Iodine and Iodine-Deficiency Disorders

Basil S Hetzel. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1. Cambridge, UK: Cambridge University Press, 2000.

The term “iodine-deficiency disorders” (IDD) is now used to denote all the effects of iodine deficiency on growth and development (Hetzel 1983). In the past, the term “goiter” was used to describe such effects, but IDD has now been generally adopted in the field of international nutrition and health. In the last 10 years, this reconceptualization has helped to focus more attention on the problem of iodine deficiency. For much of our historical treatment, however, we use the terms “goiter” and “IDD” interchangeably.

Extensive reviews of the global geographic prevalence of goiter have been published. One of these, by F. C. Kelly and W. W. Snedden, appeared as a World Health Organization (WHO) monograph in 1960. A second survey was done more recently by J. Stanbury and B. Hetzel (1980), and the reader is referred to these sources for a closer look at the many countries that still have a significant goiter problem. In general, goiter is associated with elevated areas and regions where there has been leaching of iodine from the soil due to glaciation, snow water, high rainfall, or floods. Thus the great mountain chains of the world, the European Alps, the Himalayas, and the Andes, have become well known as goiter areas, and in fact most mountainous regions throughout the world have iodine-deficient areas.

We now know that in addition to mountainous areas, flooded river valleys, such as those of the Ganges, Brahmaputra, and Irawaddy Rivers in Southeast Asia, have their soils leached of iodine and thus are also severely deficient in the mineral. These inescapable geographical facts mean that vast populations are at risk of iodine-deficiency disorders, and unfortunately it is likely that soil erosion in modern times is acting to increase the iodine-deficient areas of the world. It is, of course, axiomatic that populations totally dependent on food grown in such soil, as in systems of subsistence agriculture, will become iodine deficient.

History of Goiter and Cretinism

Descriptions and speculations about goiter and cretinism (the best-known iodine-deficiency disorders) go back to the ancient world. A historical review provides a fascinating succession of cultural concepts culminating in the twentieth century, when the causative role of iodine deficiency was established and the control of the disorders demonstrated. In the waning years of the twentieth century a global action program was organized in order to eliminate this ancient scourge of humankind by the beginning of the new millennium.

The Ancient Civilizations

An old reference to goiter is attributed to a mythical Chinese cultural hero, Shen-Nung. In his book Shennung pen-ts’ao ching (the divine husbandman’s classic on materia medica), he is said to mention the seaweed sargassa as an effective remedy for goiter. Goiter is also mentioned in the Shan Hai Ching (which probably reached its present form about the second century B.C.), which attributes the disease to the poor quality of water. Other references during the Han dynasty (206 B.C. to A.D. 220) and the Wei dynasty (A.D. 200-264) mention deep mental emotions and “certain conditions of life in the mountain regions” as causes of goiter. The treatment of goiter with sargassa weeds is mentioned by the famous early-fourth-century Chinese medical writer Ge Hong. The Chinese also employed animal thyroid in the treatment of goiter—the use of deer thyroid is mentioned in a sixth-century text. Animal thyroid continued to be used in China and is discussed again by an eminent Chinese physician, Li Shih-chen, in his well-known 1596 herbal Pen-ts’ao kang-mu (materia medica arranged according to drug descriptions and technical aspects), in which preparations of pig and deer thyroid are mentioned. The continued use of seaweed and animal thyroid over so many hundreds of years in China suggests that there was certainly some benefit derived from these measures in the treatment of goiter.

Elsewhere in the ancient world there is less mention of the disease. In ancient Hindu literature incantations against goiter may be found in the Veda Atharva dating from around 2000 B.C. According to the Ebers papyrus, tumors of the neck were also known in ancient Egypt, where they were treated surgically.

In the famous fourth-century B.C. volume Airs, Waters, and Places, attributed to Hippocrates, drinking water was regarded as a cause of goiter. At about the beginning of the Christian era, Aulus Celsus described a fleshy tumor of the neck, which he incised to find that it contained honey-like substances and even small bones and hairs (probably a longstanding goiter). It was subsequently deduced by the Roman physician Galen in the second century A.D. that the glands of the neck, including the thyroid, had the function of secreting a fluid into the larynx and the pharynx. Such views continued to be accepted for many centuries and were held by such famous seventeenth- and eighteenth-century physicians as Marcello Malpighi and Herman Boerhaave.

Medieval Europe

It is of interest to note the attention given to goiter in paintings and sculptures of the Middle Ages. The late Professor F. Merke of Berne unearthed a number of fascinating examples from manuscripts and churches. The earliest depiction of goiter and cretinism is in a book in the Austrian National Library in Vienna—the Reuner Musterbuch—dating from 1215. The book was originally from the Cistercian Abbey in Reun near the city of Graz in Styria (Austria), where goiter was highly endemic until recent times. The picture (Figure IV.B.2.1) shows a figure with three large goiters and a stupid facial expression, brandishing a fool’s staff in one hand while reaching up with the other toward a toad. This was doubtless a goitrous cretin. It was common to depict a fool grasping a cudgel as shown in this figure. The significance of the toad may be related to the popular use of live or dismembered frogs for the treatment of goiter. As Merke points out, this picture of the Reun cretin predates by some 300 years the recognition of the relationship between goiter and cretinism by Paracelsus (Philippus Aureolus Theophrastus Bombastus von Hohenheim).

According to F. de Quervain and C. Wegelin (1936), the term “cretin” most likely comes from the words “Christianus” or “Crestin” in the southeastern French dialect—referring to a bon chrétien because of the innocence of these subjects. These sufferers were in fact given special recognition in the medieval world and often regarded as angels or innocents with magical powers (Merke 1984). Clearly the Church did its best to fit them into the prevailing religious culture.

