Vitamin D in Cancer and Other Diseases: A New Wonder Biomarker?

Introduction

There is a recent surge in the interest of estimating, analyzing and associating vitamin D deficiency with a variety of clinical disorders. Vitamin D, a fat-soluble vitamin, is considered a prohormone because the body can synthesize vitamin D from its precursor (7- dehydrocholesterol) when exposed to ultraviolet light at a wavelength between 290-315 nm. Its mechanism of action also resembles that of steroid hormones. Active form of vitamin D is 1α, 25-dihydroxycholecalciferol/ 1 α, 25-dihydroxy vitamin D3/ calcitriol or 1α,25 (OH)2 D3. Adequate circulating levels of active form of this vitamin need to be maintained for normal functioning of all the systems of the body irrespective of age and gender. Insufficient levels of vitamin D may affect any system and produce the related clinical abnormality [1]. The potential of vitamin D for acting as a biomarker depends on its association with an ever increasing number of diseases which are benefitted with vitamin D supplementation [2].

Recently, the scientific evidence is accumulating to demonstrate the insufficiency of vitamin D globally. Factors, which are responsible for the worldwide prevalence of vitamin D insufficiency, may vary among countries; but the principal reason is limitation in either cutaneous synthesis or dietary intake of vitamin D or both. Even the countries where geographical location ensures plenty of sunlight throughout the year like India, vitamin D deficiency is found to be rampant. This might be a result of poor sun exposure, dark skin complexion, atmospheric pollution, vegetarian foods habits, absence of food fortification with vitamin D and poor intake of vitamin D supplements [3, 4].

The main source of vitamin D3 is synthesis in presence of sunlight and is virtually considered negligible in the food supply. It is not found in vegetables, fruits or grains and is present in low quantity in meats and other animal food sources, except for fish liver oils and plants such as waxy-leaf nightshade (Solanum glaucophyllum) [2]. Therefore, there is a great market for supplements of vitamin D available in different forms and with different names which are being increasingly prescribed in addition to the standard treatment regimens [5]. To understand the role of vitamin D deficiency in various health disorders, it is imperative to assess its role in human physiology and biochemistry. The physiological functions of active vitamin D (1α, 25- dihydroxycholecalciferol) mainly pertain to calcium homeostasis along with maintenance of health of diverse organs [6].

Vitamin D2 versus Vitamin D3

The natural form of vitamin D in all animals and the form synthesized in human skin on exposure to sunlight is cholecalciferol, vitamin D3. Ergocalciferol (vitamin D2) is a synthetic product derived by irradiation of plant sterols/ergosterol. Initially, the two forms of the vitamin were considered to be interchangeable and equivalent, however, since the availability of the measurement of serum 25(OH)D3 as an indicator of vitamin D functional status, it has become clear that vitamin D2 is substantially less potent than vitamin D3. Both of these are absorbed from the intestine and get hydroxylated at 25th position in liver. However, vitamin D2 leads to upregulation of 24- hydroxylase, converting the administered D2 and endogenous D3 to their inactive forms. Thus, administration of vitamin D2 seems to have no advantage over vitamin D3, which is the natural form of the vitamin and is less expensive [7].

Assessment of vitamin D

Ideally, assessment of vitamin D status is recommended only for those at risk for vitamin D deficiency. But due to widespread prevalence of deficiency in general population, assessment of vitamin D status is increasingly being advised to people who present with unexplained clinical features and are found not responding to treatment. The levels of 25- hydroxycholecalciferol are commonly analyzed though 1α,25-dihydroxycholecalciferol is the active form of vitamin D. This is because the serum 25(OH)D3 is the major circulating form of vitamin D and has a longer half- life (2 to 3 weeks) as compared to 1α,25(OH)2D3 (3- 4 hours). The concentration of 1α,25(OH)2D3 is 1,000 times lower than that of 25(OH)D3 in circulation. Another fact needing consideration is that vitamin D deficiency is associated with a compensatory increase of parathyroid hormone secretion, which in turn, stimulates the kidneys to produce more 1α,25-dihydroxycholecalciferol. Thus, when 25(OH)D3 levels fall due to vitamin D deficiency, the concentrations of 1α,25(OH)2D3 may still remain within normal limits or sometimes even might be elevated. Though in patients of suspected renal impairment and inherited metabolic disorders of vitamin D and phosphate metabolism, both the forms should be measured [8].

Reference Range for Vitamin D

Normal vitamin D levels range between 30-100 ng/mL. Vitamin D deficiency is generally recognized as a 25(OH)D3 level < 20 ng/mL while vitamin D insufficiency has been defined as a serum 25(OH)D3 level of 21 to 29 ng/mL. As Vitamin D is a fat soluble vitamin, toxicity may appear at levels >150ng/mL while levels >100ng/ml are considered excess levels [7].

Toxicity

Vitamin D, being fat soluble, gets stored in the body and is capable of producing serious toxic effects, including death. An excess of vitamin D causes hypercalcemia, which can cause over calcification of the bones, soft tissues, heart and kidneys as well as hypertension. Symptoms of vitamin D toxicity may include dehydration, vomiting, decreased appetite, irritability, constipation, fatigue, muscle weakness and metastatic calcification of the soft tissues and tend to appear several months after excessive intake of vitamin D. Treatment includes a low- calcium diet along with corticosteroid drugs and a full recovery may be expected within a month [7].

Other Functions

Research has shown that vitamin D receptor (VDR) is found throughout the central nervous system including the hippocampus region of the brain responsible for both memory and emotion. Vitamin D is responsible for the regulation of enzymes located in the brain and cerebrospinal fluid which aid in nerve growth, neurotransmitter production and synaptic density of neurons. It also protects nervous tissue from oxidative stress, controls the immune system response and is involved in the homeostatic processes of intracellular calcium and phosphorus levels. Vitamin D deficiency, especially during neonatal development, is believed to increase the risk of schizophrenia, multiple sclerosis and other diseases of the central nervous system [11].

Another important organ for significant role of vitamin D is the immune system. Vitamin D deficiency affects the immune system, especially T cell-mediated immunity, whereas vitamin D, in excess, actually suppresses certain aspects of the immune system [12]. Besides this, serum vitamin D levels have been correlated to muscle cell contractility and muscle strength. Low serum levels have been related to proximal muscle weakness, gait disturbance, paresthesia and discomfort within the muscles. The expression of VDR and its interaction at the molecular level with proteins that are involved in inflammation, signaling and ultimately contractile function of both skeletal and cardiac muscle is of utmost significance [13].

Vitamin D and Chronic Diseases

Rickets and osteomalacia are the classical vitamin D deficiency diseases but as the vitamin D has been shown to perform a wide spectrum of functions, its deficiency is bound to be associated with other diseases also.

Here is a brief account of different chronic diseases associated with inadequate vitamin D levels in the body:

Various Mechanisms for Role of Vitamin D in Cancer

A number of mechanisms have been put forward to explain the anti-cancer actions of vitamin D [17].

Role in Treatment and Outcome of Cancer

Vitamin D status may have a significant bearing on cancer outcome also as higher mortality in patients with colorectal carcinoma was found to be associated with groups having lower vitamin D levels. Chemotherapy for colorectal rectal carcinoma has also been reported to induce a state of vitamin D insufficiency or deficiency [24]. Similarly, increased radiosensitization has been reported in prostate carcinoma cells with vitamin D/ vitamin D analogue supplementation. 1α,25(OH)2D3 has been reported to be effective against adverse effects associated with radiotherapy as vitamin D deficiency has been found associated with increased severity of radiation-induced acute proctitis in cancer patients [25]. Thus, vitamin D plays a quite significant role at every stage of cancer as well as during treatment.

Immunity/Response to Infection

Response to infection is not found to be appropriate with suboptimal vitamin D status. Earlier when rickets was quite prevalent, children with this disorder were frequently found to die of respiratory infections. Vitamin D, in its autocrine role, has been reported to play an important role in various aspects of the immune response. Macrophages exert better phagocytic activity in individuals who received vitamin D supplementation [26].

1α, 25-dihydroxycholecalciferol or calcitriol has been identified as a potent modulator of macrophage functions as well as that of B- and T-lymphocyte mediated immune responses. Macrophages not only express VDR, but are also endowed with CYP27B1 activity. But under conditions of insufficient serum 25-hydroxy vitamin D3 levels, only limited amount of calcitriol can be produced by macrophages. The resulting impairment of macrophage activation and function might explain the high prevalence of infectious diseases in children with rickets [27].

Diabetes

Vitamin D deficiency is found associated with both type 1 and type 2 diabetes mellitus. Vitamin D possesses immunomodulatory properties also. The autoimmune nature of type 1 DM has been declared with the detection of auto-antibodies against islet β-cells and their infiltration by T cells, B cells and macrophages. A relationship between sunlight exposure and the incidence of type 1 DM has been reported by some authors [1, 5]. Substantial evidence is there to suggest that vitamin D deficiency in early life accelerates the appearance of autoimmune diabetes mellitus and that vitamin D supplementation can prevent the development of the disease. It has been known for a long time that 1α, 25- dihydroxycholecalciferol is a positive regulator of insulin secretion by pancreatic β cells. These cells are endowed with CYP27B1 activity and thus, low 25-hydroxy vitamin D levels are associated with impaired β -cell function [28].

Vitamin D receptors in pancreatic β-cells play an important role in the progression of type 2 DM. Vitamin D deficiency is related to insufficient insulin secretion, insulin resistance and β-cell dysfunction in the pancreas [29].

Hypertension and Cardiovascular Disease (CVD)

There is a strong association between vitamin D deficiency and hypertension. Vitamin D causes direct suppression of the renin–angiotensin system by acting as a negative endocrine regulator of renin gene expression in vivo. It decreases intimal thickening of blood vessels by inhibiting the accumulation of extracellular matrix within the inner vessel wall through its inhibitory effect on matrix metalloproteinases. In addition, vitamin D decreases arterial stiffness by causing upregulation of nitric oxide synthesis in endothelium. Thus, vitamin D helps in preventing hypertension as well as cardiovascular diseases [30]. Interestingly, vitamin D receptor has been identified on the surface of smooth muscle cells, endothelial cells, myocardial cells, inflammatory cells and in platelets, thus, potentially influencing thrombosis. An independent relationship has been observed between vitamin D deficiency and cardiovascular risk factors like hypertension, diabetes mellitus, obesity, metabolic syndrome, subclinical atherosclerosis and coronary calcification. An association of vitamin D deficiency has been found with cardiovascular events such as myocardial infarction, congestive heart failure and sudden cardiac death [31].

Autoimmune Disorders

Vitamin D deficiency has been found to be associated with autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) and multiple sclerosis (MS) while vitamin D supplementation prevents the onset and/or development of these diseases [4]. Insufficient vitamin D levels have been observed in patients with Hashimoto’s

thyroiditis, an autoimmune thyroid disease. It is interesting to note that both vitamin D and thyroid hormone bind to similar receptors called steroid hormone receptors. A mutant gene in the vitamin D receptor was shown to predispose people to autoimmune thyroid disease including Graves’ disease and Hashimoto’s thyroiditis [32].

Future Perspectives

It can conveniently be claimed that this article is able to achieve only the tip of the iceberg. There is a possibility for the diseases discussed above that vitamin D deficiency rather than being directly causal, may act by interfering the ability of the tissues concerned to deal adequately with both physiologic stimuli and pathologic signals. The actual etiopathogenesis of these chronic diseases, which are multifactorial in nature, cannot be elucidated until the widespread problem of vitamin D deficiency has been corrected. For many of the diseases, clinical features might be representative of insufficient vitamin D status as well as the actual disorder. To be able to deal with this question should be the aim of the future research in this direction.

Therefore, with the potential to play diverse role in so many major clinical disorders, it is just appropriate to term vitamin D a new biomarker.