Vitamin D and autoimmune thyroid diseases
Witamina D a autoimmunizacyjne choroby tarczycy
Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw
Head of Department: Professor Wojciech Zgliczyński, MD, PhD
Witamina D jest jednym z głównych czynników regulujących homeostazę wapnia i fosforu oraz metabolizm kostny. W ostatnich latach coraz więcej dowodów wskazuje na ważną rolę niedoboru witaminy D w wielu schorzeniach spoza układu kostnego, takich jak zespoły metaboliczne, choroby układu sercowo-naczyniowego, nowotwory, infekcje oraz zaburzenia autoimmunizacyjne, w tym reumatoidalne zapalenie stawów, choroba Leśniowskiego-Crohna, stwardnienie rozsiane czy cukrzyca typu 1. Wiele badań wykazało także związek między niedoborem witaminy D a chorobami autoimmunizacyjnymi tarczycy, w tym zapaleniem tarczycy Hashimoto, poporodowym zapaleniem tarczycy i chorobą Gravesa-Basedowa. W ostatnich latach coraz więcej danych wskazuje na to, że uzupełnianie niedoboru witaminy D może zapobiegać tym patologiom lub łagodzić ich przebieg. Niektóre badania sugerują także, że witamina D może mieć wpływ na czynność hormonalną gruczołu tarczowego. W artykule przedstawiono najnowsze doniesienia dotyczące związku witaminy D z procesami autoimmunizacyjnymi w tarczycy i jej czynnością hormonalną. Omówiono także wpływ suplementacji witaminą D na rozwój i przebieg autoimmunizacyjnych chorób tarczycy.
Vitamin D is one of the most important factors regulating calciuam and phosphorus homeostasis and bone metabolism. In the last years increasing evidences suggest an important role of vitamin D deficiency in many extra-skeletal disorders, such as metabolic syndromes, cardiovascular diseases, cancers, infections and autoimmune disorders, including rheumatoid arthritis, Crohn disease, multiple sclerosis and type 1 diabetes mellitus. Many studies has shown also an association of vitamin D deficiency with occurrence and development of autoimmune thyroid diseases including Hashimoto’s thyroiditis, postpartum thyroiditis and Graves’ disease. In recent years there are increasing data indicating that vitamin D supplementation may prevent these pathologies or alleviate their course. Some studies suggest also that vitamin D may influence thyroid function. This review presents current data on the relationship of vitamin D and thyroid autoimmunization and function. The effects of vitamin D supplementation on the development and progression of autoimmune thyroid disease have also been discussed.
Vitamin D is a steroid prohormone, mainly synthesized in the skin, which, after conversion to an active metabolite, regulates calcium and phosphorus metabolism and bone homeostasis. Currently, multiple data suggest, that it has also many extra-skeletal actions. Vitamin D deficiency may play an important role in pathogenesis of infections, autoimmune diseases, metabolic syndromes, cardiovascular diseases, cancers and all-cause mortality (1, 2). In recent years there have been many studies published, which showed vitamin D associations with autoimmune thyroid diseases, including Hashimoto’s thyroiditis (HT), postpartum thyroiditis (PPT) and Graves’ disease (GD) (3, 4).
Vitamin D occurs in two different forms, as cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). Cholecalciferol is mainly synthesized in the skin upon exposure to ultraviolet B radiation by 7-dehydrocholesterol reductase (DHCR7), but it can be also obtained from few dietary sources (mainly fatty fish). Ergocalciferol is derived from dietary sources – it is synthesized by plants and fungi (2). Both forms are transported to the liver and there hydroxylated to 25-hydroxyvitamin D (25(OH)D3, calcidiol) by 25-hydroxylase (CYP27A1, CYP2R1), which has little biological activity, but is the main storage form of vitamin D. Calcidiol is converted to active hormone, calcitriol (1,25(OH)2D3) by 1α-hydroxylase (CYP27B1), which is mainly expressed in kidney. This enzyme is stimulated by parathormone (PTH) and inhibited by high 1,25(OH)2D3 concentration and fibroblast growth factor 23 (FGF23). Calcitriol is inactivated by 24-hydroxylase (CYP24A1) (1, 2). Calcitriol is also produced from calcidiol by several other cell types (including immune cells), which express 1α-hydroxylase, without the above regulatory feedback, as an autocrine or paracrine cytokine (1). The main factor determining extrarenal 1,25(OH)2D3 synthesis seems to be 25(OH)D3 concentration (5). There have been found many associations between serum calcidiol level, rather than calcitriol concentration, and extraskeletal health outcomes (5). Both calcidiol and calcitriol are highly hydrophobic molecules, stored in the adipose tissue and circulating in blood bound mainly to vitamin D binding protein (DBP) (85 and 88%, respectively) and, with lower affinity, to albumin (15 and 12%, respectively) (6, 7). Less than 1% of calcitriol is free and can bind to nuclear vitamin D receptor (VDR), which acts on vitamin D response element (VDRE) of multiple target genes to exert its effects (8). VDR is found in most cells and tissues, including the thyroid (1, 8, 9). 1,25(OH)2D3 decreases cellular proliferation, induces differentiation and apoptosis, influences angiogenesis, and modulates the immune system (1, 2). A membrane-bound VDR has been also hypothesized, which would mediate rapid, non-genomic actions of 1,25(OH)2D3 (8).
Vitamin D is a potent immunomodulator. Most immune cells, including macrophages, antigen-presenting cells (APCs), lymphocytes T and B, express not only VDR, but also 1α-hydroxylase (2, 10). Generally, vitamin D activates the innate system and regulates the acquired immune response (2, 11). It inhibits major histocompatibility complex class II molecules expression on dendritic cells surface and modulates cytokine secretion, shifting the balance from a Th1 and Th17 to a Th2 phenotype (2, 10). Calcitriol also inhibits B cell proliferation, differentiation of B cells into plasma cells, immunoglobulin secretion and formation of memory B cells, as well as induces B cell apoptosis (2, 10). To summarize, vitamin D promotes immunotolerance, and, therefore, could be beneficial in autoimmune disorders (1, 2, 10).
Not only vitamin D status, but also polymorphism of genes involved in vitamin D metabolism, transport and activity was shown to be associated to susceptibility to autoimmune disorders (10).
This review presents the current data regarding the role of vitamin D in autoimmune thyroid diseases.
Vitamin D status and thyroid function
The thyroid gland secretes mainly thyroxine (T4) and, in less extend, triiodothyronine (T3), which are crucial for maintaining specific function of multiple cell types and tissues and stimulating metabolism. Thyroid function is controlled by thyrotropin (thyroid stimulating hormone – TSH) released by the pituitary. The data on associations between vitamin D status and TSH or thyroid hormone concentrations are very limited and often divergent.
Experiments on rats showed, that those fed with severely vitamin D deficient diet had lower TSH, but similar T4 levels to vitamin D sufficient animals. However, administration of high doses of calcitriol did not influence TSH or T4 concentrations (12). In streptozotocin-induced diabetic rats inhibited peripheral conversion of FT4 into FT3 secondary to reduction in deiodinase 2 (D2) expression was observed. Vitamin D greatly corrected the alterations in thyroid profile and D2 expression (13).
In human, when hospitalized patients without history of thyroid diseases were studied, TSH levels did not differ between those with 25(OH)D3 very low (≤ 10 ng/ml) and high (≥ 40 ng/dl) concentrations (9). On the contrary, in two normal population-based studies, high vitamin D status was associated with lower TSH levels. In a Thai cohort it was observed only in young subjects (14), while in Chinese – also in middle-aged and elderly ones (15). In postmenopausal women suppressed TSH was also associated with higher vitamin D levels, however the relationship was not linear (16). On the other hand, in a population of euthyroid adults Barchetta et al. showed a strong association between vitamin D deficiency and higher TSH levels (p = 0.01) (17). Those and other authors suggested, that reported seasonality in TSH secretion was associated with vitamin D status (17, 18).
Hypothyroidism was, according to Mackawy et al., as well as to Kim, associated with hypovitaminosis D (19, 20), however others did not confirm these observations (21, 22).
Bouillon et al. reported, that in hypothyroid patients serum calcidiol levels were comparable to normal subjects, while calcitriol concentrations were significantly increased (73 ± 28 ng/l vs. 42 ± 13 ng/l in control subjects; p < 0.001), probably secondary to high parathyroid hormone levels (53 ± 17 mU/l vs. 26 ± 9 mU/l in controls; p < 0.001) (21).
Very recently, in a large retrospective Canadian cohort study regarding the influence of vitamin D supplementation on thyroid function, baseline mean 25(OH)D3 concentration was significantly lower in hypothyroid subjects than in healthy controls (27.2 vs. 32.8 ng/ml) (18). Interestingly, in type 2 diabetic patients Calvo-Romero and Ramiro-Lozano found slightly higher serum thyrotropin levels in vitamin D deficient subjects (at the limit of statistical significance), however, with no effect of correction of vitamin D deficiency on TSH concentrations (23).
In untreated hyperthyroid patients unaltered calcidiol, low calcitriol and high 24,25(OH)2D3 concentrations were observed (21, 24, 25). It was explained to be a result of high bone turnover causing secondary hypoparathyroidism or of competitive inhibition of calcitriol synthesis by 24,25(OH)2D3.
However, recently, in women with gestational transient thyrotoxicosis 25(OH)D3 concentrations were found to be significantly lower than in pregnant female with normal thyroid function (26, 27). Moreover, Pan et al. showed, that calcidiol levels correlated positively with TSH and negatively with FT4 and FT3 concentrations (27).
Vitamin D status and autoimmune thyroid diseases
Autoimmune thyroid diseases are the most common organ-specific autoimmune disorders. Hashimoto thyroiditis, also known as chronic lymphocytic thyroiditis, is a typical T-cell mediated autoimmune disease, in which intrathyroidal infiltration of B and T lymphocytes is observed. It is well established, that type 1 T helper (Th1) lymphocytes participate in the development of HD. Cytokines secreted by Th1 cells activate cytotoxic T-lymphocytes and natural killer (NK) cells, leading to thyrocyte destruction. Nowadays increasing data indicate important role of other mechanisms in pathogenesis of HT (including autoantibodies, other subgroups of T helper cells such as Th17, regulatory T cells, disturbances of the process of apoptosis) (28). In Graves’ disease only a mild lymphocytic infiltration with type 2 T helper (Th2) cell subtype predominance is observed. Th2 cells induce the production of antibodies to the receptor for TSH (TRAb), which are crucial in pathophysiology of GD. The ability of vitamin D to modulate adaptive immune system may influence the pathogenesis of autoimmune thyroid disorders.
In mice previously sensitized with porcine thyroglobulin intraperitoneal injections of calcitriol and intragastrical administration of cyclosporine A reduced severity of autoimmune thyroiditis, and, when applied together, even prevented thyroid disease (29, 30). In rats with experimental autoimmune thyroiditis, 1,25(OH)2D3 also prevented or ameliorated structural disruption of thyroid gland and corrected cytokine disequilibrium (31). In mouse model of Graves’ disease, persistent hyperthyroidism was observed in vitamin D deficient, but not in vitamin D sufficient animals immunized with TSH receptor. Interestingly, before immunization vitamin D deficient mice had lower T4 concentrations. These results suggest direct modulation of thyroid function by vitamin D (32).
In the last years, several clinical studies indicated an association between vitamin D deficiency and autoimmune thyroid diseases (AITD) defined as elevated antithyroid antibodies with or without characteristic ultrasonographic features (diffuse parenchymal hypoechogenicity and/or heterogeneous echogenic pattern of thyroid gland) (20, 33-38). Many authors observed that subjects with low vitamin D concentration had more frequently elevated anti-TPO antibodies (33-37, 39) and/or anti-TG antibodies (35, 36, 40, 41). In patients with AITD anti-TPO titers were highest among subjects with lowest calcidiol concentrations (42). A meta-analysis of 20 case-control studies made by Wang et al. in 2015, showed that patients with AITD have lower calcidiol levels and are more often vitamin D deficient compared to controls (43). The same results were obtained in 90 Turkish children with AITD and HT (aged 12.3 ± 2.9 years) compared to 79 age-matched healthy controls (11.9 ± 2.3 years) (44). Recently, in a group of Italian elderly subjects (168 patients, aged 81.6 ± 9.4 years) a significantly higher prevalence of AITD was observed in vitamin D deficient subjects (25(OH)D3 < 20 ng/ml) than in those with normal calcidiol levels (28 vs. 8%, respectively, p = 0.002). In addition, in subjects with AITD a significant correlations between 25(OH)D3 and anti-TPO antibodies (r = -0.27, p = 0.03) as well as FT3 (r = 0.35, p = 0.006), but not anti-TG antibodies, TSH or FT4 were observed (45). Interestingly, Choi et al. in a cross-sectional study on 6685 subjects observed that serum calcidiol levels were significantly lower in pre-menopausal, but not in post-menopausal women with AITD (36). It may suggest connections between vitamin D and estrogens in the development of AITD.
However, no difference in the prevalence of vitamin D deficiency (25(OH)D3 < 20 ng/ml) between 100 patients with AITD (52 HT, 48 GD) and 126 healthy controls was observed by D’Aurizio et al. (11). Likewise, the relationship between low vitamin D levels and the presence of anti-TPO and anti-TG antibodies was not always observed (14, 37, 38, 41). Goswami et al. in a group of 642 subjects from India revealed only a weak inverse correlation between serum calcidiol and anti-TPO concentrations (r = -0.08, p = 0.04), but no association between vitamin D deficiency (25(OH)D3 < 10 ng/ml) and anti-TPO positivity (33). In the study of Yasmeh et al. the mean 25(OH)D3 levels were not significantly different in AITD males and healthy controls (14.24 vs. 13.26 ng/ml) and were even higher in females with AITD than in healthy ones (30.75 vs. 27.56 ng/ml). AITD females were more often vitamin D sufficient (51.7 vs. 31.1%) than control females. Furthermore, in males, a significant positive correlation between 25(OH)D3 and anti-TPO antibodies was observed (r = 0.436, p = 0.016) (46). The authors concluded that AITD is not associated with higher prevalence of vitamin D deficiency.
Since the majority of authors observed, however, an inverse correlation between anti-thyroid antibodies and calcidiol levels (33, 35-37, 39, 41), a suggestion that vitamin D deficiency is one of the potential factors in pathogenesis of autoimmune thyroid disorders occured. In contrast to those results, in a study regarding women from the Amsterdam AITD cohort (first- and second-degree relatives of overt AITD patients, euthyroid and without thyroid antibodies), neither the whole group nor a subgroup of subjects, which during a 5-year follow-up developed anti-thyroid antibodies, had lower 25(OH)D3 levels than age-matched controls. Interestingly, seronegative cohort subjects had even significantly higher calcidiol concentrations when compared to controls (47). Therefore, the authors concluded, that early stages of thyroid autoimmunity are not associated with low vitamin D levels.
There was no difference in calcidiol levels in children and adolescents with type 1 diabetes mellitus with and without thyroid antibodies (48).
In an elderly population with a high prevalence of vitamin D deficiency/insufficiency patients with type 2 diabetes were found to be 2.5 times more likely to have AITD compared to a nondiabetic individuals, but, interestingly, the higher the serum 25(OH)D3 levels were, the higher this chance was (49). In women with polycystic ovary syndrome (PCOS), 25(OH)D3 levels were significantly lower in subjects with AITD than in those without AITD (p = 0.02). However, in women with PCOS and AITD no correlation was found between calcidiol and thyroid antibodies, TSH nor thyroid hormone levels (50).
In the majority of studies regarding Hashimoto’s thyroiditis (HT), in HT patients calcidiol concentrations were lower and the prevalence of vitamin D deficiency was higher when compared with healthy controls (34, 35, 40, 51-53). It was confirmed in meta-analysis performed by Wang et al. for the subgroup of patients with HT (43).
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