The Renaissance

Felix Plattner of Basel wrote a classic description of goiter and cretinism following a 1562 visit to the Valais:

In Bremis, a village of the Valais, as I have seen myself, and in the Valley of Carinthia called Binthzgerthal [today the Pinzgau], it is usual that many infants suffer from innate folly [simplemindedness]. Besides, the head is sometimes misshapen: the tongue is huge and swollen; they are dumb; the throat is often goiterous. Thus, they present an ugly sight; and sitting in the streets and looking into the sun, and putting little sticks in between their fingers [a stick resting between their hands], twisting their bodies in various ways, with their mouths agape they provoke passersby to laughter and astonishment. (Langer 1960: 13-14)

A study of goiter in sixteenth-century art was made by H. Hunziger (1915); the disease can be readily observed in the Madonnas of the Renaissance. Works by masters such as Jan van Eyck and Lucas Van der Leyden portray it, as do other paintings in the Sienese and Vatican galleries. All this may indicate that the condition was virtually accepted as normal because it was so common. In a later period goiter is also to be seen in the paintings of Peter Paul Rubens, Rogier van der Weyden, and Albrecht Dürer.

During the Renaissance, goiter was believed to be curable by the touch of a king. According to the king’s personal physician, Henry IV of France caused 1,500 goiters to regress by touching the patient and using the formula “Le Roi te touche et Dieu te guerit.” The “touch” was also practiced by many English kings; Charles II is alleged to have touched 9,200 persons suffering from the “King’s Evil” or scrofula (with which goiter was often confused). According to newspaper reports, on March 20, 1710, Queen Anne revived the ancient custom of curing goiter and scrofula by the laying on of hands. As we pointed out, however, in the sixteenth century Paracelsus had recognized the association of goiter and cretinism and attributed the disease to a deficiency of minerals in drinking water. This reasoning rather neatly contrasts the scientific approach with the magic of the King’s Touch!

The Seventeenth Century

The study of human anatomy prospered following the sixteenth-century pioneering work of Andreas Vesalius, Matteo Realdo Colombo, Hieronymus Fabricius ab Aquapendente, and Bartolomeo Eustachi. All of these anatomists noted the thyroid gland, which was called the “glandulus laryngis” by Vesalius. Fabricius recognized the connection between the glandulus laryngis and goiter. But the first clear description of the gland was penned in Latin in 1656 by an Englishman, Thomas Wharton (the translated title is Adenography, or a Description of the Glands of the Entire Body). Nonetheless, in the seventeenth century the function of the thyroid was not understood. It was usually regarded as secreting a fluid to “humidify” the walls of the larynx, the pharynx, and the trachea. In fact, the function of the thyroid was not understood until the latter part of the nineteenth century, when it was recognized to have an “internal” secretion in the form of the thyroid hormone, and not an external one.

The Eighteenth Century

In the eighteenth century there was a great escalation in scientific observations and the reporting of such observations. Many of these were collected in Denis Diderot’s Encylopédie (1751-72), in which the term “cretin” appeared in print for the first time in an article by Diderot’s co-editor Jean Le Rond d’Alembert. His definition of a cretin was that of “an imbecile who is deaf, dumb with a goiter hanging down to the waist.”

The Nineteenth Century

Interest in and concern about the possibility of the control of goiter accelerated in the early nineteenth century when Napoleon Bonaparte ordered a systematic investigation of the disease. He did so because large numbers of young men from certain regions were being rejected as unfit for military duties. Moreover, Napoleon himself had probably seen something of the problem during his march into Italy through the goiter-infested Valais.

Iodine was isolated from the ashes of the seaweed Fucus vesicularis by B. Courtois in France in 1811, and in 1820 Jean François Coindet recommended iodine preparations for the treatment of goiter. However, soon afterward marked opposition developed to its employment because of the occurrence of symptoms of toxicity, which we now know was the result of excessive thyroid secretion.

The iodination of salt was first suggested by Jean Baptiste Boussingault, who resided for many years in Colombia in South America. The people among whom he lived obtained their salt from an abandoned mine and felt that this salt conferred special health benefits. In 1825 Boussingault analyzed the salt and found that it contained large quantities of iodine. In 1833 he suggested that iodized salt be used for the prevention of goiter. Unfortunately, an experiment carried out in France once more obscured the importance of iodine in the etiology of the disease. Goitrous families received salt fortified with 0.1 to 0.5 grams (g) of potassium iodide per kilogram (kg) of salt. But the high dosage produced symptoms of an excess thyroid secretion and consequently the treatment again fell into disrepute.

The Twentieth Century

Present-day practice in the prevention and control of goiter is based on the work of David Marine, who in 1915 declared that “endemic goitre is the easiest known disease to prevent.” Marine and his colleague, O. Kimball, carried out the first large-scale trials with iodine in Akron, Ohio, from 1916 to 1920. About 4,500 girls between 11 and 18 years of age took part in the experiment. Roughly half of this group had goiter; the other half had normal thyroid activity. Of the group, 2,190 girls were given a daily dose of 0.2 g of sodium iodide in water for 10 days in the spring and 10 days in the autumn, making a total dose of 4.0 g over the year. The remaining 2,305 girls acted as controls. Two facts stand out from the data generated by this experiment: (1) In the group receiving sodium iodide, of 908 girls with a normal thyroid prior to treatment, only 2 (0.2 percent) developed goiter; however, in the control group, of 1,257 girls with previously normal thyroid, goiter appeared in 347 (27.6 percent); (2) in the group treated for goiter, 773 out of 1,282 girls with the disease (60.4 percent) showed a considerable decrease in the size of the thyroid, whereas in the control group, spontaneous regression of the goiter occurred in only 145 out of 1,048 girls (13.8 percent).

Thus both the prophylactic and the therapeutic effects were impressive. Iodism was very rare (only 11 cases) in spite of the extremely large doses of iodine, and the symptoms disappeared within a few days of stopping the administration of sodium iodide.

