Next Article in Journal
Effect of Cod Residual Protein Supplementation on Markers of Glucose Regulation in Lean Adults: A Randomized Double-Blind Study
Next Article in Special Issue
Immunologic Effects of Vitamin D on Human Health and Disease
Previous Article in Journal
The Effect of a Family-Based Lifestyle Education Program on Dietary Habits, Hepatic Fat and Adiposity Markers in 8–12-Year-Old Children with Overweight/Obesity
Previous Article in Special Issue
Vitamin D Effects on the Immune System from Periconception through Pregnancy
 
 
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Immunomodulatory Effects of Vitamin D in Thyroid Diseases

1
Department of Translational Medicine, University of Piemonte Orientale UPO, 28100 Novara, Italy
2
Division of General Medicine, S. Giuseppe Hospital, I.R.C.C.S. Istituto Auxologico Italiano, 28824 Verbania, Italy
3
Department of Health Sciences, University of Piemonte Orientale UPO, 28100 Novara, Italy
4
Division of Endocrinology, University Hospital “Maggiore della Carità”, 28100 Novara, Italy
5
Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy
*
Author to whom correspondence should be addressed.
Nutrients 2020, 12(5), 1444; https://doi.org/10.3390/nu12051444
Received: 19 April 2020 / Revised: 12 May 2020 / Accepted: 14 May 2020 / Published: 16 May 2020
(This article belongs to the Special Issue Vitamin D on Immune Function)

Abstract

:
Vitamin D is a secosteroid with a pleiotropic role in multiple physiological processes. Besides the well-known activity on bone homeostasis, recent studies suggested a peculiar role of vitamin D in different non-skeletal pathways, including a key role in the modulation of immune responses. Recent evidences demonstrated that vitamin D acts on innate and adaptative immunity and seems to exert an immunomodulating action on autoimmune diseases and cancers. Several studies demonstrated a relationship between vitamin D deficiency, autoimmune thyroid disorders, and thyroid cancer. This review aims to summarize the evidences on the immunomodulatory effect of vitamin D on thyroid diseases.

1. Introduction

Vitamin D is a secosteroidal hormone precursor. This term encompasses several compounds, but the most represented isoforms are Ergocalciferol (or vitamin D2), available in plants, and Cholecalciferol (or vitamin D3), synthesized at the skin level from 7-dehydrocholesterol after exposure to ultraviolet B (UVB) radiation [1,2]. Vitamin D binding protein transports vitamin D isoforms to the liver, where they are converted by 25-hydroxylase enzyme to 25-hydroxyvitamin D2 (25(OH)D2) and D3 (25(OH)D3), which are the main circulating isoforms of vitamin D and reflect vitamin D status [1,3]. Considering that D3 is the most represented isoform in humans [4], from now on we will conventionally use the terminology associated with this isoform.
At physiological concentrations, 25(OH)D3 is inactive, needing to be converted into the active forms 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) by 1α-hydroxylase enzyme (encoded by CYP27B1) in the kidneys. 1α-hydroxylase activity is regulated by parathyroid hormone (PTH) levels, while high 1,25(OH)2D3 levels and fibroblast growth factor 23 (FGF23) exert a negative feedback. 1α-hydroxylase is also expressed in extra-renal sites, like bone, skin, colon, brain, and immune cells, where its regulation is independent of PTH. Inactivation of both 25(OH)D3 and 1,25(OH)2D3 is performed by 24-hydroxylase [1,2,5].
1,25(OH)2D3 binds to the Vitamin D receptor (VDR), a member of the nuclear hormone receptors family, acting on the vitamin D response element (VDRE) to control the expression of multiple genes, including those involved in the regulation of cellular cycle and angiogenesis [6]. Moreover, the existence of a membrane-bound VDR has been hypothesized mediating non-genomic, rapid effects of 1,25(OH)2D3 [7].
1,25(OH)2D3 has been recognized as a key hormone in the regulation of the musculoskeletal homeostasis. However, extra-skeletal effects of 1,25(OH)2D3 have been attracting interest in the last years, after discovering the presence of VDR in many tissue types [8,9]. Thus, different roles have been attributed to vitamin D: it contributes to the development, protection, transmission, and plasticity of the nervous system, downregulates the renin-angiotensin-aldosterone system, exerts a protective role on the vascular endothelium, and improves insulin sensitivity [10,11,12,13]. For these physiological evidences, vitamin D status has been proposed as a biomarker of general health and hypovitaminosis D has been correlated to the presence of metabolic syndrome, cardiovascular diseases, cancers, infections, neuromuscular disorders, and all-cause mortality [14,15,16].
Among the pleotropic effects of vitamin D, in the last few decades an increasing number of evidences suggested an intriguing link between vitamin D homeostasis and immune responses [17,18,19]. As such, many researchers speculated that autoimmune disorders, including type I diabetes, autoimmune thyroiditis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, could be related to vitamin D imbalance [20,21]. In this context, vitamin D could exert an important role in innate and adaptive immunity modulation (Figure 1).
Innate immunity is an immunological subsystem that includes the cells and mechanisms implicated in the first line of defense from infections. The vitamin D binding to VDR expressed by the hematopoietic system leads to the myeloid differentiation towards monocytes and granulocytes, the immune cells involved in the innate immunity. The exposure of monocytes to different pathogens increases the expression of VDR, which is involved in antimicrobial response [22]. Focusing on innate immunity, 1,25(OH)2D3 enhances antimicrobial activity of monocytes and macrophages by promoting the production of defensin β 2 and cathelicidin antimicrobial peptide (CAMP) [23,24]. Furthermore, 1,25(OH)2D3 contributes to the clearance of pathogens by inducing chemotaxis and phagocytosis of innate immune cell components [25,26]. Recent evidences suggest that vitamin D seems to be implicated in the prevention of infections by reducing the propagation of pathogens, via neutrophil extracellular traps (NETs) formation [27]. Although vitamin D enhances the antimicrobial activity of innate immunity, it seems to exert an important role in favoring immune tolerance through the downregulation of antigen presentation by monocytes [28,29]. In addition, 1,25(OH)2D3 inhibits dendritic cells chemotaxis and antigen presentation, through a downregulation of MHC II expression [30,31].
Therefore, many studies highlighted an intriguing role for vitamin D in enhancing innate immunity through different pathways.
Adaptive immunity is highly specific for each pathogenic antigen and is mediated by lymphocytes B and T. With regards to the immunomodulatory effects of vitamin D on this subsystem, vitamin D downregulates the monocytes expression of proinflammatory cytokines, including Tumor Necrosis Factor α (TNF α) and Interleukin 6 (IL-6), which are involved in the inflammatory pathway that leads to B and T lymphocytes activation and proliferation [32]. B cells express VDR both in quiescence and after activation [33]. In this context, 1,25(OH)2D3 promotes the apoptosis B cells, hence preventing their proliferation and differentiation into plasma cells [34].
T lymphocytes represent another immune target of vitamin D action: 1,25(OH)2D3 is able to suppress T cells cytotoxic activity by inhibiting the expression of Fas-ligand and exert different immunomodulatory effects on T helper (Th) cells [35]. CD4+ T cells differentiate into several distinct subsets [36]. The Th1 subset secretes proinflammatory cytokines, including IFN-γ and IL-2, and exerts a key role in the clearance process of intracellular pathogens, whereas Th2 cells are involved prevalently in immune responses to parasites. Th17 cells secrete proinflammatory cytokines, such as IL-17 and IL-22, implicated in the immune responses to bacterial and fungal infections as well as in the pathogenesis of autoimmune diseases [37,38].
In animal models, 1,25(OH)2D3 regulates CD4+ Th differentiation, inhibiting the activity of Th17 and Th1 cells [39], which are involved in different chronic inflammatory conditions through cytokines release. On the contrary, 1,25(OH)2D3 polarizes CD4+ cells towards a Th2 phenotype with a consequent upregulation of cytokines including IL-4 and IL-5 [40,41]. Finally, 1,25(OH)2D3 has been shown to induce the cellular differentiation and increase the activity of T regulatory (Treg), a key subset of CD4+ cells implicated in the maintenance of immune tolerance. These mechanisms lead to an increase of anti-inflammatory actions mediated by transforming growth factor β1 (TGF-β1) and IL-10 and [42,43,44].
In summary, vitamin D has the ability to modulate adaptive immunity, acting on different components of this immunological subsystem.
The global biological actions of 1,25(OH)2D3 reveal, therefore, an ability to interact functionally with the immune system by promoting immune tolerance and a shift from the pro-inflammatory setting to a more tolerogenic immune setting, which may link to protective effects in autoimmune diseases and inflammatory processes [1,2]. Clinical surveys have recently associated hypovitaminosis D with autoimmune thyroid disorders (AITD), including Hashimoto’s thyroiditis (HT), Graves’ disease (GD) and post-partum thyroiditis (PPT), as well as thyroid cancer tumorigenesis [45,46].
This review aims to summarize the evidences on the immunomodulatory effect of vitamin D on thyroid diseases.

2. Autoimmune Thyroid Disorders (AITDs)

AITD is the most frequent autoimmune disease with an estimated prevalence of 5% and a progressive increase in incidence, especially in the female population. Adult women have a higher risk of developing thyroid autoimmunity than men and present more frequently abnormal thyroid function in this context (7%–9% in females vs. 1%–2% in males) [47]. AITDs are T-cell mediated autoimmune disorders, resulting from an organ-specific deregulation of the immune system. The mechanisms involved in this autoimmune response have not been fully elucidated yet, though an interaction between genetic predisposition and environmental factors has been demonstrated to trigger the autoimmune process [46]. In subjects with genetic predisposition, an alteration of the physiological balance between Th1 and Th2 response may occur in case of exposure to environmental factors [48]. Moreover, a shift in the balance between Th17 and Treg cells has been recently observed in thyroid autoimmunity [49]. Environmental factors that have been recognized in association with AITD pathogenesis include iodine, radiation, smoking habit, viral infections, drugs, and stress [50].
The most common AITDs are HT and GD, which are commonly characterized by lymphocytic (T-cell CD4+ and CD8+) infiltration of the thyroid tissue and production of thyroid-specific antibodies [48,51] (Figure 2). Patients with AITD harbor an increase of activated T-cell expressing human leukocyte antigen (HLA)-DR and a decrease of CD8+ immune cells, whereas circulating B cell levels are normal [51].
The HLA-DR antigen, expressed primarily by monocytes and B cells, has also been detected on the surface of activated T cells. These DR antigens, which are cell-surface glycoproteins encoded by genes of the HLA-DR region of the MHC, are absent in resting T lymphocytes and could represent a potential marker of the immune system activation [52]. Some studies also documented that the percentage of circulating T cells expressing HLA-DR represent a biomarker capable of accurately reflecting autoimmune diseases activity [53].
As previously described, vitamin D exerts a modulating role on AITD through its specific enhancing effects on the innate immune system and inhibitory actions on the adaptive immune response [2].
Preclinical and clinical studies found an association between AITD and vitamin D deficiency [45,54]. Original evidence of a peculiar role of vitamin D in thyroid disease dates back to the late 80s to early 90s. McDonnell described an interesting homology between the VDR and the thyroid hormone receptor [55], and five years later, Berg et al. demonstrated the VDR expression on follicular thyroid cells [56]. Moreover, VDR and the thyroid hormone receptor share partners for heterodimerization [57]. In the same period, Fournier et al. investigated the effect of a combined treatment with cyclosporine A and 1,25(OH)2D3 using an experimental model of AITD in mice [58], suggesting a synergistic effect of these molecules in preventing the onset of thyroid autoimmunity and its associated histological alterations [58]. Years later, Borgogni and colleagues evaluated the effects of a non-hypercalcemic vitamin D receptor agonist, elocalcitol, on the secretion of the inflammatory chemokine CXCL10 induced by proinflammatory cytokines, as compared to methimazole. The authors demonstrated that, in human thyrocytes, elocalcitol impaired both IFN-γ and TNFα-induced CXCL10 protein intracellular pathways, whereas methimazole only aced on IFN-γ pathway. Moreover, elocalcitol reduced Th1 and Th17 cytokine secretion in CD4+ T cells and promoted a shift toward a Th2 response [59].
In murine models with induced autoimmune hyperthyroidism prompted by thyrotropin receptor immunization, hypovitaminosis D was found to induce a persistent disease, suggesting an immunomodulatory effect of vitamin D status on autoimmune hyperthyroidism [60]. In parallel, Liu and co-workers tested the effect of 1,25(OH)2D3 on Th1/Th2 cells and inflammation in female Wistar rats with experimental autoimmune thyroiditis [61]. Their results showed significantly decreased levels of thyroid autoantibodies and INF-γ in mice treated with 1,25(OH)2D3, which was associated with the maintenance of structural thyroid integrity.
From a clinical viewpoint, a meta-analysis including 20 case-control studies showed that patients with AITD harbor significantly lower serum vitamin D levels compared to healthy controls (OR 2.99, 95%CI 1.88–4.74) [62]. However, the mechanisms underlying the effects of vitamin D on AITD are still unknown but likely related to its anti-inflammatory and immunomodulatory properties.

2.1. Hashimoto’s Thyroiditis

HT represents a T-cell-mediated autoimmune disease characterized by goiter, presence of circulating anti-thyroid peroxidase (TPOAb) and/or anti-thyroglobulin (TgAb) antibodies, and intrathyroidal infiltration of B and T cells with a CD4+ Th1 predominance [46,63]. This alteration leads to varying degrees of thyroid hypofunction.
Observational and interventional studies observed that low vitamin D levels and the risk of HT onset seem to be closely associated. Indeed, patients with HT harbored a high proportion of hypovitaminosis D (over 60%). Moreover, HT is more closely related to vitamin D deficiency (<20 ng/mL) than insufficiency (21–29 ng/mL) [64,65,66,67].
The first observational study on the association between vitamin D and HT was published in 2009 [68]. Based on the evidence that vitamin D deficiency is linked to a susceptibility to type 1 diabetes [69] and multiple sclerosis [70], Goswami et al. conducted a community-based survey on 642 adults to investigate the relationship between serum vitamin D concentrations and thyroid autoimmunity. Their results highlighted a significant inverse association between 25(OH)D3 and TPOAb levels [68]. Three years later, Camurdan et al. observed that hypovitaminosis D rate was higher in children with HT compared to control group (73.1% vs. 17.6%) and confirmed the inverse association between 25(OH)D3 levels and TPOAb titer in their pediatric population [71]. This inverse correlation was substantiated in the following studies: [66,72,73,74,75]. Furthermore, different clinical studies showed that the prevalence of HT in patients with hypovitaminosis D was significantly higher than that documented in subjects with sufficient vitamin D levels, particularly among children, elderly subjects, and pre-menopausal women [64,71,76,77,78,79,80,81]. As regards thyroid function in the context of HT, Mackawy and co-workers demonstrated a strong negative association between serum vitamin D concentrations and TSH levels, leading to speculate that vitamin D deficiency in HT patients could be associated with a progression towards hypothyroidism (TSH > 5.0 m UI/L) [65].
In more recent years, these evidences prompted several research groups to evaluate the effect of vitamin D supplementation on thyroid autoimmunity. Simsek et al. prospectively evaluated 82 patients with HT, which were randomized in two groups: the first group (46 patients) was treated with cholecalciferol 1000 IU/day for one month and the second group without vitamin D replacement. Their results showed that TPOAb and TgAb levels were significantly decreased by the vitamin D replacement therapy in the first group [82]. These findings were confirmed by other prospective studies and randomized controlled trials, which added evidence that cholecalciferol supplementary treatment was related to a decrease in TPOAb and TgAb levels both in patients with vitamin D sufficiency and deficiency [83,84,85]. Moreover, an increase of 5 ng/mL in vitamin D levels was correlated to a significant decrease of 20% in the risk of HT [86].
In 2017, Mirhosseini et al. enrolled 11,017 subjects to evaluate the influence of vitamin D supplementary treatment on thyroid function and thyroid auto-antibodies levels. Their results showed that serum 25(OH)D3 levels ≥ 50 ng/mL were associated with a 30% decreased risk of hypothyroidism onset and a 32% decreased risk of increased thyroid auto-antibodies levels, leading the authors to speculate that vitamin D supplementation could exert a positive effect on thyroid function as well as provide protection from new onset of thyroid disease during a 12 months follow up [87]. In addition, in a recent 3 month randomized controlled trial (RCT) on adult females with HT, Chahardoli et al. confirmed a significant decrease of TSH levels after weekly supplementation with 50,000 IU of cholecalciferol [88].
Few studies, however, failed to document associations between vitamin D deficiency and a higher prevalence of HT [89,90], questioning on the preventive role of vitamin D in AITD. Further investigations are needed to evaluate the preventive and therapeutic effects of vitamin D in HT.
Growing evidence also documented that some VDR polymorphisms could be related to an increased incidence of HT [91]. The most frequent polymorphisms include FokI, BsmI, ApaI and TaqI. FokI polymorphism is located in exon 2 of the VDR gene and causes an alteration in the start codon leading to a truncated VDR protein [92]. The BsmI and ApaI polymorphisms, located in intron 8 of the VDR gene, lead to an altered mRNA stability, a disruption of splicing sites or a change in intronic sequences, affecting gene expression [92,93]. The TaqI polymorphism is located in exon 9 and is able to alter the mRNA stability [92,93]. FokI and ApaI polymorphisms influences serum vitamin D concentration, and BsmI polymorphism interferes with the IFN-γ production by monocytes, whereas TaqI influences the VDR expression [92,93].
In a meta-analysis on 8 studies showed that the VDR BsmI and TaqI polymorphisms were associated with HT risk [94]. Later, Inoue and co-workers demonstrated that the CC genotype for the FokI polymorphism was frequent in patients with HT [93]. Finally, a meta-analysis including 11 studies on Asian and Caucasian populations observed that the FokI polymorphism of VDR was related with a higher risk of HT only in Asian subjects [95]. All these results are in line with findings on children with type 1 diabetes [96].

2.2. Graves’ Disease

GD is the most common cause of hyperthyroidism in developed countries, affecting mostly women, with an annual incidence of 14 cases in 100,000 persons [97]. GD is characterized by the presence of TSH receptor autoantibodies (TRAb) which lead to hyperthyroidism, diffuse toxic goiter, and ophthalmopathy [98]. In GD, infiltration of lymphocytes is milder than in HT and involves mainly CD4+ Th2 cells [46]. Although several studies reported an increased prevalence of hypovitaminosis D in patients with GD, the relationship between these two conditions is not clear [99].
The first observational study evaluated vitamin D status in women with and without GD remission. The results showed that vitamin D concentrations were significantly lower in patients without remission of GD compared to subjects with remission and that the prevalence of hypovitaminosis D was twice as high as in healthy controls [100]. The same workgroup, in a prospective study, observed a significant association between low vitamin D concentrations and an increased volume of thyroid gland in women with newly onset GD [101]. In 2016, Kim et al., in a cross-sectional study including 776 AITD patients, showed that the prevalence of vitamin D insufficiency was higher in GD patients compared to healthy subjects [79]. These results were further confirmed by two cross-sectional studies, although no association was observed between vitamin D and TRAb levels [102,103]. Conversely, in a cohort of 70 GD subjects, Zhang et al. found an inverse association between serum vitamin D concentrations and TRAb levels [104].
More extensively, Xu and co-workers evaluated the relationship between serum vitamin D levels and GD through a meta-analysis including 26 case-control or cohort studies. Their results confirmed that subjects with GD were more frequently to be deficient in vitamin D than the control group (OR = 2.24, 95% CI 1.31–3.81, p < 0.001) [105].
As regards the role of vitamin D supplementary treatment during GD, current evidence is limited to only one interventional study where the effect of daily vitamin D treatment was assessed on GD recurrence. Among 210 GD patients with hypovitaminosis D, 60 received cholecalciferol (1000–2000 IU per day) whereas 150 did not. Recurrence rate was comparable between groups (38% vs. 49%) but occurred earlier in the control group (7 vs. 5 months) [106].
Several studies investigated the relationship between polymorphisms of VDR gene and GD onset risk, but results remain arguable. The first meta-analysis to evaluate this association was conducted by Zhou et al. in 2009 and included seven studies on Caucasian and Asian populations. The results showed that the presence of ApaI, BsmI, and FokI VDR polymorphisms was associated with a higher risk of GD onset in Asian population, whereas no associations were found in Caucasian cohorts [107]. More recently, a meta-analysis including eight studies found a relationship between BsmI and TaqI polymorphisms and the risk of GD onset, while no correlation was seen for ApaI and FokI [94]. Finally, Inoue et al. observed a higher prevalence of TT genotype for TaqI in subjects with GD compared to patients with HT and a higher prevalence of the C allele for ApaI in comparison with controls [93].

2.3. Post-Partum Thyroiditis

Post-partum thyroiditis (PPT) refers to the development of de novo AITD within the first year post-partum and represents one of the most common autoimmune disorders in pregnancy, with an estimated prevalence between 1% and 17% [108]. Clinical symptoms include a thyrotoxic phase during the first 3 months of onset usually followed by a phase of hypothyroidism at 3–6 months, which is reversible in 75% of patients [109,110].
Different clinical studies investigated the relationship between PPT and serum vitamin D concentrations. Krysiak et al. compared 25(OH)D3 and PTH levels between 4 groups of non-lactating women who gave birth 12 months before the beginning of the study: euthyroid women with PPT, women with hypothyroidism and PPT, women with non-autoimmune hypothyroidism, and healthy euthyroid women without AITD. Serum vitamin D concentrations were lower whereas PTH levels were higher in patients with PPT compared to subjects without AITD. Moreover, in the second part of the study, women with hypothyroidism and PPT as well as women with non-autoimmune hypothyroidism were treated for 6 months with L-thyroxine. The results showed that L-thyroxine therapy increased serum vitamin D levels and reduced PTH levels only in the first group, highlighting an intriguing relationship between vitamin D status, PPT and L-thyroxine therapy [111].
In 2016, the same group investigated whether vitamin D treatment could modify the course of thyroid autoimmunity in 38 non-lactating levo-thyroxine-treated women with PPT compared to 21 matched healthy postpartum women. Women with deficiency of vitamin D were treated with oral cholecalciferol at 4000 IU daily, whereas women with insufficiency of vitamin D and women with normal 25(OH)D3 concentrations were either treated with cholecalciferol at 2,000 IU daily or left untreated. At baseline, serum vitamin D concentrations were lower in patients with PPT compared to healthy women and were inversely associated with thyroid antibody levels. Following vitamin D treatment, TPOAb titer decreased, and this effect was more evident in women with hypovitaminosis D compared to those with normal vitamin D [112]. However, this study raised some criticism regarding the presence of potential confounders that could interfere with autoantibody titer and the vitamin D status, including the use of estrogen contraceptives, iodine status, and selenium levels [113]. Further studies are needed to define the role of vitamin D in PPT.

3. Thyroid Cancer

Thyroid cancer is the most frequent endocrine tumor with 567,000 new cases reported annually. Its incidence is significantly higher in women than in men (10.2 per 100,000 vs. 3.1 per 100,000) [114]. Thyroid cancers are usually follicular in their origin, including differentiated thyroid cancers (DTC), poorly differentiated thyroid cancers (PDTC), and anaplastic (ATC) thyroid cancers [115].
Previous irradiation to the neck, the presence of benign thyroid nodules, and a family history of thyroid neoplasia represent recognized risk factors for thyroid cancer. Recently, a higher cancer risk for hypothyroidism and hyperthyroidism has been established [116,117,118,119,120]. An important role in thyroid tumorigenesis was also attributed to environmental factors, which can influence thyroid cancer histopathological phenotype [121,122]. In this context, obesity represents a recently recognized environmental and genetic risk factor involved in thyroid carcinogenesis. Several evidences suggest a potential role for adipose tissue in regulating tumor microenvironmental pathophysiology, supported by a documented association between obesity-dependent inflammation and cancer [123]. In fact, hypoxia, chronic inflammation, and oxidative stress, could favor the development of a subgroup of DTCs characterized by resistance to both 131I treatment and chemotherapy [124]. In the context of inflammation, some evidences indicate that HT is associated with a higher risk of PTC onset [125,126], resulting from an increased cytokines production which characterizes the autoimmune process [127].
The role of inflammation in DTCs has been focused on in several studies published in the last 10 years, demonstrating an intriguing relationship between chronic inflammation and increased risk of DTC and suggesting the role of inflammatory setting in cell transformation and tumor progression [128,129,130,131,132]. In this scenario, vitamin D seems to play a peculiar role in thyroid tumorigenesis for its immunomodulatory and antineoplastic properties. In fact, vitamin D can modulate many signaling pathways in apoptotic process, cellular proliferation and differentiation, angiogenesis, invasion, and inflammatory response [46,133] (Figure 3). In vitro and in vivo studies observed that vitamin D has pro-apoptotic, pro-differentiative, anti-proliferative and anti-inflammatory properties in the context of the tumor microenvironment [46].
More in detail, vitamin D regulates mediators of apoptotic process through activation of pro-apoptotic proteins (BAX, BAK and BAD) and inhibition of anti-apoptotic elements, such as BCL-2 and BCL-XL [134,135]. Moreover, 1,25(OH)2D3 increases cyclin-dependent kinase inhibitors (CDKI) expression and influences microRNA expression, which have a negative impact on cell proliferation [136,137]. In addition, 1,25(OH)2D3 modulates intracellular kinase pathways and inhibits the elevated telomerase activity of cancer cells by decreasing telomerase reverse transcriptase (TERT) [136,138].
Recently, several studies focused on the immunomodulatory role of vitamin D in tumor-associated inflammation. Vitamin D exerts beneficial anti-inflammatory properties in different cancer types through the inhibition of prostaglandin synthesis and signaling, the suppression of p38 stress kinase signaling with a consequent inhibition of pro-inflammatory cytokines production and NF-kB signaling [136,138]. As previously described, 1,25(OH)2D3 inhibits the proliferation and differentiation of Th1 and Th17 as well as the expression of IL-2, interferon-γ, IL-17, and IL-21, and promotes the expression of IL-3, IL-4, IL-5, and IL-10 [39,40,41,139]. On this basis, Passler and co-workers suggested that the inflammatory microenvironment in DTC could be reduced by 1,25(OH)2D3 [140].
While in clinical studies, hypovitaminosis D was associated with several types of cancers [141,142,143,144], controversial data are available about low vitamin D levels and thyroid cancer [137,145,146].
Basic studies seem to validate a role for vitamin D in thyroid tumor onset and progression. Anti-neoplastic actions are mediated by the binding of vitamin D to its receptor [145] and by interacting with other transcriptional factors or cell signaling pathways [147,148,149]. Available data on this topic suggest that local vitamin D could act in early cancer stage reducing proliferation and aggressiveness of thyroid tumors through different pathways. Khadzkou et al. observed an increased VDR and 1-alpha-hydroxylase expression in PTC specimens compared to the adjacent non-neoplastic thyroid tissue, particularly in areas with lymphocyte infiltration [145]. Likewise, an enhanced expression of the VDR and the two enzymes involved in vitamin D activation and degradation (CYP24A1 and CYP27B1, respectively) in surgical samples of follicular adenomas and DTC has been demonstrated, although a decreased expression of these genes was found in lymph nodal and distant metastases [150]. Moreover, expression of VDR was found to be reduced in lymph nodes metastases of PTC compared to normal thyroid tissue and primary PTC, suggesting that VDR expression and CYP27B1 could be predictors of a favorable prognosis [145]. In lymph node metastatic PTC, the expression of VDR and CYP24A1 was decreased compared to non-metastasized PTC, and the expression of VDR was frequently lost in ATC [146]. These observations were confirmed by Yavropoulou et al., who demonstrated an enhanced expression of both VDR and CYP24A1 in PTC samples than the adjacent non-neoplastic tissue [150]. Moreover, mRNA analysis allowed to demonstrate an increased expression of VDR in PTC, which is often linked to an increased expression of the type II trans membrane serine protease-4 and extracellular matrix protein-1, which are known to be important predictors of malignant thyroid nodules [151]. More recently, Zhang and co-workers observed a higher expression of VDR in PTC compared to adjacent non-tumoral tissue in group of 78 patients who underwent surgery. In the same cohort, pre-surgical serum concentration of 1,25(OH)2D3 was found to be lower in patients with PTC compared to patients with benign thyroid nodules [152]. Moreover, through a cyclic adenosine monophosphate-mediated process, 1,25(OH)2D3 inhibited the proliferation and induced the apoptosis of PTC cells [152]. On this path, numerous in vitro studies observed that the administration of 1,25(OH)2D3 is able to decrease proliferative activity of differentiated and undifferentiated thyroid cancer cells through different signaling pathways [153,154,155,156]. Liu and coworkers demonstrated that in vitro 1,25(OH)2D3 administration is able to increase the expression of p27 and to decrease cell proliferation in cultured thyroid cancer cell lines [157]. Subsequently, the same authors evaluated the in vivo effects of 1,25(OH)2D3 supplementation on thyroid cancer growth and progression in a xenograft model [158], demonstrating the restoration of p27 in thyroid cancer cells, an effect correlated to an improved cell differentiation and a preventive role on metastatic growth. Finally, animal studies showed that 1,25(OH)2D3 supplementary treatment was associated to a reduction of tumor volume [147].
These experimental results demonstrate that vitamin D status could exert an important impact on thyroid cancer progression and that 1,25(OH)2D3 could have a beneficial effect in thyroid cancer treatment.
Despite the evidence for anti-neoplastic effects of 1,25(OH)2D3 observed in vitro studies and animal models, clinical studies showed controversial results. Several studies found that lower 25(OH)D3 levels were significantly correlated to a higher risk of thyroid cancer onset [159,160,161,162,163,164] whereas others reported opposite results [165,166,167,168].
Most studies observed significantly lower serum 25(OH)D3 concentrations in patients with DTC than individuals with benign thyroid diseases or healthy controls [159,160,162,163,164]. A recent meta-analysis including 14 case-control studies showed that pre-surgical serum 25(OH)D3 levels were lower in patients with thyroid cancer than controls, but this difference disappeared after surgery [133]. Similar results were reported by Hu et al. in meta-analysis that included 10 case-control studies, demonstrating a higher risk of thyroid cancer in individuals with hypovitaminosis D [169]. A negative prognostic role of vitamin D has also been supposed, since low 25OH-D3 levels were found to be associated with advanced disease and aggressive clinical-pathologic features [164,170,171].
Another point of discussion is the finding of a reduced conversion of 25(OH)D3 to 1,25(OH)2D3 in DTC patients, that leads to speculate a potential role of CYP24A1 gene polymorphism in thyroid carcinogenesis [161]. In fact, in recent years, Zhang et al. demonstrated lower 1,25(OH)2D3 levels in PTC compared to nodular goiter [152].
Finally, a few clinical studies evaluated the role of vitamin D supplementation in preventing thyroid cancer onset. In 2013, a systematic review on 11 studies was conducted to evaluate the relationship between dietary supplements of vitamins and minerals, including vitamin D, and the risk of thyroid cancer [172]. The results suggested that the current evidences supporting a protective role of vitamin D on thyroid cancer onset are inconclusive. One year later, the prospective US National Institutes of Health American Association of Retired Persons (NIH-AARP) Diet and Health Study did not show any clear evidence of positive or negative correlation between dietary intake of vitamin D and thyroid cancer risk [173]. No human studies on 25(OH)D3 and 1,25(OH)2D3 supplementations have been conducted yet.
Lastly, there is an underlying possibility that discrepancies existing among different studies on vitamin D role in thyroid function, autoimmunity, and cancer could depend on inter-laboratory and inter-assay variability in the methods used to measure 25(OH)D3, as well as seasonal variations of serum 25(OH)D3 concentrations and differences in the 25(OH)D3 reference levels used to define hypovitaminosis D. Moreover, the controversial results could be attributed to the cross-sectional design of studies with a low sample size and a heterogeneous population [46].

4. Conclusions

In conclusion, several studies observed a relationship between hypovitaminosis D and thyroid diseases. Supplementary treatment with cholecalciferol seems to have beneficial effects on AITD, whereas there are no clear evidences on a correlation between vitamin D supplementation and thyroid cancer risk. However, large multicenter studies are needed to investigate the impact of vitamin D supplementary treatment on meaningful long-term clinical end points in AITD and thyroid cancer.

Author Contributions

Conceptualization and methodology, C.M., M.C., P.M.; original draft preparation, C.M., M.C., A.B., M.T.S., M.Z., L.P., P.M.; review and editing, C.M., G.A., L.P., F.P., P.M.; supervision, G.A., F.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

AbbreviationDefinition
1,25(OH)2D31,25-dihydroxyvitamin D
25(OH)D325-hydroxyvitamin D
AITDAutoimmune thyroid disorders
ATCAnaplastic thyroid carcinoma
AutoAbAutoantibodies
CAMPCathelicidin antimicrobial peptide
CDKICyclin dependent kinase inhibitors
DTCDifferentiated thyroid cancers
FasLFas-ligand
FGF23Fibroblast growth factor 23
GDGraves’ disease
HLAHuman leukocyte antigen
HTHashimoto’s thyroiditis
IFNInterferon
ILInterleukin
MHCMajor histocompatibility complex
NETsNeutrophil extracellular traps
PDTCPoorly differentiated
PGProstaglandin
PPTPost-partum thyroiditis
PTCPapillary thyroid cancer
PTHParathyroid hormone
RCTRandomized controlled trial
TERTTelomerase reverse transcriptase
ThT helper
TGFTransforming growth factor
UVBUltraviolet B
TgAbAnti-thyroglobulin antibodies
TNFTumor Necrosis Factor
TPOAbAnti-thyroid peroxidase antibodies
TRAbTSH receptor autoantibodies
TregT regulatory
VDRVitamin D receptor
VDREVitamin D response element

References

  1. Prietl, B.; Treiber, G.; Pieber, T.R.; Amrein, K. Vitamin D and immune function. Nutrients 2013, 5, 2502–2521. [Google Scholar] [CrossRef] [PubMed]
  2. Bikle, D. Nonclassic actions of vitamin D. J. Clin. Endocrinol. Metab. 2009, 94, 26–34. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Muscogiuri, G.; Mitri, J.; Mathieu, C.; Badenhoop, K.; Tamer, G.; Orio, F.; Mezza, T.; Vieth, R.; Colao, A.; Pittas, A. Mechanisms in endocrinology: Vitamin D as a potential contributor in endocrine health and disease. Eur. J. Endocrinol. 2014, 171, R101–R110. [Google Scholar] [CrossRef] [PubMed][Green Version]
  4. Fang, H.; Yu, S.; Cheng, Q.; Cheng, X.; Han, J.; Qin, X.; Xia, L.; Jiang, X.; Qiu, L. Determination of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in human serum using liquid chromatography with tandem mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2016, 1027, 19–26. [Google Scholar] [CrossRef] [PubMed]
  5. Kmieć, P.; Sworczak, K. Vitamin D in thyroid disorders. Exp. Clin. Endocrinol. Diabetes 2015, 123, 386–393. [Google Scholar] [CrossRef][Green Version]
  6. Holick, M.F. Vitamin D deficiency. N. Engl. J. Med. 2007, 357, 266–281. [Google Scholar] [CrossRef]
  7. Wacker, M.; Holick, M.F. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinology 2013, 5, 51–108. [Google Scholar] [CrossRef][Green Version]
  8. Wacker, M.; Holick, M.F. Vitamin D—Effects on skeletal and extraskeletal health and the need for supplementation. Nutrients 2013, 5, 111–148. [Google Scholar] [CrossRef][Green Version]
  9. Stocklin, E.; Eggersdorfer, M. Vitamin D, an essential nutrient with versatile functions in nearly all organs. Int. J. Vitam. Nutr. Res. 2013, 83, 92–100. [Google Scholar] [CrossRef]
  10. Bellan, M.; Guzzaloni, G.; Rinaldi, M.; Merlotti, E.; Ferrari, C.; Tagliaferri, A.; Pirisi, M.; Aimaretti, G.; Scacchi, M.; Marzullo, P. Altered glucose metabolism rather than naive type 2 diabetes mellitus (T2DM) is related to vitamin D status in severe obesity. Cardiovasc. Diabetol. 2014, 13, 57. [Google Scholar] [CrossRef][Green Version]
  11. Di Somma, C.; Scarano, E.; Barrea, L.; Zhukouskaya, V.V.; Savastano, S.; Mele, C.; Scacchi, M.; Aimaretti, G.; Colao, A.; Marzullo, P. Vitamin D and Neurological Diseases: An Endocrine View. Int. J. Mol. Sci. 2017, 18, 2482. [Google Scholar] [CrossRef] [PubMed][Green Version]
  12. Tahawi, Z.; Orolinova, N.; Joshua, I.G.; Bader, M.; Fletcher, E.C. Altered vascular reactivity in arterioles of chronic intermittent hypoxic rats. J. Appl. Physiol. 2001, 90, 2007–2013. [Google Scholar] [CrossRef] [PubMed]
  13. Molinari, C.; Rizzi, M.; Squarzanti, D.F.; Pittarell, A.P.; Vacca, G.; Renò, F. 1α,25-Dihydroxycholecalciferol (Vitamin D3) induces NO-dependent endothelial cell proliferation and migration in a three-dimensional matrix. Cell Physiol. Biochem. 2013, 31, 815–822. [Google Scholar] [CrossRef] [PubMed]
  14. Grübler, M.R.; März, W.; Pilz, S.; Grammer, T.B.; Trummer, C.; Müllner, C.; Schwetz, V.; Pandis, M.; Verheyen, N.; Tomaschitz, A.; et al. Vitamin-D concentrations, cardiovascular risk and events—A review of epidemiological evidence. Rev. Endocr. Metab. Disord. 2017, 18, 259–272. [Google Scholar] [CrossRef] [PubMed]
  15. Brannon, P.M.; Yetley, E.A.; Bailey, R.L.; Picciano, M.F. Overview of the conference “Vitamin D and Health in the 21st Century: An Update”. Am. J. Clin. Nutr. 2008, 88, 483S–490S. [Google Scholar] [CrossRef][Green Version]
  16. Caristia, S.; Filigheddu, N.; Barone-Adesi, F.; Sarro, A.; Testa, T.; Magnani, C.; Aimaretti, G.; Faggiano, F.; Marzullo, P. Vitamin D as a Biomarker of Ill Health among the Over-50s: A Systematic Review of Cohort Studies. Nutrients 2019, 11, 2384. [Google Scholar] [CrossRef][Green Version]
  17. Cantorna, M.T. Vitamin D and autoimmunity: Is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc. Soc. Exp. Biol. Med. 2000, 223, 230–233. [Google Scholar] [CrossRef]
  18. van Etten, E.; Mathieu, C. Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts. J. Steroid Biochem. Mol. Biol. 2005, 97, 93–101. [Google Scholar] [CrossRef]
  19. Arnson, Y.; Amital, H.; Shoenfeld, Y. Vitamin D and autoimmunity: New aetiological and therapeutic considerations. Ann. Rheum. Dis. 2007, 66, 1137–1142. [Google Scholar] [CrossRef][Green Version]
  20. Cantorna, M.T. Vitamin D and its role in immunology: Multiple sclerosis, and inflammatory bowel disease. Prog. Biophys. Mol. Biol. 2006, 92, 60–64. [Google Scholar] [CrossRef]
  21. Adorini, L.; Penna, G. Control of autoimmune diseases by the vitamin D endocrine system. Nat. Clin. Pract. Rheumatol. 2008, 4, 404–412. [Google Scholar] [CrossRef] [PubMed]
  22. Novershtern, N.; Subramanian, A.; Lawton, L.N.; Mak, R.H.; Haining, W.N.; McConkey, M.E.; Habib, N.; Yosef, N.; Chang, C.Y.; Shay, T.; et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 2011, 144, 296–309. [Google Scholar] [CrossRef][Green Version]
  23. Gombart, A.F.; Borregaard, N.; Koeffler, H.P. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005, 19, 1067–1077. [Google Scholar] [CrossRef] [PubMed][Green Version]
  24. Wang, T.T.; Nestel, F.P.; Bourdeau, V.; Nagai, Y.; Wang, Q.; Liao, J.; Tavera-Mendoza, L.; Lin, R.; Hanrahan, J.W.; Mader, S.; et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 2004, 173, 2909–2912. [Google Scholar] [CrossRef] [PubMed][Green Version]
  25. Shin, D.M.; Yuk, J.M.; Lee, H.M.; Lee, S.H.; Son, J.W.; Harding, C.V.; Kim, J.M.; Modlin, R.L.; Jo, E.K. Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling. Cell. Microbiol. 2010, 12, 1648–1665. [Google Scholar] [CrossRef] [PubMed][Green Version]
  26. Sly, L.M.; Lopez, M.; Nauseef, W.M.; Reiner, N.E. 1alpha,25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. J. Biol. Chem. 2001, 276, 35482–35493. [Google Scholar] [CrossRef][Green Version]
  27. Agraz-Cibrian, J.M.; Giraldo, D.M.; Urcuqui-Inchima, S. 1,25-Dihydroxyvitamin D3 induces formation of neutrophil extracellular trap-like structures and modulates the transcription of genes whose products are neutrophil extracellular trap-associated proteins: A pilot study. Steroids 2019, 141, 14–22. [Google Scholar] [CrossRef]
  28. Tokuda, N.; Levy, R.B. 1,25-dihydroxyvitamin D3 stimulates phagocytosis but suppresses HLA-DR and CD13 antigen expression in human mononuclear phagocytes. Proc. Soc. Exp. Biol. Med. 1996, 211, 244–250. [Google Scholar] [CrossRef]
  29. Xu, H.; Soruri, A.; Gieseler, R.K.H.; Peters, J.H. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand. J. Immunol. 1993, 38, 535–540. [Google Scholar] [CrossRef]
  30. Griffin, M.D.; Lutz, W.H.; Phan, V.A.; Bachman, L.A.; McKean, D.J.; Kumar, R. Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem. Biophys. Res. Commun. 2000, 270, 701–708. [Google Scholar] [CrossRef]
  31. Gauzzi, M.C.; Purificato, C.; Donato, K.; Jin, Y.; Wang, L.; Daniel, K.C.; Maghazachi, A.A.; Belardelli, F.; Adorini, L.; Gessani, S. Suppressive effect of 1alpha,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: Impairment of functional activities and chemotaxis. J. Immunol. 2005, 174, 270–276. [Google Scholar] [CrossRef] [PubMed][Green Version]
  32. Zhang, Y.; Leung, D.Y.; Richers, B.N.; Liu, Y.; Remigio, L.K.; Riches, D.W.; Goleva, E. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J. Immunol. 2012, 188, 2127–2135. [Google Scholar] [CrossRef][Green Version]
  33. Rolf, L.; Muris, A.H.; Hupperts, R.; Damoiseaux, J. Illuminating vitamin D effects on B cells--the multiple sclerosis perspective. Immunology 2016, 147, 275–284. [Google Scholar] [CrossRef] [PubMed]
  34. Drozdenko, G.; Scheel, T.; Heine, G.; Baumgrass, R.; Worm, M. Impaired T cell activation and cytokine production by calcitriol-primed human B cells. Clin. Exp. Immunol. 2014, 178, 364–372. [Google Scholar] [CrossRef] [PubMed]
  35. Cippitelli, M.; Fionda, C.; Di Bona, D.; Di Rosa, F.; Lupo, A.; Piccoli, M.; Frati, L.; Santoni, A. Negative regulation of CD95 ligand gene expression by vitamin D3 in T lymphocytes. J. Immunol. 2002, 168, 1154–1166. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. Bettelli, E.; Korn, T.; Oukka, M.; Kuchroo, V.K. Induction and effector functions of T(H)17 cells. Nature 2008, 453, 1051–1057. [Google Scholar] [CrossRef]
  37. O’Shea, J.J.; Murray, P.J. Cytokine signaling modules in inflammatory responses. Immunity 2008, 28, 477–487. [Google Scholar] [CrossRef][Green Version]
  38. Korn, T.; Bettelli, E.; Oukka, M.; Kuchroo, V.K. IL-17 and Th17 Cells. Annu. Rev. Immunol. 2009, 27, 485–517. [Google Scholar] [CrossRef]
  39. Xie, Z.; Chen, J.; Zheng, C.; Wu, J.; Cheng, Y.; Zhu, S.; Lin, C.; Cao, Q.; Zhu, J.; Jin, T. 1,25-dihydroxyvitamin D3 -induced dendritic cells suppress experimental autoimmune encephalomyelitis by increasing proportions of the regulatory lymphocytes and reducing T helper type 1 and type 17 cells. Immunology 2017, 152, 414–424. [Google Scholar] [CrossRef][Green Version]
  40. Cantorna, M.T.; Waddell, A. The vitamin D receptor turns off chronically activated T cells. Ann. N. Y. Acad. Sci. 2014, 1317, 70–75. [Google Scholar] [CrossRef]
  41. Sloka, S.; Silva, C.; Wang, J.; Yong, V.W. Predominance of Th2 polarization by vitamin D through a STAT6-dependent mechanism. J. Neuroinflamm. 2011, 8, 56. [Google Scholar] [CrossRef] [PubMed][Green Version]
  42. Chambers, E.S.; Hawrylowicz, C.M. The impact of vitamin D on regulatory T cells. Curr. Allergy Asthma Rep. 2011, 11, 29–36. [Google Scholar] [CrossRef] [PubMed]
  43. Jeffery, L.E.; Wood, A.M.; Qureshi, O.S.; Hou, T.Z.; Gardner, D.; Briggs, Z.; Kaur, S.; Raza, K.; Sansom, D.M. Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses. J. Immunol. 2012, 189, 5155–5164. [Google Scholar] [CrossRef] [PubMed][Green Version]
  44. Zhou, Q.; Qin, S.; Zhang, J.; Zhon, L.; Pen, Z.L.; Xing, T. 1,25(OH)2D3 induces regulatory T cell differentiation by influencing the VDR/PLC-γ1/TGF-β1/pathway. Mol. Immunol. 2017, 91, 156–164. [Google Scholar] [CrossRef]
  45. Muscogiuri, G.; Tirabassi, G.; Bizzaro, G.; Orio, F.; Paschou, S.A.; Vryonidou, A.; Balercia, G.; Shoenfeld, Y.; Colao, A. Vitamin D and thyroid disease: To D or not to D? Eur. J. Clin. Nutr. 2015, 69, 291–296. [Google Scholar] [CrossRef]
  46. Kim, D. The role of vitamin D in thyroid diseases. Int. J. Mol. Sci. 2017, 18, 1949. [Google Scholar] [CrossRef][Green Version]
  47. McLeod, D.S.; Cooper, D.S. The incidence and prevalence of thyroid autoimmunity. Endocrine 2012, 42, 252–265. [Google Scholar] [CrossRef]
  48. Klecha, A.J.; Barreiro Arcos, M.L.; Frick, L.; Genaro, A.M.; Cremaschi, G. Immune-endocrine interactions in autoimmune thyroid diseases. Neuroimmunomodulation 2008, 15, 68–75. [Google Scholar] [CrossRef]
  49. González-Amaro, R.; Marazuela, M. T regulatory (Treg) and T helper 17 (Th17) lymphocytes in thyroid autoimmunity. Endocrine 2016, 52, 30–38. [Google Scholar] [CrossRef]
  50. Ferrari, S.M.; Fallahi, P.; Antonelli, A.; Benvenga, S. Environmental Issues in Thyroid Diseases. Front. Endocrinol. (Lausanne) 2017, 8, 50. [Google Scholar] [CrossRef][Green Version]
  51. Antonelli, A.; Ferrari, S.M.; Corrado, A.; Di Domenicantonio, A.; Fallahi, P. Autoimmune thyroid disorders. Autoimmun. Rev. 2015, 14, 174–180. [Google Scholar] [CrossRef] [PubMed]
  52. Winchester, R.J.; Kunkel, H.G. The human Ia system. Adv. Immunol. 1979, 28, 221–292. [Google Scholar] [PubMed]
  53. Viallard, J.F.; Bloch-Michel, C.; Neau-Cransac, M.; Taupin, J.L.; Garrigue, S.; Miossec, V.; Mercie, P.; Pellegrin, J.L.; Moreau, J.F. HLA-DR expression on lymphocyte subsets as a marker of disease activity in patients with systemic lupus erythematosus. Clin. Exp. Immunol. 2001, 125, 485–491. [Google Scholar] [CrossRef] [PubMed]
  54. Gallo, D.; Mortara, L.; Gariboldi, M.B.; Cattaneo, S.A.M.; Rosetti, S.; Gentile, L.; Noonan, D.M.; Premoli, P.; Cusini, C.; Tanda, M.L.; et al. Immunomodulatory effect of vitamin D and its potential role in the prevention and treatment of thyroid autoimmunity: A narrative review. J. Endocrinol. Investig. 2020, 43, 413–429. [Google Scholar] [CrossRef]
  55. McDonnell, D.P.; Pike, J.W.; O’Malley, B.W. The vitamin D receptor: A primitive steroid receptor related to thyroid hormone receptor. J. Steroid Biochem. 1988, 30, 41–46. [Google Scholar] [CrossRef]
  56. Berg, J.P.; Liane, K.M.; Bjørhovde, S.B.; Bjøro, T.; Torjesen, P.A.; Haug, E. Vitamin D receptor binding and biological effects of cholecalciferol analogues in rat thyroid cells. J. Steroid Biochem. Mol. Biol. 1994, 50, 145–150. [Google Scholar] [CrossRef]
  57. Bouillon, R.; Carmeliet, G.; Verlinden, L.; van Etten, E.; Verstuyf, A.; Luderer, H.F.; Lieben, L.; Mathieu, C.; Demay, M. Vitamin D and human health: Lessons from vitamin D receptor null mice. Endocr. Rev. 2008, 29, 726–776. [Google Scholar] [CrossRef]
  58. Fournier, C.; Gepner, P.; Sadouk, M.; Charreire, J. In vivo beneficial effects of cyclosporin A and 1,25-dihydroxyvitamin D3 on the induction of experimental autoimmune thyroiditis. Clin. Immunol. Immunopathol. 1990, 4, 53–63. [Google Scholar] [CrossRef]
  59. Borgogni, E.; Sarchielli, E.; Sottili, M.; Santarlasci, V.; Cosmi, L.; Gelmini, S.; Lombardi, A.; Cantini, G.; Perigli, G.; Luconi, M.; et al. Elocalcitol inhibits inflammatory responses in human thyroid cells and T cells. Endocrinology 2008, 149, 3626–3634. [Google Scholar] [CrossRef][Green Version]
  60. Misharin, A.; Hewison, M.; Chen, C.R.; Lagishetty, V.; Aliesky, H.A.; Mizutori, Y.; Rapoport, B.; McLachlan, S.M. Vitamin D deficiency modulates Graves’ hyperthyroidism induced in BALB/c mice by thyrotropin receptor immunization. Endocrinology 2009, 50, 1051–1060. [Google Scholar] [CrossRef][Green Version]
  61. Liu, S.; Xiong, F.; Liu, E.M.; Zhu, M.; Lei, P.Y. Effects of 1,25-dihydroxyvitamin D3 in rats with experimental autoimmune thyroiditis. J. South. Med. Univ. 2010, 30, 1573–1576. [Google Scholar]
  62. Wang, J.; Lv, S.; Chen, G.; Gao, C.; He, J.; Zhong, H.; Xu, Y. Meta-analysis of the association between vitamin D and autoimmune thyroid disease. Nutrients 2015, 7, 2485–2498. [Google Scholar] [CrossRef] [PubMed][Green Version]
  63. Caturegli, P.; De Remigis, A.; Rose, N.R. Hashimoto thyroiditis: Clinical and diagnostic criteria. Autoimmun. Rev. 2014, 13, 391–397. [Google Scholar] [CrossRef] [PubMed]
  64. Tamer, G.; Arik, S.; Tamer, I.; Coksert, D. Relative vitamin D insufficiency in Hashimoto’s thyroiditis. Thyroid 2011, 21, 891–896. [Google Scholar] [CrossRef] [PubMed]
  65. Mackawy, A.M.; Al-Ayed, B.M.; Al-Rashidi, B.M. Vitamin d deficiency and its association with thyroid disease. Int. J. Health Sci. 2013, 7, 267–275. [Google Scholar] [CrossRef] [PubMed]
  66. Unal, A.D.; Tarcin, O.; Parildar, H.; Cigerli, O.; Eroglu, H.; Demirag, N.G. Vitamin D deficiency is related to thyroid antibodies in autoimmune thyroiditis. Cent. Eur. J. Immunol. 2014, 39, 493–497. [Google Scholar] [CrossRef]
  67. Ke, W.; Sun, T.; Zhang, Y.; He, L.; Wu, Q.; Liu, J.; Zha, B. 25-Hydroxyvitamin D serum level in Hashimoto’s thyroiditis, but not Graves’ disease is relatively deficient. Endocr. J. 2017, 64, 581–587. [Google Scholar] [CrossRef][Green Version]
  68. Goswami, R.; Marwaha, R.K.; Gupta, N.; Tandon, N.; Sreenivas, V.; Tomar, N.; Ray, D.; Kanwar, R.; Agarwal, R. Prevalence of vitamin D deficiency and its relationship with thyroid autoimmunity in Asian Indians: A community-based survey. Br. J. Nutr. 2009, 102, 382–386. [Google Scholar] [CrossRef][Green Version]
  69. Infante, M.; Ricordi, C.; Sanchez, J.; Clare-Salzler, M.J.; Padilla, N.; Fuenmayor, V.; Chavez, C.; Alvarez, A.; Baidal, D.; Alejandro, R.; et al. Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes. Nutrients 2019, 11, 2185. [Google Scholar] [CrossRef][Green Version]
  70. Bartosik-Psujek, H.; Psujek, M. Vitamin D as an immune modulator in multiple sclerosis. Neurol. Neurochir. Pol. 2019, 53, 113–122. [Google Scholar] [CrossRef][Green Version]
  71. Camurdan, O.M.; Döğer, E.; Bideci, A.; Celik, N.; Cinaz, P. Vitamin D status in children with Hashimoto thyroiditis. J. Pediatr. Endocrinol. Metab. 2012, 25, 467–470. [Google Scholar] [CrossRef] [PubMed]
  72. Shin, D.Y.; Kim, K.J.; Kim, D.; Hwang, S.; Lee, E.J. Low serum vitamin D is associated with anti-thyroid peroxidase antibody in autoimmune thyroiditis. Yonsei Med. J. 2014, 55, 476–481. [Google Scholar] [CrossRef] [PubMed][Green Version]
  73. Wang, X.; Zynat, J.; Guo, Y.; Osiman, R.; Tuhuti, A.; Zhao, H.; Abdunaimu, M.; Wang, H.; Jin, X.; Xing, S. Low serum vitamin D is associated with anti-thyroid-globulin antibody in female individuals. Int. J. Endocrinol. 2015. [Google Scholar] [CrossRef] [PubMed][Green Version]
  74. ElRawi, H.A.; Ghanem, N.S.; ElSayed, N.M.; Ali, H.M.; Rashed, L.A.; Mansour, M.M. Study of Vitamin D Level and Vitamin D Receptor Polymorphism in Hypothyroid Egyptian Patients. J. Thyroid Res. 2019. [Google Scholar] [CrossRef] [PubMed][Green Version]
  75. Kim, C.Y.; Lee, Y.J.; Choi, J.H.; Lee, S.Y.; Lee, H.Y.; Jeong, D.H.; Choi, Y.J. The Association between Low Vitamin D Status and Autoimmune Thyroid Disease in Korean Premenopausal Women: The 6th Korea National Health and Nutrition Examination Survey, 2013–2014. Korean J. Fam. Med. 2019, 40, 323–328. [Google Scholar] [CrossRef] [PubMed][Green Version]
  76. Bozkurt, N.C.; Karbek, B.; Ucan, B.; Sahin, M.; Cakal, E.; Ozbek, M.; Delibasi, T. The association between severity of vitamin D deficiency and Hashimoto’s thyroiditis. Endocr. Pract. 2013, 19, 479–484. [Google Scholar] [CrossRef] [PubMed][Green Version]
  77. Choi, Y.M.; Kim, W.G.; Kim, T.Y.; Bae, S.J.; Kim, H.K.; Jang, E.K.; Jeon, M.J.; Han, J.M.; Lee, S.H.; Baek, J.H.; et al. Low levels of serum vitamin D3 are associated with autoimmune thyroid disease in pre-menopausal women. Thyroid 2014, 24, 655–661. [Google Scholar] [CrossRef]
  78. Evliyaoğlu, O.; Acar, M.; Özcabı, B.; Erginöz, E.; Bucak, F.; Ercan, O.; Kucur, M. Vitamin D deficiency and Hashimoto’s thyroiditis in children and adolescents: A critical vitamin D level for this association? J. Clin. Res. Pediatr. Endocrinol. 2015, 7, 128–133. [Google Scholar] [CrossRef]
  79. Kim, D. Low vitamin D status is associated with hypothyroid Hashimoto’s thyroiditis. Hormones 2016, 15, 385–393. [Google Scholar] [CrossRef][Green Version]
  80. Muscogiuri, G.; Mari, D.; Prolo, S.; Fatti, L.M.; Cantone, M.C.; Garagnani, P. 25 Hydroxyvitamin D deficiency and its relationship to autoimmune thyroid disease in the elderly. Int. J. Environ. Res. Public Health 2016, 13, 850. [Google Scholar] [CrossRef]
  81. Kim, M.; Song, E.; Oh, H.S.; Park, S.; Kwon, H.; Jeon, M.J.; Kim, W.G.; Kim, W.B.; Shong, Y.K.; Kim, T.Y. Vitamin D deficiency affects thyroid autoimmunity and dysfunction in iodine-replete area: Korea national health and nutrition examination survey. Endocrine 2017, 58, 332–339. [Google Scholar] [CrossRef] [PubMed]
  82. Simsek, Y.; Cakır, I.; Yetmis, M.; Dizdar, O.S.; Baspinar, O.; Gokay, F. Effects of vitamin D treatment on thyroid autoimmunity. J. Res. Med. Sci. 2016, 21, 85. [Google Scholar] [PubMed]
  83. Chaudhary, S.; Dutta, D.; Kumar, M.; Saha, S.; Mondal, S.A.; Kumar, A.; Mukhopadhyay, S. Vitamin D supplementation reduces thyroid peroxidase antibody levels in patients with autoimmune thyroid disease: An open-labeled randomized controlled trial. Indian J. Endocrinol. Metab. 2016, 20, 391–398. [Google Scholar] [PubMed]
  84. Krysiak, R.; Szkróbka, W.; Okopień, B. The effect of vitamin D on thyroid autoimmunity in levothyroxine-treated women with Hashimoto’s thyroiditis and normal vitamin D Status. Exp. Clin. Endocrinol. Diabetes 2017, 125, 229–233. [Google Scholar] [CrossRef]
  85. Krysiak, R.; Kowalcze, K.; Okopień, B. Selenomethionine potentiates the impact of vitamin D on thyroid autoimmunity in euthyroid women with Hashimoto’s thyroiditis and low vitamin D status. Pharmacol. Rep. 2018, 71, 367–373. [Google Scholar] [CrossRef]
  86. Mansournia, N.; Mansournia, M.A.; Saeedi, S.; Dehghan, J. The association between serum 25OHD levels and hypothyroid Hashimoto’s thyroiditis. J. Endocrinol. Investig. 2014, 37, 473–476. [Google Scholar] [CrossRef]
  87. Mirhosseini, N.; Brunel, L.; Muscogiuri, G.; Kimball, S. Physiological serum 25-hydroxyvitamin D concentrations are associated with improved thyroid function-observations from a community-based program. Endocrine 2017, 58, 563–573. [Google Scholar] [CrossRef][Green Version]
  88. Chahardoli, R.; Saboor-Yaraghi, A.A.; Amouzegar, A.; Khalili, D.; Vakili, A.Z.; Azizi, F. Can supplementation with vitamin D modify thyroid autoantibodies (Anti-TPO Ab, Anti-Tg Ab) and thyroid profile (T3, T4, TSH) in Hashimoto’s thyroiditis? A double blind, Randomized clinical trial. Horm. Metab. Res. 2019, 51, 296–301. [Google Scholar] [CrossRef]
  89. Effraimidis, G.; Badenhoop, K.; Tijssen, J.G.; Wiersinga, W.M. Vitamin D deficiency is not associated with early stages of thyroid autoimmunity. Eur. J. Endocrinol. 2012, 167, 43–48. [Google Scholar] [CrossRef][Green Version]
  90. Yasmeh, J.; Farpour, F.; Rizzo, V.; Kheradnam, S.; Sachmechi, I. Hashimoto thyroiditis not associated with vitamin d deficiency. Endocr. Pract. 2016, 22, 809–813. [Google Scholar] [CrossRef]
  91. Gao, X.R.; Yu, Y.G. Meta-Analysis of the Association between Vitamin D Receptor Polymorphisms and the Risk of Autoimmune Thyroid Disease. Int. J. Endocrinol. 2018, 2018, 2846943. [Google Scholar] [CrossRef] [PubMed][Green Version]
  92. van Etten, E.; Verlinden, L.; Giulietti, A.; Ramos-Lopez, E.; Branisteanu, D.D.; Ferreira, G.B.; Overbergh, L.; Verstuyf, A.; Bouillon, R.; Roep, B.O.; et al. The vitamin D receptor gene FokI polymorphism: Functional impact on the immune system. Eur. J. Immunol. 2007, 37, 395–405. [Google Scholar] [CrossRef] [PubMed]
  93. Inoue, N.; Watanabe, M.; Ishido, N.; Katsumata, Y.; Kagawa, T.; Hidaka, Y.; Iwatani, Y. The functional polymorphisms of VDR, GC and CYP2R1 are involved in the pathogenesis of autoimmune thyroid diseases. Clin. Exp. Immunol. 2014, 178, 262–269. [Google Scholar] [CrossRef] [PubMed]
  94. Feng, M.; Li, H.; Chen, S.F.; Li, W.F.; Zhang, F.B. Polymorphisms in the vitamin D receptor gene and risk of autoimmune thyroid diseases: A meta-analysis. Endocrine 2013, 43, 318–326. [Google Scholar] [CrossRef] [PubMed]
  95. Wang, X.; Cheng, W.; Ma, Y.; Zhu, J. Vitamin D receptor gene FokI but not TaqI, ApaI, BsmI polymorphism is associated with Hashimoto’s thyroiditis: A meta-analysis. Sci. Rep. 2017, 7. [Google Scholar] [CrossRef] [PubMed]
  96. Saggese, G.; Vierucci, F.; Prodam, F.; Cardinale, F.; Cetin, I.; Chiappini, E.; De’ Angelis, G.L.; Massari, M.; Miraglia Del Giudice, E.; Miraglia Del Giudice, M.; et al. Vitamin D in pediatric age: Consensus of the Italian Pediatric Society and the Italian Society of Preventive and Social Pediatrics, jointly with the Italian Federation of Pediatricians. Ital. J. Pediatr. 2018, 44, 51. [Google Scholar] [CrossRef][Green Version]
  97. Cooper, G.S.; Stroehla, B.C. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2003, 2, 119–125. [Google Scholar] [CrossRef]
  98. Menconi, F.; Marcocci, C.; Marino, M. Diagnosis and classification of Graves’ disease. Autoimmun. Rev. 2014, 13, 398–402. [Google Scholar] [CrossRef]
  99. Wiersinga, W.M. Clinical relevance of environmental factors in the pathogenesis of autoimmune thyroid disease. Endocrinol. Metab. 2016, 31, 213–222. [Google Scholar] [CrossRef]
  100. Yasuda, T.; Okamoto, Y.; Hamada, N.; Miyashita, K.; Takahara, M.; Sakamoto, F.; Miyatsuka, T.; Kitamura, T.; Katakami, N.; Kawamori, D.; et al. Serum vitamin D levels are decreased in patients without remission of Graves’ disease. Endocrine 2013, 43, 230–232. [Google Scholar] [CrossRef][Green Version]
  101. Yasuda, T.; Okamoto, Y.; Hamada, N.; Miyashita, K.; Takahara, M.; Sakamoto, F.; Miyatsuka, T.; Kitamura, T.; Katakami, N.; Kawamori, D.; et al. Serum vitamin D levels are decreased and associated with thyroid volume in female patients with newly onset Graves’ disease. Endocrine 2012, 42, 739–741. [Google Scholar] [CrossRef] [PubMed][Green Version]
  102. Planck, T.; Shahida, B.; Malm, J.; Manjer, J. Vitamin D in Graves Disease: Levels, Correlation with Laboratory and Clinical Parameters, and Genetics. Eur. Thyroid J. 2018, 7, 27–33. [Google Scholar] [CrossRef] [PubMed]
  103. Mangaraj, S.; Choudhury, A.K.; Swain, B.M.; Sarangi, P.K.; Mohanty, B.K.; Baliarsinha, A.K. Evaluation of vitamin D status and its impact on thyroid related parameters in new onset Graves’ disease—A cross-sectional observational study. Indian J. Endocrinol. Metab. 2019, 23, 35–39. [Google Scholar] [PubMed]
  104. Zhang, H.; Liang, L.; Xie, Z. Low Vitamin D Status is Associated with Increased Thyrotropin-Receptor Antibody Titer in Graves Disease. Endocr. Pract. 2015, 21, 258–263. [Google Scholar] [CrossRef]
  105. Xu, M.Y.; Cao, B.; Yin, J.; Wang, D.F.; Chen, K.L.; Lu, Q.B. Vitamin D and Graves’ disease: A meta-analysis update. Nutrients 2015, 7, 3813–3827. [Google Scholar] [CrossRef][Green Version]
  106. Cho, Y.Y.; Chung, Y.J. Vitamin D supplementation does not prevent the recurrence of Graves’ disease. Sci. Rep. 2020, 10, 16. [Google Scholar] [CrossRef][Green Version]
  107. Zhou, H.; Xu, C.; Gu, M. Vitamin D receptor (VDR) gene polymorphisms and Graves’ disease: A meta-analysis. Clin. Endocrinol. (Oxf.) 2009, 70, 938–945. [Google Scholar] [CrossRef]
  108. Stagnaro-Green, A. Postpartum thyroiditis. Best Pract. Res. Clin. Endocrinol. Metab. 2004, 18, 303–316. [Google Scholar] [CrossRef]
  109. Nettore, I.C.; Albano, L.; Ungaro, P.; Colao, A.; Macchia, P.E. Sunshine vitamin and thyroid. Rev. Endocr. Metab. Disord. 2017, 18, 347–354. [Google Scholar] [CrossRef][Green Version]
  110. Premawardhana, L.D.; Parkes, A.B.; Ammari, F.; John, R.; Darke, C.; Adams, H.; Lazarus, J.H. Postpartum thyroiditis and long-term thyroid status: Prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J. Clin. Endocrinol. Metab. 2000, 85, 71–75. [Google Scholar] [CrossRef]
  111. Krysiak, R.; Kowalska, B.; Okopien, B. Serum 25-Hydroxyvitamin D and Parathyroid Hormone Levels in Non-Lactating Women with Post-Partum Thyroiditis: The Effect of L-Thyroxine Treatment. Basic Clin. Pharmacol. Toxicol. 2015, 116, 503–507. [Google Scholar] [CrossRef] [PubMed]
  112. Krysiak, R.; Kowalcze, K.; Okopien, B. The effect of vitamin D on thyroid autoimmunity in non-lactating women with postpartum thyroiditis. Eur. J. Clin. Nutr. 2016, 70, 637–639. [Google Scholar] [CrossRef] [PubMed]
  113. Sahin, M.; Corapcioglu, D. The effect of vitamin D on thyroid autoimmunity in non-lactating women with postpartum thyroiditis. Eur. J. Clin. Nutr. 2016, 70, 864. [Google Scholar] [CrossRef] [PubMed][Green Version]
  114. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed][Green Version]
  115. Cabanillas, M.E.; McFadden, D.G.; Durante, C. Thyroid cancer. Lancet 2016, 388, 2783–2795. [Google Scholar] [CrossRef]
  116. Rees Smith, B.; McLachlan, S.M.; Furmaniak, J. Autoantibodies to the thyrotropin receptor. Endocr. Rev. 1988, 9, 106–121. [Google Scholar] [CrossRef]
  117. Valenti, T.M.; Macchia, E.; Pisa, R.; Bucalo, M.L.; Russo, V.; Colletti, I.; Compagno, V.; Abbadi, V.; Donatelli, M. Toxic adenoma and papillary thyroid carcinoma in a patient with Graves’ disease. J. Endocrinol. Investig. 1999, 22, 701–704. [Google Scholar] [CrossRef]
  118. Jonklaas, J.; Nsouli-Maktabi, H.; Soldin, S.J. Endogenous thyrotropin and triiodothyronine concentrations in individuals with thyroid cancer. Thyroid 2008, 18, 943–952. [Google Scholar] [CrossRef][Green Version]
  119. Krassas, G.E.; Poppe, K.; Glinoer, D. Thyroid function and human reproductive health. Endocr. Rev. 2010, 31, 702–755. [Google Scholar] [CrossRef][Green Version]
  120. Liang, L.; Zheng, X.C.; Hu, M.J.; Zhang, Q.; Wang, S.Y.; Huang, F. Association of benign thyroid diseases with thyroid cancer risk: A meta-analysis of prospective observational studies. J. Endocrinol. Investig. 2019, 42, 673–685. [Google Scholar] [CrossRef]
  121. Nettore, I.C.; Colao, A.; Macchia, P.E. Nutritional and Environmental Factors in Thyroid Carcinogenesis. Int. J. Environ. Res. Public Health 2018, 15, 1735. [Google Scholar] [CrossRef] [PubMed][Green Version]
  122. Vigneri, R.; Malandrino, P.; Gianì, F.; Russo, M.; Vigneri, P. Heavy metals in the volcanic environment and thyroid cancer. Mol. Cell. Endocrinol. 2017, 457, 73–80. [Google Scholar] [CrossRef] [PubMed]
  123. Marcello, M.A.; Malandrino, P.; Almeida, J.F.; Martins, M.B.; Cunha, L.L.; Bufalo, N.E.; Pellegriti, G.; Ward, L.S. The influence of the environment on the development of thyroid tumors: A new appraisal. Endocr. Relat. Cancer 2014, 21, T235–T254. [Google Scholar] [CrossRef] [PubMed]
  124. Ilie, M.I.; Lassalle, S.; Long-Mira, E.; Hofman, V.; Zangari, J.; Bénaim, G.; Bozec, A.; Guevara, N.; Haudebourg, J.; Birtwisle-Peyrottes, I.; et al. In papillary thyroid carcinoma, TIMP-1 expression correlates with BRAF (V600E) mutation status and together with hypoxia-related proteins predicts aggressive behavior. Virchows Arch. 2013, 463, 437–444. [Google Scholar] [CrossRef]
  125. Kitahara, C.M.; K Rmendiné Farkas, D.; Jørgensen, J.O.L.; Cronin-Fenton, D.; Sørensen, H.T. Benign Thyroid Diseases and Risk of Thyroid Cancer: A Nationwide Cohort Study. J. Clin. Endocrinol. Metab. 2018, 103, 2216–2224. [Google Scholar] [CrossRef]
  126. Repplinger, D.; Bargren, A.; Zhang, Y.W.; Adler, J.T.; Haymart, M.; Chen, H. Is Hashimoto’s thyroiditis a risk factor for papillary thyroid cancer? J. Surg. Res. 2008, 150, 49–52. [Google Scholar] [CrossRef][Green Version]
  127. Khatami, M. Inflammation, aging, and cancer: Tumoricidal versus tumorigenesis of immunity: A common denominator mapping chronic diseases. Cell Biochem. Biophys. 2009, 55, 55–79. [Google Scholar] [CrossRef]
  128. Guarino, V.; Castellone, M.D.; Avilla, E.; Melillo, R.M. Thyroid cancer and inflammation. Mol. Cell. Endocrinol. 2010, 321, 94–102. [Google Scholar] [CrossRef][Green Version]
  129. Melillo, R.M.; Guarino, V.; Avilla, E.; Galdiero, M.R.; Liotti, F.; Prevete, N.; Rossi, F.W.; Basolo, F.; Ugolini, C.; de Paulis, A.; et al. Mast cells have a protumorigenic role in human thyroid cancer. Oncogene 2010, 29, 6203–6215. [Google Scholar] [CrossRef][Green Version]
  130. Cunha, L.L.; Marcello, M.A.; Ward, L.S. The role of the inflammatory microenvironment in thyroid carcinogenesis. Endocr. Relat. Cancer 2014, 21, R85–R103. [Google Scholar] [CrossRef][Green Version]
  131. Resende de Paiva, C.; Grønhøj, C.; Feldt-Rasmussen, U.; von Buchwald, C. Association between Hashimoto’s Thyroiditis and Thyroid Cancer in 64,628 Patients. Front. Oncol. 2017, 7, 53. [Google Scholar] [CrossRef] [PubMed][Green Version]
  132. Pagano, L.; Mele, C.; Sama, M.T.; Zavattaro, M.; Caputo, M.; De Marchi, L.; Paggi, S.; Prodam, F.; Aimaretti, G.; Marzullo, P. Thyroid cancer phenotypes in relation to inflammation and autoimmunity. Front. Biosci. (Landmark. Ed.) 2018, 23, 2267–2282. [Google Scholar] [PubMed]
  133. Zhao, J.; Wang, H.; Zhang, Z.; Zhou, X.; Yao, J.; Zhang, R.; Liao, L.; Dong, J. Vitamin D deficiency as a risk factor for thyroid cancer: A meta-analysis of case-control studies. Nutrition 2019, 57, 5–11. [Google Scholar] [CrossRef] [PubMed]
  134. Muzza, M.; Degl’Innocenti, D.; Colombo, C.; Perrino, M.; Ravasi, E.; Rossi, S.; Cirello, V.; Beck-Peccoz, P.; Borrello, M.G.; Fugazzola, L. The tight relationship between papillary thyroid cancer, autoimmunity and inflammation: Clinical and molecular studies. Clin. Endocrinol. (Oxf.) 2010, 72, 702–708. [Google Scholar] [CrossRef]
  135. Sica, A.; Allavena, P.; Mantovani, A. Cancer related inflammation: The macrophage connection. Cancer Lett. 2008, 267, 204–215. [Google Scholar] [CrossRef]
  136. Díaz, L.; Díaz-Muñoz, M.; García-Gaytán, A.C.; Méndez, I. Mechanistic Effects of Calcitriol in Cancer Biology. Nutrients 2015, 7, 5020–5050. [Google Scholar] [CrossRef][Green Version]
  137. Clinckspoor, I.; Verlinden, L.; Mathieu, C.; Bouillon, R.; Verstuyf, A.; Decallonne, B. Vitamin D in thyroid tumorigenesis and development. Prog. Histochem. Cytochem. 2013, 48, 65–98. [Google Scholar] [CrossRef]
  138. Feldman, D.; Krishnan, A.V.; Swami, S.; Giovannucci, E.; Feldman, B.J. The role of vitamin D in reducing cancer risk and progression. Nat. Rev. Cancer 2014, 14, 342–357. [Google Scholar] [CrossRef]
  139. Lemire, J.M.; Adams, J.S.; Kermani-Arab, V.; Bakke, A.C.; Sakai, R.; Jordan, S.C. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J. Immunol. 1985, 134, 3032–3035. [Google Scholar]
  140. Passler, C.; Scheuba, C.; Prager, G.; Kaczirek, K.; Kaserer, K.; Zettinig, G.; Niederle, B. Prognostic factors of papillary and follicular thyroid cancer: Differences in an iodine-replete endemic goiter region. Endocr. Relat. Cancer 2004, 11, 131–139. [Google Scholar] [CrossRef][Green Version]
  141. Friedrich, M.; Rafi, L.; Mitschele, T.; Tilgen, W.; Schmidt, W.; Reichrath, J. Analysis of the vitamin D system in cervical carcinomas, breast cancer and ovarian cancer. Recent Results Cancer Res. 2003, 164, 239–246. [Google Scholar]
  142. Matusiak, D.; Murillo, G.; Carroll, R.E.; Mehta, R.G.; Benya, R.V. Expression of vitamin D receptor and 25-hydroxyvitamin D3-1{alpha}-hydroxylase in normal and malignant human colon. Cancer Epidemiol. Biomark. Prev. 2005, 14, 2370–2376. [Google Scholar] [CrossRef] [PubMed][Green Version]
  143. Agic, A.; Xu, H.; Altgassen, C.; Noack, F.; Wolfler, M.M.; Diedrich, K.; Friedrich, M.; Taylor, R.N.; Hornung, D. Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin D 1 alpha-hydroxylase, vitamin D 24-hydroxylase, and vitamin D 25-hydroxylase in endometriosis and gynecologic cancers. Reprod. Sci. 2007, 14, 486–497. [Google Scholar] [CrossRef] [PubMed]
  144. McCarthy, K.; Laban, C.; McVittie, C.J.; Ogunkolade, W.; Khalaf, S.; Bustin, S.; Carpenter, R.; Jenkins, P.J. The expression and function of IGFBP-3 in normal and malignant breast tissue. Anticancer Res. 2009, 29, 3785–3790. [Google Scholar] [PubMed]
  145. Khadzkou, K.; Buchwald, P.; Westin, G.; Dralle, H.; Akerström, G.; Hellman, P. 25-hydroxyvitamin D3 1alpha-hydroxylase and vitamin D receptor expression in papillary thyroid carcinoma. J. Histochem. Cytochem. 2006, 54, 355–361. [Google Scholar] [CrossRef][Green Version]
  146. Clinckspoor, I.; Hauben, E.; Verlinden, L.; Van den Bruel, A.; Vanwalleghem, L.; Vander Poorten, V.; Delaere, P.; Mathieu, C.; Verstuyf, A.; Decallonne, B. Altered expression of key players in vitamin D metabolism and signaling in malignant and benign thyroid tumors. J. Histochem. Cytochem. 2012, 60, 502–511. [Google Scholar] [CrossRef][Green Version]
  147. Liu, W.; Asa, S.L.; Ezzat, S. 1alpha,25-Dihydroxyvitamin D3 targets PTEN-dependent fibronectin expression to restore thyroid cancer cell adhesiveness. Mol. Endocrinol. 2005, 19, 2349–2357. [Google Scholar] [CrossRef][Green Version]
  148. Deeb, K.K.; Trump, D.L.; Johnson, C.S. Vitamin D signalling pathways in cancer: Potential for anticancer therapeutics. Nat. Rev. Cancer 2007, 7, 684–700. [Google Scholar] [CrossRef]
  149. Eelen, G.; Gysemans, C.; Verlinden, L.; Vanoirbeek, E.; De Clercq, P.; Van Haver, D.; Mathieu, C.; Bouillon, R.; Verstuyf, A. Mechanism and potential of the growth-inhibitory actions of vitamin D and analogs. Curr. Med. Chem. 2007, 14, 1893–1910. [Google Scholar] [CrossRef]
  150. Yavropoulou, M.P.; Panagiotou, G.; Topouridou, K.; Karayannopoulou, G.; Koletsa, T.; Zarampoukas, T.; Goropoulos, A.; Chatzaki, E.; Yovos, J.G.; Pazaitou-Panayiotou, K. Vitamin D receptor and progesterone receptor protein and gene expression in papillary thyroid carcinomas: Associations with histological features. J. Endocrinol. Investig. 2017, 40, 1327–1335. [Google Scholar] [CrossRef]
  151. Izkhakov, E.; Somjen, D.; Sharon, O.; Knoll, E.; Aizic, A.; Fliss, D.M.; Limor, R.; Stern, N. Vitamin D receptor expression is linked to potential markers of human thyroid papillary carcinoma. J. Steroid Biochem. Mol. Biol. 2016, 159, 26–30. [Google Scholar] [CrossRef] [PubMed]
  152. Zhang, T.; Zhang, H.; He, L.; Wang, Z.; Dong, W.; Sun, W.; Zhang, P. Potential Use of 1-25-dihydroxyvitamin D in the Diagnosis and Treatment of Papillary Thyroid Cancer. Med. Sci. Monit. 2018, 24, 1614–1623. [Google Scholar] [CrossRef] [PubMed][Green Version]
  153. Bennett, R.G.; Wakeley, S.E.; Hamel, F.G.; High, R.R.; Korch, C.; Goldner, W.S. Gene expression of vitamin D metabolic enzymes at baseline and in response to vitamin D treatment in thyroid cancer cell lines. Oncology 2012, 83, 264–272. [Google Scholar] [CrossRef] [PubMed][Green Version]
  154. Chiang, K.C.; Kuo, S.F.; Chen, C.H.; Ng, S.; Lin, S.F.; Yeh, C.N.; Chen, L.W.; Takano, M.; Chen, T.C.; Juang, H.H.; et al. MART-10, the vitamin D analog, is a potent drug to inhibit anaplastic thyroid cancer cell metastatic potential. Cancer Lett. 2015, 369, 76–85. [Google Scholar] [CrossRef] [PubMed]
  155. Peng, W.; Wang, K.; Zheng, R.; Derwahl, M. 1,25 dihydroxyvitamin D3 inhibits the proliferation of thyroid cancer stem-like cells via cell cycle arrest. Endocr. Res. 2016, 41, 71–80. [Google Scholar] [CrossRef]
  156. Suzuki, S.; Takenoshita, S.; Furukawa, H.; Tsuchiya, A. Antineoplastic activity of 1,25(OH)2D3 and its analogue 22-oxacalcitriol against human anaplastic thyroid carcinoma cell lines in vitro. Int. J. Mol. Med. 1999, 4, 611–614. [Google Scholar] [CrossRef]
  157. Liu, W.; Asa, S.L.; Fantus, I.G.; Walfish, P.G.; Ezzat, S. Vitamin D arrests thyroid carcinoma cell growth and induces p27 dephosphorylation and accumulation through PTEN/akt-dependent and -independent pathways. Am. J. Pathol. 2002, 160, 511–519. [Google Scholar] [CrossRef][Green Version]
  158. Dackiw, A.P.; Ezzat, S.; Huang, P.; Liu, W.; Asa, S.L. Vitamin D3 administration induces nuclear p27 accumulation, restores differentiation, and reduces tumor burden in a mouse model of metastatic follicular thyroid cancer. Endocrinology 2004, 145, 5840–5846. [Google Scholar] [CrossRef][Green Version]
  159. Heidari, Z.; Nikbakht, M.; Mashhadi, M.A.; Jahantigh, M.; Mansournia, N.; Sheikhi, V.; Mansournia, M.A. Vitamin D Deficiency Associated with Differentiated Thyroid Carcinoma: A Case-Control Study. Asian Pac. J. Cancer Prev. 2017, 18, 3419–3422. [Google Scholar]
  160. Penna-Martinez, M.; Ramos-Lopez, E.; Stern, J.; Hinsch, N.; Hansmann, M.L.; Selkinski, I.; Grünwald, F.; Vorländer, C.; Wahl, R.A.; Bechstein, W.O.; et al. Vitamin D receptor polymorphisms in differentiated thyroid carcinoma. Thyroid 2009, 19, 623–628. [Google Scholar] [CrossRef]
  161. Penna-Martinez, M.; Ramos-Lopez, E.; Stern, J.; Kahles, H.; Hinsch, N.; Hansmann, M.L.; Selkinski, I.; Grünwald, F.; Vorländer, C.; Bechstein, W.O.; et al. Impaired vitamin D activation and association with CYP24A1 haplotypes in differentiated thyroid carcinoma. Thyroid 2012, 22, 709–716. [Google Scholar] [CrossRef] [PubMed][Green Version]
  162. Roskies, M.; Dolev, Y.; Caglar, D.; Hier, M.P.; Mlynarek, A.; Majdan, A.; Payne, R.J. Vitamin D deficiency as a potentially modifiable risk factor for thyroid cancer. J. Otolaryngol. Head Neck Surg. 2012, 41, 160–163. [Google Scholar] [PubMed]
  163. Sahin, M.; Uçan, B.; Giniş, Z.; Topaloğlu, O.; Güngüneş, A.; Bozkurt, N.Ç.; Arslan, M.S.; Ünsal, İ.Ö.; Akkaymak, E.T.; Demirci, T.; et al. Vitamin D3 levels and insulin resistance in papillary thyroid cancer patients. Med. Oncol. 2013, 30, 589. [Google Scholar] [CrossRef] [PubMed]
  164. Stepien, T.; Krupinski, R.; Sopinski, J.; Kuzdak, K.; Komorowski, J.; Lawnicka, H.; Stepien, H. Decreased 1-25 dihydroxyvitamin D3 concentration in peripheral blood serum of patients with thyroid cancer. Arch. Med. Res. 2010, 41, 190–194. [Google Scholar] [CrossRef] [PubMed]
  165. Choi, Y.M.; Kim, W.G.; Kim, T.Y.; Bae, S.J.; Kim, H.K.; Jang, E.K.; Jeon, M.J.; Han, J.M.; Shong, Y.K.; Kim, W.B. Serum vitamin D3 levels are not associated with thyroid cancer prevalence in euthyroid subjects without autoimmune thyroid disease. Korean J. Intern. Med. 2017, 32, 102–108. [Google Scholar] [CrossRef] [PubMed][Green Version]
  166. Danilovic, D.L.; Ferraz-de-Souza, B.; Fabri, A.W.; Santana, N.O.; Kulcsar, M.A.; Cernea, C.R.; Marui, S.; Hoff, A.O. 25-Hydroxyvitamin D and TSH as Risk Factors or Prognostic Markers in Thyroid Carcinoma. PLoS ONE 2016, 11, e0164550. [Google Scholar] [CrossRef]
  167. Jonklaas, J.; Danielsen, M.; Wang, H. A pilot study of serum selenium, vitamin D, and thyrotropin concentrations in patients with thyroid cancer. Thyroid 2013, 23, 1079–1086. [Google Scholar] [CrossRef][Green Version]
  168. Laney, N.; Meza, J.; Lyden, E.; Erickson, J.; Treude, K.; Goldner, W. The Prevalence of Vitamin D Deficiency Is Similar between Thyroid Nodule and Thyroid Cancer Patients. Int. J. Endocrinol. 2010, 2010, 805716. [Google Scholar] [CrossRef]
  169. Hu, M.J.; Zhang, Q.; Liang, L.; Wang, S.Y.; Zheng, X.C.; Zhou, M.M.; Yang, Y.W.; Zhong, Q.; Huang, F. Association between vitamin D deficiency and risk of thyroid cancer: A case-control study and a meta-analysis. J. Endocrinol. Investig. 2018, 41, 1199–1210. [Google Scholar] [CrossRef]
  170. Kim, J.R.; Kim, B.H.; Kim, S.M.; Oh, M.Y.; Kim, W.J.; Jeon, Y.K.; Kim, S.S.; Lee, B.J.; Kim, Y.K.; Kim, I.J. Low serum 25 hydroxyvitamin D is associated with poor clinicopathologic characteristics in female patients with papillary thyroid cancer. Thyroid 2014, 24, 1618–1624. [Google Scholar] [CrossRef]
  171. Sulibhavi, A.; Rohlfing, M.L.; Jalisi, S.M.; McAneny, D.B.; Doherty, G.M.; Holick, M.F.; Noordzij, J.P. Vitamin D deficiency and its relationship to cancer stage in patients who underwent thyroidectomy for papillary thyroid carcinoma. Am. J. Otolaryngol. 2019, 40, 536–541. [Google Scholar] [CrossRef] [PubMed]
  172. Zhang, L.R.; Sawka, A.M.; Adams, L.; Hatfield, N.; Hung, R.J. Vitamin and mineral supplements and thyroid cancer: A systematic review. Eur. J. Cancer Prev. 2013, 22, 158–168. [Google Scholar] [CrossRef] [PubMed]
  173. O’Grady, T.J.; Kitahara, C.M.; DiRienzo, A.G.; Gates, M.A. The association between selenium and other micronutrients and thyroid cancer incidence in the NIH-AARP Diet and Health Study. PLoS ONE 2014, 9, e110886. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Scheme of vitamin D modulating role in immune response. As detailed in the text, vitamin D interferes with innate and adaptative immunity through different mechanisms. Arrows illustrate increase (↑), decrease (↓) or regulation/modulation (↗) of specific actions, processes, cells, or molecules. Abbreviations: CAMP, cathelicidin antimicrobial peptide; FasL, Fas-ligand; IL, Interleukin; NETs, neutrophil extracellular traps; TGF, transforming growth factor; Th, T helper; TNF, Tumor Necrosis Factor; Treg, T regulatory.
Figure 1. Scheme of vitamin D modulating role in immune response. As detailed in the text, vitamin D interferes with innate and adaptative immunity through different mechanisms. Arrows illustrate increase (↑), decrease (↓) or regulation/modulation (↗) of specific actions, processes, cells, or molecules. Abbreviations: CAMP, cathelicidin antimicrobial peptide; FasL, Fas-ligand; IL, Interleukin; NETs, neutrophil extracellular traps; TGF, transforming growth factor; Th, T helper; TNF, Tumor Necrosis Factor; Treg, T regulatory.
Nutrients 12 01444 g001
Figure 2. Scheme of the immunomodulating role of vitamin D on AITD. Arrows illustrate increase (↑), decrease (↓) or regulation/modulation (↗) of specific actions, processes, cells, or molecules. Abbreviations: autoAb, autoantibodies; GD, Graves’ disease; HT, Hashimoto’s thyroiditis; IFN, Interferon; IL, Interleukin; PPT, Post-partum thyroiditis; Th, T helper; TNF, Tumor Necrosis Factor; TPOAb, anti-thyroid peroxidase antibodies; TgAb, anti-thyroglobulin antibodies; TRAb, TSH receptor autoantibodies. Histological images are available at Histology Gallery, Yale Medical Cell Biology.
Figure 2. Scheme of the immunomodulating role of vitamin D on AITD. Arrows illustrate increase (↑), decrease (↓) or regulation/modulation (↗) of specific actions, processes, cells, or molecules. Abbreviations: autoAb, autoantibodies; GD, Graves’ disease; HT, Hashimoto’s thyroiditis; IFN, Interferon; IL, Interleukin; PPT, Post-partum thyroiditis; Th, T helper; TNF, Tumor Necrosis Factor; TPOAb, anti-thyroid peroxidase antibodies; TgAb, anti-thyroglobulin antibodies; TRAb, TSH receptor autoantibodies. Histological images are available at Histology Gallery, Yale Medical Cell Biology.
Nutrients 12 01444 g002
Figure 3. Scheme of the anti-neoplastic and anti-inflammatory role of vitamin D in thyroid tumorigenesis. Arrows illustrates increase (↑), decrease (↓), or regulation/modulation (↗) of specific actions, processes, cells, or molecules. Abbreviations: CDKI, cyclin dependent kinase inhibitors; PG, prostaglandin; TERT, telomerase reverse transcriptase.
Figure 3. Scheme of the anti-neoplastic and anti-inflammatory role of vitamin D in thyroid tumorigenesis. Arrows illustrates increase (↑), decrease (↓), or regulation/modulation (↗) of specific actions, processes, cells, or molecules. Abbreviations: CDKI, cyclin dependent kinase inhibitors; PG, prostaglandin; TERT, telomerase reverse transcriptase.
Nutrients 12 01444 g003

Share and Cite

MDPI and ACS Style

Mele, C.; Caputo, M.; Bisceglia, A.; Samà, M.T.; Zavattaro, M.; Aimaretti, G.; Pagano, L.; Prodam, F.; Marzullo, P. Immunomodulatory Effects of Vitamin D in Thyroid Diseases. Nutrients 2020, 12, 1444. https://doi.org/10.3390/nu12051444

AMA Style

Mele C, Caputo M, Bisceglia A, Samà MT, Zavattaro M, Aimaretti G, Pagano L, Prodam F, Marzullo P. Immunomodulatory Effects of Vitamin D in Thyroid Diseases. Nutrients. 2020; 12(5):1444. https://doi.org/10.3390/nu12051444

Chicago/Turabian Style

Mele, Chiara, Marina Caputo, Alessandro Bisceglia, Maria Teresa Samà, Marco Zavattaro, Gianluca Aimaretti, Loredana Pagano, Flavia Prodam, and Paolo Marzullo. 2020. "Immunomodulatory Effects of Vitamin D in Thyroid Diseases" Nutrients 12, no. 5: 1444. https://doi.org/10.3390/nu12051444

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop