Review Article
Endemic Goitre - Iodine Deficiency Disorders
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Bror-Axel Lamberg
Endemic goitre occurs when the prevalence of thyroid enlargement in the population of an area exceeds 10 %.W i t h few exceptions its cause i s iodine deficiency superimposed o n other goitrogenic factors normally present and responsible for sporadic goitre. Iodine deficiency causes significant health problems and so, the term iodine deficiency disorders (IDD) has been introduced. The earliest sign of IDD is goitre, but these disorders also include cretinism, neonatal hypothyroidism and congenital defects, as well as retardation of mental and physical development etc. IDD are a worldwide problem: WHO estimates that substantially more than 800 million people are at risk and more than 190 millions suffer from IDD; over 3 million people have cretinism and i n the largest and worst affected areas many millions suffer from mental and physical developmental defects. IDD can be totally eliminated by prophylaxis using iodine administered in salt, oil or some other vehicle. Problems over preventing iodine deficiency relate to difficulties in the handling and distribution of the iodized vehicle in some parts of the world and o n the political will t o introduce preventive schemes. In only a very few areas does the presence of goitrogenic agents in the environment cause endemic goitre despite adequate iodine supply. In a limited number of places excessive iodine from seaweed used as staple food results in endemic goitre. Key words: endemic goitre; iodine deficiency; iodine deficiency disorders. (Annals of Medicine 23: 367-372, 1991)
Introduction Goitre, an enlargement of the thyroid gland, may have many causes (Table 1). Goitrogenesis is usually the result of a multiplicity of environmental factors acting in concert with intrinsic ones. A thyroid weighing less than 25 g or with a volume smaller than 20 ml may be classified as “normal”. The term endemic goitre implies that enlargement of the thyroid is particularily frequent in a certain geographical area and that the prevalence exceeds 10 Yo among children aged 6 to 15 years or in the adult population (1). This discriminatory level has been decided upon because a higher prevalence will be related to other health problems. The predominant factor causing the prevalence of goitre to rise above 10 Yo is iodine deficiency; there are few exceptions to this rule. In the presence of other goitrogenic factors iodine deficiency plays a permissive role. Sporadic goitre is the term used when the prevalence is below 10%; the causes From the Endocrine Research Laboratory, University of Helsinki, and the Minerva Foundation Institute for Medical Research, Helsinki, Finland. Address and reprints requests: Bror-Axel Lamberg, MD, Endocrine Research laboratory, University of Helsinki, The Minerva Foundation, Tukholmankatu 2, SF-00250 Helsinki, Finland.
may be some of those listed in Table 1, but are often unknown. The relation between goitre and iodine deficiency was suspected early in the 19th century but final evidence was produced only about 100 years later when Marine and Kimball made their classical prophylactic and therapeutic experiment in Akron, Ohio in 1917-20 (2). They showed that when iodine was given to a group of schoolgirls with a normal thyroid goitre did not appear, and that any pre-existing goitre shrunk markedly. This contrasted with the observations that untreated girls who developed goitre or who had pre-existing goitre did no undergo any Table 1. Goitre producing factors. ~~
Iodine deficiency, important in endemic goitrogenesis Compounds interfering with the synthesis and secretion of thyroid hormones, abundant in the environment, of limited importance in endemic goitrogenesis (thiocyanate, thiooxazolidone, flavonoids, disulphides, phenols, phthalates, biphenyls, lithium and iodine excess) Compounds interfering with the metabolism of thyroid hormones Dyshormonogenesis, inherited and congenital defects in hormone synthesis and secretion Thyroid growth stimulating antibodies Peripheral cellular resistance to thyroid hormones Modified after Gaitan (17)
Lamberg
368 Table 2. The spectrum of iodine deficiency disorders Fetus
Neonate Child and adolescent
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Adult
Abortions Stillbirth Congenital anomalies Increased perinatal mortality Increased infant mortality Neurological cretinism: mental deficiency deaf mutism, spastic diplegia, squint Myxoedematouscretinism: dwarfism, mental deficiency Neonatal goitre Neonatal hypothyroidism Goitre Juvenile hypothyroidism impaired mental function Retarded physical development Goitre with its complications Hypothyroidism Impaired mental function Iodine induced hyperthyroidism
Hetzel (3, 26)
change in the size of their goitre. Goitre is the predominant clinical sign of iodine deficiency, which, however, has other more important clinical implications (Table 2), and this was why the concept of Iodine Deficiency Disorders, IDD was introduced in 1983 (3). In only a very few areas is endemic goitre the result of environmental goitrogens despite an adequate supply of iodine; excessive intake of iodine causes some local endemic occurrences.