Mass prophylaxis of goiter with iodized salt was first introduced in 1924 on a community scale in Michigan (Kimball 1937), where it seems probable that the last glaciation had rendered the soil iodine deficient in that state and throughout much of the Great Lakes region. Goiter surveys of schoolchildren and iodine analyses of their drinking water were carried out in four representative counties, where the average goiter rate among 65,537 children was 38.6 percent. Table salt containing 1 part in 5,000 of potassium iodide was then introduced into the children’s diet. By 1929 the average goiter rate had fallen to 9 percent. Moreover a follow-up survey conducted by B. Brush and J. Altland (1952) on 53,785 schoolchildren in the same counties showed a goiter rate of only 1.4 percent. It was also reported that in seven large hospitals in Michigan thyroidectomies accounted for only 1 percent of all operations in 1950 compared with 3.2 percent in 1939. No toxic symptoms of iodide prophylaxis were observed.

The impact of iodized salt on the control of goiter was also vividly demonstrated in Switzerland. As this country is situated in the elevated region of the European Alps, the burden of goiter and cretinism was great throughout the country. In 1923, for example, the Canton of Berne, with a population of about 700,000, had to hospitalize 700 cretins incapable of social life. But with the Cantons’ introduction of iodized salt, which proceeded throughout the 1920s, goiter rates fell steeply, and “deaf and dumb institutions” were later closed or used for other purposes.

Observations of Swiss Army recruits revealed definite evidence of this trend of rapid decline throughout the country. Between the years 1925 and 1947, the number of exemptions for military service fell from 31 to less than 1 per thousand. Moreover, following 60 years of the use of iodized salt in Switzerland, a recent review has made clear the benefits it provided in the prevention of all degrees of neurological damage in the Swiss population (Burgi, Supersaxo, and Selz 1990). Indeed, it is now clear that the “spontaneous” disappearance of cretinism throughout Europe was due to a dietary increase in iodine intake. The continued persistence of iodine deficiency and, consequently, goiter and cretinism in Europe is mainly associated with more isolated rural areas that have not undergone the sort of social and economic development that leads to dietary diversification. But even these cases could be completely prevented with the effective distribution of iodized salt.

Goiter and Iodine Deficiency

Iodine deficiency causes depletion of thyroid iodine stores with reduced daily production of the thyroid hormone (T4). A fall in the blood level of T4 triggers the secretion of increased amounts of pituitary thyroid stimulating hormone, which increases thyroid activity with hyperplasia of the thyroid. An increased efficiency of the thyroid iodide pump occurs with faster turnover of thyroid iodine, which can be seen in an increased thyroidal uptake of radioactive isotopes 131I and125I. These features were first demonstrated in the field in the now classic observations of Stanbury and colleagues (1954) in the Andes of Argentina.

Iodine deficiency is revealed by a determination of urine iodine excretion using either 24-hour samples or, more conveniently, casual samples with determination of iodine content per gram of creatinine. Normal iodine intake is 100 to 150 micrograms per day (μ g/day), which corresponds to a urinary iodine excretion in this range (Stanbury and Hetzel 1980). In general, in endemic goiter areas the intake is well below 100 • g/day and goiter is usually seen when the level is below 50 • g/day (Pretell et al. 1972). The rate increases as the iodine excretion falls so that goiter may be almost universal at levels below 10 • g/day. The iodine content of drinking water is also low in areas with endemic goiter (Karmarkar et al. 1974).

Goiter, however, can also arise from causes other than iodine deficiency. Foremost among these are a variety of agents known as goitrogens. Recent research (Ermans et al. 1980; Delange, Iteke, and Ermans 1982) has shown that staple foods from the developing world such as cassava, maize, bamboo shoots, sweet potatoes, lima beans, and millets contain cyanogenic glucosides that are capable of liberating large quantities of cyanide by hydrolysis. Not only is the cyanide toxic but the metabolite in the body is predominantly thiocyanate, which is a goitrogen. Fortunately, these glycosides are usually located in the inedible portions of most plants, or if in the edible portion, in such small quantities that they do not cause a major problem. But such is not the case with cassava, which is cultivated extensively in developing countries and represents an essential source of calories for tropical populations of more than 200 million (Delange et al. 1982).

The role of cassava in the etiology of endemic goiter and endemic cretinism was demonstrated by F. Delange and colleagues (1982) in studies conducted in nonmountainous Zaire, and their observations were confirmed by G. Maberly and colleagues (1981) in Sarawak, Malaysia. One major effect of cassava consumption can be to increase iodine loss from the body by increasing urinary excretion.

It is important to note, however, that chronic consumption of large quantities of cassava does not necessarily result in the development of endemic goiter. Such development depends on the balance between the dietary supply of iodine and the thiocyanate (SCN) generated from the cyanide (hydrocyanic acid [HCN]) content of the cassava. The cyanide content of cassava varies with the linamarin content, and this in turn varies with traditional detoxification processes—including soaking in water before consumption, which greatly reduces the HCN content. However, sun-drying of cassava (as in the Ubangi region of Zaire) is not effective in reducing the HCN content, which can, in turn, produce a high prevalence of goiter and endemic cretinism.

A normal or high iodine intake will protect against the goitrogenic effect of the SCN. In fact, a Belgian group has shown that an iodine to SCN (I:SCN) ratio greater than 7 will achieve this protection. Goiter occurs if the ratio is about 3 and will be of high prevalence when the ratio is below 2. At this low ratio endemic cretinism will also be found in the population.

In summary, four factors will determine the SCN ratio: (1) the level of iodine intake in the diet, (2) the HCN content of fresh cassava roots and leaves, (3) the efficiency of the detoxification process used during the preparation of cassava-based foods, and (4) the frequency and quantity of consumption of these foods.

Cretinism and Iodine Deficiency

The gradual disappearance of cretinism in Europe in the early decades of the twentieth century led to the condition being largely forgotten. But in the 1960s endemic cretinism was virtually rediscovered almost simultaneously in a number of the more remote areas of the world, among them New Guinea, Zaire, India, Indonesia, China, and Brazil.

The clinical manifestations of the condition found in these areas have now been reported in considerable detail (Pharoah et al. 1980), and field studies of thyroid gland function and iodine metabolism have also been made in many countries. Evidence of the association of cretinism with severe iodine deficiency and high goiter rates has been uniformly reported.

One noticeable feature of the condition since its rediscovery has been the occurrence of a wide range of defects in individuals. These range from isolated mental deficiency to deaf-mutism of varying degree to a varying severity of paralysis of the arms and legs. But there are also individuals who appear to be normal apart from some coordination defect, all of which indicates that endemic cretinism is part of a spectrum of defects within an iodine-deficient population. And endemic cretinism is, as we shall see, a community or population disease.

It was R. McCarrison, reporting in 1908 from what was then called the North West Frontier of India (including the Karakoram Mountains, which are now in northern Pakistan), who first clearly distinguished two types of endemic cretins—the “nervous” and the “myxedematous”—from a series of 203 patients whom he had studied. In the nervous type, he recognized mental defect, deaf-mutism, and a spastic diplegia (paralysis) with a spastic rigidity, affecting the legs predominantly, that produced a characteristic walk or gait. Squint was also noted. By contrast, the myxedematous type had all the characteristics of severe hypothyroidism: dry swollen skin and tongue, deep hoarse voice, apathy, and mental deficiency. McCarrison regarded this condition as identical with “sporadic cretinism.” He found deaf-mutism present in 87 percent of his 203 cases.

These two types of cretinism are also readily seen in China, where the neurological type is the predominant form. In Hetian district in Xinjiang (only some 300 kilometers east of Gilgit, where McCarrison made his original observations in the first decade of the twentieth century), a similar pattern was observed in 1982 with neurological, hypothyroid, and mixed types present (Hetzel 1989). Later, these observations in China were confirmed by S. Boyages and colleagues (1988).

It is apparent that these two types of cretinism are distinct conditions. As McCarrison recognized, the features of the myxedematous type are essentially the same as those of sporadic cretinism. However, the myxedematous type is associated with the occurrence of hypothyroidism, which causes endemic cretinism, the latter a result of endemic goiter triggered by severe iodine deficiency in an entire community. By contrast, sporadic cretinism occurs all over the world whether or not iodine deficiency is present. It is usually found with evidence of an absent or misplaced thyroid or with a congenital defect in the biosynthesis of the hormone. To prevent confusion, the term “congenital hypothyroidism” is now generally preferred to sporadic cretinism.

It is now established that endemic cretinism, in its fully developed form characterized by severe mental deficiency, deaf-mutism, and spastic diplegia, is epidemiologically associated with high rates of goiter and severe iodine deficiency (levels of 25 • g/day or less compared to a normal intake of 80-150 • g/day), whereas goiter alone is seen at levels below 50 • g/day (Pharoah et al. 1980; Hetzel and Maberly 1986; Hetzel, Potter, and Dulberg 1990). However, as mentioned previously, the apparent spontaneous disappearance of endemic cretinism in southern Europe raised considerable doubt about its relationship to iodine deficiency (Hetzel 1989).

The hypothesis that there was such a relationship was tested for the first time in a controlled trial beginning in the 1960s. Such testing was made possible by the development of a new method for correction of severe iodine deficiency in Papua New Guinea in the form of the injection of iodized oil (McCullagh 1963; Buttfield et al. 1965; Buttfield and Hetzel 1967). Iodized oil or saline injections were given to alternate families in the Jimi River District in the Western Highlands at the time of the first census (1966). Each child born subsequently was examined for evidence of motor retardation, as assessed by the usual measurements involving sitting, standing, or walking, and for evidence of deafness. Examination was carried out without knowledge as to whether the mother had received iodized oil or saline injections (Pharoah, Buttfield, and Hetzel 1971).

Infants presenting with a full syndrome of hearing and speech abnormalities, together with abnormalities of motor development with or without squint, were classified as suffering from endemic cretinism. By these criteria, there were 7 cretins born to women who had received iodized oil out of a total of 687 children. In 6 of these 7 cases, conception had occurred prior to the iodized oil injections. In the untreated group, there were 25 endemic cretins out of a total of 688 children born since the trial began. In 5 of these 25, conception had occurred prior to saline being given.

It was concluded that an injection of iodized oil given prior to a woman’s pregnancy could prevent the occurrence of the neurological syndrome of endemic cretinism in the infant. The occurrence of the syndrome in those who were pregnant at the time of oil injection indicated that the damage probably occurred during the first half of pregnancy (Pharoah et al. 1971).

Subsequent studies in Papua New Guinea have revealed a motor coordination defect in apparently normal children subjected to severe iodine deficiency during pregnancy (Connolly, Pharoah, and Hetzel 1979; Pharoah et al. 1981). There is also evidence of an associated intellectual defect (Pharoah et al. 1984; Fierro-Benitez et al. 1986). Thus it is apparent that the effects of severe iodine deficiency in pregnancy go beyond endemic cretinism to affect children in other unpleasant ways. Such observations have been confirmed in Indonesia and Spain (Bleichrodt et al. 1987) and in China (Boyages et al. 1989).

