Evidence-Based Complementary and Alternative Medicine

Hindawi
Evidence-Based Complementary and Alternative Medicine

Volume 2018, Article ID 3763565, 10 pages
https://doi.org/10.1155/2018/3763565
Review Article
Effects of Selenium Supplementation on Graves’ Disease:
A Systematic Review and Meta-Analysis
Huijuan Zheng, Junping Wei , Liansheng Wang, Qiuhong Wang,

Jing Zhao, Shuya Chen, and Fan Wei
Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences,
No. 5 Beixiange Street, Xicheng District, Beijing, 100053, China
Correspondence should be addressed to Junping Wei; [email protected]
Received 7 February 2018; Accepted 7 August 2018; Published 26 September 2018
Academic Editor: Deborah A. Kennedy
Copyright © 2018 Huijuan Zheng et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Low selenium status is associated with increased risk of Graves’ disease (GD). While several trials have discussed the efficacy of
selenium supplementation for thyroid function, in GD patients, the effectiveness of selenium intake as adjuvant therapy remains
unclear. In this systematic review and meta-analysis, we aimed to determine the efficacy of selenium supplementation on thyroid
function in GD patients. Two reviewers searched PubMed, Web of Science, the Cochrane Central Register of Controlled Trials,
and four Chinese databases for studies published up to October 31, 2017. RCTs comparing the effect of selenium supplementation
on thyroid hyperfunction in GD patients on antithyroid medication to placebo were included. Serum free thyroxine (FT4), free
triiodothyronine (FT3), thyrotrophic hormone receptor antibody (TRAb), and thyroid-stimulating hormone (TSH) levels were
assessed. Ten trials involving 796 patients were included. Random-effects meta-analyses in weighted mean difference (WMD)
were performed for 3, 6, and 9 months of supplementation and compared to placebo administration. Selenium supplementation
significantly decreased FT4 (WMD=-0.86 [confidence interval (CI)-1.20 to -0.53]; p=0.756; I2 =0.0%) and FT3 (WMD=-0.34 [CI-
0.66 to -0.02]; p=0.719; I2 =0.0%) levels at 3 months, compared to placebo administration; these findings were consistent at 6 but
not 9 months. TSH levels were more elevated in the group of patients taking selenium than in the control group at 3 and 6, but
not 9 months. TRAb levels decreased at 6 but not 9 months. At 6 months, patients on selenium supplementation were more likely
than controls to show improved thyroid function; however, the effect disappeared at 9 months. Whether these effects correlate with
clinically relevant measures remains to be demonstrated.
1. Introduction antioxidant systems. This system is accompanied by intra-

