IDD(iodine deficiency disorders) IN HUMANS AT FOUR STAGES OF DEVELOPMENT AND IN ANIMAL MODELS

These are just some of the disorders associated with iodine deficiency, and some of the most severe, such as cretinism.

 

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The spectrum of iodine deficiency disorders which occur at various stages of development is shown in Table 1. Each of the four states is considered in detail here below.

 

TABLE 1

 

THE SPECTRUM OF IODINE DEFICIENCY DISORDERS

FOETUS	Abortions
	Stillbirths
	Congenital anomalies
	Increased perinatal mortality
	Increased infant mortality
	Neurological cretinism	- mental deficiency
		deaf-mutism
		spastic diplegia
		squint
	Myxoedematous cretinism	- dwarfism
		mental deficiency
		Psychomotor defects
		Foetal hypothyroidism
NEONATE	Neonatal hypothyroidism
	Neonatal goitre
CHILD AND ADOLESCENT	Goitre Juvenile
	Hypothyroidism
	Impaired mental function
	Retarded physical development
ADULT	Goitre with its complications
	Hypothyroidism
	Impaired mental function

Source: Hetzel and Maberly, 1985.

2.1 IODINE DEFICIENCY IN THE FOETUS

Iodine deficiency in the foetus is the result of iodine deficiency in the mother. It is associated with a greater incidence of stillbirths, abortions and congenital abnormalities, which can be reduced by iodization (McMichael et al., 1980).

Another major effect of foetal iodine deficiency is endemic cretinism. This condition is still widely prevalent, affecting for example up to 10 percent of the populations living in severely iodine-deficient areas in India (Pandav and Kochupillai, 1982), Indonesia (Djokomoeljanto et al., 1983) and China (Ma et al., 1982). Its commonest form is referred to as the 'nervous' (neurological) type in contrast with the less common "myxoedematous" type characterized by hypothyroidism with dwarf ism. The differences between the two types are summarized in Table 2. The clinical features in a series of 254 cretin subjects from Papua New Guinea (Buttfield and Hetzel, 1969) are listed in Table 3. Detailed studies of bilateral hearing defects in Central Java suggest that they are a marker of great specificity (Pharoah et al., 1980).

The condition described by McCarrison in 1908 still exists in the same areas of the Karakoram Mountains and the Himalayas (Pandav and Kochupillai, 1982). Neurological, myxoedematous and mixed types are found in the Hetian District of Sinkiang, China (Fig. 1). In both China and India, the condition occurs most frequently below the mountain slopes in the fertile silt plains that have been leached of iodine by snow waters and glaciation.

In all the areas where cretinism is found, with the exception of Zaire, neurological features predominate (Buttfield and Hetzel, 1969). In Zaire the myxoedematous form is more common, possibly due to the high intake of cassava (Pharoah et al., 1980).

The common form of endemic cretinism is not usually associated with severe clinical hypothyroidism as in so-called sporadic cretinism. When mixed forms do occur, however, the neurological features are not reversed by administering thyroid hormones, unlike hypothyroidism (Fierro-Benitez et al., 1970).

The apparently spontaneous disappearance of endemic cretinism in southern Europe raised doubts about its relation to iodine deficiency. This disappearance without iodization was noted by Konig and Veraguth (1961) in Switzerland and by Costa et al. (1964) in northern Italy.

Under these circumstances it was decided in the nineteen-sixties to set up a controlled trial in the Western Highlands of Papua New Guinea to see whether endemic cretinism could be prevented by iodization. This study, carried out in collaboration with the Public Health Department, was based on the use of iodized oil in a single intramuscular injection of 4 ml of Lipiodol, which provided approximately 2 g. of iodine. This dose had previously been shown (Buttfield and Hetzel, 1967) to provide satisfactory correction of severe iodine deficiency for a period of between four and five years. Iodized oil or saline injections were given to alternate families in the Jimi River District at the time of the first census in 1966. Each child born subsequently was examined for evidence of motor retardation, as assessed by the usual tests of sitting, standing and walking, and for evidence of deafness. Examination was carried out without knowledge of whether the mother had received iodized oil or saline. Infants with the full syndrome of hearing and speech abnormalities together with abnormalities of motor development with or without squint were classified as suffering from endemic cretinism. Later follow-up confirmed the diagnoses of cretinism in these cases.

