies complicated by SCN overload. The consequences of these three conditions are prevented by the correction of iodine deficiency in the pregnant mother.

THERAPY

There is no specific therapy for neurologic endemic cretinism. These patients need rehabilitation as do patients with cerebral palsy in Western countries. Thyroid function may improve after iodine supplementation in myxedematous cretins under 4 years of age but not in older patients, suggesting that in this type of cretinism the atrophic thyroid progressively loses its functional capacity (119,120). Some researchers, however, have reported significant improvement in neuromotor and physical appearance even in 30- to 40-year-old myxedematous endemic cretins treated with injections of iodized oil (53).

PREVENTION

Endemic cretinism is prevented when iodine deficiency has been corrected (3,5,8,11,111,121). Iodization of salt introduced independently in various Swiss cantons between 1922 and 1925 resulted in a decline in endemic deaf-mutism in these cantons that could be correlated with the extent of salt iodination (122). However, it must be pointed out that in Switzerland endemic cretinism started to diminish about 10 years before the introduction of iodine prophylaxis (5), probably because of improved socioeconomic conditions, resulting in a “silent iodine prophylaxis.”

Table 49.4 summarizes the results of the controlled trials conducted during the past 20 years on the effect of iodine prophylaxis on the incidence of endemic cretinism. In Ecuador, in an attempt to study the effectiveness of iodine supplementation in early fetal life, pregnant women in the test village (Tocachi) were given iodine supplementation. Mothers who were in the sixth, seventh, eighth, and ninth months of pregnancy at the time of iodization were excluded. There have been no new cases of endemic cretinism among the infants investigated in the treated village, whereas six instances of severe and persistent mental and neuromotor deficiencies have appeared in the control village (123). The data of Pharoah and colleagues (124) indicate that iodized oil injections prevent neurologic endemic cretinism in offspring only if administered before pregnancy, indicating that the damage occurs during early fetal life.

TABLE 49.4. PREVENTION OF ENDEMIC CRETINISM BY INJECTIONS OF IODIZED OIL


Regions

Methods

Findings

References


Neurologic cretinism

  Ecuador

One village injected (Tocachi).
One village not injected (La Esperanza).
Follow-up of the children born in the two villages up to 60 mo of age.

No cretin among the 205 children born in the treated village.
Six neurologic cretins among the 447 children born in the untreated village.

123

  Papua-New Guinea

Families injected or not injected at random. Follow-up of the children up to 60 mo of age.

Six neurologic cretins among the 687 children in the treated group; in five of the six, the mother was pregnant at the time of injection.
Thirty-one cretins among the 688 children in the untreated group.

124

Myxedematous cretinism

   DRC

      Idjwi Island

Two villages injected. One village not injected. Surveys after 1, 3.5, and 5 yr in the treated villages and after 5 yr in the untreated village.

No cretin born in the treated villages. Three myxedematous cretins were born in the untreated village during the fifth year of the investigation.

140

      Ubangi

Pregnant women injected at random between the 20th and 36th wk of gestation (mean 28th wk).

 

103,111

 

Follow-up of 99 infants age 1.5–15 mo (mean 6.5 mo).

One myxedematous cretin among 44 infants in the treated group (mother injected during the last month of gestation).
Four myxedematous cretins among 45 infants in the untreated group.

  Follow-up of 671 infants and children age 0–7 yr.

In infants 0–2 yr, myxedematous cretinism in 1/192 in the treated group and 10/109 in the untreated group (p < .01). The difference disappeared in children 3–7 yr.

 


The data from DRC show that correction of iodine deficiency prevents myxedematous endemic cretinism in the offspring even if administered during pregnancy (103). Subsequent studies showed that correction of iodine deficiency in pregnant mothers does not protect the infants against hypothyroidism for more than 2 to 3 years (111). The possibility that in some children, hypothyroidism could start after the age of 3 years is consistent with the observation of Goslings and colleagues (28) that hypothyroid patients in severe endemic goiter are not necessarily affected by severe and irreversible mental retardation and of Boyages and colleagues (44) that cretins with thyroid failure may have only moderate retardation in height and bone maturation (Table 49.1).

CONCLUSION

The epidemiology, clinical manifestation, laboratory data, therapy, and prevention of endemic cretinism are presently well established. Its etiopathogenesis is much better understood. Iodine deficiency appears to be an essential factor and, if severe enough, may be the sole factor in its causation. Selenium deficiency, if present, is an additional factor that results, on the one hand, in a risk of thyroid damage during the perinatal period and, on the other hand, in an increased availability of the prohormone T4 of maternal origin to the fetal brain. Thiocyanate, if present, aggravates the effects of both iodine and selenium deficiencies, both in the mother and the fetus, as it freely crosses the placenta.

Distinction between the neurologic and myxedematous types of endemic cretinism is not required any longer for two reasons: (a) it is difficult to justify from an epidemiologic and clinical point of view, and (b) the various manifestations of cretinism are critically related to the degree, timing, and duration of the action of the different dietary goitrogenic factors, including iodine deficiency. The level of serum T4 of the mother during gestation and the transfer of maternal T4 to the fetus and neonate, especially during early gestation even before the onset of fetal thyroid function, are the determining factors in the occurrence of irreversible brain damage. The second trimester appears as the period of maximum vulnerability of the brain. Maternal hypothyroxinemia appears as the determining factor in the pathogenesis of the neurologic picture and selenium deficiency in the thyroid damage and failure in endemic cretinism, respectively. The respective importance of these two factors depends on the local goitrogenic factors in the diet.

Because of the gravity of the condition and the well-established preventive action of iodine, an efficient iodine prophylaxis is urgently needed in areas affected by endemic goiter and cretinism.

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