Selenium Supplementation for Hashimoto’s Thyroiditis: Summary of a Cochrane Systematic Review

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Selenium supplementation in people with Hashimoto's thyroiditis might reduce antibody levels and result in a decreased dosage of levothyroxine (LT4) and may provide other beneficial effects (e.g. on mood and health-related quality of life). The

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  E-Mail karger@karger.com  Clinical Thyroidology / Review Eur Thyroid J DOI: 10.1159/000356040 Selenium Supplementation for Hashimoto’s Thyroiditis: Summary of a Cochrane Systematic Review Esther J. van Zuuren a  Amira Y. Albusta c  Zbys Fedorowicz d  Ben Carter e  Hanno Pijl b   Departments of a  Dermatology and b  Endocrinology, Leiden University Medical Centre, Leiden , The Netherlands; c  College of Medicine, AMA International University of Bahrain, Manama , and d  UKCC (Bahrain Branch), The Cochrane Collaboration, Awali , Bahrain; e  Institute of Primary Care & Public Health, Cardiff University School of Medicine, Cardiff , UK    Although the changes from baseline were statistically sig-nificant in these three studies, their clinical relevance is un-clear. In conclusion, the results of these four studies, as-sessed at unclear to high risk of bias, show that evidence to support or refute the efficacy of selenium supplementation in people with Hashimoto’s thyroiditis is incomplete and not reliable to help inform clinical decision making. © 2013 European Thyroid Association Published by S. Karger AG, Basel Introduction Hashimoto’s thyroiditis or chronic lymphocytic thy-roiditis is a common autoimmune disorder which tends to run in families and affects both genders at any age, al-though it is most often seen in middle-aged women [1, 2] . Its prevalence is influenced by ethnicity, environmental factors, such as iodine and selenium status, age and gen-  Key Words Selenium · Hashimoto’s thyroiditis · Evidence-based medicine · Supplements Abstract Selenium supplementation in people with Hashimoto’s thy-roiditis might reduce antibody levels and result in a de-creased dosage of levothyroxine (LT 4  ) and may provide oth-er beneficial effects (e.g. on mood and health-related quality of life). The aim of our systematic review was to assess the effects of selenium supplementation on Hashimoto’s thy-roiditis. We searched The Cochrane Library, MEDLINE, EM-BASE and Web of Science for randomized controlled trials. Study selection, data extraction, assessment of risk of bias and analyses were carried out by two independent review authors. We assessed the quality of the evidence of included studies using GRADE. Four studies rated at unclear to high risk of bias comprising 463 participants were included. One study at high risk of bias showed statistically significant im-provement in subjective well-being with sodium selenite 200 μg plus titrated LT 4  compared with placebo plus titrated LT 4  (RR 4.67, 95% CI 1.61–13.50). Selenomethionine 200 μg as a single treatment or combined with LT 4  reduced the se-rum levels of anti-thyroid peroxidase antibodies compared with placebo (or placebo plus LT 4  ) in three studies (p < 0.001). Received: August 13, 2013 Accepted after revision: September 20, 2013 Published online: November 21, 2013 Esther van Zuuren Department of Dermatology B1-Q Leiden University Medical Centre PO Box 9600, NL–2300 RC Leiden (The Netherlands) E-Mail E.J.van_Zuuren @ lumc.nl © 2013 European Thyroid AssociationPublished by S. Karger AG, Basel2235–0640/13/0000–0000$38.00/0 www.karger.com/etj  This paper is based on a Cochrane review published in Issue 6, June 2013 of The Cochrane Library 2013 (see http://www.CochraneLi-brary.net for further information). Cochrane reviews are regularly up-dated as new evidence emerges and in response to comments and criticisms. The Cochrane Library should be consulted for the most recent version of this review.    van Zuuren /Albusta /Fedorowicz /Carter /Pijl Eur Thyroid JDOI: 10.1159/000356040 2 der [1, 2] . Clinical manifestations of the disease are caused primarily by low levels of thyroid hormones, for which the treatment is hormone replacement therapy, which usually consists of levothyroxine (LT 4  ) [3] .  