The importance of the link between iodine deficiency and brain development has led to animal model studies that shed light on the relationship and the mechanisms involved. These studies have revealed reduced brain weight with a reduced number of brain cells during and at the end of pregnancy in iodine-deficient rats, sheep, and marmosets (Hetzel, Chevadev, and Potter 1988). The effect of iodine deficiency is mediated through reduced secretion (by both the maternal and fetal thyroids), which in turn is associated with severe fetal hypothyroidism. To date, the syndrome of neurological cretinism has not been reproduced in an animal species (Hetzel et al. 1988).

The Iodine-Deficiency Disorders

Our concept of the effects of iodine deficiency has undergone a rapid evolution since 1970. Originally the problem was designated as goiter, which (although a fascinating phenomenon for many thyroidologists) cannot by itself justify a high priority for prevention programs in developing countries. As noted in the introduction, the various effects of iodine deficiency at different stages of life are now included in IDD, which has been generally adopted (Hetzel 1983; Lancet1983). These various disorders (listed in Table IV.B.2.1) occur in populations subjected to iodine deficiency, and all can be prevented by correction of the deficiency. We will now review IDD in detail by reference to the four stages of life in which it occurs.

Iodine Deficiency in the Fetus

In iodine-deficient areas there is an increased rate of abortions and stillbirths, which can be reduced by correction of iodine deficiency (McMichael, Potter, and Hetzel 1980).An increased rate of stillbirths has also been observed in iodine-deficient sheep. In iodine-deficient pastures, lamb losses can be reduced by correction of iodine deficiency, and, it has been suggested, the same is true for goats (Hetzel and Maberly 1986). Pregnancy losses have also been produced experimentally with hypothyroidism. Studies in hypothyroid guinea pigs (produced by surgical removal of the thyroid) reveal a three- to fourfold increase in abortions and stillbirths that can be virtually eliminated by replacement therapy with thyroxine during pregnancy (McMichael et al. 1980).

In this same vein, data from Zaire and Papua New Guinea indicate an increased perinatal mortality that reflects an increase in stillbirths. There is also increased infant mortality. In Zaire, the results of a controlled trial of iodized oil injections given in the latter half of pregnancy revealed a substantial fall in perinatal and infant mortality with improved birth weight (Thilly 1981). Low birth weight is generally (whatever the cause) associated with a higher rate of congenital anomalies.

Recent evidence indicates that the various effects of iodine deficiency on the fetus (including abortion, stillbirth, congenital anomalies, and the varying manifestations of cretinism) probably arise from the lowered level of thyroid hormone T4 in the iodine-deficient mother. The more severe the reduction in the level of maternal T4, the greater the threat to the integrity of the fetus—a proposition supported by animal data on the causes of abortions and stillbirths (Hetzel et al. 1990).

Iodine Deficiency in the Neonate

In former times neonatal goiter was commonly seen in iodine-deficient areas (Hetzel and Maberly 1986). Neonatal hypothyroidism remains a well-recognized cause of mental defect in the Western world. This is because the development of the brain is dependent on an adequate supply of thyroxine. Only about one-third of normal brain development occurs before delivery of the infant; the other two-thirds is completed in the first two years of life. Hence a normal level of thyroxine is extremely important both during and after pregnancy.

In many countries every newborn child is tested for the level of blood thyroxine (usually taken from a prick in the heel at the fourth and fifth days of life). If, after further investigation, the level is found to be low, and a lowered state of thyroid gland function is indicated, then replacement treatment with daily tablets of thyroxine is begun immediately. The results of such a procedure have been evaluated in several countries and deemed to be generally excellent, provided treatment is given early, meaning within the first month of life. In Western countries, the incidence of such an abnormality runs at 1 per 3,500 live births, and results from (1) the absence of the thyroid; (2) an abnormal position of the thyroid (ectopia); or (3) a defect in the “biochemical machinery” required to produce thyroxine (called a biosynthetic defect) (Burrow 1980).

A much higher incidence, however, is found in iodine-deficient environments. Indeed, observations of blood taken from the umbilical vein (in the umbilical cord), just after birth, have revealed a rate of neonatal hypothyroidism of some 10 percent in Zaire and 5 to 10 percent in northern India and Nepal (Kochupillai and Pandav 1987). In the most severely iodine-deficient environments (more than 50 percent have urinary iodine below 25 • g/gram creatinine, which is 25 percent of normal intake), the incidence of neonatal hypothyroidism is 75 to 115 per 1,000 births. By contrast in Delhi, where only mild iodine deficiency is present with a low prevalence of goiter and no cretinism, the incidence drops to 6 per 1,000. But in control areas without goiter the level is only 1 per 1,000.

In India chemical observations have been extended to studies of the Intelligence Quotient (IQ) and hearing ability of schoolchildren. It has been shown that there is a marked reduction in IQ scores in villages with a high rate of (chemical) hypothyroidism in comparison with villages without iodine deficiency. Nerve deafness is also much more common, and there is evidence of lowered growth hormone levels in the blood.

The blood level of thyroxine in the neonate is an important indicator of the severity of iodine deficiency. Monitoring of these levels is now being done in India on samples of cord blood taken by birth attendants and subsequently spread on specially prepared filter paper. The samples are then mailed to a biochemistry laboratory where radioimmunoassay is carried out. This arrangement offers a very convenient and inexpensive method for the assessment of the severity of iodine deficiency provided a suitable functioning laboratory is available. The equipment is complex and costly but automated so that large numbers of samples can be processed. Such laboratories are now being gradually established in India, China, and Indonesia, where there are very large iodine-deficient populations. Data from these laboratories indicate a much greater risk of mental defect in severely iodine-deficient populations than is indicated by the presence of cretinism. Unfortunately, because of a gross inadequacy of manpower and money, it is just not possible to diagnose and treat these infants in most developing-world countries as they are treated in the West. This problem, of course, points up the overwhelming importance of prevention.

Iodine Deficiency in Infancy and Childhood

Iodine deficiency in children is characteristically associated with goiter, the classification of which has now been standardized by the World Health Organization (Dunn et al. 1986). Girls have a higher prevalence than boys and the rate increases with age so that it reaches a maximum with adolescence. Thus observations of goiter rates in schoolchildren between the ages of 8 and 14 provide a convenient indication of the presence of iodine deficiency in a community. The congregation of children in schools is a great advantage in providing access to a population and a place where collection of urine samples for detection of urinary iodine can be conveniently carried out.

As already noted, the prevention and control of goiter in schoolchildren was first demonstrated by Marine and Kimball in Akron, Ohio, in 1917. However, Marine and Kimball (1921) recognized that goiter was only part of IDD. They said:

The prevention of goitre means vastly more than cervical (neck) deformities. It means in addition, the prevention of those forms of physical and mental degeneration such as cretinism, mutism and idiocy which are dependent on thyroid insufficiency. Further it would prevent the development of thyroid adenomas which are an integral and essential part of endemic goitre in man and due to the same stimulus. (Marine and Kimball 1921: 1070)

Recent studies of schoolchildren living in iodine-deficient areas in a number of countries indicate impaired school performance and lower IQ scores in comparison with matched groups from non-iodine-deficient areas. In Papua New Guinea, for example, children involved in the controlled trial in the Western Highlands have been tested periodically. Differences in bimanual dexterity were revealed by threading beads and putting pegs into a pegboard—differences that correlated with whether or not the mother was severely iodine deficient (Connolly et al. 1979). Indeed, critical studies using a wide range of psychological tests have shown that the mental development of children from iodine-deficient areas lags behind that of children from non-iodine-deficient areas. But the differences in psychomotor development became apparent only after the age of 2½ years (Bleichrodt et al. 1987; Boyages et al. 1989).

Another question has been whether these differences can be affected by correction of the iodine deficiency. In a pioneering study initiated in Ecuador by R. Fierro-Benitez and colleagues (1986), the long-term effects of iodized oil injections have been assessed by comparison of two highland villages. In one of them (Tocachi) such injections were administered. The other (La Esperanza) was used as a control. Particular attention was paid to 128 children aged 8 to 15 whose mothers had received iodized oil prior to the second trimester of pregnancy and, of course, a matched control group of 293 children of similar age. All children were periodically examined from birth at key stages in their development. Women in Tocachi were injected or reinjected in 1970, 1974, and 1978. Assessments in 1973, 1978, and 1981 revealed the following:

Scholastic achievement was better in the children of treated mothers when measured in terms of school year reached, for age, school dropout rate, failure rate, years repeated and school marks. There was no difference between the two groups by a certain test (Terman-Merrill, Wechsler scale, or Goodenough). Both groups were impaired in school performance—in reading, writing and mathematics, but more notably the children of untreated mothers. (Fierro-Benitez et al. 1986: 195)

The results indicate the significant role of iodine deficiency, but other factors were also important in the school performance of these Ecuadorean children, such as social deprivation and other nutritional difficulties.

In 1982 the results were reported of a controlled trial carried out with oral iodized oil in the small Bolivian Highland village of Tiquipaya, 2,645 meters above sea level (Bautista et al. 1982). Each child in the treatment group received an oral dose of 1.0 milliliter (ml) iodized oil (475 mg iodine), whereas children in the second group received 1.0 ml of a mineral oil containing no iodine but of a similar brown color. Subsequent assessment was double-blind so that the group of the child was not known to the examiners. Interestingly, on follow-up 22 months later, the urinary iodine had increased and goiter size had decreased in both groups. This reflected “contamination” of the village environment with iodine, probably the result of fecal excretion by those who had received the iodized oil injections. There were no differences between the two treatment groups in growth rate or in the performance with the tests. However, improvement in IQ could be demonstrated in all those children, regardless of their group, who showed significant reduction of goiter. This was particularly so in girls. It was concluded that correction of iodine deficiency may improve the mental performance of school-age children, but that a bigger dose should be given.

Such studies are now being conducted in a number of countries. More data are required. However, data generated to date point to significant improvement in the mental performance of schoolchildren by the correction of iodine deficiency.

Iodine Deficiency in the Adult

The common effect of iodine deficiency in adults is goiter, although characteristically there is an absence of classical clinical hypothyroidism in adults with endemic goiter. Nonetheless, laboratory evidence of hypothyroidism with reduced T4 levels is common, associated with apathy, lethargy, and lack of energy.

Iodine administration in the form of iodized salt, iodized bread, or iodized oil have all been demonstrated to be effective in the prevention of goiter in adults (Hetzel 1989). Iodine administration may also reduce existing goiter, particularly in the case of iodized oil injections. The clearly observed benefits of iodine supplementation promote ready acceptance of such measures by people living in iodine-deficient communities.

Such benefits have been well described by J. Li and X. Wang (1987) for the northeast Chinese village of Jixian. In 1978 Jixian had a population of 1,313 people, of whom 65 percent had goiter and 11.4 percent were cretins. The latter included many severe cases and the village was known locally as “the village of idiots.” The economic development of the village was retarded; girls from other villages did not want to marry into and live in that village. The intelligence of the student population was known to be low (children aged 10 had a mental development equivalent to those aged 7).

Iodized salt was introduced in 1978, and by 1982 the goiter rate had dropped to 4 percent. No cretins had been born since 1978. The attitude of the people changed greatly, with their approach to life being much more positive than before iodization. Average income increased from 43 yuan per capita in 1981 to 223 yuan in 1982 and 414 yuan by 1984—the latter higher than the average per capita income of the district.

Before iodization, no family owned a radio in the village. But after iodization 55 families acquired television sets. Some 44 girls have arrived from other villages to marry boys in Jixian, and 7 men have joined the People’s Liberation Army, whereas before men from the village had been rejected because of goiter. Such improvements in the level of living were mainly due to the correction of hypothyroidism by iodized salt.

