Iodine Deficiency Disorders

Introduction

Iodine is required for the synthesis of thyroid hormones which in turn are needed for the regulation of metabolic activities of all cells throughout the life cycle. They are also required to ensure normal growth, especially of the brain, which occurs from foetal life to the end of the third postnatal year. Consequently, if severe enough, iodine deficiency will impair thyroid function, resulting in a lower metabolic rate, growth retardation and brain damage. The long-term consequence is irreversible mental retardation.

Iodine deficiency is the most prevalent cause of preventable mental retardation in the world (reviewed by Delange, 1994).

Reconceptualizing the Problem

Up to the early 1980s, goitre was considered the single and almost exclusively cosmetic consequence of iodine deficiency. Endemic goitre was seen as an exotic disorder affecting populations in developing countries especially those living in isolated subsistence economies. The concept was then developed by Dr Basil Hetzel and others that goitre was only the tip of the iceberg and that the consequences of iodine deficiency were much broader, including physical and mental retardation, increased perinatal mortality and other defects. From about 1983, these various effects have been grouped and referred to as iodine deficiency disorders or IDD (Hetzel, 1983). To date, IDD is still poorly recognized by the medical profession in many countries and is given short shrift in some of the major textbooks on paediatric nutrition.

Due to the coordinated efforts of a series of international organizations, including the International Council for Control of Iodine Deficiency Disorders (ICCIDD), the importance of IDD is now better recognized internationally. The sustainable elimination of IDD by the year 2000 was accepted as one of the priorities in the field of nutrition by the WHO and UNICEF in 1990, and was further endorsed by the World Summit for Children the same year.

Knowledge of the impact of iodine deficiency on intellectual development and the resulting costs to societies, including delayed socio-economic development, has played a significant role in mobilizing scientists, public health administrations and political leaders the world over to deal effectively with IDD (Pandav, 1996).

Changes in approach

Up to the early 1960s, the correction of IDD was almost exclusively focused on the administration of iodine in the form of solutions of potassium iodide or Lugol's solution. In spite of several effective salt iodization programmes in the United States and in Switzerland in the early 1920s, large preventive programmes were virtually untried in the developing world. Pilot studies using iodized oil as a source of long-lasting iodine supplementation at a population level were implemented in New Guinea in the early 1950s (McCullagh, 1963).

These were followed by campaigns offering iodized oil by the intramuscular route in several countries, including Ecuador, India, Nepal, Peru and the former Zaire. These campaigns resulted in a spectacular regression of goitre for periods up to ten years after one single injection. This approach also prevented the occurrence of endemic cretinism and endemic mental retardation (Dunn, 1987, p. 127). The efficacy and safety of iodized oil used during pregnancy in the prevention of endemic goitre and cretinism have been established (Delange, 1996).

In the late 1970s, concern emerged about disease transmission through the use of syringes for intramuscular injection of iodized oil. This was mostly in connection with the AIDS epidemic. Oral iodized oil was tried and its efficacy established, but, the period of protection was observed to be much shorter. At the same time, it was felt that the use of iodized oil (by either route) was not ideal for the long term because it required use of medical personnel and depended on access to individuals and communities.

The long-term solution for the sustainable elimination of iodine deficiency would more likely take place through increasing the iodine content of the general food supply. Although there had been iodization trials using drinking water, bread and sweets, the most promising vehicle was clearly common table salt. By 1991 universal salt iodization, i.e., all salt for human and animal consumption, was identified as the preferred means of reaching populations, including those consuming salt produced by small-scale artisanal saltworks. Thus the focus shifted from treatment of cases to working with the salt industry to upgrade technologies and management. The application of salt iodization technology to developing country settings has progressed enormously during the past five years. Comprehensive technical guides are available (Sullivan et al., 1995; Mannar and Dunn, 1995).

Iodine dietary requirements

Current recommendations made by WHO for dietary intake of iodine are shown in Table 5. These are slightly higher for three vulnerable groups (young infants, pregnant and breastfeeding women) than previous recommendations made by the National Academy of Sciences in the USA (NAS, 1989). This change was based on new information from iodine balance studies in infants. Delange (1993) has since recommended intakes of 90 mg iodine per day from birth to six years of age. This recommendation has now entered paediatric practice in a number of countries in both western and eastern Europe. This recommended level covers the needs of all infants, including pre-term infants.