Selenium is an essential trace element that is required for the correct functioning of the immune system with a recommended daily intake for adults of 55 μg [4] . Natural selenium-rich sources include Brazil nuts, organ meat, muscle meat, cereals, shellfish and fish [5] . Selenomethio-nine and sodium selenite are the two most common oral forms of selenium supplementation that are available in  variable dosages (100 and 200 μg/day) [6, 7] . It has recent-ly been established that selenium plays a key role in thyroid cell physiology [8] . It is incorporated in the molecular structure of several enzymes in the thyroid gland [8, 9] . One of these enzymes, glutathione peroxidase (GPx), is critically involved in protecting the gland against oxidative damage. Thyroid peroxidase uses hydrogen peroxide (H 2  O 2  ), a free radical capable of inflicting oxidative dam-age, as a substrate in catalyzing the iodination and coupling of tyrosyl residues in thyroglobulin to produce thyroid hormone. The active form of thyroid hormone, tri-iodo-thyronine (T3), is produced by de-iodination of the pro-hormone T4 by type I and type II iodothyronine de-iodin-asesin, a two-substrate ‘ping-pong’ mechanism of reaction, along with degradation of H 2  O 2  to water by GPx. Iodothy-ronine de-iodinases are also selenoproteins, as is GPx.  If there is selenium deficiency, these two enzymes can-not function properly, which results in both ineffective production of T3 and inefficient protection against free radicals, the latter facilitating cell damage and autoim-mune destruction of the gland [6, 8, 9] . In view of the piv-otal role of selenium in thyroid physiology, it is conceiv-able that selenium supplementation may be of benefit to patients with Hashimoto’s thyroiditis, particularly in clinical situations of selenium deficiency [6] . Several studies have suggested that selenium treatment reduces antibodies levels [10] , allows lower dosage of LT 4  supple-mentation and may provide other beneficial effects (e.g. on mood and health-related quality of life; HRQoL) in patients with Hashimoto’s thyroiditis [11] . We performed a systematic review to assess the effects of selenium sup-plementation for Hashimoto’s thyroiditis, and this report is a summary of the Cochrane systematic review [12] .  Material and Methods We conducted a systematic review of randomized controlled trials (RCTs) assessing the effects of selenium supplementation in adults with Hashimoto’s thyroiditis. Selenium 100 μg or 200 μg (sodium selenite or selenomethionine) only or combined with ti-trated LT 4  (to maintain basal TSH within normal range) was com-pared with: no selenium or no selenium plus titrated LT 4  , respec-tively; placebo tablets or placebo tablets plus titrated LT 4  , respec-tively. Search Strategies We searched for RCTs in The Cochrane Library, MEDLINE, EMBASE and Web of Science and in reference lists of articles (from inception until 2 October 2012). We also examined several online trial registries for on-going trials and attempted to contact trial investigators to provide missing data or to clarify study details. Two review authors (E.J.v.Z. and A.Y.A.) independently assessed the titles and abstracts for eligible RCTs.  Outcome Measures Our three primary outcomes were: (1) change from baseline in HRQoL assessed using any validated quality-of-life instrument; (2) change from baseline in symptoms, such as mood, fatigue and muscle weakness, assessed using any validated instrument, and (3) proportion of participants reporting an adverse event throughout the study period. Secondary outcomes were: (a) change from base-line in serum levels of anti-thyroid peroxidase antibodies; (b) change from baseline in LT 4  replacement dosage, and (c) econom-ic costs.  Data Extraction and Synthesis Three review authors (E.J.v.Z., A.Y.A. and Z.F.) extracted study details and data using a structured data extraction form and any disagreements were resolved by discussion. The risk of bias in each study was assessed independently by the same 3 authors using the Cochrane Collaboration’s domain-based evaluation tool as de-scribed in Chapter 8, Section 8.5, in the Cochrane Handbook for Systematic Reviews of Interventions [13] . We presented continu-ous outcomes data on the srcinal scale as reported in each indi- vidual study. Dichotomous outcomes data were presented as risk ratios (RRs) and if significant were converted to the number need-ed to treat (NNT) for an additional beneficial outcome. All out-comes data were reported with their associated 95% CIs and were analyzed using a random-effects model and the Mantel-Haenzel test for dichotomous outcomes data and invariance analysis for continuous outcomes data, unless stated otherwise. The degree of heterogeneity between the studies was assessed using the I 2  statis-tic. We reported heterogeneity as important if it was at least mod-erate to substantial (I 2  between 50 and 90%). If heterogeneity could be explained by clinical reasoning and a coherent argument could be made for combining the studies, we planned to enter these into a meta-analysis.  Results From the searches, we identified 110 studies for ab-stract review ( fig. 1 ). Six studies were excluded after care-ful evaluation of the full text of the publication [10, 14–18] . These appeared to be controlled (i.e. nonrandom-ized) clinical trials, of which four [10, 16–18] were confirmed to be quasi-randomized after communication   Selenium for Hashimoto’s Thyroiditis Eur Thyroid JDOI: 10.1159/000356040 3 with the trialists (i.e. allocation was done on the basis of a pseudo-random sequence, e.g. odd/even hospital num-ber or date of birth, alternation). Eventually, only four studies comprising 463 participants met our inclusion criteria and were included [7, 19–21] .  