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The role of selenium, vitamin C, and zinc in benign thyroid diseases and of selenium in malignant thyroid diseases: Low selenium levels are found in subacute and silent thyroiditis and in papillary and follicular carcinoma

BMC Endocrine Disorders volume 8, Article number: 2 (2008) Cite this article

Abstract

Background

Thyroid physiology is closely related to oxidative changes. The aim of this controlled study was to evaluate the levels of nutritional anti-oxidants such as vitamin C, zinc (Zn) and selenium (Se), and to investigate any association of them with parameters of thyroid function and pathology including benign and malignant thyroid diseases.

Methods

This controlled evaluation of Se included a total of 1401 subjects (1186 adults and 215 children) distributed as follows: control group (n = 687), benign thyroid disease (85 children and 465 adults); malignant thyroid disease (2 children and 79 adults). Clinical evaluation of patients with benign thyroid disease included sonography, scintigraphy, as well as the determination of fT3, fT4, TSH, thyroid antibodies levels, Se, Zn, and vitamin C. Besides the routine oncological parameters (TG, TSH, fT4, ultrasound) Se was also determined in the cases of malignant disease. The local control groups for the evaluation of Se levels were taken from a general practice (WOMED) as well as from healthy active athletes. Blood samples were collected between 8:00 and 10:30 a.m. All patients lived in Innsbruck. Statistical analysis was done using SPSS 14.0. The Ho stated that there should be no differences in the levels of antioxidants between controls and thyroid disease patients.

Results

Among the thyroid disease patients neither vitamin C, nor Zn nor Se correlated with any of the following parameters: age, sex, BMI, body weight, thyroid scintigraphy, ultrasound pattern, thyroid function, or thyroid antibodies. The proportion of patients with benign thyroid diseases having analyte concentrations below external reference cut off levels were 8.7% of cases for vitamin C; 7.8% for Zn, and 20.3% for Se. Low Se levels in the control group were found in 12%. Se levels were significantly decreased in cases of sub-acute and silent thyroiditis (66.4 ± 23.1 μg/l and 59.3 ± 20.1 μg/l, respectively) as well as in follicular and papillary thyroid carcinoma. The mean Se level in the control group was 90.5 ± 20.8 μg/l.

Conclusion

The H0 can be accepted for vitamin C and zinc levels whereas it has to be rejected for Se. Patients with benign or malignant thyroid diseases can present low Se levels as compared to controls. Low levels of vitamin C were found in all subgroups of patients.

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Background

During thyroid hormone synthesis, thyroid tissue is exposed to H2O2 making it imperative that protective systems can prevent damage to the gland [1–5]. This tissue protection can be achieved by selenium-dependent products, e.g. the glutathione peroxidase [6–8]. Serum levels of selenium (Se) are considered to depict the adequacy regarding GPx levels and activity [9–11]. In addition to this, the determination of selenoproteins, e.g. selenoprotein P (SePP), can deliver further information on the adequacy of Se levels [12].

Several investigators have previously evaluated Se levels in patients with benign and malignant thyroid diseases. These studies demonstrated that hyperthyroidism is associated with decreased levels of Se [13–15]. Derumeaux et al. [16] also concluded that Se might have a protective role in relation to goiter, and that thyroid hypogenicity appears to be related to Se levels [16]. In the field of malignant thyroid diseases, decreased tissue levels of zinc (Zn) and Se, appear to be associated with carcinoma [17]. Studies based on the Janus serum bank have shown the value of pre-diagnostic levels of Se in relation to thyroid carcinoma [18, 19].

In experimental settings other micronutrients such as Zn have also been shown to play a role on thyroid morphology and metabolism [20]. It should be kept in mind that Zn is also an antioxidant [21], while at the same time it has important functions in relation to immune function [22, 23]. Comparable functions have been described for Zn and Se together [24, 25]. In addition to this, Martin et al. have described a positive interaction between vitamin C and Se homeostasis [26].

Besides these thyroid-related data one has to consider the importance of nutrient antioxidants in a much wider frame, i.e. in relation to their protective effects on health [27–30]. An example of this approach is the French SU.VI.MAX study, where micronutrients have been evaluated in relation to cardiovascular diseases, thyroid disease, and cancer [31, 32]. One central thought behind these studies has been stated as follows: "Insufficient intake of antioxidant vitamins and minerals may reduce the body's capacity to defend itself from the effect of activated oxygen derivatives on cell processes that play a role in the development of cancer and cardiovascular disease [33, 34]." It follows that there is a clinical relevance in the determination of base line levels of nutrient antioxidants. For this reason, we designed this investigation in order to evaluate the levels of nutritional anti-oxidants in a controlled study, i.e. comparing patients with controls.

Methods

Laboratory determinations of nutritional antioxidants

Blood samples were collected between 8:00 and 10:30 a.m. After centrifugation (1500 g, 15 minutes) serum was removed and aliquots were frozen and stored at -20°C. Selenium concentrations in human serum were determined using a graphite furnace atomic absorption spectrometer (Unicam Model Solaar, 939 QZ, Cambridge, UK) with Zeeman background correction and pyrolytic carbon-coated graphite tubes. Slit 0.5 and wavelength λ 196.0 nm were used as spectrometer parameters. Specimens were diluted 1:10 with 0.1% HNO3, 0.05% Triton ×100, and 0.05% silicone anti-foaming agent (Merck, Germany). Palladium nitrate as matrix modifier and matrix-matched standards for calibration (6.25, 12.5, 25, and 50 μg/l) were used. Multiple aliquots of a control pooled serum sample were analyzed during each batch of analyses (intra-assay CV < 4.5%). Imprecision is shown as coefficient of variation (CV). In addition, an external control, (ClinChek-Serum control, Lot No. 323; Recipe Chemicals and Instruments, Munich, Germany), was analyzed with each batch. Analyzed values were within the expected range given by the manufacturer (i.e., Level1: 46–78 μg/L, certified mean concentration: 62.0 μg/L; Level 2: 84–140 μg/L, certified mean concentration: 112 μg/L), with means of 63.8 ± 6.15 μg/L (n = 19, CV 9.6%) for Level 1, and 109.9 ± 10.15 μg/L (n = 20, CV 9.2%) for Level 2 serum analyses.

Serum zinc content was investigated according to Smith et al. [35] by employing a flame (air-acetylene burner) atomic absorption spectrometer (Unicam Model Solaar, 939, Cambridge, UK). Bandpass 0.5 nm and wavelength λ 213.9 nm were used as spectrometer parameters. Specimens were diluted 1:10 or 1:5 with double distilled water. Working standards of zinc containing 0.1, 0.25, 0.5, and 1.0 μg/ml were prepared from stock standard solution containing 1000 μg Zn/ml. Multiple aliquots of a control pooled serum sample were analyzed during each batch of analyses (intra-assay CV < 3.5%). In addition, an external control, (ClinChek-Serum control, Lot No. 323; Recipe Chemicals and Instruments, Munich, Germany) was analyzed with each batch. Analyzed values were within the expected range given by the manufacturer (i.e., Level 1: 636–1060 μg/L, certified mean concentration: 848 μg/L; Level 2: 1706–2844 μg/L, certified mean concentration: 2275 μg/L), with means of 798 ± 79 μg/L (n = 20, CV 9.9%) for Level 1, and 2037 ± 135 μg/L (n = 20, CV 6.7%) for Level 2 serum analyses.

For the determination of ascorbic acid a 100 μl volume of serum was stabilized immediately after preparation by addition of 100 μl 10% metaphosphoric acid and incubated for 10 minutes at 4°C. Thereafter the sample was centrifuged at 10000 × g and 4°C. 20 μl of the supernatant was used for determination of ascorbic acid. The HPLC method used (flow rate 1.0 ml/min, detection at 245 nm) is based on the work published by Esteve et al. [36] with some modifications. The ascorbic acid standard solution (10 mg/l) was prepared daily in deionized water Millipore-Milli Q. 4-hydroxyacetanilide was used as internal standard. Multiple aliquots of a control pooled serum sample were analyzed (intra-assay CV < 3.0%). In addition, an external quality control (Chromsystems Vitamin C Plasma control, Lot No. 1906; Chromsystems Instruments and Chemicals GmbH, Munich, Germany), was analyzed with each batch (inter-assay CV < 5.0%). Determinations of selenium, zinc and ascorbic acid were made in duplicate, and the analysts were blinded as to the case status of the specimens.

Vitamin C and zinc in patients with benign thyroid disease

In an initial phase a group of 425 consecutive adult patients attending the out-patient unit of the Clinical Department of Nuclear Medicine of the Medical University of Innsbruck were investigated. In these patients the levels of Zn and vitamin C (n = 415) were determined. The research protocol was approved by the Institutional Ethics Committee. Informed consent was obtained from each subject. Clinical evaluation included sonography, scintigraphy, and thyroid function parameters. Determinations of fT3, fT4, TSH and thyroid antibodies levels were done on the Advia Centaur system (Bayer Health Care, Austria) as described elsewhere [37].

