Lack of Vitamin D and Autoimmune Diseases of the Thyroid-Evidences Based on Meta-Analysis Lack of Vitamin D and Autoimmune Diseases of the Thyroid-Evidences Based on Meta-

Resumo: Verificar se há diferença entre médias séricas de vitamina D em portadores de doença de Graves e tireoidite de Hashimoto, quando comparados com um grupo de indivíduos sadios. Trata-se de uma revisão sistemática e metanálise de acordo com o protocolo PRISMA. Foi realizado o teste de diferença de médias com efeito aleatório e qui-quadrado de heterogeneidade, considerando um alfa <0,05 para aceitação das hipóteses. Os testes foram realizados com auxílio do software STATA® 16.0. Houve diferenças entre as médias séricas de vitamina D: grupo com doença de Graves comparado a indivíduos saudáveis (Média =10,06; IC95%=0,99-19,14); Grupo com doença de Hashimoto comparado a indivíduos saudáveis (Média = 12,49; IC95%= 5,19-19,79); grupo de crianças com Hashimoto em comparação com crianças saudáveis, (Média = 19,46 (IC95%=10,25-28,68). Os níveis médios de vitamina D sérica foram significativamente maiores em indivíduos sadios, demonstrando que a depleção desse nutriente pode estar relacionada ao processo fisiopatológico dessas doenças, levando-se em consideração a função imunomoduladora que essa vitamina exerce. Palavras-chave: Doença de Hashimoto, Doença de Graves, Deficiência de Vitamina D, Tireoidite. Abstract: To verify whether there is a difference between serum vitamin D averages in patients with Graves' disease and Hashimoto's thyroiditis, when compared with a group of healthy individuals. This is a systematic review and meta-analysis according to the PRISMA protocol. The test of difference of means with random effect and chisquare of heterogeneity was performed, considering an alpha <0.05 for acceptance of the hypotheses. The tests were performed using the STATA® 16.0 software. There were differences between serum vitamin D averages: group with Graves' disease compared to healthy individuals (Mean = 10.06; 95% CI =0.99-19.14); Group with Hashimoto's disease compared to healthy individuals (Mean = 12.49; 95% CI = 5,9 19,79); group of children with Hashimoto compared to healthy children, (Mean = 19.46; 95% CI = 10.25-28.68). The mean serum vitamin D levels were significantly higher in healthy individuals, demonstrating that the depletion of this nutrient may be related to the pathophysiological process of these diseases, taking into account the immunomodulatory function that this vitamin has.


INTRODUCTION
Autoimmune diseases are characterized by the absence of immunological tolerance, caused by the combination of environmental and genetic factors, however, the knowledge about the function of each of these susceptibility factors is not yet precise (MERRILL; MINUCCI, 2018;WEETMAN, 2003). They also involve phenotype factors, of which the main diseases they represent are Hashimoto's thyroiditis (HT) and Graves' disease (GD) (RAGUSA et al., 2019;LAZARUS;PARKES, 2002).
Autoimmune thyroid diseases are polygenic diseases, which result in the combination of genetic predisposition (specific thyroid genes and immunomodulators) and environmental stimuli (selenium, iodine, infections, stress, smoking, etc.) (KÖHLING et al., 2017;KLECHA et al. 2008). TH is a common autoimmune chronic disease of the thyroid gland, characterized by inflammation of the gland, development of diffuse goiter with elevated thyroid antibodies, which occurs through the infiltration of immune cells in the thyroid (DJUROVIC et al., 2018).
Vitamin D is a fat-soluble molecule, has hormone-like effects and comes from the skin, in the form of cholecalciferol (vitamin D3) or acquired through diet in the form of ergocalciferol (vitamin D2) (TRIPKOVIC et al., 2012). Among its functions are the regulation of the metabolism of calcium and phosphorus and the maintenance of skeletal health, bones and parathyroid gland (DOBSON et al., 2017;DASTANI;RICHARDS, 2013).
Studies carried out in recent years report the extra skeletal effects of vitamin D, associated with the deficiency of the nutrient in question (KMIEĆ; SWORCZAK, 2015) and genetic variations, relating the impaired metabolism of this vitamin to several autoimmune diseases, including autoimmune disease thyroid (INOUE et al., 2014). With this, the present research is justified by the need to determine if there is a reduction of vitamin D in Individuals with GD and HT, due to the heterogeneity between previous research results (XU et al., 2018;KE et al., 2017;MA et al., 2015). Thus, the objective was to assess the difference between the mean serum vitamin D levels, in groups of individuals diagnosed with HT and GD, comparing them with individuals without the diseases.

MATERIAL AND METHODS
This study consisted of a systematic review and meta-analysis, adopting the descriptive aspect. Meta-analysis is a method of statistical study, applied to systematic review to combine data from studies, with the objective of obtaining results in the same measure and with greater reliability (XU et al., 2015).
After consulting the Health Sciences Descriptors (DeCS), the following descriptors were In LILACS, 20 references were found, which were printed, all with availability of the title, year and place of publication, others also provided the summary. In SciELO 16 references were found and in PubMed 162 references. The repetitions and publications that were not related to the topic were excluded, resulting in 46 references, of which 19 contributed to the systematic review and meta-analysis. For the descriptive aspect, bibliographic reviews were selected that described Graves' diseases and Hashimoto's thyroiditis.
Inclusion criteria were: case-control studies, articles describing thyroid diseases and the relationship of vitamin D with individuals with Hashimoto's thyroiditis and Graves' disease, articles that compared children with the same diseases were included. Articles published in English and Portuguese were considered. The exclusion criteria were: books, course completion papers, monographs, dissertations and articles not related to the theme ( Figure 1). The evaluation, extraction and tabulation of data were based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyzes) instructions and recommendations (MOHER et al., 2009). Thus, the selected articles, for data extraction, were submitted to the evaluation of two reviewers and there were no disagreements regarding the interpretations.  Bozkurt et al.,   The pertinent results to the serum comparison of vitamin D, between individuals with Graves' disease and healthy individuals, showed a significant difference from the mean serum vitamin D (MD = 10.06; 95% CI = 0.99-19.14), indicating a mean serum nutrient equal to 10.06 nmol / L more in the control group when compared to patients with Graves' disease. The confidence interval (CI) of the diamond, which represents the difference between means (MD), does not touch the null line, confirming the significance of the result and rejecting the null hypothesis.
The results of the study by Ke et al., (2017) and Planck et al., (2017), obtained greater weight, however, of the two mentioned, only that of Planck et al., (2017), showed a significant difference.
The result of the chi-square of heterogeneity with p = 0.00 and the I² = 97%, justify the application of the randomized effect ( Figure 3).
Of the data collected, 90% obtained a statistically significant difference, between serum vitamin D averages, when comparing the group of individuals with Hashimoto's thyroiditis with the group of healthy individuals. The 10% insignificance refers to the results of Kim, (2016), this can be seen in the graph, where the confidence interval of the study crosses the null line. The test showed that serum vitamin D is on average 12.49 nmol / L more in healthy individuals, with (95% CI = 5.19 to 19.79). The heterogeneity test was significant with p = 0.00, where in combination with I² = 97%, they demonstrate assertiveness in the adopted random effect ( Figure   3).
In 100% of the studies plotted, referring to analyzes with data from children, with proof of Hashimoto's thyroiditis diagnosis, significance was evidenced in relation to the difference between serum vitamin D means, MD = 19.46 (95% CI = 10.25 -28.68), the result in question points out a difference between the averages, where the group of healthy children emerged in serum mean, with 19.46 nmol / L more of the nutrient. The heterogeneity test was significant with p = 0.01 and the I² = 80%, the results together demonstrate assertiveness in choosing the randomized effect (Figure 3). The relationship between autoimmune diseases and low serum vitamin D levels has been commonly accepted and studied by researchers. Ma et al., (2015), observed that the deficiency of 25 (OH) D or vitamin D, was significantly prevalent in patients who had some autoimmune thyroid disease, when compared to healthy individuals. Bellastella et al., (2015), concluded that the serum vitamin D level was reduced in patients with autoimmune diseases.
In the present study, serum vitamin D levels were lower in individuals diagnosed with The analyzed case-control studies showed a high prevalence of vitamin D deficiency in children with Hashimoto's thyroiditis, with an average age of 12.15 years. These children, mostly are female, also verified the incidence by other authors. It is suggested that estrogen receptors act to reduce immune surveillance, which may justify the higher occurrence in women (LEE et al., 2015).
Vitamin D supplementation can reduce morbidity or alleviate the effects of manifestations in animals with autoimmunity (ETTEN- VAN et al., 2003). Results are also described, where vitamin D supplementation can benefit humans with autoimmune diseases (PIERROT-DESEILLIGNY et al., 2012) and that childhood supplementation potentiates these benefits, reducing the risk of developing thyroid disease (ZIPITIS; AKOBENG, 2008), demonstrating the need of the nutritionist associated with the endocrinologist, in the treatment and supplementation of vitamin D.

CONCLUSION
Based on the results obtained, patients with autoimmune thyroid diseases have serum vitamin D deficiency when compared to healthy individuals. The present research showed vitamin D deficiency in patients with Graves' disease and Hashimoto's thyroiditis, regardless of age. The lack of this nutrient may be related to the pathogenesis of these diseases, as an immunomodulator. However, more research is needed to confirm this hypothesis.
ACKNOWLEDGMENT Sra. Geovana Batista Rubin -First author, contributed to the bibliographic survey and described on the subject, also contributed with the methodology of the article and discussion.
Dr. Antonio Márcio Teodoro Cordeiro Silva and Sr. Lucas Cândido Gonçalves -Both statisticians, two statisticians needed to follow the PRISMA protocol, performed and described the results. They also described the methodology of applied statistics. Lucas is a master's student at the Federal University of Goiás and Antonio Márcio is a professor at PUC Goiás, both with experience in meta-analysis.
Dr. Xisto Sena Passos and Me. Paulo Alex Neves da Silva -Applied methodology and translation into English. They also held much of the discussion and conclusion. Xisto is a professor of methodology at the Universidade Paulista de Goiânia and Paulo has training and knowledge in immunology, thus, they were of great importance and contributions.
Ma. Natália Menezes Silva -Work supervisor, followed the whole process, guiding and making the necessary corrections in the descriptive aspect. The advisor is a nutritionist and therefore played a key role. He was also responsible for placing the manuscript in the RIC rules.
Lack of Vitamin D and Autoimmune Diseases of the Thyroid -Evidences Based on Meta-Analysis