Marlena Dudek-Makuch, Pharm. D., Development Expert, Curtis Health Caps
Because approximately one billion people worldwide are vitamin D deficient, it has become an important focus of current medical research. Although the biological activity of vitamin D is mainly manifested in the regulation of calcium and phosphorus metabolism, research over the past 30 years indicates that it also regulates the immune system due to the presence of receptors for vitamin D also in the immune system. Maintaining adequate vitamin D levels has also been shown to be important in autoimmune diseases, including autoimmune thyroid disease (AITD). Recently, many studies have shown a correlation between low vitamin D levels and Graves’ disease (GD) and chronic autoimmune thyroiditis/Hashimoto thyroiditis (HT). [1, 2]
Mechanism of vitamin D action in autoimmune diseases
The process of autoimmunization requires an autoantigen to which a healthy organism shows tolerance, as well as a process that leads to the breaking of that tolerance and the initiation of the disease process. Potential autoantigens in the thyroid are thyroid-stimulating hormone (TSH) receptor (TSH-R), thyroid peroxidase (TPO) and thyroglobulin (Tg). Autoimmunity to these antigens leads to the formation of anti-thyroid antibodies. Anti-TPO and anti-Tg are usually associated with HT, and TSH-R (TRABs) with GD. 
Both GD and HT are characterized by lymphocytic infiltration in the thyroid parenchyma. In GD, the infiltrate is benign and therefore the gland remains intact; however, in HT, the lymphocytic infiltrate causes destruction of thyroid tissue, resulting in hypothyroidism.  In addition, Th1 lymphocytes are recruited in thyroid tissue, which increases the production of interferon γ and tumor necrosis factor α (TNF-α), which then stimulate the secretion of the CXCL10 cytokine by thyroid cells and produce positive feedback, initiating and perpetuating the autoimmune process.  In addition, B lymphocytes, located in secondary lymphoid follicles in thyroid tissue, spontaneously produce antibodies, making the thyroid probably the major source of autoantibodies in AITD. 
AITD has a multi factor etiology; its occurrence is associated with genetic factors, environmental factors (e.g., radiation, iodine, smoking, infection, selenium deficiency, stress, and dietary habits), and endogenous factors (e.g., body mass index, adipokines, estrogens). 
The effect of vitamin D on AITD has been widely studied in recent years. Vitamin D has been proven to play a significant role in modulating the immune system, enhancing the innate immune response while inhibiting the adaptive immune system.  There are suggestions that vitamin D acts as an immunomodulator in autoimmune diseases, including but not limited to GD or HT .
Correlation between Tsh and vitamin D levels in healthy people
Barchetta et al. investigating the seasonality of TSH levels in euthyroid adults (normal thyroid hormone levels) showed a strong inverse correlation between levels of this hormone and levels of the vitamin D metabolite calcidiol (25(OH)D3), with TSH levels being highest in autumn and winter and 25(OH)D3 levels being highest in spring and summer. 
Mackawy et al. also found an inverse relationship between vitamin D levels and TSH values, with a high prevalence of hypovitaminosis D and hypocalcemia in hypothyroid patients.  Two population-based studies have confirmed these data in young people , and in middle-aged and elderly men with negative results for anti-thyroid antibodies.  A study in Korea showed that excess iodine was associated with thyroid dysfunction only in vitamin D deficient subjects. 
Vitamin D levels in autoimmune thyroid diseases
The correlation between low vitamin D levels and increased risk of AITD has been demonstrated in multiple cross-sectional studies.
Kivity et al. described an association between vitamin D deficiency, defined as a level of 25(OH)D3) ≤ 10 ng/ml ( ≤ 25 nmol/l), and a higher incidence of AITD (mainly HT) and the presence of anti-thyroid antibodies.  Unal et al. found lower 25(OH)D3 levels in AITD subjects, with the GD group having lower levels than HT subjects, and an inverse correlation between 25(OH)D3 levels and anti-thyroid antibody titers.  Also, a 2015 meta-analysis including 3603 participants (AITD n = 1782, control n = 1821) showed lower 25(OH)D3 levels and a higher prevalence of deficiency in AITD patients compared to controls, this association was also demonstrated when HT and GD patients were analyzed separately. 
