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Коморбідний ендокринологічний пацієнт
Коморбідний ендокринологічний пацієнт

Международный эндокринологический журнал Том 17, №7, 2021

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Зв’язок між умістом вітаміну D та частотою злоякісної тиреоїдної патології

Зв’язок між умістом вітаміну D та частотою злоякісної тиреоїдної патології

Авторы: Nikitiuk L.A. (1), Korsak Yu. (2)
(1) — Uzhhorod National University, Uzhhorod, Ukraine
(2) — Nuclear Radiology Department, S. Kukura Hospital with Policlinics, Michailovce, Slovakia

Рубрики: Эндокринология

Разделы: Клинические исследования

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Резюме

Актуальність. Попри великий обсяг даних, які вказують на зв’язок вітаміну D із серцево-судинною захворюваністю, автоімунітетом, раком і з ураженнями практично усіх систем й органів, взаємозв’язок між вітаміном D і щитоподібною залозою належить до менш відомих аспектів вітаміну D у клінічній практиці. Зв’язок між дефіцитом вітаміну D і раком щитоподібної залози є суперечливим. Деякі дослідження продемонстрували, що більш високий рівень вітаміну D у сироватці крові справляє протективний ефект стосовно раку щитоподібної залози. У той же час інші дослідження вказують на протилежне. Мета даного огляду літератури — висвітлити дані сучасної літератури про вплив статусу вітаміну D на рак щитоподібної залози. Методи. Джерела літератури для огляду, опубліковані з 2005 року по червень 2021 року, були знай­дені за допомогою пошуку PubMed із використанням термінів «рак щитоподібної залози» та «вітамін D». Результати. На сьогодні великий обсяг медичної літератури доступний щодо обсерваційних досліджень, які пов’язують вітамін D із раком щитоподібної залози. Дані інтервенційних досліджень, які підтверджують позитивний вплив вітаміну D на перебіг раку щитоподібної залози, також доступні, але їх значно менше, ніж результатів обсерваційних досліджень. Короткочасний прийом високих доз перорального вітаміну D знижує рівні антитіл до тиреоїдної пероксидази. Поліморфізм гена рецептора вітаміну D пов’язують зі збільшенням частоти автоімунних захворювань щитоподібної залози. Дефіцит вітаміну D, зниження рівня циркулюючого кальцитріолу пов’язують зі збільшенням частоти раку щитоподібної залози. Поліморфізм генів рецептора вітаміну D пов’язують із впливом на частоту тиреоїдного раку. Даних про використання вітаміну D та його аналогів для лікування раку щитоподібної залози небагато. Результати свідчать про те, що дефіцит вітаміну D може мати значення як негативний прогностичний показник при папілярному раку щитоподібної залози. Тому доцільна передопераційна лабораторна оцінка вмісту вітаміну D із подальшою корекцією. Висновки. Незважаючи на велику кількість медичної літератури з обсерваційних досліджень, що пов’язують вітамін D із раком щитоподібної залози, значимі конкретні клінічні дані про вплив додаткового призначення вітаміну D на клінічні кінцеві точки при даних розладах відсутні, і вони повинні стати основною сферою досліджень у наступному десятилітті.

Background. In spite of large volume of data linking vitamin D with cardiovascular morbidity, autoimmunity, cancer, and virtually every organ system, vitamin D and thyroid is a lesser-known aspect of vitamin D in clinical practice. The association between vitamin D deficiency and thyroid cancer is controversial. Some studies have demonstrated that higher serum vitamin D levels might protect against thyroid cancer, whereas others have not, or have even indicated the opposite to to be the case. This review intends to highlight the current literature on the impact of vitamin D status on thyroid cancer. Materials and methods. References for this review were identified through searches of PubMed for articles published to from 2005 to June 2021 using the terms “thyroid cancer” and “vitamin D”. Results. A large volume of medical literature is available from observational studies linking vitamin D with thyroid cancer. Data from interventional studies documenting beneficial effects of vitamin D on thyroid autoimmunity is also available, but lesser than that from observational studies. Short-term high dose oral vitamin D supplementation reduces TPOAb titers. Certain vitamin D receptor (VDR) gene polymorphism have been linked to increased occurrence of autoimmune thyroid disorders. Vitamin D deficiency, decreased circulating calcitriol has been linked to increased thyroid cancer. Certain VDR gene polymorphisms have been linked with increased as well as decreased occurrence of thyroid cancer. Data is scant on use of vitamin D and its analogues for treating thyroid cancer. The results suggest that Vitamin D deficiency may have value as a negative prognostic indicator in papillary thyroid cancer and that pre-operative laboratory evaluation may be less useful. This is important because Vitamin D deficiency is modifiable. Conclusions. In spite of large volume of medical literature from observational studies linking vitamin D with thyroid cancer, meaningful concrete clinical data on impact of vitamin D supplementation on hard clinical end points in these disorders is lacking, and should be the primary area of research in the next decade.


