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Immunomodulatory effect of vitamin D and its potential role in the prevention and treatment of thyroid autoimmunity: a narrative review
Abstract
The main role of vitamin D is to control mineral homeostasis. However, recent studies suggested the existence of a number of extraskeletal effects. Among the latter, preclinical studies provided consistent data on the involvement of vitamin D in innate and adaptive immunity and autoimmunity. Molecular biology studies showed that both vitamin D receptor and vitamin D enzymatic complexes are expressed in a large number of cells and tissues unrelated to mineral homeostasis. In contrast, only a few randomized clinical trials in humans investigated the possible role of vitamin D in the prevention or treatment of immunological disorders. In this regard, low serum vitamin D levels have been reported in observational trials in human autoimmune disorders. The aim of the present paper was to review the potential implications of vitamin D in immune modulation, with special focus on thyroid autoimmune disorders.
... Based on the assumption that calcitriol could successfully cooperate with cyclosporine in vitro, Fournier et al. tested this combination in experimental murine models of HT, showing that calcitriol plays a synergistic role in limiting thyroid damage [72]. Animal models that used mice previously sensitized with porcine thyroglobulin showed that VitD effectively decreased the severity of thyroid inflammation or prevented thyroiditis induction compared with control mice [74]. ...
... Most of the available randomized control trials demonstrated the ability of VitD to decrease the TPOAb titer [74,[81][82][83][84]. Krysiak reported that cholecalciferol effectively reduced TPOAb titers in HT women whose hypothyroidism was well compensated by levothyroxine treatment [82]. ...
... Most of the available randomized control trials demonstrated the ability of VitD to decrease the TPOAb titer [74,[81][82][83][84]. Krysiak reported that cholecalciferol effectively reduced TPOAb titers in HT women whose hypothyroidism was well compensated by levothyroxine treatment [82]. A significant decrease in TPOAb titer (−20.3%) after cholecalciferol supplementation (1200-4000 IU/day for 4 months) was observed in 218 euthyroid HT with concomitant VitD deficiency [74]. However, the effect of VitD supplementation on hypothyroidism recovery has not been shown yet [85]. ...
Vitamin D is a secosteroid hormone that is highly involved in bone health. Mounting evidence revealed that, in addition to the regulation of mineral metabolism, vitamin D is implicated in cell proliferation and differentiation, vascular and muscular functions, and metabolic health. Since the discovery of vitamin D receptors in T cells, local production of active vitamin D was demonstrated in most immune cells, addressing the interest in the clinical implications of vitamin D status in immune surveillance against infections and autoimmune/inflammatory diseases. T cells, together with B cells, are seen as the main immune cells involved in autoimmune diseases; however, growing interest is currently focused on immune cells of the innate compartment, such as monocytes, macrophages, dendritic cells, and natural killer cells in the initiation phases of autoimmunity. Here we reviewed recent advances in the onset and regulation of Graves’ and Hashimoto’s thyroiditis, vitiligo, and multiple sclerosis in relation to the role of innate immune cells and their crosstalk with vitamin D and acquired immune cells.
... Vitamin D (VD), a seco-steroid hormone, was initially discovered during research on rickets prevention and treatment [8][9][10]. Nowadays, numerous studies have highlighted VD's crucial roles in various immune system processes [11]. VD's significance in the immune system stems from its close interaction with immune cells. ...
... Additionally, VD is closely associated with B cell function [13]. As a multifactorial autoimmune thyroid disease (AITD), GD is caused by the loss of central and peripheral immunological tolerance to thyroid antigens [11]. T and B lymphocytes play pivotal roles in AITD pathogenesis [14,15], suggesting that VD influences the development of GD by regulating these immune cells. ...
Objective
This meta-analysis aims to analyze the relationship between serum vitamin D (VD) levels and Graves’ disease (GD).
Methods
We conducted a search for publications on VD and GD in the English language. Our search encompassed databases such as PubMed, Embase, Web of Science, and the Cochrane Library, covering publications available through August 2023. A meta-analysis was performed using Cochrane RevMan 5.4 software. The standardized mean difference (SMD) and 95% confidence interval (CI) were used for outcome calculation. We used R software to test for publication bias.
Results
Twelve studies were selected, comprising 937 (22.4%) cases with GD and 3254 (77.6%) controls. The overall meta-analysis revealed that patients with GD are significantly more likely to have low VD levels (SMD = − 0.66; 95% CI: −1.05, − 0.27; p = 0.001) than those in the control group. Egger’s test results indicated no publication bias (p = 0.0791). These studies exhibited a high degree of heterogeneity (chi-square = 205.86, p < 0.00001; I² = 95%). Subgroup analysis was conducted based on assay method, geographic location, and mean age of the case group to explore the heterogeneity sources. Assay methods and geographic locations were identified as potential heterogeneity sources. Based on the mean age, there were no statistically significant differences found in the subgroup analysis of the included studies.
Conclusion
There is promising evidence that low serum VD levels may increase the risk of GD. Further rigorous and long-term trials are needed to explore the role of VD in the onset and treatment of GD.
... A role of vitamin D in the immune system has been proposed [1,2]. Thus, vitamin D is believed to enhance innate immune response and inhibit the adaptive immune system, although these effects depend on the context and on the cell type, as vitamin D is not always stimulatory on innate immunity or inhibitory on adaptive immunity [1,2]. ...
... A role of vitamin D in the immune system has been proposed [1,2]. Thus, vitamin D is believed to enhance innate immune response and inhibit the adaptive immune system, although these effects depend on the context and on the cell type, as vitamin D is not always stimulatory on innate immunity or inhibitory on adaptive immunity [1,2]. The immune actions of vitamin D have been proposed to be beneficial in autoimmune diseases. ...
... Decreased serum concentrations of selenium (Se) and vitamin D (VitD) have been reported in newly diagnosed GD patients in observational studies (6)(7)(8)(9)(10)(11)(12)(13). This could be relevant because Se, once integrated into selenoproteins (e.g., glutathione peroxidase), promotes thyrocyte defense against reactive oxygen species (ROS), the production of which is increased in hyperthyroidism (11)(12)(13). ...
... The combined treatment may have a stronger effect on cellular and innate immunity than on humoral immunity. This hypothesis is supported by the effects of VitD and Se on the proliferation, differentiation, and recruitment of dendritic cells, T helper cells, and T regulatory cells (7,10). A significantly greater and positive impact on the QoL was also observed, as, according to the results of the ThyPRO questionnaire, a more pronounced improvement in both the composite score and in social and cognition subscales was achieved in the supplemented group. ...
Prompt and stable control of hyperthyroidism is fundamental to avoid the detrimental effects of thyroid hormone excess, and antithyroid drugs, mainly methimazole (MMI), represent the first-line treatment for Graves’ disease (GD) hyperthyroidism. Decreased serum concentrations of selenium (Se) and calcifediol (25(OH)D, VitD) have been reported in newly diagnosed GD patients in observational studies. Low Se levels might exacerbate oxidative stress by compromising the antioxidant machinery’s response to reactive oxygen species, and low VitD levels might hamper the anti-inflammatory immune response. We performed a randomized controlled clinical trial (EudraCT 2017-00505011) to investigate whether Se and cholecalciferol (VitD) addition to MMI is associated with a prompter control of hyperthyroidism. Forty-two consecutive patients with newly-onset GD and marginal/insufficient Se and VitD levels were randomly assigned to treatment with either MMI monotherapy or MMI combined with Se and VitD. Se treatment was withdrawn after 180 days, while the other treatments were continued. Combination therapy resulted in a significantly greater reduction in serum FT4 concentration at 45 days (-37.9 pg/ml, CI 95%, -43.7 to -32.2 pg/ml) and 180 days (-36.5 pg/ml, CI 95%, -42 to -30.9 pg/ml) compared to MMI monotherapy (respectively: -25.7 pg/ml, CI 95%, -31.6 to -19.7 pg/ml and -22.9 pg/ml, CI 95%, -28 to -17.3 pg/ml, p 0.002). Data at 270 days confirmed this trend (-37.8 pg/ml, CI 95%, -43.6 to -32.1 pg/ml vs -24.4 pg/ml, CI 95%, -30.3 to -18.4 pg/ml). The quality of life (QoL) score was investigated by the validated “Thyroid-related Patient-Reported Outcome” questionnaire (ThyPRO). ThyPRO composite score showed a greater improvement in the intervention group at 45 days (-14.6, CI 95%, -18.8 to -10.4), 180 (-9, CI 95%, -13.9 to -4.2) and 270 days (-14.3, CI 95%, -19.5 to -9.1) compared to MMI group (respectively, -5.2, CI 95%, -9.5 to -1; -5.4, CI 95%, -10.6 to -0.2 and -3.5, CI 95%, -9 to -2.1, p 0-6 months and 6-9 months <0.05). Our results suggest that reaching optimal Se and VitD levels increases the early efficacy of MMI treatment when Se and VitD levels are suboptimal.
... Besides the undoubted involvement of vitD in musculoskeletal health, several preclinical studies supported a larger spectrum of activities (8,10,11). VitD acts as a developmental neuroactive steroid, influencing various functions of the nervous system and neurotransmitters levels (12,13). VitD receptors, along with the enzymes involved in vitD synthesis and degradation (25-hydroxylase, 1α-hydroxylase, 24-CYP24A1), are expressed by neurons, astrocytes, and oligodendrocytes distributed in brain regions (14)(15)(16)(17)(18)(19), which are therefore able to independently synthetize active vitD and to regulate its local concentrations (12,16). ...
... As central nervous system (CNS) cells, most of immune cells express the vitD receptors and the enzymes involved in vitD synthesis and degradation (10). In vitro and animal experimental studies could demonstrate that vitD promoted anti-inflammatory and tolerogenic behaviors in both innate and adaptive immune cells, at the expense of proinflammatory subsets (8,13). Several studies agreed on the existence of a relationship between vitD levels and pain, especially FMS, musculoskeletal pain, and headache (24)(25)(26)(27). ...
Several studies focused on the role of vitamin D (vitD) in pain chronification. This study focused on vitD level and pain chronification and extension in headache disorders. Eighty patients with primary headache underwent neurological examination, laboratory exams, including serum calcifediol 25(OH)D, and headache features assessment along with three questionnaires investigating depression, anxiety, and allodynia. The 86.8% of the population had migraine (48% episodic and 52% chronic). The 44.1% of patients had extracranial pain, and 47.6% suffered from allodynia. A vitD deficit, namely a serum 25(OH)D level <20 ng/ml, was detectable in 46.1% of the patients, and it occurred more frequently (p = 0.009) in patients suffering from chronic migraine (CM)–medication overuse migraine (MOH) (62.9%) than in episodic migraine (EM, 25.7%) or tension-type headache (TTH, 11.4%). The occurrence of extracranial pain and allodynia was higher in the CM-MOH than in the EM and in the TTH groups but was not related to the co-occurrence of vitD deficiency (Fisher's exact test p = 0.11 and p = 0.32, respectively). Our findings show that 25(OH)D deficit is also related to chronic headache, probably because of vitD anti-inflammatory and tolerogenic properties, reinforcing the idea of a neuroinflammatory mechanism underpinning migraine chronification.
... Besides the undoubted involvement of VitD in musculoskeletal health, several preclinical studies supported a larger spectrum of activities (8,10,11). VitD acts as a developmental neuroactive steroid, in uencing various functions of the nervous system and neurotransmitters levels (12,13). VitD receptors, along with the enzymes involved in VitD synthesis and degradation (25-hydroxylase, 1α-hydroxylase, 24-CYP24A1), are expressed by neurons, astrocytes and oligodendrocytes distributed in brain regions (14)(15)(16)(17)(18)(19), which are therefore able to independently synthetize active VitD and to regulate its local concentrations (12,16). ...
... As central nervous system (CNS) cells, most of immune cells express the vitD receptors and the enzymes involved in VitD synthesis and degradation (10). Invitro and animal experimental studies could demonstrate that VitD promoted antiin ammatory and tolerogenic behaviors in both innate and adaptive immune cells, at expense of proin ammatory subsets (8,13). Several studies agreed on the existence of a relationship between VitD levels and pain, especially FMS, musculoskeletal pain and headache (24)(25)(26)(27). ...
