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Nutritional deficiency disorders
Iodine deficiency disorders: Clinical presentations and continuing problems
Iodine deficiency disorders: Clinical presentations and continuing problems
John B. Stanbury
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
The term "iodine deficiency disorders" (IDD) has recently gained some currency as a designation for those disorders which arise in man because of a deficiency of iodine in the diet (1). The term has value because it encourages speculation and experiment. For example, does a uniquely definable syndrome of endemic proportions, such as deafmutism, in a community where goitre, the established result of chronic iodine deficiency, is endemic, have a causal relationship to iodine deficiency?
When the mean daily intake of iodine in a community is less than about 25 mg per day, many adults have sizeable goitres and substantial numbers of people have physical characteristics, including profound mental retardation, that have been recognized as being associated with a high prevalence of goitre. Individuals affected thus are called endemic cretins. When the mean daily intake of iodine is above 25 but less than 60 mg per day, goitre may also be found in some adults and in many children, but those conforming to the clinical patterns of classic cretinism will not be found, excepting occasionally older ones from an earlier time when conditions were different. Other disorders may be associated with endemic goitre but are less clearly the result of iodine deficiency. Among these are endemic mental and statural retardation, endemic neuro-motor deficiency, and endemic deaf-mutism. The origins of these disorders are difficult to identify with certainty because of complicating poverty, poor nutrition, regional genetic differences, social and educational deprivation, climate, and so on.
IDD is not a trivial problem. A quarter of the world's population subsists on a diet that is deficient in iodine, i.e. Iess than 60 g per day (2), and are at risk for I DD. Vast regions of the less well developed countries harbour large numbers of people with obvious goitre and many who show the stigmata of cretinism. IDD continues to be a major public health problem in spite of the availability of simple means of prevention, but its impact on social development remains to be fully assessed.
Endemic goitre is found almost wherever it is looked for in the developing countries, and it exists in localized regions in some of the economically advanced countries of the West (3, 4). The entire Andean chain is a major endemic region. Where iodide prophylaxis has not been introduced, large nodular glands may be seen in many adults (fig. 1), and among school children distinct enlargements of the thyroids conforming to WHO grade-1 goitre may appear in 30 or more per cent.
Cretinism must be searched out. In a monogrph published 25 years ago by the World Health Organization, Clements wrote that cretinism does not occur in the Andes (5). This error is important, because it illustrates the unreliability of hearsay evidence, and also because cretins are often sequestered from view and may not be encountered in hasty surveys. Endemic cretins are in fact quite frequently encountered in the Andes, as well as to the east of the Andes in Peru, Ecuador, Colombia, Venezuela, and Brazil (fig. 2).
A severe endemia stretches across equatorial Africa. IDD is found all the way from central Nigeria, across the Cameroon, through the Central African Republic and northern Zaire, over to the border of Uganda and Rwanda. It is also found in the Sudan and is reported farther south in Tanzania and Zimbabwe (6). There is an endemic area in Algeria, especially to the east in the Kabile region. In northern Zaire there are communities where most of the women are goitrous, and the prevalence of cretinism may reach 10 per cent of the population.
Goitre is still found in southern Germany, Austria, and Portugal (fig. 3). It is also well reported from Greece (7, 8) and is found in the Middle East. A huge belt of severe IDD stretches along the entire length of the Himalayan chain. One of the most severe areas is the Terai of north India, where 140,000 persons are at risk (9, 10). The disease is also found reaching eastward into Burma, Vietnam, Thailand, and New Guinea. The People's Republic of China has been surveyed and large pockets of severe disease have been mapped (11, 12). The disease is doubtless present in parts of the Soviet Union, but little epidemiological information is available.
SIGNIFICANCE OF ENDEMIC GOITRE
Endemic goitre in and of itself is probably not a particularly significant disorder. If the gland becomes enlarged to the point that it interferes with normal physical activity, or is cosmetically unacceptable, or if it causes undue pressure on the trachea or interferes with swallowing, then treatment is needed, and prevention would have been desirable. Usually the enlarged gland is functionally competent for the physiological needs of the subject. When the endemia is severe, hormone production may be com- promised. Evidence for an increased risk for neoplastic degeneration in these glands is scanty (13).
The significance of IDD lies primarily in its impact on growth and intellectual development. When iodine deficiency is most severe, neonatal hypothyroidism occurs (14), and cretins are found in the community. These individuals impose a burden on community resources and on family life. What may be much more important is the possibility that there are a large number of people who do not have any of the classic features of cretinism but whose linear growth, intellectual attainments, and neurological functions are compromised by iodine deficiency. If, as postulated, these people in fact exist - and there is accumulating evidence that they do - then the central significance of endemic goitre lies with them. The evidence for their existence will be examined below.
