Seaweed has been used to prevent goiter in China for centuries but it is only in the years 1910 to 1920 that systematic programs of salt fortification with iodine were introduced as a strategy for the elimination of IDD almost simultaneously in the United States (166) and in Switzerland (167).
Starting in the early 1950’s with pioneering studies in New Guinea (148, 149), supplementation with iodized oil was introduced in severely affected populations in Asia, Africa and Latin America. Initially, iodized oil was administered intramuscularly, more recently by the oral route. Follow-up studies of these programs are reported and summarized elsewhere (150, 151, 168). As indicated earlier in this chapter, iodized oil appeared as a particularly effective procedure for the elimination of IDD : goiter prevalence decreased rapidly and thyroid function reverted to normal and remained normal up to 7 years after injection of iodized oil and for 1 to 2 years after oral administration. Key factors in this success were normalisation of the thyroid iodine stores and the level of iodisation of thyroglobulin, the determining factor in impairment of thyroid function. Endemic cretinism was prevented, both in its neurological and myxedematous forms provided that iodine deficiency was corrected before or during early pregnancy. As indicated earlier, mental development was markedly improved and the frequency of stillbirths and the perinatal mortality decreased while the birthweight increased. It has to be underlined that the presence of iron deficiency anemia limits the effectiveness of iodized oil administered orally (169).
In summary, the studies using iodized oil unquestionably demonstrated that correction of iodine deficiency greatly reduced or eliminated its consequences : brain damage, mental retardation, goiter, impaired thyroid function and perinatal morbidity.
These facts were subsequently much less clearly evident when correction of iodine deficiency occurred on a large scale using iodized salt (168), which is nevertheless the universally adopted strategy aiming at the sustainable elimination of IDD.
The justification, technology and organization of programs of universal salt iodization are described in Section V.
Following the World Summit for Children of 1990 and thanks to the joint efforts and action of the 130 countries with IDD and their governments, with the financial, technical and scientific supports of major agencies of the United Nations, namely UNICEF , WHO, the World Bank ; international NGOs such as ICCIDD and bilaterals ; private partnership for example Kiwanis International and the salt industry, tremendous progress has been achieved during the last decade in insuring access to iodized salt for iodine deficient populations (See also Section V).
Table 9 provides the information available at the turn of the century (168) on iodized salt coverage in IDD affected countries. In 1999, of the 130 countries having in the past iodine deficiency as a public health problem, nearly half provided access to iodized salt for more than 50 % of the households and 20 countries for more than 90 %. Sixty-eight percent of households of the 130 countries had access to iodized salt, compared to 5 to 10 % in 1990 (62). This constitutes a remarkable success in public health, probably unprecedented in the field of non-communicable diseases.
Table 9. Status regarding access of households to iodized salt as of 1999.
|
WHO region |
Number of IDD-affected countries |
Number of countries categorized by percent of households having access to iodized salt |
Percentage of households having access to iodized salt* |
||||
|---|---|---|---|---|---|---|---|
|
No data |
<10 % |
10-50 % |
51-90 % |
>90 % |
|||
|
*Total population of each country multiplied by the % of households having access to iodized salt. Number then totaled for each region and divided by the total regional population. From WHO/ UNICEF/ ICCIDD( 62). |
|||||||
|
Africa |
44 |
8 |
6 |
8 |
19 |
3 |
63 % |
|
Americas |
19 |
0 |
0 |
3 |
6 |
10 |
90 % |
|
South-East Asia |
9 |
0 |
1 |
2 |
5 |
1 |
70 % |
|
Eastern Mediterranean |
17 |
5 |
1 |
2 |
6 |
3 |
66 % |
|
Europe |
32 |
10 |
4 |
12 |
4 |
2 |
27 % |
|
Western Pacific |
9 |
0 |
1 |
4 |
3 |
1 |
76 % |
|
Total |
130 |
23 |
13 |
31 |
43 |
20 |
68 % |
However, these figures should be interpreted cautiously because they refer only to the amount of iodized salt available to households and not to its actual intake. In addition, these figures were reached frequently only by estimation on a theoretical basis from the amount of iodized salt imported or produced in an affected country, as reported by the salt industry, divided by the total population of the country and not by house to house surveys evaluating locally the real regular use of iodized salt by the families (168). When performed cautiously, as for example in South Africa (170), these house to house surveys occasionally evidenced that the access to iodized salt was the lowest in the lowest soci-economic class of the society which is precisely the fraction of the population the most severely affected by iodine deficiency.
In addition, it has to be considered that silent iodine prophylaxis resulting from socioeconomic development also increases the iodine intake, although three times slower than active prophylaxis, at least in Italy (170 bis).
Globally, a reevaluation of the current global iodine status in the world was performed in 2003 by WHO (62 bis), based on an estimation of the median urinary iodine (UI) in 92.1% of the school-age children aged 6-12 years in the 192 WHO’s Member States. It showed that 36.5% of them still had an insufficient iodine intake indicated by a median UI below
100 μg/l, ranging from 10.1% of the WHO region of the Americas to 59.9% in the European region. Extrapolating this prevalence to the general population generated an estimate of nearly two billion individuals with insufficient iodine intake. Only 43 countries reached optimal iodine nutrition (UI of 100-200 μg/l). The number of countries in which iodine deficiency was a public health problem decreased from 110 in 1993 to 54 in 2003.
It was concluded that there has been substantial progress in the last decade towards the elimination of iodine deficiency but that continued efforts are needed and salt iodization programs need to be strengthened and monitored in order to reach the goal of eliminating IDD.
The social process for successful implementation a national IDD control program includes the following components (see Section II) : situation assessment ; communication of results to health professionals, political authorities and the public ; development of an action plan ; implementation of the plan; and finally, evaluation of its impact at population level. This last phase, monitoring, is often neglected not only because it is the last phase in the process but because it may be over shadowed by other components of the program such as implementation, which is considered as the main or occasionally even the single component to be considered. In addition, many countries affected by IDD belong to the group of countries with low income that therefore do not have the financial or technical resources for the laboratory facilities necessary to proper monitoring of salt quality and iodine status. And yet, monitoring is crucial because IDD is a disease and its prevention and therapy require trained professionals to prescribe the therapy and verify its effects. This absolute ethical duty applies equally to a single individual and to a global population.
As indicated earlier, the most cost-effective way to achieve the virtual elimination of IDD is throug Universal Salt Iodization, USI. Therefore, the indicators used in monitoring and evaluating IDD control programs include (2) :
1) Indicators to monitor and evaluate the salt iodization process (Process indicators) ;
2) Indicators to monitor the impact of salt iodization on the target populations (Impact indicators).
The process indicators are discussed in details in Chapter 6.
The impact indicators have been recently reevaluated and discussed (2). They are described in details in Chapter 6. As indicated earlier, they include in order of priority the determinations of urinary iodine, of the prevalence of goiter and of the serum levels of TSH and thyroid hormones.
Table 10 summarizes the criteria for monitoring progress towards sustainable elimination of IDD as a public health problem (2). It is now considered that iodine deficiency has been eliminated from one particular country when the access to iodized salt at household level is at least 90 %, together with a median urinary iodine of at least 100 μg/L and with less than 20 % of the samples below 50 μg/L and, finally, when at least 8 of the 10 programme indicators listed in the table are implemented.
Table 10. Summary of criteria for monitoring progress towards sustainable elimination of IDD as a public health problem
|
Indicators |
Goals |
|---|---|
|
From WHO/UNICEF/ICCIDD (2). |
|
|
Salt Iodization Proportion of households using adequately iodized salt |
> 90 % |
|
Urinary iodine Proportion below 100 μg/L Proportion below 50 μg/L |
< 50 % < 20 % |
|
Programmatic indicators
|
|
Currently, we have much less information about the impact of the salt iodization programs on IDD than on the implementation of the programs themselves. The monitoring data of all countries affected by IDD with a program of iodine supplementation are summarized country per country on the websites of WHO ( http://www3.who.int/whosis/micronutrient)and of ICCIDD ( http://www.iccidd.org)
As assessed by measurements of urinary iodine, many countries have achieved the elimination of iodine deficiency, for example Algeria, Kenya, Cameroon, Tanzania (Africa), Iran, Lebanon, Tunisia (Eastern Mediterranean), Bhutan, China, Indonesia, India, Thailand (Asia), Venezuela, Peru, Ecuador (Latin America) and Switzerland, Austria, Great Britain, Finland, Norway, Sweden, Poland, Macedonia, Croatia, the Czech Republic, Slovakia and Bulgaria in Europe.