Background: Several studies focused on the possible role of vitamin D (vitD) in pain chronicization.. The aim of this study was to assess the potential implications of VitD deficit on headache characteristics and extracranial pain extension.
Methods: Eighty consecutive patients with primary headache underwent neurological examination, laboratory exams including serum calcifediol 25(OH)D and headache features assessment along with three questionnaires investigating depression, anxiety and allodynia.
Results: The 82.6% of the population had migraine (48% episodic and 52% chronic form). The 45% of patients had extracranial pain and 47% suffered from allodynia. In the 45% of patients had a VitD deficit since the serum 25(OH)D levels fell below the cut-off level of 20 ng/ml. The occurrence of VitD deficit was significantly higher (p=0.009) in patients suffering from chronic migraine (CM)- medication overuse migraine (MOH) (64.7%) than in episodic migraine (EM) or tension type headache (TTH). The occurrence of subjects with extracranial pain and allodynia was higher, as expected, in the CM-MOH than in the EM and in the TTH groups but was not related to the co-occurrence of vit-D deficiency (Fischer’s exact test p=0.11 and p=0.32 respectively).
Conclusions: Our findings show that 25(OH)D deficit is related to chronic pain suggesting that vitD probably has anti-inflammatory and tolerogenic properties, rather than a direct antinociceptive effect, and reinforce the idea of a neuroinflammatory mechanisms underpinning migraine chronicization.
... in fact, its receptor (vitamin d receptor, vdr) is present in monocytes and activated T cells, inluencing both the innate and adaptive immunity. 109,110 Several observational studies showed a relationship between vitamin d deiciency and the risk of developing AITDs, especially HT, and a strong negative correlation has been observed between reduced vitamin d levels and TPo-ab, whereas the association of HT with vdr polymorphisms was variable. [111][112][113] Moreover, this connection could also be conirmed by the fact that, conversely, vitamin d can downregulate the expression of proinlammatory cytokines, such as interleukin 6 (il-6) and tumor necrosis factor α (TNF-α), which are responsible for T and B cells migration and proliferation and for an increase in oxidative stress levels. ...
... [111][112][113] Moreover, this connection could also be conirmed by the fact that, conversely, vitamin d can downregulate the expression of proinlammatory cytokines, such as interleukin 6 (il-6) and tumor necrosis factor α (TNF-α), which are responsible for T and B cells migration and proliferation and for an increase in oxidative stress levels. 114 in the majority of randomized controlled trials (6 out of 7) conducted up to now in HT patients, the main effect of cholecalciferol supplementation is a signiicant reduction of TPo-ab titer, but several questions remain unanswered i.e. regarding the best dosage, the best detection method, etc. 110 considering these data, an empirical approach could be to consider measuring vitamin d levels in patients affected by HT, especially when they are middle agedwomen (the most affected part of population) and/ or presenting with slightly elevated TSH levels: this passage could increase the number of patients treated with vitamin d, not only for the prevention of bone metabolism alterations, but also in order to slow down the progression of HT towards overt hypothyroidism and/or thyroid atrophy. 115 Similar considerations could be applied in gd patients, but further studies with larger cohorts of patients and more stringent selection criteria are required. ...
Introduction:
Oxidative stress has been proposed as one of the factors concurring in the pathophysiology of autoimmune thyroid diseases. Reactive oxygen species are the main expression of oxidative stress in biological systems, and their production can overcome antioxidant defenses ultimately leading to cell damage, apoptosis, and death. The present review was aimed at describing the state of the art of the relationships between oxidative stress and autoimmune thyroiditis. The most used biomarkers of oxidative stress and their correlation with thyroid function are reported.
Evidence acquisition:
We conducted a search of the literature in the English language starting from 2000, using the following search terms: "Hashimoto thyroiditis", "autoimmune thyroiditis", "hypothyroidism", "hyperthyroidism", "oxidative stress", "oxidants", "antioxidant", "advanced glycation end products". Both clinical studies and animal models were evaluated.
Evidence synthesis:
Data form clinical studies clearly indicate that the balance between oxidants and antioxidants is shifted towards the oxidative side in patients with autoimmune thyroiditis, suggesting that oxidative stress may be a key event in the pathophysiology of the disease, irrespective of thyroid function. Studies in animal models, such as the NOD.H2h4 mouse, confirm that thyroidal accumulation of ROS plays a role in the initiation and progression of autoimmune thyroiditis.
Conclusions:
Oxidant/antioxidant imbalance represent a key feature of thyroid autoimmunity. Oxidative stress parameters could be used as biochemical markers of chronic inflammation, to better predict the disease evolution along its natural history. Dietary habits and antioxidant supplements may provide protection from autoimmunity, opening new perspectives in the development of more tailored therapies.
... [18,21] Vitamin D plays a pivotal role in balancing pro-inflammatory cells such as Th1 and Th17, and anti-inflammatory cells such as Th2 and Tregs. It also exerts inhibitory effects on B cell proliferation and antigen presentation, [22][23][24][25][26][27][28][29] which potentially underlie its therapeutic potential in HT. However, the impact of vitamin D supplementation on HT remains a topic of debate. ...
Background
Hashimoto’s thyroiditis (HT) is the prevailing form of autoimmune thyroiditis and the leading cause of hypothyroidism in iodine-sufficient regions worldwide. This study aims to evaluate the efficacy of vitamin D supplementation on HT through a meta-analysis of randomized controlled trials (RCTs).
Methods
The databases searched included PubMed, and others. We included RCTs that the treatment group received vitamin D, while the control group received either a placebo or no treatment. The studies measured the baseline and endpoint levels of 25-hydroxyvitamin D [25(OH)D], thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), anti-thyroid peroxidase antibody (TPO-Ab), and thyroglobulin antibody (TG-Ab). We performed a meta-analysis to calculate the standardized mean difference (SMD) and 95% confidence interval (CI).
Results
A total of 12 studies involving 862 individuals were included. Vitamin D supplementation has a significant impact on reducing the titers of TPO-Ab (SMD = −1.084, 95% CI = −1.624 to −0.545) and TG-Ab (SMD = −0.996, 95% CI = −1.579 to −0.413) in patients with HT, and it also improves thyroid function by decreasing TSH level (SMD = −0.167, 95% CI = −0.302 to 0.031) and increasing FT3 (SMD = 0.549, 95% CI = 0.077–1.020) and FT4 (SMD = 0.734, 95% CI = 0.184–1.285) levels. Active vitamin D (calcitriol) significantly reduces the titer of TPO-Ab compared to naive forms of vitamin D (vitamin D 2 or D 3 ); treatment durations > 12 weeks result in a more effective reduction of TPO-Ab levels and a more significant increase in FT4 and FT3 levels in patients with HT (meta-regression P < .05).
Conclusion
Vitamin D supplementation may have beneficial effects on HT patients by modulating immune responses and improving thyroid function.
... We recently reported, in a randomized control trial, that in newly diagnosed GD patients the association of cholecalciferol (VitD) and selenium (Se) supplementation with methimazole (MMI), in patients with low VitD and selenium levels, significantly accelerated the control of hyperthyroidism, during the first 6 months of treatment, compared to MMI alone (11). We postulated that this might be, at least partly, due to the influence of micronutrients on the immune response, as suggested by animal and cell system-based studies (12)(13)(14)(15)(16)(17)(18)(19)(20). ...
Introduction
Methimazole (MMI) represents the conventional therapeutic agent for Graves’ disease (GD) hyperthyroidism, but MMI efficacy is limited since it marginally affects the underlying autoimmune process. In a previous study, we randomly assigned 42 newly diagnosed GD patients with insufficient vitamin D (VitD) and selenium (Se) levels to treatment with MMI alone (standard) or combined with selenomethionine and cholecalciferol (intervention) and observed a prompter resolution of hyperthyroidism in the intervention group.
Methods
In the present study, we aimed to explore changes in peripheral T regulatory (Treg) and circulating natural killer (NK) cell frequency, circulating NK cell subset distribution and function, during treatment.
Results
At baseline, circulating total CD3⁻CD56⁺NK cells and CD56bright NK cells were significantly higher in GD patients than in healthy controls (HC) (15.7 ± 9.6% vs 9.9 ± 5.6%, p=0.001; 12.2 ± 10.3% vs 7.3 ± 4.1%, p=0.02, respectively); no differences emerged in Treg cell frequency. Frequencies of total NK cells and CD56bright NK cells expressing the activation marker CD69 were significantly higher in GD patients than in HC, while total NK cells and CD56dim NK cells expressing CD161 (inhibitory receptor) were significantly lower. When co-cultured with the K562 target cell, NK cells from GD patients had a significantly lower degranulation ability compared to HC (p<0.001). Following 6 months of treatment, NK cells decreased in both the intervention and MMI-alone groups, but significantly more in the intervention group (total NK: -10.3%, CI 95% -15.8; -4.8% vs -3.6%, CI 95% -9; 1.8%, p=0.09 and CD56bright NK cells: -6.5%, CI 95% -10.1; -3 vs -0.9%, CI 95% -4.4; 2%, p=0.03). Compared to baseline, CD69⁺ NK cells significantly decreased, while degranulation ability slightly improved, although no differences emerged between the two treatment groups. Compared to baseline, Treg cell frequency increased exclusively in the intervention group (+1.1%, CI 95% 0.4; 1.7%).
Discussion
This pilot study suggested that VitD and Se supplementation, in GD patients receiving MMI treatment, modulates Treg and NK cell frequency, favoring a more pronounced reduction of NK cells and the increase of Treg cells, compared to MMI alone. Even if further studies are needed, it is possible to speculate that this immunomodulatory action might have facilitated the prompter and better control of hyperthyroidism in the supplemented group observed in the previous study.
... Vitamin D is a secosteroidal hormone precursor and has been identified as a key hormone inthe musculoskeletal, nervous system and insulin sensitivity [5][6][7]. Several studies have reported a low vitamin D status in AITD, indicating an association between vitamin D deficiency and thyroid autoimmunity [8][9][10][11][12][13]. On the other hand, a small number of studies,showed no significant association between AITDs and vitamin D deficiency [14][15][16][17]. ...
Background—PurposeRandomized controlled trials (RCTs) are the cornerstone of evidence-based medicine, yet their quality is often suboptimal. The Consolidated Standards of Reporting Trials (CONSORT) statement is a list of advice to upgrade the quality of RCTs. The aim of this study was the assessment of the quality of RCTs for vitamin D supplements in thyroid autoimmunity according to the revised CONSORT 2010 checklist.Methods
Databases were searched for RCTs involving patients with autoimmune thyroid disorders (AITDs) who received vitamin D supplements published from 2011 to 2021. A list of 37-items was used and adherence ≥75% was considered of optimal quality. The primary outcome was the mean CONSORT adherence of studies. Secondary outcomes were the estimation of compliance per CONSORT item and the examination for possible determinants of the reporting quality.ResultsThirteen eligible trials were finally included. The mean compliance was 61.15% ± 14.86%. Only threeof the studies (23%) achieved a good reporting quality (≥75%), while ten (77%) were presented with inadequate reporting (<75%). Randomization and blinding were mainly poorly reported. Impact Factor (IF) of journal was associated with the reporting quality in the univariate analysis [p = 0.033, OR = 1.65, 95%CI = (1316, 1773)]. Sample size (p = 0.067), number of authors (p = 0.118) and number of citations (p = 0.125) were marginally not significant. None of the factors showed significant results in multivariate analysis. Reporting quality and IF were strongly positively correlated [Pearson’s r = 0.740, p = 0.04].Conclusion
This study shows that mean CONSORT adherence of RCTs for Vitamin D supplementation in AITDs is moderate, reflecting that study quality and transparency could be improved with better adherence to CONSORT rules.
... An interesting contribution concerning diet, micronutrients and diet supplements came from the Gallo et al data. In their randomized controlled clinical trial (EudraCT 2017-00505011), the Authors investigated whether Selenium (Se) and cholecalciferol (VitD)) in addition to methimazole (MMI) might have been associated with hyperthyroidism, Graves' disease (GD), owning to their antioxidant and antiinflammatory properties (1,2). Forty-two consecutive patients with newly-onset GD and marginal/insufficient Se and VitD levels were randomly assigned to treatment with either MMI monotherapy or MMI combined with Se and VitD. ...