Risk of Bias of the Included Studies We assessed the studies for risk of bias and have re-ported the judgements for the individual domains in the ‘risk of bias’ table ( fig. 2 ). The overall ‘risk of bias’ of the four studies was assessed as ‘unclear risk of bias’ to ‘high risk of bias’ (plausible bias that raises some to serious doubts about the results). In two studies [7, 19] , one of the key domains, ‘sequence generation’, was assessed as high risk of bias and, in all of the studies, 4–6 domains were assessed as ‘unclear risk of bias’.  Effects of Interventions See table 2 for a summary of the key results. The primary outcome of HRQoL was not addressed in any study. Two of our secondary outcomes (‘change from baseline in LT 4  replacement dosage at the end of the study’ and ‘economic costs’) were not assessed either. One study at high risk of bias showed a statistically sig-nificant improvement in subjective well-being with so-dium selenite 200 μg plus titrated LT 4  compared with pla- 110 records identified through database searchingEMBASE (n = 24)MEDLINE (n = 50)The Cochrane Library (n = 11)Web of Science (n = 23)Other databases (n = 2)5 full-text articles excludedReasons: 1. CCT (n = 1) 2. Quasi-randomized (n = 4)Systematic reviews/meta-analyses (n = 1)HTA reports (n = 0)1 full-text article excludedReason: CCT 9 full-text articles assessedfor eligibility1 additional study identified through handsearching of reference lists of included trials,systematic reviews/meta-analyses and HTA reports0 additional records identified through other sources66 records after duplicates removed66 records screened57 records excluded4 studies (4 publications) included3 potentially relevant ongoing trials (0 publications)4 completed studies (4 publications) included in qualitative synthesis 0 studies (0 publications) included in quantitative synthesis (meta-analysis)   Fig. 1.  Study flow diagram.    van Zuuren /Albusta /Fedorowicz /Carter /Pijl Eur Thyroid JDOI: 10.1159/000356040 4 Table 1.  Characteristics of included RCTs in the review  StudyMethodsParticipantsInterventionsOutcomesKaranikaset al. [19]Vienna, Austria RCT‘blinded’36 women with autoimmune thyroiditismean age 47 yearsmean baseline selenium 75 µg/l3 monthsA: LT 4 + 200 μg sodium selenite once daily B: LT 4 + placebo once daily (1) FT 4 , TSH, anti-TPOAb(2) intracellular cytokine evaluation in CD4+ and CD8+ T cells of peripheral blood mononuclear cells(3) plasma selenium(4) subjective well-being of the patients (assessed with short form health survey, SF-12 [24])Krysiak and Okopien [20]Katowice, PolandRCT double-blind170 euthyroid women with recently diagnosed and previously untreated Hashimoto’s thyroiditismean age 38 yearsmean baseline selenium 57.5 µg/l, of women in this part of Poland (not measured in the participants)6 monthsA: LT 4 once daily B: 200 μg selenomethionine once daily C: LT 4  + 200 μg selenomethionine once daily D: placebo once daily (1) monocyte and lymphocytesuppression(2) systemic anti-inflammatory effects (3) anti-TPOAb(4) adverse eventsNegro et al. [21]Brindisi, Italy RCT169 pregnant anti-TPOAb-positive womenmean age 28 yearsmean baseline selenium 78.8 µg/lFrom 12 weeks’ gestation to 12 months’ postpartumA: 200 μg selenomethionine once daily B: placebo once daily (1) FT 4 , TSH, anti-TPOAb(2) selenium status(3) thyroid ultrasoundTurker et al. [7]Istanbul, Turkey RCT‘blinded’88 women with autoimmune thyroiditismean age 40 yearsno data on baseline selenium, but the study states that in Turkey there is mild selenium deficiency 3 monthsA: LT 4  + 200 μg selenomethionineB: LT 4  + placebo(1) TgAb, TSH, FT 4 , FT 3 (2) anti-TPOAb LT 4  = Levothyroxine; FT 4 = free thyroxine; TSH = thyroid-stimulating hormone; TPOAb = thyroid peroxidase antibodies; TgAb = thyroglobulin anti-bodies; FT 3  = free triiodothyronine.    K  a  r  a  n   i   k  a  s  e   t  a   l .   [   1   9   ]   K  r  y  s   i  a   k  a  n   d   O   k  o  p   i  e  n   [   2   0   ]   N  e  g  r  o  e   t  a   l .   [   2   1   ]   T  u  r   k  e  r  e   t  a   l .   [   7   ] Random sequence generation (selection bias) –++– Allocation concealment (selection bias) ?++? Blinding of participants and personnel (performance bias): objective outcomes ???? Blinding of participants and personnel (performance bias): subjective outcomes ???? Blinding of outcome assessment (detection bias): objective outcomes + low risk of biasunclear risk of biashigh risk of bias –?