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Mini-CAT

C.Shamrock

Clinical Question:

Pt is a 55 YOF with Graves Disease.  She is looking for a natural supplement to help decrease the size of her thyroid and nodules as well as help with Ophthalmopathy. She found an article saying Selenium may help normalize her thyroid function. She is asking her PA if this is true and if she should try it and if there’s any associated side effects.

PICO Question: Do Selenium Supplements help improve symptoms of autoimmune hyperthyroidism

PICO elements

P      Adult females

I       Selenium Supplements

C      No Selenium Supplements

O      Thyroid Volume and Thyroid Nodules, Adverse Effects, Side effects

Search Terms: Hyperthyroidism, Selenium, hormone levels, side effect, effective, therapy, females, adults, Thyroxine, T3, T4

Summary of the Evidence:

Author (Date)Level of EvidenceSample/Setting (# of subjects/ studies, cohort definition etc. )Outcome(s) studiedKey FindingsLimitations and Biases
M.Ventura et.al, 2017Meta AnalysisAnalysis of over 56 studies, largest being 6152 patientsSelenuim and Thyroid Volume, and Thyroid Nodules, Graves Gisease, cancer, immune functionOverall the studies shown improved outcomes with selenium supplementation, especially in a setting of Thyroid disease, with no significant side effects. However, the challenge remains on proper dosing to achieve maximum efficacy.Authors have no biases to report
Dharmasena A. , 2014Meta AnalysisAnalysis of 135 english language articles published on this subject over the past four decades from 1973 to 3013Therapeutic effect of Selenium in thyroid disease and thyroid associated ophtalmopathySe substitution could have a significant impact on inflammatory activity in thyroid-specific autoimmune disease and a significant improvement its ophthalmic manifestations.publication date of 2014 is out of preferred 5 year window.    
Santos et.al, 2018Meta AnalysisAuthors refer to 70 different sources but the exact number of works analyzed is not mentionedSelenium and Selenoproteins in Immune Mediated Thyroid DisordersIn patients with mild to moderate Graves’ orbitopathy, selenium supplementation seems to be beneficial and the organic formula (selenomethionine) seems to be more efficient than the inorganic formula.The article would have been more complete had the authors disclosed the amount of studies analyzed
Duntas L.H., 2012Meta AnalysisAuthors refer to 51 different sources but the exact number of works analyzed is not mentionedPathophysiology of Graves disease and ophthalmopathy. The research also extended to finding an optimal delivery method for Selenium as well as an optimal therapeutic dose.  In synergy with antithyroid drugs or immune modulators, selenium might offer an alternative therapeutic approach in patients with severe diseaseThe study date os out of the preferred 5 year window

Search results:

Is selenium effective treatment for hyperthyroidism in adults AND/OR Thyroid Volume AND/OR Thyroid Nodules

1. Up to date – search yielded results not close enough to the PICO

2. Ebsco Host – majority of research available focused on hyperthyroidism in a setting of Down Syndrome, which is not the case with my patient

3. NCBI: (Is selenium effective treatment for hyperthyroidism) AND (“Adults”) AND (“2015″[Publication Date] : “3000”[Publication Date]) yielded 193 results. The closest to PICO were:

Article 1:

Ventura M, Melo M, Carrilho F. Selenium and Thyroid Disease: From Pathophysiology to Treatment. Int J Endocrinol. 2017;2017:1297658. doi:10.1155/2017/1297658

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307254/

Why this Article?

Abstract:

We performed a review of the literature on selenium’s role in thyroid function using PubMed/MEDLINE. Results. Regarding thyroid pathology, selenium intake has been particularly associated with autoimmune disorders. The literature suggests that selenium supplementation of patients with autoimmune thyroiditis is associated with a reduction in antithyroperoxidase antibody levels, improved thyroid ultrasound features, and improved quality of life. Selenium supplementation in Graves’ orbitopathy is associated with an improvement of quality of life and eye involvement, as well as delayed progression of ocular disorders. The organic form of selenium seems to be the preferable formulation for supplementation or treatment. Conclusion. Maintaining a physiological concentration of selenium is a prerequisite to prevent thyroid disease and preserve overall health. Supplementation with the organic form is more effective, and patients with autoimmune thyroiditis seem to have benefits in immunological mechanisms. Selenium supplementation proved to be clinically beneficial in patients with mild to moderate Graves’ orbitopathy.

Strengths: This is a meta analysis including over 53 sources of works targeting efficacy of Selenium supplements in a setting of hyperthyroidism. It provides a detailed overview of the most recent evidence to answer the PICO question

Weaknesses: Many of the studies analyzed were small and operator dependent, even though it included the studies with the sample size as big as 6152 patients.

Article #2 2014

Dharmasena A. (2014). Selenium supplementation in thyroid associated ophthalmopathy: an update. International journal of ophthalmology7(2), 365–375. https://doi.org/10.3980/j.issn.2222-3959.2014.02.31

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003098/

Why this Article?

Abstract:

The therapeutic effect of selenium (Se) has already been proven in thyroid disease and thyroid associated ophthalmopathy (TAO). In spite of clear scientific proof of its benefits in TAO, there appears to be no clear agreement among the clinicians regarding its optimum dose, duration of the treatment, efficacy and safety to date. In this review, the author summarises the findings of 135 English language articles published on this subject over the past four decades from 1973 to 2013.

Conclusion: Se is a unique trace element in its structural incorporation into proteins and it is essential for optimal endocrine and immune function and moderating the inflammatory response. On the other hand, thyroid autoimmune disease, a multifactorial organ-specific autoimmune disorder, is marking a constant increase worldwide and it is thought to be caused by multiple environmental factors triggering autoimmune response in genetically susceptible individuals, though the exact mechanisms linking environmental factors to thyroid autoimmunity are not as yet well understood. Nevertheless, there is increasing evidence that nutritive and environmental factors are the main determinants in the present-day distribution of this disease and its ophthalmic manifestations. Even mild Se deficiency thought to contribute to the development and maintenance of autoimmune thyroid diseases and TAO. The patients with thyroid diseases such as GD and even thyroid cancer appear to have low levels of serum Se levels compared to the age matched controls. Several studies have shown that the Se substitution could have a significant impact on inflammatory activity in thyroid-specific autoimmune disease and a significant improvement its ophthalmic manifestations. There appears to be several mechanisms by which Se reduce the severity of TAO. These include inhibitory effect of HLA-DR molecule expression on thyrocytes, the reduction of serum TPO-Ab/TSHR-Ab concentrations, influence on the cell mediated/humoral immune pathways, anti inflammatory and anti-oxident properties of Se. These beneficial effects of Se explain why the efficacy of Se substitution is proportionate to the inflammatory activity of autoimmune thyroid disease and TAO.

Whilst it seems reasonable to recommend Se substitution to reduce the severity of TAO and autoimmune thyroid disease the Se status of the individual patients should be taken into account prior to prescribing Se supplements to avoid chronic iatrogenic overdose. In current practice, the laboratory measurements of Se are not routine in TAO, but the author propose that early assessment of Se status should become mandatory prior to Se supplementation to determine the dose and duration of supplementation of this vital micronutrient.

Strengths: This is the largest meta analysis of all my chosen articles. It includes over 136 studies summarizing a vast amount of knowledge accumulated about thyroid disease and Thyroid Ophtalmopathy in particular.  It’s focus is very specific to my PICO and it provides an excellent background of the role of Selenium in the body as well as in treatment of Thyroid Associated Ophthalmopathy.

Weaknesses: publication date of 2014 is out of preferred 5 year window.

Article #3: 2018

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316875/

Santos, L. R., Neves, C., Melo, M., & Soares, P. (2018). Selenium and Selenoproteins in Immune Mediated Thyroid Disorders. Diagnostics (Basel, Switzerland)8(4), 70. https://doi.org/10.3390/diagnostics8040070

Why this Article:

Abstract: Several authors support the idea of a potential efficacy of selenium (mainly selenomethionine) supplementation in reducing antithyroperoxidase antibody levels and improve thyroid ultrasound features. In mild Graves’ orbitopathy, selenium supplementation has been associated with a decrease of the activity, as well as with quality of life improvement. Future research is necessary to clearly understand the selenium supplementation biologic effects while considering the basal selenium levels/biomarkers, selenoprotein gene polymorphisms that may be involved, underlying comorbidities and the major clinical outcomes.

Conclusion:

Selenium supplementation is not yet recommended in international guidelines for treatment of AITD. Using a questionnaire study among Italian Endocrinologists, Negro, reported that selenium supplementation is currently used despite not being recommended in the guidelines. However, regarding Graves’ orbitopathy, the European Thyroid Association recommends a six-month trial period……In patients with mild to moderate Graves’ orbitopathy, selenium supplementation seems to be beneficial and the organic formula (selenomethionine) seems to be more efficient than the inorganic formula. Additional studies will allow for the stratification of patients that are most likely to benefit from selenium supplementation.

Strengths: Article provides the most recent evidence about using Selenuim in Graves disease treatment. It explores not only US population but also Europe where prescribing Selenium to normalize the thyroid function had been practiced for quite some time now.

Weaknesses:

Despite being a strong meta analysis, the work did not find evidence significant enough to recommend Selenium as a therapy for autoimmune thyroiditis.

Article #4 2012

Duntas L. H. (2012). The evolving role of selenium in the treatment of graves’ disease and ophthalmopathy. Journal of thyroid research2012, 736161. https://doi.org/10.1155/2012/736161

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270443/

Why this Article?

Abstract:

The aim of this review is to summarize the actions of selenium in Graves Disease and Graves Ophtalmopathy. Selenium as selenocysteine is incorporated in selenoproteins, such as glutathione peroxidase which catalyzes the degradation of hydrogen peroxide and lipid hydroperoxide that are increasingly produced in hyperthyroidism. Moreover, selenium decreases the formation of proinflammatory cytokines, while it contributes, in synergy with antithyroid drugs, to stabilization of the autoimmune process in GD and alleviation of GO. It is now to be clarified whether enforced nutritional supplementation has the same results and whether prolonging selenium administration may have an impact on the prevention of disease.

Goal: The aim of this paper is to briefly evaluate the current knowledge concerning the pathogenesis of GD and GO and discuss the evolving role of selenium within the context of its potential as a therapeutic means of intervention in these disorders.

Conclusion: In summary, selenium influences the inflammatory process in GD and GO by inhibiting various pathways though its mechanism of action is not completely clarified. It is nonetheless possible that, in synergy with antithyroid drugs or immune modulators, selenium might offer an alternative therapeutic approach in patients with severe disease. It also remains to be established whether enforced nutritional supplementation has the same effects and whether long-term selenium administration in the form of selenomethionine or as nutritional intervention may have an impact on the incidence of relapse of GD and GO.

Strengths: This is a meta analysis including over 51 sources exploring intricacies of the pathophysiology of Graves disease and ophthalmopathy. The research also extended to finding an optimal delivery method for Selenium as well as an optimal therapeutic dose.

Weaknesses: even though not much has been discovered about Graves disease since 2012, this study date is out of preferred 5 year range.

Conclusion(s):

Future research is necessary to clearly understand and, therefore, being able to establish appropriate indications on dosing and frequency of selenium supplements to combat thyroid disease. Thyroid is a sensitive organ and every patient’s chemistry is unique, making it difficult to establish the baseline selenium levels/biomarkers in order to appropriately design a course of treatment. However, the results are promising and inspiring further research.  

Clinical Bottom Line:

Even though Selenium is being used in Europe to treat mild Hyperthyroidism (sometimes off label), including that of the autoimmune type like Grave’s  disease and orbitopathy, recommending it to the patient to use on their own may carry potential risks of toxicity from an overdose and, therefore, is not warranted. However, implementing foods rich in selenium (like brazil nuts) may have benefit on her health at a minimal to no risk of Se overdose, so that could be a good place for her to start.

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