... Along similar lines, although the role of vitamin D in the mechanism of autoimmune diseases is not fully known, it is thought that vitamin D contributes to the pathophysiology of these autoimmune diseases by affecting its wide-range receptors on many innate and adaptive immune cells. 7 When all these possible effects and mechanisms are considered together, it can be concluded that vitamin D deficiency may cause activation of concurrent thyroid autoimmunity and worsening in OCD clinic. Moreover, the triggering of thyroid autoimmunity may also ...
... LATS were recognized to be immunoglobulin G antibodies Animal models suggested that vitamin D supplementation succeeded in decreasing thyroid inflammation and prevent thyroiditis induction. Recent observational studies suggested that vitamin D levels were lower in subjects with autoimmune disorders, including GD patients (28,29). Accordingly, a randomized clinical test of 30 naïve GD observed a higher decrease of thyroid hormone levels in the vitamin D-supplemented-group (30). ...
Abstract. Graves’ disease (GD), also called Basedow’s disease, owe the names respectively to the Irish physician
Robert James Graves, who described the disease in 1835, and to Karl Adolph von Basedow, who
reported the same clinical picture in Germany in 1840. Indeed, it was the Englishman Caleb Hillier Parry
to firstly report a case of hyperthyroidism and goiter in 1786, but his report was not published until 1825.
Earlier, in 1802, the Italian physician Giuseppe Flajani, described a disease characterized by the coexistence
of palpitations and exophthalmos. Graves’ disease is an autoimmune, organ-specific, disorder sustained by
auto-antibodies
stimulating the thyroid-stimulating hormone (TSH) receptor (R). It is believed that the
interaction between susceptible genes and environmental/endogen factors triggers the development of the
disease. As a consequence of TSH-R improper stimulation, hyperthyroidism and goiter are the main clinical
manifestations of the disease, accompanied, in the 25% of cases, by Graves’ orbitopathy (GO). GD is primarily
diagnosed by demonstrating the presence of thyrotoxicosis and the pathognomonic TSH-R antibodies
(TSH-RAb). In this manuscript we will refer to the disease as Graves’ disease.
... participation in bone growth by supporting the mineralization of the collagen matrix [2]. The discovery of the expression of the vitamin D receptor (VDR) in the 1970s on other cells and tissues of the body (including cancer cells) allowed, however, to draw a conclusion about its numerous extraskeletal effects [3]. Recent studies show that it influences the onset of autoimmune diseases, metabolic syndromes, infections, cardiovascular diseases and cancer [4]. ...
Vitamin D is traditionally associated with the regulation of mineral metabolism and bone homeostasis, and its deficiency is the cause of diseases such as osteoporosis or osteomalacia. However, numerous studies in recent years suggest that thanks to the common expression of the vitamin D receptor (VDR) on the cells of the body and the related additional anti-inflammatory, immunomodulating, antioxidant, anti-fibrotic vitamin D effects, it may play a role in the development and progress of autoimmune diseases and tumors. The collected data suggest that low vitamin D levels correlate with the occurrence of autoimmune diseases of the thyroid gland and that there is a significant correlation between 25(OH)D and anti-TPO or anti-Tg levels. However, these data are inconclusive and further research is needed to confirm this relationship and determine whether lowered vitamin D titer is the cause or rather the consequence of autoimmune thyroid disorders, and whether vitamin D supplementation could prove to be an effective prophylaxis and treatment.
... 1,25(OH)2D binds to the nuclear vitamin D receptor (VDR) in target tissues [5] thus regulating the expression of more than 200 genes (3-5% of the human genome) [6]. VDR and the enzyme CYP27B1 are not only found in the small intestine, skeletal and renal cells, as was thought earlier, but in almost all body cells, including thyroid and immune cells [7]. ...
The aims of this study were to evaluate: (1) associations of vitamin D with the presence/severity of Hashimoto’s thyroiditis (HT) and (2) correlations of vitamin D with thyroid-related phenotypes. Total 25(OH)D (vitamin D in the text) was measured from stored serum samples of 461 HT patients and 176 controls from a Croatian Biobank of HT patients (CROHT). (1) Vitamin D levels, and proportions of vitamin D deficiency, were compared between HT cases and controls. HT patients were additionally divided into two groups (MILD and OVERT) to take into account HT severity. (2) Correlations between vitamin D and 10 clinical phenotypes in all HT patients and two subgroups of HT patients were tested using the Spearman correlation test. Our analyses were adjusted for age, gender, BMI, smoking status and seasonality of blood sampling. (1) No significant differences in vitamin D levels, or proportions of vitamin D deficiency, were detected between HT patients of all disease stages and controls. However, a nominally significant difference in vitamin D levels between MILD and OVERT subgroups (OR = 1.038, p = 0.023) was observed. Proportions of individuals with vitamin D deficiency during winter–spring were high: all HT cases (64.69%), MILD (60.64%), OVERT (68.7%), controls (60.79%). (2) A nominally significant negative correlation between vitamin D and TSH in all HT patients (r = −0.113, p = 0.029) and a positive correlation between vitamin D and systolic blood pressure in OVERT HT patients (r = 0.205, p = 0.025) were identified. Our study indicates that there is no association between vitamin D and HT; however, there may be a subtle decrease in vitamin D levels associated with overt hypothyroidism.
... However, in those clinical trials much higher doses of vitamin D, i.e., 50 000 IU weekly for 8-12 weeks, were used (Aminian et al. 2019;Chahardoli et al. 2019). This effect has been attributed to the immunomodulatory function of vitamin D (Gallo et al. 2020). Notwithstanding, this notion has been extensively argued (Vieira et al. 2020). ...
We investigated the effect of daily intake of yogurt drink fortified with either vitamin D alone or with added calcium on resting metabolic rate (RMR), thyroid hormones and homeostatic model assessment for insulin resistance in subjects with type 2 diabetes (T2D). A total of 75 adult subjects with T2D were randomly assigned to 1 of the 3 groups to receive either D-fortified yogurt drink (DY; 1000 IU vitamin D/day), Ca-D-fortified yogurt drink (CDY; 1000 IU vitamin D plus 500 mg calcium), or plain yogurt drink for 12 weeks. All assessments were done at the baseline and after the intervention. The concentrations of anti-thyroid peroxidase antibody (anti-TPO-Ab), intact parathyroid hormone (iPTH) and thyroid stimulating hormone (TSH) had declined significantly compared with baseline values only in the CDY group. The mean RMR increased in both DY and CDY groups (p < 0.001 for both). Also, changes of serum concentrations of 25-hydroxycalciferol (B = 2.96, 95% confidence interval (CI) = 1.3 to 4.6, p = 0.001) and iPTH (B = –2.41, 95% CI = –4.5 to –0.31, p = 0.025) remained significant predictors of RMR changes even after adjustment for changes of serum concentrations of TSH (B = –18.2, 95% CI = –61.7 to 25.2, p = 0.406). Daily intake of vitamin D together with calcium at physiological doses has attenuating effect on anti-TPO-Ab and TSH. Also, vitamin D with or without added calcium causes a significant thyroid-independent increase in RMR in euthyroid subjects with T2D. Registered at clinicaltrials.gov as NCT01229891.
Novelty:Daily intake of vitamin D with calcium at physiological doses has attenuating effect on anti-TPO-Ab and TSH.
Vitamin D with or without added calcium causes a thyroid-independent increase in RMR in euthyroid subjects with T2D.
... Vitamin D is a key element in bone health maintenance, and it is necessary for patients with hip and vertebral FFs. Potential benefits on the immune system, support the recommendations of achieving optimal vitamin D status in COVID-19 subjects [10][11][12], with the goal of preventing also falls, frailty and fractures either during and after hospitalization [4]. Importantly, COVID-19 severity is increased in subjects with visceral obesity which are often characterized by low vitamin D [13]. ...
... Vitamin D has been found to play an increasingly crucial regulatory role in bone metabolism, the mucosal barrier, and the immune system in the past few decades. More recently, numerous studies have highlighted that an insufficient level of 25-hydroxyvitamin D [25(OH)D] is significantly associated with HT [123][124][125]. ...
Hashimoto's thyroiditis (HT) is the most prevalent autoimmune thyroid disease (ATD) worldwide and is strongly associated with miscarriage and even recurrent miscarriage (RM). Moreover, with a deepening understanding, emerging evidence has shown that immune dysfunctions caused by HT conditions, including imbalanced subsets of CD4+ T-helper cells, B regulatory (Breg) cells, high expression levels of CD56dim natural killer (NK) cells, and cytokines, possibly play an important role in impairing maternal tolerance to the fetus. In recent years, unprecedented progress has been made in recognizing the specific changes in immune cells and molecules in patients with HT, which will be helpful in exploring the mechanism of HT-related miscarriage. Based on these findings, research investigating some potentially more effective treatments, such as selenium (Se), vitamin D3, and intravenous immunoglobulin (IVIG), has been well developed over the past few years. In this review, we highlight some of the latest advances in the possible immunological pathogenesis of HT-related miscarriage and focus on the efficacies of treatments that have been widely introduced to clinical trials or practice described in the most recent literature.
... This would explain the weak overall size effect for genetic markers in genome-wide association studies (16,21). Precipitating factors, probably inducing epigenetic changes include sex hormones, pregnancy, cigarette smoking, stress, infection, iodine, and other potential environmental factors (17,(26)(27)(28)(29)(30)(31)(32)(33). ...
Graves' disease (GD) is a common autoimmune cause of hyperthyroidism, which is eventually related to the generation of IgG antibodies stimulating the thyrotropin receptor. Clinical manifestations of the disease reflect hyperstimulation of the gland, causing thyrocyte hyperplasia (goiter) and excessive thyroid hormone synthesis (hyperthyroidism). The above clinical manifestations are preceded by still partially unraveled pathogenic actions governed by the induction of aberrant phenotype/functions of immune cells. In this review article we investigated the potential contribution of natural killer (NK) cells, based on literature analysis, to discuss the bidirectional interplay with thyroid hormones (TH) in GD progression. We analyzed cellular and molecular NK-cell associated mechanisms potentially impacting on GD, in a view of identification of the main NK-cell subset with highest immunoregulatory role.
... In addition to classic biological effects (i.e., calcium (Ca) and phosphorus (P) metabolism, bone formation and growth, parathyroid hormone (PTH) gene expression, parathyroid cell proliferation, etc.) [8,13], the 1α,25(OH) 2 D 2/3 exerts different non-classic biological effects that could influence health status, exercise and sport performance in athletes [2,8,[14][15][16][17][18] (Table 1). The standard biological effects of 1α,25(OH) 2 D 2/3 are mainly related to its physiological concentrations in resting conditions;, moreover, further specific effects may appear when serum 25(OH)D concentrations physiologically increase after an acute bout of physical exercise (i.e., dynamic effects) [19], as observed for other exercise-related adaptive hormones [20][21][22]. ...
Vitamin D metabolites have a pleiotropic role in human physiology, both in static and dynamic conditions, and a lot of vitamin D-related biological effects could influence physical and sport performances in athletes. Probably due to different factors (e.g., drugs, doping, nutrition, ultraviolet B radiation exposure), in athletes a very high prevalence of vitamin D inadequacy (i.e., deficiency or insufficiency) has been observed. Vitamin D inadequacy in athletes could be associated with specific health risks and to alterations of functional capacities, potentially influencing the fine adjustment of physical performances during training and sport competitions. When risk factors for vitamin D inadequacy exist, a preventive vitamin D supplementation is indicated, and if a vitamin D inadequacy is diagnosed, its supplementation is recommended. Unfortunately, on these issues many concerns remain unresolved. Indeed, it is not clear if athletes should be classified as a special population at increased risk for vitamin D inadequacy; moreover, in comparison to the non-athletic population, it is still not clear if athletes should have different reference ranges and different optimal target levels for serum vitamin D, if they have additional health risks, and if they need different type of supplementations (doses) for prevention and/or replacement therapy. Moreover, in athletes also the abuse of vitamin D supplements for ergogenic purposes raise different ethical and safety concerns. In this review, the main physio-pathological, functional and clinical issues that relate vitamin D to the world of athletes are described.