Iodine Deficiency In 1952 an expert group from WHO estimated that a daily intake of iodine of 100-150 pg per day may be regarded as “normal” (4).This amount should be adequate both for correcting iodine deficiency in the food and for preventing the effects of environmental goitrogens. In fact prophylactic programmes providing more than pg per day have usually brought high prevalence rates of goitre rates down to around 10 Yo( 5 ) . The daily urinary excretion of iodine in a representative population sample is a good indication of the iodine available in a locality (6, 7). The iodine/creatinine ratio in the urine has also been used in epidemiological studies, but excessive values have been recorded in the protein deficient states that commonly occur in developing countries where iodine deficiency prevails (8). Iodine deficiency reduces intrathyroidal iodine concentration and the iodination of thyroglobulin (9). It also stimulates a more efficient uptake of iodine by the thyroid gland. Production of thyroid hormone falls and this stimulates the secretion of TSH from the pituitary gland. TSH enhances the iodine uptake and hormone production and induces a preferential secretion of triiodothyronine (T,) over thyroxine (T,) (1 0). The thyroid gland increases in size because of the growth stimulating effects of TSH
and tissue growth factors (11). An inverse relationship exists between iodine intake and the prevalence of endemic goitre (12) as well as the thyroid size as measured by ultrasound (13). Heterogeneity of the genetic outfit of thyrocytes means that some follicular cells are more susceptible to stimulation than others; nodules are formed, some of which will attain an autonomous function (14). The size and number of nodules increases with increasing age of the population. Some of the autonomous nodules may cause hyperthyroidism (14). Toxic multinodular goitre was still the predominant type of hyperthyroidism in Finland in the nineteen fifties and sixties when endemic mild to moderate goitre prevailed (15). The following scheme for a practical classification of iodine deficiency has been suggested (1, 16): Grade I (mild): urinary excretion of iodine 50-100 pg/ day (per gram of creatinine or per litre of urine). This is adequate for normal physical and mental development but some 10 to 20 Yo of the population will develop a palpable goitre; the serum TSH is normal. Grade II (moderate): urinary excretion 25-50 pg per day (per gram of creatinine or per litre of urine). Palpable goitre occurs in 20 to 50 Yo of the population and nodular goitre is common, hypothyroidism will occur and serum TSH is increased in 10 to 20 O/O of the population. Occasionally deafness and mental defects are encountered. Grade Ill (severe): urinary excretion 90 Yo of the population, hypothyroidism is common and the prevalence of cretinism is 1 to 10 %; serum TSH is increased in 30 to 50 Yo of the population.
The Role of Goitrogens Environmental goitrogenic agents are abundant (17, 18) and among well known ones are compounds derived from vegetables of the Cruciferae family, particularly the Brassica genus such as cabbage, turnips, brussel sprouts, sweet potatoes, and many others. In Zaire endemic goitre is in part due to the presence of thiocyanate, which blocks the thyroidal uptake of iodine. Thiocyanate is liberated when processing cassava (Manihot esculenta), a staple food in Zaire (19). Thiocyanate goitre is effectively counteracted by iodine and in Zaire the prevalence of goitre correlates with the urinary SCN/iodine ratio. Smoking tobacco produces thiocyanate and other goitrogenic compounds and have been shown to cause thyroid enlargment (20,Zl). 1-5-vinyl-2-thio-oxazolidone (VTO) derived from Brassicae vegetables interferes with hormone synthesis and has possibly been an additional factor to iodine deficiency in goitrogenesis in Finland (15) in the nineteen fifties (22). Similar compounds have been implicated in the endemic goitre in Western Sudan (23), where millet a staple food, contains goitrogenic flavonoids (24). Phenol derivatives, phthalates and pyridines, which are present as waste products in aqueous effluents from coal conversion processes and also in water and soil, are goitrogenic (17). These substances play an important role in local endemic areas in Colombia and in the USA (17). Excess iodine can be goitrogenic by blocking thyroid hormone synthesis, and in Japan (25) endemic goitre occurs in some coastal areas where iodine rich seaweed is commonly eaten.
Endemic Goitre - Iodine Deficiency Disorders
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Iodine Deficiency Disorders Goitre is the main visible sign of iodine deficiency and the first to be recognised, particularily in preadolescent subjects. Thus recognition of the prevalence of goitre in certain areas is, of epidemiological significance. In mild iodine deficiency the goitre itself and the nodules create clinical problems, but more serious complications occur with severe iodine deficiency (26) (Table 2). An increasing severity of iodine deficiency results in goitre appearing in younger children; and in newborn infants neonatal hypothyroidism and mental and neurological defects may occur. In severely affected areas the incidence of spontaneous abortion, stillbirths and infant mortality increase and worst of all children with cretinism are born. A certain relation exists between goitre prevalence and the appearance of other manifestations of iodine deficiency (26, 27). By combining data from various studies researchers have constructed a rough correlation curve for the prevalence of cretinism. When the goitre prevalence is 30 to 40 Yo few cretins are born but the prevalence of cretins increases continuously with increasing prevalence of goitre, reaching about 10 Yo of births at a prevalence of 70 to 80 %. Endemic cretinism is defined as a condition including mental retardation, hearing loss or deaf-mutism, neurological abnormalities such as spasticity and muscular rigidity, disorders of gait. Hypothyroid manifestations such as growth retardation are associated with severe IDD and endemic goitre and can be prevented by iodine supplementation. Two main types of cretinism are identifiable; neurological and myxoedematous, depending on which clinical signs dominate. Cretinism is caused by intrauterine deficiency of thyroid hormones and the neurological signs are due to changes during early fetal development. The pituitary gland may be enlarged, simulating a pituitary tumour (28). In severely affected areas there is a continuum of mental and psychomotor defects (27, 29). If cretinism is excluded the mental and psychomotor development in all age groups lags significantly behind that in areas that are not deficient in iodine. This may be owing to mild intrauterine damage or to persisting mild hypothyroidism and represents an important socioeconomic problem because a significant proportion of the population is affected. Since the seventies routine screening of neonatal hypothyroidism using TSH determinations from cord blood or from blood samples obtained shortly after birth has been done in many countries. This has also shown a relation between the incidence of goitre and of neonatal hypothyroidism. Both permanent and transitory neonatal hypothyroidism are more frequent in iodine deficient areas. The prevalence of raised serum TSH concentration in newborn infants is normally 1/3000-1/4000 but in areas of severe iodine deficiency it may rise to 1/10 or more as shown, for instance, in studies from India (30) and Sicily (31). A European multicentre study on newborn populations found a clearcut inverse relation between the urinary excretion of iodine and neonatal hypothyroidism (32). Transient hypothyroidism is seven times more frequent in Europe than in the USA because of the presence in Europe of areas with mild or borderline iodine deficiency (32).