Indicators

The indicators recommended by the involved agencies for assessing iodine deficiency and for defining degrees of severity are shown in Table 6. The selection of these criteria, made by an expert group convened in late 1992, was based on technical feasibility, cost and performance. They are purposely oriented towards public health action in the field and are not intended to cover the needs of an individual clinically affected by IDD.

The prevalence of goitre gives an idea of the past history of iodine nutrition at the population level. Palpation is the simplest method for measuring thyroid size. However, palpation becomes imprecise as the majority of goitres in a population diminish in size, i.e., following implementation of a national salt iodization scheme. In this case measurement of thyroid volume is more accurately performed by ultrasound. Portable ultrasound machines are available. Much of the recent IDD assessment work done in Europe was accomplished by ultrasonography transported across countries and borders by van (Delange et al., 1997). New normative values for thyroid volume in school-age children for assessment of IDD in populations were derived from this work. They were recently endorsed by WHO and ICCIDD (Table 7). These new norms are based on pooled samples of iodine-replete schoolchildren living in Europe and are applicable the world over.

Table 5: Recommended Dietary Intakes of Iodine for Populations

Age range/state	Intake mg/d (WHO, 1996)	RDA mg/d (NAS, 1989)
0-12 months	50	0-6 mths 40 6-12 mths 50
1-6 years	90	1-6 yr 70-90
7-12 years	120	7-10 yr 120
12 years to (and through) adulthood	150	150
Pregnancy	200	175
Lactation	200	200

Source: WHO (1996b, p.62) and NAS (1969, p.213)

Table 6: IDD Prevalence Indicators and Criteria fora Public Health Problem

Variable	Normal	Mild IDD	Moderate IDD	Severe IDD
Prevalence of goitre In school-age children (SAC) (%)	< 5	5-19.9	20-29.9	³ 30
Frequency of thyroid volume In SAC >97th centile by ultrasound (%)	< 5	5-19.9	20-29.9	³ 30
Median urinary Iodine In SAC and adults (mg/L)	100-200	50-99	20-49	< 20
Frequency of neonatal TSH >5 mU/L whole blood (%)	< 3	3-19.9	20-39.9	³ 40

Source: WHO/UNICEF/ICCIDD (1994, p. 28)

Table 7: Upper Limit of Normal Thyroid Volume Measured by Ultrasonography in Iodine-replete Children aged 6-15 years as a Function of Sex and Age

Age (years)	Thyroid volume - Upper limit of normal (ml)
	Boys	Girls
6	5.4	5.0
7	5.7	5.9
8	6.1	6.9
9	6.8	8.0
10	7.8	9.2
11	9.0	10.4
12	10.4	11.7
13	12.0	13.1
14	13.9	14.6
15	16.0	16.1

Source: Delange, F. et al. (1997) and WHO/ICCIDD (1997)

Urinary iodine measures current dietary intake of iodine. The frequency distribution of urinary iodine concentrations is usually skewed towards elevated values. Population status is better expressed by the median (50th per-centile) obtained from 50 to 100 casual urine samples. Twenty-four-hour urine collection is not necessary. Urinary iodine: creatine ratio need no longer be used as it does not provide additional information and is very labour-intensive.

Neonatal thyroid stimulating hormone (TSH) assesses saturation of brain cell receptors and consequently measures the supply of thyroid hormones to the developing brain. Elevated neonatal TSH is therefore the only indicator which allows prediction of possible impairment of mental development. National screening programmes for congenital hypothyroidism, most usually based on the detection of elevated TSH, are in place in all industrialized countries. Evidence of elevated neonatal TSH has also been used to generate information on the extent of IDD in crowded urban slums in developing countries for advocacy purposes (Nordenberg et al., 1993).

Magnitude

The first evaluation of the magnitude of goitre on a world scale was published by WHO in 1960 (Kelly and Snedden, 1960, p 28). The total was reported to be "not far short of 200 million". This figure is an obvious underestimation because a number of countries were not surveyed. Also, the only indicator used was goitre by palpation which can underestimate both the true prevalence of goitre and the importance of iodine deficiency.