... 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. ...
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.
... Low vitamin D values have been associated with a number of diseases as well as cardiovascular and all-cause mortality and other adverse outcomes [2][3][4][5][6][7]. This has been the main reason for the ignition of an increased number of 25(OH)D assay requests from one side and for the widespread use of vitamin D supplementation on the other side. ...
At present, there is no need and no sufficient evidence to support universal screening for vitamin D status. There are four categories of subjects in whom there is no requirement for screening, since a number of studies indicate beneficial effects of vitamin D supplementation; these are represented by children and adolescents, pregnant women, patients taking bone active drugs and subjects with documented hypovitaminosis D. In the remaining subjects, the utilization of adequate questionnaires will target with sufficient sensitivity and specificity those with hypovitaminosis D. These must be first supplemented and, at a later time, serum 25(OH)D assay should be requested to confirm attainment of sufficiency, independently of the threshold chosen. This strategy will cut costs deriving from both widespread use of vitamin D assays and vitamin D supplementation.
... Several preclinical and clinical studies observed a relationship between hypovitaminosis D and AITD [179,180]. Figure 2 illustrates the main pathophysiological correlates of vitamin D effects on AITD. ...
Vitamin D is a pleiotropic secosteroid yielding multiple actions in human physiology. Besides the canonical regulatory activity on bone metabolism, several non-classical actions have been described and the ability of vitamin D to partake in the regulation of the immune system is particularly interesting, though far stronger and convincing evidence has been collected in in vitro as compared to in vivo studies. Whether vitamin D is able to regulate at physiological concentrations the human immune system remains unproven to date. Consequently, it is not established if vitamin D status is a factor involved in the pathogenesis of immune-mediated diseases and if cholecalciferol supplementation acts as an adjuvant for autoimmune diseases. The development of autoimmunity is a heterogeneous process, which may involve different organs and systems with a wide range of clinical implications. In the present paper, we reviewed the current evidences regarding vitamin D role in the pathogenesis and management of different autoimmune diseases.
Vitamin D - A Novel Therapy for Chronic Diseases? This comprehensive book explores the vital role of vitamin D in human health, with a focus on its potential impact on various chronic diseases. Starting with the history and general information of vitamin D, the book covers various topics, including its effects on immunity, gut health, insulin resistance, cardiovascular disease, irritable bowel syndrome, depression, melanoma, and pregnancy. It provides clear and evidence-based insights into how vitamin D influences the body and its role in preventing or managing specific conditions. This book is a valuable resource for dietitians, healthcare professionals, and anyone seeking to enhance their understanding of vitamin D and its therapeutic potential. Key Features: - Covers the role of vitamin D in chronic diseases - Explores vitamin D's impact on immunity, gut health, and insulin resistance - Provides evidence-based recommendations for healthcare professionals - Accessible explanations for non-expert readers
Objective Treatment options in Graves' disease are limited, do not target the underlying autoimmunity, and relapse rates following a course of anti-thyroid drug reach 50%. Previous research has shown promising results for a role for vitamin D in Graves' disease. We aimed to investigate whether vitamin D reduces failure to enter and sustain remission in patients with Graves' disease treated with anti-thyroid drug. Design A multicenter, double-blinded, randomized, placebo-controlled trial comparing Vitamin D 70 mcg once daily (2800 IU) or placebo. The intervention was given first as add-on to anti-thyroid drug treatment, maximally 24 months, and then for 12 months after anti-thyroid drug cessation. Inclusion 2015 to 2017 and study completion December 2020. Patients included were adults with a first-time diagnosis of Graves' disease treated with anti-thyroid drug. Exclusion criteria included pregnancy and glucocorticoid treatment. The primary endpoint was failure to enter and sustain remission defined as relapse of hyperthyroidism within 12 months after anti-thyroid drug cessation, inability to stop anti-thyroid drug within 24 months, or radioiodine treatment or thyroidectomy. Two-hundred-seventy-eight patients were included, four withdrew consent. No adverse effects. Results Participants were 44±14 years at enrollment and 79% were female. The risk of failure to enter and sustain remission was 42% (95% confidence interval [CI], 33% to 50%) in the vitamin D group and 32% (24% to 40%) in the placebo group corresponding to a relative risk (RR) of 1.30 (95% CI, 0.95 to 1.78). Conclusions Vitamin D supplementation did not improve the treatment of Graves' disease in patients with a normal or insufficient vitamin D status. Thus, supplementation with high-dose vitamin D cannot be recommended for Graves' disease.
Objective:
To evaluate if berberine can act on vitamin D receptors (VDR) and thereby regulate the expression of tight junction proteins (TJPs) in irritable bowel syndrame-diarrhea-predominant (IBS-D) rats.
Methods:
The newborn rats were induced into IBS-D rat model via neonatal maternal separation combined with acetic acid chemical stimulation. After modeling, the model was evaluated and rats were divided into the control group and berberine treatment groups (0.85, 1.7 and 3.4 mg/kg, once a day for 2 weeks). The distal colon was obtained and colonic epithelial cells (CECs) were isolated and cultured after IBS-D model evaluation. The vitamin D receptor response element (VDRE) reporter gene was determined in the CECs of IBS-D rats to analyze the effect of berberine on the VDRE promoter. VDR overexpression or silencing technology was used to analyze whether VDR plays a role in promoting intestinal barrier repair, and to determine which region of VDR plays a role in berberine-regulated intestinal TJPs.
Results:
The IBS-D rat model was successfully constructed and the symptoms were improved by berberine in a dose-dependent manner (P<0.05). The activity of VDRE promoter was also effectively promoted by berberine (P<0.05). Berberine increased the expression of TJPs in IBS-D CECs (P<0.05). VDR expression was significantly increased after transfection of different domains of VDR when compared to normal control and basic plasmid groups (all P<0.05). RT-qPCR and Western blot results showed that compared with the blank group, expressions of occludin and zonula occludens-1 were significantly higher in VDR containing groups (all P<0.05). Berberine plus pCMV-Myc-VDR-N group exerted the highest expression levels of occludin and zonula occludens-1 (P<0.05).
Conclusion:
Berberine enhances intestinal mucosal barrier function of IBS-D rats by promoting VDR activity, and the main site of action is the N-terminal region of VDR.
Objective Using a hydrogen coupled methane lactulose breath test (LBT) and associated clinical indices, the link between small intestinal bacterial overgrowth (SIBO) and hypothyroidism in early pregnancy. Methods The methane hydrogen breath test included 200 patients with early-stage hypothyroidism, 200 normal pregnant women, 200 normal women of childbearing age prior to pregnancy. Comparisons were made between the incidence, smooth curve fitting, clinical signs, and clinical test results of SIBO. Results The positive rates of SIBO were 62.00%, 28.50%, and 20.50%, respectively, in the hypothyroidism during pregnancy group, the normal pregnant women group, and the normal women group before pregnancy. p < 0.001 indicates that the difference was statistically significant. Additionally, thyrotropin (TSH) and methane hydrogen exhalation volume showed a positive connection in patients with hypothyroidism during pregnancy ( p < 0.01, Std = 0.163).In the three groups, the abdominal distension symptoms of patients with SIBO were significantly higher than those of patients without SIBO( p = 0.017, p < 0.001, p < 0.001).Patients with hypothyroidism complicating SIBO had greater levels of TSH, TPOAb, C-reactive protein, and FT4, whereas their levels of vitamin D were decreased( p < 0.001,respectively).Conclusion Intestinal bacterial overgrowth and hypothyroidism during the first trimester and pregnancy are closely associated; the connection between these two conditions may also involve inflammatory agents and vitamin levels.
Objective
To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk.
Design
Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design.
Setting
Nationwide in the United States.
Participants
25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment.
Interventions
Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence.
Main outcome measures
The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others.
Results
25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease.
Conclusions
Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo).
Study registration
ClinicalTrials.gov NCT01351805 and NCT01169259
Graves’ disease is an immune system disorder that results in the overproduction of thyroid hormones (hyperthyroidism). Thyroid disorders are a societal problem of great public concern because of their high prevalence. This problem can affect the well-being and quality of life of patients. The predisposing factors leading to this disease are not yet fully established and are likely to be interconnected in a complex way.
Chemometric analysis allows for the detection of specific relationships between the medical parameter measurements obtained from the patients in an observation group, and the identification of patterns of similarity between these patients. It is not commonly used in clinical trials; however, it can provide reliable information which may help in creating more successful, individualised treatment strategies for established groups (patterns) of patients.
The aim of this review is to summarize the latest knowledge about the risk factors for Graves’ disease and considerations about using the chemometric analysis in the study of the disease.
Autoimmune disease, which are quite common, are complex and heterogeneous conditions that can be difficult to diagnose, treat and manage. Consequently, this group of disease generates a major burden on global health care systems. Despite significant efforts and advances in the field of autoimmunity, challenges persist that require a more precise approach to potentially leveraging big data composed of demographic, clinical and biomarker data combined with augmented intelligence. This book chapter provides a high-level overview of some of the challenges in autoimmunity and elaborates on progress to date.
Children's longitudinal growth is facilitated by the activity of the growth plates, cartilage discs located near the ends of the long-bones. In order to elongate these bones, growth plates must continuously generate chondrocytes. Two recent studies have demonstrated that there are stem cells and a stem cell niche in the growth plate, which govern the generation of chondrocytes during the postnatal growth period. These stem cells and their niche appear at the same time as the secondary ossification center (SOC) matures into a bone epiphysis. Thus, the mechanism of chondrocyte generation differs substantially between neonatal and postnatal age, i.e., before and after the formation of the mineralized epiphyses. Hence, at the neonatal age bone growth is based on a consumption of chondro-progenitors whereas postnatally it is based on the activity of the stem cell niche. Here we discuss potential implications of these observations in relation to longitudinal growth, including the effects of estrogens, nutrition and growth hormone.
Introduction:
Vitamin D is classically involved in maintaining bone and mineral health, but it has been shown to exert many extraskeletal functions, including pleiotropic effects on cardiovascular system.
Materials and method:
This review aims to summarize evidences in literature about vitamin D and cardiovascular outcome.
Results and conclusions:
Calcitriol or 1,25(OH)2D, the active hormone, binds to the specific nuclear receptor VDR, which is expressed in rat and human heart and vasculature and has effects on myocardiocytes, smooth cells, and endothelial cells. 25-Hydroxy-vitamin D (25OHD) represents the biomarker of vitamin D levels and reflects vitamin D status. There is consistent evidence that low serum 25OHD levels are associated with increased risk of cardiovascular diseases, including hypertension, coronary artery disease, ischemic heart disease, heart failure, stroke, and type 2 diabetes. Randomized-controlled trials and Mendelian randomization studies so far have not succeeded in proving a benefit of vitamin D supplementation. However, the latter investigations are affected by some methodological limitations, and therefore, it is still unclear if vitamin D deficiency has a causative role in cardiovascular diseases or is rather a marker of poor health in chronic disease.
Purpose
The pathogenesis of Graves’ disease (GD) and orbitopathy (GO) is not completely elucidated. On the other hand, vitamin D receptor (VDR) gene polymorphisms have been associated with vulnerability to a plethora of chronic autoimmune diseases. The primary aim of this study was to synthesize evidence on the association between VDR gene polymorphisms and GD. Secondary aim was to investigate their association with GO.
Methods
A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to December 8, 2018. Data were expressed as odds ratio (OR) with 95% confidence intervals (CI). Heterogeneity was quantified with I² index.
Results
Ten studies were included in the qualitative and quantitative analysis. TT subtype of TaqI polymorphism was associated with an increased risk of GD compared with Tt and tt polymorphisms (OR: 1.42; 95% CI, 1.05–1.94, p = 0.025), whereas tt was associated with a lower risk of GD, compared with TT and Tt polymorphisms (OR: 0.79; 95% CI, 0.62-0.99, p = 0.043). No association was found for ApaI, BsmI, and FokI polymorphisms. The bb subtype of BsmI polymorphism was associated with a lower risk in Asian, but with a higher GD risk in Caucasian populations, compared with BB/Bb subtypes. No eligible study was found regarding the association between VDR gene polymorphisms and the risk of GO.
