Review

Department of Physiopathology, Medical University of Gdan´sk, 80-211 Gdansk, Poland; fl[email protected]

* Correspondence: [email protected]

Abstract: Hashimoto’s thyroiditis (HT) is a common autoimmune disease affecting the thyroid gland, characterized by lymphocytic infiltration, damage to thyroid cells, and hypothyroidism, and often requires lifetime treatment with levothyroxine. The disease has a complex etiology, with genetic and environmental factors contributing to its development. Vitamin D deficiency has been linked to a higher prevalence of thyroid autoimmunity in certain populations, including children, adolescents, and obese individuals. Moreover, vitamin D supplementation has shown promise in reducing antithyroid antibody levels, improving thyroid function, and improving other markers of autoimmunity, such as cytokines, e.g., IP10, TNF-α, and IL-10, and the ratio of T-cell subsets, such as Th17 and Tr1. Studies suggest that by impacting various immunological mechanisms, vitamin D may help control autoimmunity and improve thyroid function and, potentially, clinical outcomes of HT patients. The article discusses the potential impact of vitamin D on various immune pathways in HT. Overall, current evidence supports the potential role of vitamin D in the prevention and management of HT, although further studies are needed to fully understand its mechanisms of action and potential therapeutic benefits.

Keywords: Hashimoto’s thyroiditis; vitamin D; autoimmunity; cytokines; anti-thyroid antibodies

Citation: Lebiedzin´ski, F.; Lisowska, K.A. Impact of Vitamin D on Immunopathology of Hashimoto’s Thyroiditis: From Theory to Practice. Nutrients 2023, 15, 3174. https:// doi.org/10.3390/nu15143174

Academic Editor: Jessica Pepe

Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Hashimoto’s thyroiditis (HT), also known as chronic lymphocytic thyroiditis and Hashimoto’s disease, is an autoimmune thyroid disease (AITD) with a complex etiopathology, which includes genetic (e.g., major histocompatibility complex (MHC) genes) and environmental factors, such as past infections, medications, and smoking, and the level of microelements, such as iodine, iron, and selenium [1,2]. With an incidence of 0.3–1.5 cases per 1000 people, HT is the most common cause of hypothyroidism in iodine-replete areas [3].

Despite much research on its immunopathology, HT remains an incurable disease with an unpredictable nature, often leading to lymphocytic destruction of the thyroid gland and the need for thyroid hormone replacement for life [4,5]. However, some studies showed that interventions within modifiable risk factors might improve immunological and clinical outcomes in HT patients. This includes, among other things, dietary changes, stress management, selenium supplementation, and vitamin D supplementation [6–9].

In this article, we aim to review the mechanisms of the immunomodulatory activity of vitamin D and its impact on the autoimmune process in Hashimoto’s thyroiditis.

The systematic literature research used Pubmed, SCOPUS, and Web of Science databases. The following keywords were used, in combinations or individually: vitamin D, thyroiditis, Hashimoto, autoimmune thyroid disease, immune system, cytokines, and supplementation. The database search focused on original research and meta-analyses presenting studies conducted on humans and animals, published between January 1999 and March 2023.

Nutrients 2023, 15, 3174. https://doi.org/10.3390/nu15143174 https://www.mdpi.com/journal/nutrients

For the trials which would present the association between vitamin D concentration and immunological parameters in HT in humans, as well as changes in immune markers after vitamin D supplementation, we researched the last decade (2013–2023), excluding case reports, narrative reviews, editorials, and commentaries.

3. Vitamin D 3.1. Sources, Metabolism, and Function

Vitamin D is a fat-soluble vitamin that plays a crucial role in bone health and calcium regulation in the body. There are two main forms of vitamin D: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is found in some plant foods, while vitamin D3 is synthesized in the skin upon exposure to sunlight [10]. When vitamin D is consumed or synthesized, it first undergoes hydroxylation in the liver, where it is converted into 25-hydroxyvitamin D (25(OH)D), which is commonly used as an indicator of vitamin D status in the body. Next, 25(OH)D is transported to the kidneys, where it undergoes a second hydroxylation step to become the biologically active form of vitamin D known as calcitriol, also known as 1,25-dihydroxyvitamin D (1,25(OH)2D) [11].

Calcitriol then binds to vitamin D receptors (VDRs) in various tissues throughout the body, including the bones, intestines, and kidneys, to regulate calcium and phosphate metabolism. In the intestines, calcitriol increases the absorption of calcium and phosphorus, while in the kidneys, it increases calcium reabsorption and phosphate excretion. Calcitriol helps regulate bone remodeling and mineralization, ensuring proper bone growth and maintenance [12].

In addition to its role in bone health, research has proved its pleiotropic effects which are significant for disease prevention [13]. Many studies have linked vitamin D to various health benefits, including mood regulation, reduced risk of chronic cardiovascular diseases, immune function, and others [14–17]. Proper levels of vitamin D are essential in the prevention of musculoskeletal [18], cardiovascular [19], dementia [20,21], cancer [22], autoimmune [15], metabolic [23], PCOS [22,24], or even kidney diseases [25]. Examples of pleiotropic actions with their clinical significance in different diseases are shown in Table 1.

Table 1. Examples of possible pleiotropic actions of vitamin D and their potential clinical significance.

1. - Promotion of osteoblast proliferation;
2. - DMP1 and BSP synthesis regulation;
3. - Activation of muscle protein synthesis.

1. - Rickets, osteoporosis, and fractures;
2. - Sarcopenia.

Musculoskeletal diseases [18]

1. - Regulation of calcium metabolism, including intracellular calcium concentration;
2. - RAAS regulation.

1. - Cardiomyocyte dysfunction;
2. - Hypertension.

Cardiovascular diseases [19]

Brain diseases [20,21] - Regulation of dopaminergic development;

1. - Schizophrenia;
2. - Alzheimer’s disease, dementia.

- Reduction in amyloid-induced cytotoxicity.

1. - Prostate cancer;
2. - Melanoma;
3. - Head and neck cancers.

1. - VEGF inhibition;
2. - Blocking cell cycle at G0/G1 stage.

Cancers [22]

Immune-mediated diseases [15]

1. - Preventing excessive T-cell activation;
2. - Inhibits the development of Th17 cells;
3. - Promotes the differentiation of regulatory T-cells.

1. - RA;
2. - AITD;
3. - SLE;
4. - MS.

Table 1. Cont.

Disease Group Vitamin D Functions Disease Prevention

Metabolic diseases [23] - Reduction in insulin resistance;

1. - Diabetes mellitus;
2. - Obesity.

- Regulation of adipogenesis.

Female reproductive system diseases [22,24]

1. - Progesterone production stimulation;
2. - Reduction in insulin resistance.

PCOS

Renal system diseases [25] - Prevention of renal fibrosis, apoptosis, and inflammation.

CKD

AITD, autoimmune thyroid disease; BSP, bone sialoprotein; CKD, chronic kidney disease; DMP, dentin matrix acidic phosphoprotein; MS, multiple sclerosis; PCOS, polycystic ovaries syndrome; RA, rheumatoid arthritis; RAAS, renin–angiotensin–aldosterone system; SLE, systemic lupus erythematosus; VEGF, vascular endothelial growth factor.

The pleiotropic actions of vitamin D are mainly considered to come from acting on the genomic level, directly regulating gene expression via VDR/RXR (vitamin D receptor/retinoid X receptor) complex. However, the research shows it also acts via non-genomic, rapid pathways, altering gene expression through epigenetic mechanisms. For example, in the immune system, as described by Hii et al. [26], vitamin D can control VDR binding to target proteins like STAT1 (signal transducer and activator of transcription 1) and IKK-β (inhibitor of nuclear factor kappa-B kinase subunit beta). This function enables vitamin D to cross-modulate gene expression mediated by non-vitamin D ligands, such as TNF-α and IFN-γ. Vitamin D may exert control over immunological and antiviral responses through this mechanism. Other non-genomic mechanisms of vitamin D action, concerning, among other things, interaction with PDIA3 (protein disulfide isomerase family member 3) and rapid intracellular calcium regulation via L-VGCC (L-type voltage-gated calcium channel) are speculated to play a role in proper bone, muscle, and brain development [27,28].