PATTERNS OF CRETINISM
Sir Robert McCarrison, working in northern India in the first decade of this century, first differentiated cretinism into two types, a myxoedematous form and a neurological form (15). Subsequent study has blurred but not eliminated the distinction, and McCarrison noted that between the two there were overlapping signs and that subjects with mixed forms were often found. The typical neurological cretin has profound mental deficiency, a characteristic facies, a shuffling gait or inability to walk at all, a spastic diplegia which tends to affect the proximal more than the distal extremities, other spastic signs, sometimes squint, shortened stature, and usually, but not always, a nodular goitre (16). In some the thyroid may be replaced by a fibrous remnant. The subject is usually, but not always, deaf and mute, or if not, usually has diminished auditory acuity in the higher frequencies and also some degree of dysarthria. Hypothyroidism may or may not be present.
The typical myxoedematous cretin, as described most vividly by the group of investigators from Brussels working in Zaire (17-19), is different. Mental deficiency is severe, and linear growth is much more attenuated than in the typical neurological cretin. Bone age may be astonishingly delayed. Hearing is usually present. Such an individual is myxoedematous, both clinically and by rigorous laboratory testing. The thyroid gland is typically not prominent, and radioactive iodine uptake values are somewhat less than those of their peers, but turnover is accelerated. Neurological signs are much less prominent. Cretins with these physical findings comprise about 90 per cent of those seen in Zaire but a much smaller percentage elsewhere (fig. 4). In all endemias subjects showing features of both types are found, although the proportions vary widely from one endemia to the next.
Recently, the neurologist DeLong has had an opportunity to examine nearly a hundred cretins from the endemias of Ecuador and Zaire (20 and personal communication). He points out that the neurological findings are, indeed, much more common among the Andean group and that signs of hypothyroidism are much more common among those from Zaire. He noted that the spasticity tends to be proximal, with relatively good preservation of distal motor function and attributes this to damage to the rubrospinal tract. He noted the preservation of many important functions, such as vision, taste, sleep patterns, thirst and hunger, body temperature control, and in most, conjugate movements of the eyes. DeLong makes the point that the myxoedematous cretins of Zaire conform much more to the clinical appearance of congenitally hypothyroid children from non-endemic regions that are untreated than do the neurological cretins.
What might be the reasons for the striking differences in the clinical manifestations of endemic cretinism in different endemias and among different subjects in the same endemia? It is possible that toxic substances in the diet may play a role The thyroid of the Zaire cretin is clearly damaged because it fails to grow in spite of astronomically high plasma levels of thyrotropic hormone (21). No specimen of such a thyroid has become available for examination. In this regard it is interesting that the Indians of southern Venezuela are deficient in iodine but do not have goitre (22). Other factors may contribute to the differences.
Differential death rates could play a role (23). Thus, possibly the African cretins born with neurological damage may fail to survive because of the rigours of the environment or the level of maternal care. Those less affected may survive, and, if iodine deficiency continues, they fail to develop; or if the supply of iodine improves, they may grow and appear in the community only as retarded persons.
One can only be astonished at the care given to the severely damaged cretins of the Andean region, as evidenced by the survival of the most extraordinarily retarded and deformed individuals, who require the total care of their parents. Without such care surivival would be impossible, and perhaps this kind of parenting is not provided in central Africa. Now that screening programmes for neonatal hypothyroidism are in progress in both regions, it will be possible to know whether there are indeed differential survival rates between the two regions. The mortality rate is high among neonatally hypothyroid infants in the central African setting (24).
Much study has been directed to a possible role of cassava in endemic goitre and cretinism (25, 26). Poorly prepared cassava yields an abundance of cyanide, which is converted to thiocyanate after ingestion, and thiocyanate competes with iodide for entry into the thyroid. A reciprocal relationship has been found in Zaire between thiocyanate in the urine and iodine in the urine, with respect to goitre (27), but no such correlation was found in a recent study in Thailand (28). At present there appears to be no convincing evidence that cassava is the determinant of the clinical differences between the two types of cretinism, but only that it may accentuate an existing iodine deficiency.
A number of observers have been struck by the frequency with which people in moderately severe to severe endemias have minor neurological deficits, but seem otherwise normal and function at a useful level in their relatively undemanding communities (fig. 5). This has led to the speculation that overt cretinism is but the tip of an iceberg of damage from iodine deficiency. Attempts to test this hypothesis have been numerous and almost invariably flawed. It is exceedingly difficult to test intellectual capacity and performance across language and cultural barriers and to extricate the role of iodine deficiency from the many other factors - dietary, social, educational, environmental, and cultural - that may contribute to such differences as may be observed.
Fierro-Benitez et al. and Dodge et al. found evidence that administration of iodized oil prior to the first trimester of pregnancy improved test performance in the progeny at a later date (29-31). Similar results have been obtained in Bolivia (32) and in Papua New Guinea (33). Bleichrodt et al. carried out intensive studies in central Java and found that administration of iodine improved the results of tests of fine motor control, but changes in intellectual function were not convincing (34, 35). Their study was marred by differences in educational attainments between the villages that were tested. Thilly et al. have concordant data from Zaire (36).
Recently Fierro-Benitez in Ecuador has examined the performance of children born of mothers who were given iodized oil prophylactically before or soon after conception. He found that the children who finished at least one year of school and were born of mothers who were injected before the second trimester of pregnancy performed better in terms of scholastic achievement and school drop-out rates and in tests of performance that measured neuromotor function but not intellectual performance (37).
None of these studies is entirely convincing by itself, but the accumulated information points in the direction of an effect of iodine administration in improving performance when given before conception, and perhaps even when given during the early post-natal years. Indeed, it is my firm opinion and that of others that the data are sufficiently convincing to strongly support major efforts at iodine prophylaxis wherever endemic goitre of more than minimal prevalence is found. Further, the finding of endemic cretinism, if more than a historic relic of a time before adequate prophylaxis was introduced, constitutes the strongest demand for a crash programme of prophylaxis.
A shocking example of failure to implement a prophylactic programme is the Indian Terai, where the Gangetic plain is populated by a huge number of people at risk for iodine deficiency disease, and by untold thousands who have already suffered irreversible damage (38, 39). Thousands of infants in this region are born every day with a risk of damage that can only promote the continuation of the social and economic backwardness of this region. Another example is Bhutan, where a recent survey has revealed a high prevalence of iodine deficiency disease (40).
There can be no question that iodine deficiency is the central cause of endemic goitre in most, if not all, endemias. Goitre does not entirely disappear from a community when iodine prophylaxis is applied because there are other recognized categories of thyroid enlargement that are not related to iodine deficiency, but these will give only a 5 per cent or less incidence of goitre in any region where the intake exceeds 100 mg of iodine daily. Among these are chronic thyroiditis, Graves' disease, familial metabolic goitre, and simple and adolescent goitre of unknown cause.
Do factors other than iodine deficiency play a contributing, accentuating, or even primary role? Gaitan has noted that iodine prophylaxis has not eliminated goitre from the endemic regions of Colombia, but the programme trivialized the endemia (41). He has identified certain sulphides that are antithyroid in action in waters from certain wells (42). Water from certain rock formations and not from others corresponds to goitre downstream (43). He also has found evidence for goitrogens in contaminated water from West Virginia where goitre occurs (as did McCarrison in northern India many years ago, ref. 3), and has found goitrogens in the effluent from certain chemical plants in the south-central United States (44).
Virtually no evidence has been found for a genetic factor. Goitrogenic activity has been detected in milk in Finland (45). Bacterial and viral aetiologies have been suggested. Does the newly described thyroid-growth-promoting immunoglobulin contribute to endemic goitre (46)? An increased plasma titre has been found in some patients with endemic goitre but not in others (47). An increase has been found in the plasma of other patients with thyroid growth from other causes, such as Graves' disease, so that its presence may be non-specific, but the possibility deserves thorough exploration because of certain anomalies that have been described, such as the lack of goitre in iodine-deficient Indians in southern Venezuela, and the lack of goitre in the myxoedematous cretins of Zaire. The pathogenesis and evolution of endemic goitre has been thoroughly investigated by Studor and is reasonably well understood (48).
As with endemic goitre, so with endemic cretinism, iodine deficiency appears to be the central, necessary, and sufficient condition. Hetzel and his colleagues in Australia have developed a sheep model for iodine deficiency (49, 50). Their ewes are fed on a fodder collected from areas known to be depleted of iodine. The progeny of these ewes are severely malformed, have underdeveloped central nervous systems, large hyperplastic goitres, and delayed intrauterine osseous development and do not survive birth by more than a few hours. The newborn iambs appear to be nearly normal if iodine is administered to the ewe at the beginning of the third trimester of pregnancy, but neuromotor performance of the matured animals has not yet been reported.