Conclusions
The TT subtype of the TaqI polymorphism was associated with a higher susceptibility for GD compared with Tt and tt. Regarding BsmI, the bb subtype was associated with increased GD risk in Caucasians, whereas it is protective in Asians.
Dendritic cells (DC) are specialized sentinel cells that bridge the innate and adaptive immune response and play a crucial role in shaping the adaptive immune response. Vitamin D, a known epidemiological risk factor for the development of several autoimmune diseases, influences the development of dendritic cells. Consequently, vitamin D metabolites are frequently used in protocols to develop therapeutic dendritic cell therapies for autoimmune diseases. However, the mechanisms by which vitamin D modulates DC function remain poorly understood. We investigated the effects of vitamin D on murine CD11c⁺ bone marrow derived DC (BMDC) function by analyzing global gene expression in CD11c⁺ BMDC generated in the presence (VitD-CD11c⁺BMDC) or absence (Veh-CD11c⁺BMDC) of the active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Seven genes were significantly increased in expression in both immature and LPS-matured VitD-CD11c⁺BMDC, one of which was CD31, a member of the immunoglobulin superfamily. Gene knockdown of CD31 enhanced the ability of VitD-CD11c⁺BMDC to prime naïve CD4⁺ T cells in vitro; conversely, increased expression of CD31 on vehicle treated CD11c⁺BMDC restrained their T cell priming abilities. Time-lapse imaging of BMDC and CD4⁺ T cells during in vitro priming revealed that CD31 reduced the BMDC–T cell interaction time. Finally, we confirmed a similar effect of 1,25(OH)2D3 on human CD34⁺ cell-derived CD11c⁺DC, whereby DC generated in the presence of 1,25(OH)2D3 had increased CD31 expression. In summary, we show that both mouse and human DC generated in the presence of 1,25(OH)2D3 upregulate CD31 expression, resulting in a reduced ability to prime CD4⁺ T cells by impairing a stable cell-cell contact.
Background:
Polymorphic alleles of the vitamin D (vitD)-binding protein (VDBP) gene are associated with discriminatory differences in circulating concentrations of 25-hydroxyvitamin D (25-D), the indicator of vitD status (sufficiency defined by the Endocrine Society as ≥75 nmol/L). Within a diverse group of children, we hypothesized that reaching recommended daily allowance (RDA) of vitD intake would have differential impact on vitD status depending on VDBP variability.
Methods:
VDBP alleles (Gc1S, Gc1F, Gc2) in 123 children (1-4 annual visits/child; ages 1-8 years) were compared for relationships with serum 25-D concentrations and daily vitD intake.
Results:
In African-American children, reaching the vitD RDA was associated with significantly higher mean serum 25-D concentrations for the 20% carrying the VDBP 1S allele than for the large majority without this allele (77 vs. 61 nmol/L 25-D; p = 0.038). Children with the Gc1S/1S homozygous genotype (30% Caucasians, 24% Hispanics, 2% African-Americans) who met RDA had 51% (39 nmol/L) greater mean serum 25-D than those below RDA (p < 0.0001).
Conclusions:
VDBP genetic variability was a significant factor affecting childhood vitD status when following RDA guidelines. This study may inform public health policy of uniformity in recommended childhood vitD dosage, especially regarding racially/ethnically associated disparities.
The discovery of Vitamin D is a multi-step history started in 1650 and culminated in 1963 with the determination of its chemical structure. The diffusion of rickets in North Europe and North America was the first reason for experimental studies. Nevertheless, in the last decades new potential actions have been revealed. Besides bone and intestine, the Vitamin D receptors have been demonstrated in different organs such as the brain, prostate, breast, colon, immune system cells, smooth muscle and heart. Not totally fulfilling the criteria of a vitamin, Vitamin D is actually considered a pleiotropic hormone with endocrine and paracrine actions. The current evidences support the role of Vitamin D in skeletal health and suggest that the treatment of Vitamin D deficiency should be desirable to reduce the risk of chronic health diseases.
Vitamin D testing and treatment is subject of controversial scientific discussions and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥ 50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25 to 30 nmol/L (10 to 12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.
The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.
Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D3 (1α,25-dihydroxyvitamin D3; 1α,25(OH)2D3) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a critical checkpoint and direct transcriptional target of 1α,25(OH)2D3 in determining the tolDC profile. Using tracer metabolomics, we show that PFKFB4 activity is essential for glucose metabolism, especially for glucose oxidation, which is elevated upon 1α,25(OH)2D3 exposure. Pharmacological inhibition of PFKFB4 reversed the 1α,25(OH)2D3-mediated shift in metabolism, DC profile and function, as determined by expression of inhibitory surface markers and secretion of regulatory cytokines and factors. Moreover, PFKFB4 inhibition in 1α,25(OH)2D3-treated DCs blocked their hallmark capacity to induce suppressive Tregs. This work demonstrates that alterations in the bioenergetic metabolism of immune cells are central to the immunomodulatory effects induced by 1α,25(OH)2D3.
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate is primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25OHD < 50 nmol/l) accelerates bone turnover, bone loss and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D deficient elderly subjects.
The VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular and animal studies strongly suggest that vitamin D signaling has many extra-skeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need of continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health.
Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
Several studies have shown the correlation between vitamin D [25(OH)D] deficiency and thyroid autoimmunity and reducing of thyroid autoantibodies in patients with normal levels of vitamin D combining with thyroid hormone replacement. However, other authors not agree with this association. It is still unclear whether the low 25(OH)D levels are the result of HT disease or a part of its cause. We studied 88 patients with HT regarding vitamin D status and thyroid autoimmunity markers as well as the relationship with cytokines produced by Th1, Th2, and Th17 cells compared with a control group of 71 euthyroid healthy subjects. The present study demonstrated that vitamin D concentrations were similar in patients HT and the control group. The reduction of free T4 levels was a predictor of vitamin D insufficiency for Hashimoto's thyroiditis, but not for the control group. Lower concentrations of TNF-α was a predictor of lower levels of vitamin D. Differences in the association between HT and vitamin D insufficiency remain unresolved in the literature. The thyroid hormone status would play a role in the maintenance of vitamin D sufficiency, and its immunomodulatory role would influence the presence of autoimmune thyroid disease. The positive correlation between free T4 and vitamin D concentrations suggests that adequate levothyroxine replacement in HT would be an essential factor in maintaining vitamin D at sufficient levels.
Purpose:
Our insight in the genetics of Hashimoto's thyroiditis (HT) has become clearer through information provided by genome-wide association studies and candidate gene studies, but remains still not fully understood. Our aim was to assess how many different genetic risk variants contribute to the development of HT.
Methods:
147 HT cases (10.2% men) and 147 controls (13.6% men) were qualified for the analysis. Intrinsic and environmental factors were controlled for. Polymorphisms (SNP) were chosen based on the literature and included markers of the genes PTPN22, CTLA4, TG, TPO among others, and of genomic regions pointed by GWAS studies. SNP were typed on a microarray. Variants in the HLA-DRB1 gene were identified by Sanger sequencing.
Results:
Multivariate predisposition to HT was modeled. Based on the investigated group, a model of seven variables was obtained. The variability explained by this model was assessed at only 5.4821% (p = 2 × 10-6), which indicates that many dozens of factors are required simultaneously to explain HT predisposition.
Conclusions:
We analyzed genetic regions commonly and most significantly associated with autoimmune thyroid disorders in the literature, on a carefully selected cohort. Our results indicated a lack of possibility to predict the risk of HT development, even with a multivariate model. We therefore conclude that strong associations of single genetic regions with HT should be interpreted with great caution. We believe that a change in the attitude towards genetic association analyses of HT predisposition is necessary. Studies including multiple factors simultaneously are needed to unravel the intricacies of genetic associations with HT.
The 1st International Conference on Controversies in Vitamin D was held in Pisa, Italy June 14‐16, 2017. The meeting's purpose was to address controversies in vitamin D research, review data available to help resolve them and suggest a research agenda to clarify areas of uncertainty. Serum 25‐hydroxyvitamin D (25 (OH)D) concentration, i.e., the sum of 25 (OH)D3 and 25 (OH)D2, remains the critical measurement for defining vitamin D status. Assay variation for 25 (OH) D has contributed to the current chaos surrounding efforts to define hypovitaminosis D. An essential requirement to develop consensus on vitamin D status is that measurement of 25 (OH) D and, in the future, other potential vitamin D biomarkers, e.g., 1α,25 (OH)2D3, 3‐epi‐25 (OH) D, 24,25 (OH)2D3, vitamin D binding protein (DBP), free/bioavailable 25 (OH) D and parathyroid hormone be standardized/harmonized, to allow pooling of research data. Vitamin D Standardization Program (VDSP) tools are described and recommended for standardizing 25 (OH) D measurement in research. In the future, similar methodology, based on National Institute for Standards and Technology (NIST) Standard Reference Materials, must be developed for other candidate markers of vitamin D status. Failure to standardize/harmonize vitamin D metabolite measurements is destined to promulgate continued chaos. At this time, 25 (OH) D values below 12 ng/mL (30 nmol/L) should be considered to be associated with an increased risk of rickets/osteomalacia while 25 (OH) D concentrations between 20‐50 ng/mL (50‐125 nmol/L) appear to be safe and sufficient in the general population for skeletal health. In an effort to bridge knowledge gaps in defining hypovitaminosis D, an international study on rickets as a multifactorial disease is proposed.
Publications from clinical trials of vitamin D supplementation have increased substantially over the last 15 years. Yet, despite the growing number of randomized controlled trials, meta-analyses of these studies have drawn inconsistent conclusions. Many meta-analyses assume that vitamin D is a pharmacological agent, and give scant consideration of it being a nutrient. This limits their potential to detect beneficial effects in participants with vitamin D deficiency. An increasing body of evidence from both observational studies and clinical trials supports the presence of thresholds in vitamin D status below which disease risk increases and vitamin supplementation has beneficial effects. Future supplementation trials which seek to replicate these findings should recruit sufficient numbers of participants with low vitamin D levels, and not give low-dose vitamin D to the placebo group. If the presence of vitamin D thresholds for beneficial effects is confirmed, this would strengthen the need for vitamin D fortification of foods.
Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25-hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice.
At the time of the clinical onset of type 1 diabetes (T1D), we investigated 82 pediatric cases in parallel with 117 non‐diabetic controls matched by age, geographic area, and time of collection. The occurrence of an enteroviral infection was evaluated in peripheral blood using a sensitive method capable of detecting virtually all human enterovirus (EV) types. While non‐diabetic controls were consistently EV‐negative, 65% of T1D cases carried EVs in blood. The vitamin D status was assessed by measuring the concentration of 25‐hydroxyvitamin D [25(OH)D] in serum. Levels of 25(OH)D were interpreted as deficiency (≤50 nmol/L), insufficiency (52.5‐72.5 nmol/L), sufficiency (75‐250 nmol/L).
In T1D cases the median serum concentration of 25(OH)D was 54.4±27.3 nmol/L vs. 74.1±28.5 nmol/L in controls (p=0.0001). Diabetic children/adolescents showed deficient levels of vitamin D 25(OH)D (i.e., 72.5 nmol/L) in 48.8% cases vs. 17.9% in non‐diabetic controls (p=0.0001). Unexpectedly, the median vitamin D concentration was significantly reduced in virus‐positive vs. virus‐negative diabetics (48.2±22.5 vs. 61.8±31.2 nmol/L; p=0.015), with deficient levels in 58.5% vs. 31.0%, respectively.
Thus, at the time of clinical onset, EV‐positive cases had reduced vitamin D levels compared to EV‐negative cases. This could indicate either that the virus‐negative children/adolescents had been hit by a non‐infectious T1D‐triggering event, or that children/adolescents with proper levels of vitamin D had been able to rapidly clear the virus. Thus, it would be important to assess whether adequate vitamin D supplementation before or during the pre‐diabetic phase of T1D may counteract the diabetogenic potential of infectious pathogens.
The association between vitamin D receptor ( VDR ) polymorphisms (rs731236, rs1544410, rs2228570, and rs7975232) and the risk of autoimmune thyroid disease (AITD) had been investigated in previous studies. However, the results of these studies remained controversial. Thus, a meta-analysis was performed to derive a more precise conclusion. All related articles were systematically searched by PubMed, Embase, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI). The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of association. The overall results indicated that VDR rs731236 and rs2228570 polymorphisms were significantly associated with a reduced risk of AITD. However, a stratification analysis based on clinical types showed that VDR rs731236 and rs2228570 polymorphisms were associated only with a reduced risk of HT. A stratification analysis by ethnicity showed that VDR rs731236 polymorphism was significantly associated with a reduced risk of AITD in Asian and African populations. VDR rs2228570 polymorphism was associated with a reduced risk of AITD in Asian populations. VDR rs1544410 polymorphism was associated with a reduced risk of AITD in European and African populations, but with an increased risk of AITD in Asian populations. VDR rs7975232 polymorphism was significantly associated with an increased risk of AITD in African populations. In conclusion, the present study suggested that VDR rs731236, rs1544410, rs2228570, and rs7975232 polymorphisms were significantly associated with AITD risk. However, more well-designed studies should be performed to verify the current results.
Objective:
The aim of this observational study was to clarify the link between vitamin D status and metabolic syndrome (MetS) in people with visceral obesity.
Design and methods:
One hundred ninety-six consecutive patients (152 women; mean age 51 ± 13 years) with visceral obesity (mean body weight 103 ± 20 kg, mean waist circumference (WC) 119 ± 13 cm) were enrolled at the Obesity Outpatient Clinic of the University of Insubria in Varese. Anthropometric measurements were recorded. Laboratory tests, including vitamin D (25(OH)D)), fasting blood glucose (FBG), lipid profile, liver and kidney function tests were assessed. Vitamin D status was defined according to the European Society of Endocrinology guidelines, MetS to the 2009 harmonized definition.
Results:
An inverse association emerged among 25(OH)D, body mass index (BMI) (P = 0.001) and WC (all P = 0.003). Serum 25(OH)D levels were inversely related to FBG and systolic blood pressure (SBP) (respectively, P = 0.01 and 0.02). Median serum 25(OH)D levels were 13.3 ng/mL (CI 95% 12; 15) in MetS and 16 ng/mL (CI 95% 14; 18) (P = 0.01) in non-MetS patients. Among patients with MetS, lower 25(OH)D concentrations were related to higher risk of hypertension (HT) (odds ratio (OR) 1.7, CI 95%, 0.7;4) and hyperglycemia (IFG)/type 2 diabetes (OR 5.5, CI 95% 2; 14).
Conclusion:
Vitamin D status and MetS are inversely correlated in visceral obesity, particularly with regard to glucose homeostasis and BP. More extensive studies are required to investigate the potential for causality.
PurposeVitamin D deficiency has been associated with an increased risk of hypothyroidism and autoimmune thyroid disease. Our aim was to investigate the influence of vitamin D supplementation on thyroid function and anti-thyroid antibody levels. Methods
We constructed a database that included 11,017 participants in a health and wellness program that provided vitamin D supplementation to target physiological serum 25-hydroxyvitmain D [25(OH)D] concentrations (>100 nmol/L). Participant measures were compared between entry to the program (baseline) and follow-up (12 ± 3 months later) using an intent-to-treat analysis. Further, a nested case-control design was utilized to examine differences in thyroid function over 1 year in hypothyroid individuals and euthyroid controls. ResultsMore than 72% of participants achieved serum 25(OH)D concentrations >100 nmol/L at follow-up, with 20% above 125 nmol/L. Hypothyroidism was detected in 2% (23% including subclinical hypothyroidism) of participants at baseline and 0.4% (or 6% with subclinical) at follow-up. Serum 25(OH)D concentrations ≥125 nmol/L were associated with a 30% reduced risk of hypothyroidism and a 32% reduced risk of elevated anti-thyroid antibodies. Hypothyroid cases were found to have higher mean serum 25(OH)D concentrations at follow-up, which was a significant positive predictor of improved thyroid function. Conclusion
The results of the current study suggest that optimal thyroid function might require serum 25(OH)D concentrations above 125 nmol/L. Vitamin D supplementation may offer a safe and economical approach to improve thyroid function and may provide protection from developing thyroid disease.
The main role of vitamin D is regulating bone metabolism and calcium and phosphorus homeostasis. Over the past few decades, the importance of vitamin D in non-skeletal actions has been studied, including the role of vitamin D in autoimmune diseases, metabolic syndromes, cardiovascular disease, cancers, and all-cause mortality. Recent evidence has demonstrated an association between low vitamin D status and autoimmune thyroid diseases such as Hashimoto’s thyroiditis and Graves’ disease, and impaired vitamin D signaling has been reported in thyroid cancers. This review will focus on recent data on the possible role of vitamin D in thyroid diseases, including autoimmune thyroid diseases and thyroid cancers.
Introduction: Vitamin D deficiency is one of the major health problems globally, and the role of Vitamin D as an immunomodulator has been recently emphasized. There is increasing evidence to suggest that Vitamin D plays a significant role in reducing the incidence of autoimmune diseases. However, at present, its role in autoimmune thyroid disease is not conclusive. Hence, in our study, we aimed to examine the relationship between thyroid peroxidase antibodies (TPOAbs) and Vitamin D deficiency in the hypothyroid patient. Subjects and Methods: One hundred and four known hypothyroid patients not on Vitamin D supplementation were included in the study. They were divided into two groups with TPOAb positive and TPOAb negative, and serum 25(OH) Vitamin D3 (25[OH] D3) was measured and compared in two groups. Thyroid hormones (TSH and T4) were also evaluated in all patients. Results: Serum 25(OH)D3 was significantly lower in TPOAb-positive patients than in TPOAb-negative patients with P = 0.038. Mean serum TSH was significantly high in TPOAb-positive hypothyroid patients than in TPOAb-negative patients with P = 0.047. Conclusion: Our study shows that patients with TPOAb positivity have more significant 25(OH)D3 deficiency and uncontrolled hypothyroidism. Our study encourages the advisability of screening for Vitamin D deficiency for all hypothyroid patients and 25(OH)D3 supplementation.
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL) cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2Y6R agonist uridine-5′-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF.
Graves disease is the most common cause of thyrotoxicosis. Although medical intervention with antithyroid drugs (ATDs) is commonly the first choice of treatment in Korea, the remission rate associated with this approach is not satisfactory. During ATD therapy, low or undetectable serum levels of thyroid-stimulating hormone (TSH) receptor antibodies (TRAbs) have been reported to affect the incidence of Graves disease remission. This study evaluated the correlation between serum 25-hydroxyvitamin D levels and TRAb levels, as well as the effect of 25-hydroxyvitamin D on the recurrence of Graves disease.
A total of 143 patients, who were diagnosed with Graves disease and treated with ATDs, were retrospectively included in our observational study. These patients were followed for more than 1 year after ATD discontinuation. The levels of serum 25-hydroxyvitamin D and TRAb (ie, thyroid-stimulating antibody [TSAb], as detected by bioassay, and TSH-binding inhibitory immunoglobulins [TBIIs]) were measured, and a thyroid function test was performed upon ATD discontinuation. Recurrence was evaluated every 3 months, and was defined as an occurrence of overt thyrotoxicosis during the follow-up period.
A total of 95 patients (66.4%) experienced recurrence with a median latency period of 182 days (ranging 28–1219 days). The serum 25-hydroxyvitamin D levels at the time of ATD discontinuation were not correlated with either TBII or TSAb. In the Cox proportional hazard regression analysis, higher free T4 levels (>1.4 ng/dL; hazard ratio [HR], 3.252; 95% confidence interval [CI], 1.022–10.347) and low levels of 25-hydroxyvitamin D (≤14.23 ng/mL) were associated with a higher probability of Graves disease recurrence (HR, 3.016; 95% CI, 1.163–7.819).
Lower serum 25-hydroxyvitamin D levels were associated with a higher incidence of Graves disease recurrence. Therefore, serum 25-hydroxyvitamin D might be an independent risk factor for predicting Graves disease recurrence after ATD discontinuation.
Maturity level of dendritic cells (DC) plays a pivotal role in initiating and regulating autoimmunity. In graves’ disease (GD), DCs have more active immune responses than those in healthy subjects. Our previous study demonstrated immunoregulatory effects of in vitro 1,25-D3 on maturation of DC in GD patients. This study aims to evaluate the effect of oral 1α-D3 on DC maturation in GD patients. Methods: Twenty five GD patients with thyrotoxicosis were divided into two groups: 12 GD patients receiving oral 1α-D3 and 13 GD patients receiving placebo, in addition to treatment of propylthiouracil. Comparison of DC maturation were performed before and after the oral 1α-D3. DC maturation was assessed based on the expression of DC markers (HLA-DR, CD80, CD40, CD83, CD14 and CD206) and the ratio of cytokines interleukin-12/IL-10.Results: After 8 weeks, 8 out of 12 GD patients in treatment group and 6 out of 13 GD patients in placebo group still had high fT4 level. The expression of CD80 decreased (p=0.48) and CD206 increased (p=0.47) insignificantly among treatment group. The IL-12/IL-10 ratio decreased along with the improvement of fT4 level in both groups. No difference of the IL-12/IL10 ratio between treatment and placebo group. Conclusion: The effects of oral 1α-D3 on DC maturation of GD patients have not been clearly demonstrated in this study yet.
INTRODUCTION:
CD28/T-cell receptor (TCR)/cytotoxic T-lymphocyte antigen 4 (CTLA4) complex controls T-cell tolerance and autoimmunity in Hashimoto's thyroiditis (HT). In addition, CD45 protein tyrosine phosphatase (PTPase) and vitamin D receptor (VDR) cooperatively interact with the TCR complex to affect autoimmune processes central to the pathogenesis of HT. Nevertheless, their role in HT aetiology has been less well established. In this study, we aimed to explore mRNA expression levels of CTLA4, CD28, CD45, and VDR in T-cells, across different outcomes of HT.
MATERIAL AND METHODS:
The study included 45 HT patients and 13 euthyroid, healthy controls. T-lymphocytes were isolated from peripheral blood mononuclear cells, total mRNA was extracted from T-cells, and gene expression was studied by reverse transcription-polymerase chain reaction (RT-PCR) and ImageQuant method relative to glyceraldehyde-3-phosphate dehydrogenase RT-PCR products.
RESULTS:
Nominally higher expression levels of VDR, CTLA4, CD28, and CD45RAB mRNA were found in unsorted T-lymphocytes of healthy controls when compared to the HT patients. No difference was observed between hypothyroid/untreated, spontaneously euthyroid and LT4-treated HT patients. VDR mRNA expression was linked to both T3 levels and CTLA4 gene expression, whilst CD45RB mRNA expression coincided with CTLA4 and CD28 transcript levels. Conversely, older age and lower T3 levels were associated with increased abundance of CD45R0 isoform in HT patients.
CONCLUSIONS:
The results suggest a cross talk between endocrine and immune functions in HT pathology: an altered peripheral T cell mRNA profile with reduced VDR, CTLA4, CD28, and CD45RAB transcript levels is accompanied by age-related shift from naive to memory/late-differentiated T cell CD45R mRNA signature and associated with thyroid hormone status in the HT patients.
Context
Autoimmune thyroid disorders have been linked to vitamin D deficiency but an effect of vitamin D supplementation is not established.
Objective
Our objective was to test whether vitamin D compared to placebo could reduce thyroid autoantibodies.
Design
Predefined additional analyses from a randomized, double-blind and placebo-controlled trial.
Setting
The study was conducted in different community centers in Oslo, Norway.
Participants
251 young adult, presumed healthy, males and females, aged 18-50 years with background from South Asia, the Middle East or Africa were included.
Intervention
Daily supplementation with 25µg (1000 IU), 10µg (400 IU) vitamin D3 or placebo for 16 weeks.
