The effects of iodine deficiency on growth and development can be considered at the various stages of life as follows :
Iodine deficiency in the fetus is the result of iodine deficiency in the mother. The consequence of iodine deficiency during pregnancy is impaired synthesis of thyroid hormones by the mother and the fetus. An insufficient supply of thyroid hormones to the developing brain may result in mental retardation (Reviews in 10-16).
The physiologic role of thyroid hormones can be defined as to insure the timed coordination of different developmental events through specific effects on the rate of cell differentiation and gene expression. 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 developing schedule during fetal and early postnatal life. The T3 which is bound to the nuclear receptors is primary dependent on its local intracellular production from T4 via type II deiodinase and not from circulating T3.
Figure 1 shows the time course of the development of the brain and of the thyroid function in the human fetus and neonate. Brain growth is characterized by two periods of maximal growth velocity (17). The first one occurs during the first and second trimesters between the third and the fifth months of gestation. This phase corresponds to neuronal multiplication, migration and organization. The second phase takes place from the third trimester onwards up to the second and third years postnatally. It corresponds to glial cell multiplication, migration and myelinisation. The first phase occurs before fetal thyroid has reached its functional capacity. It is now largely agreed that during this phase, the supply of thyroid hormones to the growing fetus is almost exclusively of maternal origin while during the second phase, the supply of thyroid hormones to the fetus is essentially of fetal origin (18).
Figure 1. Ontogenesis of thyroid function and regulation in humans during fetal and early postnatal life in relation to the velocity of brain growth. From Delange and Fisher (190) with authorization.
As a matter of fact, an important recent issue on thyroid function and regulation in the fetus is the concept that thyroid hormones are transferred from mother to fetus both before and probably after the onset of fetal thyroid function, contrasting with the previous dogma that this transfer is minimal or does not exist (19, 20). In humans, T4 can be found in the first trimester coelomic fluid from 6 weeks of gestational age, long time before the onset of secretion of T4 by the fetal thyroid, which occurs at the 24th week of gestation (21). Nuclear T3 receptors and the amount of T3 bound to these receptors increase about six to tenfold between 10 and 16 weeks, also before the secretion of hormones by the fetal thyroid (22). The T4 and T3 found in early human fetuses up to mid gestation are likely to be entirely or mostly of maternal origin. As a consequence, as recently confirmed and clarified (22 bis), infants born to women with hypothyroxinemia at 12 weeks gestation (fT4 concentrations <10th percentile) have significantly lower scores at the Neonatal Behavioural Assessment Scale than controls. These anomalies are already detectable at the age of 3 weeks of age. The transfer of thyroid hormones is decreasing but persists during later gestation as Vulsma et al (23) suggested that up to 30 % of serum T4 in cord blood at birth could be of maternal origin, although a much lower percentage has been reported by Delange et al. (24).
Other mechanisms involved in the action of thyroid hormones in the brain working to deliver a proper amount of T3 to the target cells involve the deiodinases, especially the deiodinase D3 found in the uterine implementation site and in the placenta, producing rT3 from T4 and 3’,5’-T2 from T3 and having a protective effect to avoid an excess of thyroid hormone reaching the fetus. The membrane transporters for thyroid hormones physiologically relevant in the flux of thyroid hormones through the blood stream barrier, the choroid plexus and the cellular membranes of the astrocytes and neurons are also involved (24 bis).
Studies on the effects of iodine deficiency in animals have confirmed the morphological and biochemical modifications seen in the hyperplastic goiter of man (25). More recently the effects of iodine deficiency on development, particularly those relating to the fetus, have been investigated. These studies on the rat, marmoset (Callithrix jacchus jacchus), and the sheep have been particularly concerned with fetal brain development because of its relevance to the human problem of endemic cretinism and brain damage resulting from fetal iodine deficiency.
Studies in rats have been carried out using the diet consumed by the people of Jixian village in China (26-29). This village was severely iodine deficient with 11% endemic cretinism. The diet included available main crops (maize, wheat), vegetables, and water from the area with an iodine content of 4.5 ug/kg. After the dam had received the diet for 4 months, there was obvious neonatal goiter, fetal serum T4 was 3.6 ug% compared to controls of 10.4 ug% and they had higher 125I uptake and reduced brain weight. The density of brain cells was increased in the cerebral hemispheres. The cerebellum showed delayed disappearance of the external granular layer with reduced incorporation of 3H leucine in comparison to the control group.
Other more detailed studies have been carried out on the number and distribution of dendritic spines along the apical shaft of the pyramidal cells of the cerebral cortex of the rat (30). These dendritic spines can be accurately measured and have been studied in relation to both iodine deficiency and hypothyroidism. Their appearance and development reflects the formation of synaptic contacts with afferents from other neurones. In normal rats there is a progressive increase in the number of spines from 10 to 80 days of age.
The studies have demonstrated a significant effect of an iodine deficient (Remington) diet on the number and distribution of the spines on the pyramidal cells of the visual cortex. This effect is similar to that of thyroidectomy. More detailed studies following thyroidectomy indicated the importance of the timing of the procedure. If carried out before the 10th day of life, recovery is unlikely to occur unless there is immediate replacement with L-T4. At 40 or 70 days, replacement can restore a normal distribution of spines even if there is a 30 day delay in its initiation. These differences confirm the need for early treatment of congenital hypothyroidism and prevention of iodine deficiency in the newborn infant in order to prevent brain damage and mental retardation..
Severe iodine deficiency has been produced in the marmoset (Callithrix Jacchus Jacchus) with a mixed diet of maize (60%), peas (15%), torula yeast (10%) and dried iodine deficient mutton (10%) derived from the iodine-deficient sheep to be described in the next section. The newborn iodine deficient marmosets showed some sparsity of hair growth (31). The thyroid gland was enlarged with gross reduction in plasma T4 in both mothers and newborns, greater in the second pregnancy than in the first, suggesting a greater severity of iodine deficiency. There was a significant reduction in brain weight in the newborns from the second pregnancy but not from the first. The findings were more striking in the cerebellum with reduction in weight and cell number evident and histological changes indicating as in the rat and the sheep, impaired cell acquisition. These findings demonstrate the significant effects of iodine deficiency on the primate brain.
Severe iodine deficiency has been produced in sheep (32) with a low-iodine diet of crushed maize and pelleted pea pollard (8-15 ug iodine/kg) which provided 5-8 ug iodine per day for sheep weighing 40-50 kg. The iodine deficient fetuses at 140 days were grossly different in physical appearance in comparison to the control fetuses. There was reduced weight, absence of wool growth, goiter, varying degrees of subluxation of the foot joints, and deformation of the skull. (Fig. 2) There was also delayed bone maturation as indicated by delayed appearance of epiphyses in the limbs (33). Goiter was evident from 70 days in the iodine-deficient fetuses and thyroid histology revealed hyperplasia from 56 days gestation, associated with a reduction in fetal thyroid iodine content and reduced plasma T4 values. There was a lowered brain weight and DNA content as early as 70 days, indicating a reduction in cell number probably due to delayed neuroblast multiplication which normally occurs from 40-80 days in the sheep. Findings in the cerebellum were similar to those already described in marmoset (32).
A single intramuscular injection of iodised oil (1 ml = 480 mg iodine) given to the iodine deficient mother at 100 days gestation was followed by partial restoration of the lambs brain weight and body weight with restoration of maternal and fetal plasma T4 values to normal (32).
Studies of the mechanisms involved in the sheep revealed significant effects of fetal thyroidectomy in late gestation and a significant effect of maternal thyroidectomy on brain development mid gestation. The combination of maternal thyroidectomy (carried out 6 weeks before pregnancy) and fetal thyroidectomy produced more severe effects than that of iodine deficiency associated with greater reduction in both maternal and fetal thyroid hormone levels (33). These finding confirm the importance of both maternal and fetal thyroid hormones in fetal brain development.
An increased perinatal mortality due to iodine deficiency has been shown in Zaire from the results of a controlled trial of iodised oil injections alternating with a control injection given in the latter half of pregnancy (34). There was a substantial fall in infant mortality with improved birth weight following the iodised oil injection. Low birth weight of any cause is generally associated with a higher rate of congenital anomalies and higher risk through childhood. This has been demonstrated in the longer term follow up of the controlled trial in Papua New Guinea in children up to the age of 12 years (35) and in Indonesia (36).
A reduction of infant mortality has also been reported from China following iodine supplementation of irrigation water in areas of severe iodine deficiency. Iodine replacement has probably been an important factor in the national decrease in infant mortality in this country (37).
Apart from mortality, the importance of the state of thyroid function in the neonate relates to the fact that the brain of the human infant at birth has only reached about one third of its full size and continues to grow rapidly until the end of the second year (38). The thyroid hormone, dependent on an adequate supply of iodine, is essential for normal brain development as has been confirmed by the animal studies already cited.
Studies on iodine nutrition and neonatal thyroid function in Europe in the early 1980s confirmed the continuing presence of iodine deficiency affecting neonatal thyroid function and hence a threat to early brain development (39). A series of 1076 urine samples were collected from 16 centers from 10 different countries in Europe along with an additional series from Toronto, Canada and analyzed for their iodine content. The results of these determinations are shown in Table 3. The distribution was skewed so that arithmetic means were not used, but the results were expressed in percentiles. Some very high values were seen which could be attributed to the use of iodinated contrast media for radiological investigation of the mother during pregnancy. There was a marked difference in the results from the various cities. The high levels in Rotterdam, Helsinki and Stockholm differed from the low levels in Gottingen, Heidelberg, Freiburg and Jena by a factor of more than 10. Intermediate levels were seen in Catania, Zurich and Lille.
Table 3. Frequency distributions of urinary iodine concentrations in healthy full-term infants in 14 cities in Europe and in Toronto, Canada
|
Urinary Iodine Concentration |
|||||
|---|---|---|---|---|---|
|
City |
Number of infants |
10th Percentile |
50th Percentile |
90th Percentile |
Frequency (%) of values Below 5 μg/dl |
|
The European cities are listed according to decreasing values (50th percentile). From Delange et al. (39) |
|||||
|
Toronto |
81 |
4.3 |
14.8 |
37.5 |
11.9 |
|
Rotterdam |
64 |
4.5 |
16.2 |
33.2 |
15.3 |
|
Helsinki |
39 |
4.8 |
11.2 |
31.8 |
12.8 |
|
Stockholm |
52 |
5.1 |
11.0 |
25.3 |
5.9 |
|
Catania |
14 |
2.2 |
7.1 |
11.0 |
38.4 |
|
Zurich |
62 |
2.6 |
6.2 |
12.9 |
34.4 |
|
Lille |
82 |
2.0 |
5.8 |
15.2 |
37.2 |
|
Brussels |
196 |
1.7 |
4.8 |
16.7 |
53.2 |
|
Rome |
114 |
1.5 |
4.7 |
13.8 |
53.5 |
|
Toulouse |
37 |
1.2 |
2.9 |
9.4 |
69.4 |
|
Berlin |
87 |
1.3 |
2.8 |
13.6 |
69.7 |
|
Gottingen |
81 |
0.9 |
1.5 |
4.7 |
91.3 |
|
Heidelberg |
39 |
1.1 |
1.3 |
4.0 |
89.8 |
|
Freiburg |
41 |
1.1 |
1.1 |
2.3 |
100.0 |
|
Jena |
54 |
0.4 |
0.8 |
2.2 |
100.0 |
Data on neonatal thyroid function was analysed for four cities where enough newborns (30,000 - 102,000) had been tested. The incidence of permanent congenital hypothyroidism was very similar in the four cities but the rate of transient hypothyroidism was much greater in Freiburg, associated with the lowest level of urine iodine excretion, than in Stockholm, with intermediate findings from Rome and Brussels. These data confirmed the significance of iodine intake for neonatal thyroid function.
In developing countries with more severe iodine deficiency, observations have now been made using blood taken from the umbilical vein just after birth. Neonatal chemical hypothyroidism was defined by serum levels of T4 lesser than 3 ug/dl and TSH greater than 100 uU/ml). In the most severely iodine deficient environments in Northern India, where more than 50% of the population has urinary iodine levels below 25 ug per gram creatinine, the incidence of neonatal hypothyroidism was 75 to 115 per thousand births (40). By contrast in Delhi, where only mild iodine deficiency is present with low prevalence of goiter and no cretinism, the incidence drops to 6 per thousand. In control areas without goiter the level was only one per thousand.
There is similar evidence from neonatal observations in neonates in Zaire in Africa where a rate of 10% of chemical hypothyroidism has been found (41). This hypothyroidism persists into infancy and childhood if the deficiency is not corrected, and results in retardation of physical and mental development (42). These observations indicate a much greater risk of mental defect in severely iodine deficient populations than is indicated by the presence of cretinism. They provide strong evidence for the need to correct the iodine deficiency in Europe as well as in developing countries.
Another important aspect of iodine deficiency in the neonate and child is an increased susceptibility of the thyroid gland to radioactive fall-out. Delange (43) has shown that the thyroidal uptake of radioiodine reached its maximum value in the earliest years of life and then declined progressively into adult life. The apparent thyroidal iodine turnover rate was much higher in young infants than in adults and decreased progressively with age. In order to provide the normal rate of T4 secretion, Delange (43) has estimated that the turnover rate for intrathyroidal iodine must be 25-30 times higher in young infants than in adolescents and adults. In iodine deficiency a further increase in turnover rate is required to maintain normal thyroid hormone levels (7). This is the reason for the greatly increased susceptibility of the neonate and fetus to iodine deficiency. Iodine deficiency also causes an increased uptake of the radioiodide, resulting from exposure to nuclear radiation. Protection against this increased uptake can only be provided by correction of iodine deficiency which constitutes a further urgent indicator for the correction of iodine deficiency in Europe as well as in developing countries.
There is no evidence that impairment of thyroid function evidenced in mothers and neonates in conditions of mild iodine deficiency affects the intellectual development of the children. Aghini-Lombardi et al. (44) reported that in children aged 6-10 years in an area in Tuscany who had mild iodine deficiency (64 μg iodine/day), the reaction time was delayed compared with matched controls from an iodine sufficient area (142 μg iodine/day). The cognitive abilities of the children were not affected. Similarly, it was reported that in an area of Southern Spain with mild iodine deficiency (median urinary iodine of 90 μg/L), the intelligence quotient (IQ) was significantly higher in children with urinary iodine levels above 100 μg/L (44bis).
Additional investigations conducted in areas with moderate iodine deficiency have also demonstrated the presence of definite abnormalities in the psychoneuromotor and intellectual development of children and adults who are clinically euthyroid but who do not exhibit the other signs and symptoms of endemic cretinism, that is the most severe form of brain damage caused by iodine deficiency. These studies are summarized in Table 4.
Table 4. Neuropsychointellectual Deficits in Infants and Schoolchildren in Conditions of Mild to Moderate Iodine Deficiency
|
REGIONS |
TESTS |
FINDINGS |
AUTHORS |
|---|---|---|---|
|
Spain |
Locally adpated BAYLEY McCARTHY CATTELL |
Lower psychomotor and mental development than controls |
Bleichrodt et al. 1989 (207) |
|
Italy |
|||
|
Sicily |
BENDER- GESTALT |
Low preceptual integrative motor ability Neuromuscular and neurosensorial abnormalities |
Vermiglio et al. 1990 (208) |
|
Tuscany |
WECHSLER RAVEN |
Low verbal IQ, perception, motor and attentive functions |
Fenzi et al. 1990 (209) |
|
Tuscany |
WISC Reaction time |
Lower velocity of motor response to visual stimuli |
Vitti et al. 1992 (210) Aghini-Lombardi et al. 1995 (44) |
|
India |
Verbal, pictorial learning tests Tests of motivation |
Lower capacities learning |
Tiwari et al. 1996 (211) |
|
Iran |
Bender-Gestallt Raven |
Retardation in psychomotor development |
Azizi et al. 1993 (212) |
|
Malawi |
Psychometric tests including verbal fluency |
Loss of 10 IQ points as compared to iodine-supplemented controls |
Shrestha 1994 (213) |
|
Benin |
Battery of 8 non verbal tests exploring fluid intelligence and 2 psychomotor tests |
Loss of 5 IQ points as compared to controls supplemented with iodine for one year |
van den Briel et al. 2000 (214) |
The irreversible impairment of intellectual development in these conditions represents the longterm consequence of transient neonatal hypothyroidism (45, 46, 46 bis).
In contrast, studies conducted in Albania in a moderately iodine deficient area indicated that information processing, fine motor skill and visual problem solving improved in school-children after iodine repletion of the population (46 bis). As these anomalies were reversible, they probably result from lately acquired and reversible subclinical hypothyroidism rather than from fetal and/or neonatal hypothyroidism.
In severe iodine deficiency, the anomalies found in the « normal population » are of the same type, although more frequent and more severe than the ones found in moderate iodine deficiency. The frequency distribution of IQ in apparently normal children in such conditions is shifted towards low values as compared to matched controls who were not exposed to iodine deficiency during the critical period of brain development because of correction of the deficiency in the mothers before or during early gestation (47-49 ter). More globally, in their meta-analysis of 19 studies on neuromotor and cognitive functions in conditions of moderate to severe iodine deficiency, Bleichrodt and Born (50) concluded that iodine deficiency resulted in a loss of 13.5 IQ points at the level of the global population.
A high degree of apathy has been noted in populations living in severely iodine deficient areas. This may even affect domestic animals such as dogs (25). It is apparent that reduced mental function due to cerebral hypothyroidism is widely prevalent in iodine deficient communities with effects on their capacity for initiative and decision-making (4). This indicates that iodine deficiency can be a major block to the human and social development of communities living in an iodine deficient environment and constitutes a major teratogen at the community level (9).
In addition to this impact to brain and neurointellectual development, iodine deficiency at any period in life, including during adulthood, can induce the development of goiter with mechanical complications and/or thyroid insufficiency.
Another consequence of longstanding iodine deficiency in the adult (51-54), but also in the child (55), is the development of hyperthyroidism, especially in multinodular goiters with autonomous nodules. The pathogenesis of this syndrome is discussed in section VI,3 of this chapter (side effects of iodine supplementation). It is now accepted that hyperthyroidism is one of the disorders induced by iodine deficiency.