The Demography of IDD

The prevention and control of IDD must be regarded as an urgent problem for the 1 billion of the world’s peoples living in an iodine-deficient environment. Of these, 350 million live in China and 200 million in India (World Health Organization Report 1990).

These populations are at risk of developing one or more of the iodine-deficiency conditions that can retard physical, social, and economic growth and development. Indeed, more than 5 million of the world’s people are estimated to be suffering from mental retardation as gross cretins. But in addition, three to five times this number suffer from lesser degrees of mental defect because their mothers were iodine-deficient during pregnancy (WHO 1990).

Iodine Technology for Prevention

Iodized Salt

Iodized salt has been the major preventive method used against iodine deficiency since the 1920s. However, there are serious difficulties in the production and quality maintenance of iodized salt for the millions that are iodine deficient. In Asia, the cost of iodized salt production and distribution at present is of the order of 3 to 5 cents per person per year. This must be considered cheap in relation to the benefits produced but there remain logistical problems of getting the salt to the iodine-deficient subjects. In addition, there may be problems with the iodine content—the salt may be left uncovered or exposed to heat, which leads to loss of iodine by volatilization.

Finally, there is the difficulty of getting people to consume the salt. Although the addition of iodine makes no difference to the taste of salt, the introduction of a new variety of the mineral to an area where it has been available, and its source familiar, is likely to be resisted. In the Chinese provinces of Xinjiang and Inner Mongolia, for example, the strong preference of the people for desert salt (of very low iodine content) led to a mass iodized oil injection program to prevent cretinism (Ma et al. 1982).

Iodized Oil by Injection

The value of iodized oil injection in the prevention of endemic goiter and endemic cretinism was first established in New Guinea with trials involving the use of saline injection as a control. Experience in South America and elsewhere has confirmed this value (Hetzel et al. 1980), and, in fact, the quantitative correction of severe iodine deficiency for a period of over four years by a single intramuscular injection (2 to 4 ml) has been demonstrated (Buttfield and Hetzel 1967). Iodized oil can be administered through local health services, where they exist, or by special teams. In New Guinea, public health teams carried out the injection of a population in excess of 100,000, along with the injection of triple antigen. In Nepal 4 million injections have now been given. In Indonesia some 1 million injections were given between 1974 and 1978, together with the massive distribution of iodized salt (Djokomoeljanto, Tarwotjo, and Maspaitella 1983). A further 4.9 million injections have been given by specially trained paramedical personnel in the period 1979 to 1983. In Xinjiang in China, 707,000 injections were given by “barefoot doctors” between 1978 and 1981, and a further 300,000 to 400,000 injections were being given in 1982 (Ma et al. 1982). Iodized oil is singularly appropriate for the isolated village community so characteristic of mountainous endemic goiter areas. Iodized walnut oil and iodized soybean oil are more recently developed preparations and have been used on a wide scale in China since 1980. As with iodized salt, the striking regression of goiter following iodized oil injection ensures general acceptance of the measure.

In at-risk areas the oil should be administered to all females up to the age of 45 years, and to all males up to the age of 15 years and perhaps beyond. A repeat of the injection would be required in three to five years depending on dose and age. With children the need for a repeat injection is greater than with adults, and the dose should be repeated in three years if severe iodine deficiency persists (Stanbury et al. 1974).

Disadvantages of injections are the immediate discomfort produced and the infrequent development of abscesses at the site of injection. Sensitivity phenomena have not been reported (Hetzel et al. 1980), but a potential difficulty is disease transmission through syringes (hepatitis B or HIV infection). A major problem with injections is their cost, although the expense has been reduced with mass packaging to an order of magnitude similar to the costs of iodized salt, especially when the population to be injected is restricted to women of reproductive age and to children, and a primary health-care team is available (Hetzel 1983; SEARO/WHO 1985; Dunn et al. 1986).

Iodized Oil by Mouth

The effectiveness of a single oral administration of iodized oil for one to two years has been demonstrated in South America and in Burma. But recent studies in India and China reveal that oral iodized oil lasts only half as long as a similar dose given by injection (Dunn 1987b). However, oral administration avoids the hazard of transmitting hepatitis B or HIV infection through contaminated syringes. Moreover, oral administration of iodized oil to children could be carried out through baby health centers and schools. A 1 ml dose (480 mg) covers a period of 12 months at present.

Less Common Prevention Technologies

The use of other methods of iodization such as iodized bread and iodized water has not proceeded to the mass population level but may be indicated in special situations.

Iodized Bread

Iodized bread has been used in Holland and in Australia, and detailed observations are available from the Australian island of Tasmania. Since 1949 the Tasmanian population has received iodine dietary supplements in the form of weekly tablets of potassium iodide (10 mg) given to infants, children, and pregnant women through baby health clinics, schools, and antenatal clinics whenever possible. The prevalence of endemic goiter fell progressively during the next 16 years but was not eliminated. The failure to eliminate the disease completely was traced to a lack of cooperation by a number of schools in the distribution of the iodide tablets. The distribution through the child health centers to infants and preschool children was also ineffective because of the children’s irregular attendance.

For this reason a decision was made to change the method of prophylaxis from iodide tablets to iodized bread. The use of potassium iodate up to 20 parts per million (ppm) as a bread improver was authorized by the National Health and Medical Research Council of Australia in May 1963, and the necessary legislation was passed by the Tasmanian Parliament in October 1964.

The effects of bread iodization were measured by a series of surveys of palpable goiter rates in schoolchildren. A definite decrease in the visible goiter rate was apparent by 1969. Yet studies of urinary iodide excretion and plasma inorganic iodide in May 1967 revealed no excessive intake of iodide. Correction of iodine deficiency was confirmed by evidence of a fall of 24-hour radioiodine uptake levels in hospital subjects as well as normal plasma inorganic iodine concentration and urine iodine excretion (Stewart et al. 1971).