Outcome measure
Difference in anti-thyroid peroxidase antibody (TPOAb) level between post- and pre-intervention. Additional outcomes were difference in thyroid stimulating hormone (TSH) and free fraction of thyroxin (fT4).
Results
There were no differences in change after 16 weeks on TPOAb (27 kU/L, 95% CI: -17, 72, P=.23), TSH (-0.10 mU/L 95%CI: -0.54, 0.34, P=.65) or fT4 (0.09 pmol/L, 95% CI: -0.37, 0.55, P=.70) between those receiving vitamin D supplementation or placebo. Mean Serum 25(OH)D3 increased from 26 nmol/L to 49 nmol/L in the combined supplementation group, but there were no change in the placebo group.
Conclusion
Vitamin D3 supplementation, 25µg or 10µg, for 16 weeks compared to placebo did not affect TPOAb level in this randomized, double-blind study among participants with background from South Asia, the Middle East or Africa who had low vitamin D levels at baseline.
AIM: The aim was to investigate serum vitamin D (25-OH) level among females with hypothyroidism.
MATERIALS AND METHODS: A case-control study (58 in each arm) was conducted in Arar Central Hospital, Kingdom Saudi Arabia. The cases were females with hypothyroidism, and healthy females were controls. TSH, thyroid hormones: Free T3 (FT3) and Free T4 (FT4) and haemoglobin levels were measured in all participants. Serum vitamin D (25-OH) level was measured using the spectrophotometry.
RESULTS: While there was no significant difference in the age and haemoglobin level, body mass index (BMI) was significantly higher in the cases. Compared with the controls, cases had significantly higher TSH, had significantly lower T4, and there was no significant difference in FT3 and 25 (OH) vitamin D, [16.1 (8.8-26.7) vs. 14.0 (9.5-20.3 ng/ml; P = 0.577]. Linear regression showed no association between, age, BMI, haemoglobin, TSH, FT3, FT4 and the log of 25 (OH) vitamin D levels.
CONCLUSION: There was no significant difference in vitamin D level among females with hypothyroidism and healthy controls.
Hashimoto's thyroiditis (HT) is a chronic autoimmune thyroid disease caused by an interaction between genetic factors and environmental conditions, both of which are yet to be fully understood. The management of HT depends on its clinical manifestations, commonly including diffuse or nodular goiter with euthyroidism, subclinical hypothyroidism and permanent hypothyroidism. However, in most cases of patients with HT, lifelong levothyroxine substitution is required. The additional role of diet for the management of HT is usually overlooked. A literature search regarding the importance and the influence of iodine, selenium, vitamin D and gluten on HT was conducted. In HT careful supplementation of possible deficiencies is recommended for the dietary management of these patients. The use of a diet low in gluten among HT patients with or without celiac disease (CD) is discussed.
Environmental factors are determinant for the appearance of autoimmune thyroid diseases (AITD) in susceptible subjects. Increased iodine intake, selenium, and vitamin D deficiency, exposure to radiation, from nuclear fallout or due to medical radiation, are environmental factors increasing AITD. Cigarette smoking is associated with Graves’ disease and Graves’ ophthalmopathy, while it decreases the risk of hypothyroidism and thyroid autoimmunity. Viral infections are important environmental factors in the pathogenesis of AITD, too, particularly human parvovirus B19 (EVB19) and hepatitis C virus. Among the many chemical contaminants, halogenated organochlorines and pesticides variably disrupt thyroid function. Polychlorinated biphenyls and their metabolites and polybrominated diethyl ethers bind to thyroid transport proteins, such as transthyretin, displace thyroxine, and disrupt thyroid function. Among drugs, interferon- and iodine-containing drugs have been associated with AITD. Moreover intestinal dysbiosis causes autoimmune thyroiditis. To reduce the risk to populations and also in each patient, it is necessary to comprehend the association between environmental agents and thyroid dysfunction.
Four VD receptor (VDR) gene polymorphisms (TaqI, ApaI, FokI and BsmI) have been reported to influence Hashimoto’s thyroiditis (HT) risk. However, individual studies have produced inconsistent results. We conducted a comprehensive meta-analysis of eleven case-control studies to better understand roles of the four polymorphisms in HT development. The results showed only FokI polymorphism was significantly associated with the risk of HT (F vs f: OR = 1.44, 95% CI = 1.09–1.91, P = 0.010; FF vs Ff + ff: OR = 1.72, 95% CI = 1.09–2.70, P = 0.019). Subgroup analyses demonstrated the significant effect was only present in Asian population (F vs f: OR = 1.45, 95% CI = 1.07–1.95, P = 0.016; FF vs ff: OR = 1.64, 95% CI = 1.03–2.59, P = 0.036; FF + Ff vs ff: OR = 1.34, 95% CI = 1.00–1.80, P = 0.047; FF vs Ff + ff: OR = 1.64, 95% CI = 1.03–2.64, P = 0.039), but not in Caucasian. For TaqI, ApaI and BsmI polymorphisms, no significant association was found in any model comparison. Based on the current literature, it appears that only VDR FokI polymorphism is associated with HT risk in Asian population, but not in Caucasians; and the TaqI, ApaI and BsmI polymorphisms have not positive association neither in the overall population, nor when stratified by ethnicity. Further well-designed studies with larger sample sizes and different ethnic population are needed to clarify the present findings.
Over the last three decades, it has become clear that the role of vitamin D goes beyond the regulation of calcium homeostasis and bone health. An important extraskeletal effect of vitamin D is the modulation of the immune system. In the context of autoimmune diseases, this is illustrated by correlations of vitamin D status and genetic polymorphisms in the vitamin D receptor with the incidence and severity of the disease. These correlations warrant investigation into the potential use of vitamin D in the treatment of patients with autoimmune diseases. In recent years, several clinical trials have been performed to investigate the therapeutic value of vitamin D in multiple sclerosis, rheumatoid arthritis, Crohn’s disease, type I diabetes, and systemic lupus erythematosus. Additionally, a second angle of investigation has focused on unraveling the molecular pathways used by vitamin D in order to find new potential therapeutic targets. This review will not only provide an overview of the clinical trials that have been performed but also discuss the current knowledge about the molecular mechanisms underlying the immunomodulatory effects of vitamin D and how these advances can be used in the treatment of autoimmune diseases.
Background:
Vitamin D deficiency is considered a risk factor for autoimmune diseases. Vitamin D and its analogues have been proposed as therapeutic tools in autoimmunity considering their exquisite immunoregulatory effect against over-reactivity towards tolerance. Autoimmune diseases, nowadays recognized as emerging non communicable diseases, are characterized by a significant female bias. This sexual dimorphism seems related to sex hormones, which differently affect male and female immune systems. Males show higher immunosuppression, maybe due to androgens; the greater female immunoreactivity and competence, likely related to estrogens, lead to a greater resilience to infections but also to a higher risk for autoimmunity. Higher interest could be given to vitamin D-based supplementation or therapy for autoimmune diseases in relation to gender as well.
Objective:
This review aims to discuss the role of vitamin D in autoimmune diseases with a view inside gender-related differences, in light of the interplay between vitamin D and sex hormones, especially estrogens.
Results:
Some beneficial effects against autoimmune processes seem to be allowed by vitamin D acting in synergy with estrogens. This observation suggests that possible differences of vitamin D effects depend on the context in which this hormone is active.
Conclusion:
Rather sex-related differences of "absolute" vitamin D levels, the role of gender-dependent factors affecting vitamin D action seems to be critical. Gender and sexual hormones could be included as variables when evaluating the potential power of vitamin D receptor agonists as novel pharmacological tools to approach autoimmune diseases.
Vitamin D exerts its canonical roles on the musculoskeletal system and in the calcium/phosphorus homeostasis. In the last years, increasing evidences suggested several extra-skeletal actions of this hormone, indicating that vitamin D may produce effects in almost all the body tissues. These are mediated by the presence of vitamin D receptor (VDR) and thanks to the presence of the 1-α-hydroxylase, the protein that converts the 25-hydroxyvitamin (calcidiol) to the active form 1,25-dihydroxyvitamin (calcitriol). Several studies evaluated the possible role of vitamin D in the pathogenesis of thyroid diseases, and this review will focus on the available data of the literature evaluating the association between vitamin D and thyroid function, vitamin D and autoimmune thyroid diseases, including Hashimoto’s thyroiditis, Graves’ disease and post-partum thyroiditis, and vitamin D and thyroid cancer.
Context:
The latest guidelines of the 4th International Workshop on Asymptomatic Primary Hyperparathyroidism (aPHPT) reintroduced hypercalciuria (i.e. urinary calcium > 400 mg/day) as criterion for surgery. However, the value of hypercalciuria as a predictor of nephrolithiasis and the correct cut-off values still need to be confirmed.
Objective:
To evaluate the prevalence of silent kidney stones in a large series of patients with aPHPT and the sensibility, specificity and predictive value of different cut-off values of hypercalciuria in identifying patients with nephrolithiasis.
Design:
One hundred seventy-six consecutive patients with aPHPT were evaluated at our Institution by serum and urinary parameters and kidney ultrasound.
Results:
Silent nephrolithiasis was found in 38 (21.6%) patients. In the univariate and multivariate model, hypercalciuria was a predictor of nephrolithiasis using the criterion of 400 mg/24 h [(OR 2.30, (1.11-4.82) P = 0.025], 4 mg/kg/bw [OR 2.65, (1.14-6.25) P = 0.023], gender criterion [OR 2.79, (1.15-6.79) P = 0.023] and the cut-off value derived from the ROC analysis [(> 231 mg/24 h) OR 5.02 (1.68-14.97) P = 0.004]. Despite these several predictive criteria, however, hypercalciuria had a low positive predictive value (PPV), ranging from 27.4 to 32.7%.
Conclusions:
Hypercalciuria is a predictor of nephrolithiasis, but its PPV is low.
Hashimoto’s thyroiditis (HT) is the most prevalent autoimmune disorder characterized by the destruction of thyroid cells caused by leukocytes and antibody-mediated immune processes accompanied by hypothyroidism. In recent years, evidence has emerged pointing to various roles for vitamin D, including, proliferation and differentiation of normal and cancer cells, cardiovascular function, and immunomodulation. Vitamin D deficiency has been especially demonstrated in HT patients. The aim of this study was to investigate the effect of vitamin D on circulating thyroid autoantibodies and thyroid hormones profile (T4, T3, and TSH) in females with HT. Forty-two women with HT disease were enrolled in this randomized clinical trial study and divided into vitamin D and placebo groups. Patients in the vitamin D and placebo groups received 50 000 IU vitamin D and placebo pearls, weekly for 3 months, respectively. The serum levels of 25-hydroxy vitamin D [25(OH) D], Ca++ion, anti-thyroperoxidase antibody (anti-TPO Ab), anti-thyroglobulin antibody (anti-Tg Ab), T4, T3, and TSH were measured at the baseline and at the end of the study using enzyme-linked immunosorbent assays. The results of this study showed a significant reduction of anti-Tg Ab and TSH hormone in the Vitamin D group compared to the start of the study; however, there was a no significant reduction of anti-TPO Ab in the Vitamin D group compared to the placebo group (p=0.08). No significant changes were observed in the serum levels of T3 and T4 hormones. Therefore, vitamin D supplementation can be helpful for alleviation of the disease activity in HT patients; however, further well controlled, large, longitudinal studies are needed to determine whether it can be introduced in clinical practice.
Autoimmune thyroid disease (ATD) is a chronic autoimmune thyroiditis with a complex pathogenesis including environmental factors, genetic background and immune system actions. Despite the large-scale research and discovery of new subpopulations of lymphocytes, cytokines, chemokines and their functions in the human body, the ethiology of ATD in many aspects remains a mystery. This article tries to summarize mostly the immunological aspects of this disease, including the roles of different cells types (dendritic cells, B cells, CD4+ and CD8+ T cells, NK cells and regulatory T cells) and of different cytokines (secreted by Th1/Th2/Th17/Th22 lymphocyte subpopulations and other, including the IL-23 and CXCL10). We describe the role of immunological abnormalities in the ATD pathogenesis and show that for some cells and cytokines their respective roles are not clear, and bi-directional action is possible. Finally, we propose a network of interactions between the immune cells and thyrocytes in the course of ATD.