Vitamin D supplementation in thyroid diseases
The large number of studies suggesting an association between low 25(OH)D3 levels and AITD has generated interest in evaluating the use of vitamin D supplements in the prevention and treatment of this group of conditions. Recent results support a beneficial effect of vitamin D supplementation in people with AITD, which was generally higher than the standard recommended dose (from 2000 IU/day to 60000 IU/week). 
Vitamin D supplementation may also be part of preventing the development of thyroid diseases. The 11017 participants in the wellness program had their vitamin D levels supplemented over 1 year, aiming to achieve physiological levels defined as 25(OH)D3 > 40 ng/mL (100 nmol/L). 25(OH)D3 concentrations ≥ 50 ng/ml (125 nmol/l) were found to reduce the risk of hypothyroidism by 30% and the risk of elevated anti-thyroid antibody levels by 32%. Increased 25(OH)D3 levels in hypothyroid patients have also been associated with improved thyroid function. 
In a systematic review and meta-analysis, Wang et al. showed that vitamin D supplementation significantly reduces anti-TPO (for treatment ≥6 months) and anti-Tg levels.  Koehler et al. in a retrospective study evaluated 933 patients with autoimmune thyroiditis and found a greater reduction in anti-TPO antibody levels in a subgroup of 58 patients who achieved normal 25(OH)D3 levels after supplementation compared to a control group who maintained vitamin D levels below 30 ng/ml. 
Ensuring normal 25(OH)D3 levels may also be important in terms of proper treatment response during thyroid disease therapy; lower levels are associated with a lower likelihood of remission  and a higher rate of relapse. 
Serum 25(OH)D concentrations < 20 ng/ml have been identified as an independent risk factor for therapeutic failure with radioactive iodine.  Administration of selenomethionine (200 mg) together with vitamin D (4000 IU/day) to women with HT (n = 47) was associated with a more pronounced reduction in anti-TPO/-Tg titers. 
The effect of vitamin D supplementation on the course of GD was also evaluated. It has been shown that it can delay the onset of the disease, but does not appear to prevent relapse or ameliorate the disease , however, it does have a beneficial effect on cardiovascular outcomes. 
However, it should be noted that supplementation with excessive doses of vitamin D can be harmful and there is an increased risk of fractures when 25(OH)D3 concentrations are achieved above recommended levels. 
Therefore, it appears that the most optimal approach is to aim for vitamin D levels within the ranges suggested by international guidelines. The guidelines for vitamin D supplementation for the general population and groups at risk of vitamin D deficiency in Poland specify the optimal level of 25(OH)D3 30-50 ng/ml (75-125 nmol/l), and the maximum safe level (not causing hypercalcemia) up to 100 ng/ml (250 nmol/l). 
Numerous studies have shown that vitamin D deficiency is common in people with AITD, suggesting that it may play a role in their development. Large, multicenter, randomized clinical studies support this claim, suggesting the need for supplementation in this patient group. In addition, vitamin D has also been shown to have a beneficial effect on treatment efficacy when used in combination with multiple medications.
Huang ZL. Master Dissertation.Jilin University; Jilin, China: 2013. The Study on Relationship between Serum 25-Hydroxyvitamin D3 Concentration and Hashimoto Thyroiditis.
Liu XH. Master Dissertation.Zhengzhou University; Zhengzhou, China: 2012. The Study on Relation between Vitamin D3 Level and Immune Disorder in Patients with Autoimmune Thyroid Disease
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Marlena Dudek-Makuch, PhD (Pharm.), MSc, has 20 years of professional experience in phytochemical and biological research, and scientific information (assistant professor at the Department of Pharmacognosy, Poznań University of Medical Sciences). She is an author of research and review papers on the isolation and identification of compounds of plant origin, and evaluation of their biological activity. Since 2015, she has been teaching a postgraduate course in “Herbs in practice and therapy”.
She is currently a member of the Regulatory Department, R&D Division, at CHC. In her position, she is in charge of preparing expert reports (clinical, non-clinical) for medicinal products, clinical reports for OTC switches, clinical assessments of medical devices, pharmacovigilance activities for medical devices, and safety assessment of plant-based raw materials used in medicinal products, medical devices, and dietary supplements.
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