369
Global Distribution of Iodine Deficiency Disorders Endemic goitre and IDD are substantial world wide problems. A WHO report estimated that in Asia, Africa and Latin America, where the major endemic areas are situated, 800 million people are at risk of IDD, 190 millions have them, over 3 millions people suffer from cretinism and several million suffer from mental and neurological defects (26). Thus about 15 YOof the worlds population is at risk of and 4 to 5 YO suffer from IDD. Developing countries are most affected, and in these regions the population grows rapidly, creating problems over keeping prophylactic measures abreast with this growth. Endemic goitre occurs in all parts of the world not just in hilly regions; some lowlands are also iodine deficient (18, 26, 33). In Latin America iodine prophylaxis has been effective in Mexico, Guatemala and Colombia and also in parts of Chile, Brazil and Argentina. Even so, large areas still remain with a high prevalence of endemic goitre, especially in Equador, Peru and Bolivia. In Guatemala the initially very good response to iodine prophylaxis has lately suffered a setback owing to political unrest; consequently the prevalence of goitre is again rising. Some countries still do not use iodine prophylaxis and there are some mountainous and jungle areas where iodine prophylaxis has not been practicable. Cameroon, Zaire, Zambia, Tanzania and western Sudan are the most affected areas in Africa, with prevalences up to 70 to 80% and a high rate of cretinism. The introduction of iodine prophylaxis has been greatly delayed. Goitre is also common in the Middle East, but the political position has prevented any kind of prophylactic measures being introduced. The most notorious areas in Asia, with goitre prevalences up to 70 to 80 ‘10 and cretinism, are the countries along the Himalayan mountains: Pakistan, India, Nepal, and Bhutan; but in Indonesia and China goitre and cretinism also has a high prevalence. Europe has customarily been classified as a fairly goitre free region, but a recent survey initiated by the European Thyroid Association showed that this is not so (34). Only the Nordic countries, the British Isles and Belgium are free from endemic goitre. Iodine prophylaxis has been practised in Finland for about 30 years and endemic goitre has now disappeared in those parts of the population under 40 years of age (35, 36). An incidence of goitre ranging from 30 to 80 ‘10 is found in certain parts of the Mediterranean countries and in southern Germany; cretinism still occurs in certain communities in Spain (37) and Sicily (38).
Iodine Prophylaxis Iodine prophylaxis was tried as long ago as the early nineteenth century but iodine was given in doses that were too large, causing what we now call the “JodBasedow” syndrome and no further attempts at prevention were made. About 100 years later prophylaxis with iodized salt was introduced in the USA and Switzerland. Its general effectiveness has been documented in a recent compilation of epidemiological studies from 25 countries (5). Recent information from various parts of the world have shown similar results. In many countries io-
Lamberg
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370
dine prophylaxis with iodized salt was begun between 1920 and 1940. The problems related to iodine deficiency, cretinism and mental defects were well recognised by those working in the field. Health authorities did not always regard goitre as such an important problem and its complications were insufficiently recognised. Despite various resolutions by international organisations little progress had occurred internationally even by the seventies. So the International Council for Control of Iodine Deficiency Disorders, ICCIDD, was set up in 1986 to stimulate prophylactic measures, to increase existing efforts and to initiate new ideas. ICCIDD is closely linked with WHO and UNICEF. These efforts have provoked the initiation and surveillance of prophylactic programmes in the worst affected areas throughout the world (39). The introduction and fulfilment of iodine prophylaxis depends on a country's political will and decision working capabilities. Without efforts from governmental institutions and without legislation effective measures are in most instances not to be expected, although there are examples of effective prophylaxis based on voluntary activity (15,
10 mglkg
0
SCHOOLCHILDREN
YEARS 20-25 rnglkg
35). Prophylaxis with iodized salt is the oldest method of prevention and its efficacy depends on several factors (Table 3). The concentration of iodine in the salt should be adjusted according to the salt consumption in the area concerned so as to provide the required daily amount of iodine, at least 100-150 pg per day. During recent decades the consumption of table salt has fallen markedly in many industrial countries (5). In the USA it is now about 3 glday, in Finland it has fallen from 7-8 g/day to about 4 glday and in Switzerland from 12 to 6 glday. Salt consumption is, however, much higher in some countries, for instance, in some parts of India it amounts to 15-20 glday. The concentration of iodine varies in different countries. In Europe it has usually been 10-20 mg of iodine/kg whereas in Latin America it has ranged from 30-100 mglkg. The duration of