Nutrients 2015, 7, 3813-3827; doi:10.

3390/nu7053813
OPEN ACCESS

nutrients
ISSN 2072-6643
www.mdpi.com/journal/nutrients
Review

Vitamin D and Graves’ Disease: A Meta-Analysis Update

Mei-Yan Xu 1,*, Bing Cao 2, Jian Yin 1, Dong-Fang Wang 2, Kai-Li Chen 3 and Qing-Bin Lu 2,*

1
Department of Nutrition, Aerospace Center Hospital, Beijing 100049, China;
E-Mail: 13011068860@163.com
2
School of Public Health, Peking University, Beijing 100191, China;
E-Mails: caobing@bjmu.edu.cn (B.C.); wdf@bjmu.edu.cn (D.-F.W.)
3
Department of Respiratory, Aerospace Center Hospital, Beijing 100049, China;
E-Mail: chen_kaili@sina.cn

* Authors to whom correspondence should be addressed;

E-Mails: xumeiyan1985622@126.com (M.-Y.X.); qingbinlu@bjmu.edu.cn (Q.-B.L.);
Tel./Fax: +86-10-82805453 (Q.-B.L.).

Received: 18 April 2015 / Accepted: 12 May 2015 / Published: 21 May 2015

Abstract: The association between vitamin D levels and Graves’ disease is not well studied.
This update review aims to further analyze the relationship in order to provide an actual
view of estimating the risk. We searched for the publications on vitamin D and Graves’
disease in English or Chinese on PubMed, EMBASE, Chinese National Knowledge
Infrastructure, China Biology Medical and Wanfang databases. The standardized mean
difference (SMD) and 95% confidence interval (CI) were calculated for the vitamin D
levels. Pooled odds ratio (OR) and 95% CI were calculated for vitamin D deficiency. We
also performed sensitivity analysis and meta-regression. Combining effect sizes from 26
studies for Graves’ disease as an outcome found a pooled effect of SMD = −0.77 (95% CI:
−1.12, −0.42; p < 0.001) favoring the low vitamin D level by the random effect analysis. The
meta-regression found assay method had the definite influence on heterogeneity (p = 0.048).
The patients with Graves’ disease were more likely to be deficient in vitamin D compared
to the controls (OR = 2.24, 95% CI: 1.31, 3.81) with a high heterogeneity (I2 = 84.1%,
p < 0.001). We further confirmed that low vitamin D status may increase the risk of
Graves’ disease.

Keywords: Vitamin D; Graves’ disease; meta-analysis; sensitivity analysis;

meta-regression
Nutrients 2015, 7 3814

1. Introduction

Graves’ disease is an autoimmune thyroid disease characterized in its typical presentation by

the unique association of thyrotoxicosis, goiter and ophthalmopathy [1]. As one of the most frequent
diseases among autoimmune disorders, an annual incidence of Graves’ disease was approximately
14 per 100,000 [2].
Graves’ disease is a multifactorial disease caused by a complex interaction between genetic and
environmental factors that lead to the loss of immune tolerance to thyroid antigens, and therefore to the
initiation of an immune reaction against the thyroid. For example, vitamin D receptor (VDR) gene
polymorphisms were found to be associated with the risk for Graves’ disease [3].
Several studies also explored the association between vitamin D levels and Graves’ disease [4–17].
The results of some studies demonstrated that the patients with Graves’ disease had lower vitamin D
levels or higher prevalence of vitamin D deficiency, suggesting that low levels of serum vitamin D was
associated with Graves’ disease [5–8,10–15], while other studies did not find that vitamin D deficiency
increased the risk of Graves’ disease [4,9]. The association between vitamin D levels and Graves’
disease is still under debate. Wang et al. [18] conducted the meta-analysis of the association between
vitamin D and autoimmune thyroid disease, including the Graves’ disease with 13 studies [13,19–31].
However, the study [18] neither included enough references nor analyzed the sources of high
heterogeneity. So the relationship needs to be further evaluated.
This update review aims to analyze the association between vitamin D levels and Graves’ disease in
order to provide an actual view of estimating the risk.

2. Methods

2.1. Search Strategy

We searched for publications on vitamin D and Graves’ disease in English or Chinese. PubMed,
EMBASE, Chinese National Knowledge Infrastructure (CNKI), China Biology Medical (CBM) and
Wanfang databases were searched (up to April 15 2015) by two investigators, independently. The
MeSH search terms were adapted: “Vitamin D”, “25 Hydroxyvitamin D”, “25 Hydroxyvitamin D3” in
combination with “autoimmune thyroid disease” or “Graves’ disease”.

2.2. Inclusion/Exclusion Criteria

All the studies identified were reviewed independently by two investigators and the studies were
included if they fulfilled the following criteria: (1) a case-control study or cohort study was reported;
(2) the cases were diagnosed as Graves’ disease and the control group was composed of healthy
individuals; (3) quantitative or qualitative vitamin D levels were described in the references. The
references were excluded from the meta-analysis as follows: (1) the study was not related to Graves’
diseases; (2) the reference did not describe the vitamin D level in the two groups; (3) the reference
consisted of duplicate data or publications from the included studies. The Newcastle-Ottawa Quality
Assessment Scale was used to assess the quality of the studies included in the meta-analysis and
performed by two reviewers with a third reviewer consulted in case of discrepancy.
Nutrients 2015, 7 3815

2.3. Data Extraction

The information were extracted from the included studies using a standard form by the two
reviewers. Any disagreement was resolved by discussion between the two reviewers. If consensus
could not be reached, a third reviewer was consulted. The standard form included the variables as
follows: the author, publication years, the study period, the study country, the mean age of case and
control groups, the sample sizes of two groups, assay method of vitamin D, the detection index, the
vitamin D concentrations (ng/mL) in the two groups (nmol/L to ng/mL by dividing by 2.5) or the number
of vitamin D deficiency in the two groups and the cutoff for defining vitamin D deficiency.

2.4. Outcomes Measures

The primary outcome was the vitamin D level; the secondary outcome was the vitamin D
deficiency. Comparisons were performed between the Graves’ cases and control population.

2.5. Statistical Analysis

The median and range were used to estimate the mean and variance with the method by
Hozo et al. [32]. Heterogeneity among the studies was assessed using the Cochran Q and the I2
statistic. For the Q statistic, p < 0.10 indicates statistically significant heterogeneity. For the I2 statistic,
I2 > 50% indicates a large heterogeneity. Fixed-effects model with Mantel-Haenszel method was used
if Q statistic (p < 0.10) or I2 < 0.05; otherwise, random effects model was used. The standardized mean
difference (SMD) and 95% confidence interval (CI) were calculated for the primary outcome. Pooled
odds ratio (OR) and 95% CI were calculated for the secondary outcome. In case of heterogeneity,
subgroup analysis was conducted. The Egger weighted regression test was used to statistically assess
publication bias (p < 0.05 was considered as indicative of statistically significant publication bias). All
statistical analyses were performed using Stata 12.0 (Stata Corp LP, College Station, TX, USA).

3. Results

In our study, we initially searched 501 related references, among which 171 were duplicates. When
removing the duplicates and other unrelated references (insufficient data about the vitamin D and
disease definition unrelated to the Graves’ disease in the references), 27 references met our inclusion
criteria and were recruited in the meta-analysis (Figure 1). According to the data type, 26 and 13
references were used as continuous data and categorical data on the meta-analysis of vitamin D and
Graves’ disease, respectively.

3.1. Information of the Included Studies

The information of the included studies were listed in Table 1. Most studies were published after
2012 (63.0%, 17/27) and from China (66.7%, 18/27). There were 3716 study subjects, including 1770
(47.6%) cases with Graves’ disease and 1946 (52.4%) controls. All studies received a score of more
than or equal to six, indicating good quality.
Nutrients 2015, 7 3816

Figure 1. The flow diagram of the study selection.

3.2. Continuous Data of Vitamin D Level and Graves’ Disease

The analysis included 26 studies involving 1748 cases and 1848 controls. Combining effect sizes
from 26 studies for Graves’ disease as an outcome found a pooled effect of SMD = −0.77 (95% CI:
−1.12, −0.42; p < 0.001) favoring the low vitamin D level of patients with Graves’ disease by the
random effect analysis (Figure 2), which was statistically significant compared to the control group.
However, a high degree of heterogeneity was found (I2 = 95.5%, p < 0.001).

3.3. Subgroup Analysis

We performed subgroup analysis to analyze the sources of heterogeneity (Figure 3). Six factors
were used for subgroup analysis, including mean age of case group (≥40/<40 years) (Figure 3A),
geographic location (Asia/Europe/Africa) (Figure 3B), country type (developed/developing) (Figure
3C), detection index (25(OH)D/25(OH)D3) (Figure 3D), assay method (ELISA/ECLIA/RIA/
CPBA/HPLC) (Figure 3E) and study period (before/after 2010) (Figure 3F). Figure 3 A–F shows that
the heterogeneity remained high (>80%) in all subgroups, although a slight decrease occurred in the
subgroups of assay method (Figure 3E). Interestingly, the SMDs were −0.21 (95% CI: −1.06, 0.64) in
Europe, −0.86 (95% CI: −1.27, −0.46) in Asia, and −1.17 (95% CI: −1.54, −0.81), respectively.
Nutrients 2015, 7 3817

Table1. The characteristics of the included studies in the meta-analysis.

Age of Patients Detection Assay Sample Size Quality
No. First Author Year Country Study Year
(Mean ± SD) Index Method (Case/Control) Score *
1 Li et al. [26] 2015 China/Jiangsu 2010 41 ± 10 25(OH)D CPBA 128/60 9
2 Li et al. [5] 2014 China/Shanxi 2011–2012 34 ± 14 25(OH)D3 ELISA 40/50 8
3 Zhang et al. [13] 2015 China/Hunan 2012–2012 34 ± 12 25(OH)D ELISA 70/70 8
4 Xuan et al. [10] 2014 China/Jiangsu 2013–2014 33 ± 12 25(OH)D3 ELISA 47/45 7
5 Wang Y.C. et al. [8] 2014 China/Anhui 2013 35 ± 8 25(OH)D ECLIA 60/30 7
6 Effraimidis et al. [24] 2012 Netherland 2003 42 ± 13 25(OH)D RIA 78/78 9
7 D’Aurizio et al. [22] 2015 Italy 2014 47 ± 16 25(OH)D3 CLIA 48/126 9
8 Liu et al. [27] 2014 China/Hebei 2013 34 ± 11 25(OH)D3 ECLIA 35/24 9
9 Wang Z.S. et al. [9] 2014 China/Hainan 2012–2013 32 ± 5 25(OH)D ECLIA 62/91 7
10 Zheng et al. [17] 2014 China/Zhejiang 2010–2011 36 ± 8 25(OH)D ELISA 72/39 7
11 Han et al. [16] 2013 China/Guangdong 2012–2013 36 ± 7 25(OH)D HPLC 30/20 7
12 Kang et al. [14] 2013 China/Shandong 2009–2010 43 ± 8 25(OH)D ELISA 280/439 7
13 Liang et al. [31] 2013 China/Hunan 2012–2012 34 ± 12 25(OH)D ELISA 70/70 9
14 Yasuda et al. [12] 2013 Japan 2011 38 ± 7 25(OH)D3 CPBA 54/49 8
15 Miao et al. [7] 2013 China/Liaoning 2011–2012 40 ± 15 25(OH)D ECLIA 70/70 9
16 Liu et al. [28] 2013 China/Jiangsu 2011–2012 37 ± 11 25(OH)D3 ELISA 118/50 9
17 Annerbo et al. [20] 2014 Sweden 2009–2012 41 ± 14 25(OH)D ECLIA 56/14 9
18 Liu et al. [6] 2012 China/Henan 2010–2011 42 ± 9 25(OH)D3 ECLIA 80/165 8
19 Yasuda et al. [11] 2012 Japan 2011 37 ± 13 25(OH)D3 CPBA 26/46 8
20 Jyotsna et al. [4] 2012 India 2006–2008 36 ± 11 25(OH)D RIA 80/80 7
21 Abd El Gawad et al. [19] 2012 Egypt 2011 38 ± 5 25(OH)D3 RIA 90/55 9
22 Kivity et al. [15] 2011 Israel 2006 45 ± 16 25(OH)D ECLIA 22/98 8
23 Dhanwal et al. [23] 2010 India 2010 34 ± 9 25(OH)D RIA 30/31 8
24 Kang et al. [25] 2003 China/Tianjin 2000 45 ± 12 25(OH)D RIA 74/80 7
25 Wu et al. [30] 1995 China/Shanghai 1990 NA 25(OH)D3 ECLIA 6/5 6
26 Shi et al. [29] 1993 China/Shanghai 1991 32 ± 4 25(OH)D3 ECLIA 6/6 7
27 Czernobilsky et al. [21] 1988 Germany 1988 40 ± 10 25(OH)D3 CPBA 38/55 9
ELISA, enzyme-linked immunosorbent assay; HPLC, high performance liquid chromatography; ECLIA, electrochemiluminescence immunoassay; CLIA,
chemiluminescent immunoassay method; CPBA, competitive protein binding assay; RIA, radioimmunoassay; NA, no data in the reference; SD, standard deviation; * The
quality score was evaluated by the Cochrane’s Newcastle-Ottawa Scale evaluation standard for case-control study.
Nutrients 2015, 7 3818

Figure 2. Forest plot of the studies comparing the association between vitamin D levels
and Graves’ disease by meta-analysis with the random effects analysis. SMD, standardized
mean difference.
Nutrients 2015, 7 3819

Figure 3. Cont.
Nutrients 2015, 7 3820

Figure 3. Cont.
Nutrients 2015, 7 3821

Figure 3. Forest plot of the studies comparing the association between vitamin D levels and Graves’ disease in the subgroups by
meta-analysis with the random effects analysis. SMD, standardized mean differences; (A) mean age group; (B) geographic location; (C)
country type; (D) detection index; (E) assay method; (F) study period.
Nutrients 2015, 7 3822

3.4. Meta Regression Analysis

A meta-regression was performed further to explore the possible sources of the heterogeneity. We
put the six factors in the subgroup analysis into the meta-regression. As shown in Table 2, none of the
six factors had any definite influence on heterogeneity except for assay method (p = 0.048).

Table 2. Meta-regression of the six factors.

Factor Coefficient SE 95% CI t p
Age −0.18 0.65 −1.54 1.17 −0.29 0.779
Geographic location 0.11 0.6 −1.15 1.37 0.18 0.858
Country type −1.33 0.73 −2.85 0.19 −1.83 0.083
Detection index −0.60 0.58 −1.80 0.61 −1.04 0.312
Assay method −0.58 0.27 −1.16 −0.01 −2.11 0.048
Study period −0.53 0.64 −1.86 0.81 −0.82 0.420
Constant 4.75 2.33 −0.13 9.63 2.04 0.056
SE, standard error; CI, confidence interval; t, t-value; p, p-value.

3.5. Sensitivity Analysis

The sensitivity analysis was performed and shown in Figure 4, which demonstrated stability and
reliability of the meta-analysis results through consistency of meta-analysis results and between the
different subgroups. Observed from the Figure 4, the omitted studies by Han et al. and Wang et al.
resulted in the greater change of the estimated values compared to other studies, respectively.
However, the significant relationships between the low level of vitamin D and Graves’ disease in all of
the situations were evaluated.

Figure 4. The sensitivity analysis for the association between vitamin D levels and Graves’
disease by the random effects analysis.
Nutrients 2015, 7 3823

3.6. Publication Bias

Figure 5 showed the Egger’s publication bias plot in the meta-analysis. The plots shape, as well as
the p value from Egger’s regression (p = 0.049), did not show strong evidence of publication bias.

Figure 5. The Egger’s publication bias plot for the association between vitamin D levels
and Graves’ disease.

3.7. Categorical Data of Vitamin D Level and Graves’ Disease

In total, 13 studies were included to analyze the association between vitamin D deficiency and
Graves’ disease. Due to the result of sensitivity analysis, the study by Han et al. was excluded. The
patients with Graves’ disease were more likely to be deficient in vitamin D compared to the controls
(OR = 2.24, 95% CI: 1.31, 3.81) with a high heterogeneity (I2 = 84.1%, p < 0.001) in Figure 6. We did
not find the publication bias from the Egger’s regression (p = 0.136) in Figure 7.

4. Discussion

We further analysed the relationship between vitamin D levels and Graves’ disease when including
more references on the basis of the previous meta-analysis by Wang et al. [18]. We also explored the
sources of high heterogeneity, finding that the assay method partly contributed to it.
Most current evidence confirmed a higher prevalence of low vitamin D levels or deficiency in
patients with Graves’ disease [5,6,10–12,14]. In our meta-analysis, which suggested the actual
refinement relationship, the absolute SMD value and the OR value were lower than those in the study
by Wang et al. [18], respectively. We also found that a larger significant difference between the
vitamin D levels and Graves’ disease was found in Africa compared to Asia, while no significant
difference was found in Europe, which may be due to the living standard and economic level.
However, as Rotondi et al. noted, the existence of an association, even when supported by strong
Nutrients 2015, 7 3824

statistical significance, does not automatically imply that a causal relationship exists [33]; it is
therefore necessary to perform more cohort or experimental studies to confirm the causality.

Figure 6. Forest plot of the studies comparing the association between vitamin D
deficiency and Graves’ disease by meta-analysis with the random effects analysis. OR,
odds ratio.

Figure 7. The Egger’s publication bias plot for the association between vitamin D
deficiency and Graves’ disease.
Nutrients 2015, 7 3825

The meta-regression analysis showed the assay method contributed to the heterogeneity. However,
the heterogeneity revealed only a slight drop in the subgroup analysis of the assay method. The high
heterogeneity may have also arisen due to other reasons, which could not be analyzed in the study
because of the partial loss of data or unrecognizable details, such as the characteristics of study
subjects, differences in the operating protocol, and so on.
Han et al. reported that the vitamin D level in the case group was obviously lower than that in the
control group (58.84 ± 8.01 ng/mL) [16], which was much higher than in other studies. This may be
related to the sample from healthy control or the assay method (HPLC) in the study. In the
meta-analysis on the categorical data, we omitted this study to avoid the significant influence on the
result when analyzing the categorical data.
Certain limitations were present in our study. We did not obtain the data of vitamin D deficiency in
the references with the vitamin D levels from the authors. The strength of our study was the fact that
we used a relatively wide range of references to determine the association between vitamin D and
Graves’ disease and reduced the publication bias, as well as improved the accuracy of estimating the risk.
In summary, we further confirmed that low vitamin D status may increase the risk of Graves’
disease. However, whether vitamin D deficiency favor the onset of the disease or supplement of
vitamin D has any beneficial therapeutic effect in Graves’ disease needs to be resolved.

Acknowledgments

The study was supported by the Youth Innovation Funding (2014QN09) from the Aerospace Center
Hospital, Hospital Funding (YN201411) and the Youth Talent Support Program by the School of
Public Health, Peking University. We thank Su-Yun Li from School of Public Health, Shandong
University for the technical guidance.

Author Contributions

Qing-Bin Lu and Mei-Yan Xu conceived and designed the study; Mei-Yan Xu, Jian Yin and
Dong-Fang Wang searched the references and collected data; Qing-Bin Lu and Bing Cao performed
the statistical analysis; Qing-Bin Lu and Mei-Yan Xu drafted the manuscript; Kai-Li Chen contributed
to the discussion. All the authors have read and approved the final manuscript.

Conflicts of Interest

The funding agents had no role in the design and conduct of the study; collection, management,
analysis, interpretation of the data; preparation, review, or approval of the manuscript. The authors have
nothing to disclose.

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