Use of Vitamin D in Various Disorders
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- Khadilkar, V.V. & Khadilkar, A.V. Indian J Pediatr (2013) 80: 215. doi:10.1007/s12098-012-0877-7
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Approximately 1 billion people worldwide have been identified as vitamin D deficient in the 21st century, and the number is on the rise; non-classical actions of vitamin D were initially recognized around 30 y ago when receptors for vitamin D were detected in neoplastic cells lines. The aim of this review is to provide a brief overview of the non-classical actions of vitamin D. Reports describing the associations of non skeletal actions of vitamin D, especially pertaining to the immune system, inflammatory disorders, cancers and cardiovascular disease have been summarized in this paper. Reports support a role for the active form of vitamin D in mediating normal function of both the innate and adaptive immune systems. Studies also suggest a link between vitamin D deficiency and autoimmune diseases, such as rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus and type 1diabetes. There is believed to be an inverse association between serum 25-hydroxyvitamin D concentrations and the incidence of colorectal cancer, sporadic colorectal adenoma and breast cancer. Vitamin D deficiency has been linked with various cardiovascular diseases such as hypertension, myocardial infarction, and stroke. Several epidemiological and genetic studies suggest a strong association between vitamin D and non skeletal acute and chronic disorders. However, currently, robust clinical data are still lacking to support raising intake requirements and target vitamin D plasma levels. Nonetheless, the high prevalence of vitamin D deficiency is alarming and requires implementation of clear supplementation guidelines.
KeywordsVitamin DNon skeletalDiabetesCancer
Approximately 1 billion people worldwide have been identified as vitamin D deficient in the 21st century, and the number is on the rise. Vitamin D deficiency has also been widely reported at all age groups from sun-rich countries such as India [1, 2]. The key role played by vitamin D together with calcium in bone health is well known. Vitamin D aids bone health through its primary action of promoting calcium absorption in the gut as well as by regulating serum calcium and phosphorus concentrations. Non-classical actions of vitamin D were initially recognized around 30 y ago when receptors for vitamin D were detected in neoplastic cells lines . Since then, receptors for vitamin D have been found throughout the body, including in the pancreas, intestines, muscle and nerve systems . Vitamin D is also believed to bind to receptors in the immune, neurologic, and cardiovascular systems to regulate cell cycles and organ functions there . The aim of this review is to provide a brief overview of the non-classical actions of vitamin D.
Vitamin D and the Immune System
Interaction with the immune system is one of the most well-established non-classical effects of vitamin D . However, recent reports have supported a role for the active form of vitamin D i.e., 1,25(OH)2D3 in mediating normal function of both the innate and adaptive immune systems. These effects of vitamin D are believed to be mediated through localized autocrine or paracrine synthesis of 1,25(OH)2D3 from its precursor 25-hydroxyvitamin D3 (25OHD3) . Vitamin D receptors have been found on many immune cells, such as macrophages, dendritic cells, T and B cells . Further, cathelicidins, which are a family of antimicrobial peptides found in lysosomes in macrophages and polymorphonuclear leukocytes are believed to be activated by vitamin D . Cathelicidins serve a critical role in innate immune defense against invasive bacterial infection . They were originally found in neutrophils but have since then been detected in many other cells including epithelial cells and macrophages and can be activated by the 1,25(OH)2D3, the active form of vitamin D . Cathelicidins have been identified as a target for transcriptional regulation by liganded vitamin D receptor, its gene promoter contains a functional vitamin D response element . Regulation of this antibacterial protein by the active form of vitamin D has been described for a wide variety of cell types other than macrophages, including keratinocytes, lung epithelial cells, placental trophoblasts, myeloid cell lines, etc. [13–16].
Vitamin D deficiency has also been specifically associated with increased risk of respiratory diseases including infections such as influenza and Mycobacterium tuberculosis and chronic respiratory diseases such as cystic fibrosis, interstitial lung disease and chronic obstructive pulmonary disease. Several studies across ethnic backgrounds have demonstrated a positive association between prevalence of tuberculosis and decreased concentrations of vitamin D  A meta-analysis of studies demonstrated that participants with tuberculosis had significantly lower serum 25(OH)D concentrations compared to matched controls . Several cross-sectional studies have reported an association of vitamin D deficiency with decreased lung function . Similarly, a link has also been suggested between maternal vitamin D status and childhood respiratory disease. In a population based study on 1,724 children from Spain, authors found that higher maternal circulating 25(OH)D concentrations in pregnancy were independently associated with lower risk of lower respiratory tract infections in offspring in the first year of life, but not with wheezing or asthma in childhood .
Vitamin D and Inflammation
The role of vitamin D deficiency in the development of autoimmune diseases has, in the last 2–3 decades gained considerable interest. Studies suggest a link between vitamin D deficiency and autoimmune diseases, such as rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus [21, 22]. Prospective studies on the involvement of vitamin D in autoimmune disorders are understandably limited, but most cross-sectional studies show an inverse relationship between concentrations of vitamin D and disease activity [23, 24]. In vitro studies suggest that when vitamin D was added, many immunological abnormalities characteristic of SLE were reversed, thus suggesting that vitamin deficiency shifts the immunological response towards the loss of tolerance . In another study on patients with rheumatoid arthritis, authors concluded that the serum concentrations of vitamin D were inversely related to disease activity and this relationship, was independent of PTH secretion or activity .
Growing evidence indicates that vitamin D deficiency is associated with type 1 diabetes . Type 1 diabetic patients from the British population had lower circulating levels of 25(OH) D than similarly aged healthy subjects. Further, three key 25(OH)D metabolism genes have a consistent association with type 1 diabetes risk, indicating a possible etiological role for vitamin D deficiency in type 1 diabetes . Studies also indicate reduced risk of type 1 diabetes after maternal intake of vitamin D supplements during pregnancy. In a study from Norway which aimed to test whether lower maternal serum concentrations of 25-hydroxy-vitamin D (25-OH D) during pregnancy were associated with an increased risk of childhood-onset type 1 diabetes, authors found that the odds of type 1 diabetes were more than twofold higher for the offspring of women with the lowest levels of 25-OH D compared with the offspring of those with levels above the upper quartile .
Vitamin D and Cancer
An inverse relationship has been found between sunlight exposure and rates of incidence of death for certain cancers in particular geographic areas . Evidence of a possible cancer-protective role for vitamin D has also been observed in laboratory studies of the effect of vitamin D treatment on cancer cells in culture. In these studies, vitamin D promoted the differentiation and death (apoptosis). These effects are related to the repression of the expression of antiapoptotic proteins such as Bcl2 of cancer cells, and it slowed their proliferation by inducing cell cycle arrest and the accumulation of cells in the G0/G1 phase of the cell cycle . Other studies suggest that based on the evidence demonstrating antiinflammatory effects of vitamin D, it may play a role in delaying or preventing cancer development and/or progression .
A number of observational studies have investigated whether people with higher vitamin D concentrations or intakes have lower risks of cancers, such as colorectal and breast cancer. Associations of vitamin D with risks of prostate, pancreatic, and other, rarer cancers have also been examined. These studies have largely yielded inconsistent results because of the challenges of conducting observational studies of diet .
Randomized clinical trials designed to investigate the effects of vitamin D intake on bone health have suggested that higher vitamin D intakes may reduce the risk of cancers. One study involved nearly 1,200 healthy postmenopausal women who took daily supplements of calcium (1,400 mg or 1,500 mg) and vitamin D (1,100 IU vitamin D) or a placebo for 4 y. The women who took the supplements had a 60 % lower overall incidence of cancer; however, the study did not include a group where subjects were taking vitamin D only. Moreover, the primary outcome of the study was fracture incidence; thus, it was not designed to measure cancer incidence. This limits the ability to draw conclusions about the effect of vitamin D intake on cancer risk .
In 2008, the International Agency for Research on Cancer (IARC) released a report, Vitamin D and Cancer, on the current state of knowledge of a causal association between vitamin D status and cancer risk. Overall conclusions of the IARC Working Group on vitamin D and cancer state that from observational studies, there is an inverse association between serum 25-hydroxyvitamin D concentrations and the incidence of colorectal cancer, sporadic colorectal adenoma and breast cancer. There is however, the report states, there seems to be only limited evidence of an association between low serum 25-hydroxyvitamin D and the incidence of prostate cancer as well as other cancers .
Vitamin D and Cardiovascular Disease
Vitamin D deficiency has been linked with various cardiovascular diseases (CVD) such as hypertension, myocardial infarction, and stroke. It has also been associated with cardiovascular-related diseases, such as diabetes, congestive heart failure, peripheral vascular disease and atherosclerosis . Studies suggest a role for vitamin D in maintaining cardiovascular health through both the direct action of the vitamin on cardiomyocytes, where vitamin D receptors have been found, and the indirect actions on circulating hormone and calcium concentrations [37, 38]. Several mechanisms have been proposed to explain how decreased vitamin D concentrations may contribute to CVD: vitamin D has been shown to inhibit vascular proliferation, to increase the synthesis of matrix G1A protein, to suppress levels of the proinflammatory cytokines tumor necrosis factor-α and interleukins . Vitamin D is also believed to upregulate the level of anti-inflammatory cytokine interleukin which inhibits vascular calcification . In addition, low vitamin D concentrations have been associated with elevated serum PTH levels and these are also believed to contribute to CVD risk . Thus, some researchers believe that the evidence is strong enough to recommend screening for vitamin D deficiency in patients with CVD or CVD risk.
Hypotheses on vitamin D status and colorectal cancer, cardiovascular diseases and all-cause mortality should be tested in appropriately designed randomised controlled trials.
Along with the above mentioned associations, vitamin D deficiency has also been linked to cognitive impairment and dementia . Associations have also been noted between low 25-hydroxyvitamin D [25(OH)D] and Alzheimer’s disease and dementia in both Europe and the US. Further, inadequate vitamin D status has been associated with higher prevalence rates of obesity .
In the last 2–3 decades, deficiency of vitamin D has been linked to many acute and chronic conditions and diseases. Several epidemiological and genetic studies have been published which have shown strong evidence of this association. The anti-tumor properties of vitamin D could be explored for therapeutic purposes in breast cancer. Role of vitamin D in immunological response suggests that in future, it may play a role in the prevention and treatment of these disorders. However, currently, robust clinical data are still lacking to support raising intake requirements and target vitamin D plasma levels based on a role for vitamin D in preventing non skeletal disorders and scientific evidence still indicates that the key role of vitamin D is in musculoskeletal health. Nonetheless, the high prevalence of vitamin D deficiency is alarming and requires implementation of clear supplementation guidelines.
Conflict of Interest
Role of Funding Source
AVK and VVK both contributed to the literature survey and preparation of manuscript. and analysis. VVK will act as a guarantor