prophylaxis in another relevant factor. The presence of goitrogenic factors in the food or in the environment increases the demand for iodine but the effects of some goitrogenic agents are not prevented by iodine supplementation. Potassium iodide, KI, has been customarily added to salt, but potassium iodate, KIO,, is more stable (40). The iodized compound is heavier than sodium chloride and falls to the bottom of the bags during storage. Many practical problems are related to production methods and to the quality of the salt, the method of iodization and the storage and distribution of salt to the populace (40). After iodine prophylaxis has been started the first diseases to disappear are cretinism and neonatal defects; these improvement will occur even with low iodine concentrations in the salt. The newborn infants thyroid gland shrinks, a change occurring even if prevention is started
Table 3. Factors influencing the efficacy of iodized salt Iodine concentration in the salt Amount of iodine required (100-150 pg/day) Duration of prophylaxis Handling and distribution of salt Individual food habits Goitrogenic factors Lamberg (5)
POPULATION
60
.
o POPULATION SCHOOLCHILDREN
t\ \
40
20
0
5
10
16
20
26
30
YEARS
Figuresla and lb. Prevalence of goitre before and after introduction of iodized salt. Data from Switzerland (CH) (upper part) were obtained when iodine concentration was still 5 mg Kl/kg salt The figures show urinary excretion of iodine in pg/day, asterisk indicates pg l/g creatinine. Each curve represents a separate sample and does not indicate the general trend in the different countries. Po = Poland, Yu = Yugoslavia. Hu = Hungary, Br = Brazil, Ch = China, In = India, Por = Portugal, Me = Mexico, Bu = Bulgaria, 60 = Bohemia and Moravia, Slo = Slovakia, SF = Finland (during the 20 to 30 years period an important proportion of the iodine was derived from milk and milk products) (Lamberg, ref. 5 )
during pregnancy (41). In children the thyroid diminishes in size and the nodules disappear. The effect on the prevalence of goitre is seen in Figures 1a and 1b (5), but it takes many decades before the effects are visible in the whole population (36, 42). Experiences from Finland show that toxic nodular goitre previously the predominant type of hyperthyroidism has markedly regressed in parallell with the disappearance of the endemic goitre (15, 43). Concomitantly, there are changes in the biochemical parameters of thyroid function: the uptake of radioactive iodine by the thyroid and the TJT, ratio falls and concentrations of serum TSH, if initially raised, will decline (35).
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Endemic Goitre - Iodine Deficiency Disorders Since prophylactic iodized salt cannot be effectively introduced in all regions other solutions have been introduced. Injection of lodized oil is the most important alternative method and is used in many areas where goitre is endemic (16, 4 4 , 45). lodized oil may also be given by mouth. The effect is fast and clearly seen in the prompt disappearance of cretinism and neonatal hypothyroidism. There is also a rapid regression of the prevalence of goitre in newborn and young children (46, 47). Concomitantly biochemical abnormalities return to normal. The effect lasts for one to two years, depending on the severity of iodine deficiency and the loss of the benefits is evident by an increase in the prevalence of goitres. The treatment (injection of 480-960 mg of iodine in adults) should be repeated at one to two year intervals. The most important target groups are women in the childbearing age (including pregnant women), children and young adults (45). In a few areas tap water (38, 48) and bread (44) have been iodized. In smaller populations iodine can be administered in any form for example, potassium iodide or Lugols solution. In endemic areas farm animals also suffer from iodine deficiency, which, for instance, reduces milk production in cows (49). Effective iodine prophylaxis for farm animals will inturn increase the iodine intake by the human population through milk, dairy products and eggs. This is so, for instance, in Finland, where the present daily intake of iodine is about 300 pglday (35,50) of which about two thirds is derived from these products and less than one third from iodized salt (50). A temporary rise in the incidence of hyperthyroidism may occur during the first years after the introduction of iodine prophylaxis (5, 18). This is partly owing to the increased iodine supply for hormone synthesis in autonomous nodules or in patients with latent or subclinical Graves's disease. But the possible stimulation of autoimmune processes by increased iodine intake has been recently suggested as a contributory factor (51). Hyperthyroidism is not a big problem today even in elderly people, particularily when compared to the health problems caused by IDD. Recently, the possible role that increased iodine intake may have on the initiation of autoimmune thyroiditis has been questioned (52, 53). This is, however, unresolved and requires further studies. Another question is whether the large amount of iodine provided to mothers through iodized oil may have some adverse effects on their offspring despite its obvious advantages in eliminating cretinism and antenatal deformities.