Weight, height and medication were recorded for each patient. Thyroid ultrasound was done using a Siemens Sonoline Antares equipped with a VFX13-5 transducer (Siemens, Erlangen, Germany). RM carried out the ultrasound examinations. Thyroid scintigraphy was done on a Siemens Orbiter gamma camera (Siemens, Erlangen, Germany) after i.v. application of 37 MBq of 99mTc pertechnetate. Based on the clinical history, the laboratory tests and the imaging procedures, a final diagnosis was given in each case. The final diagnoses included: normal thyroid function (negative thyroid serology), Graves' disease (positive TSH receptor antibodies), Hashimoto's disease (positive thyroid serology), sub-acute thyroiditis and silent thyroiditis [38]. Thyroid function was classified as normal, hypothyroid or hyperthyroid based on the measured levels of fT3, fT4 and TSH [37, 39, 40]

Se levels in patients with thyroid disease

The study included 465 adult patients and 85 pediatric patients presenting benign thyroid disease, and 164 patients with malignant thyroid disease taking thyroid medication. Laboratory and ultrasound examinations were the same as described above. Thyroid scintigraphy was done neither in the pediatric group nor in the group with thyroid carcinoma.

Control groups for the evaluation of Se

A control group for the evaluation of Se levels was taken from a general practice (WOMED, n = 554; 468 females, mean age 41 ± 11 years; 46 males, mean age 37 ± 15 years). These patients were clinically investigated by RM and HM. The geographical origin of this control group was similar to that of the thyroid patients, i.e. all subjects lived in the province of Tirol in Austria. By this, differences due to different geographical origin were minimized. In this group of patients the following laboratory investigations were available: kidney function tests, liver function tests, red and white cell counts, electrolytes, and thyroid function tests. The major diagnoses in this group were: burn-out syndrome, depression, infertility, menopause, GI disorder and DM. None of these entities is known to be associated with alterations in Se levels. A second group of medically controlled subjects included 133 active winter sport athletes not having overt thyroid disease. This group included 44 females and 89 males with a mean age of 18.7 ± 4.5 years. Regular medical examinations did not reveal any pathology that can be associated to changes in Se levels. In the subgroup of 24 ski jumpers, a total of additional 124 biochemical parameters including red and white blood counts, liver function, kidney function, electrolytes, immunoglobulins, iron metabolism, vitamin B as well as an aminogram were analyzed. Correlation studies were done in relation to Se levels.

Statistical analysis

Statistical analysis was done using SPSS version 14. Explorative analyses of correlation were carried out between diagnostic parameters of thyroid function (fT3, fT4, TSH, and thyroid antibodies) and the measured levels of antioxidants. Thyroid characteristics as seen in ultrasound and scintigraphy were coded and compared by cross tabulation with the categorized levels of nutritional antioxidants. In order to allow for qualitative comparison with recent data dealing with the nutritional status of adult Europeans, the cut-off levels for Se, Zn, and vitamin C were taken from Galan et al. [34]. These levels correspond to: 0.75 μM for Se; 10.7 μM for Zn; and 11.4 μM for vitamin C. Additional external reference levels for Se were taken from publications that have evaluated the concentration of Se needed to achieve full expression of Se related products, i.e. deiodinase, glutathione peroxidase (GPx) and selenoprotein P (SePP) [41–43]. Results were categorized as being below or above these cut off levels as well as a percentual fraction of the reference levels. Finally, differences among the diagnostic groups for each parameter were analyzed by one way ANOVA using Bonferroni's correction. For all evaluations a p-value < 0.01 was taken as significant. The Ho stated that there are no differences in the levels of antioxidants between controls and thyroid disease patients.

Results

General aspects

Neither vitamin C, nor Zn, nor Se levels showed any correlation with sex, age, weight, height, BMI, thyroid function, ultrasound pattern, nor thyroid morphology. Lack of association between Se and BMI was also seen even after classifying the BMI results into subgroups as has been done recently by Meplan et al. [44]. The descriptive statistics of BMI levels in our study were: mean 23.57 ± 4.5 kg/m2 (S.D.), the 95th percentile corresponded to a value of 31.7 kg/m2.

In the group of patients with benign thyroid diseases there were no differences in the levels of Zn or vitamin C according to the classification of disease type (Table 1). Due to this lack of correlation, determinations of vitamin C and Zn were not carried out in the subsequent cases, i.e. pediatric cases and in the group of patients with thyroid malignancy.

Table 1 Zn and vitamin C levels in the patients with benign thyroid disease
Full size table

Comparison of analyte levels with published threshold values – the nutritional aspect of the study

In spite of the lack of association of between vitamin C or Zn levels in relation to thyroid disease it should be stressed that the overall proportion of thyroid patients having vitamin C concentrations below the threshold levels reported in the SU.Vi.MAX study [34] was 8.4% of cases for vitamin C and 7.73% for Zn. The figure for Zn is similar to the reported one, the figure for vitamin C exceeds the levels reported.

The percentage of subjects having low levels of Se as compared to the functional threshold level known to be necessary for the maintenance of optimal plasma glutathione peroxidase [45] is shown in Table 2. In this qualitative comparison the largest proportions of cases having low Se levels were seen in children with hyperthyroidism and polyendocrinopathy, as well as in adults with subacute and silent thyroiditis, and in follicular carcinoma.

Table 2 Percentage of subjects with Se levels below the threshold for optimal plasma glutathione peroxidase [45]
Full size table

Table 3 shows another qualitative analysis in relation to the threshold levels known to be necessary for optimal deiodinase activity, plasma glutathione peroxidase and selenoprotein P levels [41, 42]. While the mean Se value found in our study was sufficient to cover the requirements for deiodinase activity, it was not sufficient neither for platelet glutathione peroxidase nor for selenoprotein P expression.

Table 3 Se levels expressed in percentage of threshold levels in relation to deiodinases (IDI), plasma glutathione peroxidase (GPx), and selenoprotein P (SePP) [41,42]
Full size table

Quantitative analyses of the Se status

Control group

Initial one-way ANOVA showed no difference in the Se levels in relation to the diagnostic subgroups contained in the adult control group (burn-out, depression, infertility, menopause, GI disorders, and DM). It should be mentioned that none of these conditions is known to produce alterations in the concentration of Se. The mean Se level for the non-thyroid disease control group was 90.5 ± 20.8 μg/l; the 5th percentile corresponded to 65.7 μg/l, and the 95th percentile to 129 μg/l. The control group consisting of active athletes did not differ from the adult control group.

Selenium status in benign and malignant thyroid disease

One-way analysis of variance of all Se samples, i.e. thyroid vs. non-thyroid disease patients, revealed significantly diminished levels (p < 0.001) for all thyroid disease patients. Among the groups of patients with benign thyroid disease, the Se levels of those with subacute and with silent thyroiditis were significantly lower as compared to the other diagnostic groups. In sub-acute and silent thyroiditis the measured levels were: 66.4 ± 23.1 μg/l and 59.3 ± 20.1 μg/l, respectively. In the groups of patients with thyroid malignancy, those presenting follicular and papillary types of carcinoma showed also diminished Se concentrations (76.9 ± 21.1 μg/l and 80.4 ± 19.8 μg/l, respectively). Children with thyroid disease and polyendocrinopathy had low Se levels similar to those found in adults with thyroiditis (mean 66.9 μg/l). The minimal levels of Se were observed in the group of adult patients with benign thyroid disease (range 20.7 to 30 μg/l) (Table 4).

Table 4 One-way ANOVA (Bonferroni) analysis of the Se levels
Full size table

Correlation analyses for Se and TSH, Se and BMI and of Se and thyreoglobulin failed to demonstrate any significant association. In a similar fashion, the ample biochemical analysis of the ski jumper control group with 124 parameters revealed no associations for Se in relation to white and red blood counts, electrolytes, liver and kidney function tests, cortisol, testosterone, iron, folic acid, vitamin B12, immunoglobulins, and aminogram data including methionine levels.

Discussion

General evaluation in relation to external reference levels

Our study was designed as a controlled one in order to evaluate the levels of nutritional antioxidants, i.e. Se, Zn and vitamin C, in relation to morphological and functional parameters of benign and malignant thyroid disease. These nutritional parameters were chosen due to their physiological role in inflammation [46] as well as in anti-oxidative processes [47]. Oxidative processes in general are matter of current research in both benign and malignant disease since they are linked to aging, to general disease conditions as well as to increased mortality rates in the general population [27, 30, 48–51]. Through the use of local control groups we expected to be able to differentiate the normal and the pathological conditions [52]. Based on one way ANOVA analysis Ho could be rejected for Se levels, i.e. Se levels are indeed different between patients and controls.

From a nutritional, qualitative point of view, our study documents diminished levels of vitamin C and Se in our patients as compared to recent data from the SU.VI.MAX study [34]. On the other hand, plasma Zn levels were found to be unrelated to thyroid function or morphology. Due to the predominantly intracellular distribution of Zn [53–59] a different analytical approach, i.e. determination of erythrocyte Zn levels, might have been more adequate to differentiate patients with hyperthyroidism from those with thyroiditis [60–64] as well as those with thyroid associated orbitopathy [46].

