Survey on selenium clinical supplementation in autoimmune thyroid disease

in European Thyroid Journal
Authors:
Liliana Ribeiro Santos Internal Medicine Department, Hospital of Santa Maria, Lisbon, Portugal
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

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Inês Vasconcelos Bessa Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
Health Investigation and Innovation Institute (i3S), University of Porto, Porto, Portugal

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Adriana Gaspar da Rocha Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
Health Investigation and Innovation Institute (i3S), University of Porto, Porto, Portugal
Public Health Unit, ACES Baixo Mondego, Coimbra, Portugal

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Celestino Neves Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
Department of Endocrinology, Hospital University Centre of São João, Porto, Portugal

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Cláudia Freitas Department of Endocrinology, Hospital University Centre of Porto, Porto, Portugal

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Paula Soares Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
Health Investigation and Innovation Institute (i3S), University of Porto, Porto, Portugal
Department of Pathology, Faculty of Medicine of the University of Porto, Porto, Portugal

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https://orcid.org/0000-0001-9607-6998

Correspondence should be addressed to Paula Soares: psoares@ipatimup.pt

*(L R Santos and I V Bessa contributed equally to this work)

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Objective

Previous trials show that selenium could be a very useful tool in the control and treatment of autoimmune thyroid diseases. In this cross-sectional study, through a survey, we aim to evaluate Portuguese endocrinologists' perception and pattern of prescription of selenium supplements in these diseases and verify its agreement with current guidelines.

Methods

The endocrinologists registered in the Portuguese Medical Association were sent an email with a web-based questionnaire, regarding their knowledge and use of selenium supplements in thyroid autoimmune pathology.

Results

A total of 105 physicians (33% of the total) submitted the survey. The selenium serum concentration in the general population was unknown to 80% of respondents. Over a third of respondents have never prescribed selenium for autoimmune thyroid disease. However, 89% are not afraid of recommending it, and 61% indicate Graves’ orbitopathy as the pathology they would supplement. In Hashimoto’s thyroiditis, 36% of respondents use selenium occasionally or frequently, and this percentage rises to 60% in Graves’ disease.

Conclusions

Although recommendations only encompass mild Graves’ orbitopathy, selenium is prescribed across the spectrum of autoimmune thyroid diseases, probably due to recent studies that consistently show improvement of biochemical hallmarks in these patients. Further investigation is required on the impact of selenium supplements on primarily clinical outcomes and to identify disorders and/or patients who will benefit the most. Also, there is still insufficient knowledge of this field in the medical community, and evidence-based practice should continue to be promoted by endocrinology societies.

Abstract

Objective

Previous trials show that selenium could be a very useful tool in the control and treatment of autoimmune thyroid diseases. In this cross-sectional study, through a survey, we aim to evaluate Portuguese endocrinologists' perception and pattern of prescription of selenium supplements in these diseases and verify its agreement with current guidelines.

Methods

The endocrinologists registered in the Portuguese Medical Association were sent an email with a web-based questionnaire, regarding their knowledge and use of selenium supplements in thyroid autoimmune pathology.

Results

A total of 105 physicians (33% of the total) submitted the survey. The selenium serum concentration in the general population was unknown to 80% of respondents. Over a third of respondents have never prescribed selenium for autoimmune thyroid disease. However, 89% are not afraid of recommending it, and 61% indicate Graves’ orbitopathy as the pathology they would supplement. In Hashimoto’s thyroiditis, 36% of respondents use selenium occasionally or frequently, and this percentage rises to 60% in Graves’ disease.

Conclusions

Although recommendations only encompass mild Graves’ orbitopathy, selenium is prescribed across the spectrum of autoimmune thyroid diseases, probably due to recent studies that consistently show improvement of biochemical hallmarks in these patients. Further investigation is required on the impact of selenium supplements on primarily clinical outcomes and to identify disorders and/or patients who will benefit the most. Also, there is still insufficient knowledge of this field in the medical community, and evidence-based practice should continue to be promoted by endocrinology societies.

Introduction

Autoimmune thyroid disease (AITD) is one of the most prevalent groups of autoimmune diseases (1). Hashimoto’s thyroiditis (HT) and Graves' disease (GD) are the most significant AITDs (2), GD being around ten times less common and tends to appear in younger patients than HT. In about one-third of GD patients, ophthalmic signs eventually emerge (3). These disorders have shared susceptibility factors, and studies have demonstrated concordance rates of 55% in monozygotic twins, compared with only 3% in dizygotic twins, suggesting that genetic factors contribute to the pathogenesis. AITD can place patients at a higher risk for relevant conditions, such as cardiovascular diseases, osteoporosis, and infertility (4). Moreover, these disorders have great impact on the quality of life (QoL) of patients, with symptoms including mood disorders, changes in bowel habits, weight and sleep variations, and orbital involvement (5).

The relevance of selenium (Se) in thyroid diseases has been subject of investigation since, in the 1990s, it was found as a fundamental element for enzymes involved in the metabolism of the thyroid hormones (6). The selenoproteins encoded by the human genome have great importance in antioxidant and anti-inflammatory mechanisms, as well as in the production of active thyroid hormone (6). Thyroid gland has higher concentrations of Se than almost all other organs, reflecting its importance in thyroid metabolism (7). Furthermore, inborn errors in selenoprotein genes (e.g. SECISBP2, DIO1, DIO2, and TRU-TCA1-1) have been identified in patients with thyroid disorders, and some of these mutations can cause reduced deiodinase activities and other thyroid function abnormalities, such as low serum levels of triiodothyronine (T3) and high levels of thyroxine (T4) and reverse T3 (8). Thyrocytes express several selenoproteins: glutathione peroxidase selenoproteins, like GPX1 and GPX3, that protect from excessive H₂O₂, whereas GPX4 can degrade lipid hydroperoxides in mitochondria and cell membranes (9); type 1/2 iodothyronine deiodinase (DIO1 and DIO2 ) that can activate T4 by converting it into T3 (7); selenoprotein S which is involved in the inflammatory response in the endoplasmic reticulum (ER), by translocation of misfolded proteins from its lumen to the cytosol, where they are degraded (10). In fact, polymorphic forms of selenoprotein S lead to the accumulation of misfolded proteins in the ER, which triggers the rise of proinflammatory cytokines involved in the pathogenesis of chronic autoimmune thyroiditis (HT) (10, 11). Our previous study showed that individuals with some of these genotypes were significantly more likely to have Hashimoto’s thyroiditis (HT) (11).

The antioxidant and anti-inflammatory effects of selenoproteins motivate the use of selenium supplementation (Se-Su) in the treatment of both HT and GD (9). It was hypothesised that low Se dietary levels enhanced the development of thyroid autoantibodies (12), which is corroborated by ongoing epidemiological studies, that link low Se status with an increased risk of HT and GD (6, 13, 14, 15, 16, 17). A relationship between Se supply, thyroid disease risk (hyperthyroidism), and sexual dimorphism was also advanced (18) in Chinese populations, where higher Se serum levels seemed to confer protection from hyperthyroidism in men.