While sunlight is the most efficient way to obtain vitamin D, it can also be found in certain foods such as fatty fish, egg yolks, dairy, and grain products [29]. However, obtaining enough vitamin D through diet or sunlight alone can be challenging for numerous high-risk groups, which include, among other things, individuals over 65 years of age, dark-skinned populations, patients with cancer, autoimmune diseases, malabsorption syndromes, cardiovascular diseases, diabetes, and people with body mass index (BMI) > 30 [30,31]. According to a recent pooled analysis of 7.9 million participants by Cui et al. [32], 15.7% of the global population is vitamin D deficient. At the same time, other studies indicate that the prevalence of vitamin D deficiency in Europe may be as high as 40%, and the prevalence of severe vitamin D deficiency—13% [33]. Because of the scale of the problem, the need for widespread correction of vitamin D status, mainly with supplementation, is often considered a public health problem [34].

1. 3.2. The Role of Vitamin D in the Immune System

Vitamin D significantly impacts the immune system, as VDRs are present in many peripheral blood mononuclear cells, including T and B cells and antigen-presenting cells (APCs) [35]. Via genomic pathways, calcitriol influences the transcriptional activity of genes involved in immune cell functioning and regulates processes such as cell differentiation, the cell cycle, programmed cell death, stress response, and fighting infections. For example, Vitamin D may induce the expression of antibiotic peptides, such as CAMP/LL-37 (cathelicidin antimicrobial peptide LL-37), which destroy the cell membranes of bacteria and viruses [36]. Vitamin D also enhances autophagy in macrophages, which helps clear viruses from the cells, including SARS-CoV-2 [37].

Furthermore, vitamin D plays a significant role in preventing autoimmune processes [15,38,39]. Vitamin D downregulates MHC class II and co-stimulatory molecules expressed on dendritic cells (DCs), which are major APCs, thus preventing excessive T-cell

activation [40]. Vitamin D also suppresses DC cytokine production and promotes the expression of anti-inflammatory cytokines, such as interleukin 1 (IL-10) [41]. In T cells, vitamin D suppresses the proliferation and differentiation of CD4+ T cells (helper T cells, Th cells) and promotes their differentiation into Th2 cells, which helps maintain Th1/Th2 balance [42]. Vitamin D also inhibits the development of Th17 cells and promotes the differentiation of regulatory T cells (Tregs) that prevent an increased autoimmune response by, among other things, secreting anti-inflammatory cytokines [43]. B cells, which produce antibodies, also express VDR. Vitamin D has been found to affect B cells in various ways, including the inhibition of naive B cell differentiation or maturation to plasma cells, which may potentially reduce autoantibody production [44].

It should be emphasized that the positive influence of vitamin D on the immune system at the cellular and molecular level also translates into improved clinical outcomes for patients with autoimmune diseases. Several clinical trials and observational studies have demonstrated that vitamin D supplementation may benefit the prevalence and disease activity of multiple autoimmune conditions, e.g., rheumatoid arthritis [45], inflammatory bowel disease [46], and vitiligo [47]. For example, the VITAL randomized controlled trial from 2022, which included 25,871 participants from the United States, showed that vitamin D supplementation of 2000 IU/day for five years reduced the risk of developing any autoimmune disease by 22% [48]. Multiple meta-analyses also proved that vitamin D deficiency increases the risk of developing various autoimmune conditions, including AITD [49–53].

1. 4.1. Etiological Factors Affecting the Development of HT
2. 4.2. Immunopathological Processes in HT on the Level of Cells and Cytokines

From the morphopathological perspective, HT disease typically leads to thyroid enlargement with nodule development. In HT, there is an extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers. The CD4:CD8 ratio in the infiltrate is 4:1. The atrophy of the colloid bodies is lined by Hürthle cells [59,60].

Many studies show that, from the immunological viewpoint, the main contributors to the development of HT are (1) Th1/Th2 cell imbalance and (2) Th1 cell activity enhancement [16], which lead to disturbances in the complex interplay between different immune components. The characteristics of thyroid autoimmunity in HT on the cellular and molecular levels were reviewed by Luty et al. in detail [61].

First, the presence of environmental/genetic factors leads to the activation of APCs, mainly DCs, which present allo- and autoantigens to naive CD4+ T cells, leading to their differentiation into Th1, Th2, Th17, Th22, or Tregs (Figure 1). Second, cytokines produced

by Th1, including IL-12 and IFN-γ, induce the expression of MHC II on thyroid cells, further promoting the differentiation of the naive CD4+ T cells into Th1. Finally, Th1 cells, through IFN-γ, IL-2, and TGF-β, induce the activation of CD8+ T cells (cytotoxic T cells, Tc cells).

CD8+ T cells, through secreted perforins and granzymes or via Fas-FasL cascade [62], destroy thyroid cells, which leads to the release of proinflammatory cytokines and chemokines. This leads to an amplification feedback loop that initiates and sustains the immune process. Cytokines released by thyrocytes contribute to (1) the migration and activation of pathological Th17 cells (IL-6, TNF-α, IL-1β, and TGF-β) and (2) the suppression of Tregs (IL-6, IFN-γ, IL-8, IL-1β, and CXCL10), which usually inhibit excessive T-cell-mediated cytotoxicity [63]. Moreover, the microenvironment in the infiltrated thyroid promotes the

differentiation of proinflammatory Th22 cells. The destruction of the thyroid gland and the strengthening of the autoimmune process also occur through the humoral response. Infiltrating B cells (triggered by Th2 cytokines, i.e., IL-4, IL-5, and IL-10) release autoantibodies (mainly anti-TPO and anti-Tg), which can further lead to the destruction of thyrocytes in the mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC) [61].

1. 5.1. Immunomodulatory Potential of Vitamin D in HT
2. 5.2. Association between Vitamin D, the Occurrence of HT, and Antibody Levels

The association between vitamin D and HT remains controversial. Many studies to date investigated this topic in various populations, and the results still have some inconsistency. Some work, including observations from the Croatian Biobank of HT patients

and other comparative studies, did not detect an association between vitamin D levels and the prevalence of HT [79–81]. However, large-scale studies, including systematic reviews and meta-analyses, confirm the association between low vitamin D and HT. Metaanalysis of observational studies by Taheriniya et al. [53] showed lower vitamin D levels in patients with HT than in healthy subjects. Similar results were shown in meta-analyses by Wang et al. [71] and Štefanic´ and Tokic´ [72]; HT patients were more likely to have lower 25(OH)D than a healthy population. In studies by Kim et al. [82,83] on the Korean population, including a nationwide survey of 4181 participants, vitamin D deficiency was significantly associated with a high prevalence of thyroid autoimmunity. Other studies showed that low 25(OH)D correlates with HT in children and adolescents [84], as well as in obese subjects [85]. Moreover, some studies suggest an association between serum 25(OH)D levels and the clinical presentation of HT, including the severity of hypothyroidism and the prevalence of mild cognitive impairment [79,86].

Apart from the correlation between vitamin D status and the prevalence of HT, several studies investigated the association between vitamin D and antithyroid antibody levels. In the comparative study by Aktas¸ et al. [87], there was a negative correlation between 25(OH)D level and anti-TPO in 130 patients diagnosed with HT. Similar results were obtained by Bozkurt et al. [88], who also demonstrated that vitamin D deficiency severity correlated with the duration of HT, thyroid volume, and antibody levels. Interestingly, Sayki Arslan et al. [89] also discovered that anti-TPO positivity was significantly more common in healthy subjects (HT not diagnosed) with vitamin D deficiency compared to those with a normal 25(OH)D level.

1. 5.3. Association between Vitamin D Levels and Immunological Parameters in HT

Most studies that evaluated the immunity of HT concerning vitamin D focus on thyroid autoantibody titers as markers of the autoimmunological process. However, the potential impact of vitamin D may concern various other immunological mechanisms. Few studies assessed the association of vitamin D and HT in the context of different immune pathways, with varying results. For example, in HT patients, Botehlo et al. [90] showed no significant correlation between 25(OH)D status and IL-2, IL-4, and IFN-γ serum levels. However, a positive correlation was observed between vitamin D and IL-17, TNF-α, and IL-5. According to the authors, the lower TNF-α and IL-17 levels, which correlated with low vitamin D status, could be explained by the control of cytotoxicity by long-time treatment of HT. As stated by Korzeniowska et al. [91], levothyroxine may contribute to stabilizing the inflammatory process in HT. In a study by Wencai Ke et al. [92], serum 25(OH)D levels were not associated with IL-4, IL-17, and TNF-α in newly diagnosed or treated patients with HT. However, vitamin D concentrations were relatively deficient in those subjects.

Feng et al. [93] discovered that, amongst Chinese children with HT, serum IL-21 concentration was positively correlated with antithyroid antibodies, while the serum concentration of 25(OH)D had a significant negative correlation with serum IL-21. According to the investigators, the results showed that vitamin D levels and IL-21 might be involved in the occurrence and development of HT.

It is worth noting that the results by Hisbiyah et al. [94], who investigated children with Down syndrome and HT. Contrary to most studies, they found a positive correlation between vitamin D and antithyroid antibody levels. They also found no correlation between vitamin D and NF-κB (nuclear factor-kappa B), suggesting that vitamin D could not affect NF-κB, a transcription factor whose pathway, according to Giuliani et al. [95], can also play a role in thyroid autoimmunity. However, the authors concluded that vitamin D could suppress IFN-γ, which is involved in, i.e., the suppression of Tregs expression and the activation of CD8+ T cells in HT. [61]

Roehlen et al. [96] presented even more insights into the mechanisms of vitamin D immunoregulation. They investigated if the immunoregulatory function of vitamin D can be related to FOXO3a gene polymorphisms and SIRT1 (sirtuin 1 histone deacetylase) in HT and DTC (differentiated thyroid cancer). SIRT1 and FOXO3a are proteins that regulate

cellular processes related to aging and disease [97]. FOXO3a is a transcription factor that regulates the expression of multiple genes associated with, i.e., cell proliferation, apoptosis, and cellular stress [98], while SIRT1 is a deacetylase that modifies the activity of various proteins, e.g., p53, NF-κB, and FOXO3a [99]. SIRT1 activates FOXO3a through deacetylation, leading to the upregulation of genes involved in stress resistance and longevity. In vitro, vitamin D exerted an anti-proliferative effect in Th cells that was blocked by SIRT1 inhibition and accompanied by elevated FOXO3a gene expression. The authors concluded that the SIRT1-FOXO3a axis is one of the downstream targets of vitamin D immunoregulatory effects. Moreover, they identified two single nucleotide polymorphisms in the FOXO3a gene (rs9400239T and rs4945816C) that may constitute genetic risk factors for HT [96].

Tokic et al. [100] discovered that T cells from HT patients exhibited lower CTLA4, CD28, and CD45RAB gene expression than healthy controls. All these molecules may play a role in thyroid autoimmunity. The CD28/T-cell receptor (TCR)/CTLA4 complex regulates T-cell homeostasis and tolerance in HT, while CD45 protein tyrosine phosphatase (PTPase) cooperates with the vitamin D receptor to interact with the TCR complex and influence the Th1/Th17/Treg pathways that are critical to the development of HT.

The association between vitamin D status, antithyroid antibody levels, and different immunological parameters in different studies is summarized in Table 2.

Table 2. The association between vitamin D status, antithyroid antibody levels, and different immunological parameters in different studies.

Bozkurt et al., 2013 [88] Case–control study

1. - 180 treated HT patients;
2. - 180 newly diagnosed HT patients;
3. - 180 HC.

1. - 25(OH)D levels of HT patients were significantly lower than controls;
2. - 25(OH)D deficiency severity correlated with duration of HT, thyroid volume, and antithyroid antibody levels.

The prevalence of 25(OH)D deficiency in HT patients was significantly higher than that in the control group

1. - 90 HT patients;
2. - 79 HC.

Evliyaog˘lu et al., 2015 [84] Case–control study

Arslan et al., 2015 [89] Cross-sectional study 155 HC

1. - Anti-TPO positivity was significantly more common in those with 25(OH)D deficiency, as compared to those with a normal 25(OH)D level.
2. - A significant weak inverse correlation between anti-TPO positivity and the 25(OH)D level.

1. (a) The continuous 25(OH)D by AITD * status:
2. (b) The presence of 25(OH)D deficiency:

HT patients had lower 25(OH)D levels and were more likely to have a 25(OH)D deficiency

Wang et al., 2015 [71] Meta-analysis

1. - 994 AITD patients;
2. - 1035 HC.

1. Kim et al., 2016 [82]
2. Kim et al., 2017 [83]

Anti-TPO positivity was more prevalent in the 25(OH)D deficient group than in insufficient and sufficient 25(OH)D groups

Cross-sectional study; a nationwide survey

4181 participants

25(OH)D levels were not associated with thyroid function, antithyroid antibodies, and serum cytokines IL-4, IL-17, and TNF-α in patients with AITD *

1. - 124 HT patients;
2. - 51 GD patients.

Wencai Ke et al., 2017 [92] Cross-sectional study

Nominally higher expression levels of VDR mRNA were found in T cells of healthy controls when compared to the HT patients

1. - 45 HT patients;
2. - 13 HC.

Tokic et al., 2017 [100] Cross-sectional study

25(OH)D deficiency is significantly associated with HT in overweight and obese subjects

261 overweight and obese subjects

De Pergola et al., 2018 [85] Cross-sectional study

A positive correlation between 25(OH)D and fT4, IL-17, TNF-α and IL-5 in HT group

1. - 88 HT patients;
2. - 71 HC.

Botelho et al., 2018 [90] Cross-sectional study

Jun Xu et al., 2018 [86] Case–control study

1. - 194 patients with HT;
2. - 200 HC.

1. - HT patients with MCI had significantly lower 25(OH)D levels than patients without MCI.
2. - 25(OH)D levels of ≤34.0 and ≥47.1 nmol/L were significantly associated with cognitive impairment in patients with HT.

Aktas¸, 2019 [87] Retrospective cohort study 130 HT patients

1. - 25(OH)D deficiency was associated with HT.
2. - A negative correlation between 25(OH)D levels and anti-TPO.

Feng et al., 2020 [93] Cross-sectional study

1. - 36 HT patients;
2. - 54 GD patients;
3. - 30 HC.

1. - 25(OH)D was lower, while IL-21 was higher in HT patients than in control.
2. - 25(OH)D was negatively correlated with anti-TPO and anti-Tg.
3. - IL-21 concentration was positively correlated with anti-TPOAb, anti-Tg, and TRAb in the HT group.
4. - 25(OH)D had a significant negative correlation with serum IL-21 concentration in HT.

Štefanic´ and Tokic´, 2020 [55] Meta-analysis

1. - 2695 HT patients;
2. - 2263 HC.

Lower serum 25(OH) in HT compared to healthy controls

Cvek et al., 2021 [79]

Case–control study; observations from biobank data

1. - 461 HT patients;
2. - 176 HC.

1. - No significant differences in 25(OH)D levels between HT patients and controls.
2. - A subtle decrease in 25(OH)D levels associated with overt HT, compared to mild HT.

Hanna et al., 2021 [80] Case–control study

1. - 112 HT patients;
2. - 48 hypothyroid non-HT controls.

25(OH)D level was statistically indifferent between HT and control groups

Significantly lower 25(OH)D level among HT patients compared to healthy controls

1. - 1375 HT patients;
2. - 1065 HC.

Taheriniya et al., 2021 [53] Meta-analysis

Hisbiyah et al., 2022 [94] Cross-sectional study

80 Down syndrome patients (children)

1. - Participants with sufficient 25(OH)D had significantly higher anti-TPO and anti-Tg
2. - 25(OH)D levels were significantly negatively correlated with IFN-γ and positively correlated with anti-TPO-Ab and anti-Tg.

No significant association between 25(OH)D and thyroid autoantibodies, thyroid hormones, and thyroid volume

Prospective case–control study

1. - 57 HT patients;
2. - 41 HC.

Filipova et al., 2023 [81]

25(OH)D, 25-hydroxycholecalciferol; AITD, autoimmune thyroid disease; anti-TPO, antithyroid peroxidase antibodies; fT4, free thyroxine; GD, Graves’ disease; HC, healthy controls; HT, Hashimoto’s thyroiditis; MCI, mild cognitive impairment; TRAb, TSH receptor antibody; VD, vitamin D; * AITD patients included Graves’ disease and Hashimoto’s thyroiditis patients.

5.4. Changes in Immunological Parameters and HT Outcomes after Vitamin D Supplementation

Several studies investigated immunological and inflammatory changes after vitamin D supplementation in patients with HT. Most results show a significant improvement in markers of immunity after the intervention. Krysiak et al. [101–103] conducted experiments amongst various HT populations in Poland (e.g., men with HT and alopecia [101], men with HT and testosterone deficiency [102], and euthyroid women with HT [102,103]), in which they assessed anti-TPO and anti-Tg levels after six months of 2000–4000 IU daily vitamin D supplementation. In these studies, 25(OH)D concentration increased (often achieving levels exceeding 30 ng/mL, which are adequate, according to Polish, as well as Central and European guidelines [104,105], and antithyroid antibody levels significantly decreased. The reduction in antibody titers was also present in the subjects with normal baseline vitamin D status [7]. In addition, researchers discovered many factors that impacted the effect of vitamin D on antithyroid antibodies. Dehydroepiandrosterone, simvastatin, and selenomethionine potentiated the effect, while hyperprolactinemia and a gluten-free diet (GFD) attenuated it [103,106–109]. GFD inhibiting the reduction in antithyroid antibodies by vitamin D is particularly interesting, as it adds another argument to the discussion about whether a gluten-free diet should be considered for non-celiac autoimmune disorders, which remains a controversial topic [110,111]. Authors explained that GFD patients might

have ingested smaller amounts of unsaturated fatty acids, iron, and calcium, contributing to proper intestinal vitamin D absorption [109].