 

TABLE 2

 

COMPARATIVE CLINICAL FEATURES IN NEUROLOGICAL
AND HYPOTHYROID CRETINISM

	Neurological cretin	Hypothyroid cretin
Mental retardation	Present, often severe	Present, less severe
Deaf-mutism	Usually present	Absent
Cerebral diplegia	Often present	Absent
Stature	Usually normal	Severe growth retardation usual
General features	No physical signs of hypothyroidism	Coarse dry skin, husky voice
Reflexes	Excessively brisk	Delayed relaxation
ECG	Normal	Small voltage QRS complexes and other abnormalities of hypothyroidism
X-ray limbs	Normal	Epiphyseal dysgenesis
Effect of thyroid hormones	No effect	Improvement

Source: Hetzel and Maberly, 1986

TABLE 3

 

ENDEMIC CRETINISM IN PAPUA NEW GUINEA - CLINICAL FEATURES

	Number	Percentage
Males	129	(51%)
Females	125	(49%)
Total	254
Visible goitre rate	165	(26%)
Deaf-mutism (partial and complete)	177	(70%)
Characteristic vacant faces	161	(64%)
Brisk reflexes	156	(61%)
Extensor plantar response	122	(48%)
Mental abnormalities	120	(47%)
Flexural deformities	70	(28%)
Muscular incoordination	65	(26%)
Dvarfism	65	(26%)

Source: Buttfield and Hetzel, 1969

Full details were published (Pharoah et al., 1971) and the results of the follow-up are shown in Table 4 and Fig. 2.

It was concluded that an injection of iodized oil given prior to pregnancy could prevent the neurological syndrome of endemic cretinism in the infant. The presence of the syndrome in women who were pregnant at the time of injection indicated that the damage probably occurred during the first half of the pregnancy.

In the light of recent experimental findings (Obregon et al., 1984) it is most likely that this is because of reduced maternal thyroid hormone availability to the foetus, and not because of iodine deficiency of the foetus itself as originally suggested (Pharoah et al., 1971). It is now known that the foetus in its early stages depends on maternal thyroid hormones which cross the placenta (Obregon et al., 1984 al.,1984; Woods et al., 1984). This possibility is supported by other evidence from Papua New Guinea indicating a relationship betweem maternal thyroxine levels and psychomotor development in the child (Pharoah et al., 1984).

Figure 1. Severe IDD: a dwarfed cretin woman with a barefoot doctor of the same age from the Hetian district in Sinkiang, China (Courtesy of Dr. Ma Tai of Tianjin. Reproduced from Hetzel, 1983, with permission).

 

 

Recent studies in Papua New Guinea and Indonesia have demonstrated the existence of a coordination defect in otherwise normal children exposed to severe iodine deficiency in pregnancy (Bleichrodt et al., 1980; Connolly et al., 1979). Lesser degrees of neurological damage are also observed (isolated deaf-mutism and mental deficiency) which probably reflect less severe foetal iodine deficiency. In China, these less severe forms are called 'cretinoids' (Ma et al., 1982).

 

2.2 IODINE DEFICIENCY IN THE NEONATE

The availability of methods for neonatal screening in developed countries (Burrow, 1980) has led to their application in developing countries such as India and Zaire. In India observations on cord blood in iodine-deficient areas indicate as many as 4 percent of neonates with serum thyroxine levels below 3 mcg percent (Kochupillai et al., 1984). In Zaire up to 10 percent of neonates have been observed with low thyroxine levels (Ermans et al., 1980a). These frequencies should be compared with 0.02 percent in most developed countries with normal iodine nutrition (Burrow, 1980).

In a further study from Zaire, the effect of an injection of iodized oil on birth weight, perinatal and infant mortality, and development quotient was assessed by comparison with an untreated group (Thilly, 1981). The findings are shown in Table 5. They indicate substantial improvements in birth weight of infants, with reductions in perinatal and infant mortality and improvement in the development quotient. These findings indicate the necessity of iodine and normal thyroid function for general foetal development and neonatal health. Longer-term benefits evident in children up to the age of 10 to 12 years have been shown in controlled studies following injections of iodized oil before or during pregnancy (Connolly et al., 1979; Pharoah et al., 1984; Fierro-Benitez et al., 1986). These include improved psychomotor performance and improved school performance.

