**Aging and Subclinical Thyroid Dysfunction**

Corrêa V. M. da Costa and D. Rosenthal

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55194

## **1. Introduction**

[241] Raverot G, Castinetti F, Jouanneau E, Morange I, Figarella-Branger D, Dufour H, Trouillas J, Brue T. Pituitary carcinomas and aggressive pituitary tumours: merits and pitfalls of temozolomide treatment. Clinical Endocrinology 2012;76(6) 769-75.

84 Hot Topics in Endocrine and Endocrine-Related Diseases

[242] Salehi F, Scheithauer BW, Kros JM, Lau Q, Fealey M, Erickson D, Kovacs K, Horvath E, Lloyd RV. MGMT promoter methylation and immunoexpression in aggressive pi‐ tuitary adenomas and carcinomas. Journal of Neuro-oncology 2011;104(3) 647-57.

#### **1.1. Endocrinology of aging**

Aging is inevitable. Although it has been intensively studied and discussed, its cause(s) are still in the realm of hypotheses. Two main theories hold the center of the stage at the moment: 1) aging occurs in accordance with genetic pre- programmed events or 2) it is not genetically programmed but results from an accumulation of random events [1, 2]. Either way, changes in cellular/molecular function are common denominators to be found in all processes that characterize biological aging, but these changes occur with different timing and specificity among different cells, tissues or organs [3]. This chapter will briefly review some important aspects of current knowledge about aging process and its impact on thyroidal function.

The endocrine system is as affected by aging as are other systems. Yet, again, not all of its components are affected at the same time or in the same way. During aging, physiologic functions decline gradually, cellular protein synthesis is diminished as well as immune function. There is also an increase in fat mass, a loss of muscle mass and strength, and a decrease in bone mineral density that contribute to declining health status.

Two important clinical changes occur in endocrine activity during aging, involving pancreas and thyroid gland. About 40% of individuals between the ages of 65 and 74 years and 50% of those older than 80 years have impaired glucose tolerance or diabetes mellitus, and in almost 50% of elderly adults with diabetes the disease is undiagnosed [4]. Pancreatic secretion, insulin receptor and insulin signaling pathways changes associated with aging are critical components of the endocrinology of aging. In addition to relatively decreased insulin secretion by the beta cells, peripheral insulin resistance related to poor diet, physical inactivity, increased abdominal fat mass, and decreased lean body mass contribute to the deterioration of glucose metabolism

© 2013 da Costa and Rosenthal; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[4]. Other hormonal systems exhibit lowered circulating hormone concentrations during normal aging, and these changes have been considered mainly physiologic. The decrease in human gonadic function with consequent decline in circulating estrogen and testosterone, and increase in serum gonadotropins (FSH and LH), is a classic example. A decrease in growth hormone (GH) and insulin-like growth factor-I (IGF-I) are most probably due do a decline in hypothalamic growth hormone releasing hormone (GHRH), and also a part of the aging process in mammals [4, 5]. The aged adrenal cortex is affected in its capacity to produce dehydroepiandrosterone (DHEA). In contrast the glucocorticoids produced in the adrenal cortex fasciculate layer tend to be more responsive to stimuli, have a slightly delayed clearance rate, and are less entrained to the circadian phase in aged subjects than in young ones. Although not all authors agree [6], most report that healthy elder subjects have higher cortisol levels presumably in response to increased corticotrophin (ACTH) secretion [7, 8]. It is difficult to evaluate - in humans - if this discordance is gender-related. An increased hypothalamuspituitary-adrenal activity is also seen in aged rats, more due to an increase in hypothalamic vasopressin (AVP) synthesis and secretion than to increases in corticotrophin releasing hormone (CRH), and may be related to a decrease in glucocorticoid receptor activity both at the hypothalamus/pituitary and at peripheral tissues [9, 10].

With improvements in biochemical testing and increasing numbers of relatively asymptomatic individuals being subjected to blood testing, subclinical hypothyroidism and subclinical hyperthyroidism have become the most frequent thyroid disease. The clinical complications and functional consequences and effects on quality of life have been extensively addressed as well as the therapeutic options, however because of the lack of large randomized clinical trials,

Aging and Subclinical Thyroid Dysfunction http://dx.doi.org/10.5772/55194 87

Normal aging is accompanied by a slight decrease in pituitary thyrotropin (TSH) release and especially by decreased peripheral metabolism of T4, which results in a gradual age-dependent decline in serum triiodothyronine (T3) concentrations without changes in T4 levels [11]. This slight decrease in plasma T3 concentrations occurs largely within the broad normal range of the healthy elderly population and has not been clearly related to functional changes during the aging process. The deleterious effects of overt thyroid dysfunction in elderly individuals are clearly recognized, but the clinical relevance of mild forms of hypothyroidism and hyperthyroidism are a matter of debate. The prevalence of thyroid disease increases with age and all forms of thyroid disease are encountered. However, the clinical manifestations are different from those encountered in younger patients. In the elderly, autoimmune hypothyr‐ oidism is particularly prevalent. Hyperthyroidism is mainly characterized by cardiovascular symptoms and is frequently due to toxic nodular goiters. Thyroid carcinoma is also more

Molecular biology studies have considerably broadened our knowledge of thyroid tumori‐ genesis. Follicular cell proliferation is mainly regulated by TSH but also is controlled by extracellular growth factors that essentially modify intra- cellular signaling pathways after binding to membrane receptors. It is known that "in *vitro"* TSH stimulates cell cycle progression and proliferation in cooperation with insulin or IGF-I in various thyrocyte culture systems, including rat thyroid cell lines (FRTL-5, WRT and PCCl-3), and in primary cultures of rat, dog, sheep and human thyroid cells [16]. Park *et al.* demonstrated that the TSH proliferative effect is, at least in part, mediated by an increase in expression of an adaptor molecule of the IGF-I receptor (p66Shc) [17]. These data suggest that the synergistic proliferative effect of TSH and

Tumor growth occurs when the normal equilibrium of regulatory pathways is disrupted, either through enhancement of stimulatory pathways or deficient inhibitory pathways [18]. Epide‐ miological studies show that cancer is primarily a disease of the aged. Cancer rates increase dramatically in humans beginning in the sixth and seventh decades of life. Although the complex relationship between cancer and aging has long been recognized, a clear understand‐ ing of the mechanisms underlying this relationship has remained elusive. Recently, Hinkal and Donehower reviewing this issue focused on a decline in function of tumor-suppressing genes like p53 during aging, associated with the development of tumors in many different tissues in mice. Among the hundreds of tumor-suppressing genes now identified, p53 may be the most important. The p53 gene is mutated in over half of all human cancers, and it has been

the evidence for choosing one treatment over another is minimal [14].

insulin/IGF-I on the thyroid gland may also occur "in *vivo".*

aggressive [15].

## **2. Problem statement**

#### **2.1. Aging and thyroid dysfunction**

Age-related thyroid dysfunction is common. Lowered plasma thyroxine (T4) and increased thyrotropin concentrations occur in 5% to 10% of elderly women [11]. Autoimmunity or an age-associated disease frequently are the primarily cause of these abnormalities rather than a natural consequence of the aging process. Several immunological abnormalities have been described in aging process. A well-recognized age-associated immune abnormality is the general production of both organ- and nonorgan-specific autoantibodies. Aging is frequently associated with the appearance of thyroid autoantibodies, but the biological and clinical significance of this is still unknown. Some data have shown that these thyroid autoantibodies are rare in healthy centenarians and in other highly selected aged populations, whereas they are frequently observed in unselected or hospitalized elderly patients, thus suggesting that these autoantibodies are not the consequence of the aging process itself, but rather are related to age-associated disease [12].

Thyroid autoimmunity and subclinical hypothyroidism have also been implicated in the pathogenesis of other age-associated disorders like coronary heart disease [13]. A major, unresolved issue is whether, and to what extent, the complex physiological changes seen in the hypothalamus-pituitary-thyroid axis contribute to the pathogenesis of age-associated diseases such as atherosclerosis, coronary heart disease and neurological disorders [11].

With improvements in biochemical testing and increasing numbers of relatively asymptomatic individuals being subjected to blood testing, subclinical hypothyroidism and subclinical hyperthyroidism have become the most frequent thyroid disease. The clinical complications and functional consequences and effects on quality of life have been extensively addressed as well as the therapeutic options, however because of the lack of large randomized clinical trials, the evidence for choosing one treatment over another is minimal [14].

[4]. Other hormonal systems exhibit lowered circulating hormone concentrations during normal aging, and these changes have been considered mainly physiologic. The decrease in human gonadic function with consequent decline in circulating estrogen and testosterone, and increase in serum gonadotropins (FSH and LH), is a classic example. A decrease in growth hormone (GH) and insulin-like growth factor-I (IGF-I) are most probably due do a decline in hypothalamic growth hormone releasing hormone (GHRH), and also a part of the aging process in mammals [4, 5]. The aged adrenal cortex is affected in its capacity to produce dehydroepiandrosterone (DHEA). In contrast the glucocorticoids produced in the adrenal cortex fasciculate layer tend to be more responsive to stimuli, have a slightly delayed clearance rate, and are less entrained to the circadian phase in aged subjects than in young ones. Although not all authors agree [6], most report that healthy elder subjects have higher cortisol levels presumably in response to increased corticotrophin (ACTH) secretion [7, 8]. It is difficult to evaluate - in humans - if this discordance is gender-related. An increased hypothalamuspituitary-adrenal activity is also seen in aged rats, more due to an increase in hypothalamic vasopressin (AVP) synthesis and secretion than to increases in corticotrophin releasing hormone (CRH), and may be related to a decrease in glucocorticoid receptor activity both at

Age-related thyroid dysfunction is common. Lowered plasma thyroxine (T4) and increased thyrotropin concentrations occur in 5% to 10% of elderly women [11]. Autoimmunity or an age-associated disease frequently are the primarily cause of these abnormalities rather than a natural consequence of the aging process. Several immunological abnormalities have been described in aging process. A well-recognized age-associated immune abnormality is the general production of both organ- and nonorgan-specific autoantibodies. Aging is frequently associated with the appearance of thyroid autoantibodies, but the biological and clinical significance of this is still unknown. Some data have shown that these thyroid autoantibodies are rare in healthy centenarians and in other highly selected aged populations, whereas they are frequently observed in unselected or hospitalized elderly patients, thus suggesting that these autoantibodies are not the consequence of the aging process itself, but rather are related

Thyroid autoimmunity and subclinical hypothyroidism have also been implicated in the pathogenesis of other age-associated disorders like coronary heart disease [13]. A major, unresolved issue is whether, and to what extent, the complex physiological changes seen in the hypothalamus-pituitary-thyroid axis contribute to the pathogenesis of age-associated diseases such as atherosclerosis, coronary heart disease and neurological disorders [11].

the hypothalamus/pituitary and at peripheral tissues [9, 10].

**2. Problem statement**

to age-associated disease [12].

**2.1. Aging and thyroid dysfunction**

86 Hot Topics in Endocrine and Endocrine-Related Diseases

Normal aging is accompanied by a slight decrease in pituitary thyrotropin (TSH) release and especially by decreased peripheral metabolism of T4, which results in a gradual age-dependent decline in serum triiodothyronine (T3) concentrations without changes in T4 levels [11]. This slight decrease in plasma T3 concentrations occurs largely within the broad normal range of the healthy elderly population and has not been clearly related to functional changes during the aging process. The deleterious effects of overt thyroid dysfunction in elderly individuals are clearly recognized, but the clinical relevance of mild forms of hypothyroidism and hyperthyroidism are a matter of debate. The prevalence of thyroid disease increases with age and all forms of thyroid disease are encountered. However, the clinical manifestations are different from those encountered in younger patients. In the elderly, autoimmune hypothyr‐ oidism is particularly prevalent. Hyperthyroidism is mainly characterized by cardiovascular symptoms and is frequently due to toxic nodular goiters. Thyroid carcinoma is also more aggressive [15].

Molecular biology studies have considerably broadened our knowledge of thyroid tumori‐ genesis. Follicular cell proliferation is mainly regulated by TSH but also is controlled by extracellular growth factors that essentially modify intra- cellular signaling pathways after binding to membrane receptors. It is known that "in *vitro"* TSH stimulates cell cycle progression and proliferation in cooperation with insulin or IGF-I in various thyrocyte culture systems, including rat thyroid cell lines (FRTL-5, WRT and PCCl-3), and in primary cultures of rat, dog, sheep and human thyroid cells [16]. Park *et al.* demonstrated that the TSH proliferative effect is, at least in part, mediated by an increase in expression of an adaptor molecule of the IGF-I receptor (p66Shc) [17]. These data suggest that the synergistic proliferative effect of TSH and insulin/IGF-I on the thyroid gland may also occur "in *vivo".*

Tumor growth occurs when the normal equilibrium of regulatory pathways is disrupted, either through enhancement of stimulatory pathways or deficient inhibitory pathways [18]. Epide‐ miological studies show that cancer is primarily a disease of the aged. Cancer rates increase dramatically in humans beginning in the sixth and seventh decades of life. Although the complex relationship between cancer and aging has long been recognized, a clear understand‐ ing of the mechanisms underlying this relationship has remained elusive. Recently, Hinkal and Donehower reviewing this issue focused on a decline in function of tumor-suppressing genes like p53 during aging, associated with the development of tumors in many different tissues in mice. Among the hundreds of tumor-suppressing genes now identified, p53 may be the most important. The p53 gene is mutated in over half of all human cancers, and it has been estimated that more than 80% of human cancers have dysfunctional p53 signaling [19]. In fact, decreased expression of tumor- suppressing genes, may be associated with higher cancer incidence in aged subjects, but one can not discard higher function of genes involved in cellular proliferation probably also present in aged subjects.

physiological alterations associated with aging. However, direct age-related changes need to be distinguished from indirect alterations caused by simultaneous thyroid or non- thyroidal illness, or other physiological or pathophysiological states whose incidence increases with age. Several changes formerly believed to be a direct result of the aging process have subsequently been shown to be due to the increased prevalence of subclinical thyroid disease and/or the result of non-thyroidal illness. This makes interpretation of thyroid function tests difficult in

Aging and Subclinical Thyroid Dysfunction http://dx.doi.org/10.5772/55194 89

Pituitary thyrotropin (TSH) stimulates all steps of thyroid hormones biosynthesis and is the major regulator of the thyroid gland morphology and function. TSH production and secretion are stimulated by the hypothalamic thyrotropin-releasing hormone (TRH) and suppressed by

In a revision of several population studies Surks and Hollowell report that the TSH distribution of aged humans - without thyroid disease - progressively shift to higher concentrations, suggesting that the prevalence of subclinical hypothyroidism could have been overestimated in many other studies [24]. The main point that is being discussed for some time by endocri‐ nologists is whether the increase in the serum immunoreactive TSH of aged subjects, and related changes in thyroid function, are a "physiologic" consequence of aging on the hypo‐ thalamus-pituitary-thyroid axis or if they reflect alterations induced by acute or chronic nonthyroid illnesses and/or use of drugs, both more frequent in the elder population [25, 26].

In fact there are strong evidences pointing to a decrease hypothalamus-pituitary-thyroid axis activity with aging, be it in humans [27, 28] or in rats [29, 30, 31]. Thyroid hormone production and metabolism are altered by aging. Serum T4 and T3 are significantly reduced in old male rats, but the serum T3 seems to be less affected in elder female rat [30, 31, 32]. Decreases in serum T3, associated or not with lower T4, are present in aged humans [26], however it should be emphasized that although significantly decreased the thyroid hormone and TSH concen‐

The decrease in T3 levels, and in the metabolism of T4 in elder subjects has been attributed to a diminished 5'- deiodinase type I (D1) activity. In fact, we and others have found lower hepatic and thyroid D1 activity in aging rats, but males seem to be more affected than females [30, 33, 34]. The resulting lower serum T3/T4 ratio can also be attributed, at least in part, to a prefer‐ ential release of T3 by the thyroid of the aged rat, both basal and after TSH stimulation [35]. The effect of aging on pituitary deiodinases type 1 and type 2 (D1, D2) is still awaiting further confirmatory studies. Donda and Lemarchand-Beraud found an increase of D1 and deiodinase type 2 (D2) activities in the pituitary of old male rats, while we found both pituitary deiodinase activities to be decreased in the old female rat [36]. No further information seems to be available, although suggestions of a "partial central hypothyroidism" and less efficient response of the hypothalamic-pituitary axis to lower circulating thyroid hormones are found

Hypothalamic TRH content is reduced in aged rats [32, 35] and thyrotroph response to TRH is mostly reported as decreased, both in rats [29, 32, 36] and [37, 38] in humans. Non-stimulated

thyroid hormones, in a classic negative feedback control system.

trations mostly remain within the range considered as normal.

the elderly [11].

often enough [32].

Ras proteins are involved in the transduction of growth factor signals by surface receptors, and are key components of downstream signaling through several pathways. Ras activation of the Raf serine/threonine kinases, and activation of the ERK mitogen-activated protein kinases (MAPKs) is an important signaling pathway for many Ras effects [20]. Thyroidal proliferation can be induced by growth factors, and it is known that oncogenic mutations of Ras-family genes play an important role in malignant transformation and tumor progression in the follicular epithelium of the thyroid gland. In fact, De Vita *et al.* showed in FRTL5 thyroid cells that the overexpression of mutated RAS gene inhibits the expression of thyroid differen‐ tiation markers in a dose-dependent way [63]. Overexpression of three different Ras isoforms (H-, K- and N-Ras) exert similar effects on the thyroid phenotype: loss of thyroid differentia‐ tion, with decrease in thyroidal differentiation markers proteins as thyroglobulin, thyroper‐ oxidase, Na+/I- symporter, TSH receptor, thyroid oxidase and thyroid specific combination of transcription factors, Titf 1, Foxe 2 and Pax 8 [21].

Ras proteins comprise a group of 20- to 25-KDa proteins that are involved in transduction of signals elicited by activated surface receptors, acting as molecular switches in many processes governing cellular growth and differentiation. The Ras-pERK pathway can also be modulated by thyroid hormones. In the hypothyroid rat there is a clear positive modulation of Ras, but this does not affect pERK, which shows a slight decrease. In contrast, thyroidal pERK increases in T4-induced hyperthyroidism, but there are no changes in RAS expression [22].

Effects of aging on Ras expression are still very much unexplored. In rat thyroids from both genders aging duplicated Ras expression, but its signal transduction by pERK was decreased, suggesting a failure in this pathway [23]. These results could be involved in the impaired thyroidal function observed in old rats. Ras activation of Raf serine/threonine kinases, and activation of the ERK mitogenactivated protein kinases is an important signaling pathway for many Ras effects, the others being the activation of phosphatidylinositol-3 kinase or the Ralsmall GTPases. As far as we know, an increase in the protooncogene Ras expression in the thyroid from aged rats has not been detected previously. Further studies are required to elucidate the pathways involved in this increases in Ras expression during the aging process, and to correlate them with the known morphologic and functional changes that affect the aging thyroid gland.

#### **2.2. Aging and hypothalamus-pituitary-thyroid axis**

The effect of aging on the hypothalamus-pituitary-thyroid function is still a subject of contro‐ versies. The hypothalamus-pituitary-thyroid axis undergoes a significant number of complex physiological alterations associated with aging. However, direct age-related changes need to be distinguished from indirect alterations caused by simultaneous thyroid or non- thyroidal illness, or other physiological or pathophysiological states whose incidence increases with age. Several changes formerly believed to be a direct result of the aging process have subsequently been shown to be due to the increased prevalence of subclinical thyroid disease and/or the result of non-thyroidal illness. This makes interpretation of thyroid function tests difficult in the elderly [11].

estimated that more than 80% of human cancers have dysfunctional p53 signaling [19]. In fact, decreased expression of tumor- suppressing genes, may be associated with higher cancer incidence in aged subjects, but one can not discard higher function of genes involved in cellular

Ras proteins are involved in the transduction of growth factor signals by surface receptors, and are key components of downstream signaling through several pathways. Ras activation of the Raf serine/threonine kinases, and activation of the ERK mitogen-activated protein kinases (MAPKs) is an important signaling pathway for many Ras effects [20]. Thyroidal proliferation can be induced by growth factors, and it is known that oncogenic mutations of Ras-family genes play an important role in malignant transformation and tumor progression in the follicular epithelium of the thyroid gland. In fact, De Vita *et al.* showed in FRTL5 thyroid cells that the overexpression of mutated RAS gene inhibits the expression of thyroid differen‐ tiation markers in a dose-dependent way [63]. Overexpression of three different Ras isoforms (H-, K- and N-Ras) exert similar effects on the thyroid phenotype: loss of thyroid differentia‐ tion, with decrease in thyroidal differentiation markers proteins as thyroglobulin, thyroper‐ oxidase, Na+/I- symporter, TSH receptor, thyroid oxidase and thyroid specific combination of

Ras proteins comprise a group of 20- to 25-KDa proteins that are involved in transduction of signals elicited by activated surface receptors, acting as molecular switches in many processes governing cellular growth and differentiation. The Ras-pERK pathway can also be modulated by thyroid hormones. In the hypothyroid rat there is a clear positive modulation of Ras, but this does not affect pERK, which shows a slight decrease. In contrast, thyroidal pERK increases

Effects of aging on Ras expression are still very much unexplored. In rat thyroids from both genders aging duplicated Ras expression, but its signal transduction by pERK was decreased, suggesting a failure in this pathway [23]. These results could be involved in the impaired thyroidal function observed in old rats. Ras activation of Raf serine/threonine kinases, and activation of the ERK mitogenactivated protein kinases is an important signaling pathway for many Ras effects, the others being the activation of phosphatidylinositol-3 kinase or the Ralsmall GTPases. As far as we know, an increase in the protooncogene Ras expression in the thyroid from aged rats has not been detected previously. Further studies are required to elucidate the pathways involved in this increases in Ras expression during the aging process, and to correlate them with the known morphologic and functional changes that affect the aging

The effect of aging on the hypothalamus-pituitary-thyroid function is still a subject of contro‐ versies. The hypothalamus-pituitary-thyroid axis undergoes a significant number of complex

in T4-induced hyperthyroidism, but there are no changes in RAS expression [22].

proliferation probably also present in aged subjects.