Individual Se intake differs across the world, ranging from deficient intake to toxic intake, partly due to variations in Se content in the soil, which is high in parts of China, Japan, Venezuela, and North America but considerably lower in many European countries (13, 18, 19). In Portugal, few available studies report variable levels of Se in the population, according to the region: mean serum Se was 81 ± 14 μg/L in women (and 88 ± 15 μg/L in men), in a study from healthy people living in the continent and 110 ± 25 μg/L and 104 ± 21 μg/L in Madeira Island and Azores archipelago, respectively (20, 21). Selenomethionine is the main form of Se in plants, especially cereals, and the most important in human diets. In Portugal, like in other countries, fish was the food richest in Se (22). On the contrary, inorganic compounds like sodium selenate and selenite are scarcely found in diet, but are often found in soils, and used in supplementation (23).

Current international guidelines do not yet recommend inclusion of Se-Su in the treatment of HT and GD without eye involvement, but the European Thyroid Association (ETA) recommends Se in patients with mild Graves’ orbitopathy (GO) (24, 25). This recommendation is based on a 2011 European randomised, controlled trial (26), which evaluated the effect of 200 μg/day sodium selenite for 6 months in euthyroid patients with mild GO. The authors reported improved QoL, less orbital symptoms, and slower progression to severe forms in patients receiving Se-Su, benefits sustained in a 12-month follow-up (26). Unfortunately, these findings have not been replicated yet and this remains the only study on the effects of Se-Su in AITD that led to Se introduction in guidelines. Se-Su, however, is not considered in the guidelines from the American Thyroid Association (ATA), probably because Se levels tend to be considerably higher in North America and lower in many European countries. Nevertheless, several trials and studies have continued the investigation of Se-Su effects in different AITDs (Table 1) (15, 16, 17, 27, 28, 29, 30, 31, 32, 33, 34). Overall, in patients with HT, Se-Su has resulted in higher antioxidant activity (27), reduced thyroid autoantibody titre (34), lower levels of thyroid-stimulating hormone (TSH) (32), higher Tregs (32), and reduced expression of proinflammatory cytokines (34). Se-treated AITD patients might have improvement in the echoic thyroid pattern (29), and anxiety and depression scales were significantly better in supplemented patients, which suggests that Se-Su could improve patients’ mood more effectively (34). On the other hand, a subsequent systematic review and meta-analysis, including trials in chronic autoimmune thyroiditis concluded that the evidence in clinical parameters, such as effects of Se-Su on disease remission, progression, lowered levothyroxine dose, or improved quality of life, are scarce (35). For GD without eye involvement, patients with Se-Su were more likely to show improved thyroid function and faster remission of hyperthyroidism, with decrease in the levels of free T3, free T4, and autoantibody titre, along with an increase in TSH levels (16, 28). Whether these effects correlate with clinically relevant long-term outcomes remains to be demonstrated.

Table 1

Summary of the most recent and relevant studies on Selenium in AITDa.

Study Year Study type Sample Pathology Main conclusion
Zuo et al. (16) 2021 Systematic review and meta-analysis 17 studies AITD Se-containing supplements greatly reduced the levels of FT3, FT4, and TPOAb in AITD patients.
Lumyongsatien et al. (24) 2021 Observational 100 patients GO Relative Se insufficiency (≤93 µg/L) is a potential risk factor for severe GO development.
Xu et al. (25) 2019 Clinical trial 103 patients GD The decrease in the levels of FT3, FT4, TRAb, TPOAb, and TGAb, along with an increase in TSH levels, was greater in the group of GD patients with Se-Su.
Zheng et al. (17) 2018 Systematic review and meta-analysis 10 studies GD Se-Su in GD significantly decreased TRAb, FT4, and FT3 levels and elevated TSH. At 6 months, patients on Se-Su were more likely to show improved thyroid function.
Hu et al. (26) 2021 Clinical trial 126 patients HT Se‐treated HT group had significantly lower thyroid autoantibodies (TPOAb, TGAb) and TSH and significantly higher Tregs and antioxidant activity.
Sun et al. (27) 2021 Clinical trial 138 patients HT TGAb, TPOAb, and IL-2 /TNF-α levels decreased more in the HT group receiving Se in addition to levothyroxine. After treatment, anxiety and depression scales were significantly better in this group, which suggested that Se-Su could improve patients’ mood more effectively.
Rostami et al. (28) 2020 Observational 99 patients HT HT patients had lower Se levels than controls. Se-deficient patients exhibited higher TSH levels, thyroid volume, antibody titres, and urinary iodine compared to Se-sufficient ones (P < 0.001).
Pace et al. (29) 2020 Observational 101 patients HT TSH was significantly decreased in patients treated with Se and Se plus myo-inositol and there was echoic pattern improvement in both these treated HT groups.
Tian et al. (30) 2020 Clinical trial 60 patients HT Total antioxidant capacity was increased in patients with Se-Su. TPOAb titre in these patients decreased significantly.
Wang et al. (31) 2018 Clinical trial 364 patients HT Se supplementation significantly reduced TPOAb titres and increased glutathione peroxidase activity in patients with HT.
Wichman et al. (15) 2016 Systematic review and meta-analysis 16 studies HT Se-Su significantly reduced serum TPOAb levels after 3, 6, and 12 months in the HT group levothyroxine-treated and after 3 months in the HT group not treated with levothyroxine.

aOnly original studies and systematic reviews with meta-analysis were included.

AITD, autoimmune thyroid disease; FT3, free triiodothyronine; FT4, free thyroxine; GD, Graves' disease; GO, Graves' ophthalmopathy; HT, Hashimoto thyroiditis; IL-2 /TNF-α, proinflammatory cytokines; Se-Su, selenium supplementation; TGAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TRAb, TSH-receptor antibody; Tregs, regulatory T cells; TSH, thyroid-stimulating hormone.

To sum up, AITDs are a prevalent group of thyroid diseases with great impact on the QoL of patients. Previous studies show that Se supplements can be a useful tool to reduce AITD morbidity. In this study, we report the results of a survey, to evaluate the perception and pattern of prescription of Se supplements by endocrinologists in Portugal, and verify the concordance between its current clinical evidence and the actual use in endocrinological medical practice.

Materials and methods

In this cross-sectional study, a web-based survey was constructed with Survey-Monkey®, an open-access web platform. The questionnaire included 50 questions, regarding the knowledge and use of Se supplements in AITDs, and was based on previous questionnaires published (36, 37). The target population included the endocrinologists registered in the Portuguese Medical Association that, at the time, were a total of 323 members (260 specialists plus 63 residents).

Through the Portuguese Society of Endocrinology, Diabetes and Metabolism (SPEDM), an initial email with the questionnaire was sent in October 2019 to these physicians. Two reminders were later sent by the secretariat. Survey responses were anonymously collected and stored by the survey service up to December 2019. Repeated submissions from the same IP address were automatically blocked. This consisted of a non-probabilistic sampling method, dispensing previous sample calculation.

Summary statistics were provided by Survey-Monkey®. Chi-square test was used to evaluate the questionnaire response rates. Data were analysed using SPSS statistics version 19 software (IBM). This questionnaire did not include any sensible patient data and patient consent was not applicable. The study received ethical approval by the Committee for Ethical and Responsible Conduct of Research (CECRI-i3S 11/2022).

Results

Response rate and respondent demographics

From the 323 endocrinologists, a total of 105 (33%) answered our survey, and from the 50 questions, 38 (76%) were answered by all participants. Of a total of 5250 questions from all the surveys of the 105 participants, only 18 (0.34%) were skipped. Of the respondents, 70% were female, the mode age was 31–50 years, and the duration of medical practice was over 10 years in 57% (Fig. 1). Forty-six per cent of the participants worked at a central university hospital, with a minority (11%) working in private practice. There were respondents from the different regions of the country (North, Centre, South, and Autonomous Regions) with the majority of them (61%) from the two main hospital centres in Portugal – Lisbon and Oporto (Fig. 1).

Figure 1
Figure 1

Respondents’ demographics. Az/Md, Azores or Madeira.

Citation: European Thyroid Journal 12, 2; 10.1530/ETJ-22-0090

Autoimmune thyroid diseases in clinical practice

The first key question in the survey was ‘Do you follow patients with autoimmune thyroid disease weekly?’, and 95% of the endocrinologists answered yes, with 50% (n = 52) of them following over 20 thyroid pathology outpatients weekly and 13% over 50. As for each disease, 55% of the respondents stated following over 50 HT outpatients, and in GD, 15% stated following over 50 outpatients and 43%, 20–50 outpatients (Fig. 2). Almost all (95%) endocrinologists stated that they do not use QoL scales in their thyroid pathology patients.

Figure 2
Figure 2

Respondents' auto immune thyroid disease (AITD) patients load in clinical practice. HT, Hashimoto thyroiditis; GD, Graves disease.

Citation: European Thyroid Journal 12, 2; 10.1530/ETJ-22-0090

Selenium in AITD

When asked if it would be beneficial to carry out a clinical trial on Se-Su in Portugal, only 4% answered ‘No’, and 59% said they would be interested in participating in it. The Se serum concentration in the general population was unknown to 80% of respondents. The majority of the respondents (65%) never performed Se measurement in the patients, only 6% stated that they assayed serum Se, before or after supplementation. Almost a third of the participants do not ask about nutritional history or use of selenium-containing supplements before prescribing Se-Su, 24% do so occasionally and 17% do that always. As for the geographic location and consequent Se concentration in soil, only 11% take it in consideration when deciding on Se-Su. Taking in consideration the different types of Se supplements, pills exclusively composed by Se were preferred by 53% and multivitamins by 14%. The respondents considered organic Se-Su to be better than inorganic (28%vs 7%), but most of them (59%) stated they had no idea. As for the sources of Se, 73% selected vegetable-based food as the richest source. The respondents were asked how often they prescribe Se-Su in AITD, with 9% answering ‘frequently’, 34% ‘occasionally’, 20% ‘it depends on which pathology’, and 36% ‘never’ (Fig. 3). Besides that, 89% stated they are not afraid of prescribing Se-Su (Fig. 3). On another question, 61% chose GO as the pathology they would supplement with Se, 18% chose HT, and 8% GD (Fig. 3).

Figure 3
Figure 3

Respondents' general pattern of prescription of Selenium Supplements in auto immune thyroid disease (AITD). CT, clinical trials; HT, Hashimoto thyroiditis; GD, Graves disease; GO, Graves orbitopathy; LTCH, levothyroxine-treated clinical hypothyroidism; PWHT, pregnant woman with Hashimoto's Thyroiditis; Se, selenium.

Citation: European Thyroid Journal 12, 2; 10.1530/ETJ-22-0090

Hashimoto’s thyroiditis

In HT, 19% of the endocrinologists believe that clinical evidence is favourable towards the use of Se-Su in HT, 43% did not know, and 38% think it is not, but, from these, 58% believe Se-Su might be effective and still recommend it (Fig. 4). Furthermore, 6% of the respondents recommend these supplements in HT frequently or always, 30% occasionally, and 46% never (Fig. 5). In HT, the most favoured purposes of Se-Su were reducing antibody titres (17%) and improving QoL (17%).

Figure 4
Figure 4

Respondents' knowledge on the clinical evidence of selenium supplementation in each auto immune thyroid disease (AITD).

Citation: European Thyroid Journal 12, 2; 10.1530/ETJ-22-0090

Figure 5
Figure 5

Respondents' pattern of prescription of selenium supplements in each auto immune thyroid disease (AITD).

Citation: European Thyroid Journal 12, 2; 10.1530/ETJ-22-0090

Graves’ disease

For GD, 57% of the inquired think that clinical evidence supports the use of Se-Su in GD, 15% think it does not, and 28% stated they do not know (Fig. 4). Moreover, 27% of them recommend these supplements frequently or always, 33% occasionally, and 16% never (Fig. 5).

Considering the purpose of the use of Se-Su in GD, 24% of endocrinologists state that it is inducing the remission of the disease, 16% stated as reducing antibody titres, and 11% stated as improving QoL.

Graves’ orbitopathy

In GO, 66% of the endocrinologists believe that clinical evidence is favourable towards the use of Se-Su, 7% think it is not, and 27% stated they do not know (Fig. 4). Furthermore, 42% of them recommend these supplements frequently or always, 23% occasionally, and 12% never (Fig. 5). From the different forms of GO where clinicians think Se-Su is recommended, the respondents were divided between all (38%), only mild (20%), only moderate (12%), only severe (3%), with the rest stating not knowing. In addition, 29% of the respondents declare that the purpose of Se-Su in GO is to induce the remission of the ocular disease, 14% to reduce autoantibodies, and 12% to improve QoL. The dose that more endocrinologists thought to be adequate was 200 μg/day (32%), followed by 100 μg/day (26%), and 63% would recommend this medication from weeks to months and then reassess the patient.

Other AITD-related conditions

On the other hand, in pregnant women, subclinical hypothyroidism (SH), and levothyroxine-treated clinical hypothyroidism (LTCH), the majority of respondents (65%, 59%, and 60%, respectively) do not know if clinical evidence considers Se-Su to be beneficial (Fig. 4). In pregnancy, only 11% has ever recommended it (Fig. 5), with 59% having no idea how this supplementation could benefit these patients.

