Iodine Deficiency, Still a Global Problem?

Iodine Deficiency Disorders are a major public health problem worldwide affecting all groups of people of which children and lactating women are the most vulnerable categories. At a global scale, aproximately 2 billion people suffer of iodine deficiency (ID) of which aproximately 50 million present with clinical manifestations. Assesing iodine levels through different methods has proven to have a key role when discussing treatment options. Screening programs, and early ID diagnostic is important for pregnant women's follow-up, especially in known countries with iodine dificiency. Universal salt iodization programs have been proposed over the world, but unfortunately have covered about 71% of the world's population. The aim of this article is to adress the current standings of iodine status and influence on general population with a general focus on newborns and pregnant women and to review the worldwide perspective on available prevention methods.

Introduction

IDD is considered a major public health problem worldwide affecting all groups of people of which children and lactating women are the most vulnerable categories. At a global scale, aproximatey 2 billion people suffer of ID of which aproximately 50 million present with clinical manifestations [1]. ID in daily food intake may result in a inadequate secretion of thyroid hormones, with major clinical consequences, especially neurological findings [2]. Although it may affect any age, ID consequences may appear from the foetus stage, due to an insufficient iod food intake in the mother’s diet. Thus, the most vulnerable age period is no doubt the womb as well as the natal stage, when differentiation, growth and brain development may be influenced by the inadequate quantities of Iodine and by the thyroid hormones with general consequences related to ireversible neurological disorders and mental retardation [3,4].

Assesing iodine levels through different methods has proven to have a key role when discussing treatment options. Screening programs, and early ID diagnostic is important for pregnant women’s follow-up, especially in known countries with iodine dificiency. Universal salt iodization programs have been proposed over the world, even though have successfully covered only 71% of the population [5,6].

The aim of this article is to adress the current standings of iodine status and influence on general population with a general focus on newborns and pregnant women and to review the worldwide perspective on available prevention methods.

What is Iodine Deficiency and what is its influence in pregnant women and newborns?

According to World Health Organization (WHO), the International Council for Control of Iodine Deficiency Disorders (ICCIDD) and the United Nations Children’s Fund (UNICEF), a median urinary iodine concentration (UIC) below 100μg/l for nonpregnant woman and children defines an iodine deficient population, while the normal values for pregnant women should be between 150-249μg/l) [7]. To put it in other words, both pregnant and lactating women have increased needs of iodine and therefore, numerous studies were conducted to see in which way the metabolism of the iodine is altered during pregnancy.

First of all, the renal loss of iodine is more significant in pregnant women presumably because of the fact that pregnancy is associated with an increase in renal function which is suggested by the mid-pregnancy 75% high renal plasma flow and from the late first trimester 50% higher glomerular filtration rate until the woman gives birth [8].

Changes occur in the thyroid gland as well, including a 50 % higher thyroid absolute iodine uptake (AIU), which is related to almost 50% increase of hormone production in the first preganancy trimester [9]. Even from the early beginning of a pregnancy, human chorionic gonadotropin (hCG) can be detected at higher levels than usual. When hCG level raises it stimulates the thyroid gland to produce more thyroid hormones (thyroxine-T4 and triiodothyronine-T3). In addition, another effect of hCG is to reduce the activity of iodothyronine deiodinase type 3 in the utero-placenta unit, an enzyme whose role is to inactivate T4 and T3 [10,11]. Due to these facts, in early pregnancy, serum thyroid-stimulating hormone (TSH) has decreased levels, thus, a shift in the balance between serum rT3 and T3, in maternal circulation, may be noted.

To sum up, iodine levels during pregnancy may be caused by increased renal iodide clearance and increased thyroid hormone production to which we can add other factors such as the iodide transfered across the placenta to the fetus and a gradual 50% increase in protein-bound T4 and T3.

When and how ID affects the development of the newborn?

Pregnancy requires higher amounts of micronutrients and macronutrients than usual in order to maintain the health of both, mother and growing foetus. One of the most widespread micronutrient deficiencies worldwide is that of iodine. Iodine is a particularly important microelement in human physiology, required for normal physical growth during gestation and early life, and it is an essential component of the hormones produced by the thyroid gland whose absence or inadequate level can cause significant clinical manifestations such as increased risk of stillbirths, abortions, perinatal mortality, congenital abnormalities, cretinism, impaired growth [12,13,14,15,16,17].

Iodine deficiency disorders (IDD) generally refers to all the iodine deficiency effects in a population which may be prevented with a proper intake [18].

Brain development is a complex process that begins from early pregnancy and goes on for the first years of the newborn`s life. This is the reason why ID`s most serious consequences are the neurological ones [19,20]. Thyroid hormones are essential for a normal neurological development, being involved in myelination, cell differentiation and migration, growth, metabolism, sexual developement, body temperature [21].

During pregnancy and lactation, two periods of increased demands, the fetus and infants are not capable to produce their own thyroid hormones. Thus, an important contribution is brought by the placenta which provides a connection between maternal and fetal circulation and after birth an adequate iodine concentration in breastmilk (BMIC) is essential [22]. According to Vulsma et al. measureable T4 in cord serum was found in newborns who were not supposed to be able to synthesize thyroid hormones [23].

Many studies have correlated the the degree of ID with the thyroid functionality. The results showed that thyroid dysfunction may start to develop in pregnancy when urinary iodine excretion drops around 50μg/l.

It is well known that children born from mothers with severe ID during pregnancy have serious neurological disorders such as cretinism and mental retardation. Even more, the newborn may be characterized by a short stature, deafness and spasticity, all these clinical aspects being illustrative for the neurological cretinism [24]. Furthermore, Bath et al. [25] studied the connections between maternal iodine status and child IQ at the age of 8 and the ability to read at the age of 9. Thus, studies revealed the fact that the smallest quartile for verbal IQ, reading accuracy, and reading comprehension was more common in children of mothers with iodine to creatinine ratio below 150μg/g. Lower school performances have also been linked to mild ID [26].

The main clinical sign of ID in affected population is endemic goiter (EG) which represents thyroid`s manner to adapt to an inadequate intake of iodine. Hence, TRH will be stimulated, TSH will grow and the consequence of prolongued TRH is the development of goiter.

Even if goiter is considered the cardinal sign of ID, in children, the most serious consequences are observed in growth and development. Decrease in insulin-like growth factor 1 (IGF) and IGF binding protein 3 (IGFBP) concentrations are also often associated with ID [27,28].

Questions have been raised regarding the connection between autism spectrum disorder (ASD) and ID. Even though ASD is a pluriethiological pathology including environmental, genetic, social factors, some studies performed in Egypt showed that more than half of the children with ASD were iodine deficient and another study performed in US reavealed that autistic children had 45% lower iodine content in their hair than healthy children [29,30]. Also another Polish study aimed to asses boys iodine status with severe autism compared to their healthy peers and also to analyze the link between urinary iodine, thyroid hormones, body mass index and ASD symptomatology. Although some symptoms are connected to ID in maturing boys further investigation is needed in order to see if the iodine supplementation can reverse some clinical manifestations [31].

Moreover, the incidence of ID and its effects in children with a diagnosis of attention deficit/ hyperactivity disorder (ADHD) was investigated. A study including 89 children diagnosed with ADHD of whom 71.9% had mild iodine deficiency showed there was no significant relationship between urinary iodine levels with Wechsler intelligence scale for Children (WISC-R). However, subtest scores and Conners’parent rating scales (CPRS) revealed an association between urinary iodine levels and hyperactivity section of Conners` teacher rating scales (CTRS) [32].

Excessive iodine intake

ID interferes with the normal thyroid function, but an iodine excess that comes as a correction of a previous ID, as a higher intake than normal, can also affect the gland’s proper function, leading to an autoimmune disease, goiter, hypothyroidism, iodine-induced thyrotoxicosis or thyroid cancer. Healthy adults can tolerate iodine levels of 600-1100μg iodine/day without facing any side effects, however the safer upper level of intake in children or adults suffering from autoimmune thyroid disease should be much lower. Hence, the recommended daily intake is 150μg/day [33]. As far as breastfeeding women are concerned, a threshold for iodine intake has not been considered even though there are studies describing high levels of iodine in the breast milk [34,35,36].

In areas where people are exposed to a high level of iodine for a long time, a higher prevalence of the thyroid enlargement and subclinical hypothyroidism has been noticed especially in coastal areas of Japan because of their daily intake of seaweeds or Eastern China, due to drinking water from shallow wells with a high content of iodine [37,38]. The pathogenic mechanisms which lead to a thyroid misfunction might be the iodine effect on the thyroid as well as reversible inhibition of thyroid function by excess iodine (the Wolff-Chaikoff effect).

There are studies showing that an excess of iodine is a risk factor for the development of thyroid autoimmunity not only for animal models, but also for human population because iodine can have a both direct (intracellular oxidative stress) and indirect (activation of proinflammatory phenomena that recruit immunocompetent cells) effect on thyrocites. In fact, a study illustrateed how the incidence of Hashimoto's thyroiditis increased after the introduction of iodine prophylaxis [39], The same result was noticed in Slovenia 10 years after they increased the potassium iodide per kg of salt from 10 to 25mg [40].

Jod-Basedow phenomenon is an iodine-induced thyrotoxicosis which appears when TSH-independent thyrocites are stimulated by iodine. Among the susceptible patients are the ones with Graves- Basedow disease and also the ones with nodular goiter living in moderate to mild iodine-deficient areas, if the population is facing an increasement in the iodine intake in a short period of time. A lot of cases of Jod-Basedow phenomenon appeared in Tasmania after the introduction of iodized bread and iodine enriched foods imported from Australia [41]. Similarly, in Austria, increasing the quantity of potassium iodide per kg of salt from 10 to 20mg was followed by a bigger number of cases of thyrotoxicosis [42]. However, introducing the prophilaxy with salt ionization should decrease the number of people with toxic nodular goitre and a decrease in the susceptible population for Jod-Basedow phenomenon should be expected.

Thyroid cancer incidence has increased dramatically worldwide in the last years and iodine supplementation is thought to have a potential contribution [43]. However, some studies pointed out that the iodine intake does not affect the overall incidence of thyroid cancer [44]. While in areas with severe ID the PTC/FTC ratio was 0.19-1.7, in areas with mild ID the PTC/FTC ratio was 1.6-3.7 and in places where the iodine intake was high the same ratio had values between 3.4-6.5 [45,46]. Thus, the histotype distribution of differentiated thyroid cancer seems to be more influenced by iodine supplementation rather than the incidence in a population.

Methods of assessing iodine status

There are several methods iodine status assessment in pregnant women but among these methods the one that brings the most significant information is the median UIC in ‘a representative sample [18].

Urinary iodine excretion in nonpregnant adults and schoolchildren in a certain area may be used as an indicator of iodine status in pregnant women living in the same area, but the results are not conclusive because, even in an iodine insufficient area, once a woman becomes pregnant she can change her diet leading to a higher dietary iodine intake. Moreover, urinary iodine excretion represents an indicator which highlights the iodine intake for the last hours or days. In order to diagnose ID for individuals more than one sample per 24 hours needs to be analyzed. As a consequence, to quantify urinary iodine excretion, 24-hour samples of urine have to be collected and analyzed [47].

Therefore, UIC is recommended by WHO, UNICEF, and ICCIDD to asses the iodine level. UIC is calculated per urine volume. One of the disadvanteges is the fact that UIC varies with the fluid intake, this being the reason why the selection of a representative sample might be difficult. On the other hand, UIC has the advantage of being a low cost technique. The simplest way for both the doctor and the pacient would be to collect a urine sample when a pregnant woman comes to the hospital for a routine control, but that sample might not be illustrative because of a diet change in diet that may have occurred on that specific day. However, when performing an abdominal ultrasound some clinicians recommend high fluid intake to pregnant women for a better image of the fetus, leading to a diluted urine sample with a lower iodine concentration. In order to avoid this situation a urine sample may be collected when the woman visits the hospital and at the same time she can be provided with a vial for urine sampling to use it on a typical day at home.

Currently, the iodine/creatinine ratio (μg iodine/gram creatinine) is being used to adjust the variation of the urinary volume. Once again an adjustment had to be made because creatine varries with age and gender and in order to calculate the 24-hour urinary iodine excretion (μg iodine/24 hours) the iodine/creatinine ratio is multiplied by an estimated age- and gender specific 24-hour creatinine excretion iodine/creatinine ratio is multiplied by an estimated age and gender specific 24-hour creatinine excretion. Also UIC has a diurnal variation and tends to be lowered by fasting [48].

Serum thyroid stimulating hormone may be used as an indicator of iodine nutrition but it is not a sensitive marker of ID for children and pregnant women. Even though, ID tends to lower T4 and increase serum thyroid stimulating hormone (TSH), there are studies which revealed the fact that TSH often remains in the normal range [49]. In contrast, TSH is a sensitive indicator of iodine status in newborns. In neonates the thyroid contains less iodine but its turnover is higher and thus TSH will continue to be stimulated when the supply of iodine is low because the turnover will remain increased. In populations with mild to moderate ID, TSH tends to be lowered with age due to thyroid autonomy [50].

Although serum thyroglobulin is a thyroid specific protein whose levels in serum represent a valid marker of ID in population studies [51,52], a high serum thyroglobulin concentration may also be present in various thyroid disorders as a result of physiological changes in Thyroid size can be an indicator of a pathology and also it can be used as a long-term indicator of iodine status. In the past clinical examination was the main option used to estimate the thyroid size, however in a mild iodine deficiency this technique proved to have poor sensitivity and specificity [54]. Nowdays thyroid ultra-sonography is preferable in order to evaluate the thyroid size in mild ID because is a non-invasive, safe and painless technique which offers information not only about the size of the glad but also to look for nodules, to see if a thyroid nodule has substantially grown over time, or to perform ultrasound-guided thyroid biopsy [55].

Salt ionization

Prophylactic measures for IDD are no doubt necessary. Salt iodization, the use of iodised oil or the fortification of milk, bread and water, should be taken into consideration. With all the efforts considered, nowadays there are still some ID areas and billions of people are confrunting this condition. Despite the fact that salt ionization is an easy and affordable method to avoid the consequences of ID, there are plenty of European countries who did not develop prevention programs, which led to the persistency of a mild to moderate iodine shortage [56]. Even in countries where endemic cretinism or endemic goiter disappeared, prophylactic measures have to be continued and sustained indefinitely since ID may reappear in time. What makes a difference between the ID and other nutrients deficits is the fact that iodine status is linked more to geography rather than socio-economic development since the soil is deficient in iodine in large geographic areas, worldwide. [57,58,59].

Universal salt iodization is the first-line strategy which has been accepted as a safe and cost-effective measure to ensure sufficient iodine intake by all individuals [60]. In contrast, it is important to keep in mind that high levels of salt represents a risk factor cardiovascular diseases. Hence, one of the main recommendations for lifestyle modification in patients with cardiovascular diseases is to reduce the dietary amount of sodium [61,62]. In pacients having ID, a restrictive diet with a salt intake below 5g/day will lead to more severe effects of the ID [63]. For example, in Poland, there is a great variety of products that represent a source of iodine such as water containing iodine naturally or enriched with iodine in the production process or meat and milk which comes from animals whose food has been enriched with iodine. Also, pharmaceutical products containing iodine come in handy when salt ionization is not enough. Consequently, when salt iodization fails and the iodine intake is still low, daily iodine supplementation is recommended especially to pregnant women, lactating women and infants [64,65]. As we mentioned before, pregnant women have a higher risk of ID due to the 50% increased requirments for maintaing normal maternal thyroid hormone levels [55].

However, the problem that is still debatable is what to do when the median exceeds UIC≥100μg/l, but is lower than the 150μg/l recommended in pregnancy in an iodine suffiecient area. Should all pregnant woman take iodine supplements or the median UIC should be increased to 150μg/l by the mean of salt iodization? There are different points of view regarding this matter and the discordance in guidance from different authorities reflects the lack of information about the proper dosage of iodine that should be recommended in pregnancy. WHO/UNICEF/ICCIDD reached a consensus regarding this dilemma which says that a pregnant woman who lives in a country with a median UIC ≥100μg/l more than 2 years should not be advised to take iodine supplements [66]. On the other hand, the American Thyroid Association considers that iodine-containing supplements should be taken by all pregnant women, disregarding the iodine status in the area they come from [67]. Another approach of this problem has been stated by The European Thyroid Association who considers that the ideal solution is to create intrathyroidal stores of iodine by giving euthyroid to pregnant and lactating women containing 150μg iodine/day even before conception [68].

The opposing points of view led to other inquiries. Thus, it is important to determine which degree of iodine deficit during pregnancy is associated with brain damage. Analyzing the existing data stressed that, where endemic cretinism was frequently diagnosed, UIC was below 20μg/day[69,70]. Of great importance is the fact that a lower degree of ID often leads to other neurological impairments and abnormal behaviour [70,71]. While values of UIC<50μg/day are associated with a certain degree of brain issues, it seems that mild ID (UIC in the range of 50-99μg/day) is not harmful for the newborn. There is no convincing evidence that pregnant women with UIC below 100μg/day who took iodine supplements had a better outcome of pregnancy [70,72].

Conclusions

Iodine represents a critical agent in the thyroid function. Iodine deficiency should focus more on prevention and early diagnosis, as future supplementation of iodine after a certain age surely does not reverse neurological disorders or reduce the size of large nodular goiters. Future complications may be prevented through different testing methods which are capable of easily identifying iodine deficiency, starting from alimentary questionnairies to urine tests as well as the thyroid hormones level.

Acknowledgement

Biban B.G. and Lichiardopol C performed the literature search and wrote the paper.

Table 1

Methods	Advantages	Disadvatanges
Median urinary iodine concentration (μg/L)	affordable	varries with the ingestion of fluids
	relatively easy to collect in most population groups
		important to avoid contamination
	can be measured in spot urine specimens from a representative sample of the target group
		does not provide direct information on thyroid function, but a low value suggests a population is at higher risk of developing thyroid disorders
	can be used for all categories of people
		not valuable for individual assesment
		evaluate  the iodine intake for the last few days
		a large number of samples need to be collected because of the great variability of biological products
		requires laboratory equipment and trained technicians.
Thyroid stimulating hormone (mIU/L)	sensitive indicator of iodine status in the newborn period	not useful if iodine antiseptics used at birth
	minimal costs if a congenital hypothyroidism screening program is already in place	relatively insensitive indicator of iodine nutrition in school-aged children and adults.
	simple technique	requires a standardized, sensitive assay
	can be measured from a dried blood sample
		relatively sophisticated equipment required to quantitatively measure TSH
	blood spots can be collected and stored for weeks in dry rooms with low temperature
		should be taken by heel-prick at least 48 hours after delivery or from the cord right after birth in order to avoid physiological newborn surge
Serum or whole blood thyroglobulin (μg/L)	simple technique	expensive immunoassay
	collection of samples is easy	standard reference material is available, but needs validation
	samples can be stored in cold, dry rooms
	international reference range available
	well correlated with the severity of iodine deficiency as measured by UI.
	Can be used to measure the improvement of  thyroid function within several months after iodine repletion
	more sensitive indicator of iodine repletion than TSH or T4.
T3/T4	reflects the function of the thyroid	poor indicators of iodine status
Goiter Physical examination	simple and quick	poor sensitivity and specificity
	requires no special equipment
		response to iodine intake appears after a long period of time
		experienced examiner
Goiter ultrasound	noninvasive, quick and safe	requires experience and training
	feasible even in remote areas using portable equipment
		responds only slowly to changes in iodine intake
	international reference values available
		requires expensive equipment