The argument is sometimes made that cretins are often euthyroid (51). This might be expected if iodine becomes available after the critical period when the damage is done. Many of these cretins have functioning thyroids, and if given a supply of iodine there is no reason why production of thyroid hormone should not begin and permit a euthyroid state. There is nothing anomalous about a euthyroid cretin, nor does the finding of such a cretin constitute an argument against iodine deficiency as the cause of the initial damage.
The vexing problem remains: why is there such breadth to the clinical spectrum of endemic cretinism? Some possible answers are suggested earlier and can be tested. While the question is interesting and in need of pursuit, the fact is that cretinism does not appear in newborns after iodine has been supplied to the population at risk.
Addition of iodide or iodate to table salt is the standard method of preventing iodine deficiency disease. Cretinism vanishes, and the prevalence of goitre almost invariably drops to 5 per cent or less if the iodine actually reaches the consumer. The programmes in North America and most of the countries of Europe have been highly successful. A programme with iodated salt was most successful in the highly endemic region of Guatemala until recently, when it has been permitted to lapse, and goitre appears to be returning to that country.
Programmes of iodized salt have failed where the iodization was not properly done or where hot and humid conditions caused the disappearance of the iodide into the containers or the atmosphere or most commonly where manufacture was sloppy or neglected. Recently three containers of iodized salt were purchased from a local merchant in the United States and sent to Dr. H. Burgi in Switzerland for analysis. The labelled content of iodine corresponded closely to the results of analyses. Thus, it is possible to iodize salt and have it retain its concentration for a long period of time under varying conditions. But the iodine must be added in the correct amount, and the salt stored and transported under proper conditions. Quite recently some analyses of commercial iodized salt in a Latin American country showed that the content was far below that specified on the label.
It would seem that such an important disease which has such a simple method of prevention would no longer exist. A number of conditions account for failure. Thyroid disease to the casual observer does not have the drama or startling impact of a disease like smallpox or diphtheria. It fails to catch the eye of the politician in the seat of government. It tends to be a rural disease, and politicians often do not appear in the rural areas where the disease exists. Goitre is found among people who often have little if any voice in their governments. It may be taken for granted and seen as a part of life or the normal state. Its impact at the subtle level of a decline in intellectual performance may not be recognized. The very existence of goitre and cretinism may escape the interest of local health personnel.
One colleague visiting in the sub-Himalayan region was told by the local physician that cretinism did not exist in his district, but many cretins were found in the houses and back yards of the poor living in shacks on the hills above the village. The medical officer had never visited beyond the village. I recently spent a day visiting villages and finding cretins with a journalist from the capital city of a Latin American country He had never been in a village in his own country and was astounded by what he saw.
Indifference or ignorance at the level of either responsible governmental health personnel or ministries or governmental inflexibility are probably the most important factors contributing to the continuing existence of iodine deficiency disease. India, with one of the largest populations at risk in the world, has talked about iodization of salt for at least 25 years, and the proposed programmes are still entrapped in the Laocoonian coils of the federal bureacracy. To a large degree iodine deficiency disease is a social-political problem, rather than a medical-biological one.
There are, of course, regions in the developing countries where iodization of salt is not at present a solution because there are no widely used commercial channels for the merchandising of salt, or because the salt enters the country through multiple ports so that iodization is not practical, or because the salt comes from cottage industries or other local sources and the scale is too small to make iodization practicable. For such places iodized oil is an alternative. iodized poppy-seed oil (or certain other vegetable oils which have unsaturated double bonds) can be injected intramuscularly or taken orally. The iodine is released very slowly. A single dose of 2 ml may supply the iodine needs for the individual for two years or more if given intramuscularly. Highly successful programmes are in progress in several countries, including Zaire, Ecuador, Peru, Papua New Guinea, and Indonesia. All evidence points to the safety and effectiveness of these programmes. Iodized oil is particularly useful when the lag time of a salt iodization programme and the urgency of the situation are such that an immediate interruption of the iodine deficiency state is imperative. This is the nature of affairs in the Indian Terai at the present moment iodized oil prophylactic programmes have certain drawbacks. They require substantial logistical support. Administration must be by sterile needle. Personnel must be appropriately trained. Records must be kept. The rare occurrence of post-injection thyrotoxicosis implies the need for occasional medical monitoring (but not different from after iodized salt administration). For a given time span of protection, iodized oil is more expensive than iodized salt. In spite of these drawbacks. iodized oil offers great hope to millions who otherwise may wait for months or years before the risk of iodine deficiency disease is no longer a threat to their children. The feasibility of iodized oil by mouth is currently being explored.