88 Hot Topics in Endocrine and Endocrine-Related Diseases

transcription factors, Titf 1, Foxe 2 and Pax 8 [21].

**2.2. Aging and hypothalamus-pituitary-thyroid axis**

thyroid gland.

Pituitary thyrotropin (TSH) stimulates all steps of thyroid hormones biosynthesis and is the major regulator of the thyroid gland morphology and function. TSH production and secretion are stimulated by the hypothalamic thyrotropin-releasing hormone (TRH) and suppressed by thyroid hormones, in a classic negative feedback control system.

In a revision of several population studies Surks and Hollowell report that the TSH distribution of aged humans - without thyroid disease - progressively shift to higher concentrations, suggesting that the prevalence of subclinical hypothyroidism could have been overestimated in many other studies [24]. The main point that is being discussed for some time by endocri‐ nologists is whether the increase in the serum immunoreactive TSH of aged subjects, and related changes in thyroid function, are a "physiologic" consequence of aging on the hypo‐ thalamus-pituitary-thyroid axis or if they reflect alterations induced by acute or chronic nonthyroid illnesses and/or use of drugs, both more frequent in the elder population [25, 26].

In fact there are strong evidences pointing to a decrease hypothalamus-pituitary-thyroid axis activity with aging, be it in humans [27, 28] or in rats [29, 30, 31]. Thyroid hormone production and metabolism are altered by aging. Serum T4 and T3 are significantly reduced in old male rats, but the serum T3 seems to be less affected in elder female rat [30, 31, 32]. Decreases in serum T3, associated or not with lower T4, are present in aged humans [26], however it should be emphasized that although significantly decreased the thyroid hormone and TSH concen‐ trations mostly remain within the range considered as normal.

The decrease in T3 levels, and in the metabolism of T4 in elder subjects has been attributed to a diminished 5'- deiodinase type I (D1) activity. In fact, we and others have found lower hepatic and thyroid D1 activity in aging rats, but males seem to be more affected than females [30, 33, 34]. The resulting lower serum T3/T4 ratio can also be attributed, at least in part, to a prefer‐ ential release of T3 by the thyroid of the aged rat, both basal and after TSH stimulation [35]. The effect of aging on pituitary deiodinases type 1 and type 2 (D1, D2) is still awaiting further confirmatory studies. Donda and Lemarchand-Beraud found an increase of D1 and deiodinase type 2 (D2) activities in the pituitary of old male rats, while we found both pituitary deiodinase activities to be decreased in the old female rat [36]. No further information seems to be available, although suggestions of a "partial central hypothyroidism" and less efficient response of the hypothalamic-pituitary axis to lower circulating thyroid hormones are found often enough [32].

Hypothalamic TRH content is reduced in aged rats [32, 35] and thyrotroph response to TRH is mostly reported as decreased, both in rats [29, 32, 36] and [37, 38] in humans. Non-stimulated TSH concentration has also been reported as relatively diminished by aging in a large popu‐ lation of older persons without hyperthyroidism, and in aging patients with resistance to thyroid hormone (and their non-affected relatives) [27].

Thus, at the moment, we must consider that the hypothalamus-pituitary-thyroid axis is affected at all three levels by normal aging, and a reduced responsiveness of target cells/tissues to the effects of thyroid hormones levels rounds-off the picture of a mild state of "total" hypothyroidism that occurs during the aging process, and that may vary according to gender and species evaluated.

Aging also affect thyroid morphology, Messina *et al.* reported a reduction of the hypothalamus-pituitary-thyroid axis activity, with anatomical (weight) and physiological (uptake of iodine and hormone synthesis) age-related adaptations, that result in a reduction of thyroid function [41]. Nevertheless, the authors consider this state as different from hypothyroidism since the thyroid hormones tend to remain within the range considered as normal. In F344 rats, the follicular area and the area of the follicular lumen increased and the height of follicular epithelial cells decreased at 20.5 months, indicating low thyrocyte activity; concomitantly serum T3, T4 and TSH concentrations also decreased with age, confirming that in F344 male rats the aged thyroid shows structural and

Aging and Subclinical Thyroid Dysfunction http://dx.doi.org/10.5772/55194 91

The term "subclinical hypothyroidism" was first introduced in the early 1970s coincident with the introduction of serum TSH measurements. Subclinical hypothyroidism is defined biochemically as a high serum TSH concentration and normal serum free T4 and T3 concentrations. Some investigators also consider patients who have normal basal serum TSH and supranormal serum TSH responses to thyrotropin-releasing hormone (TRH) to have subclinical hypothyroidism. By definitions, patients with subclinical

The term "subclinical hypothyroidism" was first introduced in the early 1970s coincident with the introduction of serum TSH measurements. Subclinical hypothyroidism is defined bio‐ chemically as a high serum TSH concentration and normal serum free T4 and T3 concentra‐ tions. Some investigators also consider patients who have normal basal serum TSH and supranormal serum TSH responses to thyrotropin-releasing hormone (TRH) to have subclin‐ ical hypothyroidism. By definitions, patients with subclinical hypothyroidism cannot be

Subclinical hypothyroidism is present in about 4% to 8.5% of adults in the United States who are without known thyroid disease [44]. Subtle thyroid dysfunction often affects the oldest-old fraction of the elderly population (i.e., those >85 years). In 85-year-old healthy individuals, hypothyroidism was in the subsequent 4 years associated with lower all-

Subclinical hypothyroidism is present in about 4% to 8.5% of adults in the United States who are without known thyroid disease [44]. Subtle thyroid dysfunction often affects the oldest-old fraction of the elderly population (i.e., those >85 years). In 85-year-old healthy individuals, hypothyroidism was in the subsequent 4 years associated with lower all-cause and cardiovascular mortality

Figure 1 summarizes our current knowledge on aging process and its impact on thyroidal function and regulation.

Figure 1. A schematic view of aging effects on thyroid regulation and function.

**Figure 1.** A schematic view of aging effects on thyroid regulation and function.

hypothyroidism cannot be identified on the basis of symptoms and signs [43].

identified on the basis of symptoms and signs [43].

**2.3. Subclinical hypothyroidism** 

**2.3. Subclinical hypothyroidism**

functional changes [42].

In fact, Carlé *et al.* detected four-fold higher average serum TSH in younger (0-20 years) than in the older (80+ years) patients with untreated primary, spontaneous autoimmune hypothyr‐ oidism, while there was no age-dependent variation in serum T4. The well-known inverse linear correlation between T4 and log TSH was maintained in both groups, but the serum TSH/ T4 ratio was lower in the elder patients than in the young ones. Thus, for the same degree of thyroid failure, the serum TSH is lower among the elderly. Since serum T4 is the parameter best associated with the degree of tissue hypothyroidism, a lower TSH at diagnosis/follow-up of elder patients may suggest that their degree of hypothyroidism is less severe than it really is. Furthermore, and of interest for the clinical endocrinologist, a longer time may be needed after thyroid hormone withdrawal before elder patients with thyroid cancer reach sufficiently high TSH values to allow an effective radioiodine treatment [28].

The increase of pituitary thyrotroph hormonal secretion, when stimulated by the low levels of thyroid hormones, is also significantly impaired in the old rat, even when the thyroid hor‐ mones levels are dramatically reduced by MMI treatment [31]. "Normal" circulating levels of TSH are frequently seen in aged rats, in spite of their low serum thyroid hormone levels [30, 31, 36]. This may be attributed to the secretion of a TSH with increased sialylation and diminished biological activity [39] as reported in some types of central hypothyroidism [40] and/or to a diminished response of the thyroid to TSH (less TSH receptors or defective transduction of its signal). A diminished effect of a less biologically active TSH can explain the low thyroid hormone concentration of the aged rat, that could be in part mediated by a decrease in the TPO and Tg expression as found by us in the thyroid gland of aged male (but not female) rat [30].

Thus, at the moment, we must consider that the hypothalamus-pituitary-thyroid axis is affected at all three levels by normal aging, and a reduced responsiveness of target cells/tissues to the effects of thyroid hormones levels rounds-off the picture of a mild state of "total" hypothyroidism that occurs during the aging process, and that may vary according to gender and species evaluated.

Aging also affect thyroid morphology, Messina *et al.* reported a reduction of the hypothalamuspituitary-thyroid axis activity, with anatomical (weight) and physiological (uptake of iodine and hormone synthesis) age-related adaptations, that result in a reduction of thyroid function [41]. Nevertheless, the authors consider this state as different from hypothyroidism since the thyroid hormones tend to remain within the range considered as normal. In F344 rats, the follicular area and the area of the follicular lumen increased and the height of follicular epithelial cells decreased at 20.5 months, indicating low thyrocyte activity; concomitantly serum T3, T4 and TSH concentrations also decreased with age, confirming that in F344 male rats the aged thyroid shows structural and functional changes [42].

Figure 1 summarizes our current knowledge on aging process and its impact on thyroidal function and regulation.

Thus, at the moment, we must consider that the hypothalamus-pituitary-thyroid axis is affected at all three levels by normal aging, and a reduced responsiveness of target cells/tissues to the effects of thyroid hormones levels rounds-off the picture of a mild state of "total" hypothyroidism that occurs during the aging process, and that may vary according to gender and species evaluated.

Aging also affect thyroid morphology, Messina *et al.* reported a reduction of the hypothalamus-pituitary-thyroid axis activity, with anatomical (weight) and physiological (uptake of iodine and hormone synthesis) age-related adaptations, that result in a reduction of thyroid function [41]. Nevertheless, the authors consider this state as different from hypothyroidism since the thyroid hormones tend to remain within the range considered as normal. In F344 rats, the follicular area and the area of the follicular lumen increased

Figure 1 summarizes our current knowledge on aging process and its impact on thyroidal function and regulation.

Figure 1. A schematic view of aging effects on thyroid regulation and function. **Figure 1.** A schematic view of aging effects on thyroid regulation and function.

#### **2.3. Subclinical hypothyroidism**  The term "subclinical hypothyroidism" was first introduced in the early 1970s coincident with the introduction of serum TSH **2.3. Subclinical hypothyroidism**

functional changes [42].

TSH concentration has also been reported as relatively diminished by aging in a large popu‐ lation of older persons without hyperthyroidism, and in aging patients with resistance to

In fact, Carlé *et al.* detected four-fold higher average serum TSH in younger (0-20 years) than in the older (80+ years) patients with untreated primary, spontaneous autoimmune hypothyr‐ oidism, while there was no age-dependent variation in serum T4. The well-known inverse linear correlation between T4 and log TSH was maintained in both groups, but the serum TSH/ T4 ratio was lower in the elder patients than in the young ones. Thus, for the same degree of thyroid failure, the serum TSH is lower among the elderly. Since serum T4 is the parameter best associated with the degree of tissue hypothyroidism, a lower TSH at diagnosis/follow-up of elder patients may suggest that their degree of hypothyroidism is less severe than it really is. Furthermore, and of interest for the clinical endocrinologist, a longer time may be needed after thyroid hormone withdrawal before elder patients with thyroid cancer reach sufficiently

The increase of pituitary thyrotroph hormonal secretion, when stimulated by the low levels of thyroid hormones, is also significantly impaired in the old rat, even when the thyroid hor‐ mones levels are dramatically reduced by MMI treatment [31]. "Normal" circulating levels of TSH are frequently seen in aged rats, in spite of their low serum thyroid hormone levels [30, 31, 36]. This may be attributed to the secretion of a TSH with increased sialylation and diminished biological activity [39] as reported in some types of central hypothyroidism [40] and/or to a diminished response of the thyroid to TSH (less TSH receptors or defective transduction of its signal). A diminished effect of a less biologically active TSH can explain the low thyroid hormone concentration of the aged rat, that could be in part mediated by a decrease in the TPO and Tg expression as found by us in the thyroid gland of aged male (but not female)

Thus, at the moment, we must consider that the hypothalamus-pituitary-thyroid axis is affected at all three levels by normal aging, and a reduced responsiveness of target cells/tissues to the effects of thyroid hormones levels rounds-off the picture of a mild state of "total" hypothyroidism that occurs during the aging process, and that may vary according to gender

Aging also affect thyroid morphology, Messina *et al.* reported a reduction of the hypothalamuspituitary-thyroid axis activity, with anatomical (weight) and physiological (uptake of iodine and hormone synthesis) age-related adaptations, that result in a reduction of thyroid function [41]. Nevertheless, the authors consider this state as different from hypothyroidism since the thyroid hormones tend to remain within the range considered as normal. In F344 rats, the follicular area and the area of the follicular lumen increased and the height of follicular epithelial cells decreased at 20.5 months, indicating low thyrocyte activity; concomitantly serum T3, T4 and TSH concentrations also decreased with age, confirming that in F344 male

Figure 1 summarizes our current knowledge on aging process and its impact on thyroidal

thyroid hormone (and their non-affected relatives) [27].

90 Hot Topics in Endocrine and Endocrine-Related Diseases

high TSH values to allow an effective radioiodine treatment [28].

rats the aged thyroid shows structural and functional changes [42].

rat [30].

and species evaluated.

function and regulation.

measurements. Subclinical hypothyroidism is defined biochemically as a high serum TSH concentration and normal serum free T4 and T3 concentrations. Some investigators also consider patients who have normal basal serum TSH and supranormal serum TSH responses to thyrotropin-releasing hormone (TRH) to have subclinical hypothyroidism. By definitions, patients with subclinical hypothyroidism cannot be identified on the basis of symptoms and signs [43]. Subclinical hypothyroidism is present in about 4% to 8.5% of adults in the United States who are without known thyroid disease [44]. Subtle thyroid dysfunction often affects the oldest-old fraction of the elderly population (i.e., those >85 years). In 85-year-old healthy individuals, hypothyroidism was in the subsequent 4 years associated with lower all-cause and cardiovascular mortality The term "subclinical hypothyroidism" was first introduced in the early 1970s coincident with the introduction of serum TSH measurements. Subclinical hypothyroidism is defined bio‐ chemically as a high serum TSH concentration and normal serum free T4 and T3 concentra‐ tions. Some investigators also consider patients who have normal basal serum TSH and supranormal serum TSH responses to thyrotropin-releasing hormone (TRH) to have subclin‐ ical hypothyroidism. By definitions, patients with subclinical hypothyroidism cannot be identified on the basis of symptoms and signs [43].

Subclinical hypothyroidism is present in about 4% to 8.5% of adults in the United States who are without known thyroid disease [44]. Subtle thyroid dysfunction often affects the oldest-old fraction of the elderly population (i.e., those >85 years). In 85-year-old healthy individuals, hypothyroidism was in the subsequent 4 years associated with lower allcause and cardiovascular mortality rates compared with euthyroid individuals [45]. In a group of 400 men with a mean age of 78 years, Van den Beld and colleagues [46] showed that low serum levels of free T4 and T3 (with normal reverse T3 [rT3]) concentrations were associated with better physical performance and 4-year survival, whereas subjects with low serum levels of T3 and high rT3 concentrations did not show a survival advantage and had lower levels of physical activity. These two studies support the concept that some degree of physiologically decreased thyroid activity at the tissue level may have favorable effects in the oldest-old subjects, but caution should be exercised when interpreting the predic‐ tive value of thyroid dysfunction in the elderly, which may produce contradictory results if not considered in the appropriate context [15].

thyroid hypofunction has been related to longevity [58]. Part of the heterogeneity in these studies may be related to differences in participants' age, sex or TSH level. In a recent metaanalysis combining data on 55,287 participants from 11 prospective studies, subclinical hypothyroidism was associated with an increased risk of coronary heart disease and mortality in patients with TSH levels higher than 10 IU/L, these associations did not differ in age, sex or

Aging and Subclinical Thyroid Dysfunction http://dx.doi.org/10.5772/55194 93

Treatment of subclinical hypothyroidism remains controversial [52, 53, 59]. Although there are no randomized controlled trials documenting decreased cardiovascular morbidity or mortality, some studies have suggested that treatment of subclinical hypothyroidism may result in improvement of cardiovascular risk factors, such as insulin sensitivity, glucose metabolism, soluble intercellular adhesion molecule-1 [60], endothelial progenitor cell levels [61], abnormalities in high-density lipoprotein metabolism [62], and common carotid intimamedia thickness [63]. According to the American Association of Clinical Endocrinologists, treatment is indicated in patients with TSH levels above 10 IU/ml or in patients with TSH levels between 5 and 10 IU/ml along with goiter or positive anti-thyroid peroxidase antibodies, since these patients have increased rates of progression to overt hypothyroidism. However, it should be kept in mind that TSH levels are sometimes transiently elevated, due to recovery from nonthyroidal illness or medication use. As a result, it has been recommended that TSH measure‐ ment should be repeated after 6–8 weeks in order to confirm the diagnosis of subclinical

The prevalence of thyroid disease increases with age but very often presents different clinical manifestations from those found in younger patients. Autoimmune hypothyroidism is particularly prevalent in the elderly, and may be one of the factors that underlies an increased serum TSH reported by various studies in this population [64]. Hyperthyroidism is less common in among older subject, is frequently due to toxic nodular goiters, is mainly charac‐ terized by cardiovascular symptoms, and its manifestations are generally milder than in the younger patients. The associated decrease in TSH may also be less marked than that found in Graves' disease. Thus, the question of whether changes in circulating TSH levels in the elderly indicate a "physiologic adaptation" or are a reflection of associated health disturbances is still

The effect of aging on the hypothalamus-pituitary-thyroid function is still a subject of contro‐ versies. Normal aging is accompanied by a slight decrease in pituitary thyrotropin release and especially by decreased peripheral degradation of T4, which results in a gradual age-depend‐ ent decline in serum triiodothyronine concentrations without changes in T4 levels. This slight decrease in plasma T3 concentrations occurs largely within the broad normal range of the healthy elderly population and has not been clearly related to functional changes during the

hypothyroidism, prior to any consideration of initiating therapy [52].

pertinent and awaiting further evaluation.

**3. Conclusion**

aging process.

ethnicity [51].

Subclinical hypothyroidism has been associated with heart failure [48] and with increased odds of metabolic syndrome [49], but the significance of increased serum TSH in elder subjects is still *sub judice*. Thus, treatment of subclinical hypothyroidism to prevent heart failure and cardiovascular disease in older people should be better evaluated in large randomized clinical trials.

Thyroid hormones have an important role in many organic functions and their deficiency causes a wide spectrum of clinical presentations and symptoms. Neuromuscular manifesta‐ tions are well established in overt hypothyroidism and impaired muscle function is frequently observed. Thyroid hormone deficiency may also interfere substantially with various aspects of physical, mental and social well-being. The evidence for improvement of psychiatric symptoms with hormonal treatment of hypothyroidism, and the use of T3 to potentiate the response to treatment of depressive disorders suggest a direct relationship between thyroid hormones and psychiatric symptoms. Neurobiological evidence seems to corroborate the hypothesis of an organic basis of the effects of thyroid hormone on the brain and on psychiatric symptoms. There is some evidence that subclinical hypothyroidism may also be responsible for findings classically described in hypothyroidism. Symptoms and signs of hypothyroidism have been frequently found in subclinical hypothyroidism patients, as reported by many authors. In fact, Reuters et al described an improvement in some physical aspects of quality of life after L-T4 treatment in patients with subclinical hypothyroidism [50].