 

TABLE 4

 

CHILDREN BORN IN JIMI RIVER SUBDISTRICT (PAPUA NEW GUINEA)
TO TREATED AND UNTREATED MOTHERS FROM 1966

Treatment received by mother	Total no. of new births	No. of children examined	No. of deaths recorded	No. of endemic cretins
Iodized oil	498	412	66	7 (1)
Untreated	534	406	97	25 (2)

Source: Pharoah et al., 1971 See also Fig. 3

(1) Mothers of 6 already were pregnant when injected with oil
(2) Mothers of 5 already were pregnant when injected with saline solution

TABLE 5

 

EFFECT OF INJECTION OF IODIZED OIL GIVEN DURING PREGNANCY, IN ZAIRE

	Not treated		Treated
Birth weight (g.±)	2634 ± 552	(98)	2837 ± 542	(112)
Perinatal mortality per 1 000	188	(123)	98	(129)
Infant mortality per 1 000	250	(263)	167	(252)
Developmental quotient	104 ± 24	(66)	115 ± 16	(72)

Modified from Thilly, 1981
Sample size in brackets

All differences were significant (P<0.05).

 

Figure 2. The results of a controlled trial of iodized oil injection in the Jimi River district of the highlands of Papua New Guinea. Alternate mothers were given an injection of iodized oil and saline in September 1966. All newborn children were followed up for the next five years. Each dot represents a cretin child. The figure shows the disappearance of cretin children among births to mothers given iodized oil injections in comparison with their persistence in the untreated group. (Reproduced from Pharoah et al., 1971 with permission)

 

2.3 IODINE DEFICIENCY IN CHILDREN AND ADOLESCENTS

Iodine deficiency in this period is characteristically associated with endemic goitre. Prevalence increases with age, reaching a maximum after the first decade of life. The condition can be effectively prevented by iodization using various methods following the original demonstration by Marine and Kimball in 1921.

Recent studies of children in China (Wang Dong et al., 1985) indicate a higher general prevalence of lowered intellectual performance (as measured by IQ and other tests modified for use in China) in iodine-deficient areas compared with areas without iodine deficiency.

There is increasing evidence of impaired mental function in apparently normal children living in iodine-deficient areas. Recent observations by Bleichrodt et al. (1987) indicate lower scores in measured mental and perceptual development in children in a severely iodine-deficient area in Spain, compared with a control group carefully matched by socioeconomic status and educational level. Similar data are available from Chile (Muzzo et al., 1986).

A recent study from a mountain village in Bolivia suggests that improved intelligence in school-age children followed the oral administration of iodized oil in a fully controlled study (Bautista et al., 1982). The improvement was related to reduction of goitre and was particularly evident in girls. iodization programmes have been shown to increase the level of circulating thyroid hormones in children in India (Sooch et al., 1973) and in China (Zhu, 1983). These changes occur whether or not the child is goitrous and indicate a mild degree of hypothyroidism without any obvious symptoms.

The major determinant of brain (and pituitary) triiodothyronine (T-3) is serum thyroxine (T-4) and not serum T-3 (Crantz and Larsen, 1980). Low levels of brain T-3 have been demonstrated in iodine-deficient rats in association with reduced levels of serum T-4 and the animals have been restored to normal with correction of the iodine deficiency (de Escobar et al., 1986).

These findings provide a rationale for suboptimal brain function in subjects with goitre and lowered serum T-4 levels and its improvement following correction of iodine deficiency (Bautista et al., 1982; Fierro-Benitez et al., 1974, 1986).