Discussion

Se-Su is a recent but recurrent theme in medical meetings and there is growing evidence about its effects on some diseases, namely AITD. The relevance of our study on the knowledge and usage of Se-Su in AITD is supported by the strong epidemiology of these diseases (1) and reflected in our results, with over 95% of participants stating that they follow patients with AITD daily or weekly. Moreover, a majority of respondents have over 50 outpatients with HT and 20 with GD/GO. Most have the perception that Se-Su could be beneficial for AITD patients and state that it would be important to run a clinical trial on Se-Su in Portugal.

As pointed out in previous studies, in many European countries, individuals do not achieve the recommended levels of Se intake (70 μg/day by the European Food Safety Authority) (38). Portuguese studies on Se are scarce, yet the available data point to low contents in cultivation soils and plants, indicating that daily intakes fail to meet European recommendations (39). These low levels are known to be associated with a higher risk of HT and GD (6).

Despite this and the fact that multiple trials have shown that Se can be an important tool in the treatment of AITD (Table 1), our survey has shown that many gaps in the therapeutic use of these supplements remain. Around 80% of our respondents do not have an idea about the levels of Se in the Portuguese population, and only 6% of them have ever dosed Se levels on their patients before supplementation.

Sixty per cent of the clinicians do not have an opinion concerning the best type of Se supplements, organic, inorganic, or both, and the majority of the remaining considered organic Se-Su to be better than inorganic. One reason that could deter physicians from prescribing Se-Su is the possibility of toxicity. In fact, selenium excess, a condition designated as Selenosis, can be manifested when serum Se concentration exceeds 400 μg/day. It was first described in populations of the Hubei Province in China and the associated symptoms include garlic breath, hair and nail loss, disorders of the nervous system (paralysis), skin diseases, and poor dental health (19). Situations of life-threatening toxicity by Se are extremely rare in humans and have been reported to be associated with miscalculated supplement formulations or accidental overdose (40). A study reported an increased risk of diabetes type 2 in patients taking selenium at 200 μg/day (41). These results were challenged by a recent analysis of USA NHANES survey where the authors found that, on the contrary, high Se is associated with higher survival in type 2 diabetic patients (42). Nevertheless, in Europe, where baseline Se is low, there are no studies reporting toxicity from Se supplements at the recommended dosage (below or up to 200 μg/day). It is clear that more information is necessary and needs to be shared, namely, soil levels of Se and populational studies in Se dosing, studies that are missing in most of the European countries. This lack of information about Se, in general, may help to explain the discrepancy found in our survey: although almost 90% of respondents state they are not afraid of prescribing Se supplements, more than 30% have never done it, and another third did so only occasionally.

Taking a closer look, when asked in which AITD they would choose to use Se-Su, over 60% of the inquired chose ‘Graves’ Orbitopathy’‘, with any of the other options having much less adhesion. This is in agreement with the current guidelines that support Se-Su only for the treatment of mild GO (25).

In HT, more than a third of all responding physicians prescribe Se-Su, and even though current guidelines do not yet recommend its use, of the respondents who were aware of this fact, over half believe that it might be effective and recommend it. This relatively high rate of prescription may result from the acquaintance of several studies that advocate Se benefits in Hashimoto’s treatment (Table 1). Some of the latest studies (27, 28, 31, 34) have consistently shown that Se-Su-treated HT patients have reduced thyroid autoantibodies and TSH levels. A 2016 systematic review and meta-analysis of 16 studies (17) also concluded that Se-Su significantly reduces serum antibody levels. A 2021 clinical trial (32) demonstrated that Se-Su can lead to increased GPX3 and Tregs activity, and another recent study (29) observed an improvement of the echoic thyroid pattern in Se-treated patients. Beyond that, in the clinical trial from 2021 (34), 138 HT patients were randomly divided into 2 comparable groups, one treated with levothyroxine and the other with a combination of levothyroxine plus Se-Su. This study’s results showed that the combination group had lower thyroglobulin antibody, thyroid peroxidase antibody (TPOAb), and proinflammatory cytokines and also better anxiety and depression scales, which suggest that Se-Su may help improve patients’ mood and QoL. This study showed improvement of Se-treated patients in a clinically relevant outcome, and this too may help to justify why endocrinologists are using supplementation in HT. Overall, Se-Su outcomes observed in the cited scientific evidence agree with our survey’s most-voted purposes for supplementing patients with chronic autoimmune thyroiditis (‘reducing antibody titres’ and ‘improving QoL’).

In a similar way, but at a higher rate, 60% of respondents state using Se-Su in GD without eye involvement treatment, despite present guidelines only advise its use to patients with ophthalmopathy (25). In our study, Se is reported as widely prescribed in GD patients and many endocrinologists think that this is supported by clinical evidence. In fact, there is a 2018 systematic review (16), which included ten studies, that concluded that GD patients using Se-Su as part of their treatment were more likely to show improved thyroid function (with significantly decreased TSH-receptor antibody (TRAb), free T4, and free T3 levels and elevated TSH), when compared to GD patients without Se-Su. A recent clinical trial came to similar conclusions (28). The improvement in hyperthyroidism analytical markers and GD’s autoantibodies, reported by latest studies, is consistent with the two most-voted purposes of Se-Su in GD by our respondents, which were ‘inducing the remission of the disease’ and ‘reducing antibody titres’. It should be noted that the fact that guidelines advocate the use of Se in GO might lead physicians to use it in GD patients without orbitopathy as well, and there is a great similarity between both diseases in our survey responses, particularly if compared to HT results which are far more different (Fig. 4 and 5).

As for GO, since ETA guidelines recommend Se-Su (24), our survey’s responses were not so surprising, with only 12% saying they have never prescribed Se in this pathology. Around two-thirds of the respondents answered positively when asked if clinical evidence supports Se-Su use in GO, in accordance with current directives. According to ETA, a 6-month Se-Su in patients with mild GO is recommended, as it benefits QoL, ocular symptoms, and disease progression to more severe forms (24, 25). These outcomes are compatible with one of the most highlighted by our respondents (remission of the ocular disease). Concerning Se-Su length, almost two-thirds of the endocrinologists would recommend it from weeks to months and then reassess the patient, which is in line with ETA’s guideline. As for the dose, although it is not specified in the guideline, in the clinical trial in which it has been grounded (26), the authors used 200 μg/day, which was also the dose most thought to be adequate by our respondents. In the question about in which class of GO they think Se-Su is recommended, only mild GO was included in that study (26) and in the ETA recommendations (24). Almost 40% of the responses stated that Se-Su is recommended ‘in all forms’ of GO. This shows that our respondents’ Se-Su prescription in GO might go beyond those specified in the guidelines, possibly due to its proven efficacy across all GD patients (16, 28).

Our study did not address with as much detail other AITD conditions, such as SH, LTCH, and pregnant women, and Se-Su in these situations is not sufficiently documented. In a randomised, placebo-controlled study of TPOAb-positive pregnant women, postpartum thyroid dysfunction and permanent hypothyroidism were significantly lower in the group treated with Se during pregnancy and the postpartum period (43). No other study came to such relevant conclusions, although in a recent meta-analysis, Se-Su seems to have a protective role against postpartum depression (44). A placebo-controlled clinical trial for subclinical hypothyroidism was not able to demonstrate that Se-Su had any significant effect on serum TPOAb and TSH levels (45). Therefore, facing this lack of evidence, it is not surprising that in these AITD-related conditions, most clinicians either do not recommend Se or have no information.

Previous surveys on Se-Su medical use in thyroid autoimmune disease have come to results consistent with ours. A 2016 Italian study showed that physicians still had limited knowledge of the coverage of Se-Su in AITD and that Se use is widely considered in practice, often beyond what is supported by scientific evidence, with over 80% of its 815 respondents prescribing Se for HT at least sometimes (46). A 2018 ETA survey similarly concluded that, in HT (37), a majority of ETA members recommended Se-Su (65%vs 36% in our study) and 40% (vs 60% in our study) in Graves’ without orbitopathy (36).

We can identify some limitations to our study. The data collection was performed through an anonymous questionnaire sent by email, so it is not possible to know who the questionnaire reached and who it did not. Also, the ones who answered were not randomly picked from the total but by choice of the respondents. Therefore, we are facing a non-probabilistic sampling method, and this implies that the results cannot be extrapolated to the entire Portuguese endocrinologist community. We had 105 responses, reflecting the frequently low adherence rates in this kind of study, using surveys. Nevertheless, the percentage of respondents (33% in our study) is similar to those obtained in some previous studies, namely, less than 30% in the 2018 ETA survey on the use of Se in HT (37) and GD (36).

The results of our survey lead us to the conclusion that more investigation is still required regarding the usefulness of Se-Su in AITD. Despite recommendations only extending to patients with mild GO, Se-Su is used by clinicians across the spectrum of AITDs, due to studies consistently showing improvement of disease biochemical hallmarks. More information should be given to clinicians in this field, as it may be a tool of significant benefit in some AITD. A basic knowledge that is still missing concerns is the Se status in the European population in general and in the Portuguese in particular, which would inform endocrinologists whether they are prescribing within reasonable limits. Medical associations could provide educational projects to promote evidence-based medical care by its members, and future clinical trials should help identify conditions and/or patients who will benefit the most from Se supplements.

Declaration of interest

The authors declare no conflict of interest.

Funding

This article is partly supported by the project ‘Cancer Research on Therapy Resistance: From Basic Mechanisms to Novel Targets’ NORTE-01-0145-FEDER-000051, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) and by Programa Operacional Regional do Norte under the project ‘The Porto Comprehensive Cancer Center’ with the reference NORTE-01-0145-FEDER-072678 – Consórcio PORTO.CCC – Porto.Comprehensive Cancer Center. The funders had no role in study design or preparation of the manuscript.

Author contribution statement

Conceptualization, LRS and PS; Methodology, LRS and AGR; Software, LRS and IVB; Formal analysis, LRS, AGR and IVB; Resources, SPEDM, PS; Data curation, LRS; Writing – original draft preparation, LRS, IVB and PS; Writing – review and editing, all authors; Supervision and project administration, PS.

Acknowledgements

The authors acknowledge the Sociedade Portuguesa de Endocrinologia Diabetes e Metabolismo for the support given to the dissemination of the enquiry, particularly, the members of the Thyroid Study Group. The authors are indebted to all the endocrinologists who filled the questionnaire.

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  • 2

    Weetman AP Autoimmune thyroid disease. Autoimmunity 2004 37 337340. (https://doi.org/10.1080/08916930410001705394)

  • 3

    Santos LR, Neves C, Melo M, Soares P. Selenium and selenoproteins in immune mediated thyroid disorders. Diagnostics 2018 8 70. (https://doi.org/10.3390/diagnostics8040070)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Wang JW, Liao XX, Li T. Thyroid autoimmunity in adverse fertility and pregnancy outcomes: timing of assisted reproductive technology in AITD women. Journal of Translational Internal Medicine 2021 9 7683. (https://doi.org/10.2478/jtim-2021-0001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Kuś A, Kjaergaard AD, Marouli E, Del Greco F, Sterenborg RBTM, Chaker L, Peeters RP, Bednarczuk T, Åsvold BO & Burgess S et al.Thyroid function and mood disorders: a Mendelian randomization study. Thyroid 2021 31 11711181. (https://doi.org/10.1089/thy.2020.0884)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Winther KH, Rayman MP, Bonnema SJ, Hegedüs L. Selenium in thyroid disorders—essential knowledge for clinicians. Nature Reviews. Endocrinology 2020 16 165176. (https://doi.org/10.1038/s41574-019-0311-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Kohrle J, Jakob F, Contempré B, Dumont JE. Selenium, the thyroid, and the endocrine system. Endocrine Reviews 2005 26 944984. (https://doi.org/10.1210/er.2001-0034)

  • 8

    Dumitrescu AM, Refetoff S. Inherited defects of thyroid hormone metabolism. Annales d'Endocrinologie 2011 72 9598. (https://doi.org/10.1016/j.ando.2011.03.011)

  • 9

    Schomburg L Selenium, selenoproteins and the thyroid gland: interactions in health and disease. Nature Reviews. Endocrinology 2011 8 160171. (https://doi.org/10.1038/nrendo.2011.174)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Curran JE, Jowett JB, Elliott KS, Gao Y, Gluschenko K, Wang J, Azim DMA, Cai G, Mahaney MC & Comuzzie AG et al.Genetic variation in selenoprotein S influences inflammatory response. Nature Genetics 2005 37 12341241. (https://doi.org/10.1038/ng1655)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Santos LR, Durães C, Mendes A, Prazeres H, Alvelos MI, Moreira CS, Canedo P, Esteves C, Neves C & Carvalho D et al.A polymorphism in the promoter region of the selenoprotein S gene (SEPS1) contributes to Hashimoto's thyroiditis susceptibility. Journal of Clinical Endocrinology and Metabolism 2014 99 E719E723. (https://doi.org/10.1210/jc.2013-3539)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    McLachlan SM, Aliesky H, Banuelos B, Hee SSQ, Rapoport B. Variable effects of dietary selenium in mice that spontaneously develop a spectrum of thyroid autoantibodies. Endocrinology 2017 158 37543764. (https://doi.org/10.1210/en.2017-00275)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Rayman MP Selenium and human health. Lancet 2012 379 12561268. (https://doi.org/10.1016/S0140-6736(1161452-9)