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Endemic Goitre - Iodine Deficiency Disorders
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Bror-Axel Lamberg
Endemic goitre occurs when the prevalence of thyroid enlargement in the population of an area exceeds 10 %.W i t h few exceptions its cause i s iodine deficiency superimposed o n other goitrogenic factors normally present and responsible for sporadic goitre. Iodine deficiency causes significant health problems and so, the term iodine deficiency disorders (IDD) has been introduced. The earliest sign of IDD is goitre, but these disorders also include cretinism, neonatal hypothyroidism and congenital defects, as well as retardation of mental and physical development etc. IDD are a worldwide problem: WHO estimates that substantially more than 800 million people are at risk and more than 190 millions suffer from IDD; over 3 million people have cretinism and i n the largest and worst affected areas many millions suffer from mental and physical developmental defects. IDD can be totally eliminated by prophylaxis using iodine administered in salt, oil or some other vehicle. Problems over preventing iodine deficiency relate to difficulties in the handling and distribution of the iodized vehicle in some parts of the world and o n the political will t o introduce preventive schemes. In only a very few areas does the presence of goitrogenic agents in the environment cause endemic goitre despite adequate iodine supply. In a limited number of places excessive iodine from seaweed used as staple food results in endemic goitre. Key words: endemic goitre; iodine deficiency; iodine deficiency disorders. (Annals of Medicine 23: 367-372, 1991)
Introduction Goitre, an enlargement of the thyroid gland, may have many causes (Table 1). Goitrogenesis is usually the result of a multiplicity of environmental factors acting in concert with intrinsic ones. A thyroid weighing less than 25 g or with a volume smaller than 20 ml may be classified as “normal”. The term endemic goitre implies that enlargement of the thyroid is particularily frequent in a certain geographical area and that the prevalence exceeds 10 Yo among children aged 6 to 15 years or in the adult population (1). This discriminatory level has been decided upon because a higher prevalence will be related to other health problems. The predominant factor causing the prevalence of goitre to rise above 10 Yo is iodine deficiency; there are few exceptions to this rule. In the presence of other goitrogenic factors iodine deficiency plays a permissive role. Sporadic goitre is the term used when the prevalence is below 10%; the causes From the Endocrine Research Laboratory, University of Helsinki, and the Minerva Foundation Institute for Medical Research, Helsinki, Finland. Address and reprints requests: Bror-Axel Lamberg, MD, Endocrine Research laboratory, University of Helsinki, The Minerva Foundation, Tukholmankatu 2, SF-00250 Helsinki, Finland.
may be some of those listed in Table 1, but are often unknown. The relation between goitre and iodine deficiency was suspected early in the 19th century but final evidence was produced only about 100 years later when Marine and Kimball made their classical prophylactic and therapeutic experiment in Akron, Ohio in 1917-20 (2). They showed that when iodine was given to a group of schoolgirls with a normal thyroid goitre did not appear, and that any pre-existing goitre shrunk markedly. This contrasted with the observations that untreated girls who developed goitre or who had pre-existing goitre did no undergo any Table 1. Goitre producing factors. ~~
Iodine deficiency, important in endemic goitrogenesis Compounds interfering with the synthesis and secretion of thyroid hormones, abundant in the environment, of limited importance in endemic goitrogenesis (thiocyanate, thiooxazolidone, flavonoids, disulphides, phenols, phthalates, biphenyls, lithium and iodine excess) Compounds interfering with the metabolism of thyroid hormones Dyshormonogenesis, inherited and congenital defects in hormone synthesis and secretion Thyroid growth stimulating antibodies Peripheral cellular resistance to thyroid hormones Modified after Gaitan (17)
Lamberg
368 Table 2. The spectrum of iodine deficiency disorders Fetus
Neonate Child and adolescent
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Adult
Abortions Stillbirth Congenital anomalies Increased perinatal mortality Increased infant mortality Neurological cretinism: mental deficiency deaf mutism, spastic diplegia, squint Myxoedematouscretinism: dwarfism, mental deficiency Neonatal goitre Neonatal hypothyroidism Goitre Juvenile hypothyroidism impaired mental function Retarded physical development Goitre with its complications Hypothyroidism Impaired mental function Iodine induced hyperthyroidism
Hetzel (3, 26)
change in the size of their goitre. Goitre is the predominant clinical sign of iodine deficiency, which, however, has other more important clinical implications (Table 2), and this was why the concept of Iodine Deficiency Disorders, IDD was introduced in 1983 (3). In only a very few areas is endemic goitre the result of environmental goitrogens despite an adequate supply of iodine; excessive intake of iodine causes some local endemic occurrences.
Iodine Deficiency In 1952 an expert group from WHO estimated that a daily intake of iodine of 100-150 pg per day may be regarded as “normal” (4).This amount should be adequate both for correcting iodine deficiency in the food and for preventing the effects of environmental goitrogens. In fact prophylactic programmes providing more than pg per day have usually brought high prevalence rates of goitre rates down to around 10 Yo( 5 ) . The daily urinary excretion of iodine in a representative population sample is a good indication of the iodine available in a locality (6, 7). The iodine/creatinine ratio in the urine has also been used in epidemiological studies, but excessive values have been recorded in the protein deficient states that commonly occur in developing countries where iodine deficiency prevails (8). Iodine deficiency reduces intrathyroidal iodine concentration and the iodination of thyroglobulin (9). It also stimulates a more efficient uptake of iodine by the thyroid gland. Production of thyroid hormone falls and this stimulates the secretion of TSH from the pituitary gland. TSH enhances the iodine uptake and hormone production and induces a preferential secretion of triiodothyronine (T,) over thyroxine (T,) (1 0). The thyroid gland increases in size because of the growth stimulating effects of TSH
and tissue growth factors (11). An inverse relationship exists between iodine intake and the prevalence of endemic goitre (12) as well as the thyroid size as measured by ultrasound (13). Heterogeneity of the genetic outfit of thyrocytes means that some follicular cells are more susceptible to stimulation than others; nodules are formed, some of which will attain an autonomous function (14). The size and number of nodules increases with increasing age of the population. Some of the autonomous nodules may cause hyperthyroidism (14). Toxic multinodular goitre was still the predominant type of hyperthyroidism in Finland in the nineteen fifties and sixties when endemic mild to moderate goitre prevailed (15). The following scheme for a practical classification of iodine deficiency has been suggested (1, 16): Grade I (mild): urinary excretion of iodine 50-100 pg/ day (per gram of creatinine or per litre of urine). This is adequate for normal physical and mental development but some 10 to 20 Yo of the population will develop a palpable goitre; the serum TSH is normal. Grade II (moderate): urinary excretion 25-50 pg per day (per gram of creatinine or per litre of urine). Palpable goitre occurs in 20 to 50 Yo of the population and nodular goitre is common, hypothyroidism will occur and serum TSH is increased in 10 to 20 O/O of the population. Occasionally deafness and mental defects are encountered. Grade Ill (severe): urinary excretion 90 Yo of the population, hypothyroidism is common and the prevalence of cretinism is 1 to 10 %; serum TSH is increased in 30 to 50 Yo of the population.
The Role of Goitrogens Environmental goitrogenic agents are abundant (17, 18) and among well known ones are compounds derived from vegetables of the Cruciferae family, particularly the Brassica genus such as cabbage, turnips, brussel sprouts, sweet potatoes, and many others. In Zaire endemic goitre is in part due to the presence of thiocyanate, which blocks the thyroidal uptake of iodine. Thiocyanate is liberated when processing cassava (Manihot esculenta), a staple food in Zaire (19). Thiocyanate goitre is effectively counteracted by iodine and in Zaire the prevalence of goitre correlates with the urinary SCN/iodine ratio. Smoking tobacco produces thiocyanate and other goitrogenic compounds and have been shown to cause thyroid enlargment (20,Zl). 1-5-vinyl-2-thio-oxazolidone (VTO) derived from Brassicae vegetables interferes with hormone synthesis and has possibly been an additional factor to iodine deficiency in goitrogenesis in Finland (15) in the nineteen fifties (22). Similar compounds have been implicated in the endemic goitre in Western Sudan (23), where millet a staple food, contains goitrogenic flavonoids (24). Phenol derivatives, phthalates and pyridines, which are present as waste products in aqueous effluents from coal conversion processes and also in water and soil, are goitrogenic (17). These substances play an important role in local endemic areas in Colombia and in the USA (17). Excess iodine can be goitrogenic by blocking thyroid hormone synthesis, and in Japan (25) endemic goitre occurs in some coastal areas where iodine rich seaweed is commonly eaten.
Endemic Goitre - Iodine Deficiency Disorders
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Iodine Deficiency Disorders Goitre is the main visible sign of iodine deficiency and the first to be recognised, particularily in preadolescent subjects. Thus recognition of the prevalence of goitre in certain areas is, of epidemiological significance. In mild iodine deficiency the goitre itself and the nodules create clinical problems, but more serious complications occur with severe iodine deficiency (26) (Table 2). An increasing severity of iodine deficiency results in goitre appearing in younger children; and in newborn infants neonatal hypothyroidism and mental and neurological defects may occur. In severely affected areas the incidence of spontaneous abortion, stillbirths and infant mortality increase and worst of all children with cretinism are born. A certain relation exists between goitre prevalence and the appearance of other manifestations of iodine deficiency (26, 27). By combining data from various studies researchers have constructed a rough correlation curve for the prevalence of cretinism. When the goitre prevalence is 30 to 40 Yo few cretins are born but the prevalence of cretins increases continuously with increasing prevalence of goitre, reaching about 10 Yo of births at a prevalence of 70 to 80 %. Endemic cretinism is defined as a condition including mental retardation, hearing loss or deaf-mutism, neurological abnormalities such as spasticity and muscular rigidity, disorders of gait. Hypothyroid manifestations such as growth retardation are associated with severe IDD and endemic goitre and can be prevented by iodine supplementation. Two main types of cretinism are identifiable; neurological and myxoedematous, depending on which clinical signs dominate. Cretinism is caused by intrauterine deficiency of thyroid hormones and the neurological signs are due to changes during early fetal development. The pituitary gland may be enlarged, simulating a pituitary tumour (28). In severely affected areas there is a continuum of mental and psychomotor defects (27, 29). If cretinism is excluded the mental and psychomotor development in all age groups lags significantly behind that in areas that are not deficient in iodine. This may be owing to mild intrauterine damage or to persisting mild hypothyroidism and represents an important socioeconomic problem because a significant proportion of the population is affected. Since the seventies routine screening of neonatal hypothyroidism using TSH determinations from cord blood or from blood samples obtained shortly after birth has been done in many countries. This has also shown a relation between the incidence of goitre and of neonatal hypothyroidism. Both permanent and transitory neonatal hypothyroidism are more frequent in iodine deficient areas. The prevalence of raised serum TSH concentration in newborn infants is normally 1/3000-1/4000 but in areas of severe iodine deficiency it may rise to 1/10 or more as shown, for instance, in studies from India (30) and Sicily (31). A European multicentre study on newborn populations found a clearcut inverse relation between the urinary excretion of iodine and neonatal hypothyroidism (32). Transient hypothyroidism is seven times more frequent in Europe than in the USA because of the presence in Europe of areas with mild or borderline iodine deficiency (32).
369
Global Distribution of Iodine Deficiency Disorders Endemic goitre and IDD are substantial world wide problems. A WHO report estimated that in Asia, Africa and Latin America, where the major endemic areas are situated, 800 million people are at risk of IDD, 190 millions have them, over 3 millions people suffer from cretinism and several million suffer from mental and neurological defects (26). Thus about 15 YOof the worlds population is at risk of and 4 to 5 YO suffer from IDD. Developing countries are most affected, and in these regions the population grows rapidly, creating problems over keeping prophylactic measures abreast with this growth. Endemic goitre occurs in all parts of the world not just in hilly regions; some lowlands are also iodine deficient (18, 26, 33). In Latin America iodine prophylaxis has been effective in Mexico, Guatemala and Colombia and also in parts of Chile, Brazil and Argentina. Even so, large areas still remain with a high prevalence of endemic goitre, especially in Equador, Peru and Bolivia. In Guatemala the initially very good response to iodine prophylaxis has lately suffered a setback owing to political unrest; consequently the prevalence of goitre is again rising. Some countries still do not use iodine prophylaxis and there are some mountainous and jungle areas where iodine prophylaxis has not been practicable. Cameroon, Zaire, Zambia, Tanzania and western Sudan are the most affected areas in Africa, with prevalences up to 70 to 80% and a high rate of cretinism. The introduction of iodine prophylaxis has been greatly delayed. Goitre is also common in the Middle East, but the political position has prevented any kind of prophylactic measures being introduced. The most notorious areas in Asia, with goitre prevalences up to 70 to 80 ‘10 and cretinism, are the countries along the Himalayan mountains: Pakistan, India, Nepal, and Bhutan; but in Indonesia and China goitre and cretinism also has a high prevalence. Europe has customarily been classified as a fairly goitre free region, but a recent survey initiated by the European Thyroid Association showed that this is not so (34). Only the Nordic countries, the British Isles and Belgium are free from endemic goitre. Iodine prophylaxis has been practised in Finland for about 30 years and endemic goitre has now disappeared in those parts of the population under 40 years of age (35, 36). An incidence of goitre ranging from 30 to 80 ‘10 is found in certain parts of the Mediterranean countries and in southern Germany; cretinism still occurs in certain communities in Spain (37) and Sicily (38).
Iodine Prophylaxis Iodine prophylaxis was tried as long ago as the early nineteenth century but iodine was given in doses that were too large, causing what we now call the “JodBasedow” syndrome and no further attempts at prevention were made. About 100 years later prophylaxis with iodized salt was introduced in the USA and Switzerland. Its general effectiveness has been documented in a recent compilation of epidemiological studies from 25 countries (5). Recent information from various parts of the world have shown similar results. In many countries io-
Lamberg
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370
dine prophylaxis with iodized salt was begun between 1920 and 1940. The problems related to iodine deficiency, cretinism and mental defects were well recognised by those working in the field. Health authorities did not always regard goitre as such an important problem and its complications were insufficiently recognised. Despite various resolutions by international organisations little progress had occurred internationally even by the seventies. So the International Council for Control of Iodine Deficiency Disorders, ICCIDD, was set up in 1986 to stimulate prophylactic measures, to increase existing efforts and to initiate new ideas. ICCIDD is closely linked with WHO and UNICEF. These efforts have provoked the initiation and surveillance of prophylactic programmes in the worst affected areas throughout the world (39). The introduction and fulfilment of iodine prophylaxis depends on a country's political will and decision working capabilities. Without efforts from governmental institutions and without legislation effective measures are in most instances not to be expected, although there are examples of effective prophylaxis based on voluntary activity (15,
10 mglkg
0
SCHOOLCHILDREN
YEARS 20-25 rnglkg
35). Prophylaxis with iodized salt is the oldest method of prevention and its efficacy depends on several factors (Table 3). The concentration of iodine in the salt should be adjusted according to the salt consumption in the area concerned so as to provide the required daily amount of iodine, at least 100-150 pg per day. During recent decades the consumption of table salt has fallen markedly in many industrial countries (5). In the USA it is now about 3 glday, in Finland it has fallen from 7-8 g/day to about 4 glday and in Switzerland from 12 to 6 glday. Salt consumption is, however, much higher in some countries, for instance, in some parts of India it amounts to 15-20 glday. The concentration of iodine varies in different countries. In Europe it has usually been 10-20 mg of iodine/kg whereas in Latin America it has ranged from 30-100 mglkg. The duration of prophylaxis in another relevant factor. The presence of goitrogenic factors in the food or in the environment increases the demand for iodine but the effects of some goitrogenic agents are not prevented by iodine supplementation. Potassium iodide, KI, has been customarily added to salt, but potassium iodate, KIO,, is more stable (40). The iodized compound is heavier than sodium chloride and falls to the bottom of the bags during storage. Many practical problems are related to production methods and to the quality of the salt, the method of iodization and the storage and distribution of salt to the populace (40). After iodine prophylaxis has been started the first diseases to disappear are cretinism and neonatal defects; these improvement will occur even with low iodine concentrations in the salt. The newborn infants thyroid gland shrinks, a change occurring even if prevention is started
Table 3. Factors influencing the efficacy of iodized salt Iodine concentration in the salt Amount of iodine required (100-150 pg/day) Duration of prophylaxis Handling and distribution of salt Individual food habits Goitrogenic factors Lamberg (5)
POPULATION
60
.
o POPULATION SCHOOLCHILDREN
t\ \
40
20
0
5
10
16
20
26
30
YEARS
Figuresla and lb. Prevalence of goitre before and after introduction of iodized salt. Data from Switzerland (CH) (upper part) were obtained when iodine concentration was still 5 mg Kl/kg salt The figures show urinary excretion of iodine in pg/day, asterisk indicates pg l/g creatinine. Each curve represents a separate sample and does not indicate the general trend in the different countries. Po = Poland, Yu = Yugoslavia. Hu = Hungary, Br = Brazil, Ch = China, In = India, Por = Portugal, Me = Mexico, Bu = Bulgaria, 60 = Bohemia and Moravia, Slo = Slovakia, SF = Finland (during the 20 to 30 years period an important proportion of the iodine was derived from milk and milk products) (Lamberg, ref. 5 )
during pregnancy (41). In children the thyroid diminishes in size and the nodules disappear. The effect on the prevalence of goitre is seen in Figures 1a and 1b (5), but it takes many decades before the effects are visible in the whole population (36, 42). Experiences from Finland show that toxic nodular goitre previously the predominant type of hyperthyroidism has markedly regressed in parallell with the disappearance of the endemic goitre (15, 43). Concomitantly, there are changes in the biochemical parameters of thyroid function: the uptake of radioactive iodine by the thyroid and the TJT, ratio falls and concentrations of serum TSH, if initially raised, will decline (35).
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Endemic Goitre - Iodine Deficiency Disorders Since prophylactic iodized salt cannot be effectively introduced in all regions other solutions have been introduced. Injection of lodized oil is the most important alternative method and is used in many areas where goitre is endemic (16, 4 4 , 45). lodized oil may also be given by mouth. The effect is fast and clearly seen in the prompt disappearance of cretinism and neonatal hypothyroidism. There is also a rapid regression of the prevalence of goitre in newborn and young children (46, 47). Concomitantly biochemical abnormalities return to normal. The effect lasts for one to two years, depending on the severity of iodine deficiency and the loss of the benefits is evident by an increase in the prevalence of goitres. The treatment (injection of 480-960 mg of iodine in adults) should be repeated at one to two year intervals. The most important target groups are women in the childbearing age (including pregnant women), children and young adults (45). In a few areas tap water (38, 48) and bread (44) have been iodized. In smaller populations iodine can be administered in any form for example, potassium iodide or Lugols solution. In endemic areas farm animals also suffer from iodine deficiency, which, for instance, reduces milk production in cows (49). Effective iodine prophylaxis for farm animals will inturn increase the iodine intake by the human population through milk, dairy products and eggs. This is so, for instance, in Finland, where the present daily intake of iodine is about 300 pglday (35,50) of which about two thirds is derived from these products and less than one third from iodized salt (50). A temporary rise in the incidence of hyperthyroidism may occur during the first years after the introduction of iodine prophylaxis (5, 18). This is partly owing to the increased iodine supply for hormone synthesis in autonomous nodules or in patients with latent or subclinical Graves's disease. But the possible stimulation of autoimmune processes by increased iodine intake has been recently suggested as a contributory factor (51). Hyperthyroidism is not a big problem today even in elderly people, particularily when compared to the health problems caused by IDD. Recently, the possible role that increased iodine intake may have on the initiation of autoimmune thyroiditis has been questioned (52, 53). This is, however, unresolved and requires further studies. Another question is whether the large amount of iodine provided to mothers through iodized oil may have some adverse effects on their offspring despite its obvious advantages in eliminating cretinism and antenatal deformities.
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