The role of vitamin C in thyroid disease

Clinical studies on the importance of vitamin C in relation to thyroid disease are scarce. In 1977 Dubey et al. described low levels of ascorbic acid in patients with hyperthyroidism [65]. Similar results have been presented by Ademoglu et al. [66] and Alicigüzel et al. [67]. Mohar Kumar et al. described also low levels of vitamin C in hyperthyroidism, while at the same time lipid peroxides, glucose, and HbA1C levels were elevated [68]. It follows that both data from the literature as well as from our study show that vitamin C levels can be low in patients with benign thyroid disease. Low levels of vitamin C can predispose to endothelial changes [69, 70], a situation which can also be negatively influenced by diminished thyroid function [71, 72]. Our failure to demonstrate an association between vitamin C levels and benign thyroid disease could be explained through the relatively short half life of vitamin C of 10–20 days [73]. Nonetheless, interactions between vitamin C and Se have been described [26, 74–77] by which low levels of vitamin C could affect Se metabolism and action.

Se in relation to amino acids and other biochemical parameters and BMI

Early studies on the bioavailability of selenomethionine mentioned potential interactions between methionine and Se uptake [78]. Based on an extensive biochemical analysis with 124 parameters including an aminogram, we were not able to find any relation between Se and the parameters studied including methionine. The association between Se and methionine appears to be possible within the frame of malnutrition together with methionine deficiency as has been shown in experimental settings [79]. In our study, none of the patients presented malnutrition.

In the recent analysis of genetic SePP polymorphisms, Méplan et al. identified an association of BMI with Se levels for subjects having a BMI > 25 kg/m2 [44]. In our study we were not able to find a similar association.

Se in benign and malignant thyroid disease

Previous investigators have looked at Se levels in whole blood in relation to hyperthyroidism [13]. Beckett et al. reported lower values of Se for untreated Graves' disease (mean 88.9 μg/l) as compared to treated patients (mean 107.2 μg/l). The authors suggested that hyperthyroidism is responsible for low Se levels. Aihara et al. have also shown low erythrocyte levels of Se in cases of hyperthyroidism [80]. Using plasma determinations, Reglinski et al. have also shown low Se levels in hyperthyroidism [14]. These authors were able to document an increase in Se concentration after anti-thyroid treatment, however the mean Se value was still lower than that of the controls [14]. The question of Se normalization after remission of hyperthyroidism has been looked at recently by Wertenbruch et al. [81]. The authors could not find a normalization of Se in the remission phase: Se levels in Graves' disease without and with remission were 71.7 μg/l and 73 μg/l, respectively. In our study we have not found any relation between thyroid function parameters and Se levels in benign thyroid disease, so that we cannot lend support to Beckett's theory. Furthermore, we did not find any relation between Se and thyroid function parameters in the group of oncological patients who were taking T4 medication in a suppressive dose.

An analysis based on whole blood determinations of Se done by Kucharzewski et al. reported lower Se levels for thyroid carcinoma, nodular goiter, Graves' disease and thyroiditis as compared to normals [15]. While their study revealed lower Se levels in the 21 patients with thyroid carcinoma, there was no information as to the histological type of carcinoma. Out of 164 patients with thyroid carcinoma investigated by us only those with follicular or papillary types had low Se levels. Due to study design, we cannot fully confirm the observations obtained from the JANUS serum bank relating pre-diagnostic low Se levels with thyroid carcinoma [18]. Our data has discarded any association between Se and Tg.

Selenium levels in pediatric patients

Dealing with Se levels in children differs from adult subjects since an age related increase can be seen. Se levels in children in the pre-school and school age are similar to those found in adults while younger patients have lower levels [82, 83]. In 1992 Tiran et al. failed to observe this increase of Se levels for Austrian children [84, 85]. The Se levels reported by Tiran et al. are far below the levels required for adequate expression of selenoproteins. Even though the mean level of Se in our pediatric patients is higher than that seen in 1992, a tendency to lower Se values can be seen in children with hyperthyroidism and with polyendocrinopathy. These situations have not been described before in the literature. Low levels of Se have been reported in Polish pediatric patients presenting thyroid diseases due to iodine deficiency [86]. Even after correction of iodine deficiency, children still had low Se levels [87]. Due to iodine supplementation programs in Austria, iodine deficiency is now rare [88], however Se levels can still be suboptimal, as we have documented here. On experimental grounds, Ruz et al. have nicely demonstrated the effects of single and combined deficiency situations involving iodine, Se, and Zn [20].

Situations leading to low Se levels

Since our results point out the fact that a significant proportion of patients with thyroid disease have low levels of Se, it is important to analyze some of the known causes related to low Se levels [45, 89, 90] which might play a role in our patients. The central regulator of Se levels is the adequacy of supply, so that malnutrition in different degrees will lead to low Se levels [90–92]. Minor surgical interventions [93] and intensive care situations [94, 95] can also induce a drop of Se concentrations. Nutritional studies have shown that feeding a low Se diet for 30 days can induce a drop of the plasma Se levels [96]. None of these conditions, however, were found in our subjects.

Stressful life events have been implicated in the etiology of thyroid disorders [97–103] and psychological stress per se can lead to diminished levels of Se [104]. In addition to this both physical and psychological stress can also induce changes in trace elements [105], e.g. to low levels of Mg [106], and low Mg levels can affect Se absorption [107, 108]. In a previous study we have documented an altered relationship between Mg and Ca in patients with thyroid associated orbitopathy [46], thus lending support to this postulate.

In a general sense, viral infections can be considered to pose a stress to the organism [109–114]. Se deficit can increase the virulence of some infections such as with coxsackie virus in relation to heart disease [115]. Several authors have even proposed a viral etiology of thyroiditis, however this has not been confirmed neither in De Quervain's thyroiditis nor in Graves' disease [116–119]. Should a Se deficiency be present a-priori, viral infections can turn aggressive at least in animal models [120]. Similar associations have been described in HIV infections [121], however Beltran et al. could not find evidence for an autoimmune mechanism of thyroid disease in HIV patients [122].

Low Se levels can be seen in association with the acute phase of several pathological conditions [123]. Maehira et al. extended these observations by in-vitro experiments where it could be shown that low Se influences the activation of NF-Kappa-B, whereas a state of normal Se inhibits the NF-Kappa-B mechanisms that can lead to increased CRP levels [124]. An inflammatory reaction appears to depend on the interaction between IL-6, TNF and selenoprotein S [125]. Selenium and parameters of infection or inflammation have been recently described as a situation of negative correlation between Se and CRP and IL-6 [95]. Results from the MONICA/KORA Augsburg study have shown that normal Se levels are related to vitamins C and E as well as to low CRP values [126].

In a study presented by Pearce et al. [127] a central role of elevated CRP levels in thyroid disease could not be found. Severe health impairment such as found in sepsis and multiorgan failure, on the other hand, can indeed alter Se levels [95]. Clinical practice with thyroid disease patients however, does not lend evidence to the presence of a severe infection at the time an out-patient consultation takes place. A different situation could be expected in cases of chronic infection or parenteral nutrition [128].

Biochemical changes in Se deficiency

Besides the diminished levels of Se in cases of deficiency a series of Se-dependent proteins can be found to be altered in such situations. This has been shown elegantly in Finland after Se supplementation was introduced in the 1980s: supplementation with Se led to an increase of the levels of Se and of SePP. Once Se repletion was achieved, SePP levels did not change significantly when Se was given [42]. In cases of Se deficiency, the changes in SePP are tissue specific [129]. In addition to this feature a recent study has documented the influence of gender and genetic polymorphisms on the response pattern of SePP to Se supplementation [44]. Analyses of Se together with selenoproteins, which can be considered to be a better indicator of Se status [130, 131], have not been carried out in cases of thyroid disease.

What to do in face of low Se levels in patient with thyroid disease?

The description of deficient nutritional situations belongs to the classical approach used in nutrition research in order to identify causes and to treat them by substitution [132]. In the previous section we have tried to delineate some of the changes that can be expected to happen within the setting of low Se levels in relation to inflammation and which might change during supplementation. The use of nutrient supplementation which is not based on the determination of nutrient levels cannot be expected to achieve beneficial effects since the needed dose and the target parameters might be incorrect. In addition, the chemical form of the nutrient has to be chosen adequately [133]. Reading the description of the individual studies cited in the meta analysis done by Bjelakovic et al. [134] it is easy to recognize why the analysts did not find positive effects of supplementation procedures: some studies did not measure the basal levels prior to intervention, and the doses and chemical forms of the preparations differed greatly.