Estimates of populations affected by IDD about the time of the World Summit for Children were around 600 million people (WHO, 1990). It was not until 1994 that IDD, and not only goitre, was assessed country by country and for all regions. This new work applied the concept of risk of IDD, defined as 'living in areas with iodine deficiency and a total goitre rate above five per cent'.

By applying this criterion (and lowering the goitre rate cutoff from ten to five per cent), IDD was found to be a significant public health problem in 118 countries, affecting 1572 million people worldwide. This was higher than all previous estimates. In addition, some 655 million were affected by goitre, that is, 12% of the global population. This survey also yielded key information which provided the main motivation to eliminate IDD as a public health problem: some 11.2 million humans were affected by overt endemic cretinism and another 43 million people were affected by some degree of mental impairment (WHO/UNICEF/ICCIDD, 1993, p. 5).

Trends in Salt Iodization Rates since 1992

Rates of salt iodization in all regions have increased significantly since publication of the Second Report in 1992. These trends have been documented by the series of Progress of Nations reports put out by UNICEF, as well as periodic reports by WHO. In 1994, UNICEF helped to draw considerable media attention to the reporting of salt iodization rates by ranking countries according to efforts made to iodize salt. At that time 12 of the most seriously affected countries had household rates ranging from zero to 95% (UNICEF, 1994, p. 9).

In 1996, WHO reported on salt iodization rates for those countries with a population over one million and where IDD was recognized to be a public health problem, or where IDD would be a public health problem if salt iodization programmes ceased (WHO, 1996a).

Nineteen countries for which information was available were iodizing more than 90% of all salt produced for human consumption. A further 15 countries were iodizing more than 70% of their salt. Thus more than one half (57%) of the population of surveyed countries (some 2500 million) were obtaining iodine through consumption of iodized salt. In many of the remaining countries surveyed, the infrastructure to produce iodized salt had already been established and the proportion of salt iodized was judged likely to reach or exceed 90% by the year 2000. For this to occur, awareness of the importance of the problem and its cost-effective solution, as well as appropriate national and international political choice, would need to be maintained.

Some countries with an IDD public health problem which were unable to fully implement universal salt iodization (USI) were using iodized oil as a temporary measure.

Thirty-eight countries reported using iodized oil supplements, up from 21 countries in 1992. WHO stated however that 'no country has yet been identified in which universal salt iodization has been demonstrated to be impossible or less cost-effective than any feasible alternative' (WHO, 1996a).

During 1995 and 1996, UNICEF conducted household surveys on the use of iodized salt as part of their cluster surveys designed to evaluate progress towards the Summit goals. UNICEF reported towards the end of 1996 that 27 countries had reached the goal of 90% iodization (UNICEF, 1996, p. 20). A further 15 countries reported between 75% and 90% of household salt was iodized. Forty-eight developing countries with IDD which had no significant salt iodization programmes in 1994 now iodized more than half of their salt. Nigeria, with the largest population in Africa, reported reaching 97% salt iodization. The Democratic Republic of the Congo (formerly Zaire), where severe iodine deficiency has been documented for many decades, was reported to have access to iodized salt.

An updated report on salt iodization produced by UNICEF in 1997 summarized further impressive progress (UNICEF, 1997). This report provided more examples of very poor countries with historically severe IDD reaching significant national objectives. For example, Laos and Nepal reported iodization rates of more than 75%. All countries in South Asia and South-East Asia, including China, have national iodization schemes in place. Progress has also been impressive in Sub-Saharan Africa where all but four countries have implemented salt iodization programmes. While iodization rates tend to be lower in Sub-Saharan African, with only 11 of the 40 countries in this region reporting more than 75% of salt adequately iodized, progress continues to be made and momentum is high.

Progress has been dramatic in Central and South America, which have historically had very high prevalences of IDD. Half of the countries in this region iodize more than 90% of their salt. This can be attributed in part to longstanding and effective legislation. In 20 countries in this region, more than 90% of salt is iodized and in an additional 14 countries the rate is between 75% and 90%. There are still some countries in other regions where special efforts need to be made, including Afghanistan, Azerbaijan, Estonia, Kyrgyzstan, Latvia and Lithuania, where special efforts need to be exerted to set up effective programmes.

In summary, the implementation of universal salt iodization on a worldwide basis is a remarkable achievement that will have lasting effects on the lives of many millions of people. IDD elimination could, in due course, be named the most spectacular public health success of this century. It bears repeating, however, that the management systems put in place so far are fragile. They are extremely vulnerable to a range of both national or international factors that could easily interupt the supply of adequately iodized salt to families and communities. Vigilance, care and good monitoring (discussed below) are needed well into the future.

Table 8: Proportion of total population at risk of IDD by region in 1994 and 1997

WHO Region	% Population at risk of IDD
	1994	1997
Africa	32.8	23.4
Americas	23.1	6.6
Eastern Mediterranean	42.6	30.3
Europe	16.7	10.7
South-East Asia	35.9	14.4
Western Pacific	27.2	9.8
Total	28.9	13.7

Source: WHO/UNICEF/ICCIDD (1994) and WHO (1997a)

Trends in the Prevalence of Goitre and Urinary Iodine

The decline in the proportion of the global population at risk of IDD following implementation of universal salt iodization is shown in Table 8. Between 1994 and 1997 this figure decreased from 28.9% to 13.7%, a reduction of over one half. Further progress may be especially challenging because of limited access to populations not yet reached.

Table 9: Impact of Salt Iodization on Goitre Prevalence and Urinary Iodine over a Nine-Year Period in Peru

Variables			1986	1995
Iodized salt
	Production (30-40 ppm) (% needs)		56	112
	Consumption at household (%)		20	81
	Iodine level at household (%)
		0 ppm	32	3.2
		> 20 ppm	36	75
Follow up of clusters of SAC
	(Sierra + Silva)
	Population at risk (M)		6	1.2
	Urinary Iodine (mg/L)		70	139
	TGR (median %)		47.7	10.8

Source: ICCIDD (1996a)

Table 10: Impact of Salt Iodization on Goitre Prevalence and Urinary Iodine over a Nine-Year Period in Cameroon

Variables			1990	1991	1992	1993	1994	May 1995	November 1995
Iodized Salt
	Iodine level at household (%)			USI
		0 ppm			33.5	21.2	13.7	8.5	9.6
		> 50 ppm			13.8	49.3	71.5	85.2	60.8
Follow up of a cluster of SAC
	Urinary Iodine (mg/L)		67			68			104
	TGR (%)		64.2			38.9		16.8	21.1

Source: From Lantum and Delange (unpublished)

Table 11: Impact of Salt Iodization on Goitre Prevalence and Urinary Iodine over a Nine-Year Period in Bhutan

Variables			1985	1996
Iodized Salt
	Production (60 ppm) % needs		0	> 100
	Iodine level at household (%)
		0 ppm	100	0
		> 15-20 ppm	0	82
Follow up of clusters of SAC
	Urinary Iodine		62% < 50 mg/L	76% > 100 mg/L
	TGR (%)		64.5	14

Source: Adapted from: Royal Government of Bhutan (1996)

The relationship between implementation of universal salt iodization and its biological impact at the population level has not yet been documented on a global basis using national data. This is being planned by the ACC/SCN for the Fourth Report. The relationship between rising iodization rates and median urinary iodine (or goitre prevalence) is not necessarily a straightforward one, however, because of the nature of the indicators and the way survey data are collected. The rate of salt iodization can easily be established on a national basis if the number of production or importation sites is limited. Surveys to determine use of iodized salt in the household reflect better access at the family level. In contrast, surveys to determine goitre prevalence and urinary iodine are often performed at selected sites. Median urinary levels and goitre prevalence vary markedly from one region to another in the same country. In this case, national figures do not exist and statistical methods have not yet been developed to produce them with accuracy.

A number of country case studies are now available; three sets of results are presented in Tables 9 to 11. In each of these studies, longitudinal follow-up was organized in sentinel sites by national authorities. An evaluation was then carried out by nationals in partnership with an international team, including senior members of ICCIDD.

In Bhutan, Cameroon and Peru, the increase in availability and consumption of adequately iodized salt at the household level was accompanied by an almost complete normalization of urinary iodine levels and a dramatic reduction in the prevalence of goitre. In Peru, within a period of nine years, the population at risk of IDD decreased from 6 to 1.2 million (ICCIDD, 1996a).

Peru did not have endemic cretinism in the past, but its neighbour, Ecuador, had both endemic cretinism and mental retardation. Both these conditions are now prevented by the salt iodization programme. Both Cameroon and Bhutan had endemic cretinism in the past, up to ten per cent in Bhutan. These dramatic consequences of iodine deficiency are now also prevented in Bhutan.

Trends in the Prevention of Mental Retardation

The main effect of dietary iodine deficiency is on the developing brain. The prevalence of the most severe form of brain damage, i.e. endemic cretinism, can be as high as one to ten per cent of the total population. This was seen in the past in parts of Bhutan, Democratic Republic of the Congo and Ecuador before the introduction of control programmes (Delange, 1994). The incidence of neonatal hypothyroidism, one of the mechanisms involved in the pathogenesis of endemic cretinism, can be as high as ten per cent of neonates. This rate is around 1/4000 (0.025 per cent) in iodine replete populations. Endemic cretinism is prevented by the correction of iodine deficiency in populations especially before and during pregnancy.

Cretinism is an extreme form of brain damage resulting from iodine deficiency. Even in populations known to be at risk of IDD where there is no evident cretinism, there is a downward shift in the frequency distribution of IQ in schoolchildren. This has been documented in Italy and Spain (Stanbury, 1993). The Ministry of Health of Indonesia estimated that before its current preventive campaign, 140 million IQ points were lost each year due to iodine deficiency (ICCIDD, 1996). A meta-analysis has indicated that iodine deficiency reduced the average population cognitive capacity by 10% to 15% (Bleichrodt and Born, 1993).

It was estimated that, up to 1990, about 40 million infants - one-third of all babies born each year in the world - were at some risk of mental impairment due to inadequate iodine in the maternal diet. In 1997, because of the worldwide increase in the use of iodized salt, 12 million children were expected to be spared that risk. In addition, the number of babies born as cretins was expected to have dropped by more than half, from around 120,000 in 1990 to under 55,000 worldwide (UNICEF, 1997a, p. 54).

Further research into the impact of iodine deficiency on intellectual development in conditions of mild deficiency (such as exist in Europe) would be beneficial.

Programme Monitoring

The massive implementation of salt iodization described in this Report is a spectacular achievement, but is not sufficient to ensure the sustainable elimination of IDD. Once set up, a salt iodization scheme needs constant monitoring so that corrective actions can take place without delay. Quality control of iodized salt production and consumption as well as surveys of representative groups are the main tools of monitoring (Dunn, 1996). Clinical and biochemical evidence of adequate iodine intake, regression of goitre and prevention of mental retardation are also important aspects of programme monitoring. Indeed in a Resolution made during the 49^th World Health Assembly in 1996, WHO urged Member States to

'increase efforts for the sustainability of the elimination of IDD by continuing monitoring, training and technical support, including advice on appropriate health legislation, and social communication...'

Criteria for monitoring progress towards the goal of IDD elimination as a public health problem have been established by WHO/UNICEF/ICCIDD (1994, p.36). These criteria include both process and impact indicators: i.e., the proportion of households consuming effectively iodized salt should be above 90%, less than 20% of the population should have urinary iodine <50 mg/L and the prevalence of enlarged thyroids by palpation or ultrasound should be below five percent. A cut-off for neonatal TSH was also presented: 97% of newborns should be < 5 mU/L of whole blood.

Iodized salt The goal is to ensure that 90% of household salt is adequately iodized. The level of iodization required to provide 150 mg of iodine per day via iodized salt is influenced by several factors. These include average salt intake, degree of iodine deficiency in the region, and estimated iodine loss from producer to consumer. Consequently the level of iodization at the production site will vary from one country to another and has varied from five to 100 ppm. Current recommendations are contained in WHO/UNICEF/ICCIDD (1996). They are 20 to 40 ppm at the site of production in order to ensure a median concentration of iodine of 100 to 200 mg/L in the urine.

Regular quality control of iodine concentration in salt at the production site can be done by titration methods or, in the case of imported salt, at the border by using rapid test kits. Periodic monitoring of salt iodine levels in retail shops, schools and households should also be performed using rapid test kits. Recent survey work conducted in Africa has indicated a need to continually improve available test kits, even for qualitative assessment which determines simply the presence or absence of iodine.

The second criteria is urinary iodine. The value 100 mg/L, recommended as the minimal desirable population median, was chosen because 100 mg corresponds to the requirements for daily synthesis of thyroid hormones. It also corresponds to the level below which iodine stores in the thyroid start to decrease. Monitoring urinary iodine is the best way to assess current access of populations to iodine. Unfortunately, at the moment, this still requires the transfer of samples collected in the field to well-equipped laboratories. There is an urgent need for rapid field test kits for urinary iodine and some applied research is being undertaken.

The third criteria is thyroid size. The cut-off of five per cent was proposed considering that in iodine replete populations up to five per cent of the population may have abnormal thyroid enlargement due to factors other than iodine deficiency.

Neonatal TSH The cut-off of not more than three per cent of values >5 mU/L was selected because it corresponds to the frequency found in iodine replete areas, such as Australia where this has been extensively documented (reviewed by Delange 1997). One good example of the use of neonatal thyroid screening to monitor an IDD programme is in Poland. Before salt iodization in Poland, the frequency of neonatal TSH above the cut-off point was about 40%. The normal value is below three per cent. Implementation of salt iodization was followed by a rapid shift of neonatal TSH to tower values. Four years later, the frequency of abnormal neonatal TSH was only about ten per cent and continues to decline (Delange, 1997). Neonatal thyroid screening implies technology and cost. However, because of the extreme sensitivity of this indicator we are likely to see more developing countries implementing neonatal TSH to monitor IDD control programmes in the near future.

Iodine-Induced Hyperthyroidism The critical importance of monitoring was recently illustrated by cases of iodine-induced hyperthyroidism (IIH) in Zimbabwe and possibly the former Zaire (Todd et al., 1995; and Bourdoux et al., 1996). IIH is included in the spectrum of abnormalities which can result from iodine deficiency and its correction. It is a severe condition and can be fatal. In these two countries, IIH resulted from the sudden introduction of uncontrolled and excessively iodized salt. In Zimbabwe 14 deaths occurred. IIH is fortunately extremely rare and measures can be put in place to identify and appropriately treat cases. Furthermore, the occurrence of new cases spontaneously decreases after a couple of years. It classically affects old individuals with large nodular goitres. The conditions of maximum risk are long-standing severe iodine deficiency and massive and rapid introduction of excessively iodized salt.

Other Control Measures

Iodized oil As indicated earlier, this procedure was initially used in emergency in severely affected areas where salt iodization was not feasible. About 12 million closes of iodized oil have been administered worldwide since 1955. Spectacular results have been achieved in terms of prevention and correction of goitre and prevention of endemic goitre and endemic cretinism, especially when the iodine supplementation was administered before or during early gestation. There are anecdotal reports from women participating in these programmes of feeling better and stronger after receiving capsules of iodized oil. This is conceivable considering the extremely low values of serum levels of thyroid hormones before the introduction of an iodized oil programme in severely affected populations. Extremely rare side-effects have been noted (Stanbury, in press) and the cost is low, some five US cents per individual per year of protection.

Iodized oil will remain an important technology well into the future for some parts of some countries. Iodized oil may also be of great value in emergency settings when dramatic political events disrupt the supply of iodized salt. It will be of use, as well, in circumstances of severe relapse of IDD due to rapid socio-economic decline, for example in the former USSR.

Iodized water Drinking water can be iodized by release of iodine from elastomers or by dropping iodine into the community water supply. This method has been tried on a pilot basis in a number of countries including: Burkina Faso, Cambodia, Central African Republic, Chile, China, Malaysia, Mali, Mexico, Sudan and Thailand, as well as Sicily in Europe and the US. An evaluation of these trials was carried out by the ICCIDD in 1996 (ICCIDD, 1997). Results showed that, when properly monitored, water iodization is efficacious in controlling iodine deficiency. Side-effects such as IIH are rare, and are probably similar in frequency to other methods. It is generally more expensive than iodized salt in large-scale national programmes. Its main use will be for targeted populations where special circumstances make iodized water more cost-effective and quicker to implement. One limitation is that water iodization is unlikely to be sustainable in poor rural communities and thus may require continual external funding. Water iodization can frequently compare favourably with iodized oil in terms of cost.

Iodized bread Pilot studies in the iodization of bread were conducted, especially in Russia, and these appeared efficious (Gerasimov et al., 1997). However, iodization of bread is probably not effective on a large scale in many countries because of marked regional differences in bread intake.