Other studies in different populations also obtained a reduction in antithyroid antibody levels after vitamin D supplementation. For example, Mazokopakis et al. [112] achieved a significant reduction in anti-TPO and anti-Tg with doses from 1200 to 4000 IU every day for 4 months (aiming to maintain serum 25(OH)D levels of 40 ng/mL) in Greek patients. Similar results were also obtained in Indian patients (60,000 IU weekly for 8 weeks reduced anti-TPO by 46.73%) [113] and amongst Iranian children with HT [114]. Noteworthy are also the results from Sinsek et al. [115], who demonstrated a significant reduction in anti-TPO and anti-Tg amongst Turkish HT and GD patients with only one month of 1000 IU daily vitamin D. A meta-analysis by Zhang et al. [70] also showed that vitamin D supplementation reduces anti-TPO and anti-Tg titers, especially with a supplementation duration of over 3 months.

Particularly intriguing are the outcomes of the community-based program conducted in Canada. The program database included 11,017 participants that were provided with vitamin D to achieve 25(OH)D concentrations exceeding 100 nmol/L (>40 ng/mL). After 12 months of follow-up, a significant reduction in antithyroid antibodies was observed [116]. Among subjects with elevated antithyroid antibody levels at baseline and follow-up, 77.5% were within the reference range for anti-TG and 42.2% for anti-TPO. In addition, serum 25(OH)D concentrations ≥ 125 nmol/L were associated with a 32% reduced risk of elevated antithyroid antibodies. Moreover, achieving correct vitamin D concentration was associated with substantial improvement in thyroid function, including reduced TSH levels and the severity of symptoms. This effect was especially amongst subjects with subclinical hypothyroidism, which was reduced by 72% at follow-up.

Although most studies on antithyroid antibodies after vitamin D gave consistent outcomes, it should be mentioned that some investigations showed contrary results. Vondra et al. [117] detected no decrease in antithyroid antibodies after three months of 4300 IU/day 25(OH)D supplementation, which could be explained by their relatively low initial levels. However, in a study by Behera et al. [118], amongst 23 HT patients from a coastal province of India, a significant increase in anti-TPO occurred after weekly 60,000 IU vitamin D supplementation for 8 weeks. The authors stated that they were unable to explain this effect.

Besides antibody levels, several researchers explored how vitamin D supplementation can affect other immunological markers. Robat-Jazi et al. [119] supplemented 40 HT female patients with 50,000 IU of 25(OH)D weekly for 3 months. At the baseline and follow-up, they assessed the serum levels of inflammatory factors, such as TNF-α, IFN-γ, and the chemokine CXCL10 (or IP10, interferon gamma-induced protein 10). IP10 is involved in the activation of T cells and the regulation of immune cell migration and proliferation. It may also contribute to the breakdown of immune tolerance by promoting the activation of autoreactive T cells in the thyroid [61,120]. IP10 is elevated in several other autoimmune diseases, including RA, MS, and SLE [121]. In this study, the serum levels of IFN-γ, TNF-α, and IP10 decreased significantly after the intervention suggesting the potential of vitamin D to control the inflammatory axis of IFNγ-IP10 and TNF-α in HT. A clinical trial conducted by Nodehi et al. [122] assessed the frequency of CD4+ T-cell subsets before and after the 3-month supplementation of 50,000 IU weekly vitamin D. The supplementation provided beneficial immunological effects by causing a significant decrease in Th17/Tr1 (regulatory T cells type 1) ratio. However, the activity of IL-10 in Tr1 cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

The changes in antithyroid antibody levels and different immunological parameters

cells increased in the vitamin D group, compared to that in the placebo group, with no

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vit-

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statistical significance.

statistical significance. The changes in antithyroid antibody levels and different immunological parameters

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11 of 17

Changes in 25(OH)D Levels

Other Changes in

Changes in

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Table 3. Changes in antithyroid antibody

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

after vitamin D supplementation in different studies are summarized in Table 3.

Dose and Supplementation Duration

Changes in

11 of 17

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

statistical significance.

statistical significance.

statistical significance.

Parameters

Titers

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Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Changes in Changes in

Changes in Anti-TPO Titers Mazokopakis et al., 2015 [112]

Changes in 25(OH)D

Other Changes in Immunological Parameters

Changes in 25(OH)D Levels

Other Changes in Immunological

Changes in Anti-TPO

Other Changes in Immunological Parameters

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

cells increased in the vitamin D group, compar statistical significance.

Changes in

Dose and Supplementation Duration

Dose and Supplementation Duration

Changes in Anti-Tg Titers

2023, 15, 3174

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Author, Year Dose and Supplementation Duration

Changes in 25(OH)D Levels

Changes in Anti-TPO Titers

Changes in Anti-Tg Titers

Author, Year

Author, Year

Mazokopakis et al.,

Table 3. Changes in antithyroid antibody

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

statistical significance.

⬆ ⬇ ⬇

Other Changes in

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

The changes in antithyroid antibody levels and different immunological parameters

2023, 15

Nutrients 2023, 15, 3174 11 of 17

Nutrients 2023, 15, 3174

Dose and Supplementation Duration

Changes in Anti-Tg Titers

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Table 3. Changes in antithyroid antibody

Table 3. Changes in antithyroid antibody

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Changes in antithyroid antibody

Table 3. amin D supplementation in different studies.

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

Changes in Changes in

Changes in Anti-TPO Titers Mazokopakis et al., 2015 [112]

Changes in 25(OH)D

Other Changes in Immunological Parameters

Changes in Anti-TPO Titers

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

Mazokopakis et al., 2015 [112]

Chaudhary et al., 2016 [113]

statistical significance.

Changes in

Dose and Supplementation Duration

Dose and Supplementation

Changes in

Mazokopakis et al., 2015 [112]

achieve 25(OH)D concentration ⬆ ⬇

⬇

⬇

60,000 IU weekly, 8 weeks ⬇ Simsek et al., 2016 [115]

Levels

Titers

Author, Year

Author, Year

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

Nutrients 2023, 15, 3174

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Changes in 25(OH)D Levels

Other Changes in Immunological

Changes in Anti-TPO Titers

Changes in 25(OH)D Levels

Other Changes in Immunological

Changes in Anti-TPO Titers

Changes in 25(OH)D Levels

Other Changes in Immunological Parameters

Changes in 25(OH)D

Changes in Anti-TPO

Other Changes in Immunological Parameters

Changes in Anti-TPO Titers

Levels Parameters

Levels

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

Mazokopakis et al., 2015 [112]

Dose and Supplementation Duration

Dose and Supplementation Duration

Dose and Supplementation Duration

Dose and Supplementation Duration

Changes in Anti-Tg Titers

amin D supplementation in different studies.

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Chaudhary et al., 2016 [113] 60,000 IU weekly, 8 weeks

1000 IU daily, 1 month ⬇

achieve 25(OH)D concentration ⬆

⬇

Chaudhary et al., 2016 [113]

Chaudhary et al., 2016

Author, Year

Author, Year

Author, Year

Author, Year

statistical significance.