  • 14

    Fan Y, Xu S, Zhang H, Cao W, Wang K, Chen G, Di H, Cao M, Liu C. Selenium supplementation for autoimmune thyroiditis: a systematic review and meta-analysis. International Journal of Endocrinology 2014 2014 904573. (https://doi.org/10.1155/2014/904573)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Wichman J, Winther KH, Bonnema SJ, Hegedüs L. Selenium supplementation significantly reduces thyroid autoantibody levels in patients with chronic autoimmune thyroiditis: a systematic review and meta-analysis. Thyroid 2016 26 16811692. (https://doi.org/10.1089/thy.2016.0256)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Zheng H, Wei J, Wang L, Wang Q, Zhao J, Chen S, Wei F. Effects of selenium supplementation on Graves’ disease: a systematic review and meta-analysis. Evidence-Based Complementary and Alternative Medicine: eCAM 2018 2018 3763565. (https://doi.org/10.1155/2018/3763565)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Zuo Y, Li Y, Gu X, Lei Z. The correlation between selenium levels and autoimmune thyroid disease: a systematic review and meta-analysis. Annals of Palliative Medicine 2021 10 43984408. (https://doi.org/10.21037/apm-21-449)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Samuels MH Higher selenium intake reduces the prevalence of hyperthyroidism in men, but does not affect Graves' disease clinical severity in a mouse model. Clinical Thyroidology 2019 31 182184. (https://doi.org/10.1089/ct.2019;31.182-184)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Johnson CC, Fordyce FM, Rayman MP. Symposium on ‘Geographical and geological influences on nutrition’: factors controlling the distribution of selenium in the environment and their impact on health and nutrition. Proceedings of the Nutrition Society 2010 69 119132. (https://doi.org/10.1017/S0029665109991807)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Viegas-Crespo AM, Torres I, Mira ML, Neve J. Selenium status in two populations from Madeira island with different dietary habits. In New Aspects of Trace Element Research, pp. 89–91. Eds . London, UK: Smith-Gordon, Chemistry, 1999.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Lopes PA, Santos MC, Vicente L, Rodrigues MO, Pavão ML, Neve J, Viegas-Crespo AM. Trace element status (Se, Cu, Zn) in healthy Portuguese subjects of Lisbon population: a reference study. Biological Trace Element Research 2004 101 117. (https://doi.org/10.1385/BTER:101:1:01)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Rayman MP Food-chain selenium and human health: emphasis on intake. British Journal of Nutrition 2008 100 254268. (https://doi.org/10.1017/S0007114508939830)

  • 23

    Rayman MP, Infante HG, Sargent M. Food-chain selenium and human health: spotlight on speciation. British Journal of Nutrition 2008 100 238253. (https://doi.org/10.1017/S0007114508922522)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM & European Group on Graves' Orbitopathy (EUGOGO). The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. European Thyroid Journal 2016 5 926. (https://doi.org/10.1159/000443828)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid Association guideline for the management of Graves’ hyperthyroidism. European Thyroid Journal 2018 7 167186. (https://doi.org/10.1159/000490384)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S & Boboridis K et al.Selenium and the course of mild Graves' orbitopathy. New England Journal of Medicine 2011 364 19201931. (https://doi.org/10.1056/NEJMoa1012985)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Wang W, Mao J, Zhao J, Lu J, Yan L, Du J, Lu Z, Wang H, Xu M & Bai X et al.Decreased thyroid peroxidase antibody titer in response to selenium supplementation in autoimmune thyroiditis and the influence of a selenoprotein P gene polymorphism: a prospective, multicenter study in China. Thyroid 2018 28 16741681. (https://doi.org/10.1089/thy.2017.0230)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Xu B, Wu D, Ying H, Zhang Y. A pilot study on the beneficial effects of additional selenium supplementation to methimazole for treating patients with Graves' disease. Turkish Journal of Medical Sciences 2019 49 715722. (https://doi.org/10.3906/sag-1808-67)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Pace C, Tumino D, Russo M, Le Moli R, Naselli A, Borzì G, Malandrino P, Frasca F. Role of selenium and myo-inositol supplementation on autoimmune thyroiditis progression. Endocrine Journal 2020 67 10931098. (https://doi.org/10.1507/endocrj.EJ20-0062)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Rostami R, Nourooz-Zadeh S, Mohammadi A, Khalkhali HR, Ferns G, Nourooz-Zadeh J. Serum selenium status and its interrelationship with serum biomarkers of thyroid function and antioxidant defense in Hashimoto’s thyroiditis. Antioxidants 2020 9 1070. (https://doi.org/10.3390/antiox9111070)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Tian X, Li N, Su R, Dai C, Zhang R. Selenium supplementation may decrease thyroid peroxidase antibody titer via reducing oxidative stress in euthyroid patients with autoimmune thyroiditis. International Journal of Endocrinology 2020 2020 9210572. (https://doi.org/10.1155/2020/9210572)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Hu Y, Feng W, Chen H, Shi H, Jiang L, Zheng X, Liu X, Zhang W, Ge Y & Liu Y et al.Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto’s thyroiditis: a prospective randomized‐controlled trial. Clinical and Translational Science 2021 14 13901402. (https://doi.org/10.1111/cts.12993)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Lumyongsatien M, Bhaktikamala U, Thongtong P, Sintuwong S, Nimitwongsakul O, Kanokkantapong J, Pongpirul K. Relative selenium insufficiency is a risk factor for developing severe Graves’ orbitopathy: a case–control study. BMJ Open Ophthalmology 2021 6 e000713. (https://doi.org/10.1136/bmjophth-2021-000713)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Sun C, Zhu M, Li L, Fan H, Lv F, Zhu D. Clinical observation of levothyroxine sodium combined with selenium in the treatment of patients with chronic lymphocytic thyroiditis and hypothyroidism and the effects on thyroid function, mood, and inflammatory factors. Evidence-Based Complementary and Alternative Medicine: eCAM 2021 2021 5471281. (https://doi.org/10.1155/2021/5471281)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Winther KH, Wichman JEM, Bonnema SJ, Hegedüs L. Insufficient documentation for clinical efficacy of selenium supplementation in chronic autoimmune thyroiditis, based on a systematic review and meta-analysis. Endocrine 2017 55 376385. (doi:. (https://doi.org/10.1007/s12020-016-1098-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Negro R, Hegedüs L, Attanasio R, Papini E, Winther KH. A 2018 European Thyroid Association survey on the use of selenium supplementation in Graves’ hyperthyroidism and Graves’ orbitopathy. European Thyroid Journal 2019 8 715. (https://doi.org/10.1159/000494837)

    • PubMed
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    • Export Citation
  • 37

    Winther KH, Papini E, Attanasio R, Negro R, Hegedüs L. A 2018 European Thyroid Association survey on the use of selenium supplementation in Hashimoto’s thyroiditis. European Thyroid Journal 2020 9 99105. (https://doi.org/10.1159/000504781)

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  • 38

    EFSA Panel on Dietetic Products N, Allergies. Scientific opinion on dietary reference values for selenium. EFSA Journal 2014 12 3846. (https://doi.org/10.2903/j.efsa.2014.3846)

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  • 39

    Galinha C, Freitas MC, Pacheco AMG, Kameník J, Kučera J, Anawar HM, Coutinho J, Maçãs B, Almeida AS. Selenium determination in cereal plants and cultivation soils by radiochemical neutron activation analysis. Journal of Radioanalytical and Nuclear Chemistry 2012 294 349354. (https://doi.org/10.1007/s10967-011-1510-3)

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  • 40

    Spiller HA, Pfiefer E. Two fatal cases of selenium toxicity. Forensic Science International 2007 171 6772. (https://doi.org/10.1016/j.forsciint.2006.06.077)

  • 41

    Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, Cappuccio FP, Ceriello A, Reid ME. Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Annals of Internal Medicine 2007 147 217223. (https://doi.org/10.7326/0003-4819-147-4-200708210-00175)

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  • 42

    Qiu Z, Geng T, Wan Z, Lu Q, Guo J, Liu L, Pan A, Liu G. Serum selenium concentrations and risk of all-cause and heart disease mortality among individuals with type 2 diabetes. American Journal of Clinical Nutrition 2022 115 5360. (https://doi.org/10.1093/ajcn/nqab241)

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  • 43

    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. Journal of Clinical Endocrinology and Metabolism 2007 92 12631268. (https://doi.org/10.1210/jc.2006-1821)

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  • 44

    Sajjadi SS, Foshati S, Haddadian-Khouzani S, Rouhani MH. The role of selenium in depression: a systematic review and meta-analysis of human observational and interventional studies. Scientific Reports 2022 12 1045. (https://doi.org/10.1038/s41598-022-05078-1)

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  • 45

    Mahmoudi L, Mobasseri M, Ostadrahimi A, Pourmoradian S, Soleimanzadeh H, Kafili B. Effect of selenium-enriched yeast supplementation on serum thyroid-stimulating hormone and anti-thyroid peroxidase antibody levels in subclinical hypothyroidism: randomized controlled trial. Advanced Biomedical Research 2021 10 33. (https://doi.org/10.4103/abr.abr_252_20)

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  • 46

    Negro R, Attanasio R, Grimaldi F, Marcocci C, Guglielmi R, Papini E. A 2016 Italian survey about the clinical use of selenium in thyroid disease. European Thyroid Journal 2016 5 164170. (https://doi.org/10.1159/000447667)

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    • Export Citation

 

  • Collapse
  • Expand
  • Figure 1

    Respondents’ demographics. Az/Md, Azores or Madeira.

  • Figure 2

    Respondents' auto immune thyroid disease (AITD) patients load in clinical practice. HT, Hashimoto thyroiditis; GD, Graves disease.

  • Figure 3

    Respondents' general pattern of prescription of Selenium Supplements in auto immune thyroid disease (AITD). CT, clinical trials; HT, Hashimoto thyroiditis; GD, Graves disease; GO, Graves orbitopathy; LTCH, levothyroxine-treated clinical hypothyroidism; PWHT, pregnant woman with Hashimoto's Thyroiditis; Se, selenium.

  • Figure 4

    Respondents' knowledge on the clinical evidence of selenium supplementation in each auto immune thyroid disease (AITD).

  • Figure 5

    Respondents' pattern of prescription of selenium supplements in each auto immune thyroid disease (AITD).

  • 1

    Garmendia Madariaga A, Santos Palacios S, Guillén-Grima F, Galofré JC. The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 2014 99 923931. (https://doi.org/10.1210/jc.2013-2409)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Weetman AP Autoimmune thyroid disease. Autoimmunity 2004 37 337340. (https://doi.org/10.1080/08916930410001705394)

  • 3

    Santos LR, Neves C, Melo M, Soares P. Selenium and selenoproteins in immune mediated thyroid disorders. Diagnostics 2018 8 70. (https://doi.org/10.3390/diagnostics8040070)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Wang JW, Liao XX, Li T. Thyroid autoimmunity in adverse fertility and pregnancy outcomes: timing of assisted reproductive technology in AITD women. Journal of Translational Internal Medicine 2021 9 7683. (https://doi.org/10.2478/jtim-2021-0001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Kuś A, Kjaergaard AD, Marouli E, Del Greco F, Sterenborg RBTM, Chaker L, Peeters RP, Bednarczuk T, Åsvold BO & Burgess S et al.Thyroid function and mood disorders: a Mendelian randomization study. Thyroid 2021 31 11711181. (https://doi.org/10.1089/thy.2020.0884)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Winther KH, Rayman MP, Bonnema SJ, Hegedüs L. Selenium in thyroid disorders—essential knowledge for clinicians. Nature Reviews. Endocrinology 2020 16 165176. (https://doi.org/10.1038/s41574-019-0311-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Kohrle J, Jakob F, Contempré B, Dumont JE. Selenium, the thyroid, and the endocrine system. Endocrine Reviews 2005 26 944984. (https://doi.org/10.1210/er.2001-0034)

  • 8

    Dumitrescu AM, Refetoff S. Inherited defects of thyroid hormone metabolism. Annales d'Endocrinologie 2011 72 9598. (https://doi.org/10.1016/j.ando.2011.03.011)

  • 9

    Schomburg L Selenium, selenoproteins and the thyroid gland: interactions in health and disease. Nature Reviews. Endocrinology 2011 8 160171. (https://doi.org/10.1038/nrendo.2011.174)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Curran JE, Jowett JB, Elliott KS, Gao Y, Gluschenko K, Wang J, Azim DMA, Cai G, Mahaney MC & Comuzzie AG et al.Genetic variation in selenoprotein S influences inflammatory response. Nature Genetics 2005 37 12341241. (https://doi.org/10.1038/ng1655)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Santos LR, Durães C, Mendes A, Prazeres H, Alvelos MI, Moreira CS, Canedo P, Esteves C, Neves C & Carvalho D et al.A polymorphism in the promoter region of the selenoprotein S gene (SEPS1) contributes to Hashimoto's thyroiditis susceptibility. Journal of Clinical Endocrinology and Metabolism 2014 99 E719E723. (https://doi.org/10.1210/jc.2013-3539)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    McLachlan SM, Aliesky H, Banuelos B, Hee SSQ, Rapoport B. Variable effects of dietary selenium in mice that spontaneously develop a spectrum of thyroid autoantibodies. Endocrinology 2017 158 37543764. (https://doi.org/10.1210/en.2017-00275)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Rayman MP Selenium and human health. Lancet 2012 379 12561268. (https://doi.org/10.1016/S0140-6736(1161452-9)

  • 14

    Fan Y, Xu S, Zhang H, Cao W, Wang K, Chen G, Di H, Cao M, Liu C. Selenium supplementation for autoimmune thyroiditis: a systematic review and meta-analysis. International Journal of Endocrinology 2014 2014 904573. (https://doi.org/10.1155/2014/904573)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Wichman J, Winther KH, Bonnema SJ, Hegedüs L. Selenium supplementation significantly reduces thyroid autoantibody levels in patients with chronic autoimmune thyroiditis: a systematic review and meta-analysis. Thyroid 2016 26 16811692. (https://doi.org/10.1089/thy.2016.0256)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Zheng H, Wei J, Wang L, Wang Q, Zhao J, Chen S, Wei F. Effects of selenium supplementation on Graves’ disease: a systematic review and meta-analysis. Evidence-Based Complementary and Alternative Medicine: eCAM 2018 2018 3763565. (https://doi.org/10.1155/2018/3763565)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Zuo Y, Li Y, Gu X, Lei Z. The correlation between selenium levels and autoimmune thyroid disease: a systematic review and meta-analysis. Annals of Palliative Medicine 2021 10 43984408. (https://doi.org/10.21037/apm-21-449)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Samuels MH Higher selenium intake reduces the prevalence of hyperthyroidism in men, but does not affect Graves' disease clinical severity in a mouse model. Clinical Thyroidology 2019 31 182184. (https://doi.org/10.1089/ct.2019;31.182-184)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Johnson CC, Fordyce FM, Rayman MP. Symposium on ‘Geographical and geological influences on nutrition’: factors controlling the distribution of selenium in the environment and their impact on health and nutrition. Proceedings of the Nutrition Society 2010 69 119132. (https://doi.org/10.1017/S0029665109991807)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Viegas-Crespo AM, Torres I, Mira ML, Neve J. Selenium status in two populations from Madeira island with different dietary habits. In New Aspects of Trace Element Research, pp. 89–91. Eds . London, UK: Smith-Gordon, Chemistry, 1999.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Lopes PA, Santos MC, Vicente L, Rodrigues MO, Pavão ML, Neve J, Viegas-Crespo AM. Trace element status (Se, Cu, Zn) in healthy Portuguese subjects of Lisbon population: a reference study. Biological Trace Element Research 2004 101 117. (https://doi.org/10.1385/BTER:101:1:01)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Rayman MP Food-chain selenium and human health: emphasis on intake. British Journal of Nutrition 2008 100 254268. (https://doi.org/10.1017/S0007114508939830)

  • 23

    Rayman MP, Infante HG, Sargent M. Food-chain selenium and human health: spotlight on speciation. British Journal of Nutrition 2008 100 238253. (https://doi.org/10.1017/S0007114508922522)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM & European Group on Graves' Orbitopathy (EUGOGO). The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. European Thyroid Journal 2016 5 926. (https://doi.org/10.1159/000443828)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid Association guideline for the management of Graves’ hyperthyroidism. European Thyroid Journal 2018 7 167186. (https://doi.org/10.1159/000490384)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S & Boboridis K et al.Selenium and the course of mild Graves' orbitopathy. New England Journal of Medicine 2011 364 19201931. (https://doi.org/10.1056/NEJMoa1012985)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Wang W, Mao J, Zhao J, Lu J, Yan L, Du J, Lu Z, Wang H, Xu M & Bai X et al.Decreased thyroid peroxidase antibody titer in response to selenium supplementation in autoimmune thyroiditis and the influence of a selenoprotein P gene polymorphism: a prospective, multicenter study in China. Thyroid 2018 28 16741681. (https://doi.org/10.1089/thy.2017.0230)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Xu B, Wu D, Ying H, Zhang Y. A pilot study on the beneficial effects of additional selenium supplementation to methimazole for treating patients with Graves' disease. Turkish Journal of Medical Sciences 2019 49 715722. (https://doi.org/10.3906/sag-1808-67)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Pace C, Tumino D, Russo M, Le Moli R, Naselli A, Borzì G, Malandrino P, Frasca F. Role of selenium and myo-inositol supplementation on autoimmune thyroiditis progression. Endocrine Journal 2020 67 10931098. (https://doi.org/10.1507/endocrj.EJ20-0062)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Rostami R, Nourooz-Zadeh S, Mohammadi A, Khalkhali HR, Ferns G, Nourooz-Zadeh J. Serum selenium status and its interrelationship with serum biomarkers of thyroid function and antioxidant defense in Hashimoto’s thyroiditis. Antioxidants 2020 9 1070. (https://doi.org/10.3390/antiox9111070)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Tian X, Li N, Su R, Dai C, Zhang R. Selenium supplementation may decrease thyroid peroxidase antibody titer via reducing oxidative stress in euthyroid patients with autoimmune thyroiditis. International Journal of Endocrinology 2020 2020 9210572. (https://doi.org/10.1155/2020/9210572)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Hu Y, Feng W, Chen H, Shi H, Jiang L, Zheng X, Liu X, Zhang W, Ge Y & Liu Y et al.Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto’s thyroiditis: a prospective randomized‐controlled trial. Clinical and Translational Science 2021 14 13901402. (https://doi.org/10.1111/cts.12993)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Lumyongsatien M, Bhaktikamala U, Thongtong P, Sintuwong S, Nimitwongsakul O, Kanokkantapong J, Pongpirul K. Relative selenium insufficiency is a risk factor for developing severe Graves’ orbitopathy: a case–control study. BMJ Open Ophthalmology 2021 6 e000713. (https://doi.org/10.1136/bmjophth-2021-000713)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Sun C, Zhu M, Li L, Fan H, Lv F, Zhu D. Clinical observation of levothyroxine sodium combined with selenium in the treatment of patients with chronic lymphocytic thyroiditis and hypothyroidism and the effects on thyroid function, mood, and inflammatory factors. Evidence-Based Complementary and Alternative Medicine: eCAM 2021 2021 5471281. (https://doi.org/10.1155/2021/5471281)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Winther KH, Wichman JEM, Bonnema SJ, Hegedüs L. Insufficient documentation for clinical efficacy of selenium supplementation in chronic autoimmune thyroiditis, based on a systematic review and meta-analysis. Endocrine 2017 55 376385. (doi:. (https://doi.org/10.1007/s12020-016-1098-z)

    • PubMed
    • Search Google Scholar
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  • 36

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