Purpose
In patients with type 1 diabetes (T1D), the prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 10 to 53% and contrasting evidence suggests that vitamin D deficiency may favor liver fat accumulation. Here, we investigated the association between vitamin D status and NAFLD in adults with T1D.
Methods
220 consecutive adult T1D patients on multiple daily injections or continuous subcutaneous insulin infusion and not taking calcium or vitamin D supplements were included. Patient characteristics, 25(OH)D serum levels, and metabolic parameters were analyzed. Vitamin D status was defined as sufficiency ( ≥ 75 nmol/L; 30 ng/ml), insufficiency (50–75 nmol/L; 20–30 ng/ml), or deficiency ( < 50 nmol/L; 20 ng/ml). NAFLD was diagnosed at ultrasound examination and graded 0–3.
Results
NAFLD was present in 57 patients (29.5%): 51 grade 1, 5 grade 2, and 1 grade 3. Median 25(OH)D levels were 53 nmol/L (IQR 38–70) in patients with NAFLD and 50 nmol/L (34–69) in patients without (p = 0.46). At multivariable analysis, NAFLD was not associated with 25(OH)D levels (p = 0.42) or vitamin D deficiency (p = 0.55), while BMI (OR 1.16, 95% CI 1.07–1.27) and serum triglycerides (OR 1.02, 95% CI 1.01–1.03) were independently associated with NAFLD.
Conclusions
Vitamin D status appears to have no link with low-grade NAFLD in patients with type 1 diabetes.
Context
Vitamin D is classically recognized as a regulator of calcium and phosphorus metabolism. Recent advances in the measurement of vitamin D metabolites, diagnosis of vitamin D deficiency, and clinical observations have led to an appreciation that along with its role in skeletal metabolism, vitamin D may well have an important role in non-classical settings. Measurement of the circulating form of vitamin D that best describes total body stores, namely 25-hydroxyvitamin D, can be unreliable despite many sophisticated methodologies that have been proposed and implemented. Similarly, evidence from clinical studies showing a beneficial role of vitamin D in different disease states has been controversial and at times speculative. Moreover, the target concentrations of 25-hydroxyvitamin D to address a number of putative links between vitamin D inadequacy and non-skeletal diseases are further areas of uncertainty.
Methods
To address these issues, an International Conference on “Controversies in Vitamin D” was held in Pisa, Italy, in June, 2017. Three main topics were addressed: 1) vitamin D assays and definition of hypovitaminosis D; 2) skeletal and extra-skeletal effects of vitamin D; 3) therapeutics of vitamin D.
Results
This report provides a summary of the deliberations of the expert panels of the Conference.
Conclusions
Despite great advances in our appreciation of vitamin D metabolism, measurements, biological actions on classical and non-classical tissues, and therapeutics, all of which this report summarizes, much more work remains to be done so that our knowledge base can become even more secure.
Background
Hypovitaminosis D is associated with an adverse prognosis in colon cancer patients, possibly due to the effects of the vitamin on the immune system. Antibody-dependent cell-mediated cytotoxicity (ADCC) significantly contributes to the anti-tumor effects of monoclonal antibodies, including cetuximab, an epidermal growth factor receptor (EGFR)-targeted monoclonal antibody that is frequently added to chemotherapy in the treatment of colon cancer.
Objective
The present study evaluates the association between vitamin D serum levels and the ability of ex vivo NK cells to support cetuximab-mediated ADCC in colon cancer cell lines.
Methods
Blood samples were obtained from 124 healthy volunteers and serum vitamin D was determined by RIA. NK cells were isolated from each sample and added to human colorectal carcinoma cells with or without cetuximab, and ADCC was assessed using a colorimetric lactate dehydrogenase assay.
Results
Correlation analysis indicates a significant, gender- and age-independent association between vitamin D levels and cetuximab-induced ADCC on HT29 cells, where NK cells from samples with vitamin D < 20 ng/mL are significantly less efficient in inducing ADCC. A confirmatory study on two additional colon cancer cell lines yielded similar results.
Conclusions
These data suggest that vitamin D supplementation in vitamin-deficient/insufficient colorectal cancer patients could improve cetuximab-induced ADCC.
Purpose:
Although vitamin D is reportedly associated with various cancers, the association between vitamin D and thyroid cancer is indefinite. We aimed to investigate whether this association applies to thyroid cancer (TC).
Methods:
A total of 276 Chinese Han people were recruited in a current matched case-control study. Multivariable conditional logistic regression was computed to estimate the association between plasma 25(OH)D and papillary thyroid cancer (PTC). In addition, we searched relevant studies in PubMed and Web of Science databases before December 2017 to conduct a meta-analysis.
Results:
In our case-control study, plasma 25(OH)D concentration was inversely associated with PTC risk (highest tertile vs lowest tertile: adjusted OR = 0.25; 95% CI 0.10, 0.61; Ptrend = 0.003). This association was independent of body mass index and physical activity (all adjusted Pinteraction > 0.05). A total of 11 studies were included in the meta-analysis, among which ten studies have been published and one was our case-control study. Compared with 25(OH)D non-deficient group, the pooled OR of TC was 1.42 (95% CI 1.17, 1.73) in the deficient group. Similarly, blood 25(OH)D levels in patients with TC were tend to be lower than those in the controls (SMD = - 0.20, 95% CI - 0.36, - 0.03).
Conclusions:
A high level of circulating 25(OH)D was associated with a decreased TC risk. This association has important significance in public health and should, therefore, be further studied.
Objective:
The aim was to compare the vitamin D levels in patients with Graves disease (GD) with the general population and to correlate the vitamin D levels with laboratory and clinical parameters in GD. Moreover, we examined the genetic variation in genes involved in the vitamin D metabolism and their association with GD.
Methods:
The levels of vitamin D were compared in 292 patients with newly diagnosed GD and 2,305 controls. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR), vitamin D binding protein (DBP), and 1-α-hydroxylase (CYP27B1) were examined for association with GD and/or Graves ophthalmopathy (GO) in 708 patients and 1,178 controls.
Results:
Patients with GD had significantly lower vitamin D levels compared to controls (55.0 ± 23.2 vs. 87.2 ± 27.6 nmol/L,p< 0.001). In patients with GD (n= 219), there was no association between the levels of vitamin D at diagnosis and free thyroxine (fT4), free triiodothyronine (fT3), thyrotropin receptor antibodies (TRAb), GO at diagnosis, or relapse after terminating treatment with antithyroid drugs. Two SNPs in VDR were associated with GD: rs10735810 (OR = 1.36, 95% CI: 1.02-1.36,p= 0.02) and rs1544410 (OR = 1.47, 95% CI: 1.03-1.47,p= 0.02). There was no difference in the mean vitamin D level between genotypes in either rs10735810 or rs154410.
Conclusions:
Patients with GD had lower vitamin D levels compared to the general population; however, the vitamin D levels did not affect the laboratory or clinical parameters of GD. SNPs in the VDR influenced the risk of GD through mechanisms other than reducing the vitamin D levels.
Purpose:
Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in reproductive age women. The aim of this studywas to evaluate the effects of vitamin D supplementation in combination with low-calorie diet on anthropometric indices, reproductive hormones and menstrual regularity in overweight and obese PCOS women.
Methods:
In this randomized controlled clinical trial, 60 PCOS women with vitamin D insufficiency were randomly assigned to 12 weeks of either (1) weight-loss intervention + 50,000 IU/week oral vitamin D3 or (2) weight-loss intervention + placebo. At the beginning and end of the study, the anthropometric indices, body composition, 25-hydroxyvitamin D, total testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG) and free androgen index (FAI) were measured and regularity of menses was compared among the two groups.
Result:
After 12-week intervention, median of serum 25-hydroxyvitamin D3 significantly increased from 18.5 (10.75-20) ng/ml to 42.69 (34-53.25) ng/ml in vitamin D group compared to placebo group (p < 001). Moreover, there was a significant improvement in frequency regular menstrual cycle (p = 0.01). Mean of weight, body mass index, fat mass, waist and hip circumference and waist-to-hip ratio significantly decreased in both groups, but was not different between two groups. Mean of total testosterone insignificantly decreased from 0.7 to 0.5 ng/ml in vitamin D group (p = 0.18). In addition, we did not observe significant differences regarding DHEAS, FAI and SHBG between two groups.
Conclusions:
In women with PCOS, androgen profile did not change with vitamin D supplementation when combined with low-calorie diet, but menstrual frequency significantly improved.
Clinical trial registration number:
IRCT2016062710826N19.
Randomised trials reported up to Dec 31, 2012, did not confirm that vitamin D supplementation could protect from non-skeletal health conditions affecting adults, as was expected on the basis of data from observational studies. To examine whether the more recently published meta-analyses and trials would change past conclusions, we systematically reviewed meta-analyses of vitamin D supplementation and non-skeletal disorders published between Jan 1, 2013, and May 31, 2017, that included study participants of all ages, including pregnant women. We also searched for randomised trials not included in meta-analyses. We identified 87 meta-analyses, of which 52 were excluded because they contained less recent literature or were of suboptimal quality. We retrieved 202 articles on trials that were not included in meta-analyses. Recent meta-analyses reinforce the finding that 10-20 μg per day of vitamin D can reduce all-cause mortality and cancer mortality in middle-aged and older people. Although vitamin D doses were greater than those assessed in the past, we found no new evidence that supplementation could have an effect on most non-skeletal conditions, including cardiovascular disease, adiposity, glucose metabolism, mood disorders, muscular function, tuberculosis, and colorectal adenomas, or on maternal and perinatal conditions. New data on cancer outcomes were scarce. The compilation of results from 83 trials showed that vitamin D supplementation had no significant effect on biomarkers of systemic inflammation. The main new finding highlighted by this systematic review is that vitamin D supplementation might help to prevent common upper respiratory tract infections and asthma exacerbations. There remains little evidence to suggest that vitamin D supplementation has an effect on most conditions, including chronic inflammation, despite use of increased doses of vitamin D, strengthening the hypothesis that low vitamin D status is a consequence of ill health, rather than its cause. We further hypothesise that vitamin D supplementation could exert immunomodulatory effects that strengthen resistance to acute infections, which would reduce the risk of death in debilitated individuals. We identified many meta-analyses of suboptimal quality, which is of concern. Future systematic reviews on vitamin D should be based on data sharing so that data for participants with the same outcomes measured in the same way can be pooled to generate stronger evidence.
Background:
Rapid, easy and reliable measurement of the major vitamin D metabolites is required in order to fulfill the needs of a clinical routine laboratory. To overcome these challenges, we have developed and validated a LC-MS/MS method for the quantification of 25-hydroxyvitamin D2 and D3, epi-25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3.
Methods:
Sample preparation was based on precipitation and centrifugation of 100μL of patient serum, followed by injection into the LC-MS/MS system. Samples from Vitamin D Standardization Program (n=80) and patient samples (n=281) have been compared with a reference LC-MS/MS method. For the analytical validation NIST and Labquality quality control materials were used.
Results:
Mean intra-assay and inter-assay imprecision were <6.0 and 6.4% and mean recoveries were within 95-104%. LOQ's were 0.5μg/L for 24,25(OH)2D3, 1.1μg/L for 25(OH)D3 and epi-25(OH)D3 and 1.7μg/L for 25(OH)D2. A 3% bias obtained between the proposed and the reference method satisfies Vitamin D Standardization Program recommendations.
Conclusions:
We present a rapid, easy, reliable and cost-effective method completely adequate for routine testing, which permits the measurement of the ratio of 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D, Vitamin D Metabolite Ratio (VMR), in serum samples.
Background:
Vitamin D deficiency is becoming an increasing problem worldwide. It should not be underestimated, not only due to the well-known consequences vitamin D deficiency has on bone health, but primarily because recent studies have shown how the biologically active form of vitamin D - 1,25(OH)2D - is involved in many biological processes, including immune system modulation. Moreover, the presence of a vitamin D receptor was discovered in almost all immune cells and some of its polymorphi