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

⬆ ⬇

60,000 IU weekly, 8 weeks ⬆ ⬇ Simsek et al., 2016 [115]

60,000 IU weekly, 8 weeks ⬆ ⬇ Simsek et al., 2016 [115]

2023, 15

Nutrients 2023, 15, 3174 11 of 17

Nutrients 2023, 15, 3174

Anti-Tg Titers

Anti-Tg Titers

Anti-Tg Titers

Mazokopakis et al., 2015 [112]

Simsek et al., 2016 [115] 1000 IU daily, 1 month

achieve 25(OH)D concentration ⬆ ⬇

⬇

⬇

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

Table 3. Changes in antithyroid antibody

Changes in

Changes in

Changes in

Other Changes in

Changes in

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

Dose and Supplementation Duration

Dose and Supplementation Duration

Dose and Supplementation

Changes in Anti-Tg Titers

Nutrients 2023, 15, 3174 11 of 17

Nutrients 2023, 15, 3174 11 of 17

Nutrients 2023, 15, 3174

Mirhosseini et al., 2017 [116]

Chaudhary et al., 2016 [113]

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Changes in 25(OH)D

Other Changes in Immunological

Changes in Anti-TPO

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Author, Year

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1000 IU daily, 1 month ⬇

⬇ ⬇

60,000 IU weekly, 8 weeks ⬇

1000 IU daily, 1 month

Dose and Supplementation Duration

Changes in Anti-Tg Titers

Mazokopakis et al.,

Mazokopakis et al.,

Mazokopakis et al.,

Mazokopakis et al., 2015 [112]

⬇

Mirhosseini et al., 2017 [116]

Author, Year

⬆ ⬇

⬆ ⬇ ⬇

⬆ ⬇

CRP

Parameters Mazokopakis et al., 2015 [112]

Levels Mazokopakis et al., 2015 [112]

Levels Parameters

Levels

Titers

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

Chaudhary et al., 2016 [113]

Chaudhary et al., 2016 [113]

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

Changes in 25(OH)D Levels

Other Changes in Immunological Parameters

Changes in Anti-TPO Titers

Changes in 25(OH)D Levels

Other Changes in Immunological Parameters

Changes in Anti-TPO Titers

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

, 3174

⬆

60,000 IU weekly, 8 weeks ⬇ Simsek et al., 2016

60,000 IU weekly, 8 weeks ⬆ ⬇ Simsek et al., 2016

Changes in antithyroid antibody

Table 3. amin D supplementation in different studies.

Dose and Supplementation Duration

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

1200–4000 IU daily, aiming to achieve 25(OH)D concentration ⬆ ⬇

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Nutrients 2023, 15, 3174 11 of 17

Nutrients 2023, 15, 3174 11 of 17

Changes in 25(OH)D Levels

Other Changes in Immunological

Changes in Anti-TPO

⬆ ⬇ ⬇

1000 IU daily, 1 month ⬆ ⬇ ⬇

, 3174 11 of 17

statistical significance.

Author, Year

Author, Year

Mirhosseini et al., 2017 [116]

Mirhosseini et al., 2017 [116]

Vondra et al., 2017 [117]

Mazokopakis et al., 2015 [112]

Dose and Supplementation Duration

achieve 25(OH)D concentration ⬆ CRP ⬇ ⬇ ⬇

⬆ CRP ⬇ ⬇ ⬇

⬆ CRP ⬇ ⬇

4300 IU daily, 3 months CRP ⬌ ⬆

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

Duration

Anti-Tg Titers

Anti-Tg Titers

CRP

Vondra et al., 2017 [117] 4300 IU daily, 3 months

[115]

⬆

⬆

1200–4000 IU daily, aiming to

Chaudhary et al., 2016

, 3174

Chaudhary et al., 2016

Chaudhary et al., 2016

Chaudhary et al., 2016

Author, Year

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

60,000 IU weekly, 8 weeks ⬆ ⬇ Simsek et al., 2016

Mazokopakis et al.,

60,000 IU weekly, 8 weeks ⬆ ⬇ Simsek et al., 2016

60,000 IU weekly, 8 weeks ⬆ ⬇

60,000 IU weekly, 8 weeks ⬆ ⬇ Simsek et al., 2016

⬆ ⬇ ⬇

1000 IU daily, 1 month ⬆ ⬇ ⬇

1000 IU daily, 1 month ⬆ ⬇

statistical significance.

⬆ ⬇ ⬇

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Other Changes in Immunological Parameters Mazokopakis et al., 2015 [112]

Changes in 25(OH)D Levels Mazokopakis et al.,

- Th17/Tr1 ratio

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

Th17/Tr1 ratio IL-10 ⬆

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

achieve 25(OH)D concentration ⬆ CRP ⬇

achieve 25(OH)D concentration CRP ⬇

Mazokopakis et al.,

Mazokopakis et al.,

Vondra et al., 2017

Vondra et al., 2017

50,000 IU weekly, 3 months

of >40 ng/mL, 4 months

Author, Year

Author, Year

25(OH)D

Chaudhary et al., 2016

Chaudhary et al., 2016

Chaudhary et al., 2016

cells increased in the vitamin D group, compared to that in the placebo group, with no

cells increased in the vitamin D group, compared to that in the placebo group, with no

Nodehi et al., 2019 [122] 50,000 IU weekly, 3 months

achieve 25(OH)D concentration ⬆ ⬇

achieve 25(OH)D concentration ⬆

Doses modified with the aim to

Doses modified with the aim to

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

⬆ CRP ⬌

4300 IU daily, 3 months ⬆ Nodehi et al., 2019

cells increased in the vitamin D group, compared to that in the placebo group, with no

4300 IU daily, 3 months CRP ⬌ Nodehi et al., 2019 [122]

[122]

2017 [116]

60,000 IU weekly, 8 weeks ⬆ Simsek et al., 2016 [115]

1000 IU daily, 1 month ⬆

1000 IU daily, 1 month ⬆ ⬇

1000 IU daily, 1 month ⬆

Duration

Duration

1000 IU daily, 1 month

60,000 IU weekly, 8 weeks Simsek et al., 2016 [115]

60,000 IU weekly, 8 weeks Simsek et al., 2016 [115]

Mirhosseini et al., 2017 [116]

Mirhosseini et al., 2017 [116]

Mazokopakis et al., 2015 [112]

11 of 17

Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

⬆

CRP ⬇

CRP ⬇

⬆

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

Other Changes in Immunological Parameters

Changes in Anti-TPO

- IL-10

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

Other Changes in

Dose and Supplementation Duration

Changes in Anti-Tg Titers

- ⬇

- Th17/Tr1 ratio ⬇

- Th17/Tr1 ratio ⬇

Dose and Supplementation Duration

Dose and Supplementation

Changes in Anti-Tg Titers

Aghili et al., 2020 [114]

Vondra et al., 2017 [117]

[113] Simsek et al., 2016 [115]

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

Author, Year

25(OH)D Levels

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

of >40 ng/mL, 1 year

of >40 ng/mL, 1 year

50,000 IU weekly, 3 months ⬆

Varied depending on initial and rechecked 25(OH)D concentrations

⬇

⬆ ⬆

4300 IU daily, 3 months ⬆ Nodehi et al., 2019 [122]

Author, Year

Chaudhary et al., 2016 [113]

50,000 IU weekly, 3 months

50,000 IU weekly, 3 months

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Table 3. Changes in antithyroid antibody

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

and rechecked 25(OH)D concentrations

1000 IU daily, 1 month ⬆ ⬇

1000 IU daily, 1 month ⬆

1000 IU daily, 1 month ⬆

Mirhosseini et al., 2017 [116]

Mirhosseini et al.,

Mirhosseini et al.,

60,000 IU weekly, 8 weeks ⬆ Simsek et al., 2016

60,000 IU weekly, 8 weeks ⬆ Simsek et al., 2016 [115]

Aghili et al., 2020 [114]

achieve 25(OH)D concentration ⬆ ⬇

⬇

⬇

⬇

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

⬆ ⬇

⬆ CRP ⬇

CRP ⬇

Vondra et al., 2017 [117]

Vondra et al., 2017 [117]

Chaudhary et al., 2016 [113]

Changes in Changes in

Changes in 25(OH)D Levels

Other Changes in Immunological Parameters

Changes in Anti-TPO Titers

Changes in Anti-TPO

Levels Parameters Mazokopakis et al., 2015 [112]

Levels

Titers

1000 IU daily, 1 month ⬇

⬆ CRP ⬆

4300 IU daily, 3 months CRP ⬆ Nodehi et al., 2019 [122]

4300 IU daily, 3 months CRP ⬆ Nodehi et al., 2019 [122]

60,000 IU weekly, 8 weeks Simsek et al., 2016 [115]

Changes in

Dose and Supplementation Duration

Dose and Supplementation Duration

Changes in

- ⬇

- Th17/Tr1 ratio ⬇

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

cells increased in the vitamin D group, compared to that in the placebo group, with no statistical significance.

Varied depending on initial and rechecked 25(OH)D concentrations

Varied depending on initial and rechecked 25(OH)D con-

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year Vondra et al., 2017 [117]

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Author, Year

Author, Year

Immunological

25(OH)D

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Aghili et al., 2020

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

Mirhosseini et al., 2017 [116]

Mirhosseini et al., 2017 [116]

Mirhosseini et al., 2017 [116]

Mazokopakis et al.,

1000 IU daily, 1 month ⬆ ⬇

Changes in 25(OH)D

Changes in Anti-TPO Titers

Changes in 25(OH)D

Other Changes in Immunological

Changes in Anti-TPO Titers

1000 IU daily, 1 month ⬆

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

⬆

⬇

Mazokopakis et al.,

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

Behera et al., 2020

⬆

⬆

⬆

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Chaudhary et al., 2016 [113]

Chaudhary et al., 2016 [113]

Vondra et al., 2017 [117]

Behera et al., 2020 [118]

⬆

⬆

Vondra et al., 2017 [117]

Vondra et al., 2017 [117]

Dose and Supplementation Duration

Dose and Supplementation Duration

Dose and Supplementation Duration

Th17/Tr1 ratio

⬆

[114]

⬆

60,000 IU weekly, 8 weeks ⬇ Simsek et al., 2016 [115]

4300 IU daily, 3 months ⬆ Nodehi et al., 2019 [122]

Mirhosseini et al., 2017 [116]

4300 IU daily, 3 months ⬆ Nodehi et al., 2019 [122]

4300 IU daily, 3 months ⬆ CRP ⬆

50,000 IU weekly, 3 months ⬆

60,000 IU weekly, 8 weeks Simsek et al., 2016 [115]

4300 IU daily, 3 months Nodehi et al., 2019 [122]

Author, Year

Author, Year

Author, Year

50,000 IU weekly, 3 months

50,000 IU weekly, 3 months

Table 3. Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

1000 IU daily, 1 month

The changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies are summarized in Table 3.

CRP ⬇

Varied depending on initial and rechecked 25(OH)D concentrations

- ⬆

- IL-10 ⬆ Aghili et al., 2020 [114]

- IL-10 ⬆ Aghili et al., 2020

Anti-Tg Titers

Anti-Tg Titers

Anti-Tg Titers

Changes in 25(OH)D Levels

Other Changes in Immunological Parameters

Changes in

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

1200–4000 IU daily, aiming to achieve 25(OH)D concentration of >40 ng/mL, 4 months

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Aghili et al., 2020 [114]

Levels Parameters

Levels Parameters

Levels

Parameters Titers

Krysiak et al., 2016–2022 [7,101–103,106–108]

2000–4000 IU daily for 6 months

Changes in Anti-Tg Titers 1200–4000 IU daily, aiming to

Dose and Supplementation Duration

Mazokopakis et al., 2015 [112]

Mazokopakis et al., 2015 [112]

⬆ ⬇

⬇

Mirhosseini et al., 2017 [116]

Mirhosseini et al., 2017 [116]

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

Changes in 25(OH)D Levels

Changes in Anti-TPO Titers

Changes in 25(OH)D Levels

Changes in Anti-TPO Titers

achieve 25(OH)D concentration ⬆ ⬇

⬇

⬇

Changes in 25(OH)D Levels

Other Changes in Immunological Parameters

Vondra et al., 2017 [117]

Vondra et al., 2017 [117]

Chaudhary et al., 2016 [113]

Th17/Tr1 ratio

Th17/Tr1 ratio

⬆ CRP ⬇

⬆ ⬇

Varied depending on initial and rechecked 25(OH)D concentrations

Varied depending on initial and rechecked 25(OH)D concentrations

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Chaudhary et al., 2016 [113]

Chaudhary et al., 2016 [113]

Behera et al., 2020 [118]

Behera et al., 2020

⬆ ⬇

1000 IU daily, 1 month ⬇

1000 IU daily, 1 month ⬇

Krysiak et al., 2016– 2022 [7,101–103,106– 108]

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆ Nodehi et al., 2019

4300 IU daily, 3 months ⬆ CRP ⬌ Nodehi et al., 2019

4300 IU daily, 3 months ⬆ Nodehi et al., 2019

60,000 IU weekly, 8 weeks ⬆ ⬇ Simsek et al., 2016

Dose and Supplementation Duration

Changes in Anti-Tg Titers

Dose and Supplementation Duration

Changes in Anti-Tg Titers

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

Dose and Supplementation Duration

Changes in Anti-Tg Titers

50,000 IU weekly, 3 months

60,000 IU weekly, 8 weeks ⬆ ⬇ Simsek et al., 2016 [115]

60,000 IU weekly, 8 weeks ⬆ Simsek et al., 2016 [115]

1200–4000 IU daily, aiming to achieve 25(OH)D concentration ⬆ ⬇

1200–4000 IU daily, aiming to achieve 25(OH)D concentration ⬇

1200–4000 IU daily, aiming to achieve 25(OH)D concentration ⬆ ⬇

Mirhosseini et al., 2017 [116]

⬆ ⬆

⬆ ⬆

⬆ ⬆

- IL-10 ⬆

2000–4000 IU daily for 6 months

Changes in 25(OH)D

Other Changes in Immunological

Changes in Anti-TPO Titers

Author, Year

Immunological Parameters

Author, Year

Immunological Parameters

Vondra et al., 2017 [117]

- IL-10 ⬆

- IL-10 ⬆ Varied depending on initial

- IL-10 ⬆

⬆ ⬇ ⬇

⬆ ⬇ ⬇

⬆ ⬇

⬆ CRP ⬇ ⬇

Author, Year

Anti-TPO Titers

Mazokopakis et al., 2015 [112]

Mazokopakis et al., 2015 [112]

Mazokopakis et al., 2015 [112]

Titers

⬆ ⬇ ⬇

4300 IU daily, 3 months CRP ⬌ ⬆

Table 3. Changes in antithyroid antibody amin D supplementation in different studies.

Dose and Supplementation Duration

Changes in Anti-Tg Titers

CRP

Krysiak et al., 2022 [109] 4000 IU daily for 6 months

Changes in antithyroid antibody levels and different immunological parameters after vitamin D supplementation in different studies.

months

Author, Year

60,000 IU weekly, 2 months,

- Th17/Tr1 ratio ⬇ IL-10 ⬆

Doses modified with the aim to

Doses modified with the aim to

Varied depending on initial

- Th17/Tr1 ratio

-

Varied depending on initial

Varied depending on initial

Chaudhary et al., 2016

Chaudhary et al., 2016

Vondra et al., 2017

Vondra et al., 2017 [117]

Behera et al., 2020 [118]

50,000 IU weekly, 3 months ⬆

⬆

50,000 IU weekly, 3 months ⬆

⬆ ⬇ ⬇

⬆ Simsek et al., 2016 [115]

⬆ Nodehi et al., 2019 Th17/Tr1 ratio ⬇

CRP ⬌ Nodehi et al., 2019 [122]

1000 IU daily, 1 month

⬆

CRP ⬇

CRP ⬇

Th17/Tr1 ratio IL-10 ⬆

⬆

⬇

⬇

- IFN-γ

2000–4000 IU daily for 6

2000–4000 IU daily for 6

Krysiak et al., 2022 [109]

Mazokopakis et al.,

Mazokopakis et al.,

50,000 IU weekly, 3 months

4300 IU daily, 3 months ⬆ Nodehi et al., 2019 [122]

2017 [116]

2017 [116]

Mazokopakis et al.,

[114]

[114]

[114]

Chaudhary et al., 2016

Chaudhary et al., 2016

Chaudhary et al., 2016

Changes in

Other Changes in

Changes in Anti-TPO Titers

Behera et al., 2020

Behera et al., 2020

⬆

⬆

⬇

Changes in

Other Changes in

Changes in

4000 IU daily for 6 months CRP ⬌ ⬇

Robat-Jazi et al., 2022 [119] 50,000 IU weekly, 3 months

achieve 25(OH)D concentration ⬆

achieve 25(OH)D concentration ⬇

2022 [7,101–103,106–

2022 [7,101–103,106–

achieve 25(OH)D concentration ⬆ ⬇ ⬇

months

months 2000–4000 IU daily for 6 months

1200–4000 IU daily, aiming to

[122]

- IP10

60,000 IU weekly, 8 weeks ⬆ Simsek et al., 2016

60,000 IU weekly, 8 weeks ⬇ Simsek et al., 2016

60,000 IU weekly, 8 weeks ⬆ Simsek et al., 2016

⬆

⬆

⬆

of >40 ng/mL, 1 year

of >40 ng/mL, 1 year

centrations Behera et al., 2020

Varied depending on initial

Varied depending on initial and rechecked 25(OH)D concentrations Behera et al., 2020

Varied depending on initial and rechecked 25(OH)D concentrations Behera et al., 2020

centrations Behera et al., 2020

Doses modified with the aim to

centrations

centrations

Changes in Anti-Tg Titers 1200–4000 IU daily, aiming to

Dose and Supplementation Duration

then 60,000 IU monthly, 4 months

then 60,000 IU monthly, 4 months

of >40 ng/mL, 4 months

[117]

Dose and Supplementation Duration

Changes in Anti-Tg Titers

Simsek et al., 2016 [115]

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Th17/Tr1 ratio

months

⬆

⬇

- TNF-α

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

⬆ CRP ⬇ ⬇ ⬇

⬆ CRP ⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

months

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 ⬆ ⬆

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

- IL-10 ⬆ Varied depending on initial

- IL-10 ⬆ Varied depending on initial

Chaudhary et al., 2016

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

⬆ CRP ⬌ ⬆ ⬆

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ Nodehi et al., 2019

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

2015 [112]

Aghili et al., 2020

60,000 IU weekly, 8 weeks ⬆ ⬇

50,000 IU weekly, 3 months ⬆

[114]

[114]

[114]

2017 [116]

Levels

Parameters

Behera et al., 2020

Behera et al., 2020

Levels

Parameters

Titers

⬆ ⬇ ⬇

⬆ ⬇ ⬇

2017 [116]

2017 [116]

⬆ ⬇ ⬇

Krysiak et al., 2022

Krysiak et al., 2022

⬆ ⬆

of >40 ng/mL, 4 months

⬆ ⬆

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1

and rechecked 25(OH)D concentrations

⬆ ⬆

1000 IU daily, 1 month ⬆ ⬇ ⬇ Doses modified with the aim to

1000 IU daily, 1 month ⬆ ⬇ ⬇ Doses modified with the aim to

1000 IU daily, 1 month ⬆ ⬇

then 60,000 IU monthly, 4 months

centrations 60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

of >40 ng/mL, 1 year 4300 IU daily, 3 months ⬆ CRP ⬌ ⬆

Krysiak et al., 2016– 2022 [7,101–103,106–

⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇

50,000 IU weekly, 3 months ⬆

⬇

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

60,000 IU weekly, 8 weeks ⬆ ⬇

60,000 IU weekly, 8 weeks ⬆ ⬇

60,000 IU weekly, 8 weeks ⬆ ⬇

months

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

Mirhosseini et al., 2017 [116]

1. - ⬇
2. - ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10

⬆ ⬇ ⬇

⬆ ⬇ ⬇

⬆ ⬇

achieve 25(OH)D concentration ⬆ CRP ⬇ ⬇ ⬇

⬆ CRP ⬇ ⬇ ⬇

⬆ ⬇ ⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4

and rechecked 25(OH)D con- ⬆ ⬇ ⬇

and rechecked 25(OH)D con- ⬆ ⬇ ⬇

Varied depending on initial and rechecked 25(OH)D con- ⬆

60,000 IU weekly, 8 weeks ⬆ ⬇

Vondra et al., 2017

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆ Varied depending on initial and rechecked 25(OH)D concentrations 60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

50,000 IU weekly, 3 months ⬆

achieve 25(OH)D concentration ⬆ ⬇

1000 IU daily, 1 month ⬆ ⬇

⬇ ⬇

regulatory T cell;

, an increase;

, a decrease;

, no significant change.

4300 IU daily, 3 months ⬆ CRP ⬌

months

Doses modified with the aim to

Aghili et al., 2020

- γ ⬇

- IFN-γ ⬇

4300 IU daily, 3 months Nodehi et al., 2019

- IFN-γ

⬆

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

Krysiak et al., 2016– 2022 [7,101–103,106–

Mirhosseini et al., 2017 [116]

50,000 IU weekly, 3 months

50,000 IU weekly, 3 months

50,000 IU weekly, 3 months

⬆

Varied depending on initial and rechecked 25(OH)D concentrations

Krysiak et al., 2022

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

feron gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; , an increase; , a decrease; ⬌, no significant change.

Vondra et al., 2017

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 ⬆ ⬆

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

1000 IU daily, 1 month

months

Aghili et al., 2020

months

50,000 IU weekly, 3 months

of >40 ng/mL, 1 year 4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

of >40 ng/mL, 1 year Vondra et al., 2017

of >40 ng/mL, 1 year 4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

4000 IU daily for 6 months

4000 IU daily for 6 months

4300 IU daily, 3 months Nodehi et al., 2019

4300 IU daily, 3 months

50,000 IU weekly, 3 months

⬇ ⬇

⬇

- IL-10 ⬆ Varied depending on initial and rechecked 25(OH)D concentrations

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

60,000 IU weekly, 8 weeks ⬆ ⬇

⬇

⬆ CRP ⬇ ⬇ ⬇

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

Krysiak et al., 2016– 2022 [7,101–103,106– 108]

Krysiak et al., 2016– 2022 [7,101–103,106– 108]

- IL-10 ⬆ Varied depending on initial and rechecked 25(OH)D concentrations

[122] - IL-10 ⬆ Aghili et al., 2020 [114]

⬆ ⬆

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influencing DC-dependent T-cell activation, downregulating HLA class II gene expression in the thyroid, preventing excessive B-cell response, and balancing the Th17/Treg cell ratio. While laboratory insights into vitamin D function in HT are valuable, it is also crucial to examine the real-world clinical outcomes, including associations between vitamin D and symptoms, thyroid, and immune system function, as well as the impact of vitamin D on disease manifestation and progression. While some research has shown no association between 25(OH)D concentration and the prevalence of HT, several large-scale studies, systematic reviews, and meta-analyses have confirmed a link between low 25(OH)D levels and HT. Additionally, numerous studies have demonstrated a negative correlation between vitamin D levels and antithyroid antibody levels.

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

Behera et al., 2020 [118]

50,000 IU weekly, 3 months ⬆ - ⬇

50,000 IU weekly, 3 months ⬆ IP10 ⬇

⬇

⬆ CRP ⬇ ⬇ ⬇

⬆ CRP ⬇ ⬇ ⬇

γ α

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌ change.

γ, inter-

⬆ CRP ⬇ ⬇ ⬇

⬆ ⬇ ⬇

⬆

⬆

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ Nodehi et al., 2019

1. - γ ⬇
2. - ⬇
3. - α ⬇ γ

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

⬆ ⬆

1. - ⬇
2. - ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

Krysiak et al., 2022

Varied depending on initial and rechecked 25(OH)D concentrations

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

2000–4000 IU daily for 6 months

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆ Varied depending on initial and rechecked 25(OH)D concentrations

50,000 IU weekly, 3 months ⬆

Robat-Jazi et al., 2022

α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant change.

- α ⬇

- TNF-α ⬇

⬆ CRP ⬇ ⬇ ⬇

⬆ ⬇ ⬇

⬆ ⬇ ⬇

1000 IU daily, 1 month ⬆ ⬇ ⬇

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

⬇

⬇

⬇ ⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

⬆ ⬇ ⬇

⬆

⬆ ⬇ ⬌

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

Behera et al., 2020

2000–4000 IU daily for 6

2000–4000 IU daily for 6 months

⬆ ⬆

⬆ ⬆

⬆ ⬆

γ α

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant change.

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

50,000 IU weekly, 3 months ⬆ Varied depending on initial and rechecked 25(OH)D concentrations

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

50,000 IU weekly, 3 months ⬆ Varied depending on initial and rechecked 25(OH)D concentrations

50,000 IU weekly, 3 months ⬆

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

Krysiak et al., 2022 [109]

Krysiak et al., 2022 [109]

⬆ ⬇ ⬇

⬆ ⬇ ⬇

Krysiak et al., 2016– 2022 [7,101–103,106– 108]

Varied depending on initial and rechecked 25(OH)D concentrations

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌

4000 IU daily for 6 months ⬆

Robat-Jazi et al., 2022

Doses modified with the aim to achieve 25(OH)D concentration of >40 ng/mL, 1 year

2000–4000 IU daily for 6 months

Aghili et al., 2020

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influencing DC-dependent T-cell activation, downregulating HLA class II gene expression in the thyroid, preventing excessive B-cell response, and balancing the Th17/Treg cell ratio. While laboratory insights into vitamin D function in HT are valuable, it is also crucial to examine the real-world clinical outcomes, including associations between vitamin D and symptoms, thyroid, and immune system function, as well as the impact of vitamin D on

50,000 IU weekly, 3 months ⬆

⬇

50,000 IU weekly, 3 months ⬆

⬇

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

⬇

⬇

⬆ ⬇

months

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

⬆ ⬇ ⬇

⬆ ⬇ ⬇

⬆ ⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 ⬆ ⬆

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌ change.

γ, inter-

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

⬆ ⬇ ⬌

⬆ CRP ⬇ ⬇ ⬇

50,000 IU weekly, 3 months ⬆ Varied depending on initial

CRP ⬇ ⬇ ⬇

Varied depending on initial and rechecked 25(OH)D concentrations

Behera et al., 2020 [118]

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

α ⬆ ⬇ ⬌

α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant change.

Krysiak et al., 2016– 2022 [7,101–103,106–

-

⬆ ⬆

⬆

Aghili et al., 2020

50,000 IU weekly, 3 months ⬆ Varied depending on initial and rechecked 25(OH)D concentrations

50,000 IU weekly, 3 months ⬆ Varied depending on initial and rechecked 25(OH)D concentrations

50,000 IU weekly, 3 months ⬆ Varied depending on initial

⬆ ⬇ ⬇

⬆ ⬇ ⬇

⬆ ⬇

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

Robat-Jazi et al., 2022 [119]

Robat-Jazi et al., 2022 [119]

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

⬆ ⬇ ⬇

⬆ ⬇ ⬇

⬆ ⬇

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

⬇

tive protein; IL-10; interleukin 10; IFN-γ, inter-

γ, inter-

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌ change.

γ, interα, tumor

Krysiak et al., 2022 [109]

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

50,000 IU weekly, 3 months ⬆ Varied depending on initial and rechecked 25(OH)D concentrations

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influencing DC-dependent T-cell activation, downregulating HLA class II gene expression in the thyroid, preventing excessive B-cell response, and balancing the Th17/Treg cell ratio. While laboratory insights into vitamin D function in HT are valuable, it is also crucial to examine the real-world clinical outcomes, including associations between vitamin D and symptoms, thyroid, and immune system function, as well as the impact of vitamin D on

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇

months

Behera et al., 2020

50,000 IU weekly, 3 months ⬆

⬇

α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant change.

α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant change.

4300 IU daily, 3 months ⬆ CRP ⬌ ⬆ ⬆

CRP ⬌ ⬆ ⬆

and rechecked 25(OH)D con- ⬆ ⬇ ⬇

⬆ ⬆

⬆ ⬆

⬆ ⬆

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

Krysiak et al., 2016– 2022 [7,101–103,106– 108]

2000–4000 IU daily for 6

necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

⬆ ⬇ ⬇

⬆ ⬇ ⬇

and rechecked 25(OH)D con- ⬆ ⬇ ⬇

⬆ ⬇ ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

Krysiak et al., 2022

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant change.

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFNferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNFnecrosis factor alpha; Tr1, type 1 regulatory T cell; , an increase; change.

⬆ ⬇ ⬇

⬆

50,000 IU weekly, 3 months ⬆

⬇

Behera et al., 2020

50,000 IU weekly, 3 months ⬆

⬇

months

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influencing DC-dependent T-cell activation, downregulating HLA class II gene expression in the thyroid, preventing excessive B-cell response, and balancing the Th17/Treg cell ratio. While laboratory insights into vitamin D function in HT are valuable, it is also crucial to examine the real-world clinical outcomes, including associations between vitamin D and symptoms, thyroid, and immune system function, as well as the impact of vitamin D on

⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇

6. Conclusions

⬆ ⬆

⬆ ⬆

⬆ ⬆

1. - Th17/Tr1 ratio ⬇
2. - IL-10 ⬆

Th17/Tr1 ratio ⬇ IL-10 ⬆

Robat-Jazi et al., 2022 [119]

⬆ ⬇ ⬇

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant change.

50,000 IU weekly, 3 months ⬆ Varied depending on initial

50,000 IU weekly, 3 months ⬆

⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 ⬆ ⬆

Krysiak et al., 2016– 2022 [7,101–103,106–

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influencing DC-dependent T-cell activation, downregulating HLA class II gene expression in the thyroid, preventing excessive B-cell response, and balancing the Th17/Treg cell ratio. While laboratory insights into vitamin D function in HT are valuable, it is also crucial to examine the real-world clinical outcomes, including associations between vitamin D and symptoms, thyroid, and immune system function, as well as the impact of vitamin D on

necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; change.

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

1. - γ ⬇
2. - ⬇
3. - α ⬇ γ

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 months

⬆ ⬇ ⬇

⬆ ⬇ ⬇

⬆ ⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 ⬆ ⬆

Krysiak et al., 2022 [109]

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant

6. Conclusions

γ, inter-

6. Conclusions

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

Robat-Jazi et al., 2022

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌

Krysiak et al., 2016– 2022 [7,101–103,106–

months

⬆ ⬆

⬆ ⬆

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

⬇

⬇

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 ⬆

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; , no significant change.

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFNferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNFnecrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; change.

⬆

⬆

⬆

and rechecked 25(OH)D con- ⬆

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influencing DC-dependent T-cell activation, downregulating HLA class II gene expression in the thyroid, preventing excessive B-cell response, and balancing the Th17/Treg cell ratio. While laboratory insights into vitamin D function in HT are valuable, it is also crucial to

⬇ ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇
3. - TNF-α ⬇

Krysiak et al., 2022

Besides the correlation between vitamin D status and HT prevalence, research has explored the association between vitamin D and other immunological parameters in HT, such as cytokines and T-cell subsets. While the results have been mixed, some studies have shown a significant negative correlation between 25(OH)D concentration and inflammatory cytokines.

6. Conclusions

⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇

2000–4000 IU daily for 6

Robat-Jazi et al., 2022 [119]

system function, as well as the impact of vitamin D on

50,000 IU weekly, 3 months ⬆

⬇

⬆ ⬇ ⬇

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌ change.

γ, inter-

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

⬇

2000–4000 IU daily for 6 months

2000–4000 IU daily for 6 months

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influencing DC-dependent T-cell activation, downregulating HLA class II gene expression in

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influ-

2000–4000 IU daily for 6

Krysiak et al., 2022

60,000 IU weekly, 2 months, then 60,000 IU monthly, 4 ⬆ ⬆

⬆ ⬇ ⬇

⬆ ⬇ ⬇

α ⬆ ⬇ ⬌

⬆ ⬇ ⬇

α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell; ⬆, an increase; ⬇, a decrease; ⬌, no significant change.

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇

1. - γ ⬇
2. - ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇ ⬇

1. - IFN-γ ⬇
2. - IP10 ⬇ ⬇

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that vitamin D may have an immunomodulatory effect on HT by, among other things, influ-

2000–4000 IU daily for 6

⬆

6. Conclusions

Robat-Jazi et al., 2022

⬆ ⬇ ⬇

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

50,000 IU weekly, 3 months ⬆

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, interferon gamma; IP10, interferon gamma-induced protein 10; Th17, T helper 17 cell; TNF-α, tumor necrosis factor alpha; Tr1, type 1 regulatory T cell;

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-γ, inter-

25(OH)D, 25-hydroxycholecalciferol; CRP, C-reactive protein; IL-10; interleukin 10; IFN-

6. Conclusions

- IFN-γ ⬇

- IFN-γ ⬇

- IFN-γ ⬇

4000 IU daily for 6 months ⬆ CRP ⬌ ⬇ ⬇

In conclusion, the relationship between vitamin D and Hashimoto’s thyroiditis has been the subject of numerous studies with varying results. Recent findings indicate that

Robat-Jazi et al., 2022

4000 IU daily for 6 months ⬆

4000 IU daily for 6 months

4000 IU daily for 6 months

50,000 IU weekly, 3 months

50,000 IU weekly, 3 months

50,000 IU weekly, 3 months

Research on the effects of vitamin D supplementation in HT patients has shown promising results, with most studies reporting a significant improvement in immunological markers after the intervention. However, a few studies have yielded contrasting findings. Overall, the available evidence suggests that vitamin D supplementation may have beneficial immunomodulatory effects in HT patients, but further research is necessary to determine the optimal dosing, duration, and potential interactions with other treatments or dietary factors.

Future studies need to continue investigating the complex relationship between vitamin D and HT and the impact of vitamin D supplementation on various immunological markers and clinical outcomes. This knowledge will contribute to a better understanding of the role of vitamin D in HT pathogenesis and inform potential therapeutic strategies for individuals with HT.

Author Contributions: F.L.: conceptualization, methodology, writing original draft, K.A.L.: review and editing, supervision. All authors have read and agreed to the published version of the manuscript.

Funding: This research was funded by the statutory funds of the Medical University of Gdan´sk (grant number 02-0058/07).

Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest.