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EDITORIAL
Year : 2013  |  Volume : 10  |  Issue : 1  |  Page : 1-3

Vitamin D and thyroid: Autoimmunity and cancer


Department of Endocrinology and Metabolism, IPGMER and SSKM Hospital, Kolkata, West Bengal, India

Date of Web Publication10-Jan-2013

Correspondence Address:
Sujoy Ghosh
Department of Endocrinology and Metabolism, IPGMER and SSKM Hospital, 244 AJC Bose Road, Kolkata- 700 020, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-0354.105837

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How to cite this article:
Dutta D, Ghosh S. Vitamin D and thyroid: Autoimmunity and cancer. Thyroid Res Pract 2013;10:1-3

How to cite this URL:
Dutta D, Ghosh S. Vitamin D and thyroid: Autoimmunity and cancer. Thyroid Res Pract [serial online] 2013 [cited 2020 Aug 12];10:1-3. Available from: http://www.thetrp.net/text.asp?2013/10/1/1/105837


  Introduction Top


Vitamin-D, a prohormone is a major regulator of mineral homeostasis by binding to specific nuclear receptor (Vitamin D receptor/ VDR) belonging to the steroid/thyroid hormone receptor family. Nonclassical actions of vitamin-D (beyond bone and mineral metabolism) are increasingly being discovered, which include antiproliferative, prodifferentiative, and immunomodulatory roles. [1] Vitamin-D deficiency has been linked with increased risk of malignancies (prostate, breast, and colorectal), decreased muscle mass, increased falls, diabetes, and endothelial dysfunction. [1]


  Vitamin-D Metabolism and Thyroid Top


25-OH-vitamin-D [25(OH)D] is the predominant circulatory form of vitamin-D and is taken up by the cells of the proximal convoluted tubules in the kidney, which is the predominant site for synthesis of activated vitamin-D [1,25(OH)2D] as a result of the increased expression of 1α-hydroxylase. [2] VDR is ubiquitous with documented expression in more than 39 different tissues across the body including thyroid. [3] The main ligand of VDR, 1,25(OH)2D activates VDR to modulate the expression of more than 900 different genes. [4]


  Vitamin-D, Autoimmunity and Thyroid Top


Serum 1,25(OH)2D has been observed to be significantly lower in patients with autoimmune as compared with nonautoimmune hyperthyroidism. [5] Vitamin-D plays an important role in regulation of innate immunity as well as adaptive immunity. 1,25(OH)2D acting through VDR on monocytes, lymphocytes and T cells, modulate their activity leading to a shift toward activated Th2 cells. [6] 1,25(OH)2D downregulates the expression of HLA class-II molecules on thyrocytes, inhibits lymphocyte proliferation and secretion of cytokines. [7] 1,25(OH)2D activates VDR which induces the expression of cathelicidin and β-defensin, which are antimicrobial peptides (AmPs). [8] Infections, especially by slow growing bacteria are believed to have a role in the development of several autoimmune disease including Rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, and even Hashimoto's thyroiditis [9],[10] by disregulating VDR thus altering innate immunity. [11] Low levels of 25(OH)D along with elevated levels of 1,25(OH)2D has been documented in several autoimmune disorders. [12] It has been suggested that VDR dysregulation resulting from infections or disease results in decreased CYP24 activity resulting in increased 1,25(OH)2D levels which in turn result in decreased 25(OH)D levels as a result of the physiologic negative feedback. [13]

1,25(OH)2D besides activating VDR also has an affinity for other nuclear receptors, especially in the excess state. They include glucocorticoid, androgen, progesterone receptor, and also both α and β thyroid receptor where it inhibits T3 (triiodothyronine) binding, the primary ligand for thyroid receptor. [14]

Stefanic et al. showed that haplotypic variants within the VDR gene 3′-region, the region linked with VDR mRNA expression, could be associated with development of Hashimoto's thyroiditis. [15] Vitamin-D binding protein (DBP) is the primary carrier of 1,25(OH)2D is the blood with serum levels of 1,25(OH)2D correlating with the DBP levels. [16] DBP is also essential for 1,25(OH)2D cellular endocytosis. [17] DBP can independently activate macrophages. [18] DBP polymorphisms have been associated with rheumatoid arthritis, male osteoporosis and glucose homeostasis. [18],[19],[20] Allelic variants of the DBP gene [intron 8 (TAAA)N repeat polymorphism] has been demonstrated to increase susceptibility to Graves' disease. [21]

Vitamin-D thus through modulation of both innate and acquired immunity has an important role in the development of autoimmune thyroid disease. How the correction of this deficiency modulates thyroid autoimmunity in the population needs to be evaluated.


  Vitamin-D and Thyroid Cancer Top


Active vitamin-D promotes cellular differentiation and inhibits cellular growth by binding to its nuclear receptor (VDR), which subsequently forms heterodimer with retinoic receptors (RXR,RAR) as has been observed in colon and breast cancer. [22],[23] Inhibiting cellular proliferation, promoting differentiation, inhibiting angiogenesis, and augmenting the effects of standard chemotherapy are some of the mechanisms believed to have a role in the anticancer effects of vitamin-D. [1],[24]

VDR has been demonstrated on normal thyroid follicular cells as well as on papillary thyroid cancer (PTC) cells. [25],[26] Khadzkou et al. demonstrated increased expression of 1α-hydroxylase and VDR in PTC tissue but not in normal thyroid tissue. [26]

Lower serum 1,25(OH)2D but not 25(OH)D has been documented in patients with thyroid cancer as compared with normal individuals. [27]

The ff FokI polymorphism of VDR (associated with increased risk of breast and ovarian cancer) was found to have a positive correlation with occurrence of follicular thyroid cancer (FTC) as compared with normal controls. [28],[29] Increased expression of 24-hydroxylase in resistant thyroid cancer cell lines (SW1736 and 8505C) have been documented. [30] Increased 24-hydroxylase leads to increased conversion of active vitamin-D 1,25(OH)2D to the inactive 24,25(OH)2D, leading to less 1,25(OH)2D being available for binding to VDR, thus inducing a state of vitamin-D resistance. [31]

Vitamin-D analogue 22-oxa-calcitriol has been shown to have an inhibitory effect on the proliferating PTC cells in the culture. [27],[32] The differentiating and antiproliferative effect of vitamin-D on thyroid cancer cell lines is believed to be due to dephosphorylation and accumulation of nuclear p27. [33],[34] High dose of vitamin-D analogue DR3R for 2 years resulted in disease stabilization and nonprogression for a large locally aggressive PTC not amenable for surgical resection. [35]

Hence it may be said that VDR modulation may have an important role in the treatment of thyroid cancer, with initial reports being promising.


  Vitamin-D and Thyroid: Indian Perspective Top


Goswami et al. in study of hospital staff of 642 individuals, demonstrated a high prevalence of both vitamin-D deficiency [87% having 25(OH)D<25 nmol/L] as well as thyroid autoimmunity (21% anti-TPO antibody positive) among Indians. [36] Hence the relation between vitamin-D status and thyroid dysfunction is more relevant in the Indian context and further studies are needed from India, especially on the effects of correcting vitamin-D deficiency on thyroid function.

 
  References Top

1.Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 2005;26:662-87.  Back to cited text no. 1
    
2.Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 1999;96:507-15.  Back to cited text no. 2
    
3.Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 2006;126:789-99.  Back to cited text no. 3
    
4.Wang TT, Tavera-Mendoza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y, et al. Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol 2005;19: 2685-95.  Back to cited text no. 4
    
5.Czernobilsky H, Scharla S, Schmidt-Gayk H, Ziegler R. Enhanced suppression of 1,25(OH)2D3 and intact parathyroid hormone in Graves' disease as compared to toxic nodular goiter. Calcif Tissue Int 1988;42:5-12.  Back to cited text no. 5
    
6.Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: New aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137-42.  Back to cited text no. 6
    