 

2.4 IODINE DEFICIENCY IN ADULTS

The common result of iodine deficiency in adults is endemic goitre. One of its accompanying effects is a high degree of apathy as noted in populations living in iodine-deficient areas in northern India. This may even affect domestic animals such as dogs. It is apparent that reduced mental function is widely prevalent in iodine-deficient communities with effects on their capacity for initiative and decision-making. Characteristically there is an absence of classical clinical hypothyroidism, but laboratory evidence of hypothyroidism with reduced T-4 levels is common (Fig. 3). This is often accompanied by normal T-3 and raised TSH levels (Maberly et al., 1978; Zhu, 1983; Patel et al., 1973; Goslings et al., 1977).

Iodine administration in the form of iodized salt (Zhu, 1983), iodized bread (Clements, 1960) or iodized oil (Buttfield and Hetzel, 1967) have all been demonstrated as effective in preventing goitre in adults. Iodine supplementation may also reduce existing goitre (Fig.4). This is particularly true of iodized oil injections. The obvious benefit leads to ready acceptance of the measure by people living in iodine-deficient communities.

A rise in circulating thyroxine can be easily demonstrated in adult subjects following iodization (Fig. 3). As already pointed out, this could mean a rise in brain T-3 levels with improvement in brain function.

Figure 3. Effect of a single injection of iodized oil on the level of thyroid hormone (serum protein-bound iodine PBI) in subjects in the Papua New Guinea highlands. Each dot represents an individual. The horizontal lines show the mean level for each group. The figure shows that a single injection of iodized oil causes a rise in the level of thyroid hormone for up to four and a half years. (Reproduced from Buttfield and Hetzel, 1967, with permission). WHO 70219

Figure 4. Disappearance of goitre from the neck of a middle-aged woman in Papua New Guinea three months after the injection of iodized oil. (Reproduced from Buttfield and Hetzel, 1967, with permission). - A

 

 

Figure 4. Disappearance of goitre from the neck of a middle-aged woman in Papua New Guinea three months after the injection of iodized oil. (Reproduced from Buttfield and Hetzel, 1967, with permission). - B

 

 

The general social effects of iodization are demonstrated by the case of the Chinese village of Jixian near Jamusi in Heilongyang Province, northeast China (Li et al., 1985). In 1978 there were 1,313 people in the village with a goitre rate of 65 percent, and 11.4 percent of cretins. The cretins included many severe cases which caused the village to be known locally as "the village of idiots". Its economic development was hindered - for example, no truck driver or teacher was available. Girls from other villages did not want to marry and live there. The intelligence of the student population was known to be low; children aged 10 had a mental development equivalent to others aged 7. Iodized salt was introduced in 1978. The goitre rate had dropped to 4 percent by 1982. No cretins were born after 1978. The attitude of the people changed greatly - they were much more positive in their approach to life, in contrast with their attitude before iodization. The average income had increased from 43 Yuan per head in 1981 to 223 Yuan in 1982 and 414 Yuan in 1984, higher than the average per-caput income in the district. In 1983 cereals were exported for the first time. Before iodization, no family had a radio, but now 55 families had a TV set. Forty-four girls came from other villages to marry boys in Jixian. Seven men joined the People's Liberation Army whereas before they had been rejected because of goitre. These effects were due mainly to the correction of hypo-thyroidism by iodized salt. The social impact of IDD control programmes needs to be investigated further.

 

2.5 ANIMAL MODELS

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2.5.1 IODINE DEFICIENCY IN SHEEP
2.5.2. IODINE DEFICIENCY IN MARMOSETS
2.5.3 IODINE DEFICIENCY IN RATS

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The significant role of iodine deficiency in the etiology of endemic goitre has been confirmed by extensive studies in animals. The major morphological and functional abnormalities can be readily reproduced as originally shown by Marine and co-workers (Marine and Williams, 1908; Marine and Lenhart, 1909).

Experimental iodine-deficient goitre is usually diffuse, but with long-standing deficiency, nodules appear in rats which show an increased number of cells and follicles. As Marine originally demonstrated, when the iodine deficiency subsides the goitre becomes of colloid type and does not return to normal.

In the last decade, systematic experimental studies of the effects of iodine deficiency on development, particularly foetal development, have been carried out. The most extensive studies have been done with sheep but more recently the effects on rats and on marmosets (Callithrix Jacchis Jacchis) have also been studied. These studies have been particularly concerned with foetal brain development because of its relevance to the human problem of endemic cretinism and other forms of brain damage due to foetal iodine deficiency (Hetzel and Hay, 1979) (see Section 2.1). More recently animal models using rats have been established in China with diets closely resembling those consumed in endemic areas.

 

2.5.1 IODINE DEFICIENCY IN SHEEP

Severe iodine deficiency has been produced in sheep with a low-iodine diet of crushed maize and pelleted pea pollard (8-15 mcg of iodine/kg of diet) which provided 5-8 mcg of iodine per day. After five months, although body weights were maintained, iodine deficiency was evident with the appearance of goitre, low plasma T-4 and T-3 values, elevated TSH levels and low daily urinary excretion of iodine. Control animals received the same diet but were given an injection of iodized oil before pregnancy. The ewes were mated with normal fertile rams, dates of conception established, and foetuses delivered at 56, 70, 98 and 140 days' gestation by hysterotomy (Potter et al., 1982).

Goitre was evident from 70 days in the iodine-deficient foetuses, and thyroid histology revealed evidence of hyperplasia from 56 days' gestation. The increase in thyroid weight was associated with a reduction in foetal thyroid iodine content, reduced plasma T-4 values and increased plasma TSH.

At 140 days the iodine-deficient foetuses were grossly different in physical appearance from the control foetuses. There was reduced weight, absence of wool growth, goitre, varying degrees of subluxation of the foot joints, and deformation of the skull. Delayed bone maturation as indicated by delayed appearance of epiphyses in the limbs was also present (Fig. 5).

There was a lowered brain weight and brain DNA as early as 70 days, indicating a reduction in cell number probably due to slowed neuroblast multiplication which normally occurs from 40-80 days in sheep (Hetzel and Potter, 1983).

Retardation of foetal brain development in severe dietary iodine deficiency was revealed also by histological studies at 140 days gestation (Potter et al., 1982). Delayed maturation of the cerebellum was shown by reduced migration of cells from the external granular layer to the internal granular layer and increased density of Purkinje cells. The greater density of Purkinje cells indicated a reduction in Purkinje cell arborization. In the cerebral hemispheres the cells were more densely packed in the motor and visual areas while the pyramidal neurons in the hippocampus were denser, indicating severe retardation in neuropil growth.

The effect of iodine administration on this retarded foetal brain development caused by iodine deficiency was investigated with a single intramuscular injection of oil containing 500 mg of iodine given at 100 days' gestation. The difference between foetal brain weights in iodine-deficient and control sheep was reduced from 10.8 percent to 6 percent by the iodized oil injection. The difference in body weight was also reduced and maternal and foetal plasma T-4 values were restored to normal (Hetzel et al., 1984).

The effects of severe iodine deficiency on the sheep's foetal brain development were more extensive but similar to those of foetal thyroidectomy carried out at 50-60 days or at 98 days. Maternal thyroidectomy carried out some six weeks before pregnancy had a significant effect on foetal brain development in mid-gestation. The combination of maternal thyroidectomy and foetal thyroidectomy at 98 days produced more severe effects than those of iodine deficiency alone.

The findings following maternal, foetal and combined thyroidectomy suggest that the effect of iodine deficiency on foetal brain development is mediated by the combination of reduced maternal and foetal thyroid secretion and not by a direct effect of iodine. The effect of reduced maternal secretion occurs in the first half of pregnancy and the effect of reduced foetal secretion in the latter half (Hetzel et al., 1984). This conclusion is consistent with recent evidence of the passage of maternal thyroxine in rats across the placental barrier early in pregnancy (Obregon et al., 1984; Woods et al., 1984).

Figure 5. Effects of a severe iodine deficiency on lamb development during pregnancy. (A) A 140-day-old lamb foetus subjected to severe iodine deficiency through feeding the mother an iodine-deficient diet (5-8 mcg per day) for 6 months prior to and during pregnancy (full term: 150 days), compared with (B) a control lamb of the same age fed the same diet with the addition of an iodine-supplement. The iodine-deficient lamb shoved absence of wool coat, subluxation of the leg joints and a dome-like appearance of the head due to delayed skeletal retardation. The brain was smaller and contained a lower number of cells, compared with the control. - A

 

 

Figure 5. Effects of a severe iodine deficiency on lamb development during pregnancy. (A) A 140-day-old lamb foetus subjected to severe iodine deficiency through feeding the mother an iodine-deficient diet (5-8 mcg per day) for 6 months prior to and during pregnancy (full term: 150 days), compared with (B) a control lamb of the same age fed the same diet with the addition of an iodine-supplement. The iodine-deficient lamb shoved absence of wool coat, subluxation of the leg joints and a dome-like appearance of the head due to delayed skeletal retardation. The brain was smaller and contained a lower number of cells, compared with the control. - B

 

 

 

2.5.2. IODINE DEFICIENCY IN MARMOSETS

Severe iodine deficiency has been produced in marmosets with a mixed diet of maize (60 percent), peas (15 percent), torula yeast (10 percent) and dried iodine-deficient mutton (10 percent) derived from the iodine-deficient sheep produced in the study described in the section above on sheep. There was a gross reduction in maternal T-4 levels with greatly reduced thyroid iodine. After a year on the diet, the animals were allowed to become pregnant and the newborn animals were studied following the first pregnancy and again following the second pregnancy. Significant effects on brain development were apparent in the first pregnancy and more striking ones in the second. There was other evidence of hypothyroidism in the form of impaired hair growth and some skull deformity but there were no striking effects on epiphyseal development. In general the findings in this primate resembled those in sheep (Potter et al., 1984).

 

2.5.3 IODINE DEFICIENCY IN RATS

Studies on rats using diets consumed in two endemic areas in China were carried out. In both instances foetal hypothyroidism was produced.

The most extensive studies were carried out by Li et al. (1985) using the diet consumed by the people of Jixian village in northern Heilongyang province. This village, as already noted (Section 2.4), was severely iodine-deficient with an endemic cretin rate of 11.4 percent. The diet included available main crops (maize, wheat), vegetables from the area with an iodine content of 4.5 mcg/kg (Li et al., 1985) and water (1.0 mcg of iodine per litre). The rats were housed and fed in a specially constructed animal laboratory in the village. Control animals received the same diet with the addition of iodine providing 54.7 mcg iodine/kg. Special attention was paid to the foetal thyroid and brain during gestation (16-20 days) and birth (1-60 days). After the mother had received the diet for four months, there was obvious neonatal goitre (T-4 3.6 mcg percent compared with controls 10.4 mcg percent), and higher 1(125) uptake, with 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 tritium labelled leucine in comparison with the control group.

Similar effects have been reported with the iodine-deficient diet (mainly rice) being consumed in south China in Guijou province (Zhong et al., 1983).

Extensive studies have also been carried out with mice, using the iodine-deficient diet consumed in Chemeng, Inner Mongolia. There were definite effects on learning capacity observable in over 10 generations (Ma et al., 1983).

So far, in these Chinese models the effects observed are those of foetal hypothyroidism as in sheep and marmosets. In spite of the predominant occurrence of neurological cretinism in the two endemic areas studied in north-east and south China, this condition has not yet been reproduced in rats. This may yet occur in succeeding generations and with more extended observations into the post-natal period. There may, however, be other environmental factors which together with iodine deficiency produce the condition.

Other studies of iodine-deficient rats by Escobar et al. (1986) have demonstrated a decreased reproductive competence in The adult rats, with a reduced number of viable embryos. These findings are consistent with human data indicating reproductive failure (stillbirths) which can be prevented by correction of iodine deficiency (McMichael et al., 1980). The demonstration of cerebral hypothyroidism in iodine-deficient rats has already been cited.

Implications of Results from Animal Models

These results from animal models provide strong support for the human observations of the major effects of iodine deficiency on growth and development. When taken together they have major policy implications.

The implications of these human and animal observations are that iodine deficiency is responsible for a massive problem of reduced mental function due to the lowered level of thyroid resources in the blood affecting the brain. This condition can be reversed by increasing iodine intake, which means that millions of people living in iodine-deficient regions can benefit from removal of this impediment to the achievement of their genetic potential.

 

 

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