However, in spite of the tremendous improvement of the implementation of programs of iodized salt, still 35.2% of the general population in the world had a urinary iodine below 100μg per liter in 2003 (171) and the percentage of the world population affected by goiter has apparently not changed between 1990 (12 %) (4) and 1999 (13 %) (2). The situation is at least partly explained by the fact that the denominator of the fraction has changed during the last ten years : the figure for 1999 includes a number of countries from Central and Eastern Europe and from Africa which are often severely affected and that were not considered in the 1990 figure.
Also, surprisingly enough, few longitudinal or case control studies address the influence of USI on the other main disorders induced by iodine deficiency, such as impairment of thyroid function, low birth weight, perinatal mortality and morbidity and the prevention of mental retardation. The oft-quoted statement that correction of iodine deficiency protects 85 million neonates from brain damage and mental retardation annually is politically attractive but scientifically very questionable as it results simply from a multiplication of the birth rate of the affected countries by the percentage of access to iodized salt at household level. Both figures lack precision. Moreover, this calculation implies that 100 % of the neonates born in iodine deficient areas before the implementation of programs of iodine supplementation were mentally deficient, which is a gross over estimation.
Finally, partnership evaluation of country programs using for example the ThyroMobil model (168) indicated that in some countries, poorly monitored programs of salt iodization resulted in largely excessive iodine intake associated with risks of adverse health consequences such as iodine-induced hyperthyroidism, IIH.
As discussed so far in this chapter, iodine deficiency is associated with the development of thyroid function abnormalities. Similarly, iodine excess, including following overcorrection of a previous state of iodine deficiency, can also impair thyroid function. The effect of iodine on the thyroid gland is complex with a U shaped relation between iodine intake and risk of thyroid diseases as both low and high iodine intake are associated with an increased risk. It is stated that normal adults can tolerate up to about 1000 μg iodine/day without any side effects (172). However this upper limit of normal is much lower in a population which was exposed to iodine deficiency in the past. The optimal level of iodine intake to prevent any thyroid disease may be a relatively narrow range around the recommended daily intake at 150 μg (173).
The possible side effects of iodine excess are as follows :
When the iodine intake is chronically high, as for example in coastal areas of Japan (83) and China (84) due to the chronic intake of seaweeds rich in iodine such as laminaria or in Eastern China because of the high iodine content of the drinking water from shallow wells (84), the prevalence of thyroid enlargement and goiter is high as compared to normal populations and the prevalence of subclinical hypothyroidism is elevated. The mechanisms behind this impairment of thyroid function are probably both iodine enhancement of thyroid autoimmunity and reversible inhibition of thyroid function by excess iodine (Wolff-Chaikoff effect) in susceptible subjects (174). However, this type of thyroid failure has not been observed after correction of iodine deficiency, including in neonates after the administration of huge doses of iodized oil to their mothers during pregnancy (156). Increased thyroid volume in children due to iodine excess has been observed only when the median urinary iodine is above 500 μg/l (174 bis).
Iodine-induced hyperthyroidism (IIH) is the main complication of iodine prophylaxis. It has been reported in almost all iodine supplementation programs (175) but, as shown for example in Iran, is rare following a well executed program of iodine supplementation (175 bis). The outbreak most extensively investigated occurred in Tasmania in the late 1960’s following iodine supplementation simultaneously by tablets of iodide, iodized bread and the use of iodophors by the milk industry (176). The incidence of hyperthyroidism increased from 24 per 100 000 in 1963 to 125 per 100 000 in 1967. The disease occurred most frequently in individuals over 40 years of age with multinodular goiters and preexisting heart diseases. The most severe manifestations were cardiovascular and were occasionally lethal. The epidemic lasted from some 10 to 12 years and was followed by an incidence of hyperthyroidism somewhat below that existing prior to the epidemic.
The problem of IIH was recently reactivated when it was reported that the introduction of iodized salt in Zimbabwe resulted in a sharp increase in the incidence of IIH from 3/100 000 to 7/100 000 over 18 months (177). A high risk of IIH was also reported from Eastern Congo following the introduction of iodized salt (178). A multicentre study conducted in seven African countries, including Zimbabwe and Congo (179) showed that the occurrence of IIH in the last two countries was due to the sudden introduction of poorly monitored and excessively iodized salt in populations which had been severely iodine deficient for very long periods in the past. The conclusion of the multicentre study was that the risk of IIH is related to a rapid increment of iodine intake resulting in a state of acute iodine overload. As already mentioned, on the contrary, a high frequency of hyperthyroidism was not reported in populations which could adjust their thyroid function and regulation to a chronically high iodine intake.
IIH following iodine supplementation cannot be entirely avoided even when supplementation uses only physiological amounts of iodine. In a well controlled longitudinal study in Switzerland the incidence of hyperthyroidism increased by 27 % during the year after the iodine supply was increased from 90 μg/day to the recommended value of 150 μg/day (180).
Contrasting with these different reports, IIH was not reported in Iran : a single intramuscular injection of 1 ml iodized oil containing 480 mg iodine to 3420 patients with simple goiter in an area with moderate iodine deficiency (mean urinary iodine : 35.8 g/l), followed by a clinical and laboratory evaluation every 3 months for one year and every 6 months for the next 4 years revealed an incidence of hyperthyroidism of 0.6 %, mostly during the first 5 months after the injection. The figure is close to the ratio observed in spontaneous thyrotoxicosis in this population (0.4 %) (181). Similarly, a clinical and biochemical three-year survey of the effects of iodized oil injection in all 198 schoolchildren of the Kiga village in a mountainous region of Iran where the prevalence of visible goiters was 93 % and the mean urinary iodine was 11.4 μg/g creatinine before intervention did not reveal any case of iodine-induced hyperthyroidism. Rather, serum T4 increased from 5.0 to 9.5 μg/dl, TSH and Tg decreased from 20.3 to 2.2 mU/L and from 132 to 23 ng/ml respectively (182) and the prevalence of goiter decreased substantially.
Similarly reinsuring results were obtained during a long term biochemical monitoring after oral administration of iodized oil to severe iodine deficient schoolchildren in Romania (183).
The reason for the development of iodine-induced hyperthyroidism after iodine supplementation has now been identified (184) : iodine deficiency increases thyrocytes proliferation and mutation rates which, in turn, trigger the development of multifocal autonomous growth with scattered cell clones harbouring activation mutations of the TSH receptors. Measurement of total intrathyroidal iodine by means of X-rays fluorescence scanning showed that only some nodules keep their capacity to store iodine, become autonomous and can result in hyperthyroidism after iodine supplementation (185).
It thus appears that IIH is one of the Iodine Deficiency Disorders. It appears to be largely unavoidable in the early phase of iodine supplementation. It affects principally the elderly with longlasting autonomous nodules. Its incidence reverts to normal or even below normal after one to ten years of iodine supplementation.
Another possibility is the aggravation or even the induction of autoimmune thyroiditis by iodine supplementation. In experimental conditions, excessive iodine intake can precipitate spontaneous thyroiditis in genetically predisposed strains of beagles, rats or chickens (see review in ref. 186). The mechanism involved in iodine-induced thyroiditis in animal models could be that elevated dietary iodine triggers thyroid autoimmune reactivity by increasing the immunogenecity of thyroglobulin or by inducing damage of the thyroid and cell injury by free radicals.
Attention was drawn to the possibility of iodine-induced thyroiditis in humans when studies conducted in the United States following the implementation of salt iodization showed an increased frequency of Hashimoto’s thyroiditis seen in goiters removed by surgery (187).
Later on, studies following the introduction of iodized oil in Greece pointed out the possible development of thyroid autoantibodies (188). More recently, Kahaly et al. (189) reported the development of thyroid autoantibodies in 6 out of 31 patients with endemic goiter treated during 6 months with a supra physiological dose of 500 μg potassium iodide (KI) per day. The development of lymphocytic infiltration in the thyroids was reported. Finally, cross sectional studies of populations with different degrees of iodine supply performed in Italy (51), Great Britain (52) and more recently in Denmark and Iceland (53) showed that the frequency of thyroid autoantibodies and hypothyroidism is higher in iodine replete populations than in iodine deficient populations. Similarly, generally speaking, it is recognized that the frequency of thyroid antibodies (190) and of autoimmune thyroiditis (191) is higher in the United States than in Europe while the iodine intake is lower in Europe.
Acute massive iodine overload (daily consumption of at least 50 mg iodine daily) in healthy American workers resulted on a sharp increase in the level of thyroid peroxidase antibody values together with elevated prevalence of goiter and serum TSH values. The prevalence of all abnormalities decreased after removal of iodine excess (192).
However, to the best of our knowledge, although cross sectional studies associated endemic goiter and the presence of thyroid autoantibodies for example in Sri Lanka (193) no large epidemiological metabolic or clinical surveys have been performed which have analyzed the impact of large scale programs of iodine supplementation on the occurrence of clinically significant iodine-induced thyroiditis with public health consequences on thyroid function. The longterm prospective study presently organized in Denmark (194) could provide an adequate answer to the question as to whether correction of iodine deficiency results in clinically significant development of thyroid autoantibodies and thyroid failure.
The mechanisms possibly involved in the role of iodine in thyroid autoimmunity include the damage to the thyroid by the generation of free radicals, a direct injury to the thyrocytes through the strong necrotic effect of iodide and an enhancement of autoimmunogenic properties of thyroglobulin (191).
In conclusion (195, 196), the fear for auto-immune thyroid disorders must not be a limitation to iodine prophylaxis as long as the amount of iodine supplementation is reasonable.
In animals, the chronic stimulation of the thyroid by TSH is known to produce thyroid neoplasms (197). However, the relationship between thyroid cancer and endemic goiter has often been debated without agreement being reached on many aspects, including on a possible causal relationship (198-202).
Iodine supplementation is accompanied by a change in the epidemiological pattern of thyroid cancer with an increased prevalence of occult papillary cancer discovered at autopsy (201, 202). Therefore, the prognosis of thyroid cancer is significantly improved following iodine supplementation due to a shift towards differentiated forms of thyroid cancer that are diagnosed at earlier stages.
Moreover, careful monitoring of the incidence of thyroid cancer in Switzerland following iodine supplementation showed that the incidence of thyroid cancers steadily decreased from 2 to 3 per 100 000 in 1950 to 1 to 2 per 100 000 in 1988, i.e. during a period when iodine intake increased and reached an optimal value (203).
Finally, fine-needle aspiration biopsies were performed in Poland between 1985 and 1999 in 3,572 patients treated by thyroidectomy and were compared to the results of postoperative histopathological examinations. The particular interest of that study is that Poland used to be an endemic goiter area and that iodine deficiency was progressively corrected during the study period 1985-1999. The frequency of neoplastic lesions significantly decreased throughout the examined period and the ratio of the papillary/follicular carcinomas increased. However, the frequency of cytologically diagnosed chronic thyroiditis increased from 1.5 to 5.7 % (204).
Overall, it appears that correction of iodine deficiency decreases the risk of, and the morbidity from, thyroid cancer.
In conclusion, it appears that the benefits of correcting iodine deficiency far outweigh its risks (186, 205, 206). Iodine-induced hyperthyroidism and other adverse effects can be almost entirely avoided by adequate and sustained quality assurance and monitoring of iodine supplementation which should also confirm adequate iodine intake.
The progress towards correction of iodine deficiency globally in the past decade is a public health success unprecedented with a non infectious disease and the sustainable elimination of this public scourge is within reach.