Other forms of prophylaxis have been used. Bread has been iodinated, and in Tasmania (52) this resulted in a small epidemic of thyrotoxicosis. Recently a system has been devised for introducing a casette containing iodine crystals into a bypass of a city water supply in a town in Sicily where endemic goitre was found (53). The cost on a per-capita-per-year basis was acceptably low, and the technique was effective in reducing the prevalence of childhood goitre. While this method may be effective, in most parts of the world where endemic goitre is found there are no public water systems that would lend themselves to this form of supplementation.
SOME QUESTIONS IN NEED OF ANSWERS
1. What are the determinants of the differences between myxoedematous and neurological cretinism? Are there dietary components that damage the foetal thyroid in the myxoedematous type, or does a differential death rate account for the epidemiological differences? What is the outcome of neonatally identified hypothyroid subjects in endemic areas with thyroid hormone replacement therapy? Would iodized oil be adequate treatment for such infants?
2. What are the audiometric findings in cretins of both types who appear to be able to hear? What can be learned from evoked auditory and ocular potentials in these patients?
3. How much catch-up growth can be gained in the young myxoedematous cretin by hormonal or iodine treatment ?
4. What has been the death rate among neonatally identified hypothyroid subjects in endemic regions?
5. What is the true rate of hyperthyroidism after administration of iodized oil? Reports vary quite widely, but there is no careful study with frequent follow-up. Is the hyperthyroid state really transient, as has been claimed?
6. What is the incidence of hyperthyroidism after oral vs. intramuscular administration? What are the relative retention rates over several months following the two routes of administration? What is the mode of transport of the iodine after the two paths of administration? It is possible that the iodine is transported by different mechanisms if it reaches the liver first or is mobilized from a muscle depot.
7. Are there less expensive ways of dispensing iodized oil than by commercial purchase and distribution by highly trained personnel?
8. What if any is the role of thyroid-growth-stimulating immunoglobulin in endemic goitre? Is this factor absent in the myxoedematous cretins of Zaire and the goitre-free iodine-deficient Indians of the Alto Orinoco? Does this substance rise with production of goitre experimentally, as with a goitrogen? Does it disappear with thyroidectomy; i.e., is its source the thyroid itself?
9. Can a more convincing study be devised that will unequivocally demonstrate whether prophylaxis with iodized salt or oil improves neuromotor function, intellectual development, or skeletal growth?
10. Do the goitrogens that have been identified in effluent water from sedimentary rocks in Colombia, well water from Colombia, and stream water from goitrous regions of Kentucky have a real role in causing goitre? What is the chemical identity of these substances? Can their blocking effect be overcome by administration of iodine?
11. Does iodine have any role in foetal development before the foetal thyroid begins to function? Is the placenta normal in iodine deficiency? Do maternal thyroid hormones cross the placenta and affect the foetus before the foetal thyroid starts functioning? Will a metabolically active iodine-free thyroxine analogue support normal foetal growth in the mother on a very low iodine diet?
12. What is the real role of iodine and of the thyroid hormones in the development of the ear? Is the structure of the middle and inner ears of the cretin sheep model of Hetzel et al. normal? Why do these animals not survive? Is it due to failure of some key enzyme to mature, or is it because of pulmonary failure, or does the circulatory shift that normally occurs at birth fail to happen?
Endemic goitre continues to be a major public health problem in many of the developing countries. Probably a quarter of the world's population is at risk. In many endemias, especially those of India and central Africa, the disease and its accompanying disorders are responsible for serious disability and contribute to economic and social backwardness. While mild endemic goitre constitutes no particular disadvantage, when moderately severe or severe, the larger goitres may be a serious burden to the medical care system, and the attendant cretinism and lesser degrees of neuromuscular and intellectual impairment are surely important iodine deficiency disease is readily preventable by measures that are cost effective. Low viability of the disorder on the one hand and governmental inattention on the other are responsible for continued high prevalence rates. While there is ample information to support immediate implementation of prophylactic programmes in regions of endemic iodine deficiency disease, there remain interesting questions for research, the answers to some of which at least might affect the design and execution of prophylactic programmes and would certainly advance our understanding of iodine deficiency disease.
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