cellular antioxidant enzymes, such as superoxide dismutase
Graves’ disease (GD) is an autoimmune thyroid disease which (SOD), glutathione reductase and glutathione peroxidase
entails the stimulation of the receptor of the thyroid- (GPx) [5, 6].
stimulating hormone (TSH) by the thyrotrophic hormone The trace element selenium—as an antioxidant—is essen-
receptor antibody (TRAb), leading to an increase in thyroid tial for healthy thyroid hormone metabolism and function [7,
hormone synthesis and release [1]. GD is the main cause of 8]. Selenium—in the form of selenocysteine—is incorporated
hyperthyroidism in adults and is characterized by subnormal in selenoproteins, such as glutathione peroxidase, which
serum TSH levels and increased serum levels of free thyroxine catalyzes the degradation of hydrogen peroxide and lipid
(FT4) and/or triiodothyronine (T3) [2]. In GD, the basal hydroperoxide, the production of which is increased in cases
metabolic status of patients is accelerated, resulting in a of GD [9, 10]. Selenoproteins have an irreplaceable role in
marked increase in the proportion of free radicals and reac- thyroid autoimmune processes, and selenium deficiency has a
tive oxygen species (ROS) [3, 4]. The available literature pivotal influence on the initiation and progression of autoim-
currently focuses on the role of oxidative stress in the mune thyroid disease [11]. According to a Danish study, the
pathogenesis of GD and the protective effects of potent serum selenium levels of patients with newly diagnosed GD
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2 Evidence-Based Complementary and Alternative Medicine
were generally lower than those of random controls [12]. In between selenium intake alone or in combination with methi-
addition, serum selenium levels >120 𝜇g/l were observed in mazole (MMI) and placebo intake alone or in combination
the remission group of one study, indicating a positive cor- with MMI, or no treatment. Outcomes included data on pre-
relation with the outcomes of GD [13]. In cases of recurrent intervention and postintervention thyroid function (e.g., FT3,
hyperthyroidism caused by GD, selenium supplementation FT4, TSH, and TRAb levels).
can enhance the efficacy of antithyroid drugs and ameliorate Studies were excluded if they were systematic reviews or
thyroid function [14]. Graves’ ophthalmopathy (GO) is also meta-analyses, if they were nonrandomized studies, posters,
associated with low selenium status [15], and relative sele- or just abstracts, if they involved participants with a thyroid
nium deficiency should be considered an independent risk disease other than GD, or if they reported only categorical
factor for GO patients [16]. In a randomized, double-blind, data as outcomes.
placebo-controlled trial population in Italy, selenium sup-
plementation was found to significantly improve the quality 2.3. Data Extraction and Quality Assessment. Full-text arti-
of life and ocular involvement and delay the progression of cles were evaluated if the inclusion and exclusion criteria
the disease [17]. Several trials have investigated the effect of could not be found. For studies that fulfilled the inclusion
selenium intake on thyroid autoantibodies in autoimmune criteria, two reviewers (Wang QH and Zhao J) independently
thyroiditis patients. In a 2016 meta-analysis, based on 16 extracted data using standard data extraction templates.
controlled trials, significant lower levels of serum thyroid Detailed information was extracted: baseline characteristics
peroxidase antibody (TPOAb) and thyroglobulin antibody (the first author, country, and publication date), included
(TgAb) were observed in those with selenium intake [18]. population and intervention characteristics (sample size,
Similar conclusions were reached in another meta-analysis baseline mean age, sex, and duration of intervention), and
including nine studies, in 2014 [19]. Therefore, an increasing outcomes (including at least one of the following levels: FT3,
amount of attention has been paid to the role of selenium in FT4, TSH, and TRAb). Any disagreements were resolved by
the treatment of GD. discussion.
In recent times, there have been conflicting reports as The methodological quality of the included RCTs was
to whether selenium supplementation can benefit GD treat- evaluated by the Jadad scale in the following domains: ran-
ment. Some researchers have reported the obvious improve- domization, blinding, and the description of withdrawals and
ment of selenium supplementation as an adjuvant therapy in dropouts [30]. A cut-off score of 3 was used to indicate high-
patients with GD [14], while others observed only an insigni- quality studies, based on previously conducted studies. Data
ficant modification in the control of hyperthyroidism after extraction and quality assessment were performed indepen-
selenium intake [20]. To our knowledge, till date, no relevant dently by two investigators, and discrepancies in opinions
systemic review or meta-analysis on the efficacy of selenium were resolved through discussions and a consensus.
intake in thyroid function in GD patients has been conducted.
Therefore, in this study, we carried out a systemic review and 2.4. Data Synthesis and Analysis. The effect of treatment in
meta-analysis of randomized controlled trials (RCTs), assess- each study was estimated by evaluating changes from the
ing the effect of selenium supplementation on individuals baseline for continuous outcomes. In case that mean ± stan-
with GD. dard deviations were not provided explicitly, they would be
calculated by other available data [31]. For some studies pro-
2. Methods viding more than one time-point outcome during the inter-
vention, data of the last time-point were used for the analyses.
2.1. Data Search and Sources. The following electronic data- Heterogeneity between the results of different studies was
bases were searched to identify relevant studies published evaluated by the Cochran Q and the I2 statistic, with a P value
from inception to up to October 31, 2017: PubMed, the <0.1 and I2 >50% indicating statistically significant [32]. A
Cochrane Central Register of Controlled Trials, Web of Sci- random-effects model would be chosen to pool results if the
ence, China National Knowledge Infrastructure, as well as the heterogeneity was significant. Otherwise, a fixed effect model
databases of the Chinese Ministry of Science & Technology would be used. In case of heterogeneity, subgroup analyses
(Wangfang), China Biological Medicine, and Chinese Science and sensitivity analyses were conducted. Furthermore, Begg’s
and Technology Periodicals (VIP). The initial computer- and Egger’s tests were used to assess the extent of publication
based search terms were conducted using medical subject bias. Meta-analysis was conducted using Stata12.0, and the
headings and common text words related to GD, thyrotoxico- two-sided P value significance level was set at P <0.05.
sis and selenium. The search had no language restriction. In
addition, the reference lists of retrieved included trials were
3. Results
searched manually to identify eligible studies. Two review
authors (Zheng HJ and Wang LS) independently scanned 3.1. Characteristics and Quality of the Studies. As shown in
the titles and abstracts of retrieved records for eligibility. Figure 1, the initial search strategy identified 86 potentially
Where discrepancies in opinion existed, they were resolved eligible articles, and seven additional articles were added to
by consensus or after consulting a third party (Wei JP). the search result by a manual search. Of these 93 records, 37
duplicates of the same articles were excluded and 32 irrelevant
2.2. Selection of Studies. The inclusion criteria for this review studies or none RCTs were discarded. After a detailed assess-
were RCTs in adults with GD, which compared the efficacy ment of the full text, an additional 14 articles were removed.
Evidence-Based Complementary and Alternative Medicine 3
Articles identiﬁed through Articles identiﬁed through hand

database search(n=86) search (n=7)
Duplicated articles (n=37)
Articles remained aer excluding the duplicates

(n=56)
Articles excluded by title/abstract

(n=32)
Irrelevant studies;
None RCTs.
Full-text articles assessed for eligibility (n=24)
Articles excluded aer full-text

review (n=14)
None RCTs (n=5)
Study protocol(n = 3)
Not full article (n = 2)
No relevant outcome (n = 4)
Articles included in the meta-analysis (n=10)
Figure 1: Flow diagram of search and selection processes.
A total of 10 RCTs met all the eligibility inclusion criteria and 3.3. Effects of Selenium Supplementation on FT4 Levels. The
were included in the final meta-analysis. overall pooled results of the studies reporting FT4 levels (nine
Table 1 summarizes the detailed characteristics and qual- trials, 736 participants) indicated a significant decrease in the
ity of the included RCTs. Most of the included studies were FT4 levels among participants in the selenium treated group
published after 2015 (70.0%, 7/10) and were conducted in when compared to the control participants, at 3 months (two
China (70.0%, 7/10). The sample sizes of the individual trials studies: SMD −0.86 mmHg, 95% CI: −1.20 to -0.53 mmHg;
ranged from 30 to 241 participants, with a total of 796 P for heterogeneity = 0.756, I2 = 0%) and 6 months (four
participants. The participants’ ages ranged from 28 to 45 years studies: SMD −1.01%, 95% CI: −1.43% to −0.60%; I2 =57.4%,
at the time of intervention, and the percentage of women P=0.071), but not at 9 months (three studies: SMD 0.03%, 95%
ranged from 27% to 90%. All the included trials had two parts: CI: −0.29% to 0.35%; I2 =38.9%, P=0.195) (Figure 3). When
administration of the standard antithyroid drug MMI (doses each trial was individually removed, the overall SMD for the
ranged from 5 mg/d to 30 mg/d) plus selenium (doses ranged FT4 levels remained largely unchanged.
from 100 ug/d to 300 ug/d) and MMI with or without placebo.
The duration of follow-up ranged from 3 to 9 months. The 3.4. Effects of Selenium Supplementation on TSH Levels. A
quality scores of the included RCTs ranged from 2 to 5 total of seven trials, involving 651 participants, showed that
points. All the studies adopted the random assignment of pa- selenium supplementation was associated with a significant
tients, and six RCTs did not describe the method of ran- increase in the TSH levels, at 6 months (three studies: SMD
domization used [21, 22, 24, 25, 28, 29]. Only two of the 3.12%, 95% CI: 1.73% to 4.5%; I2=90.3%, P=0) when compared
RCTs were double-blinded [23, 26]. All the RCTs had defined to the control group, but not at 3 months (one study: SMD
inclusion and exclusion criteria for the patients and provided 0.21%, 95% CI: -0.15% to 0.57%) or 9 months (three studies:
a statement of the number withdrawals in each group, along SMD -2.27%, 95% CI: -4.74% to 0.21%; I2 =97.8%, P=0)
with the reasons for the same. (Figure 4). The overall SMD for the TSH levels remained
largely unchanged when each trial was individually removed.
3.2. Effects of Selenium Supplementation on FT3 Levels. The
results of nine trials, involving 736 participants, were includ-
ed in the meta-analysis. Compared with the control group, 3.5. Effects of Selenium Supplementation on TRAb Levels. Six
the pooled estimate showed a significant decrease in the FT3 studies with 736 participants reported the effects of selenium
levels in the selenium treated group, at 3 months (two studies: supplementation on TRAb levels. Compared with those in
SMD −0.34%, 95% CI: −0.66% to −0.02%; I2 =0%, P=0.719) the control group, patients who underwent selenium supple-
and 6 months (four studies: SMD −0.67%, 95% CI: −0.97% mentation displayed a significant decrease in TRAb levels at
to −0.36%; I2 =27.1%, P=0.249), but not at 9 months (three 6 months (three studies: SMD -2.31%, 95% CI: −4.63% to
studies: SMD 0.01%, 95% CI: −0.44% to −0.46%; I2 =65.8%, 0.00%; I2=97.1%, P=0), but not at 9 months (three studies:
P=0.054) (Figure 2). Sensitivity analyses showed that the SMD -1.34%, 95% CI: -2.38% to -0.29%; I2=95.8%, P=0)
pooled results were largely unchanged when each trial was (Figure 5). The pooled results remained largely unchanged
individually removed. when the trials were individually removed.
4
Table 1: Characteristics and quality of the included randomized controlled trials.

Study N (Case: Intervention Age % Duration Main Jadad
Country
(reference Outcome
Control) Case Control (years) female in months scores
number) measures
MMI 20 mg/d +
Tang et al. [21],
China 241(121/120) Selenious yeast MMI 20 mg/d 28 75 9 FT3, FT4, TSH, TRAb 2
2017
tablet 200 ug/d
MMI 15-30 mg/d +
Fu et al. [22], MMI
China 60 (30/30) Selenious yeast 38 58 6 TRAb 2
2017 15-30 mg/d
tablet 300 ug/d
MMI 10 mg/d +
Kahaly et al. MMI 10 mg/d
Germany 61 (29/32) Sodium selenite 45 27 9 FT3, FT4, TSH, TRAb 5
[23], 2017 +placebo
300 ug/d
MMI 5-30 mg/d +
Leo et al. [20], L- MMI
Italy 30 (15/15) 40 90 3 FT3, FT4, 3
2016 selenomethionine 5-30 mg/d
166 ug/d
MMI 18 mg/d +
Wang et al. [24],
China 41 (21/20) Sodium selenite MMI 18 mg/d 38 82 6 FT3, FT4, TSH, TRAb 2
2016
200 ug/d
MMI 15-30 mg/d +
Gong et al. [25], MMI
China 80 (40/40) Selenious yeast 36 56 6 FT3, FT4, TSH, TRAb 2
2015 15-30 mg/d
tablet 200 ug/d
MMI 30 mg/d +
Calissendorff et MMI 30 mg/d
Sweden 38 (19/19) Selenious yeast 39 82 9 FT3, FT4, TSH, TRAb 5
al. [26], 2015 +placebo
tablet 200 ug/d
Table 1: Continued.
Study N (Case: Intervention Age % Duration Main Jadad
Country
(reference Outcome
Control) Case Control (years) female in months scores
number) measures
MMI 5-30 mg/d +
Lai et al. [27], MMI