The frequency of subclinical hypothyroidism, varies from 6.5 to 15% in elder subjects [51, 52] Subclinical hypothyroidism has been associated with clustering of cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidaemia and hyperuricaemia [53], as well as with the development of insulin resistance, which is evident both in vivo and in vitro studies. The latter may be attributed to decreased insulin-stimulated rates of glucose transport in cells, due to impaired translocation of GLUT4 glucose transporters on the plasma membrane [54].

Multiple studies, with conflicting results, have examined the association of subclinical hypothyroidism with cardiovascular risk and mortality. A recent reanalysis of the Whickham Survey suggested a clear association of subclinical hypothyroidism with ischemic heart disease and mortality [55]. However, a meta-analysis of 15 observational studies indicated that increased cardiovascular risk is evident only in younger individuals with subclinical hypo‐ thyroidism [56]. In patients with type 2 diabetes mellitus, subclinical hypothyroidism has been found to be associated with reduced all-cause mortality [57]. Furthermore, age-related subtle thyroid hypofunction has been related to longevity [58]. Part of the heterogeneity in these studies may be related to differences in participants' age, sex or TSH level. In a recent metaanalysis combining data on 55,287 participants from 11 prospective studies, subclinical hypothyroidism was associated with an increased risk of coronary heart disease and mortality in patients with TSH levels higher than 10 IU/L, these associations did not differ in age, sex or ethnicity [51].

Treatment of subclinical hypothyroidism remains controversial [52, 53, 59]. Although there are no randomized controlled trials documenting decreased cardiovascular morbidity or mortality, some studies have suggested that treatment of subclinical hypothyroidism may result in improvement of cardiovascular risk factors, such as insulin sensitivity, glucose metabolism, soluble intercellular adhesion molecule-1 [60], endothelial progenitor cell levels [61], abnormalities in high-density lipoprotein metabolism [62], and common carotid intimamedia thickness [63]. According to the American Association of Clinical Endocrinologists, treatment is indicated in patients with TSH levels above 10 IU/ml or in patients with TSH levels between 5 and 10 IU/ml along with goiter or positive anti-thyroid peroxidase antibodies, since these patients have increased rates of progression to overt hypothyroidism. However, it should be kept in mind that TSH levels are sometimes transiently elevated, due to recovery from nonthyroidal illness or medication use. As a result, it has been recommended that TSH measure‐ ment should be repeated after 6–8 weeks in order to confirm the diagnosis of subclinical hypothyroidism, prior to any consideration of initiating therapy [52].

The prevalence of thyroid disease increases with age but very often presents different clinical manifestations from those found in younger patients. Autoimmune hypothyroidism is particularly prevalent in the elderly, and may be one of the factors that underlies an increased serum TSH reported by various studies in this population [64]. Hyperthyroidism is less common in among older subject, is frequently due to toxic nodular goiters, is mainly charac‐ terized by cardiovascular symptoms, and its manifestations are generally milder than in the younger patients. The associated decrease in TSH may also be less marked than that found in Graves' disease. Thus, the question of whether changes in circulating TSH levels in the elderly indicate a "physiologic adaptation" or are a reflection of associated health disturbances is still pertinent and awaiting further evaluation.

## **3. Conclusion**

cause and cardiovascular mortality rates compared with euthyroid individuals [45]. In a group of 400 men with a mean age of 78 years, Van den Beld and colleagues [46] showed that low serum levels of free T4 and T3 (with normal reverse T3 [rT3]) concentrations were associated with better physical performance and 4-year survival, whereas subjects with low serum levels of T3 and high rT3 concentrations did not show a survival advantage and had lower levels of physical activity. These two studies support the concept that some degree of physiologically decreased thyroid activity at the tissue level may have favorable effects in the oldest-old subjects, but caution should be exercised when interpreting the predic‐ tive value of thyroid dysfunction in the elderly, which may produce contradictory results

Subclinical hypothyroidism has been associated with heart failure [48] and with increased odds of metabolic syndrome [49], but the significance of increased serum TSH in elder subjects is still *sub judice*. Thus, treatment of subclinical hypothyroidism to prevent heart failure and cardiovascular disease in older people should be better evaluated in large randomized clinical

Thyroid hormones have an important role in many organic functions and their deficiency causes a wide spectrum of clinical presentations and symptoms. Neuromuscular manifesta‐ tions are well established in overt hypothyroidism and impaired muscle function is frequently observed. Thyroid hormone deficiency may also interfere substantially with various aspects of physical, mental and social well-being. The evidence for improvement of psychiatric symptoms with hormonal treatment of hypothyroidism, and the use of T3 to potentiate the response to treatment of depressive disorders suggest a direct relationship between thyroid hormones and psychiatric symptoms. Neurobiological evidence seems to corroborate the hypothesis of an organic basis of the effects of thyroid hormone on the brain and on psychiatric symptoms. There is some evidence that subclinical hypothyroidism may also be responsible for findings classically described in hypothyroidism. Symptoms and signs of hypothyroidism have been frequently found in subclinical hypothyroidism patients, as reported by many authors. In fact, Reuters et al described an improvement in some physical aspects of quality of

The frequency of subclinical hypothyroidism, varies from 6.5 to 15% in elder subjects [51, 52] Subclinical hypothyroidism has been associated with clustering of cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidaemia and hyperuricaemia [53], as well as with the development of insulin resistance, which is evident both in vivo and in vitro studies. The latter may be attributed to decreased insulin-stimulated rates of glucose transport in cells, due to impaired translocation of GLUT4 glucose transporters on the plasma membrane [54]. Multiple studies, with conflicting results, have examined the association of subclinical hypothyroidism with cardiovascular risk and mortality. A recent reanalysis of the Whickham Survey suggested a clear association of subclinical hypothyroidism with ischemic heart disease and mortality [55]. However, a meta-analysis of 15 observational studies indicated that increased cardiovascular risk is evident only in younger individuals with subclinical hypo‐ thyroidism [56]. In patients with type 2 diabetes mellitus, subclinical hypothyroidism has been found to be associated with reduced all-cause mortality [57]. Furthermore, age-related subtle

life after L-T4 treatment in patients with subclinical hypothyroidism [50].

if not considered in the appropriate context [15].

92 Hot Topics in Endocrine and Endocrine-Related Diseases

trials.

The effect of aging on the hypothalamus-pituitary-thyroid function is still a subject of contro‐ versies. Normal aging is accompanied by a slight decrease in pituitary thyrotropin release and especially by decreased peripheral degradation of T4, which results in a gradual age-depend‐ ent decline in serum triiodothyronine concentrations without changes in T4 levels. This slight decrease in plasma T3 concentrations occurs largely within the broad normal range of the healthy elderly population and has not been clearly related to functional changes during the aging process.

The frequency of subclinical hypothyroidism, varies from 6.5 to 15% in older subjects and treatment of subclinical hypothyroidism remains controversial. However, it should be kept in mind that TSH levels are sometimes transiently elevated, due to recovery from nonthyroidal illness or medication use.

[9] Keck ME, Hatzinger M, Wotjak CT, Landgraf R, Holsboer F, Neumann ID. Aging al‐ ters intrahypothalamic release patterns of vasopressin and oxitocin in rats. Eur J

Aging and Subclinical Thyroid Dysfunction http://dx.doi.org/10.5772/55194 95

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## **Author details**

Corrêa V. M. da Costa\* and D. Rosenthal

\*Address all correspondence to: vmccosta@biof.ufrj.br

Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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[50] Reuters, VS, Almeida CP, Teixeira PFS, Vigário PS, Ferreira MM, Castro CLN, Brasil, MA, Costa AJL, Buescu A, Vaisman M Effects of subclinical hypothyroidism treat‐ ment on psychiatric symptoms, muscular complaints, and quality of life. Arquivos

[51] Rodondi N, den Elzen WPJ, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J Subclinical hypothyroidism and the risk of coronary heart disease and

[52] Klubo-Gwiezdzinska J, Wartofsky L. Thyrotropin blood levels, subclinical hypothyr‐

[53] Ceresini G, Morganti S, Maggio M, Usberti E, Fiorino I, Artoni A, Teresi G, Belli S, Ridolfi V, Valenti G, Ceda GP. Subclinical thyroid disease in elderly subjects. Acta Bi‐

[54] Maratou E, Hadjidakis D, Kollias A, Tsegka K, Peppa M, Alevizaki M, Mitrou P, Lambadiari V, Boutati E, Nikzas D, Tountas N, Economopoulos T, Raptis SA, Dimi‐ triadis G. Studies of insulin resistance in patients with clinical and subclinical hypo‐

[55] Razvi S, Jola U, Weaver JU, Vanderpump MP, Pearce SHS. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of

[56] Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SHS. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a

[57] Ssthyapalan T, Manuchehri AM, Rigby AS, Atkin SL. Subclinical hypothyroidism is associated with reduced all-cause mortality in patients with type 2 diabetes. Diabetes

[58] Consonello A, Montesanto A, Berardelli M, De Rango F, Dato S, Mari V, Mazzei B, Lattanzio F, Passarino G.. A cross-section analysis of FT3 age-related changes in a group of old and oldest-old subjects, including centenarians' relatives, shows that a down-regulated thyroid function has a familial component and is related to longevi‐

[59] Vilar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev 2007;18(3):CD003419.

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**Chapter 4**

**Detection of Iodine Deficiency Disorders**

Imre Zoltán Kun, Zsuzsanna Szántó, József Balázs,

Additional information is available at the end of the chapter

Anisie Năsălean and Camelia Gliga

http://dx.doi.org/10.5772/54188

**1. Introduction**

Dunn, 2005).

**1.1. Physiological aspects**

**(Goiter and Hypothyroidism) in School-Children**

**Living in Endemic Mountainous Regions, After**

**the Implementation of Universal Salt Iodization**

Iodine and thyroid hormones are indispensable for somatic growth and development of sev‐ eral organs and systems in the fetus and infant. Their most important action is on the devel‐ opment of central nervous system in the critical period of life: from the fetal life up to the third year of age (Dobbing & Sands, 1973; Delong, 1989; Delange, 2000; Koibuchi & Chin, 2000). Thyroid hormone primary is involved in myelination and neuronal-glial cell differen‐ tiation (Bernal, 2005), brain maturation, and is crucial in the development and maintenance

Insufficient dietary iodine intake is the most important etiological factor of disorders caused by iodine deficiency, but goitrogens (perchlorates, thiocyanates), physiological pe‐ riods with high requirement of iodine (puberty, pregnancy, lactating period), increased urinary iodine excretion (nephrosis syndrome), high thyroxine binding globuline level (hyperestrogenism, oral contraceptives), lack of selenium, latent thyroid enzyme defects and autoimmune thyroid processes may contribute as well (Brook et al., 2008; Delange &

> © 2013 Kun et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

of normal physiological processes (Joffe & Sokolov, 1994, Neale et al., 2007).

**1.2. Etiology and pathophysiology of Iodine Deficiency Disorders (IDD)**

**Detection of Iodine Deficiency Disorders (Goiter and Hypothyroidism) in School-Children Living in Endemic Mountainous Regions, After the Implementation of Universal Salt Iodization**

Imre Zoltán Kun, Zsuzsanna Szántó, József Balázs, Anisie Năsălean and Camelia Gliga

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54188

**1. Introduction**

## **1.1. Physiological aspects**

Iodine and thyroid hormones are indispensable for somatic growth and development of sev‐ eral organs and systems in the fetus and infant. Their most important action is on the devel‐ opment of central nervous system in the critical period of life: from the fetal life up to the third year of age (Dobbing & Sands, 1973; Delong, 1989; Delange, 2000; Koibuchi & Chin, 2000). Thyroid hormone primary is involved in myelination and neuronal-glial cell differen‐ tiation (Bernal, 2005), brain maturation, and is crucial in the development and maintenance of normal physiological processes (Joffe & Sokolov, 1994, Neale et al., 2007).

## **1.2. Etiology and pathophysiology of Iodine Deficiency Disorders (IDD)**

Insufficient dietary iodine intake is the most important etiological factor of disorders caused by iodine deficiency, but goitrogens (perchlorates, thiocyanates), physiological pe‐ riods with high requirement of iodine (puberty, pregnancy, lactating period), increased urinary iodine excretion (nephrosis syndrome), high thyroxine binding globuline level (hyperestrogenism, oral contraceptives), lack of selenium, latent thyroid enzyme defects and autoimmune thyroid processes may contribute as well (Brook et al., 2008; Delange & Dunn, 2005).

© 2013 Kun et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Insufficient iodine intake leads to reduced thyroid hormone production, and all the conse‐ quences of iodine deficiency.

intelligence quotient may be reduced with about 10-15% in children living in mild, moderate

Detection of Iodine Deficiency Disorders (Goiter and Hypothyroidism) in School-Children…

http://dx.doi.org/10.5772/54188

103

The attention deficit and hyperactivity disorders (AD-HD) appear significantly more fre‐ quently in mild-moderate iodine-deficient geographical areas than in iodine-replete regions (Vermiglio et al., 2004). AD-HD was often observed in developed European countries

Several regions worldwide are believed to be iodine deficient of different degree, but the true extent is not fully known. 50% of the world population was estimated to live in coun‐ tries with iodine deficiency. IDD represented a major public health problem in the whole world at the end of the 20th and the beginning of the 21th century. In 1999 IDD did affect 2.225 billion people (38.4% of the world population) in 130 countries. About 700 million peo‐ ple (12.6% of the population) had goiter (WHO et al., 1999). In 1994, 43 million individuals

**Europe** is considered a mild to moderate iodine-deficient continent. Endemic goiter was of‐ ten reported in Europe, especially in mountainous areas. The reevaluation of iodine status in the late 1980's indicated that most European countries were still iodine deficient (Gutekunst & Scriba, 1989). Thus, programs for the elimination of iodine deficiency were initiated in several regions. In 1997 a study involving 26 European countries showed mild to severe io‐ dine deficiency in many regions, and a dramatic return of the deficiency within 5 to 7 years after the interruption of iodized salt program (Delange et al., 1998). In 1999 the World Health Organization (WHO), the United Nations Children's Fund (UNICEF) and the Inter‐ national Council for the Control of Iodine Deficiency Disorders (ICCIDD) reported that 18 countries in Western and Central Europe, including Romania and 14 countries in Eastern Europe were still affected by iodine deficiency; then Denmark, France and Ireland were add‐ ed to them. About 275 million people (31.6% of the population) were affected by IDD, and

**Romania** was considered an European endemic region at the end of the 20th century, where goiter frequency was very variable in different areas. The highest frequency was reported in hilly-mountainous regions, such as Maramureş (mountainous northern zone) the Carpathi‐ an Mountains, as well as the Transylvanian Basin (located at the center of the country). In 1993 the incidence of goiter was 1.19-26.45% in school-age children. In 1994-1995 the Thyro‐ mobil project realized in Braşov and Timişoara districts detected goiter by ultrasound in 13.5% of boys and in 10.1% of girls with age between 6-12 years. The incidence of goiter as‐ sessed by physical examination was 2.9-36.3% in 16 counties (Simescu & Ionescu, 1998). In conclusion, at the end of the 20th century iodine deficiency disorders remained a serious

During 2002-2004 the evaluation of iodine status in the whole territory of Romania has shown that 80% of the counties (especially rural regions) were moderately iodine defi‐ cient areas, the prevalence of endemic goiter was 0-40% and urinary iodine excretion

known currently with mild-moderate iodine deficiency (Vermiglio et al., 2004).

were estimated to be mentally handicapped as a consequence of iodine deficiency.

iodine deficient areas (Bleichrodt & Born, 1994).

130 million had goiter (15%) (WHO et al., 1999).

public health problem in our contry.

**1.4. Epidemiology**

Iodine deficiency occuring during the critical period of life induces the most damaging com‐ plications: irreversible mental retardation and cretenism (Hetzel, 1983; Stanbury, 1994; De‐ lange, 2001; Boyages, 1994, Bleichrodt, 1994). In severely endemic areas, cretenism may affect up to 5-15% of the population, being the most common cause of mental retardation (Glinoer, 2001, Morreale de Escobar et al., 2004; Pearce, 2009). However, milder brain im‐ pairments appear most frequently, such as poor school performance, reduced intellectual ability, impaired work capacity (Stanbury, 1994), apathy, lassitude, diminished mental ca‐ pacity, verbal and hearing impairments.

In children iodine deficiency causes goiter and reduced growth velocity as well. During time diffuse goiters can transform into uni- or multinodular goiters. These nodules can become autonomous, inducing hyperthyroidism, especially after administration of iodine.

#### **1.3. Clinical aspects – High-risk populational groups**

Iodine deficiency induces a large spectrum of organic and functional consequences grouped under the general heading of iodine deficiency disorders (IDD) (Hetzel, 1983). IDD reflect this public health problem more relevantly than the term "goiter". This group of disturban‐ ces is characterised by all of the ill-effects of iodine deficiency specific to different physiolog‐ ical stages (fetus, newborn, infant, schoolchild, adolescent, adult, especially pregnant woman) (Hetzel, 1983; Stanbury, et al., 1998; Lauberg et al., 2000; de Benoist et al., 2004; De‐ lange & Dunn, 2005), that can be prevented by adequate intake of iodine.

The population groups being at the highest risk to develop IDD and severe consequen‐ ces are fetuses, children under 2 years of age, pregnant and lactating women. The most devastating outcome of IDD is increased perinatal mortality and mental retardation. In infants iodine deficiency is the most frequent cause of preventable mental damage worldwide (de Benoist et al., 2004).

In school-age children and adolescents the main clinical manifestations are diffuse endemic goiter, subclinical thyroid dysfunctions (mainly hypothyroidism and rarely hyperthyroid‐ ism), and impaired mental function, retarded physical development as the impact of iodine deficiency on the central nervous system. The iodine-deficient thyroid gland in children is highly susceptible to nuclear radiation (Hetzel, 1983; Stanbury et al., 1998; Lauberg et al., 2000; de Benoist et al., 2004; Delange & Dunn, 2005, Zimmermann, 2009, Andersson et al., 2007).

In moderate iodine-deficient regions hypothyroidism may appear in children (Brook et al., 2008), at the same time delayed neurodevelopment with defective neuromotor and cognitive ability were also met (Vermiglio et al., 1990; Bleichrodt & Born, 1994; Pop et al., 2003).

Clinically euthyroid school-children in iodine-deficient regions have subtle or overt neuropsychointellectual deficits compared to iodine-sufficient children in the same ethnic, demo‐ graphic, nutritional and socioeconomic system (Vermiglio et al., 1990; Fenzi et al., 1990). The intelligence quotient may be reduced with about 10-15% in children living in mild, moderate iodine deficient areas (Bleichrodt & Born, 1994).

The attention deficit and hyperactivity disorders (AD-HD) appear significantly more fre‐ quently in mild-moderate iodine-deficient geographical areas than in iodine-replete regions (Vermiglio et al., 2004). AD-HD was often observed in developed European countries known currently with mild-moderate iodine deficiency (Vermiglio et al., 2004).

#### **1.4. Epidemiology**

Insufficient iodine intake leads to reduced thyroid hormone production, and all the conse‐

Iodine deficiency occuring during the critical period of life induces the most damaging com‐ plications: irreversible mental retardation and cretenism (Hetzel, 1983; Stanbury, 1994; De‐ lange, 2001; Boyages, 1994, Bleichrodt, 1994). In severely endemic areas, cretenism may affect up to 5-15% of the population, being the most common cause of mental retardation (Glinoer, 2001, Morreale de Escobar et al., 2004; Pearce, 2009). However, milder brain im‐ pairments appear most frequently, such as poor school performance, reduced intellectual ability, impaired work capacity (Stanbury, 1994), apathy, lassitude, diminished mental ca‐

In children iodine deficiency causes goiter and reduced growth velocity as well. During time diffuse goiters can transform into uni- or multinodular goiters. These nodules can become

Iodine deficiency induces a large spectrum of organic and functional consequences grouped under the general heading of iodine deficiency disorders (IDD) (Hetzel, 1983). IDD reflect this public health problem more relevantly than the term "goiter". This group of disturban‐ ces is characterised by all of the ill-effects of iodine deficiency specific to different physiolog‐ ical stages (fetus, newborn, infant, schoolchild, adolescent, adult, especially pregnant woman) (Hetzel, 1983; Stanbury, et al., 1998; Lauberg et al., 2000; de Benoist et al., 2004; De‐

The population groups being at the highest risk to develop IDD and severe consequen‐ ces are fetuses, children under 2 years of age, pregnant and lactating women. The most devastating outcome of IDD is increased perinatal mortality and mental retardation. In infants iodine deficiency is the most frequent cause of preventable mental damage

In school-age children and adolescents the main clinical manifestations are diffuse endemic goiter, subclinical thyroid dysfunctions (mainly hypothyroidism and rarely hyperthyroid‐ ism), and impaired mental function, retarded physical development as the impact of iodine deficiency on the central nervous system. The iodine-deficient thyroid gland in children is highly susceptible to nuclear radiation (Hetzel, 1983; Stanbury et al., 1998; Lauberg et al., 2000; de Benoist et al., 2004; Delange & Dunn, 2005, Zimmermann, 2009, Andersson et al.,

In moderate iodine-deficient regions hypothyroidism may appear in children (Brook et al., 2008), at the same time delayed neurodevelopment with defective neuromotor and cognitive ability were also met (Vermiglio et al., 1990; Bleichrodt & Born, 1994; Pop et al., 2003).

Clinically euthyroid school-children in iodine-deficient regions have subtle or overt neuropsychointellectual deficits compared to iodine-sufficient children in the same ethnic, demo‐ graphic, nutritional and socioeconomic system (Vermiglio et al., 1990; Fenzi et al., 1990). The

autonomous, inducing hyperthyroidism, especially after administration of iodine.

lange & Dunn, 2005), that can be prevented by adequate intake of iodine.

quences of iodine deficiency.

102 Hot Topics in Endocrine and Endocrine-Related Diseases

pacity, verbal and hearing impairments.

worldwide (de Benoist et al., 2004).

2007).

**1.3. Clinical aspects – High-risk populational groups**

Several regions worldwide are believed to be iodine deficient of different degree, but the true extent is not fully known. 50% of the world population was estimated to live in coun‐ tries with iodine deficiency. IDD represented a major public health problem in the whole world at the end of the 20th and the beginning of the 21th century. In 1999 IDD did affect 2.225 billion people (38.4% of the world population) in 130 countries. About 700 million peo‐ ple (12.6% of the population) had goiter (WHO et al., 1999). In 1994, 43 million individuals were estimated to be mentally handicapped as a consequence of iodine deficiency.

**Europe** is considered a mild to moderate iodine-deficient continent. Endemic goiter was of‐ ten reported in Europe, especially in mountainous areas. The reevaluation of iodine status in the late 1980's indicated that most European countries were still iodine deficient (Gutekunst & Scriba, 1989). Thus, programs for the elimination of iodine deficiency were initiated in several regions. In 1997 a study involving 26 European countries showed mild to severe io‐ dine deficiency in many regions, and a dramatic return of the deficiency within 5 to 7 years after the interruption of iodized salt program (Delange et al., 1998). In 1999 the World Health Organization (WHO), the United Nations Children's Fund (UNICEF) and the Inter‐ national Council for the Control of Iodine Deficiency Disorders (ICCIDD) reported that 18 countries in Western and Central Europe, including Romania and 14 countries in Eastern Europe were still affected by iodine deficiency; then Denmark, France and Ireland were add‐ ed to them. About 275 million people (31.6% of the population) were affected by IDD, and 130 million had goiter (15%) (WHO et al., 1999).

**Romania** was considered an European endemic region at the end of the 20th century, where goiter frequency was very variable in different areas. The highest frequency was reported in hilly-mountainous regions, such as Maramureş (mountainous northern zone) the Carpathi‐ an Mountains, as well as the Transylvanian Basin (located at the center of the country). In 1993 the incidence of goiter was 1.19-26.45% in school-age children. In 1994-1995 the Thyro‐ mobil project realized in Braşov and Timişoara districts detected goiter by ultrasound in 13.5% of boys and in 10.1% of girls with age between 6-12 years. The incidence of goiter as‐ sessed by physical examination was 2.9-36.3% in 16 counties (Simescu & Ionescu, 1998). In conclusion, at the end of the 20th century iodine deficiency disorders remained a serious public health problem in our contry.

During 2002-2004 the evaluation of iodine status in the whole territory of Romania has shown that 80% of the counties (especially rural regions) were moderately iodine defi‐ cient areas, the prevalence of endemic goiter was 0-40% and urinary iodine excretion (UIE) was reduced in 2/3 of studied individuals, detecting very low levels in pregnant women (Goldner, 2005).

ritory) and Dobrogea (south-eastern region), as well as Bucharest, the capital of the country (Simescu, 1999). The nationwide surveys conducted in 2002 have shown that non-iodized salt was still present in Romanian households: 31% of the households in urban and 37% in

Detection of Iodine Deficiency Disorders (Goiter and Hypothyroidism) in School-Children…

http://dx.doi.org/10.5772/54188

105

In the frame of the general strategy the following measurements were taken: a govern‐ mental decision (No. 586/5 June 2002) was adopted regarding universal salt iodization (mean KIO3 content of salt 34±8.5mg/kg − i.e. 25.5-42.5mg/kg, higher than previously); the use of iodized alimentary salt has become mandatory since 2003, and the compulso‐ ry iodization of salt used in baking industry was decided in 2004. In addition, the Na‐ tional Committee for universal salt iodization and IDD elimination (with multisectorial participation) was founded in 2004; in the same year the National Strategy on the elimi‐ nation of IDD during 2004-2012 was elaborated and adopted by governmental decision (Government of Romania, 2005). In 2005 the National Strategy on the elimination of IDD was founded in the Institute of Public Health Bucureşti. Consequently, the use of iodized salt in households increased to 96% in 2004 (compared to 53% in 2002) according to data furnished by the Institute of Mother and Child's Protection, but on the other hand io‐ dine content of alimentary salt proved to be insufficient (63%). Therefore, iodine supple‐ mentation was necessary, and 10% of school-children received iodine tablets, prescribed by general practitioners. Consequently the iodine-supplementation of school-children and pregnant women has improved considerably after the first 2 years of obligatory use of iodized alimentary salt, the urinary iodine excretion (UIE) becoming almost normal. With all the efforts IDD was still persisting in 2005, requiring enforced monitoring system of iodized salt production and consumption, strengthen the health promotion network etc.

**1.7. Indicators to assess baseline IDD status and to monitor and evaluate the IDD control**

Individual evaluation of IDD is based on clinical exam (physical examination to determine thyroid size and signs of thyroid dysfunctions, inclusion the case into populational group at risk for IDD, psychoneurosomatic assessment of children and adolescents), as well as labo‐ ratory and imagistical findings (UIE, TSH, FT4, FT3, radioiodine uptake, thyroid ultrasound

The epidemiological evaluation of a geoclimatic area includes the determination of io‐ dine content of the water and soil, and the assessment of different types of IDD in the population by indicators of iodine status at baseline and during the salt iodization pro‐ gram (impact indicators: median UIE, goiter frequency and high TSH levels) and by indi‐ cators evaluating the degree of successfullness and sustainability of the salt iodization

Indicators used to assess the iodine status of school-age children are median UIE, the prevalence of goiter determined by inspection/palpation or ultrasound, and the level of

and scintigraphy, fine-needle aspiration biopsy of thyroid nodules).

programs (sustainability indicators).

thyroglobulin (Tg).

rural localities (Government of Romania, 2005).

(Goldner, 2005).

**programs**

**Mureş County** is a 6,700 square km large hilly-mountainous region in Transylvanian Ba‐ sin, located in the center of Romania, populated with about 600,000 inhabitants. Similar investigations were performed here in 1950's (Cornea, 1957), which were continued until the '80 years, some of the results being published (Vasilescu et al., 1986, Hetzel et al., 1987). After that IDD survey by modern methods (UIE and thyroid ultrasound volume‐ try) were recommended. In 1998-1999 school-children from localities near the superior and middle hydrographical basin of the river Mureş, including Târgu Mureş (the capital city of Mureş County) were screened. The results showed mild iodine deficiency in most rural localities, moderate iodine deficiency in some villages, and normal iodine state in Târgu Mureş (Balázs et al., 1998, 2000/a,2000/b). Our survey targeting neonatal and ma‐ ternal screening, performed during 2001-2006, investigated the impact of universal salt iodization on the iodine status of these high-risk populations, and it showed that Mureş County is a moderately mild iodine-deficient area (Kun et al., 2003, Kun, 2006, Kun et al., 2007, Szántó et al., 2007).

#### **1.5. Official strategies to eliminate iodine deficiency disorders worldwide**

In 1990 the heads of States and Governments and other senior officials on the occasion of the World Summit for Children assumed a solemn obligation to eliminate the iodine deficiency disorders. In 2002 an international agreement for the long-term elimination of IDD until 2005 was accepted at the special Session of UNO dedicated to childhood health. The World Health Organization criteria to eliminate IDD through universal iodization of alimentary salt were the use of iodized salt at least in 90% of households, adequate iodine-concentration of salt (20-40mg/kg), and the implementation in practice of these measurements at least within two years. Reviewing the IDD status in Europe, a marked improvement in the status of iodine nutrition was observed, especially in the central parts of the continent (Delange, 2002; Vitti et al., 2003, Gerasimov, 2002).

#### **1.6. National strategy on the elimination of IDD in Romania**

The legislative measures for the elimination of endemic goiter were controlled for decades by the 637/1955 and the 1056/1962 Governmental Decisions, which ordered among others the distribution of potassium iodide (KI) tablets in school-age children. Thus, legislation on salt iodization did exist, but being not enforced it could not eradicate goiter. So, several Ro‐ manian counties, especially hilly-mountainous and rural regions remained iodine deficient according to the above presented data. In 1995 a new governmental order (No. 779/1995) proposed to review the prevention measures of IDD. In 1997 the 21 National Program of the Romanian Ministry of Health intentioned to reduce the frequency of IDD with at least 10% during the following 5 years. Romania has been taken part at the European strategy to elimi‐ nate iodine deficiency in Europe on the basis of the WHO criteria from 2002. Extended sur‐ veys were performed in Braşov County, Banat (in the central and the western region of the country, respectively, both being parts of the Thyromobil project), Moldova (the eastern ter‐ ritory) and Dobrogea (south-eastern region), as well as Bucharest, the capital of the country (Simescu, 1999). The nationwide surveys conducted in 2002 have shown that non-iodized salt was still present in Romanian households: 31% of the households in urban and 37% in rural localities (Government of Romania, 2005).

(UIE) was reduced in 2/3 of studied individuals, detecting very low levels in pregnant

**Mureş County** is a 6,700 square km large hilly-mountainous region in Transylvanian Ba‐ sin, located in the center of Romania, populated with about 600,000 inhabitants. Similar investigations were performed here in 1950's (Cornea, 1957), which were continued until the '80 years, some of the results being published (Vasilescu et al., 1986, Hetzel et al., 1987). After that IDD survey by modern methods (UIE and thyroid ultrasound volume‐ try) were recommended. In 1998-1999 school-children from localities near the superior and middle hydrographical basin of the river Mureş, including Târgu Mureş (the capital city of Mureş County) were screened. The results showed mild iodine deficiency in most rural localities, moderate iodine deficiency in some villages, and normal iodine state in Târgu Mureş (Balázs et al., 1998, 2000/a,2000/b). Our survey targeting neonatal and ma‐ ternal screening, performed during 2001-2006, investigated the impact of universal salt iodization on the iodine status of these high-risk populations, and it showed that Mureş County is a moderately mild iodine-deficient area (Kun et al., 2003, Kun, 2006, Kun et

**1.5. Official strategies to eliminate iodine deficiency disorders worldwide**

In 1990 the heads of States and Governments and other senior officials on the occasion of the World Summit for Children assumed a solemn obligation to eliminate the iodine deficiency disorders. In 2002 an international agreement for the long-term elimination of IDD until 2005 was accepted at the special Session of UNO dedicated to childhood health. The World Health Organization criteria to eliminate IDD through universal iodization of alimentary salt were the use of iodized salt at least in 90% of households, adequate iodine-concentration of salt (20-40mg/kg), and the implementation in practice of these measurements at least within two years. Reviewing the IDD status in Europe, a marked improvement in the status of iodine nutrition was observed, especially in the central parts of the continent (Delange,

The legislative measures for the elimination of endemic goiter were controlled for decades by the 637/1955 and the 1056/1962 Governmental Decisions, which ordered among others the distribution of potassium iodide (KI) tablets in school-age children. Thus, legislation on salt iodization did exist, but being not enforced it could not eradicate goiter. So, several Ro‐ manian counties, especially hilly-mountainous and rural regions remained iodine deficient according to the above presented data. In 1995 a new governmental order (No. 779/1995) proposed to review the prevention measures of IDD. In 1997 the 21 National Program of the Romanian Ministry of Health intentioned to reduce the frequency of IDD with at least 10% during the following 5 years. Romania has been taken part at the European strategy to elimi‐ nate iodine deficiency in Europe on the basis of the WHO criteria from 2002. Extended sur‐ veys were performed in Braşov County, Banat (in the central and the western region of the country, respectively, both being parts of the Thyromobil project), Moldova (the eastern ter‐

women (Goldner, 2005).

104 Hot Topics in Endocrine and Endocrine-Related Diseases

al., 2007, Szántó et al., 2007).

2002; Vitti et al., 2003, Gerasimov, 2002).

**1.6. National strategy on the elimination of IDD in Romania**

In the frame of the general strategy the following measurements were taken: a govern‐ mental decision (No. 586/5 June 2002) was adopted regarding universal salt iodization (mean KIO3 content of salt 34±8.5mg/kg − i.e. 25.5-42.5mg/kg, higher than previously); the use of iodized alimentary salt has become mandatory since 2003, and the compulso‐ ry iodization of salt used in baking industry was decided in 2004. In addition, the Na‐ tional Committee for universal salt iodization and IDD elimination (with multisectorial participation) was founded in 2004; in the same year the National Strategy on the elimi‐ nation of IDD during 2004-2012 was elaborated and adopted by governmental decision (Government of Romania, 2005). In 2005 the National Strategy on the elimination of IDD was founded in the Institute of Public Health Bucureşti. Consequently, the use of iodized salt in households increased to 96% in 2004 (compared to 53% in 2002) according to data furnished by the Institute of Mother and Child's Protection, but on the other hand io‐ dine content of alimentary salt proved to be insufficient (63%). Therefore, iodine supple‐ mentation was necessary, and 10% of school-children received iodine tablets, prescribed by general practitioners. Consequently the iodine-supplementation of school-children and pregnant women has improved considerably after the first 2 years of obligatory use of iodized alimentary salt, the urinary iodine excretion (UIE) becoming almost normal. With all the efforts IDD was still persisting in 2005, requiring enforced monitoring system of iodized salt production and consumption, strengthen the health promotion network etc. (Goldner, 2005).

#### **1.7. Indicators to assess baseline IDD status and to monitor and evaluate the IDD control programs**

Individual evaluation of IDD is based on clinical exam (physical examination to determine thyroid size and signs of thyroid dysfunctions, inclusion the case into populational group at risk for IDD, psychoneurosomatic assessment of children and adolescents), as well as labo‐ ratory and imagistical findings (UIE, TSH, FT4, FT3, radioiodine uptake, thyroid ultrasound and scintigraphy, fine-needle aspiration biopsy of thyroid nodules).

The epidemiological evaluation of a geoclimatic area includes the determination of io‐ dine content of the water and soil, and the assessment of different types of IDD in the population by indicators of iodine status at baseline and during the salt iodization pro‐ gram (impact indicators: median UIE, goiter frequency and high TSH levels) and by indi‐ cators evaluating the degree of successfullness and sustainability of the salt iodization programs (sustainability indicators).

Indicators used to assess the iodine status of school-age children are median UIE, the prevalence of goiter determined by inspection/palpation or ultrasound, and the level of thyroglobulin (Tg).

**Urinary iodine excretion (UIE)** is a sensitive tool to indicate the present iodine status, being useful to evaluate the recent changes of iodine intake in the target population (Gorstein, 2001).

ed, because the values provided on the basis of data collected in Europe (Delange et al., 1997) were overestimated by 30% (Zimmermann et al., 2001). Reliable new values have

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A geographical region is defined as iodine-deficient if the median UIE is below 100μg/L or the prevalence of goiter is higher than 5% among school-age children (aged 6 to 12 years)

The **serum TSH level** as an indicator of iodine status is particularly used in neonatal screen‐ ing programs. A region is considered iodine-deficient if the frequency of serum TSH>5mIU/L is higher than 3% (WHO et al., 1994; 2001). In school-children the level of TSH measured together with free-thyroxine (FT4) determines the thyroid dysfunction (subclinical

The major goal of IDD elimination programs is to ensure the sustained elimination of iodine deficiency. The sustainability is evaluated by median UIE, besides other sustainability indi‐ cators (the proportion of households consuming adequately iodized salt, and programmatic indicators, such as the effectiveness of public health authorities and salt industry to monitor and control the whole procession). Sustained elimination of iodine deficiency is ensured if the proportion of target population with UIE<100μg/L is under 50%, and of those with

The human body needs very small amount of iodine (in average 200μg/day), but the in‐ take should be continuous. The recommended daily iodine intake varies by references. In 2001 the WHO/UNICEF/ICCIDD recommended 120μg/day iodine for school-children (6 to 12 years) and 150 μg for individuals above 12 years, but with these amounts the rec‐ ommended UIE of 100-200μg/L was not obtained, reaching only 55-80μg/L. In addition to table salt, iodization of animal food and bottled table water can contribute to iodine

Iodine deficiency continues to be a major public health problem in many parts of the world. World statistics show that 1.6 billion people are at risk of being affected by the reduced iodine in their diet, 50 million children are suffering of IDD and every year 100.000 children are born with cretenism worldwide. In 2002 a number of 14 countries of Western and Central Europe have reached a normal status of iodine nutrition, 3 coun‐ tries were close to iodine sufficiency, but 13 countries, including Romania did remain

The WHO/UNICEF/ICCIDD report published in 2007 stated that 70% of the world popula‐ tion had access to iodized salt (Andersson et al., 2007), although only 41 countries world‐ wide can be classified as consuming adequate iodine. Using the median UIE of <100μg/L as the current indicator for insufficient iodine intake, 2 billion people remain at risk for iodine

been provided in iodine-sufficient school-children (Zimmermann et al., 2004).

or overt hypothyroidism) which has appeared in the context of iodine deficiency.

(WHO et al., 2001).

UIE<50μg/L is below 20% (WHO et al., 2001).

intake (Andersson et al., 2007; Szybinski, 2011).

**1.9. Current iodine status worldwide**

with persisting IDD (Delange, 2002).

**1.8. Iodine requirement, IDD prophylaxis in school-age children**


**Table 1.** The degree of iodine deficiency in school-age children based on the median UIE, according to WHO classification (WHO et al., 2001).

The **frequency of goiter** (total goiter prevalence – TGP) reflects the population's history of iodine nutrition but not its present iodine status, because thyroid size becomes normal for months or years after the correction of iodine deficiency. This indicator is useful to assess the severity of IDD at baseline and the long-term impact of control programs (de Benoist et al., 2004), but it is of limited usefulness in assessing the impact of programs once salt iodiza‐ tion has commenced (WHO et al., 2001).


**Table 2.** The degree of iodine deficiency in school-age children based on goiter prevalence, according to WHO classification (WHO et al., 1994, 2001).

The screening of thyroid volume assessed by inspection and palpation may furnish sub‐ jective bias in as much as 30-40% of the cases (Delange, 1994; Gutekunst & Teichert, 1993; WHO et al., 1994; Vitti et al., 1994), being imprecise mostly for small goiters. There‐ fore, thyroid ultrasound (US) is a far better method to detect goiter in population, espe‐ cially in children (Gutekunst & Teichert, 1993). It determines more accurately and objectively the thyroid size, but there is no agreement on reference values. The upper normal limit of thyroid volume in children living in normal iodine-supply regions was elaborated (Delange et al., 1997). In the following years the reevaluation of previous measurements and the standardization of values in iodine-deficient regions were suggest‐ ed, because the values provided on the basis of data collected in Europe (Delange et al., 1997) were overestimated by 30% (Zimmermann et al., 2001). Reliable new values have been provided in iodine-sufficient school-children (Zimmermann et al., 2004).

A geographical region is defined as iodine-deficient if the median UIE is below 100μg/L or the prevalence of goiter is higher than 5% among school-age children (aged 6 to 12 years) (WHO et al., 2001).

The **serum TSH level** as an indicator of iodine status is particularly used in neonatal screen‐ ing programs. A region is considered iodine-deficient if the frequency of serum TSH>5mIU/L is higher than 3% (WHO et al., 1994; 2001). In school-children the level of TSH measured together with free-thyroxine (FT4) determines the thyroid dysfunction (subclinical or overt hypothyroidism) which has appeared in the context of iodine deficiency.

The major goal of IDD elimination programs is to ensure the sustained elimination of iodine deficiency. The sustainability is evaluated by median UIE, besides other sustainability indi‐ cators (the proportion of households consuming adequately iodized salt, and programmatic indicators, such as the effectiveness of public health authorities and salt industry to monitor and control the whole procession). Sustained elimination of iodine deficiency is ensured if the proportion of target population with UIE<100μg/L is under 50%, and of those with UIE<50μg/L is below 20% (WHO et al., 2001).

#### **1.8. Iodine requirement, IDD prophylaxis in school-age children**

The human body needs very small amount of iodine (in average 200μg/day), but the in‐ take should be continuous. The recommended daily iodine intake varies by references. In 2001 the WHO/UNICEF/ICCIDD recommended 120μg/day iodine for school-children (6 to 12 years) and 150 μg for individuals above 12 years, but with these amounts the rec‐ ommended UIE of 100-200μg/L was not obtained, reaching only 55-80μg/L. In addition to table salt, iodization of animal food and bottled table water can contribute to iodine intake (Andersson et al., 2007; Szybinski, 2011).

#### **1.9. Current iodine status worldwide**

**Urinary iodine excretion (UIE)** is a sensitive tool to indicate the present iodine status, being useful to evaluate the recent changes of iodine intake in the target population

**Median UIE (μg/L) Iodine deficiency Iodine intake** < 20 severe insufficient 20-49 moderate insufficient 50-99 mild insufficient

The **frequency of goiter** (total goiter prevalence – TGP) reflects the population's history of iodine nutrition but not its present iodine status, because thyroid size becomes normal for months or years after the correction of iodine deficiency. This indicator is useful to assess the severity of IDD at baseline and the long-term impact of control programs (de Benoist et al., 2004), but it is of limited usefulness in assessing the impact of programs once salt iodiza‐

Mean serum Tg level [ng/mL] 10-19.9 20-39.9 ≥40

**Table 2.** The degree of iodine deficiency in school-age children based on goiter prevalence, according to WHO

The screening of thyroid volume assessed by inspection and palpation may furnish sub‐ jective bias in as much as 30-40% of the cases (Delange, 1994; Gutekunst & Teichert, 1993; WHO et al., 1994; Vitti et al., 1994), being imprecise mostly for small goiters. There‐ fore, thyroid ultrasound (US) is a far better method to detect goiter in population, espe‐ cially in children (Gutekunst & Teichert, 1993). It determines more accurately and objectively the thyroid size, but there is no agreement on reference values. The upper normal limit of thyroid volume in children living in normal iodine-supply regions was elaborated (Delange et al., 1997). In the following years the reevaluation of previous measurements and the standardization of values in iodine-deficient regions were suggest‐

**The degree of iodine deficiency mild moderate severe**

5-19.9 20-29.9 ≥30

5-19.9 20-29.9 ≥30

**Table 1.** The degree of iodine deficiency in school-age children based on the median UIE, according to WHO

(Gorstein, 2001).

classification (WHO et al., 2001).

tion has commenced (WHO et al., 2001).

106 Hot Topics in Endocrine and Endocrine-Related Diseases

**Indicator**

Prevalence of goiter assessed by inspection and palpation [%]

Frequency of thyroid volume >97th percentile by ultrasound\* [%]

\*corresponding to the upper normal limit of thyroid volume

classification (WHO et al., 1994, 2001).

Iodine deficiency continues to be a major public health problem in many parts of the world. World statistics show that 1.6 billion people are at risk of being affected by the reduced iodine in their diet, 50 million children are suffering of IDD and every year 100.000 children are born with cretenism worldwide. In 2002 a number of 14 countries of Western and Central Europe have reached a normal status of iodine nutrition, 3 coun‐ tries were close to iodine sufficiency, but 13 countries, including Romania did remain with persisting IDD (Delange, 2002).

The WHO/UNICEF/ICCIDD report published in 2007 stated that 70% of the world popula‐ tion had access to iodized salt (Andersson et al., 2007), although only 41 countries world‐ wide can be classified as consuming adequate iodine. Using the median UIE of <100μg/L as the current indicator for insufficient iodine intake, 2 billion people remain at risk for iodine deficiency (Andersson et al., 2007). The recent WHO/ICCIDD study on IDD carried out in 2011 showed that national surveys covered 114 countries, and since 2007 new data have been obtained from 74 countries. From these data it emerged that populations of 37 coun‐ tries were still classified as iodine deficient, of which 9 had moderate and 28 mild deficiency. IDD in population show a declining tendency, from 54% in 2003 to 47% in 2007 and 37% in 2011. Corresponding results for school-age children were 36.5%, 31.5% and 30.5%, respec‐ tively. However, only 32% of these studies were carried out in known iodine deficient areas. In the European Union only 44% of population live in iodine sufficient areas (Andersson, 2011). The experience accumulated thus far has shown that the prevention and control of io‐ dine deficiency requires monitoring to be sustainable.

The endocrinologists arrived to schools located in the mentioned geographical areas, and the children of classes between Vth-VIIIth were examined at the school's health room. This screening activity was previously planed, thus the children were told not to eat on the morn‐

Caşva 11.51±1.89 34 21 55 Glăjărie 11.80±1.32 20 10 30 Ibăneşti 12.80±1.23 24 26 50 Total 12.05±1.64 78 (57.7%) 57 (42.3%) 135

**Table 3.** Mean age and gender distribution of school-children living in the studied mountainous villages of Mureş County

**Methods.** Data recording was completed with initials, age, gender, hight, weight, physical examination, laboratory and imagistic information for every child. In all cases physical ex‐ amination and thyroid ultrasonography were performed, then urine and blood samples were collected in order to measure UIE, the level of TSH (thyrotropin), free-thyroxine (FT4)

Samples of drinking water and alimentary salt accesible in the local food marts in every lo‐

Firstly family and personal history were taken, than physical examination and thyroid ultra‐

*Family history* of thyroid dysfunctions, goiter, or any known thyroid disease of parents and other relatives was clarified. In the case of 82 children we could take a valuable familial

**Physical examination** consisted of general examination of organs and segments of the body,

**Anthropometric parameters** were determined. *Hight* and *weight* were measured and com‐ pared to the standard, being calculated the height-SDS and weight-SDS. Normal height and weight charts of Prader for both sexes from Switzerland reported in 1989 were used, as these are accepted for children living in Romania and similar charts adapted for the Romanian

We distributed the casuistry in cohorts with/without hypothyroidism, with/without iodine deficiency, and the mean height and weight of the group was calculated, as well as the data

**Local examination** of the anterior and lateral cervical regions including the regional lymph nodes represents an important part of the investigation. Inspection and palpation of thyroid gland provided information about the size, consistency and surface of the thyroid, as well as

**(years) No. boys No. girls Total number**

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109

ing of investigations.

**Locality Mean age**

and anti-thyroid peroxidase antibodies (TPO-Ab).

sonography were performed.

population are not available.

cality were collected in order to measure their iodine content.

anamnesis. Personal history of thyroid disease also was registered.

focusing on the possible signs and symptoms of thyroid disorders.

between groups were compared by statistical means.

Endemic cretinism as the most severe complication of IDD was practically eradicated as late as the second half of the 20th century by prophylactic programs conducted worldwide, but serious consequences of IDD are persisting and currently iodine deficiency still remained a major populational health problem.

The iodine status of Mureş County has not been evaluated since 2000. Similarly, the impact of universal salt iodization program initiated in 2003 was not studied in Mureş County. In 2006 we proposed to evaluate the outcome of universal salt iodization in school-age children from iodine-deficient regions of Mureş County, after the legislative changes targeting the improvement of iodine status in Romania were initiated.

## **2. Objectives**

Our primary objective was to evaluate the impact of universal salt iodization (with in‐ creased KIO3-content) at school-age children living in formerly iodine-deficient areas from Mures County (mainly from rural mountainous regions). Secondly, we proposed to assess the frequency and grade of endemic goiter, as well as of thyroid dysfunctions in children from these well known iodine-deficient regions. Additionaly, we intended to diagnose other etiological factors of goiter and hypothyroidism, such as juvenile chronic autoimmune thy‐ roiditis (Hashimoto's disease).

## **3. Material and methods**

**Material**. The target population was school-age children, having 8-14 years of age of both sexes, living in mountainous rural localities of Mureş County known as iodine deficient re‐ gions in 1999-2000, before the implementation of universal salt iodization.

In October 2006 the team of endocrinologists from Endocrinology Clinic Târgu Mureş inves‐ tigated 135 school-children (Vth-VIIIth classes) from three villages known as endemic areas in Gurghiu Valley: 55 children from Caşva, 30 from Glăjărie and 50 from Ibăneşti. The total population of these three localities is estimated by the censuses of population and housing realized in Romania in 2002: Caşva had 569, Glăjărie 1797 and Ibăneşti 2377 inhabitants.

The endocrinologists arrived to schools located in the mentioned geographical areas, and the children of classes between Vth-VIIIth were examined at the school's health room. This screening activity was previously planed, thus the children were told not to eat on the morn‐ ing of investigations.

deficiency (Andersson et al., 2007). The recent WHO/ICCIDD study on IDD carried out in 2011 showed that national surveys covered 114 countries, and since 2007 new data have been obtained from 74 countries. From these data it emerged that populations of 37 coun‐ tries were still classified as iodine deficient, of which 9 had moderate and 28 mild deficiency. IDD in population show a declining tendency, from 54% in 2003 to 47% in 2007 and 37% in 2011. Corresponding results for school-age children were 36.5%, 31.5% and 30.5%, respec‐ tively. However, only 32% of these studies were carried out in known iodine deficient areas. In the European Union only 44% of population live in iodine sufficient areas (Andersson, 2011). The experience accumulated thus far has shown that the prevention and control of io‐

Endemic cretinism as the most severe complication of IDD was practically eradicated as late as the second half of the 20th century by prophylactic programs conducted worldwide, but serious consequences of IDD are persisting and currently iodine deficiency still remained a

The iodine status of Mureş County has not been evaluated since 2000. Similarly, the impact of universal salt iodization program initiated in 2003 was not studied in Mureş County. In 2006 we proposed to evaluate the outcome of universal salt iodization in school-age children from iodine-deficient regions of Mureş County, after the legislative changes targeting the

Our primary objective was to evaluate the impact of universal salt iodization (with in‐ creased KIO3-content) at school-age children living in formerly iodine-deficient areas from Mures County (mainly from rural mountainous regions). Secondly, we proposed to assess the frequency and grade of endemic goiter, as well as of thyroid dysfunctions in children from these well known iodine-deficient regions. Additionaly, we intended to diagnose other etiological factors of goiter and hypothyroidism, such as juvenile chronic autoimmune thy‐

**Material**. The target population was school-age children, having 8-14 years of age of both sexes, living in mountainous rural localities of Mureş County known as iodine deficient re‐

In October 2006 the team of endocrinologists from Endocrinology Clinic Târgu Mureş inves‐ tigated 135 school-children (Vth-VIIIth classes) from three villages known as endemic areas in Gurghiu Valley: 55 children from Caşva, 30 from Glăjărie and 50 from Ibăneşti. The total population of these three localities is estimated by the censuses of population and housing realized in Romania in 2002: Caşva had 569, Glăjărie 1797 and Ibăneşti 2377 inhabitants.

gions in 1999-2000, before the implementation of universal salt iodization.

dine deficiency requires monitoring to be sustainable.

improvement of iodine status in Romania were initiated.

major populational health problem.

108 Hot Topics in Endocrine and Endocrine-Related Diseases

**2. Objectives**

roiditis (Hashimoto's disease).

**3. Material and methods**


**Table 3.** Mean age and gender distribution of school-children living in the studied mountainous villages of Mureş County

**Methods.** Data recording was completed with initials, age, gender, hight, weight, physical examination, laboratory and imagistic information for every child. In all cases physical ex‐ amination and thyroid ultrasonography were performed, then urine and blood samples were collected in order to measure UIE, the level of TSH (thyrotropin), free-thyroxine (FT4) and anti-thyroid peroxidase antibodies (TPO-Ab).

Samples of drinking water and alimentary salt accesible in the local food marts in every lo‐ cality were collected in order to measure their iodine content.

Firstly family and personal history were taken, than physical examination and thyroid ultra‐ sonography were performed.

*Family history* of thyroid dysfunctions, goiter, or any known thyroid disease of parents and other relatives was clarified. In the case of 82 children we could take a valuable familial anamnesis. Personal history of thyroid disease also was registered.

**Physical examination** consisted of general examination of organs and segments of the body, focusing on the possible signs and symptoms of thyroid disorders.

**Anthropometric parameters** were determined. *Hight* and *weight* were measured and com‐ pared to the standard, being calculated the height-SDS and weight-SDS. Normal height and weight charts of Prader for both sexes from Switzerland reported in 1989 were used, as these are accepted for children living in Romania and similar charts adapted for the Romanian population are not available.

We distributed the casuistry in cohorts with/without hypothyroidism, with/without iodine deficiency, and the mean height and weight of the group was calculated, as well as the data between groups were compared by statistical means.

**Local examination** of the anterior and lateral cervical regions including the regional lymph nodes represents an important part of the investigation. Inspection and palpation of thyroid gland provided information about the size, consistency and surface of the thyroid, as well as the existence of palpable thyroid nodules and cervical lymph node enlargement. Goiter was clinically defined according to the WHO criteria in 1960 for the classification of thyroid size (Perez et al., 1960). Goiter was diagnosed if its size was grade 1a (palpable thyroid lobes larger than the terminal phalanges of the subject's thumbs), grade 1b (visible with the ex‐ tended neck), grade 2 (visible with the head in normal position, but the goiter does not ex‐ tends beyond the medial edge of the sternocleidomastoidian muscles) or grade 3 (visible at a distance and it extends beyond the previous limits) (Perez et al., 1960). Nodules in the thy‐ roid that is otherwise not enlarged fall into grade 1 category (Delange & Dunn, 2005). The inspection and palpation of the anterior and lateral cervical regions were effectuated at all school-age children included in our study.

**Median P97 of thyroid volume (mL)**

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111

**Age (years)** 6 7 8 9 10 11 12 13 14 15 **Boys** 2.91 3.29 3.71 4.19 4.73 5.34 6.03 - - - **Girls** 2.84 3.26 3.76 4.32 4.98 5.73 6.59 - - - **BSA (kg/m2)** 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 **Boys** 2.95 3.32 3.73 4.2 4.73 5.32 5.98 6.73 7.57 - **Girls** 2.91 3.32 3.79 4.32 4.92 5.61 6.40 7.29 8.32 -

**Table 5.** Age- and BSA-ajusted median values (97th percentile – P97) for thyroid volume measured by ultrasound for

The standards of normal thyroid volume according to age and BSA are very different in the references, so at last we evaluated our results on the basis of the values obtained in the re‐ gion surrounding Iaşi, (in Moldova, eastern part of Romania) provided by the team of endo‐

**Intellectual capacity** of 59 children was evaluated by school performances provided by the school's teaching and medical stuff. School performance spectrum was distributed into four

In order to measure **urinary iodine excretion** (UIE), the 24-hours urine was collected, than the whole urine quantity was mixed and a 50mL sample was retained and transported to the laboratory. Urinary iodine concentration was determined with the colorimetric procedure based on the Sandell-Kolthoff reaction, using ammonium persulfate (WHO et al., 2001;

After obtaining absolute urinary iodine levels for individuals, mean and median UIE values

**Urinary iodine excretion measurement** expressed in μg/L refers to the median value of the UIE calculated for the target population. We estimated the impact of universal salt iodiza‐ tion to eliminate iodine deficiency at school-age children by the interpretation of UIE based

The assessment of **thyroid function** was also performed. Serum TSH, FT4 and TPO-Ab lev‐ els were determined from 5 mL total blood collected by venipuncture into heparinized

**Serum TSH and free-T4** levels were measured from venous blood in the morning in all chil‐ dren included in the study. Third generation ECLIA (electrochemiluminescence immunoas‐ say) was applied at the Central Laboratory of Emergency Clinical Hospital Mureş County. Normal range for TSH was considered between 0.27-4.2mIU/L and for FT4 between 0.932-1.71ng/dL. We evaluated the presence and the severity of hypothyroidism, being diag‐ nosed overt primary hypothyroidism in case of high TSH with reduced FT4, and subclinical

form if TSH was increased and FT4 normal or at the lower normal limit.

children living in iodine-sufficent areas (Zimmermann et al., 2004).

crinologists from Iaşi (Vulpoi et al., 2002; Zbranca et al., 2008).

subgroups: very good, good, mediocre and low capacity.

Dunn et al., 1993).

on WHO criteria (Table 1).

tubes.

were calculated for our studied groups.

**Thyroid ultrasound** (US) was performed in all cases by a portable instrument (Sono Ace 600 − SA-600) using a 7.5-MHz linear transducer. The volume of thyroid lobes was measured and the total thyroid volume was calculated. The structure of thyroid tissue and the pres‐ ence/absence of thyroid nodules were also investigated.

The volume of each thyroid lobe was calculated by the formula: V = lenght × width × depth × 0.479 (all values expressed in cm), than they were added together to obtain the total volume of the gland. The isthmus was ignored unless a nodule was present. In our study the volume of lobes was calculated automatically by the computer of the US equipment.

We evaluated our data according to values of ultrasound provided by the Thyromobil project performed in Europe (Delange et al., 1997 – Table 4.) and to data furnished by Zim‐ mermann et al. (Zimmermann et al., 2004 – Table 5.) for all children with age between 6-12 years. The thyroid volume measured in 13-14 years-old adolescents was compared to values provided by Delange et al., 1997.

The measured thyroid volumes were also adjusted to the body surface area (BSA) and the obtained data were evaluated according to the upper normal limits (Table 5).

Body surface area was calculated using a variant of Dubois formula:

BSA (m²) = 0.007184 x Height(cm)0.725 x Weight(kg)0.425.

After evaluation of thyroid volume for every children, the frequency and the grade of goiter was determined in the cohort.


**Table 4.** Age- and BSA-adjusted upper normal limit of thyroid volume measured by ultrasound for children living in iodine-sufficent areas (Delange et al., 1997).


the existence of palpable thyroid nodules and cervical lymph node enlargement. Goiter was clinically defined according to the WHO criteria in 1960 for the classification of thyroid size (Perez et al., 1960). Goiter was diagnosed if its size was grade 1a (palpable thyroid lobes larger than the terminal phalanges of the subject's thumbs), grade 1b (visible with the ex‐ tended neck), grade 2 (visible with the head in normal position, but the goiter does not ex‐ tends beyond the medial edge of the sternocleidomastoidian muscles) or grade 3 (visible at a distance and it extends beyond the previous limits) (Perez et al., 1960). Nodules in the thy‐ roid that is otherwise not enlarged fall into grade 1 category (Delange & Dunn, 2005). The inspection and palpation of the anterior and lateral cervical regions were effectuated at all

**Thyroid ultrasound** (US) was performed in all cases by a portable instrument (Sono Ace 600 − SA-600) using a 7.5-MHz linear transducer. The volume of thyroid lobes was measured and the total thyroid volume was calculated. The structure of thyroid tissue and the pres‐

The volume of each thyroid lobe was calculated by the formula: V = lenght × width × depth × 0.479 (all values expressed in cm), than they were added together to obtain the total volume of the gland. The isthmus was ignored unless a nodule was present. In our study the volume

We evaluated our data according to values of ultrasound provided by the Thyromobil project performed in Europe (Delange et al., 1997 – Table 4.) and to data furnished by Zim‐ mermann et al. (Zimmermann et al., 2004 – Table 5.) for all children with age between 6-12 years. The thyroid volume measured in 13-14 years-old adolescents was compared to values

The measured thyroid volumes were also adjusted to the body surface area (BSA) and the

After evaluation of thyroid volume for every children, the frequency and the grade of goiter

**Age (years)** 6 7 8 9 10 11 12 13 14 15 **Boys** 5.4 5.7 6.1 6.8 7.8 9.0 10.4 12.0 13.9 16.0 **Girls** 5.0 5.9 6.9 8.0 9.2 10.4 11.7 13.1 14.6 16.1 **BSA (kg/m2)** 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 **Boys** 4.7 5.3 6.0 7.0 8.0 9.3 10.7 12.2 14.0 15.8 **Girls** 4.8 5.9 7.1 8.3 9.5 10.7 11.9 13.1 14.3 15.6

**Table 4.** Age- and BSA-adjusted upper normal limit of thyroid volume measured by ultrasound for children living in

of lobes was calculated automatically by the computer of the US equipment.

obtained data were evaluated according to the upper normal limits (Table 5).

Body surface area was calculated using a variant of Dubois formula:

**Upper normal limit of thyroid volume (mL)**

BSA (m²) = 0.007184 x Height(cm)0.725 x Weight(kg)0.425.

school-age children included in our study.

110 Hot Topics in Endocrine and Endocrine-Related Diseases

provided by Delange et al., 1997.

was determined in the cohort.

iodine-sufficent areas (Delange et al., 1997).

ence/absence of thyroid nodules were also investigated.

**Table 5.** Age- and BSA-ajusted median values (97th percentile – P97) for thyroid volume measured by ultrasound for children living in iodine-sufficent areas (Zimmermann et al., 2004).

The standards of normal thyroid volume according to age and BSA are very different in the references, so at last we evaluated our results on the basis of the values obtained in the re‐ gion surrounding Iaşi, (in Moldova, eastern part of Romania) provided by the team of endo‐ crinologists from Iaşi (Vulpoi et al., 2002; Zbranca et al., 2008).

**Intellectual capacity** of 59 children was evaluated by school performances provided by the school's teaching and medical stuff. School performance spectrum was distributed into four subgroups: very good, good, mediocre and low capacity.

In order to measure **urinary iodine excretion** (UIE), the 24-hours urine was collected, than the whole urine quantity was mixed and a 50mL sample was retained and transported to the laboratory. Urinary iodine concentration was determined with the colorimetric procedure based on the Sandell-Kolthoff reaction, using ammonium persulfate (WHO et al., 2001; Dunn et al., 1993).

After obtaining absolute urinary iodine levels for individuals, mean and median UIE values were calculated for our studied groups.

**Urinary iodine excretion measurement** expressed in μg/L refers to the median value of the UIE calculated for the target population. We estimated the impact of universal salt iodiza‐ tion to eliminate iodine deficiency at school-age children by the interpretation of UIE based on WHO criteria (Table 1).

The assessment of **thyroid function** was also performed. Serum TSH, FT4 and TPO-Ab lev‐ els were determined from 5 mL total blood collected by venipuncture into heparinized tubes.

**Serum TSH and free-T4** levels were measured from venous blood in the morning in all chil‐ dren included in the study. Third generation ECLIA (electrochemiluminescence immunoas‐ say) was applied at the Central Laboratory of Emergency Clinical Hospital Mureş County. Normal range for TSH was considered between 0.27-4.2mIU/L and for FT4 between 0.932-1.71ng/dL. We evaluated the presence and the severity of hypothyroidism, being diag‐ nosed overt primary hypothyroidism in case of high TSH with reduced FT4, and subclinical form if TSH was increased and FT4 normal or at the lower normal limit.

The level of **anti-thyroid peroxidase antibodies** (TPO-Ab) was measured in every schoolchildren. Values under 50IU/mL were considered normal. TPO-Ab above 50IU/mL indicates the presence of juvenile form of Hashimoto's thyroiditis.

Physical examination of the anterior and lateral cervical regions has shown a 51.1% owerall goiter frequency. In all cases diffuse goiter was palpable. In more than half of the cases only small goiter (grade Ia) was present, and goiter grade II was met very rare‐

> 27.3% (15/55)

26.7% (8/30)

30% (15/50)

Total 135 48.1% 28.1% 16.3% 6.7% 51.1%

**Thyroid volume assessment by ultrasound** Thyroid ultrasound was performed in every child enrolled in our study in 2006, the data regarding thyroid volume were calculated in

8 5 2.77 5.23 3.16 3.67±1.04

9 7 3.18 4.87 3.67 3.82±0.63

10 10 4.11 10.24 5.29 5.82±1.77

11 24 3.62 8.37 6.36 6.01±1.61

12 26 2.65 21 5.71 6.46±3.42

13 33 4.45 16.04 7.86 8.42±3.09

14 30 3.61 13.18 7.73 8.17±2.47

**Table 8.** Age-related minimum, maximum, median, and mean thyroid volume measured by ultrasound in the

**Thyroid size on physical examination Owerall goiter**

**Thyroid volume [mL] Min. Max. Median Mean**

5.4% (3/55)

3.3% (1/30)

10% (5/50)

43.6% (24/55)

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113

46.7% (14/30)

62% (31/50)

**Grade 0 Grade Ia Grade Ib Grade II frequency**

Detection of Iodine Deficiency Disorders (Goiter and Hypothyroidism) in School-Children…

10.9% (6/55)

16.7% (5/30)

22% (11/50)

ly (6.7% of all children).

Caşva 55

Glăjărie 30

Ibăneşti 50

**Age [years]**

investigated school-children

**Number of cases**

> 56.4% (31/55)

> 53.3% (16/30)

> 36% (18/50)

**Table 7.** The distribution of thyroid size according to WHO classification

function to age and BSA (Tables 8. and 9.).

**Subjects [number]**

**Locality**

**Iodine content of drinking water** in each village in question was measured. Water samples were collected from the main fountains used by the majority of inhabitants in every locali‐ ties, and from the water supply network in the school, respectively. These samples were processed by the Laboratory Unit Mureş of the Romanian Academic Research Institute. The iodine-concentration of water under 50μg/L was considered low.

**Iodine content of alimentary salt** available in the local food marts was also determined. Ac‐ cording to the legislative measures the iodine content of the salt must be between 25.5-42.5mg/kg of potassium iodate (KIO3).

The collected data were systematised and statistically processed. The parameters between groups were compared statistically with T-Student test and Chi-square-test. Homologue pa‐ rameters between the groups were considered statistically different, if P-value<0.05.

## **4. Results**

**Anthropometric parameters** of the 135 school-age children living in the three studied moun‐ tainous villages (Caşva, Glăjărie, Ibăneşti,) show similar distribution (Table 6.). From the whole cohort 6 children had height below --2SD (mean -2.27±0.24).

**Family history** was positive for thyroid disturbances (including goiter) in 11 children from the 82 cases with precise data (13.4%). A proportion of 54.5% of children (6/11) with positive family history presented goiter and/or hypothyroidism vs. 32.4% (23/71) of individuals without family history for thyroid condition. The difference between the groups was not sig‐ nificant (P-value: 0.18, OR: 2.50, 95%CI: 0.69-9.07).


W- and H-SDS: weight and height standard deviation score

**Table 6.** Anthropometric parameters of school-age children living in mountainous villages from Mureş County

Physical examination of the anterior and lateral cervical regions has shown a 51.1% owerall goiter frequency. In all cases diffuse goiter was palpable. In more than half of the cases only small goiter (grade Ia) was present, and goiter grade II was met very rare‐ ly (6.7% of all children).


**Table 7.** The distribution of thyroid size according to WHO classification

The level of **anti-thyroid peroxidase antibodies** (TPO-Ab) was measured in every schoolchildren. Values under 50IU/mL were considered normal. TPO-Ab above 50IU/mL indicates

**Iodine content of drinking water** in each village in question was measured. Water samples were collected from the main fountains used by the majority of inhabitants in every locali‐ ties, and from the water supply network in the school, respectively. These samples were processed by the Laboratory Unit Mureş of the Romanian Academic Research Institute. The

**Iodine content of alimentary salt** available in the local food marts was also determined. Ac‐ cording to the legislative measures the iodine content of the salt must be between

The collected data were systematised and statistically processed. The parameters between groups were compared statistically with T-Student test and Chi-square-test. Homologue pa‐

**Anthropometric parameters** of the 135 school-age children living in the three studied moun‐ tainous villages (Caşva, Glăjărie, Ibăneşti,) show similar distribution (Table 6.). From the

**Family history** was positive for thyroid disturbances (including goiter) in 11 children from the 82 cases with precise data (13.4%). A proportion of 54.5% of children (6/11) with positive family history presented goiter and/or hypothyroidism vs. 32.4% (23/71) of individuals without family history for thyroid condition. The difference between the groups was not sig‐

Mean W-SDS [SD] +0.13±1.06 +0.32±1.18 -0.11±1.20 +0.08±1.15 Minimum W-SDS [SD] -2.26 -2.58 -2.88 -2.88 Median W-SDS [SD] -0.06 +0.34 +0.005 +0.18 Maximum W-SDS [SD] +3.18 +2.44 +2.79 +3.18 Mean H-SDS [SD] -0.10±0.98 +0.07±1.10 +0.02±1.05 -0.01±1.03 Minimum H-SDS [SD] -2.28 -2.72 -2.30 -2.72 Median H-SDS [SD] -0.04 +0.005 +0.18 0.00 Maximum H-SDS [SD] +2.33 +2.20 +2.43 +2.43

**Table 6.** Anthropometric parameters of school-age children living in mountainous villages from Mureş County

**Studied villages from Mureş County**

**Caşva Glăjărie Ibăneşti**

**whole cohort**

rameters between the groups were considered statistically different, if P-value<0.05.

the presence of juvenile form of Hashimoto's thyroiditis.

25.5-42.5mg/kg of potassium iodate (KIO3).

112 Hot Topics in Endocrine and Endocrine-Related Diseases

**4. Results**

iodine-concentration of water under 50μg/L was considered low.

whole cohort 6 children had height below --2SD (mean -2.27±0.24).

nificant (P-value: 0.18, OR: 2.50, 95%CI: 0.69-9.07).

W- and H-SDS: weight and height standard deviation score

**Parameter**

**Thyroid volume assessment by ultrasound** Thyroid ultrasound was performed in every child enrolled in our study in 2006, the data regarding thyroid volume were calculated in function to age and BSA (Tables 8. and 9.).


**Table 8.** Age-related minimum, maximum, median, and mean thyroid volume measured by ultrasound in the investigated school-children


The frequency of goiter in the whole investigated group was 20% (27 children from the total number of 135 cases), compared to standards provided by Vulpoi et al., 2002, Zbranca et al.,

The frequency of goiter assessed by physical examination and ultrasound were compared, and distributed regarding to gender. The overall goiter frequency provided by ultrasound was significantly higher in girls than in boys (28% vs. 14.1%). Thyroid enlargement was al‐ most similar in both sexes in the subgroup from Caşva, twice and more than three times higher in girls from Glăjărie and Ibăneşti, respectively, although stratified data according to

**examination Frequency of goiter assessed by ultrasound**

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**Girls Boys Girls Boys**

Not significant (NS) Not significant (NS)

NS NS

NS NS

**P:0.11, RR:1.32, 95%CI:0.959-1.841 P:0.052, RR:1.99, 95%CI:1.001-3.959**

localities show non-significant differences between the subgroups (Table 10).

Caşva 47.6% (10/21) 41.1% (14/34) 14.2% (3/21) 17.6% (6/34)

Glăjărie 50% (5/10) 45% (9/20) 20% (2/10) 10% (2/20)

Ibăneşti 73% (19/26) 50% (12/24) 42.3% (11/26) 12.5% (3/24)

Total 59.6% (34/57) 44.8% (35/78) 28% (16/57) 14.1% (11/78)

**Table 10.** Gender distribution of frequency of goiter assessed by physical examination and thyroid ultrasound

We divided the cohort in two groups according to age: one group with children between 6-12 years (72 cases) and the other with subjects between 12-14 years (63 cases). The frequen‐ cy of goiter assessed by physical examination in the first group was 40.2% (29/72) with no difference between sexes (48.2% in girls and 41.8% in boys), and 58.7% (37/63) in the second group with difference almost significant between sexes (71.4% in girls and 48.5% in boys, P:

In 2006, at about 2-2.5 years after the implementation in practice of universal salt iodization the mean UIE of the 135 children living in the three mentioned villages from Gurghiu Valley was 85.37±60.05μg/L. The median UIE of 74.88μg/L indicates globally a mild iodine deficien‐

cy, but stratified data show large interindividual variations within children.

**Frequency of goiter assessed by physical**

2008. All cases of goiter were diffuse.

0.078, OR: 2.64, 95%CI: 0.9221-7.599).

**Urinary iodine excretion measurement**

**Locality**

**Table 9.** BSA-related minimum, maximum, median, and mean thyroid volume measured by ultrasound in the investigated school-children

The thyroid volume of every child was compared to data furnished by Delange et al. in 1997 and Zimmermann et al. in 2004 (see Tables 4. and 5.), then the frequency of goiter in the studied villages from Mureş County was determined.

**Figure 1.** The frequency of goiter in school-children living in mountainous villages from Mureş County, Romania. Goi‐ ter 1 – the results evaluated according to Delange et al. 1997; Goiter 2 – the results were classified corresponding to data of Zimmermann et al. 2004.

Figure 1. shows a very variable goiter frequency according to the used standards, being situ‐ ated between 5.4-57.7% in Caşva, between 0-82.1% in Glăjărie and between 4-63.6% in Ibăneşti. Evaluation of our results based on the normal values provided by Iaşi County, a formerly iodine-deficient Romanian region (Zbranca et al., 2008), shows that goiter was de‐ tected in 9 (16.3%) children living in Caşva, in 4 (13.3%) school-children from Glăjărie, and in 14 (28%) subjects from Ibăneşti.

The frequency of goiter in the whole investigated group was 20% (27 children from the total number of 135 cases), compared to standards provided by Vulpoi et al., 2002, Zbranca et al., 2008. All cases of goiter were diffuse.

The frequency of goiter assessed by physical examination and ultrasound were compared, and distributed regarding to gender. The overall goiter frequency provided by ultrasound was significantly higher in girls than in boys (28% vs. 14.1%). Thyroid enlargement was al‐ most similar in both sexes in the subgroup from Caşva, twice and more than three times higher in girls from Glăjărie and Ibăneşti, respectively, although stratified data according to localities show non-significant differences between the subgroups (Table 10).


**Table 10.** Gender distribution of frequency of goiter assessed by physical examination and thyroid ultrasound

We divided the cohort in two groups according to age: one group with children between 6-12 years (72 cases) and the other with subjects between 12-14 years (63 cases). The frequen‐ cy of goiter assessed by physical examination in the first group was 40.2% (29/72) with no difference between sexes (48.2% in girls and 41.8% in boys), and 58.7% (37/63) in the second group with difference almost significant between sexes (71.4% in girls and 48.5% in boys, P: 0.078, OR: 2.64, 95%CI: 0.9221-7.599).

#### **Urinary iodine excretion measurement**

**BSA [m2]**

investigated school-children

5.4

in 14 (28%) subjects from Ibăneşti.

data of Zimmermann et al. 2004.

9.1

41.6

Frequency of goiter (%)

**Subjects [number]**

114 Hot Topics in Endocrine and Endocrine-Related Diseases

studied villages from Mureş County was determined.

57.7

**Thyroid volume [mL] Min. Max. Median Mean**

0.8 1 2.77 0.9 1 7.15 1.0 11 2.95 9.03 4.66 4.70±1.64 1.1 17 3.18 6.80 4.87 4.78±1.01 1.2 24 2.65 9.02 5.34 5.78±1.89 1.3 18 3.15 11.78 6.71 7.29±2.38 1.4 30 3.62 14.80 6.78 7.06±2.83 1.5 19 5.60 14.55 7.61 8.86±2.69 1.6 5 6.62 9.41 7.85 7.93±1.01 1.7 9 7.17 21.00 10.73 11.80±4.39

**Table 9.** BSA-related minimum, maximum, median, and mean thyroid volume measured by ultrasound in the

The thyroid volume of every child was compared to data furnished by Delange et al. in 1997 and Zimmermann et al. in 2004 (see Tables 4. and 5.), then the frequency of goiter in the

82.1

<sup>0</sup> <sup>4</sup>

**Figure 1.** The frequency of goiter in school-children living in mountainous villages from Mureş County, Romania. Goi‐ ter 1 – the results evaluated according to Delange et al. 1997; Goiter 2 – the results were classified corresponding to

Figure 1. shows a very variable goiter frequency according to the used standards, being situ‐ ated between 5.4-57.7% in Caşva, between 0-82.1% in Glăjărie and between 4-63.6% in Ibăneşti. Evaluation of our results based on the normal values provided by Iaşi County, a formerly iodine-deficient Romanian region (Zbranca et al., 2008), shows that goiter was de‐ tected in 9 (16.3%) children living in Caşva, in 4 (13.3%) school-children from Glăjărie, and

16

22.2

63.6

Goiter 1 (age-related) Goiter 1 (BSA-related) Goiter 2 (age-related) Goiter 2 (BSA-related)

6.6

Caşva Glăjărie Ibăneşti

65.2

In 2006, at about 2-2.5 years after the implementation in practice of universal salt iodization the mean UIE of the 135 children living in the three mentioned villages from Gurghiu Valley was 85.37±60.05μg/L. The median UIE of 74.88μg/L indicates globally a mild iodine deficien‐ cy, but stratified data show large interindividual variations within children.

(4 mild overt and 1 subclinical form). In Ibăneşti 10 subjects (20%) were diagnosed with thy‐

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117

**TPO-Ab** was negative (<50IU/mL) in all 135 cases, which means that juvenile chronic auto‐ immune thyroiditis was not met in this cohort, and hypothyroidism was not caused by this

We did not found considerable or significant differences of somatic development in children

**Intellectual performances** of 59 children were recorded, and than we distributed them into two groups: one (1. subgroup) with children having mediocre and low learning capacity (32 cases), and the other (2. subgroup) consisting of individuals with good or very good per‐ formances (27 cases). The goiter frequency based on ultrasound was 22.5% in the first, and 17.8% in the second group (P-value >0.05). We compared the mean UIE, TSH and FT<sup>4</sup> be‐ tween the subgroups of children with different school performances, but we did not found significant differences, excepting a tendency of reducing school performances with the grad‐

Our results recorded in 2006 show that the **water sample** from Caşva contains 3.8μg/L io‐ dine, and the iodized alimentary salt 16.02mg/kg (which was lower than the ordered con‐ centration of 34±8.5mg/kg). In Glăjărie the iodine content of the water from the central fountain was 1.0μg/L, from the parish yard 1.9μg/L, in the running water from the school 0.45μg/L and from the medical unit 4.2 μg/L. The iodine content of water from Ibăneşti was 0.6μg/L and of the iodized alimentary salt 51.64mg/kg (which was higher than the allowed

2.20+0.71 2.27+1.37

Mean FT4 (ng/dL) Mean TSH (mIU/L) Mean FT4 trendline Mean TSH trendline

> school performance

roid insufficiency (6 mild overt and 4 subclinical).

thyroid disease, rather it was induced by iodine deficiency.

with or without iodine-deficiency, with or without hypothyroidism.

ually increasing values of TSH and decreasing levels of FT4 (Figure 3.).

1.01+0.15 1.05+0.11 1.21+0.11 1.11+-0.10

low mediocre good very good

**Figure 3.** The mean TSH and FT4 levels in subgroups of children distributed according to school performances

2.45+0.95

We did not detect any case of hyperthyroidism.

upper normal concentration).

0 0.5 1 1.5 2 2.5 3 3.5 4

2.60+1.31

Absolute values

**Figure 2.** Distribution of individual values of UIE in school-children living in the three studied villages from Mureş County in 2006

UIE below normal range was detected in 68.1% of the cohort. The proportion of UIE <50μg/L reached 30.3%, and that of UIE <100μg/L was 68.1%, which are above the maximal values (20% for UIE <50μg/L and 50% for UIE <100μg/L) of adequate iodine-supply condi‐ tions. A large part of the group (60.9%) had mildly or moderately low UIE.


**Table 11.** The indicators of iodine status and of universal salt iodization program sustainability in school-children from mountainous villages in 2006

**Thyroid function.** In the whole group mean TSH level was 2.32±1.04mIU/L and mean FT4 concentration 1.07±0.12ng/dL. These values are situated in the normal range, but individual hormonal results showed primary hypothyroidism in 24 (17,7%) children. Fifteen of them had mild overt hypothyroidism and 9 subclinical form, the mean TSH being 5.28±0.73mIU/L (normal: 0.27-4.2) and mean FT4 0.86±0.05ng/dL (normal: 0.932-1.70).

In Caşva the mean TSH was normal (2.34±1.00mIU/L). Nine (16.3%) children had primary hypothyroidism. In Glăjărie the mean TSH and FT4 were also normal (2.12±0.93mIU/L and 1.08±0.13, respectively), and 5 school-children (16.6%) were detected with hypothyroidism (4 mild overt and 1 subclinical form). In Ibăneşti 10 subjects (20%) were diagnosed with thy‐ roid insufficiency (6 mild overt and 4 subclinical).

We did not detect any case of hyperthyroidism.

**Indicators of iodine status**

Frequency of cases with UIE<100μg/L [%]

Frequency of cases with UIE<50μg/L [%]

[%]

Frequency of goiter assessed by US

mountainous villages in 2006

County in 2006

UIE [mg/L]

116 Hot Topics in Endocrine and Endocrine-Related Diseases

Casva Glăjărie Ibănesti

**Figure 2.** Distribution of individual values of UIE in school-children living in the three studied villages from Mureş

UIE below normal range was detected in 68.1% of the cohort. The proportion of UIE <50μg/L reached 30.3%, and that of UIE <100μg/L was 68.1%, which are above the maximal values (20% for UIE <50μg/L and 50% for UIE <100μg/L) of adequate iodine-supply condi‐

Mean UIE [μg/L] 72.91 75.42 117.84 85.37 Median UIE [μg/L] 67.00 53.50 81.00 74.88 Mean UIE ± SD [μg/L] 72.91±48.63 75.42±60.30 117.84±91.95 85.37±60.05

**Data from the studied villages**

**Caşva Glăjărie Ibăneşti**

76.6 (23/30 cases)

36.6 (11/30 cases)

13.3 (4/30 cases)

**Table 11.** The indicators of iodine status and of universal salt iodization program sustainability in school-children from

**Thyroid function.** In the whole group mean TSH level was 2.32±1.04mIU/L and mean FT4 concentration 1.07±0.12ng/dL. These values are situated in the normal range, but individual hormonal results showed primary hypothyroidism in 24 (17,7%) children. Fifteen of them had mild overt hypothyroidism and 9 subclinical form, the mean TSH being 5.28±0.73mIU/L

In Caşva the mean TSH was normal (2.34±1.00mIU/L). Nine (16.3%) children had primary hypothyroidism. In Glăjărie the mean TSH and FT4 were also normal (2.12±0.93mIU/L and 1.08±0.13, respectively), and 5 school-children (16.6%) were detected with hypothyroidism

64 (32/50 cases)

16 (8/50 cases)

28 (14/50 cases) **Whole cohort**

68.1 (92/135)

30.3 (41/135)

20 (27/135)

tions. A large part of the group (60.9%) had mildly or moderately low UIE.

67.3 (37/55 cases)

40 (22/55 cases)

16.3 (9/55 cases)

(normal: 0.27-4.2) and mean FT4 0.86±0.05ng/dL (normal: 0.932-1.70).

**TPO-Ab** was negative (<50IU/mL) in all 135 cases, which means that juvenile chronic auto‐ immune thyroiditis was not met in this cohort, and hypothyroidism was not caused by this thyroid disease, rather it was induced by iodine deficiency.

We did not found considerable or significant differences of somatic development in children with or without iodine-deficiency, with or without hypothyroidism.

**Intellectual performances** of 59 children were recorded, and than we distributed them into two groups: one (1. subgroup) with children having mediocre and low learning capacity (32 cases), and the other (2. subgroup) consisting of individuals with good or very good per‐ formances (27 cases). The goiter frequency based on ultrasound was 22.5% in the first, and 17.8% in the second group (P-value >0.05). We compared the mean UIE, TSH and FT<sup>4</sup> be‐ tween the subgroups of children with different school performances, but we did not found significant differences, excepting a tendency of reducing school performances with the grad‐ ually increasing values of TSH and decreasing levels of FT4 (Figure 3.).

Our results recorded in 2006 show that the **water sample** from Caşva contains 3.8μg/L io‐ dine, and the iodized alimentary salt 16.02mg/kg (which was lower than the ordered con‐ centration of 34±8.5mg/kg). In Glăjărie the iodine content of the water from the central fountain was 1.0μg/L, from the parish yard 1.9μg/L, in the running water from the school 0.45μg/L and from the medical unit 4.2 μg/L. The iodine content of water from Ibăneşti was 0.6μg/L and of the iodized alimentary salt 51.64mg/kg (which was higher than the allowed upper normal concentration).

**Figure 3.** The mean TSH and FT4 levels in subgroups of children distributed according to school performances

## **5. Discussion**

In 2003 the Romanian governmental decision regarding universal salt iodization was im‐ plemented into practice, and in 2006, after about 2.5-3 years, we evaluated the impact of this program in regions of Mureş County known as moderate or mild iodine deficient.

two localities), and the distribution between sexes is almost 1:1 (differing evidently from boys:girls-ratio of 2:1 in Glăjărie and 3:2 in Caşva). Taking into account that the girls from Ibăneşti were older, between 12-14-years, the pubertal stage was higher in this group. Balázs et al. (1998) have reported the increased incidence of grade Ib and II goiter in children with pubertal onset compared to those being in prepubertal stage, as pubertal onset is an important facilitating factor for goiter development. This is in con‐ cordance with our data, too, related to gender. The overall goiter frequency provided by ultrasound was significantly higher in girls than in boys (28% vs. 14.1%): although goiter appeared almost with the same frequency in both sexes from Caşva (14.2% in girls and 17.6% in boys), but it was more than 3-times more frequent in girls than in boys living in Ibăneşti (42.3% vs. 12.5%). Euthyroid pubertal goiter is especially fre‐ quent in adolescents, because iodine metabolism is accelerated during this period of life

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Than we compared our data obtained in 2006 to the results recorded during April-June 1999 at school-age children living in Deda, a mountainous rural locality, presumed as iodine defi‐ cient area. In that study 36.22% of the children had goiter, mainly of small size, without con‐ siderable differences between the sexes (Balázs et al., 2000/a) – the goiter being assessed by inspection/palpation. This result is similar to that in the present study (40.2% in children with age between 6-12 years), without any significant differences between the groups. It must be emphasized, that the lack of gender differences may be attributed to inspection/ palpation method for the diagnosis of goiter. Taking into account the subjectivity and bias of physical examination of thyroid gland, especially in young children, as this method of eval‐ uation estimates goiter presence with an error as much as 30-40%, our interpretation was

The objective determination of thyroid volume by ultrasound provided the exact size of the thyroid, however it was difficult to chose the adequate standards for the normal thyroid vol‐ ume fitting to the goiter estimation in our region. The references published during the last 2-3 decades provide very variable standards for the upper normal limit of thyroid utra‐

We evaluated firstly the age- and BSA-adjusted goiter frequency compared to the reference values provided by the Thyromobile survey accross Europe (Delange et al., 1997), and there‐ after we reevaluated the results according to parameters published by Zimmermann (2004), but we obtained very different results (Figure 1.). After all we chose the standards provided by a team of endocrinologists from Iaşi performed on a cohort living in a formerly iodine deficient Romanian region (Vulpoi et al., 2002; Zbranca et al., 2008). Thus, goiter frequency in our cohort assessed by ultrasound was 20%, with a considerable difference between the

In the study of Balázs et al. (2000/a) thyroid ultrasonography was also performed in 83 chil‐ dren living in Târgu Mureş. The mean thyroid volume determined by ultrasound among

ter evaluated by ultrasound was detected in 33.73% of the children, mainly small goiters

(grade Ia), predominantly in girls (about 2/3 in girls and 1/3 in boys).

, adjusted to a mean body surface area of 1.23±0.14 m<sup>2</sup>

. Goi‐

(Delange & Ermans, 1967).

based mainly on thyroid ultrasound.

sexes (28% in girls and 14.1% in boys).

these children was 5.22±1.51cm3

sound volumetry adjusted for age, gender and BSA.

In order to evaluate the impact of universal salt iodization program in Romania in the con‐ text of national strategy on the elimination of iodine deficiency disorders from 2003, we compared our results reflecting iodine status in localities from Mureş County after the im‐ plementation of this program with those before it. Thus, we compared the indicators of io‐ dine status in Mureş County reported in 1998-1999 by Balázs et al. (1998; 2000/a; 2000/b), before the governmental measures, with the same indicators measured by us in 2006. The mentioned data in 1998/99 were obtained in the superior and middle hydrographic basin of the Mureş river, investigating a group of 508 school-children living in areas surrounding lo‐ cality Deda (situated in a mountainous region in Mureş County). From the 508 school-age children 26.97% (137 cases) were living in urban and 73.03% (371) in rural localities.

Physical examination of thyroid gland by palpation and inspection was performed in both studies (in 1998/99 and in that presented now). Thyroid size determined by local physical examination was evaluated according to WHO criteria (0, Ia, Ib, II, III subgroups) in the mentioned former studies. According to the Bourdoux classification the volume of thyroid gland was enlarged by palpation in 45.27% of children: grade Ia goiter observed in 29.92% (152 cases), grade Ib in 14.17% (72), and grade II in 1.18% (6 children). Those studies high‐ lighted the high frequency of low grade goiter in rural localities in comparison with a lower frequency observed in urban regions (Balázs et al., 1998).

In the present work physical examination shows an owerall goiter frequency of 51.9%, pre‐ vailing small goiters (grade Ia) in all studied villages (more than half of goiters), large goi‐ ters being very rare (grade II only in 6.7% of all cohort). Comparing the data of the two series we could not found any improvement in the overall frequency of goiter (45.28% in 1999 vs. 51.1% in 2006), but we must take into account, that in the previous study children came from several localities (including Târgu Mureş, the capital city of Mureş County) with different iodine status (mild or moderate iodine deficient, as well as with normal iodine sup‐ ply). A considerable number of the enrolled children were from Târgu Mureş, a city which proved to be without iodine deficiency. In the present work we focused on mountainous vil‐ lages, known before as iodine deficient regions, some of them (Caşva and Glăjărie) known partly isolated in socioeconomical and geographical point of view.

In our study physical examination of thyroid gland shows variable goiter frequency in the three localities: it is the highest in Ibăneşti (62.0%) vs. the other two localities (46.7% in Glăjărie and 43.6% in Caşva). This result is not in concordance with the fact that Ibăneşti is the largest among the three localities, with better socioeconomical status and lesser isolated. An explanation might reside in the differences in age, gender and pubertal stage of the children. In Ibăneşti the mean chronological age of school-age chil‐ dren enrolled in the study is higher (12.05 years vs. 11.51 and 11.80 years in the other two localities), and the distribution between sexes is almost 1:1 (differing evidently from boys:girls-ratio of 2:1 in Glăjărie and 3:2 in Caşva). Taking into account that the girls from Ibăneşti were older, between 12-14-years, the pubertal stage was higher in this group. Balázs et al. (1998) have reported the increased incidence of grade Ib and II goiter in children with pubertal onset compared to those being in prepubertal stage, as pubertal onset is an important facilitating factor for goiter development. This is in con‐ cordance with our data, too, related to gender. The overall goiter frequency provided by ultrasound was significantly higher in girls than in boys (28% vs. 14.1%): although goiter appeared almost with the same frequency in both sexes from Caşva (14.2% in girls and 17.6% in boys), but it was more than 3-times more frequent in girls than in boys living in Ibăneşti (42.3% vs. 12.5%). Euthyroid pubertal goiter is especially fre‐ quent in adolescents, because iodine metabolism is accelerated during this period of life (Delange & Ermans, 1967).

**5. Discussion**

118 Hot Topics in Endocrine and Endocrine-Related Diseases

In 2003 the Romanian governmental decision regarding universal salt iodization was im‐ plemented into practice, and in 2006, after about 2.5-3 years, we evaluated the impact of this program in regions of Mureş County known as moderate or mild iodine deficient.

In order to evaluate the impact of universal salt iodization program in Romania in the con‐ text of national strategy on the elimination of iodine deficiency disorders from 2003, we compared our results reflecting iodine status in localities from Mureş County after the im‐ plementation of this program with those before it. Thus, we compared the indicators of io‐ dine status in Mureş County reported in 1998-1999 by Balázs et al. (1998; 2000/a; 2000/b), before the governmental measures, with the same indicators measured by us in 2006. The mentioned data in 1998/99 were obtained in the superior and middle hydrographic basin of the Mureş river, investigating a group of 508 school-children living in areas surrounding lo‐ cality Deda (situated in a mountainous region in Mureş County). From the 508 school-age

children 26.97% (137 cases) were living in urban and 73.03% (371) in rural localities.

frequency observed in urban regions (Balázs et al., 1998).

partly isolated in socioeconomical and geographical point of view.

Physical examination of thyroid gland by palpation and inspection was performed in both studies (in 1998/99 and in that presented now). Thyroid size determined by local physical examination was evaluated according to WHO criteria (0, Ia, Ib, II, III subgroups) in the mentioned former studies. According to the Bourdoux classification the volume of thyroid gland was enlarged by palpation in 45.27% of children: grade Ia goiter observed in 29.92% (152 cases), grade Ib in 14.17% (72), and grade II in 1.18% (6 children). Those studies high‐ lighted the high frequency of low grade goiter in rural localities in comparison with a lower

In the present work physical examination shows an owerall goiter frequency of 51.9%, pre‐ vailing small goiters (grade Ia) in all studied villages (more than half of goiters), large goi‐ ters being very rare (grade II only in 6.7% of all cohort). Comparing the data of the two series we could not found any improvement in the overall frequency of goiter (45.28% in 1999 vs. 51.1% in 2006), but we must take into account, that in the previous study children came from several localities (including Târgu Mureş, the capital city of Mureş County) with different iodine status (mild or moderate iodine deficient, as well as with normal iodine sup‐ ply). A considerable number of the enrolled children were from Târgu Mureş, a city which proved to be without iodine deficiency. In the present work we focused on mountainous vil‐ lages, known before as iodine deficient regions, some of them (Caşva and Glăjărie) known

In our study physical examination of thyroid gland shows variable goiter frequency in the three localities: it is the highest in Ibăneşti (62.0%) vs. the other two localities (46.7% in Glăjărie and 43.6% in Caşva). This result is not in concordance with the fact that Ibăneşti is the largest among the three localities, with better socioeconomical status and lesser isolated. An explanation might reside in the differences in age, gender and pubertal stage of the children. In Ibăneşti the mean chronological age of school-age chil‐ dren enrolled in the study is higher (12.05 years vs. 11.51 and 11.80 years in the other Than we compared our data obtained in 2006 to the results recorded during April-June 1999 at school-age children living in Deda, a mountainous rural locality, presumed as iodine defi‐ cient area. In that study 36.22% of the children had goiter, mainly of small size, without con‐ siderable differences between the sexes (Balázs et al., 2000/a) – the goiter being assessed by inspection/palpation. This result is similar to that in the present study (40.2% in children with age between 6-12 years), without any significant differences between the groups. It must be emphasized, that the lack of gender differences may be attributed to inspection/ palpation method for the diagnosis of goiter. Taking into account the subjectivity and bias of physical examination of thyroid gland, especially in young children, as this method of eval‐ uation estimates goiter presence with an error as much as 30-40%, our interpretation was based mainly on thyroid ultrasound.

The objective determination of thyroid volume by ultrasound provided the exact size of the thyroid, however it was difficult to chose the adequate standards for the normal thyroid vol‐ ume fitting to the goiter estimation in our region. The references published during the last 2-3 decades provide very variable standards for the upper normal limit of thyroid utra‐ sound volumetry adjusted for age, gender and BSA.

We evaluated firstly the age- and BSA-adjusted goiter frequency compared to the reference values provided by the Thyromobile survey accross Europe (Delange et al., 1997), and there‐ after we reevaluated the results according to parameters published by Zimmermann (2004), but we obtained very different results (Figure 1.). After all we chose the standards provided by a team of endocrinologists from Iaşi performed on a cohort living in a formerly iodine deficient Romanian region (Vulpoi et al., 2002; Zbranca et al., 2008). Thus, goiter frequency in our cohort assessed by ultrasound was 20%, with a considerable difference between the sexes (28% in girls and 14.1% in boys).

In the study of Balázs et al. (2000/a) thyroid ultrasonography was also performed in 83 chil‐ dren living in Târgu Mureş. The mean thyroid volume determined by ultrasound among these children was 5.22±1.51cm3 , adjusted to a mean body surface area of 1.23±0.14 m<sup>2</sup> . Goi‐ ter evaluated by ultrasound was detected in 33.73% of the children, mainly small goiters (grade Ia), predominantly in girls (about 2/3 in girls and 1/3 in boys).

The 20% of goiter frequency (diagnosed by ultrasound) detected in school-age children by us, reflects a mild/moderate iodine deficiency in the studied three mountainous villages from Mureş County in 2006. The stratified results of each locality showed that Caşva and Glăjărie were mildy iodine deficient areas (reflected by 16.3 and 13.3% goiter, respectively), and Ibăneşti moderately iodine deficient (with 28% goiter).

performed in 1998/99, the results of the present work show large interindividual varia‐

Detection of Iodine Deficiency Disorders (Goiter and Hypothyroidism) in School-Children…

Values below normal range (UIE <100μg/L) were detected in 68.1% of our cohort, which is improved compared to data obtained in 1998/1999. Indead, the proportion of cases with nor‐ mal UIE has increased significantly in 2006 compared to that determined in 1998/1999 (31.9% vs. 6.9%, P-value<0.0001, RR: 1.268, 95%CI: 1.183-1.581). However, this increase has not attained yet the most important criteria of normal iodine-supply conditions, i.e. the max‐ imal value of 50% UIE <100μg/L (the 68.1% is still above of this limit with 18.1%); similarly, in our present study the proportion of UIE <50μg/L is 30.3%, for normal iodine-supply it must be ≤20%. These results show that the universal salt iodization program could not be

The iodine status of the studied localities from Mureş County in 2006 was evaluated by the following indicators: median UIE for the current iodine status, frequency of goiter assessed by ultrasound for the history of iodine nutrition of the previous months-years, and the fre‐ quency of UIE concentrations below 100μg/L and below 50μg/L for the sustainability of uni‐

**Caşva Glăjărie Ibăneşti**

mild iodine deficiency

mild iodine deficiency

**Table 12.** The interpretation of indicators showing the iodine status among school-children in the three mountainous

During 2006 the frequency of goiter in school-age children was 20% which is improved to that observed in 1998/99 (33.73%), but it has not reached normal levels yet, being situ‐ ated at the borderline between mild and moderate iodine deficiency (5-19.9% and 20-29.9%, respectively). Our results show an improved iodine status in 2006: the mean UIE rose to 85.37±60.05μg/L, median UIE to 74.88μg/L, and 30.8% of children had nor‐ mal urinary iodine excretion. Analysing separately the groups in every village, the mean UIE are different in some degree: 72.91±48.63μg/L in Caşva, 75.42±60.30μg/L in Glăjărie and 117.84±91.95 μg/L in Ibăneşti. Median UIE has improved compared to the situation in 1998/99, but it remained at subnormal levels, indicating a mild iodine deficiency in all three villages. The indicators for the estimation of sustained elimination of iodine defi‐ ciency were at subnormal levels. Studies performed during 2002-2004 reported an im‐

mild iodine deficiency

moderate iodine deficiency

not ensured not ensured not ensured not ensured

**Whole cohort**

http://dx.doi.org/10.5772/54188

121

mild iodine deficiency

mild/moderate iodine deficiency

ensured at an optimal level, being not sustained continuously.

**Interpretation of indicators Data from every studied villages**

mild iodine deficiency

mild iodine deficiency

versal salt iodization program (Table 12.).

Current iodine status in 2006 (by

Sustained elimination of iodine deficiency (by % cases with UIE<100μg/L and UIE<50μg/L)

Former iodine status (before 2006) (by

median UIE)

frequency of goiter)

villages in 2006

tions of UIE (SD: ±60.05μg/L).

So, we observed a significant reduction of goiter frequency after the measures taken in the frame of universal salt iodization, compared to the results obtained by Balázs et al. in 1998/99 (the overall goiter frequency 20% in 2006 vs. 33.73% in 1999 − P-value: 0.025, RR: 1.687, 95%CI: 1.073-2.652). As thyroid enlargement reflects the former iodine status, i.e. the history of iodine nutrition for the previous several months/1-2 years, this means a significant improvement of iodine status in the studied regions, reflecting the beneficial outcome of universal salt iodization.

Urinary iodine excretion reflects the present iodine status of a geographical region. Determi‐ nation of UIE with Sandell-Kolthoff reaction, using ammonium persulfate was the laborato‐ ry method used in the both series of study (realized in 1998/99 and in 2006) performed in Mureş County, so the absolute values could be compared.

In 1998/99 the majority of rural localities situated on the superior and middle hydrographi‐ cal basin of the river Mureş were mildly iodine-deficient areas, the rest being moderately de‐ ficient. The mean UIE was 100.22μg/L, but with a high interindividual variation: SD ± 73.37 (Balázs et al., 1998). The mountainous rural region of Deda was considered moderately io‐ dine deficient in 1998, the normal UIE being detected only in 6.9% of cases, and the mean UIE being 59.95±30.22μg/L. Although in Târgu Mureş the mean UIE was within the normal range (130.05±75.45μg/L), normal individual UIE levels >100μg/L were observed only in 56.79% of the children (Balázs et al., 1998; 2000/a; 2000/b).

In 2006, at about 2-2.5 years after the implementation in practice of universal salt iodization the mean urinary iodine excretion measured in the 135 school-age children living in the three mentioned villages from Gurghiu Valley was 85.37±60.05μg/L. Median value of 74.88μg/L indicates an overall mild iodine deficiency. In order to compare this result with that from 1999, the median UIE in 1999 was calculated based on the mean UIE in 1999 (59.95±30.22μg/L) using the formula recommended by WHO (median UIE = 1.128 + 0.864 × mean UIE – WHO et al., 2001). Thus, the estimated median UIE was 52.29μg/L before the universal salt iodization program.

The median UIE compared to the previous studies shows also a considerable improvement in the iodine status of rural regions from Mureş County, being in concordance with the sig‐ nificant reduction of goiter frequency discussed previously. So, we observed better median UIE in Ibăneşti (81.00μg/L), in contrast with Glăjărie, known as the most isolated and with less socioeconomical background (having the lowest median UIE: 53.50μg/L).

In the studies performed before universal salt Iodization highly variable interindividual UIE concentrations were observed, although the mean value indicated only a mild iodine deficiency. Normal UIE was found only in 6.9% of school-age children, which means a frequency of cases with UIE<100μg/L of 93.1%. In 2006 a large proportion (68.1%) of studied school-children had still mildly or moderately low UIE. Similarly to the studies performed in 1998/99, the results of the present work show large interindividual varia‐ tions of UIE (SD: ±60.05μg/L).

The 20% of goiter frequency (diagnosed by ultrasound) detected in school-age children by us, reflects a mild/moderate iodine deficiency in the studied three mountainous villages from Mureş County in 2006. The stratified results of each locality showed that Caşva and Glăjărie were mildy iodine deficient areas (reflected by 16.3 and 13.3% goiter, respectively),

So, we observed a significant reduction of goiter frequency after the measures taken in the frame of universal salt iodization, compared to the results obtained by Balázs et al. in 1998/99 (the overall goiter frequency 20% in 2006 vs. 33.73% in 1999 − P-value: 0.025, RR: 1.687, 95%CI: 1.073-2.652). As thyroid enlargement reflects the former iodine status, i.e. the history of iodine nutrition for the previous several months/1-2 years, this means a significant improvement of iodine status in the studied regions, reflecting the beneficial outcome of

Urinary iodine excretion reflects the present iodine status of a geographical region. Determi‐ nation of UIE with Sandell-Kolthoff reaction, using ammonium persulfate was the laborato‐ ry method used in the both series of study (realized in 1998/99 and in 2006) performed in

In 1998/99 the majority of rural localities situated on the superior and middle hydrographi‐ cal basin of the river Mureş were mildly iodine-deficient areas, the rest being moderately de‐ ficient. The mean UIE was 100.22μg/L, but with a high interindividual variation: SD ± 73.37 (Balázs et al., 1998). The mountainous rural region of Deda was considered moderately io‐ dine deficient in 1998, the normal UIE being detected only in 6.9% of cases, and the mean UIE being 59.95±30.22μg/L. Although in Târgu Mureş the mean UIE was within the normal range (130.05±75.45μg/L), normal individual UIE levels >100μg/L were observed only in

In 2006, at about 2-2.5 years after the implementation in practice of universal salt iodization the mean urinary iodine excretion measured in the 135 school-age children living in the three mentioned villages from Gurghiu Valley was 85.37±60.05μg/L. Median value of 74.88μg/L indicates an overall mild iodine deficiency. In order to compare this result with that from 1999, the median UIE in 1999 was calculated based on the mean UIE in 1999 (59.95±30.22μg/L) using the formula recommended by WHO (median UIE = 1.128 + 0.864 × mean UIE – WHO et al., 2001). Thus, the estimated median UIE was 52.29μg/L before the

The median UIE compared to the previous studies shows also a considerable improvement in the iodine status of rural regions from Mureş County, being in concordance with the sig‐ nificant reduction of goiter frequency discussed previously. So, we observed better median UIE in Ibăneşti (81.00μg/L), in contrast with Glăjărie, known as the most isolated and with

In the studies performed before universal salt Iodization highly variable interindividual UIE concentrations were observed, although the mean value indicated only a mild iodine deficiency. Normal UIE was found only in 6.9% of school-age children, which means a frequency of cases with UIE<100μg/L of 93.1%. In 2006 a large proportion (68.1%) of studied school-children had still mildly or moderately low UIE. Similarly to the studies

less socioeconomical background (having the lowest median UIE: 53.50μg/L).

and Ibăneşti moderately iodine deficient (with 28% goiter).

120 Hot Topics in Endocrine and Endocrine-Related Diseases

Mureş County, so the absolute values could be compared.

56.79% of the children (Balázs et al., 1998; 2000/a; 2000/b).

universal salt iodization program.

universal salt iodization.

Values below normal range (UIE <100μg/L) were detected in 68.1% of our cohort, which is improved compared to data obtained in 1998/1999. Indead, the proportion of cases with nor‐ mal UIE has increased significantly in 2006 compared to that determined in 1998/1999 (31.9% vs. 6.9%, P-value<0.0001, RR: 1.268, 95%CI: 1.183-1.581). However, this increase has not attained yet the most important criteria of normal iodine-supply conditions, i.e. the max‐ imal value of 50% UIE <100μg/L (the 68.1% is still above of this limit with 18.1%); similarly, in our present study the proportion of UIE <50μg/L is 30.3%, for normal iodine-supply it must be ≤20%. These results show that the universal salt iodization program could not be ensured at an optimal level, being not sustained continuously.

The iodine status of the studied localities from Mureş County in 2006 was evaluated by the following indicators: median UIE for the current iodine status, frequency of goiter assessed by ultrasound for the history of iodine nutrition of the previous months-years, and the fre‐ quency of UIE concentrations below 100μg/L and below 50μg/L for the sustainability of uni‐ versal salt iodization program (Table 12.).


**Table 12.** The interpretation of indicators showing the iodine status among school-children in the three mountainous villages in 2006

During 2006 the frequency of goiter in school-age children was 20% which is improved to that observed in 1998/99 (33.73%), but it has not reached normal levels yet, being situ‐ ated at the borderline between mild and moderate iodine deficiency (5-19.9% and 20-29.9%, respectively). Our results show an improved iodine status in 2006: the mean UIE rose to 85.37±60.05μg/L, median UIE to 74.88μg/L, and 30.8% of children had nor‐ mal urinary iodine excretion. Analysing separately the groups in every village, the mean UIE are different in some degree: 72.91±48.63μg/L in Caşva, 75.42±60.30μg/L in Glăjărie and 117.84±91.95 μg/L in Ibăneşti. Median UIE has improved compared to the situation in 1998/99, but it remained at subnormal levels, indicating a mild iodine deficiency in all three villages. The indicators for the estimation of sustained elimination of iodine defi‐ ciency were at subnormal levels. Studies performed during 2002-2004 reported an im‐ provement of overall median UIE in school-age Romanian children from 70 (in urban) and 60μg/L (in rural areas) in 2002 to 105 and 100μg/L, respectively, until 2004. At the Second National Conference for the elimination of IDD held at Bucharest in 2005, the Mother and Child Care Institute "Alfred Rusescu" reported that in children of 6-7-years of age the overall iodine status tended to normalize, the median UIE reaching 100μg/L (Stănescu, 2005). Although the median UIE became almost normal (105 in urban and 100μg/L in rural localities), a large interindividual variation were found, reflected by the SD of ±60μg/L (Stănescu, 2005). Important differences between iodine status of rural and urban environment were observed. Mild iodine deficiency was recorded in 33.5% of the population, 11% presented moderate and 2.4% severe forms (Stănescu, 2005), although 96.3% of the housholds used iodized salt. These results could derive from the facts that more than half of the families used salt with inadequate iodine content (under 15mg io‐ dine/kg salt), 3/4 of the families consumed iodized salt but in an inadequate manner (adding salt before and during cooking) which reduces the content of iodine; the fre‐ quency of iodized salt consumption is higher in families with the higher educational lev‐ el of the mother.

The persistence of moderate iodine deficiency in some zones of Romania was attributed to the insufficient iodization level of the salt and waist during storage, to the uncontrolled sell‐ ing of industrial salt as alimentary salt, to the lack of control measures in import of salt, to the inadequate monitoring system and the lack of efficient measures to realize entirely the governmental decision, as well as the resistency of alimentary industry (e.g. meat processing

Detection of Iodine Deficiency Disorders (Goiter and Hypothyroidism) in School-Children…

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123

We must remark the presence of hypothyroidism related to iodine deficiency in 17.7% of the investigated school-children, TPO-Ab being normal in all of them. Although, all cases of hy‐ pothyroidism were mildly overt or subclinical forms (15 and 9, respectively), we must take into account that even mild iodine and thyroid hormone deficiencies conduct to psycho‐ neurological damages, the characteristical complication of latent deficiency being AD-HD syndrome in developed countries. Chronic iodine deficiency leads to suboptimal intellectual development. Recent studies performed in the European countries, known with iodine pre‐ vention programs initiated decades ago, and thougth that iodine deficiency was eliminated, sustaine surprisingly the presence of mild iodine deficiency in many countries and implica‐ tion of this in school performances, psychological and neurological status. These mild defi‐ cits probably results from transient hypothyroidism during the first 2-years of life, i.e. during the critical period of brain development (Delange, 2002). Besides iodine deficiency, an increase in iodine intake can also lead to a small but significant increase in the incidence

of hypothyroidism, probably attributable to autoregulation of thyroid function.

In conclusion, the rural mountainous zones of Mureş County known before as moderate/ mild iodine-deficient areas, became *mild-deficient*, due to the new measures of iodine preven‐ tion. In these areas universal salt iodization is not sufficient, being necessary to apply peri‐ odically special prophylactic measures (iodine tablets), too, primarily to prepubertal and

This work underlines considerable improvement of iodine nutrition in mountainous rural regions of Mureş County after the implementation in practice of universal salt iodization in Romania since 2003, although these areas remained mildly (some moderately) iodine defi‐ cient at about 2.5-3 years after the IDD elimination strategy was intitiated. On one hand the prophylactic measures with higher iodine content of alimentary salt (KIO3 25.5-42.5mg/kg) might not be sufficient for the full correction of iodine deficiency in these isolated mountain‐ ous rural regions, on the other hand special attention is required to monitorize continuously the market and reaching programs, as well as the sustainability of the prophylactic program must be ensured. In these areas special measures, i.e. iodine supplementation to the highrisk populational groups are periodically required in addition to universal salt iodization, especially as iodine deficiency occured with hypothyroidism in 17.7% of school-children. The elimination of mild-moderate iodine deficiency in school-age children living in moun‐ tainous rural localities presumes special measures by the daily administration of 0.1-0.2 mg

industry) to utilize iodized salt (Goldner, 2005).

pubertal children.

**6. Conclusions**

iodine tablets.

In conclusion, on the basis of the indicators for iodine status the mountainous villages locat‐ ed in Mureş Conty, known as mild/moderate iodine deficient regions in 1999, remained in the same iodine deficiency category during 2006, however the absolute values of indicators were considerably, some even significantly improved. The indicators situated before at the lower limit of mild/moderate iodine deficiency interval, after-wise were shifted to the mid‐ dle zone and upper limit of this range. The universal salt iodization had a beneficial impact on iodine deficient rural regions, as expected, but its sustainability must be maintained, i.e. the effectiveness of public health authorities and salt industry to monitor and control the whole procession must be consolidated. The elimination strategy of IDD in mountainous ru‐ ral areas remains a very important public health program, as the iodine content of water and soil is very low here. Water samples taken from the main water-provision points from every village showed that the iodine content of drinking water was very low in every locality, as expected in mountainous rural regions. Thus general measures to increase the iodine con‐ tent of the water should be applied. The iodine content of the running water measured in 1998/99 and 2006 was very variable (the mean value being X=10.15μg/L, SD±9.85 − Balázs et al., 1998), but in all cases the iodine concentration was much more under the accepted value (levels above 50μg/L being considered normal). Iodine content of alimentary salt found at the market of the three villages was in some cases under the prescribed level of 34±8mg/kg. The usage of iodized alimentary salt in households reached 96% in 2004 compared to 53% in the previous years (Goldner, 2005; Stănescu, 2005), but the alimentary salt was insufficient iodized (in 63% of cases, Goldner, 2005). A proportion of 74.5% of the sample of salt tested which was used in the market and for the panification had a standard iodine content of 15-25 mg/kg (Goldner, 2005), which was under the prescribed concentration. In spite of exis‐ tent legislation to mandatory sale of iodized table salt on the market, about 12% of popula‐ tion consumes not iodized salt (Nanu, 2005), especially in rural environment.

The persistence of moderate iodine deficiency in some zones of Romania was attributed to the insufficient iodization level of the salt and waist during storage, to the uncontrolled sell‐ ing of industrial salt as alimentary salt, to the lack of control measures in import of salt, to the inadequate monitoring system and the lack of efficient measures to realize entirely the governmental decision, as well as the resistency of alimentary industry (e.g. meat processing industry) to utilize iodized salt (Goldner, 2005).

We must remark the presence of hypothyroidism related to iodine deficiency in 17.7% of the investigated school-children, TPO-Ab being normal in all of them. Although, all cases of hy‐ pothyroidism were mildly overt or subclinical forms (15 and 9, respectively), we must take into account that even mild iodine and thyroid hormone deficiencies conduct to psycho‐ neurological damages, the characteristical complication of latent deficiency being AD-HD syndrome in developed countries. Chronic iodine deficiency leads to suboptimal intellectual development. Recent studies performed in the European countries, known with iodine pre‐ vention programs initiated decades ago, and thougth that iodine deficiency was eliminated, sustaine surprisingly the presence of mild iodine deficiency in many countries and implica‐ tion of this in school performances, psychological and neurological status. These mild defi‐ cits probably results from transient hypothyroidism during the first 2-years of life, i.e. during the critical period of brain development (Delange, 2002). Besides iodine deficiency, an increase in iodine intake can also lead to a small but significant increase in the incidence of hypothyroidism, probably attributable to autoregulation of thyroid function.

In conclusion, the rural mountainous zones of Mureş County known before as moderate/ mild iodine-deficient areas, became *mild-deficient*, due to the new measures of iodine preven‐ tion. In these areas universal salt iodization is not sufficient, being necessary to apply peri‐ odically special prophylactic measures (iodine tablets), too, primarily to prepubertal and pubertal children.

## **6. Conclusions**

provement of overall median UIE in school-age Romanian children from 70 (in urban) and 60μg/L (in rural areas) in 2002 to 105 and 100μg/L, respectively, until 2004. At the Second National Conference for the elimination of IDD held at Bucharest in 2005, the Mother and Child Care Institute "Alfred Rusescu" reported that in children of 6-7-years of age the overall iodine status tended to normalize, the median UIE reaching 100μg/L (Stănescu, 2005). Although the median UIE became almost normal (105 in urban and 100μg/L in rural localities), a large interindividual variation were found, reflected by the SD of ±60μg/L (Stănescu, 2005). Important differences between iodine status of rural and urban environment were observed. Mild iodine deficiency was recorded in 33.5% of the population, 11% presented moderate and 2.4% severe forms (Stănescu, 2005), although 96.3% of the housholds used iodized salt. These results could derive from the facts that more than half of the families used salt with inadequate iodine content (under 15mg io‐ dine/kg salt), 3/4 of the families consumed iodized salt but in an inadequate manner (adding salt before and during cooking) which reduces the content of iodine; the fre‐ quency of iodized salt consumption is higher in families with the higher educational lev‐

In conclusion, on the basis of the indicators for iodine status the mountainous villages locat‐ ed in Mureş Conty, known as mild/moderate iodine deficient regions in 1999, remained in the same iodine deficiency category during 2006, however the absolute values of indicators were considerably, some even significantly improved. The indicators situated before at the lower limit of mild/moderate iodine deficiency interval, after-wise were shifted to the mid‐ dle zone and upper limit of this range. The universal salt iodization had a beneficial impact on iodine deficient rural regions, as expected, but its sustainability must be maintained, i.e. the effectiveness of public health authorities and salt industry to monitor and control the whole procession must be consolidated. The elimination strategy of IDD in mountainous ru‐ ral areas remains a very important public health program, as the iodine content of water and soil is very low here. Water samples taken from the main water-provision points from every village showed that the iodine content of drinking water was very low in every locality, as expected in mountainous rural regions. Thus general measures to increase the iodine con‐ tent of the water should be applied. The iodine content of the running water measured in 1998/99 and 2006 was very variable (the mean value being X=10.15μg/L, SD±9.85 − Balázs et al., 1998), but in all cases the iodine concentration was much more under the accepted value (levels above 50μg/L being considered normal). Iodine content of alimentary salt found at the market of the three villages was in some cases under the prescribed level of 34±8mg/kg. The usage of iodized alimentary salt in households reached 96% in 2004 compared to 53% in the previous years (Goldner, 2005; Stănescu, 2005), but the alimentary salt was insufficient iodized (in 63% of cases, Goldner, 2005). A proportion of 74.5% of the sample of salt tested which was used in the market and for the panification had a standard iodine content of 15-25 mg/kg (Goldner, 2005), which was under the prescribed concentration. In spite of exis‐ tent legislation to mandatory sale of iodized table salt on the market, about 12% of popula‐

tion consumes not iodized salt (Nanu, 2005), especially in rural environment.

el of the mother.

122 Hot Topics in Endocrine and Endocrine-Related Diseases

This work underlines considerable improvement of iodine nutrition in mountainous rural regions of Mureş County after the implementation in practice of universal salt iodization in Romania since 2003, although these areas remained mildly (some moderately) iodine defi‐ cient at about 2.5-3 years after the IDD elimination strategy was intitiated. On one hand the prophylactic measures with higher iodine content of alimentary salt (KIO3 25.5-42.5mg/kg) might not be sufficient for the full correction of iodine deficiency in these isolated mountain‐ ous rural regions, on the other hand special attention is required to monitorize continuously the market and reaching programs, as well as the sustainability of the prophylactic program must be ensured. In these areas special measures, i.e. iodine supplementation to the highrisk populational groups are periodically required in addition to universal salt iodization, especially as iodine deficiency occured with hypothyroidism in 17.7% of school-children. The elimination of mild-moderate iodine deficiency in school-age children living in moun‐ tainous rural localities presumes special measures by the daily administration of 0.1-0.2 mg iodine tablets.

## **Author details**

Imre Zoltán Kun1,2, Zsuzsanna Szántó1 , József Balázs2 , Anisie Năsălean<sup>2</sup> and Camelia Gliga1,2 [9] Brook Charles DG, Brown Rosalind S (2008) Handbook of clinical Pediatric Endocri‐

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**Chapter 5**

**Diabetes and Its Hepatic Complication**

After food intake, blood glucose levels rise and insulin is released by the pancreas to main‐ tain homeostasis. In the diabetic state, the absence or deficient action of insulin in target tis‐ sues is the cause of hyperglycemia and abnormalities in the metabolism of proteins, fats and carbohydrates. In addition, chronic hyperglycemia, characteristic of diabetes, is responsible for organic dysfunction, being eyes, kidneys, nervous system, heart and blood vessels the most important affected organs. Diabetes mellitus (DM) is a heterogeneous dysregulation of carbohydrate metabolism, characterized by chronic hyperglycemia resulting from impaired glucose metabolism and the subsequent increase in blood serum glucose concentration. The pathogenic equation for DM presents a complex interrelation of metabolic, genetic and envi‐ ronmental factors, as well as inflammatory mediators. Among the latter, it is mostly unclear whether they reflect the disease process or are simply signs of systemic or local responses to

DM affects about 26 million individuals in America and at least 250 million people world‐ wide (World Health Organization), causing about 5% of all deaths. Besides, the number of affected people is expected to duplicate by 2030 unless urgent measures are taken [2, 3]. Ev‐ ery day, 200 children under 14 years are affected by type 1 diabetes, and this number in‐ creases by 3 per cent each year, whereas the analogous increment for preschool children

Rats and mice are animals commonly used for studying the effects of diabetes. Type 2 DM can be induced in animal models through dietary modification such as the administration of

and reproduction in any medium, provided the original work is properly cited.

© 2013 Ingaramo et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

reaches 6 per cent [4]. All these data point out the epidemic character of DM.

**2. Animal models for the study of diabetes**

Paola I. Ingaramo, Daniel E. Francés,

http://dx.doi.org/10.5772/53684

**1. Introduction**

the disease [1].

María T. Ronco and Cristina E. Carnovale

Additional information is available at the end of the chapter