Ключевые слова

рак щитоподібної залози; 25-гідроксивітамін D; дефіцит вітаміну D

thyroid cancer; 25-Hydroxyvitamin D; vitamin D deficiency

doi: http://dx.doi.org/10.22141/2224-0721.17.7.2021.244971

Introduction

The last two decades have seen an exponential increase in medical literature (basic, translational and clinical studies) linking Vitamin D to various organ systems in the body. Apart from the classical and well known impact of vitamin D on bone and muscle health [1] vitamin D is believed to have a beneficial effect on endothelial dysfunction (microalbuminuria) [2], cardiovascular function and events, insulin resistance [3], diabetes prevention, better immune function and response to anti-tubercular therapy in patients with tuberculosis, immune-modulatory effects in patients with autoimmune disorders (lupus, rheumatoid arthritis), prevention and remission of multiple sclerosis, better response to immunotherapy in patients post organ transplantation, gonadal function, among the growing list of pleotropic effects of vitamin D [4]. The reason for this role of vitamin D is perhaps because vitamin D receptor (VDR) is virtually expressed in every tissue and organ system of the body [5]. Vitamin D mediates its effect though VDR and activation of VDR-responsive genes. This review intends to highlight the current literature on the impact of vitamin D status on thyroid cancer.
Thyroid cancer is the most common cancer in endocrine system worldwide. Based on recent data, thyroid cancer is the fifth most common cancer in women. This malignancy accounts for 1.3 % of cancer diagnosis with 0.5 % of cancer-related mortalities each year. Thyroid cancers include undifferentiated cancers with high mortality, such as anaplastic cancers and differentiated cancers with good prognosis such as papillary thyroid carcinoma and follicular cancer. Differentiated thyroid cancers consists more than 90 % of all thyroid cancers [6–8].
In recent years incidence of thyroid cancer has increased around the world [9]. The fact that the increased incidence of thyroid cancer is caused by the increase in the use of tools such as thyroid sonography or other imaging techniques, or the incidence of thyroid cancer has actually increased for unknown reasons, is not clear. In addition to the increased incidence of small cancers diagnosed during sonography, large cancer incidence has also increased. Despite the early detection of thyroid cancer, the related mortality has increased, too [10]. Therefore, other factors could be involved. Currently, the known risk factors for thyroid cancer are: a family history of thyroid cancer, history of head and neck radiation in childhood, exposure to ionizing radiation and the use of inadequate or excessive iodine. But none of these can explain the recent increase in the incidence of thyroid cancer. More recently, other factors such as chemical toxins, insulin resistance, obesity and diabetes, nutritional factors, and vitamin D deficiency, have been proposed as potential risk factors for thyroid cancer [11].
The role of vitamin D deficiency in the pathogenesis of breast, colon, prostate and pancreatic cancer has been suggested [12]. Association between vitamin D and thyroid cancer in humans is not clear, some previous articles have demonstrated the association between Vitamin D deficiency and thyroid cancer, while other studies have not shown such a relationship [13, 14]. However, studies on the effect of vitamin D on the thyroid cancer are limited. 
The aim of this study was to investigate the relationship between serum levels of vitamin D and thyroid cancers and assess the role of this parameter as a potential new risk factor in the incidence of thyroid cancer.

Materials and methods

References for this review were identified through searches of PubMed for articles published to from 1905 to August 2021 using the terms “thyroid” and “Vitamin D”. Databases including PubMed, Cochrane library, Sinomed, CNKI, and clinical trial register centers, were searched for case-control studies of vitamin D in thyroid cancer.

Results

Vitamin D through VDR has both direct and indirect effects on cellular proliferation, differentiation, apoptosis, inflammation, invasion, angiogenesis, and metastasis [15]. Calcitriol increases the expression of cyclin dependent kinase inhibitors (CDKI), which have potent negative impact on cell proliferation. Vitamin D influences microRNA expression which also has an additional negative influence on cell growth and proliferation [16]. Calcitriol has been shown to inhibit the proliferation of thyroid cancer stem cells. Calcitriol reduced tumor size and prevented metastatic growth in SCID mice that were implanted with human thyroid follicular carcinoma-derived (WRO) cells [17]. VDR polymorphisms has been demonstrated to have an impact on vitamin D metabolism in thyroid tissue, which may modulate the anti-tumor effect of vitamin D in papillary thyroid cancer (PTC). VDR expression in human thyroid cancer cells has been linked to increased ECM protein-1 (ECM1) and type II trans-membrane serine protease 4 (TPMRSS4) expression, which are tissue markers of increased local invasion and metastasis [18], highlighting the potential role of vitamin D analogues in down regulating VDR and thus having a beneficial impact on thyroid cancer. Studies have shown that the efficacy of VDR agonist therapy to decrease viable thyroid cancer cell count depends on the FF FokI VDR genotype polymorphisms [19]. 
Lower circulating levels of calcitriol have been documented in patients with differentiated thyroid carcinoma [20]. In a study involving 212 patients with thyroid nodules, presence of vitamin D deficiency in the peroperative state was associated with higher occurrence of malignancy on post-operative histopathologic evaluation (75 % vs. 37.5 %) [21]. A significantly lower serum 25(OH)D was documented in 344 patients with PTC as compared to healthy controls [22]. In 548 women undergoing thyroidectomy for PTC, the pre-surgery serum 25(OH)D was significantly lower in patients with tumor diameter more than 1 cm and/or tumor metastasis [23]. In another study, serum calcitriol was significantly lower in 172 patients with differentiated thyroid carcinoma when compared to 321 healthy controls [24]. The same authors demonstrated an association between differentiated thyroid cancer and low 25(OH)D and calcitriol levels in certain CYP24A1 haplotypes [25].
A significant number of negative literatures are also available where they have found no relation between the vitamin D status and the occurrence and severity of thyroid malignancy. Preoperative serum 25(OH)D was not a predictor of disease aggressiveness or poor outcomes among 820 patients with PTC [26]. In another study involving 433 patients with thyroid nodules who underwent thyroidectomy, quartiles of serum 25(OH)D was not a predictor of malignancy or benign lesions [27]. Population screening of 5186 individuals revealed that serum 25(OH)D was not a predictor of malignancy in the general population [28]. In another study involving 177 patients with papillary thyroid cancer, it was not the vitamin D or adipocytokine status, but the occurrence of obesity, especially central obesity, which was the strongest predictor of malignancy [29].
The aim of next meta-analysis [30] was to investigate the association between vitamin D deficicency and thyroid cancer and propose that vitamin D deficiency is a risk factor for thyroid cancer. This was a meta-analysis of 14 articles of the association between vitamin D deficiency and thyroid cancer. A fixed-effect model was used to merge the standardized mean difference value of serum 25(OH)D levels. The pooled effect showed that the levels of serum 25(OH)D were lower in patients with thyroid cancer preoperatively than in the controls (–0.22; 95% confidence interval [CI] –0.36 to –0.09; P = 0.001). There was no difference after thyroid cancer patients underwent thyroidectomy (–0.19; 95% CI –0.47 to 0.10; P = 0.21). A fixed-effect model was used to pool the odds ratio of thyroid cancer and vitamin D deficiency. It showed that the pooled odds ratio from six studies was 1.30 (95% CI 1.00–1.69; P = 0.05). Subgroup analysis of 25(OH)D levels between different pathologic characteristics in patients with thyroid cancer was summarized, but no statistical differences were determined. Lower serum 25(OH)D levels were associated with increased risk for thyroid cancer. On the other hand, vitamin D deficiency may act as a risk factor for thyroid cancer.
As imaging technology improves and more thyroid nodules and malignancies are identified, it is important to recognize factors associated with malignancy and poor prognosis. Vitamin D has proven useful as a prognostic tool for other cancers and may be similarly useful in thyroid cancer. Other study [31] explores the relationship of vitamin D to PTC stage while accounting for socioeconomic covariates. The medical records of all patients who underwent thyroidectomy at one institution between 2000 and 2015 were reviewed. Subjects with non-papillary thyroid cancer pathology, prior malignancy, and without vitamin D levels were excluded. The remaining 334 patient records were examined for cancer stage, vitamin D levels, vitamin D deficiency listed in history, and demographic and comorbid factors. Vitamin D laboratory values showed no significant relationship to cancer stage (p = 0.871), but patients with vitamin D deficiency documented in the medical record were more likely to have advanced disease (28.6 % versus 14.7 %; p = 0.028). The patients with documented vitamin D deficiency also had lower 25(OH)D levels (21.5 ng/ml versus 26.5 ng/ml, p = 0.008) and were more likely to be on vitamin D supplementation (92.6 % versus 41.8 %, p < 0.001). The results suggest that vitamin D deficiency may have value as a negative prognostic indicator in PTC and that pre-operative laboratory evaluation may be less useful. This is important because vitamin D deficiency is modifiable. 
A. Bains et al. [32] provided evidence from both clinical studies as well as molecular studies of metabolic targets, including VDR and activating enzymes exerting an effect on PTC tissue, which indicate that vitamin D may play a significant prognostic role in PTC. 
Genetic polymorphisms of VDR, cytochrome P450, and factors, which modulate vitamin D metabolism, signaling and action, play an important role in the pathogenesis of different cancers including thyroid cancer [33]. Increased activity of vitamin D-inactivating CYP24A1 gene in PTC has been linked to increased tumor malignity (mainly vascular invasion, lymph node metastasis, tumor size), suggesting that CYP24A1 may be directly involved in thyroid carcinogenesis [34]. Polymorphism of VDR of alleles AA and FF of the ApaI (rs7975232), FokI (rs10735810) and haplotype tABF are believed to confer protection from follicular thyroid carcinoma [35]. The haplotype tABF is believed to be associated with an increased FTC risk [36].

Conclusions

To conclude, in spite of large volume of literature available linking vitamin D deficiency, VDR gene polymorphisms, calcitriol metabolism with thyroid cancer, there is scant data from interventional studies on the same, which should be the major area for research in the next decade [37, 38]. However it must be realized that as of today, vitamin D should not be considered as a panacea for all illness including thyroid disorders. 
 
Received 29.09.2021
Revised 27.10.2021
Accepted 02.11.2021

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