Study of the relationship between vitamin D deficiency, sunlight incidence and skeletal/extra skeletal diseases

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Vitamin D (VD) has a unique metabolism, mainly being obtained through synthesis in the skin under the influence of sunlight, whereas intake by nutrition traditionally plays a relatively minor role (Pliz et al., 2018). VD is an essential nutrient with hormone-like activity which regulates calcium and bone metabolism. It is known that non-skeletal cells express vitamin D receptor (VDR), and as such interact with the active form of vitamin D, i.e. 1,25-dihydroxyvitamin D. Furthermore, most of these cells express extra-renal forms of 1α-hydroxylase enzyme, and the active form of vitamin D is known to regulate quite a number of genes, including those implicated in proliferation, differentiation, and apoptosis. It has recently been described that the pathophysiology of autoimmune thyroid disease, adrenal disease, and hyperparathyroidism has a VD component (Muscogiuri & Bhattoa, 2018).

VDR are present in numerous tissues such as the gut, renal tubules, bone, pancreas, skin, brain, prostate, breast, colon, immune system cells, hematopoietic cells, and muscle cells (Holick, 2007; Mandarino, Monteiro Júnior, Salgado, Lages, & Salgado Filho, 2015). Vitamin D plays a role in regulating cell proliferation and differentiation and in modulating the innate and adaptive immune response. In addition, vitamin D correlates with changes in cytokines and prevents inflammation induced by changes in myometrial cells mediated by the nuclear factor kappa B pathway (Kjalarsdottir et al., 2019). In addition, vitamin D regulates calcium influx through the R-Type voltage-gated calcium channel during glucose-stimulated insulin secretion, thereby modulating the capacity of beta cells to secrete insulin (Momentti, Estadella, & Pisani, 2018).

Vitamin D is also involved in promoting peripheral tolerance and limiting chronic inflammatory diseases. Renal transplant recipients are likely to have low vitamin D levels, which may influence their immune status (Myszka et al., 2018). Recent studies have examined the role of vitamin D in immunomodulation, including the development and regulation of iNKT cells. Indeed, iNKT cells and CD4/CD8 intraepithelial lymphocytes are developmentally and functionally dependent on sufficient levels of vitamin D. Although the effects of vitamin D on iNKT cell development have been elucidated, it is not clear as to whether vitamin D deficiency (or VDR knockout) results in a proinflammatory or anti-inflammatory state (Smyk et al., 2018). As a result, vitamin D can be related to many diseases.

Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extra skeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications, and premature deaths (Pliz et al., 2018). Moreover, the genetic variations of VDR have revealed their association with the risk of metabolic syndrome (Karuwanarint et al., 2018). Relatively high rates of subclinical vitamin D deficiency have been reported in infants, children, and adolescents in several studies, especially from low-income countries (Salerno et al., 2018). Studies have shown that a high prevalence of vitamin D deficiency was observed associated with metabolic disorders in both obese adults and adolescents. Therefore, it is necessary to develop strategies for the prevention and control of obesity and vitamin D deficiency (Teixeira et al., 2018).

Numerous drugs with vitamin D activity are available for clinical use, and it may not be easy for a non-specialist to select the most suitable drugs for individual patients. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. Available drugs with a vitamin D-like activity do not have the same pharmacological actions and present side effects. They have specific characteristics which may be useful to know in order to select the best choice to prescribe to individual patients (Mazzaferro, Goldsmith, Larsson, Massy, & Cozzolino, 2014). In view of the above, this study aims to verify a relationship between vitamin D levels and some disorders in order to generate additional information about vitamin D protector effects.

Regarding the association between vitamin D and diseases, clinical and epidemiological studies are still controversial and randomized control trials in humans do not yet exist to conclusively support a beneficial effect of vitamin D in health (Feldman, Krishnan, Swami, Giovannucci, & Feldman, 2014). A study suggested that vitamin D deficiency potentially increases the risk for diseases caused by higher adiposity and oxidative stress (Zhang et al., 2014). Our analyses have shown that vitamin D insufficiency/deficiency is significantly prevalent in patients with hypercholesterolemy, hypertriglyceridemia, cancer, diabetes, hepatobiliary diseases and urinary system diseases (Figure 1, 2), which may be related to increased oxidative stress in some patients. However, further studies are necessary in order to understand the molecular mechanisms for which vitamin D deficiency may influence the onset of these diseases.As in our study (Figure 1, 2), other studies support an association between vitamin D and cholesterol levels (Cutillas-Marco, Prosper, Grant, & Morales-Suárez-Varela, 2013). Vitamin D supplementation in pregnant women with gestational diabetes mellitus had beneficial effects on glycemia, total-cholesterol, and LDL-cholesterol concentrations, but did not affect inflammation and oxidative stress (Asemi, Hashemi, Karamali, Samimi, & Esmaillzadeh, 2013). Vitamin D also protected against atherosclerosis in hypercholesterolemic swine by controlling cholesterol efflux, macrophage polarization, and increasing the CYP27A1 activation (Yin et al., 2015). VDR activation increases CYP7A1 expression to decrease cholesterol levels (Chow et al., 2014). Additionally, vitamin D supplementation might improve serum lipid concentrations in statin-treated patients with hypercholesterolemy. Moreover, Vitamin D might be an adjuvant therapy for patients with hypercholesterolemy (Qin, Zhao, Chen, Yin, & Wang, 2015).In addition, low vitamin D levels appear to be associated with hypertriglyceridemia, insulin resistance, and metabolic syndrome in obese patients (Jiang, Peng, Chen, Wu, & Zhang, 2019). There is a possible beneficial contribution of plasma vitamin D in the hypertriglyceridemia pathogenesis through a decrease in inflammation (Guasch et al., 2012). Low serum vitamin D concentrations are associated with high triglyceride levels (Rodríguez-Rodríguez, Ortega, González-Rodríguez, & López-Sobaler, 2011); this is also shown in our work (Figures 1, 2). A study found that decreased vitamin D levels are associated with increased insulin resistance, triglyceride levels, and blood pressure in older Korean adults, and confirmed the risk of ‘hypertriglyceridemia’ in vitamin D deficient subjects (Park et al., 2012).