Thus bread iodization was effective in correcting iodine deficiency in Tasmania in the 1960s. However, today there is a greater diversity of sources for dietary iodine. It is readily available from milk due to the use of iodophors in the dairy industry, and it is also available from ice cream due to the use of alginate as a thickener.

Iodized Water

Reduction in goiter rate from 61 percent to 30 percent with 79 percent of goiters showing visible reduction has been demonstrated following water iodization in Sarawak (Maberly, Eastman, and Corcoran 1981). Similar results have been obtained with preliminary studies in Thailand by Romsai Suwanik and his group at the Siriraj Hospital, Bangkok, and in Sicily (Hetzel 1989). Iodized water may be a more convenient preventive measure than iodized salt and there may be less likelihood of iodine-induced thyrotoxicosis. Certainly this method is appropriate at the village level if a specific source of drinking water can be identified.

The Hazards of Iodization

A mild increase in incidence of thyrotoxicosis has been described following iodized salt programs in Europe and South America and following the introduction of iodized bread in Holland and Tasmania. A few cases have been noted following iodized oil administration in South America. That no cases have yet been described in New Guinea, India, or Zaire is probably due to the scattered nature of the population in small villages and limited opportunities for observation. In Tasmania it was apparent that a rise in incidence of thyrotoxicosis accompanied a rise in iodine intake from below normal to normal levels due to iodized bread, which was finally introduced in April 1966 (Stewart et al. 1971). The condition can be readily controlled with antithyroid drugs or radio-iodine. Nonetheless, in general, iodization should be minimized for those over the age of 40 because of the risk of thyrotoxicosis (Stanbury et al. 1974; Hetzel 1983).

International Action toward Elimination

Since 1978, there has been increasing concern about a lag in the application of our new knowledge of the iodine-deficiency disorders and their prevention (Stanbury and Hetzel 1980; Hetzel 1983). A symposium at the Fourth Asian Congress of Nutrition in Bangkok in 1983 brought the problem to the attention of the international nutrition community with the preparation of a comprehensive report on the “Prevention and Control of Iodine Deficiency Disorders for the United Nations System” (Lancet 1983).

This report, which was subsequently published (Hetzel 1988b), indicated the need for the establishment of an expert group of scientists and other health professionals committed to bridging the wide gap between research and action. At a WHO/UNICEF Intercountry Meeting in March 1985, in Delhi, a group of 12 such experts agreed to found the International Council for Control of Iodine Deficiency Disorders (ICCIDD). In 1986 an International Board was established and the ICCIDD was formally inaugurated at Kathmandu, Nepal (Lancet 1986a).

The ICCIDD has welcomed as members all who have concern for and expertise in IDD and IDD control (Lancet 1986a). The main role of the ICCIDD is to make such expertise available to international agencies and national governments who have responsibility for the control of IDD, and so bridge the great gap between available knowledge and its application. At the inaugural meeting in Kathmandu, Nepal, a global review of the IDD problem took place along with an appraisal of current expertise in iodine technology and IDD control programs. This meeting led to the first ICCIDD monograph (Lancet 1986b; Hetzel, Dunn, and Stanbury 1987).

The ICCIDD is now a global, multidisciplinary group, consisting of some 300 members from 70 countries, and has a quarterly newsletter and a secretariat in Adelaide, Australia. Support since 1985 has been received from UNICEF (New York) and the Australian government and since 1991 from the Canadian government.

Since 1987, the ICCIDD has become fully active in facilitating interagency cooperation in the prevention and control of IDD by holding a series of inter-agency meetings and establishing regional inter-agency working groups (particularly involving WHO and UNICEF, but also some of the bilaterals). A Global Action Plan has now been endorsed by the UN agencies to take account of these developments. The purpose of the Global Action Plan is to provide global and regional support for the establishment and monitoring of effective national IDD control programs. It includes activities at the national, regional, and global levels.

At the national level, such activities include initial assessments, national seminars, communication packages, intersectoral planning with a National IDD Control Commission, evaluation, and monitoring with laboratory services. In Indonesia and China, International Working Groups have now been established by ICCIDD in collaboration with WHO and UNICEF.

At the regional level, the development of a series of regional IDD working groups provides for the necessary close working relationship between ICCIDD, WHO, and UNICEF. The IDD Task Force for Africa has been particularly successful in developing a coordinated strategy involving both multilateral and bilateral agencies.

At the global level, major functions include advocacy and the provision of public information, as well as the maintenance of a global monitoring system.

In view of the progress already achieved and the promising potential of current and planned national prevention and control programs, the goal of eliminating IDD as a major public health problem by the year 2000 was reaffirmed by the 1990 World Health Assembly (World Health Organization Report 1990). An escalation of funding now became an essential step in the achievement of this goal.

In September 1990, the World Summit for Children held at the United Nations in New York was attended by 71 heads of state and 80 other government representatives. The World Summit signed a Declaration and approved a Plan of Action that included the elimination of IDD as a public health problem by the year 2000.

This summit was followed in October 1991 by a conference entitled “Ending Hidden Hunger,” which was a policy and promotional meeting on micronutrients including iodine, vitamin A, and iron. It was attended by multidisciplinary delegations from 55 countries with major IDD problems. These delegates were nominated by heads of state in response to an invitation by the director general of the World Health Organization, H. Nakajima, and the executive director of UNICEF, James Grant. At this meeting there was a firm commitment to the goal of eliminating IDD and vitamin A deficiency and reducing iron deficiency by one-third of 1990 levels. These various developments encourage the hope that very significant progress would be made toward the elimination of IDD during the last decade of the twentieth century with great benefits to the quality of life of the many millions affected (Hetzel 1989).