7.Tokuda N, Mano T, Levy RB. 1,25-Dihydroxyvitamin D3 antagonizes interferon-gamma-induced expression of class II major histocompatibility antigens on thyroid follicular and testicular Leydig cells. Endocrinology 1990;127:1419-27.  Back to cited text no. 7
    
8.Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004;173:2909-12.  Back to cited text no. 8
    
9.Rook GA, Stanford JL. Slow bacterial infections or autoimmunity? Immunol Today 1992;13:160-4.  Back to cited text no. 9
    
10.Prummel MF, Strieder T, Wiersinga WM. The environment and autoimmune thyroid diseases. Eur J Endocrinol 2004;150:605-18.  Back to cited text no. 10
    
11.Marshall TG. Vitamin D discovery outpaces FDA decision making. Bioessays 2008;30:173-82.  Back to cited text no. 11
    
12.Waterhouse J. High levels of active 1,25-dihydroxyvitamin D despite low levels of the 25-hydroxyvitamin D precursor - implications of dysregulated vitamin D for diagnosis and treatment of chronic disease. In: Vitamin D: new research. New York: Nova Science Publishers; 2006. p. 1-23.  Back to cited text no. 12
    
13.Proal AD, Paul JA, Trevor MG. Dysregulation of the vitamin D Nuclear Receptor May Contribute to the Higher Prevalence of Some Autoimmune Diseases in Women. Ann N Y Acad Sci 2009;1173:252-9.  Back to cited text no. 13
    
14.Stefaniæ M, Papiæ S, Suver M, Glavas-Obrovac L, Karner I. Association of vitamin D receptor gene 3′-variants with Hashimoto's thyroiditis in the Croatian population. Int J Immunogenet 2008;35:125-31.  Back to cited text no. 14
    
15.Bouillon R, Van Assche FA, Van Baelen H, Heyns W, De Moor P. Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxyvitamin D3. Significance of the free 1,25- dihydroxyvitamin D3 concentration. J Clin Invest 1981;67:589-96.  Back to cited text no. 15
    
16.Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 1999;96:507-15.  Back to cited text no. 16
    
17.White P, Cooke N. The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol Metab 2000;11:320-7.  Back to cited text no. 17
    
18.Papiha SS, Pal B. Gc (vitamin D binding protein) subtypes in rheumatoid arthritis. Hum Genet 1985;70:278-80.  Back to cited text no. 18
    
19.Papiha SS, Allcroft LC, Kanan RM, Francis RM, Datta HK. Vitamin D binding protein gene in male osteoporosis: Association of plasma DBP and bone mineral density with (TAAA)(n)-Alu polymorphism in DBP. Calcif Tissue Int 1999;65:262-6.  Back to cited text no. 19
    
20.Baier LJ, Dobberfuhl AM, Pratley RE, Hanson RL, Bogardus C. Variations in the vitamin D-binding protein (Gc locus) are associated with oral glucose tolerance in nondiabetic Pima Indians. J Clin Endocrinol Metab 1998;83:2993-6.  Back to cited text no. 20
    
21.Pani MA, Regulla K, Segni M, Hofmann S, Hüfner M, Pasquino AM, Usadel KH, Badenhoop K. et al. A polymorphism within the vitamin D-binding protein gene is associated with Graves' disease but not with Hashimoto's thyroiditis. J Clin Endocrinol Metab 2002;87:2564-7.  Back to cited text no. 21
    
22.Thomas MG, Sylvester PA, Newcomb P, Longman RJ. Vitamin D receptor expression in colorectal cancer. J Clin Pathol 1999;52:181-3.  Back to cited text no. 22
    
23.Verlinden L, Verstuyf A, Van Camp M, Marcelis S, Sabbe K, Zhao XY, et al. Two novel 14-Epi-analogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res 2000;60:2673-9.  Back to cited text no. 23
    
24.Ma Y, Yu WD, Hershberger PA, Flynn G, Kong RX, Trump DL, Johnson CS et al. 1alpha, 25-Dihydroxyvitamin D3 potentiates cisplatin antitumor activity by p73 induction in a squamous cell carcinoma model. Mol Cancer Ther 2008;7:3047-55.  Back to cited text no. 24
    
25.De Clercq P, et al. Lamberg-Allardt C, Valtonen E, Polojarvi M, Stewen P. Characterization of a 1,25-dihydroxy-vitamin D3 receptor in FRTL-5 cells. Evidence for an inhibitory effect of 1,25-dihydroxyvitamin D3 on thyrotropin-induced iodide uptake. Mol Cell Endocrinol 1991;81:25-31.  Back to cited text no. 25
    
26.Suzuki S, Takenoshita S, Furukawa H, Tsuchiya A. Antineoplastic activity of 1,25(OH)2D3 and its analogue 22-oxacalcitriol against human anaplastic thyroid carcinoma cell lines in vitro. Int J Mol Med 1999;4:611-4.  Back to cited text no. 26
    
27.Khadzkou K, Buchwald P, Westin G, Dralle H, Akerstrom G, Hellman P. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D receptor expression in papillary thyroid carcinoma. J Histochem Cytochem 2006;54:355-61.  Back to cited text no. 27
    
28.Laney N, Meza J, Lyden E, Erickson J, Treude K, Goldner W. The prevalence of vitamin D deficiency is similar between thyroid nodule and thyroid cancer patients. Int J Endocrinol 2010;2010:805716.  Back to cited text no. 28
    
29.Penna-Martinez M, Ramos-Lopez E, Stern J, Hinsch N, Hansmann ML, Selkinski I, Grunwald F, Vorlander C, Wahl RA, Bechstein WO, Zeuzem S, Holzer K, Badenhoop K et al. Vitamin D receptor polymorphisms in differentiated thyroid carcinoma. Thyroid 2009;19:623-8.  Back to cited text no. 29
    
30.Tworoger SS, Gates MA, Lee IM, Buring JE, Titus-Ernstoff L, Cramer D, Hankinson SE et al. Polymorphisms in the vitamin D receptor and risk of ovarian cancer in four studies. Cancer Res 2009;69:1885-91.  Back to cited text no. 30
    
31.lbertson DG, Ylstra B, Segraves R, Collins C, Dairkee SH, Kowbel D, KuoWL, Gray JW, PinkelD et al. Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nat Genet 2000;25:144-6.  Back to cited text no. 31
    
32.Okano K, Usa T, Ohtsuru A, Tsukazaki T, Miyazaki Y, Yonekura A, Namba H, et al. Effect of 22-oxa-1,25-dihydroxyvitamin D3 on human thyroid cancer cell growth. Endocr J 1999;46:243-52.  Back to cited text no. 32
    
33.Liu W, Asa SL, Fantus IG, Walfish PG, Ezzat S. Vitamin D arrests thyroid carcinoma cell growth and induces p27 dephosphorylation and accumulation through PTEN/akt-dependent and -independent pathways. Am J Pathol 2002;160:511-9.  Back to cited text no. 33
    
34.Dackiw AP, Ezzat S, Huang P, Liu W, Asa SL. Vitamin D3 administration induces nuclear p27 accumulation, restores differentiation, and reduces tumor burden in a mouse model of metastatic follicular thyroid cancer. Endocrinology 2004;145:5840-6.  Back to cited text no. 34
    
35.Morishita M, Ohtsuru A, Kumagai A, Namba H, Sato N, Hayashi T, Yamashita S et al. Vitamin D3 treatment for locally advanced thyroid cancer: A case report. Endocr J 2005;52:613-6.  Back to cited text no. 35
    
36.Goswami R,Marwaha RK, Gupta N, Tandon N, Sreenivas V, Tomar N, Ray D, Kanwar R, Agarwal R. et al. Prevalence of vitamin D deficiency and its relationship with thyroid autoimmunity in Asian Indians: A community-based survey. Br J Nutr 2009;102:382-6.  Back to cited text no. 36
    



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