At the time we carried out this study, several Se supplementation trials for patients with autoimmune thyroid disease were published [135–138]. In these studies the common denominator was the drop in the level of thyroid antibodies, i.e. a better nutritional status induced changes in the humoral arm of the immune system. The study by Gärtner et al. utilized 200 μg of a liquid formulation of sodium selenite over a period of 3 months. In the verum group Se levels increased from 0.87 to 1.09 μM; at the same time thyroid peroxidase antibody levels dropped by 37% [135]. Duntas et al. [136] carried out "arbitrary" evaluations in a subgroup of the patients studied. They found a basal Se level of 75 μg/l. Intervention was done using selenomethionine at a dose of 200 μg/d and were able to observe a greater drop of thyroid antibody levels of 46% after 3 months, and of 55.5% after 6 months of therapy. Turker and colleagues compared the efficacy of 100 μg and 200 μg of selenomethionine concluding that better effects could be reached by the higher dose [137]. Mazopakis et al. [138] used a dose of 200 μg selenomethionine and observed also a drop in the levels of thyroid peroxidase antibodies. None of the studies found changes in the levels of thyroid hormones. Finally Negro et al. [139] studied a group of pregnant women who presented thyroid peroxidase antibodies. The base-line Se levels ranged between 78.2 and 80.9 μg/l. Under treatment with 200 μg selenomethionine, Se levels remained significantly elevated, app. 105 μg/l, while the untreated group showed a transient drop of Se at 30 weeks of pregnancy. Se supplementation was associated with a lower incidence of hypothyroidism and thyroid inflammation. In our previous preliminary series Se substitution with 200 μg of selenomethionine was instituted when Se levels were lower than 70 μg/l. Besides a drop of thyroid antibodies, we were also able to document an increase of thyroid function, i.e. latent hypothyroidism was corrected [140].

Conclusion

From a global point of view, we can state that nutritional deficiencies in relation to Se and vitamin C have been found in our study of Austrian patients. These findings contradict the official Austrian opinion contained in the Austrian Nutrition Report 2003 [141].

Within the wide spectrum of patients with thyroid disease studied herein, the most salient feature is that of diminished levels of Se in cases of sub-acute and silent thyroiditis, as well as in the setting of pediatric patients with hyperthyroidism and polyendocrinopathy, and in cases of differentiated thyroid carcinoma. The mechanisms that lead to low Se levels are not yet known. Loss of differentiation of thyroid carcinoma has been recently postulated to be related to Se metabolism and indirectly to octreotide uptake [142].

References

  1. 1.

    Nilsson M: Iodide handling by the thyroid epithelial cell. Exp Clin Endocrinol Diabetes. 2001, 109: 13-17. 10.1055/s-2001-11014.

    CAS  PubMed  Google Scholar 

  2. 2.

    Sugawara M, Sugawara Y, Wen K, Giulivi C: Generation of oxygen free radicals in thyroid cells and inhibition of thyroid peroxidase. Exp Biol Med (Maywood). 2002, 227: 141-146.

    CAS  Google Scholar 

  3. 3.

    Demelash A, Karlsson JO, Nilsson M, Bjorkman U: Selenium has a protective role in caspase-3-dependent apoptosis induced by H2O2 in primary cultured pig thyrocytes. Eur J Endocrinol. 2004, 150: 841-849. 10.1530/eje.0.1500841.

    CAS  PubMed  Google Scholar 

  4. 4.

    Köhrle J, Jakob F, Contempre B, Dumont JE: Selenium, the thyroid, and the endocrine system. Endocr Rev. 2005, 26: 944-984. 10.1210/er.2001-0034.

    PubMed  Google Scholar 

  5. 5.

    Landex NL, Thomsen J, Kayser L: Methimazole increases H2O2 toxicity in human thyroid epithelial cells. Acta Histochem. 2006, 108: 431-439. 10.1016/j.acthis.2006.08.001.

    CAS  PubMed  Google Scholar 

  6. 6.

    Ekholm R, Björkman U: Glutathione peroxidase degrades intracellular hydrogen peroxide and thereby inhibits intracellular protein iodination in thyroid epithelium. Endocrinology. 1997, 138: 2871-2878. 10.1210/en.138.7.2871.

    CAS  PubMed  Google Scholar 

  7. 7.

    Beckett GJ, Arthur JR: Selenium and endocrine systems. J Endocrinol. 2005, 184: 455-465. 10.1677/joe.1.05971.

    CAS  PubMed  Google Scholar 

  8. 8.

    Song Y, Driessens N, Costa M, De D, Detours V, Corvilain B, Maenhaut C, Miot F, Van Sande J, Many MC, Dumont JE: Roles of hydrogen peroxide in thyroid physiology and disease. J Clin Endocrinol Metab. 2007, 92: 3764-3773. 10.1210/jc.2007-0660.

    CAS  PubMed  Google Scholar 

  9. 9.

    Whanger PD, Beilstein MA, Thomson CD, Robinson MF, Howe M: Blood selenium and glutathione peroxidase activity of populations in New Zealand, Oregon, and South Dakota. FASEB J. 1988, 2: 2996-3002.

    CAS  PubMed  Google Scholar 

  10. 10.

    Thomson CD, Robinson MF, Butler JA, Whanger PD: Long-term supplementation with selenate and selenomethionine: selenium and glutathione peroxidase (EC 1.11.1.9) in blood components of New Zealand women. Br J Nutr. 1993, 69: 577-588. 10.1079/BJN19930057.

    CAS  PubMed  Google Scholar 

  11. 11.

    Duffield AJ, Thomson CD, Hill KE, Williams S: An estimation of selenium requirements for New Zealanders. Am J Clin Nutr. 1999, 70: 896-903.

    CAS  PubMed  Google Scholar 

  12. 12.

    Persson-Moschos M, Huang W, Srikumar TS, Akesson B, Lindeberg S: Selenoprotein P in serum as a biochemical marker of selenium status. Analyst. 1995, 120: 833-836. 10.1039/an9952000833.

    CAS  PubMed  Google Scholar 

  13. 13.

    Beckett GJ, Peterson FE, Choudhury K, Rae PW, Nicol F, Wu PS, Toft AD, Smith AF, Arthur JR: Inter-relationships between selenium and thyroid hormone metabolism in the rat and man. J Trace Elem Electrolytes Health Dis. 1991, 5: 265-267.

    CAS  PubMed  Google Scholar 

  14. 14.

    Reglinski J, Smith WE, Wilson R, Halls DJ, McKillop JH, Thomson JA: Selenium in Graves' disease. Clin Chim Acta. 1992, 211: 189-190. 10.1016/0009-8981(92)90195-V.

    CAS  PubMed  Google Scholar 

  15. 15.

    Kucharzewski M, Braziewicz J, Majewska U, Gozdz S: Concentration of selenium in the whole blood and the thyroid tissue of patients with various thyroid diseases. Biol Trace Elem Res. 2002, 88: 25-30. 10.1385/BTER:88:1:25.

    CAS  PubMed  Google Scholar 

  16. 16.

    Derumeaux H, Valeix P, Castetbon K, Bensimon M, Boutron-Ruault MC, Arnaud J, Hercberg S: Association of selenium with thyroid volume and echostructure in 35- to 60-year-old French adults. Eur J Endocrinol. 2003, 148: 309-315. 10.1530/eje.0.1480309.

    CAS  PubMed  Google Scholar 

  17. 17.

    Kucharzewski M, Braziewicz J, Majewska U, Gozdz S: Copper, zinc, and selenium in whole blood and thyroid tissue of people with various thyroid diseases. Biol Trace Elem Res. 2003, 93: 9-18. 10.1385/BTER:93:1-3:9.

    CAS  PubMed  Google Scholar 

  18. 18.

    Jellum E, Andersen A, Lund-Larsen P, Theodorsen L, Orjasaeter H: Experiences of the Janus Serum Bank in Norway. Environ Health Perspect. 1995, 103 Suppl 3: 85-88. 10.2307/3432566.

    CAS  PubMed  Google Scholar 

  19. 19.

    Glattre E, Thomassen Y, Thoresen SO, Haldorsen T, Lund-Larsen PG, Theodorsen L, Aaseth J: Prediagnostic serum selenium in a case-control study of thyroid cancer. Int J Epidemiol. 1989, 18: 45-49. 10.1093/ije/18.1.45.

    CAS  PubMed  Google Scholar 

  20. 20.

    Ruz M, Codoceo J, Galgani J, Munoz L, Gras N, Muzzo S, Leiva L, Bosco C: Single and multiple selenium-zinc-iodine deficiencies affect rat thyroid metabolism and ultrastructure. J Nutr. 1999, 129: 174-180.

    CAS  PubMed  Google Scholar 

  21. 21.

    Powell SR: The antioxidant properties of zinc. J Nutr. 2000, 130: 1447S-1454S.

    CAS  PubMed  Google Scholar 

  22. 22.

    Bodey B, Bodey B, Siegel SE, Kaiser HE: The role of zinc in pre- and postnatal mammalian thymic immunohistogenesis. In Vivo. 1998, 12: 695-722.

    CAS  PubMed  Google Scholar 

  23. 23.

    Savino W, Dardenne M: Neuroendocrine control of thymus physiology. Endocr Rev. 2000, 21: 412-443. 10.1210/er.21.4.412.

    CAS  PubMed  Google Scholar 

  24. 24.

    Bettger WJ: Zinc and selenium, site-specific versus general antioxidation. Can J Physiol Pharmacol. 1993, 71: 721-724.

    CAS  PubMed  Google Scholar 

  25. 25.

    Erickson KL, Medina EA, Hubbard NE: Micronutrients and innate immunity. J Infect Dis. 2000, 182 Suppl 1: S5-10. 10.1086/315922.

    CAS  PubMed  Google Scholar 

  26. 26.

    Martin RF, Young VR, Blumberg J, Janghorbani M: Ascorbic acid-selenite interactions in humans studied with an oral dose of 74SeO3(2-). Am J Clin Nutr. 1989, 49: 862-869.

    CAS  PubMed  Google Scholar 

  27. 27.

    Finkel T, Holbrook NJ: Oxidants, oxidative stress and the biology of ageing. Nature. 2000, 408: 239-247. 10.1038/35041687.

    CAS  PubMed  Google Scholar 

  28. 28.

    Pratico D: Antioxidants and endothelium protection. Atherosclerosis. 2005, 181: 215-224. 10.1016/j.atherosclerosis.2005.03.005.

    CAS  PubMed  Google Scholar 

  29. 29.

    Giugliano D, Ceriello A, Esposito K: The effects of diet on inflammation: emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006, 48: 677-685. 10.1016/j.jacc.2006.03.052.

    CAS  PubMed  Google Scholar 

  30. 30.

    Walston J, Xue Q, Semba RD, Ferrucci L, Cappola AR, Ricks M, Guralnik J, Fried LP: Serum antioxidants, inflammation, and total mortality in older women. Am J Epidemiol. 2006, 163: 18-26. 10.1093/aje/kwj007.

    CAS  PubMed  Google Scholar 

  31. 31.

    Girodon F, Blache D, Monget AL, Lombart M, Brunet-Lecompte P, Arnaud J, Richard MJ, Galan P: Effect of a two-year supplementation with low doses of antioxidant vitamins and/or minerals in elderly subjects on levels of nutrients and antioxidant defense parameters. J Am Coll Nutr. 1997, 16: 357-365.

    CAS  PubMed  Google Scholar 

  32. 32.

    Hercberg S, Galan P, Preziosi P, Roussel AM, Arnaud J, Richard MJ, Malvy D, Paul-Dauphin A, Briancon S, Favier A: Background and rationale behind the SU.VI.MAX Study, a prevention trial using nutritional doses of a combination of antioxidant vitamins and minerals to reduce cardiovascular diseases and cancers. SUpplementation en VItamines et Mineraux AntioXydants Study. Int J Vitam Nutr Res. 1998, 68: 3-20.

    CAS  PubMed  Google Scholar 

  33. 33.

    SU.VI.MAX. [http://istna.uren.smbh.univ-paris13.fr/sites/suvimax_en/]

  34. 34.

    Galan P, Briancon S, Favier A, Bertrais S, Preziosi P, Faure H, Arnaud J, Arnault N, Czernichow S, Mennen L, Hercberg S: Antioxidant status and risk of cancer in the SU.VI.MAX study: is the effect of supplementation dependent on baseline levels?. Br J Nutr. 2005, 94: 125-132. 10.1079/BJN20051462.

    CAS  PubMed  Google Scholar 

  35. 35.

    Smith JC, Butrimovitz GP, Purdy WC: Direct measurement of zinc in plasma by atomic absorption spectroscopy. Clin Chem. 1979, 25: 1487-1491.

    CAS  PubMed  Google Scholar 

  36. 36.

    Esteve MJ, Farre R, Frigola A, Garcia-Cantabella JM: Determination of ascorbic and dehydroascorbic acids in blood plasma and serum by liquid chromatography. J Chromatogr B Biomed Sci Appl. 1997, 688: 345-349. 10.1016/S0378-4347(96)00248-4.

    CAS  PubMed  Google Scholar 

  37. 37.

    Moncayo R, Moncayo H, Virgolini I: Reference values for thyrotropin. Thyroid. 2005, 15: 1204-1205.

    PubMed  Google Scholar 

  38. 38.

    Sheu SY, Schmid KW: [Inflammatory diseases of the thyroid gland. Epidemiology, symptoms and morphology]. Pathologe. 2003, 24: 339-347. 10.1007/s00292-003-0628-7.

    PubMed  Google Scholar 

  39. 39.

    Dayan CM: Interpretation of thyroid function tests. Lancet. 2001, 357: 619-624. 10.1016/S0140-6736(00)04060-5.

    CAS  PubMed  Google Scholar 

  40. 40.

    Moncayo H, Dapunt O, Moncayo R: Diagnostic accuracy of basal TSH determinations based on the intravenous TRH stimulation test: An evaluation of 2570 tests and comparison with the literature. BMC Endocrine Disorders. 2007, 7: 5-10.1186/1472-6823-7-5.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Alfthan G, Aro A, Arvilommi H, Huttunen JK: Selenium metabolism and platelet glutathione peroxidase activity in healthy Finnish men: effects of selenium yeast, selenite, and selenate. Am J Clin Nutr. 1991, 53: 120-125.

    CAS  PubMed  Google Scholar 

  42. 42.

    Persson-Moschos M, Alfthan G, Akesson B: Plasma selenoprotein P levels of healthy males in different selenium status after oral supplementation with different forms of selenium. Eur J Clin Nutr. 1998, 52: 363-367. 10.1038/sj.ejcn.1600565.

    CAS  PubMed  Google Scholar 

  43. 43.

    Thomson CD, McLachlan SK, Grant AM, Paterson E, Lillico AJ: The effect of selenium on thyroid status in a population with marginal selenium and iodine status. Br J Nutr. 2005, 94: 962-968. 10.1079/BJN20051564.

    CAS  PubMed  Google Scholar 

  44. 44.

    Meplan C, Crosley LK, Nicol F, Beckett GJ, Howie AF, Hill KE, Horgan G, Mathers JC, Arthur JR, Hesketh JE: Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender-specific manner (the SELGEN study). FASEB J. 2007, .:

    Google Scholar 

  45. 45.

    Rayman MP: The argument for increasing selenium intake. Proc Nutr Soc. 2002, 61: 203-215. 10.1079/PNS2002153.

    CAS  PubMed  Google Scholar 

  46. 46.

    Moncayo R, Moncayo H: A musculoskeletal model of low grade connective tissue inflammation in patients with thyroid associated ophthalmopathy (TAO): the WOMED concept of lateral tension and its general implications in disease. BMC Musculoskelet Disord. 2007, 8: 17-10.1186/1471-2474-8-17.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Fang YZ, Yang S, Wu G: Free radicals, antioxidants, and nutrition. Nutrition. 2002, 18: 872-879. 10.1016/S0899-9007(02)00916-4.

    CAS  PubMed  Google Scholar 

  48. 48.

    Harman D: Aging: A theory based on free radical and radiation chemistry. J Gerontol. 1956, 11: 298-300.

    CAS  PubMed  Google Scholar 

  49. 49.

    Machlin LJ, Bendich A: Free radical tissue damage: protective role of antioxidant nutrients. FASEB J. 1987, 1: 441-445.

    CAS  PubMed  Google Scholar 

  50. 50.

    Ahsan H, Ali A, Ali R: Oxygen free radicals and systemic autoimmunity. Clin Exp Immunol. 2003, 131: 398-404. 10.1046/j.1365-2249.2003.02104.x.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Ray AL, Semba RD, Walston J, Ferrucci L, Cappola AR, Ricks MO, Xue QL, Fried LP: Low Serum Selenium and Total Carotenoids Predict Mortality among Older Women Living in the Community: The Women's Health and Aging Studies. J Nutr. 2006, 136: 172-176.

    CAS  PubMed  Google Scholar 

  52. 52.

    Beckerling A, Braun W, Sommer M: Process of measuring in clinical medicine--implications of different definitions in clinical therapeutic studies. Digestion. 2004, 70: 139-145. 10.1159/000081292.

    PubMed  Google Scholar 

  53. 53.

    Sheline GE, Charikoff IL, Jones HB, Montgomery ML: Studies on the metabolism of zinc with the aid of its radioactive isotope. II. The distribution of administered radioactive zinc in the tissues of mice and dogs. J Biol Chem. 1943, 149: 139-151.

    CAS  Google Scholar 

  54. 54.

    Bergman B, Söremark R: Autoradiographic studies on the distribution of zinc-65 in mice. J Nutr. 1968, 94: 6-12.

    CAS  PubMed  Google Scholar 

  55. 55.

    Chesters JK, Will M: The assessment of zinc status of an animal from the uptake of 65Zn by the cells of whole blood in vitro. Br J Nutr. 1978, 39: 297-306. 10.1079/BJN19780039.

    CAS  PubMed  Google Scholar 

  56. 56.

    Southon S, Gee JM, Bayliss CE, Wyatt GM, Horn N, Johnson IT: Intestinal microflora, morphology and enzyme activity in zinc-deficient and Zn-supplemented rats. Br J Nutr. 1986, 55: 603-611. 10.1079/BJN19860065.

    CAS  PubMed  Google Scholar 

  57. 57.

    Matsusaka N, Sakamoto H, Sato I, Shinagawa K, Kobayashi H, Nishimura Y: Whole-body retention and fetal uptake of 65Zn in pregnant mice fed a Zn-deficient diet. J Radiat Res (Tokyo). 1995, 36: 196-202.

    CAS  Google Scholar 

  58. 58.

    Sato I, Matsusaka N, Tsuda S, Suzuki T, Kobayashi H: Effect of dietary zinc content on 65Zn metabolism in mice. J Vet Med Sci. 1997, 59: 1017-1021. 10.1292/jvms.59.1017.

    CAS  PubMed  Google Scholar 

  59. 59.

    Tapiero H, Tew KD: Trace elements in human physiology and pathology: zinc and metallothioneins. Biomed Pharmacother. 2003, 57: 399-411. 10.1016/S0753-3322(03)00081-7.

    CAS  PubMed  Google Scholar 

  60. 60.

    Swaminathan R, Segall NH, Chapman C, Morgan DB: Red-blood-cell composition in thyroid disease. Lancet. 1976, 2: 1382-1385. 10.1016/S0140-6736(76)91920-6.

    CAS  PubMed  Google Scholar 

  61. 61.

    Nishi Y, Kawate R, Usui T: Zinc metabolism in thyroid disease. Postgrad Med J. 1980, 56: 833-837.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Dolev E, Deuster PA, Solomon B, Trostmann UH, Wartofsky L, Burman KD: Alterations in magnesium and zinc metabolism in thyroid disease. Metabolism. 1988, 37: 61-67. 10.1016/0026-0495(88)90030-3.

    CAS  PubMed  Google Scholar 

  63. 63.

    Yoshida K, Kiso Y, Watanabe T, Kaise K, Kaise N, Fukazawa H, Yamamoto M, Sakurada T, Yoshinaga K: Erythrocyte zinc concentration in patients with subacute thyroiditis. J Clin Endocrinol Metab. 1990, 70: 788-791.

    CAS  PubMed  Google Scholar 

  64. 64.

    Liu N, Liu P, Xu Q, Zhu L, Zhao Z, Wang Z, Li Y, Feng W, Zhu L: Elements in erythrocytes of population with different thyroid hormone status. Biol Trace Elem Res. 2001, 84: 37-43. 10.1385/BTER:84:1-3:037.

    CAS  PubMed  Google Scholar 

  65. 65.

    Dubey SS, Singh RP, Udupa KN: Ascorbic acid status of hyperthyroid patients. Indian J Med Res. 1977, 65: 865-870.

    CAS  PubMed  Google Scholar 

  66. 66.

    Ademoglu E, Gokkusu C, Yarman S, Azizlerli H: The effect of methimazole on the oxidant and antioxidant system in patients with hyperthyroidism. Pharmacol Res. 1998, 38: 93-96. 10.1006/phrs.1998.0336.

    CAS  PubMed  Google Scholar 

  67. 67.

    Alicigüzel Y, Özdem SN, Özdem SS, Karayalcin U, Siedlak SL, Perry G, Smith MA: Erythrocyte, plasma, and serum antioxidant activities in untreated toxic multinodular goiter patients. Free Radic Biol Med. 2001, 30: 665-670. 10.1016/S0891-5849(00)00509-8.

    PubMed  Google Scholar 

  68. 68.

    Mohan Kumar KM, Bobby Z, Selvaraj N, Kumar DA, Chandra KB, Sen SK, Ramesh R, Ranganathan P: Possible link between glycated hemoglobin and lipid peroxidation in hyperthyroidism. Clin Chim Acta. 2004, 342: 187-192. 10.1016/j.cccn.2003.12.027.

    CAS  PubMed  Google Scholar 

  69. 69.

    Price KD, Price CS, Reynolds RD: Hyperglycemia-induced ascorbic acid deficiency promotes endothelial dysfunction and the development of atherosclerosis. Atherosclerosis. 2001, 158: 1-12. 10.1016/S0021-9150(01)00569-X.

    CAS  PubMed  Google Scholar 

  70. 70.

    Woollard KJ, Loryman CJ, Meredith E, Bevan R, Shaw JA, Lunec J, Griffiths HR: Effects of oral vitamin C on monocyte: endothelial cell adhesion in healthy subjects. Biochem Biophys Res Commun. 2002, 294: 1161-1168. 10.1016/S0006-291X(02)00603-4.

    CAS  PubMed  Google Scholar 

  71. 71.

    Fernandez-Real JM, Lopez-Bermejo A, Castro A, Casamitjana R, Ricart W: Thyroid function is intrinsically linked to insulin sensitivity and endothelium-dependent vasodilation in healthy euthyroid subjects. J Clin Endocrinol Metab. 2006, 91: 3337-3343. 10.1210/jc.2006-0841.

    CAS  PubMed  Google Scholar 

  72. 72.

    Owen PJ, Rajiv C, Vinereanu D, Mathew T, Fraser AG, Lazarus JH: Subclinical hypothyroidism, arterial stiffness, and myocardial reserve. J Clin Endocrinol Metab. 2006, 91: 2126-2132. 10.1210/jc.2005-2108.

    CAS  PubMed  Google Scholar 

  73. 73.

    Hornig D: Metabolism and requirements of ascorbic acid in man. S Afr Med J. 1981, 60: 818-823.

    CAS  PubMed  Google Scholar 

  74. 74.

    Poovaiah BP, Potter BD, Omaye ST: Dietary ascorbic acid and selenium relationships in the guinea pig. Ann Nutr Metab. 1987, 31: 9-17.

    CAS  PubMed  Google Scholar 

  75. 75.

    Novotny JA, Milner JA: Impact of ascorbic acid on selenium-induced growth inhibition of canine mammary tumor cells in vitro. J Nutr Biochem. 1993, 4: 341-345. 10.1016/0955-2863(93)90079-C.

    CAS  Google Scholar 

  76. 76.

    Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, Ottersen OP, Shin CY, Ko KH, Kim WK, Kim DS, Chun W, Ali S, Kim HC: Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. Neuroscience. 2005, 133: 715-727. 10.1016/j.neuroscience.2005.02.030.

    CAS  PubMed  Google Scholar 

  77. 77.

    Bertinato J, Hidiroglou N, Peace R, Cockell KA, Trick KD, Jee P, Giroux A, Madere R, Bonacci G, Iskandar M, Hayward S, Giles N, L'Abbe MR: Sparing effects of selenium and ascorbic acid on vitamin C and E in guinea pig tissues. Nutr J. 2007, 6: 7-10.1186/1475-2891-6-7.

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Luo XM, Wei HJ, Yang CL, Xing J, Liu X, Qiao CH, Feng YM, Liu J, Liu YX, Wu Q: Bioavailability of selenium to residents in a low-selenium area of China. Am J Clin Nutr. 1985, 42: 439-448.

    CAS  PubMed  Google Scholar 

  79. 79.

    Waschulewski IH, Sunde RA: Effect of dietary methionine on utilization of tissue selenium from dietary selenomethionine for glutathione peroxidase in the rat. J Nutr. 1988, 118: 367-374.

    CAS  PubMed  Google Scholar 

  80. 80.

    Aihara K, Nishi Y, Hatano S, Kihara M, Yoshimitsu K, Takeichi N, Ito T, Ezaki H, Usui T: Zinc, copper, manganese, and selenium metabolism in thyroid disease. Am J Clin Nutr. 1984, 40: 26-35.

    CAS  PubMed  Google Scholar 

  81. 81.

    Wertenbruch T, Willenberg HS, Sagert C, Nguyen TB, Bahlo M, Feldkamp J, Groeger C, Hermsen D, Scherbaum WA, Schott M: Serum selenium levels in patients with remission and relapse of Graves' disease. Med Chem. 2007, 3: 281-284. 10.2174/157340607780620662.

    CAS  PubMed  Google Scholar 

  82. 82.

    Muntau AC, Streiter M, Kappler M, Röschinger W, Schmid I, Rehnert A, Schramel P, Roscher AA: Age-related reference values for serum selenium concentrations in infants and children. Clin Chem. 2002, 48: 555-560.

    CAS  PubMed  Google Scholar 

  83. 83.

    Micetic-Turk D, Turk Z, Radolli L: Serum selenium values in healthy children aged 1-18 years in NE Slovenia. Eur J Clin Nutr. 1996, 50: 192-194.

    CAS  PubMed  Google Scholar 

  84. 84.

    Tiran B, Tiran A, Petek W, Rossipal E, Wawschinek O: Selenium status of healthy children and adults in Styria (Austria). Investigation of a possible undersupply in the Styrian population. Trace Elem Med. 1992, 9: 75-79.

    CAS  Google Scholar 

  85. 85.

    Rossipal E, Tiran B: Selenium and glutathione peroxidase levels in healthy infants and children in Austria and the influence of nutrition regimens on these levels. Nutrition. 1995, 11: 573-575.

    CAS  PubMed  Google Scholar 

  86. 86.

    Zagrodzki P, Szmigiel H, Ratajczak R, Szybinski Z, Zachwieja Z: The role of selenium in iodine metabolism in children with goiter. Environ Health Perspect. 2000, 108: 67-71. 10.2307/3454297.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Brzozowska M, Kretowski A, Podkowicz K, Szmitkowski M, Borawska M, Kinalska I: [Evaluation of influence of selenium, copper, zinc and iron concentrations on thyroid gland size in school children with normal ioduria]. Pol Merkur Lekarski. 2006, 20: 672-677.

    CAS  PubMed  Google Scholar 

  88. 88.

    Vitti P, Delange F, Pinchera A, Zimmermann M, Dunn JT: Europe is iodine deficient. Lancet. 2003, 361: 1226-10.1016/S0140-6736(03)12935-2.

    PubMed  Google Scholar 

  89. 89.

    Rayman MP: The importance of selenium to human health. Lancet. 2000, 356: 233-241. 10.1016/S0140-6736(00)02490-9.

    CAS  PubMed  Google Scholar 

  90. 90.

    Sempertegui F, Estrella B, Vallejo W, Tapia L, Herrera D, Moscoso F, Ceron G, Griffiths JK, Hamer DH: Selenium serum concentrations in malnourished Ecuadorian children: a case-control study. Int J Vitam Nutr Res. 2003, 73: 181-186. 10.1024/0300-9831.73.3.181.

    CAS  PubMed  Google Scholar 

  91. 91.

    Bates CJ, Thane CW, Prentice A, Delves HT: Selenium status and its correlates in a British national diet and nutrition survey: people aged 65 years and over. J Trace Elem Med Biol. 2002, 16: 1-8. 10.1016/S0946-672X(02)80002-5.

    CAS  PubMed  Google Scholar 

  92. 92.

    Larsson CL, Johansson GK: Dietary intake and nutritional status of young vegans and omnivores in Sweden. Am J Clin Nutr. 2002, 76: 100-106.

    CAS  PubMed  Google Scholar 

  93. 93.

    Nichol C, Herdman J, Sattar N, O'Dwyer PJ, St JOR, Littlejohn D, Fell G: Changes in the concentrations of plasma selenium and selenoproteins after minor elective surgery: further evidence for a negative acute phase response?. Clin Chem. 1998, 44: 1764-1766.

    CAS  PubMed  Google Scholar 

  94. 94.

    Hawker FH, Stewart PM, Snitch PJ: Effects of acute illness on selenium homeostasis. Crit Care Med. 1990, 18: 442-446. 10.1097/00003246-199004000-00020.

    CAS  PubMed  Google Scholar 

  95. 95.

    Sakr Y, Reinhart K, Bloos F, Marx G, Russwurm S, Bauer M, Brunkhorst F: Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure. Br J Anaesth. 2007, 98: 775-784. 10.1093/bja/aem091.

    CAS  PubMed  Google Scholar 

  96. 96.

    Martin RF, Janghorbani M, Young VR: Experimental selenium restriction in healthy adult humans: changes in selenium metabolism studied with stable-isotope methodology. Am J Clin Nutr. 1989, 49: 854-861.

    CAS  PubMed  Google Scholar 

  97. 97.

    Fukao A, Takamatsu J, Murakami Y, Sakane S, Miyauchi A, Kuma K, Hayashi S, Hanafusa T: The relationship of psychological factors to the prognosis of hyperthyroidism in antithyroid drug-treated patients with Graves' disease. Clin Endocrinol (Oxf). 2003, 58: 550-555. 10.1046/j.1365-2265.2003.01625.x.

    Google Scholar 

  98. 98.

    Gray J, Hoffenberg R: Thyrotoxicosis and stress. Q J Med. 1985, 54: 153-160.

    CAS  PubMed  Google Scholar 

  99. 99.

    Harris T, Creed F, Brugha TS: Stressful life events and Graves' disease. Br J Psychiatry. 1992, 161: 535-541.

    CAS  PubMed  Google Scholar 

  100. 100.

    Harsch I, Paschke R, Usadel KH: The possible etiological role of psychological disturbances in Graves' disease. Acta Med Austriaca. 1992, 19 Suppl 1: 62-65.

    CAS  PubMed  Google Scholar 

  101. 101.

    Kung AW: Life events, daily stresses and coping in patients with Graves' disease. Clin Endocrinol (Oxf). 1995, 42: 303-308.

    CAS  Google Scholar 

  102. 102.

    Matos-Santos A, Nobre EL, Costa JG, Nogueira PJ, Macedo A, Galvao-Teles A, de Castro JJ: Relationship between the number and impact of stressful life events and the onset of Graves' disease and toxic nodular goitre. Clin Endocrinol (Oxf). 2001, 55: 15-19. 10.1046/j.1365-2265.2001.01332.x.

    CAS  Google Scholar 

  103. 103.

    Mizokami T, Wu LA, El Kaissi S, Wall JR: Stress and thyroid autoimmunity. Thyroid. 2004, 14: 1047-1055. 10.1089/thy.2004.14.1047.

    CAS  PubMed  Google Scholar 

  104. 104.

    Pizent A, Jurasovic J, Pavlovic M, Telisman S: Serum copper, zinc and selenium levels with regard to psychological stress in men. J Trace Elem Med Biol. 1999, 13: 34-39.

    CAS  PubMed  Google Scholar 

  105. 105.

    Singh A, Smoak BL, Patterson KY, LeMay LG, Veillon C, Deuster PA: Biochemical indices of selected trace minerals in men: effect of stress. Am J Clin Nutr. 1991, 53: 126-131.

    CAS  PubMed  Google Scholar 

  106. 106.

    Grases G, Perez-Castello JA, Sanchis P, Casero A, Perello J, Isern B, Rigo E, Grases F: Anxiety and stress among science students. Study of calcium and magnesium alterations. Magnes Res. 2006, 19: 102-106.

    CAS  PubMed  Google Scholar 

  107. 107.

    Jimenez A, Planells E, Aranda P, Sanchez-Vinas M, Llopis J: Changes in bioavailability and tissue distribution of selenium caused by magnesium deficiency in rats. J Am Coll Nutr. 1997, 16: 175-180.

    CAS  PubMed  Google Scholar 

  108. 108.

    Planells E, Sanchez-Morito N, Montellano MA, Aranda P, Llopis J: Effect of magnesium deficiency on enterocyte Ca, Fe, Cu, Zn, Mn and Se content. J Physiol Biochem. 2000, 56: 217-222.

    CAS  PubMed  Google Scholar 

  109. 109.

    Beck MA, Kolbeck PC, Rohr LH, Shi Q, Morris VC, Levander OA: Benign human enterovirus becomes virulent in selenium-deficient mice. J Med Virol. 1994, 43: 166-170. 10.1002/jmv.1890430213.

    CAS  PubMed  Google Scholar 

  110. 110.

    Beck MA: Nutritionally induced oxidative stress: effect on viral disease. Am J Clin Nutr. 2000, 71: 1676S-1681S.

    CAS  PubMed  Google Scholar 

  111. 111.

    Beck MA, Handy J, Levander OA: The role of oxidative stress in viral infections. Ann N Y Acad Sci. 2000, 917: 906-912.

    CAS  PubMed  Google Scholar 

  112. 112.

    Beck MA, Handy J, Levander OA: Host nutritional status: the neglected virulence factor. Trends Microbiol. 2004, 12: 417-423. 10.1016/j.tim.2004.07.007.

    CAS  PubMed  Google Scholar 

  113. 113.

    Field CJ, Johnson IR, Schley PD: Nutrients and their role in host resistance to infection. J Leukoc Biol. 2002, 71: 16-32.

    CAS  PubMed  Google Scholar 

  114. 114.

    Jaspers I, Zhang W, Brighton LE, Carson JL, Styblo M, Beck MA: Selenium deficiency alters epithelial cell morphology and responses to influenza. Free Radic Biol Med. 2007, 42: 1826-1837. 10.1016/j.freeradbiomed.2007.03.017.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Xie B, Zhou JF, Lu Q, Li CJ, Chen P: Oxidative stress in patients with acute coxsackie virus myocarditis. Biomed Environ Sci. 2002, 15: 48-57.

    PubMed  Google Scholar 

  116. 116.

    Yanagawa T, Ito K, Kaplan EL, Ishikawa N, DeGroot LJ: Absence of association between human spumaretrovirus and Graves' disease. Thyroid. 1995, 5: 379-382.

    CAS  PubMed  Google Scholar 

  117. 117.

    Debons-Guillemin MC, Valla J, Gazeau J, Wybier-Franqui J, Giron ML, Toubert ME, Canivet M, Peries J: No evidence of spumaretrovirus infection markers in 19 cases of De Quervain's thyroiditis. AIDS Res Hum Retroviruses. 1992, 8: 1547-

    CAS  PubMed  Google Scholar 

  118. 118.

    Fierabracci A, Upton CP, Hajibagheri N, Bottazzo GF: Lack of detection of retroviral particles (HIAP-1) in the H9 T cell line co-cultured with thyrocytes of Graves' disease. J Autoimmun. 2001, 16: 457-462. 10.1006/jaut.2001.0508.

    CAS  PubMed  Google Scholar 

  119. 119.

    Ciampolillo A, Marini V, Mirakian R, Buscema M, Schulz T, Pujol-Borrell R, Bottazzo GF: Retrovirus-like sequences in Graves' disease: implications for human autoimmunity. Lancet. 1989, 1: 1096-1100. 10.1016/S0140-6736(89)92382-9.

    CAS  PubMed  Google Scholar 

  120. 120.

    Beck MA, Williams-Toone D, Levander OA: Coxsackievirus B3-resistant mice become susceptible in Se/vitamin E deficiency. Free Radic Biol Med. 2003, 34: 1263-1270. 10.1016/S0891-5849(03)00101-1.

    CAS  PubMed  Google Scholar 

  121. 121.

    Gladyshev VN, Stadtman TC, Hatfield DL, Jeang KT: Levels of major selenoproteins in T cells decrease during HIV infection and low molecular mass selenium compounds increase. Proc Natl Acad Sci U S A. 1999, 96: 835-839. 10.1073/pnas.96.3.835.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Beltran S, Lescure FX, El E, Schmit JL, Desailloud R: Subclinical hypothyroidism in HIV-infected patients is not an autoimmune disease. Horm Res. 2006, 66: 21-26. 10.1159/000093228.

    CAS  PubMed  Google Scholar 

  123. 123.

    Maehira F, Luyo GA, Miyagi I, Oshiro M, Yamane N, Kuba M, Nakazato Y: Alterations of serum selenium concentrations in the acute phase of pathological conditions. Clin Chim Acta. 2002, 316: 137-146. 10.1016/S0009-8981(01)00744-6.

    CAS  PubMed  Google Scholar 

  124. 124.

    Maehira F, Miyagi I, Eguchi Y: Selenium regulates transcription factor NF-kappaB activation during the acute phase reaction. Clin Chim Acta. 2003, 334: 163-171. 10.1016/S0009-8981(03)00223-7.

    CAS  PubMed  Google Scholar 

  125. 125.

    Curran JE, Jowett JB, Elliott KS, Gao Y, Gluschenko K, Wang J, Abel Azim DM, Cai G, Mahaney MC, Comuzzie AG, Dyer TD, Walder KR, Zimmet P, MacCluer JW, Collier GR, Kissebah AH, Blangero J: Genetic variation in selenoprotein S influences inflammatory response. Nat Genet. 2005, 37: 1234-1241. 10.1038/ng1655.

    CAS  PubMed  Google Scholar 

  126. 126.

    Scheurig AC, Thorand B, Fischer B, Heier M, Koenig W: Association between the intake of vitamins and trace elements from supplements and C-reactive protein: results of the MONICA/KORA Augsburg study. Eur J Clin Nutr. 2007, .:

    Google Scholar 

  127. 127.

    Pearce EN, Bogazzi F, Martino E, Brogioni S, Pardini E, Pellegrini G, Parkes AB, Lazarus JH, Pinchera A, Braverman LE: The prevalence of elevated serum C-reactive protein levels in inflammatory and noninflammatory thyroid disease. Thyroid. 2003, 13: 643-648. 10.1089/105072503322239989.

    PubMed  Google Scholar 

  128. 128.

    Ishida T, Himeno K, Torigoe Y, Inoue M, Wakisaka O, Tabuki T, Ono H, Honda K, Mori T, Seike M, Yoshimatsu H, Sakata T: Selenium deficiency in a patient with Crohn's disease receiving long-term total parenteral nutrition. Intern Med. 2003, 42: 154-157. 10.2169/internalmedicine.42.154.

    PubMed  Google Scholar 

  129. 129.

    Allan CB, Lacourciere GM, Stadtman TC: Responsiveness of selenoproteins to dietary selenium. Annu Rev Nutr. 1999, 19: 1-16. 10.1146/annurev.nutr.19.1.1.

    CAS  PubMed  Google Scholar 

  130. 130.

    Hill KE, Xia Y, Akesson B, Boeglin ME, Burk RF: Selenoprotein P concentration in plasma is an index of selenium status in selenium-deficient and selenium-supplemented Chinese subjects. J Nutr. 1996, 126: 138-145.

    CAS  PubMed  Google Scholar 

  131. 131.

    Xia Y, Hill KE, Byrne DW, Xu J, Burk RF: Effectiveness of selenium supplements in a low-selenium area of China. Am J Clin Nutr. 2005, 81: 829-834.

    CAS  PubMed  Google Scholar 

  132. 132.

    Sandstead HH, Klevay LM: History of nutrition symposium: trace element nutrition and human health. J Nutr. 2000, 130: 483S-484S.

    CAS  PubMed  Google Scholar 

  133. 133.

    Burk RF, Norsworthy BK, Hill KE, Motley AK, Byrne DW: Effects of chemical form of selenium on plasma biomarkers in a high-dose human supplementation trial. Cancer Epidemiol Biomarkers Prev. 2006, 15: 804-810. 10.1158/1055-9965.EPI-05-0950.

    CAS  PubMed  Google Scholar 

  134. 134.

    Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C: Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis. JAMA. 2007, 297: 842-857. 10.1001/jama.297.8.842.

    CAS  PubMed  Google Scholar 

  135. 135.

    Gärtner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW: Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab. 2002, 87: 1687-1691. 10.1210/jc.87.4.1687.

    PubMed  Google Scholar 

  136. 136.

    Duntas LH, Mantzou M, Koutras DA: Effects of a six month treatment with selenomethionine in patients with autoimmune thyroiditis. Eur J Endocrinol. 2003, 148: 389-393. 10.1530/eje.0.1480389.

    CAS  PubMed  Google Scholar 

  137. 137.

    Turker O, Kumanlioglu K, Karapolat I, Dogan I: Selenium treatment in autoimmune thyroiditis: 9-month follow-up with variable doses. J Endocrinol. 2006, 190: 151-156. 10.1677/joe.1.06661.

    CAS  PubMed  Google Scholar 

  138. 138.

    Mazokopakis EE, Papadakis JA, Papadomanolaki MG, Batistakis AG, Giannakopoulos TG, Protopapadakis EE, Ganotakis ES: Effects of 12 Months Treatment with l-Selenomethionine on Serum Anti-TPO Levels in Patients with Hashimoto's Thyroiditis. Thyroid. 2007, 17: 609-612. 10.1089/thy.2007.0040.

    CAS  PubMed  Google Scholar 

  139. 139.

    Negro R, Greco G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H: The Influence of Selenium Supplementation on Postpartum Thyroid Status in Pregnant Women with Thyroid Peroxidase Autoantibodies. J Clin Endocrinol Metab. 2007, 92: 1263-1268. 10.1210/jc.2006-1821.

    CAS  PubMed  Google Scholar 

  140. 140.

    Moncayo R, Moncayo H, Kapelari K: Nutritional treatment of incipient thyroid autoimmune disease. Influence of selenium supplementation on thyroid function and morphology in children and young adults. Clin Nutr. 2005, 24: 530-531. 10.1016/j.clnu.2005.05.013.

    PubMed  Google Scholar 

  141. 141.

    Elmadfa I: Austrian nutrition report 2003. Edited by: Elmadfa I. 2003, 1

    Google Scholar 

  142. 142.

    Moncayo R: Cubilin and megalin in radiation-induced renal injury with labelled somatostatin analogues: are we just dealing with the kidney?. Eur J Nucl Med Mol Imaging. 2005, 32: 1131-1135. 10.1007/s00259-005-1885-x.

    CAS  PubMed  Google Scholar 

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Acknowledgements

At an early stage of the study, Dr. Erika Artner carried out the laboratory determinations.

The first draft of this study appeared in 2005 written by Roy Moncayo: Master Thesis, Master of Advanced Studies (Health and Fitness), Sports Institute, University of Salzburg.

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Affiliations

  1. WOMED, Karl-Kapferer-Strasse 5, Innsbruck, Austria

    Roy Moncayo & Helga Moncayo

  2. Clinical Department of Nuclear Medicine, Medical University of Innsbruck, Austria

    Roy Moncayo, Alexander Kroiss, Manfred Oberwinkler, Fatih Karakolcu & Matthias Starzinger

  3. Clinical Department of Pediatrics, Medical University of Innsbruck, Austria

    Klaus Kapelari

  4. Biocenter, Division of Clinical Biochemistry, Innsbruck Medical University, Austria

    Heribert Talasz

Authors
  1. Roy Moncayo
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  2. Alexander Kroiss
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  3. Manfred Oberwinkler
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  4. Fatih Karakolcu
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  5. Matthias Starzinger
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  6. Klaus Kapelari
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  7. Heribert Talasz
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  8. Helga Moncayo
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Corresponding author

Correspondence to Roy Moncayo.

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Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

Thyroid disease patients were examined by RM, FK, MO, and AK. RM, MO, and FK managed the data base for the patients with benign thyroid disease. MS worked with the oncological thyroid cases. HT carried out the laboratory determinations of the nutritional factors. KK examined and managed the pediatric patients. RM and HM examined and managed the clinical and laboratory data of the control population for Se (WOMED group). RM and HM wrote the manuscript. All authors read and approved the final manuscript.

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Moncayo, R., Kroiss, A., Oberwinkler, M. et al. The role of selenium, vitamin C, and zinc in benign thyroid diseases and of selenium in malignant thyroid diseases: Low selenium levels are found in subacute and silent thyroiditis and in papillary and follicular carcinoma. BMC Endocr Disord 8, 2 (2008). https://doi.org/10.1186/1472-6823-8-2

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Keywords

  • Thyroid Carcinoma
  • Thyroid Disease
  • Iodine Deficiency
  • Benign Thyroid Disease
  • Thyroid Peroxidase Antibody

BMC Endocrine Disorders

ISSN: 1472-6823

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