In addition to the relationships between vitamin D and metabolic diseases, epidemiologic data also suggest that the incidence and severity of many types of cancer inversely correlate with indices of vitamin D status. Vitamin D regulates numerous cellular pathways which could have a role in determining cancer risk and prognosis. Although epidemiological and early clinical trials are inconsistent, results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer (Feldman et al., 2014). The VDR is expressed in epithelial cells at risk for carcinogenesis, including cells in skin, breast, prostate, and colon, providing a direct molecular link by which vitamin D status impacts carcinogenesis (Welsh, 2012).

Furthermore, vitamin D associated polymorphisms were associated with colorectal, breast, and prostate cancer risk (Ordóñez-Mena & Brenner, 2014). New studies are needed to answer important questions which remain about the timing of VD exposure in relation to cancer etiology during the life span (e.g. adolescence or adulthood), the VD dose-response/optimal levels required for the most benefits, and in which stages of carcinogenesis (incidence or progression) VD is most relevant (Giovannucci, 2008).

There is a high prevalence of vitamin D deficiency in children with non-alcoholic fatty liver disease; however, no association was found between vitamin D deficiency and the severity of the disease on biopsies. This differs from adult studies in which vitamin D deficiency correlates with histological severity, suggesting diff erences in the risk factors for consequences of pediatric non-alcoholic fatty liver disease (Hourigan et al., 2015). Another study showed that vitamin D levels are inversely associated with non-alcoholic steatohepatitis in children with non-alcoholic fatty liver disease (Nobili et al., 2014). These data corroborate with those observed in our study, in which we observed that vitamin D status was inversely related to the incidence of liver diseases (Figures 1, 2). Further studies are needed to determine whether patients at risk of developing impaired liver function should be screened for vitamin D deficiency for preventive purposes (Skaaby et al., 2014). Although the exact vitamin D mechanisms have not been fully elucidated in chronic liver diseases, VD can be beneficial in treating these disorders; therefore, new studies are needed to validate VD clinical application (Chen, Shi, & Tang, 2014).

Another group in which a high prevalence of VD deficiency is observed is the adult and pediatric patients’ with chronic kidney disease (CKD), as one of the characteristics of CKD is that it can be caused by VD metabolism deregulation (Dusso, González, & Martin, 2011). A recent meta-analysis found an association between treatment with active VD and decreased mortality in patients with CKD (Bover et al., 2015). The presence of CKD and diabetes mellitus could be associated with resistance to correct the vitamin D deficiency with therapy. The underlying mechanism needs to be evaluated in prospective studies. Furthermore, the disturbed signaling of VDR has been demonstrated in patients with cardiac disorders and chronic kidney disease ((Alshayeb, Wall, Showkat, Quarles, & Mangold, 2013). Finally, some findings suggest that glomerular filtration rate and parathyroid hormone are significantly associated with VD metabolism in men without CKD (Karhapää et al., 2012). No significant statistical differences were observed in relation to neurological diseases, cardiovascular diseases or hypertension (Figure 1, 2). However, other mechanisms, pathways, and mediators in addition to vitamin D are involved with the pathophysiology of neurological diseases, cardiovascular diseases, and hypertension. Overall, vitamin D deficient patients have significantly more illnesses or disorders when compared to sufficient vitamin D patients (p < 0.05).Moreover, we found relationships between bone diseases, thyroid diseases, and VD levels. However, it is important to highlight that findings from recent meta-analyses regarding vitamin D supplementation without co-administration of calcium have not shown fracture prevention, possibly because of inappropriate doses or because the intervention was not targeted to deficient populations. Almost half of older adults (older than 50 years) continue to use VD supplements. The widespread use of vitamin D for osteoporosis prevention without specific risk factors for VD deficiency seems to be inappropriate (Reid, Bolland, & Grey, 2014). Supplementation with low doses of vitamin D in children additionally did not improve bone mineral density (Milart, Jobs, Tłustochowicz, Pogonowska, & Kalicki, 2018).

Furthermore, we evaluated whether countries with low solar incidence have higher mortality rates by cancer, diabetes mellitus, coronary heart disease, multiple sclerosis, hypertension, and Parkinson's disease when compared to countries with high solar incidence (Figure 3). Our results showed that countries with low annual solar incidence have significantly higher cancer death rates and multiple sclerosis death rates. This may be due to the participation of vitamin D as a regulator of cellular oxidative stress (Mokhtari, Hekmatdoost, & Nourian, 2017) and the immune system (Yang, Leung, Adamopoulos, & Gershwin, 2013). The sunlight can reflect the VD concentrations because our analysis is consistent with a possible variation in serum vitamin D concentration between countries. Besides, an extra analysis (Figure 4) showed that low solar incidence countries have significantly greater cancer deaths rate when compared with high solar incidence countries, even when we analyzed both high and low life expectancy countries apart (See Chart in the Supplementary Material). In this way, the life expectancy is not significantly biasing our cancer analyses.

Although the precise causes of multiple sclerosis remain unknown, some evidence points towards hypovitaminosis D. Vitamin D is an immunomodulation factor and has a potential to be effective in preventing and treating autoimmune diseases, including MS (Collongues, Patte-Mensah, De Seze, Mensah-Nyagan, & Derfuss, 2018). Studies point to a participation of vitamin D in inducing T regulator cell and inhibiting Th1 and Th17 cells, acting in the pathogenesis of autoimmune processes (Altieri et al., 2017). In fact, epidemiological studies linking vitamin D to MS range from half-century-old findings of latitude gradients and emigrational risk patterns to modern, nested, case-control bio bank studies. These observations show an association although causation has yet to be proven (Salzer, Biström, & Sundström, 2014).

Alterations in the oxidant/antioxidant balance and lower vitamin D levels may contribute to the pathophysiology of MS (Polachini et al., 2016). There is epidemiological evidence that the risk of developing MS is increased in association with low levels of sun exposure, possibly because this is associated with low vitamin D status (Lucas, Byrne, Correale, Ilschner, & Hart, 2015). Another study suggested a protective effect from sun exposure and/or vitamin D in MS, as our study suggests. These data include geographic variations in MS occurrence, temporal trends, genetics, biobank, and questionnaire data (Salzer et al., 2014). To sum up, vitamin D deficiency is considered a risk factor for MS; however, there is no direct evidence for the effects of vitamin D on MS progression (Alharbi, 2015).

Related to cancer, the sunlight was inversely correlated with mortality rates for breast, colon, esophageal, gastric, and rectal cancers. In addition, low cancer survival rates may be due to lower serum 25-hydroxyvitamin D for black Americans. This may be attributed to low vitamin D production from solar ultraviolet-B irradiance due to darker skin (Grant, 2006). In another work, our group demonstrated that countries with high solar incidence have significantly lower AD death rates when compared to countries with low solar incidence, suggesting that vitamin D deficiency is involved with Alzheimer's disease progression (Câmara, Souza, & Dalmolin, 2018). Optimal serum VD levels are reported to be associated with many health benefits; however, few studies have determined predictive factors using national-level data. In another study, the strongest predictor of vitamin D inadequacy was non-Hispanic Black ethnicity. Other potential predictors included smoking, vitamin D supplements, collecting samples in winter, female gender, and lack of health care, among others (Lee, Lee, Maneno, Johnson, & Wutoh, 2019).

Regarding the strengths of our study, we highlight the power of the sample (99%) due to the participation of 212 patients. In other words, at a given significance level (0.05), the power of the test is increased by having a larger sample size. The region in which the study was conducted can be considered another strength since there are no significant seasonal variations in Natal/Brazil and the solar incidence is almost constant throughout the year (NASA Earth Data, 2019). New analyses are required to evaluate the role of VD deficiency in the disorders mentioned here and others. However, the numerous causal factors of some diseases, such as viruses or drugs, make it even more difficult to evaluate the influence of vitamin D on some diseases. Additionally, the exact role of VD deficiency in the establishment and progression of several diseases is not yet well elucidated and further research is essential to uncover the molecular mechanisms for which vitamin D may be involved in the onset and/or development of these diseases.

According to this research and literature, vitamin D insufficiency/deficiency can be associated with bone diseases, thyroid diseases, hypercholesterolemy, hypertriglyceridemia, cancers, diabetes, hepatobiliary diseases, and urinary system diseases. The role of vitamin D in cancers and Multiple Sclerosis can be reinforced by sunlight data. In addition, we suggest that the role of vitamin D in cancers is not influenced by life expectancy. However, further research is necessary to elucidate some vitamin D actions. These studies may bring some therapeutic contributions to several diseases.

This work has been financed by the governmental Brazilian agency National Council for Scientific and Technological Development (CNPq, Portuguese: Conselho Nacional de Desenvolvimento Científico e Tecnológico), grant 444856/2014-5. The scholarships were financed by governmental Brazilian agency Coordination for the Improvement of Higher Education Personnel (CAPES, Portuguese: Coordenação de Aperfeiçoamento Pessoal de Nível Superior).