+ +–+ Blinding of outcome assessment (detection bias): subjective outcomes ???? Incomplete outcome data (attrition bias): subjective outcomes +??? Incomplete outcome data (attrition bias): objective outcomes ?++? Selective reporting (reporting bias) ++?+ Other bias ++++   Fig. 2.  Risk of bias summary: review of the authors’ judgments about each risk of bias item for each included study.    C  o   l  o  r  v  e  r  s   i  o  n   a  v  a   i   l  a   b   l  e  o  n   l   i  n  e   Selenium for Hashimoto’s Thyroiditis Eur Thyroid JDOI: 10.1159/000356040 5 cebo plus titrated LT 4  [19] . In three studies [7, 20, 21] , selenomethionine 200 μg supplementation was associat-ed with a decrease in serum levels of anti-thyroid peroxi-dase antibodies, and although the changes from baseline were statistically significant, their clinical significance is unclear. Pooling of the studies by Krysiak and Okopien [20] and Negro et al. [20] was not feasible due to extreme heterogeneity (I 2  = 99%).  This reduction in serum anti-thyroid peroxidase an-tibodies was not confirmed in the study which assessed sodium selenite 200 μg plus titrated LT 4  [19] . The two studies that reported on adverse events demonstrated that selenium supplementation did not lead to a statisti-cally significant increase in the number of adverse events when compared with placebo. The effectiveness and safety of selenium (+ LT 4  ) versus placebo (+ LT 4  ) are presented in a GRADE summary of findings table ( ta-ble 3 ) [22] .  Discussion Based on the four studies assessed at unclear to high risk of bias that provided limited data, no clinically rele- vant conclusions can be drawn. As Hashimoto’s thyroid-itis is associated with many debilitating symptoms, out-comes, such as change in HRQoL, and improvement in symptoms, such as mood, fatigue and muscle weakness, are important and clinically meaningful markers. The re-sults of these studies provide incomplete evidence to sup-port or refute the efficacy of selenium in people with Hashimoto’s thyroiditis. We identified three on-going studies that may eventually help to fill in some of the gaps in evidence for the efficacy of selenium as a supplement in people with Hashimoto’s thyroiditis. Another systematic review, which attempted ‘to sum-marize available data and provide an evidence-based rec-ommendation regarding selenium supplementation in Table 2.  Summary of results of included studies StudyInterventionsSummary outcomesCommentsKaranikaset al. [19]A: LT 4 + 200 μg sodium selenite once daily B: LT 4 + placebo once daily Subjective well-being was improved in 14/18 women receiving sodium selenite compared with 3/18 in the placebo group (RR 4.67, 95% CI 1.61   –   13.50; p = 0.004; number needed to treat = 2; 95% CI 2   –   3)Anti-TPOAb changed from 524 ± 452 IU/ml at baseline to 505 ± 464 IU/ml for the sodium selenite group and from 521 ± 349 to 527 ± 354 IU/ml for the placebo groupThe mean difference was estimated to be –25 (95% CI –181 to 131; p = 0.75; 36 participants)This study was assessed as high risk of bias as randomization seemed to be based on prognostic factors, with no mention of stratified randomizationAlthough it was stated to be a blinded study, the report did not provide sufficient detail about the specific measures used to blind study participants and personnel from knowledge of which intervention a participant receivedKrysiak and Okopien [20]A: LT 4 once daily B: 200 μg selenomethionine once daily C: LT 4  + 200 μg selenomethionine once daily D: placebo once daily B versus D: the mean difference in anti-TPOAb wasestimated as –917 IU/ml (95% CI –1,029.16 to –804.84;p < 0.001; 85 participants) No adverse events were reported in either groupC versus D: the mean difference was estimated to be –1,508 U/ml (95% CI –1,672 to –1,345; p < 0.001; 86 participants) In group C, 1/43 reported an adverse event versus 0/42 in group D (RR 2.93, 95% CI 0.12   –   70.00)Negro et al.[21]A: 200 μg selenomethionine once daily B: placebo once daily The mean difference in anti-TPOAb was estimated as –345.0 IU/ml (95% CI –358.79 to –331.21; p < 0.001; 169 participants)No report on any blinding might have influenced assessment of thyroid ultrasoundTurker et al. [7]A: LT 4  + 200 μg selenomethionineB: LT 4  + placeboThe mean difference in anti-TPOAb was estimated to be –235 IU/ml (95% CI –374 to –95; p = 0.001; 88 participants)1/48 reported an adverse event (gastric discomfort) in group A versus 0/40 in group B (RR 2.63, 95% CI 0.11   –   62.95)This study was assessed as high risk of bias as randomization seemed to be based on prognostic factors, with no mention of stratified randomizationAlthough it stated to be a blinded study the report did not provide sufficient detail about the specific measures used to blind study participants and personnel from knowledge of which intervention a participant received TPOAb= Thyroid peroxidase antibodies.
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