China 120 (60/60) Selenious yeast 40 77 3 FT3, FT4, TSH, TRAb 3
2014 5-30 mg/d
tablet 100 ug/d
MMI 20 mg/d +
Du et al. [28],
China 70 (38/32) Selenious yeast MMI 20 mg/d 36 59 6 FT3, FT4, TSH 2
2014
tablet 150 ug/d
MMI 20 mg/d +
Wang et al. [29],
China 55 (30/25) Selenious yeast MMI 20 mg/d 37 27 6 FT3, FT4 2
2013
tablet 200 ug/d
MMI: methylimidazole; FT4: free thyroxine; FT3: free triiodothyronine; TRAb: thyrotrophic hormone receptor antibody; TSH: thyroid-stimulating hormone.
5
Figure 3: Forest plot of selenium supplementation effects on FT4 levels. CI: confidence interval; SMD: standard mean difference.
Figure 2: Forest plot of selenium supplementation effects on FT3 levels. CI: confidence interval; SMD: standard mean difference.
6
7
Figure 5: Forest plot of selenium supplementation effects on TRAb levels. CI: confidence interval; SMD: standard mean difference.
Figure 4: Forest plot of selenium supplementation effects on TSH levels. CI: confidence interval; SMD: standard mean difference.
3.6. Publication Bias. For any of the outcomes, there was no by GD and a risk predictor of relapse at the time of antithy-
evidence of significant publication bias from either Egger’s roid drug withdrawal [36]. Epidemiological data suggest an
test or Begg’s test (all P >0.05). increased prevalence of autoimmune thyroid diseases under
conditions of selenium deficiency [12, 37]. Our finding is
4. Discussion consistent with those of other meta-analyses supporting
selenium supplementation for autoimmune thyroiditis. A
GD is associated with an increase in the ROS, dimin- systematic review and meta-analysis by Toulis KA et al. [38]
ished endogenous antioxidative capacity, and lowered sele- reported that selenium supplementation was associated with
nium status. Since selenoenzymes are important for antiox- a significant decrease in the levels of TPOAb in the treatment
idant defense, adjuvant supplementation with selenium may of Hashimoto’s thyroiditis. The immunomodulatory effects of
improve the outcome of patients with GD [5, 6]. However, to selenium supplementation may be the mechanisms respon-
date, the clinical trials focusing on selenium supplementation sible for the treatment of autoimmune thyroid disease [39].
as adjuvant therapy have shown equivocal results. This is the In a mouse model of autoimmune thyroiditis, selenium was
first systematic review and meta-analysis assessing the effec- found to effectively reduce lymphocytic infiltration of the
tiveness of selenium supplementation when used in addition thyroid and upregulate the regulatory T cells with increased
to standard treatment to normalize the thyroid function in GPx and thioredoxin reductase expressions [40]. Another
patients with hyperthyroidism caused by GD. This meta- study showed that selenoprotein K deficiency may decrease
analysis included data from all the eligible RCTs that had Ca(2+) flux during immune cell activation, in mice, causing
a selenium supplementation duration of 3 or 6 months and an impaired immune response [41]. The role of selenium has
which produced clinically important and statistically signifi- also been studied in the case of GO. A European multicenter
cant effects on the FT4, FT3, TSH, and TRAb levels in patients RCT designed by the European Group of Graves’ Orbitopathy
with GD; nevertheless, selenium supplementation with a group evaluated the effect of selenium compared with placebo
duration of 9 months was no more effective in controlling on patients with GO and found a significant improvement
GD than in the control. This may be attributed to the fact in ophthalmological symptoms and quality of life after a 6-
that the health effects of selenium have an inextricable U- month intervention period [17]. With regards to the bene-
shaped link with status; only two of the ten trials in this meta- ficial effects of the antioxidant agent—selenium—in GO, a
analysis measure sequentially selenium serum levels in GD possible cellular mechanism through which selenium acts
patients under adjuvant supplemental selenium treatment, was recently proposed, which states that it may inhibit cell
so we cannot find out whether selenium supplementation proliferation and the secretion of proinflammatory cytokines
was more effective for those who had lower selenium serum such as tumor necrosis factor alpha and interferon gamma
levels by subgroup analysis. However, we may find some [42].
supporting evidence from two trials among patients with Although some aspects of this meta-analysis could be im-
GD reported selenium status before and following supple- proved, it also has several strengths. It is, to date, the first com-
mentation [20, 23], which showed that the serum levels prehensive analysis to quantitatively assess the impact of sele-
of selenium at baseline in the range of 109-115ug/l and no nium supplementation on hyperthyroidism caused by GD. In
selenium deficiency in the vast majority of their patients addition, relevant trials were identified using a scientific and
during and after treatment. As to both of the two studies that comprehensive search strategy. Finally, this meta-analysis
failed to show an adjuvant role of selenium in the short-term helps to increase the available evidence on selenium for use
control of hyperthyroidism, this might be due to selenium in the endocrine field. Data from a 2016 Italian questionnaire
supplementation not offering any advantage if selenium study [43] showed that 85.2% of endocrinologists considered
intake is adequate, and selenium is likely useful if the patient using selenium in daily clinical practice for thyroid disease
is selenium-deficient [33]. and about 21.5% of respondents would recommend selenium
The positive findings with regards to the FT3, FT4, and for GD without GO and 25% for GD with mild GO. Therefore,
TSH levels at 3 and 6 months after selenium supplementation selenium supplementation is prescribed, despite not being
in our meta-analysis are in accordance with the findings of recommended in international guidelines for the manage-
trials examining a wide range of conditions. In one trial ment of hyperthyroidism.
which focused on individuals in an area with severe iodine Our study has some limitations. First, the available evi-
and selenium deficiency, serum T4 and FT3 levels decreased dence on the routine use of selenium supplementation in the
significantly after 2 months of selenium supplementation, but treatment of GD patients is insufficient and the correspond-
no increase was observed in the serum TSH levels [34]. It has ing RCTs were limited by their small sample sizes. Second,
been shown in selenium-deficient rats that protein iodination substantial heterogeneity was detected in the pooled results
in the thyroid gland was enhanced, and type I deiodinase of TSH and TRAb among the included trials. As some of
activity was inhibited in the absence of selenium, resulting the studies did not provide enough clinical information, we
in increased thyroid hormone synthesis and elevated serum could not perform thorough analyses to explore the source
T4 and T3 values [35]. Our meta-analysis indicated that of heterogeneity. Most of the studies included did not discuss
selenium supplementation effectively reduces TRAb levels at the disease-process and did not report selenium status of the
6 months. According to the evidence available, a reduction study populations, using not exactly the same selenocom-
in the circulating TRAb titers is clinically relevant, as TRAb pounds and dosages. With the aggravation of the disease,
is considered a surrogate marker of hyperthyroidism caused the absorption rate and the effect of selenium would reduce.
Evidence-Based Complementary and Alternative Medicine 9
Meanwhile, the absorption in different selenocompounds Acknowledgments

varied and the number of studies is not yet sufficiently high to
be able to compare the effects of different selenocompounds This work was supported by the National Natural Science
and dosages from these divergent results. So it may lead to Foundation of China (Grant no. 81573961).
high heterogeneity. Nonetheless, a random-effects model
was adopted to pool estimations when appropriate, so as References
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Hindawi

Huijuan Zheng, Junping Wei , Liansheng Wang, Qiuhong Wang,

Correspondence should be addressed to Junping Wei; [email protected]

Received 7 February 2018; Accepted 7 August 2018; Published 26 September 2018

Academic Editor: Deborah A. Kennedy

1. Introduction antioxidant systems. This system is accompanied by intra-

Articles identiﬁed through Articles identiﬁed through hand

Duplicated articles (n=37)

Articles remained aer excluding the duplicates

Articles excluded by title/abstract

Full-text articles assessed for eligibility (n=24)

Articles excluded aer full-text

Articles included in the meta-analysis (n=10)

Figure 1: Flow diagram of search and selection processes.

Table 1: Characteristics and quality of the included randomized controlled trials.

Lai et al. [27], MMI

Meanwhile, the absorption in different selenocompounds Acknowledgments

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