INTRODUCTION:

Vitamin D, the sunshine vitamin, as the major source it is obtained from Sunlight. Though it can also be acquired orally all the way through food and supplements. Vitamin D requires hepatic metabolism to produce 25-hydroxyvitamin D (25 (OH)D) which is the recognized dietary biomarker for vitamin D status [1,2]. Almost in the past two decades, significant progress has been made in the study of vitamin D. Primarily, the essential role of vitamin D is in the development of skeletal integrity, but current factsare escalating that vitamin D generates favorable effects on extra-skeletal tissues and that the amounts needed for optimal well-being are possibly advanced than formerly thought [3].

In combination with parathyroid hormone (PTH), vitamin D is accountable for the control of calcium and phosphate homeostasis.

Vitamin D deficiency leads to calcium deficit, myopathy, and osteomalacia in adults and rickets in children. Increasing evidence also indicates that vitamin D controls the secretion of parathyroid hormone, plays a role in the Renin Angiotensin Aldosterone System (RAAS), regulates the immune system, and may directly affect cardiac muscle [4]. Consequently, vitamin D has an immense effect on forming and preserving sturdy bones. Moreover, recently it has been found that vitamin D receptors be present at various range of cells and as a result, it has a biological outcome on more than only mineral metabolism. The aim of this information is to assess key feature relating to vitamin D deficiency, its causes, and its influences on major conditions/diseases. Thus, following a general literature review on deficiency and its causes, an overview of persistent alarming on ailments due to vitamin D deficit. This methodical approach encloses of reviews listed in Pubmed during the precedent 2 decades.

VITAMIN D –BIOSYNTHESIS:

The two prime biologically inert precursors of fat-soluble vitamin D are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol), the former is present in human form and the latter is present in plants and invertebrates. Primarily vitamin D is synthesized internally in the skin as vitamin D3 (cholecalciferol) when exposed to ultraviolet B (UVB-270-300nm) radiation in sunlight, but little amounts can also be acquired from animal foods such as oily fish, egg and meat (Table-1). Vitamin D3, that moves in the body attaches to vitamin D binding protein and is quickly transformed into its major circulating form, 25-hydroxyvitamin D (25 (OH)D), by the liver. This 25 (OH)D, along with the persuade of parathormone, mostly converted to the active form 1,25 DHCC by the help of an enzyme 1-alpha-hydroxylase in the kidney. A negligible amount of 25 (OH)D is also converted into 24,25 DHCC [5].Though several additional tissues in the body can convert 25(OH)D to 1,25 DHCC, only the renal conversion appreciably contributes to the circulating 1,25 DHCC levels [6]. The synthesis and regulation of vitamin D is clearly described in the Figure:1

The active form i.e., 1,25 DHCC is responsible for many of its biologic role in multiple tissues, including effects on hormone secretion, regulation of immune responses, and modulation of cellular proliferation and differentiation, by controlling gene transcription through the vitamin D receptor (VDR). Serum calcium, phosphorus, and parathyroid hormone (PTH) regulate the circulating levels of 1,25 (OH)₂D by which makes the hormone an inadequate indicator of vitamin D status. Instead, the status is best reflected by the serum 25 (OH)D concentration, which represents the combined amounts of synthesized and dietary vitamin D [7,8].

Table 1: ⁽¹⁰⁾

NATURAL SOURCES	VITAMIN D CONTENT
Exposure to sunlight UVB (5 to 10 minutes of exposure)	3000 IU of vitamin D3
Salmon, fresh, wild (3.5 oz)	600-1000 IU of vitamin D3
Salmon, fresh, farmed (3.5 oz)	100-250 IU of vitamin D3 or D2
Salmon, canned (3.5 oz)	300-600 IU of vitamin D3
Tuna, canned (3.6 oz)	230 IU of vitamin D3
Cod liver oil (1 tsp)	400-1000 IU of vitamin D3
Mushrooms, fresh (3.5 oz)	100 IU of vitamin D2
Egg yolk	20 IU of vitamin D3 or D2

*IU- International unit (1 IU OF VITAMIN D =25 ng)

HYPOVITAMINOSIS D:

The status of Vitamin D has been evaluated by determining the serum DHCC (1,25 dihydroxychole calciferol) levels; While there is no agreement in the finest levels of serum DHCC as it varies with countries, but it is defined by Current International Osteoporosis Foundation guidelines (Table: 1) as vitamin D insufficiency as 1,25 DHCC levels less than 50 nmol/L (20 ng/mL) and deficiency as levels less than 25 nmol/L (10 ng/mL)⁹.

Figure 1: Synthesis and regulation of Vitamin D

Global Status of Vitamin D	Serum 1,25 (DHCC Levels)		Clinical Manifestations
Global Status of Vitamin D	ng/mL	nmol/L	Clinical Manifestations
Deficiency	≤ 10	≤ 25	Hyperparathyroidism, Rickets, Osteomalacia
Insufficiency	10-20	25-50	high PTH levels, decreased bone mineral density
Hypovitaminosis D	20-28	≥ 50 -70	Less stores of vitamin D, slightly elevated PTH levels
Sufficiency	28-40	70-100	No clinical symptoms

*To convert values for 25-hydroxyvitamin D to ng/ml, divide by 2.50.

The different causes of vitamin D deficiency can be categorized into two wide groups [10]. The primary group comprises of people due to deficient exposure to ultraviolet radiation, there occurs a scarce conversion of inactive vitamin D to DHCC. This is usually seen in the darker skin public, aged persons, less mobilized groups, those working in the organization and extreme consumer of sunscreen [11-13]. The Risk Factors for vitamin D Deficiency are mentioned in the table:2 [14]. The subsequent group embraces the various therapeutic and physical conditions that can direct to vitamin D deficiency [15-19].

Risk Factors for Vitamin D Deficiency

Aged population

Institutionalized or home-bound

Sunscreen usage

Dark pigmentation

Air Pollution

Higher Latitudes

Smoking

Adiposity

Malabsorption syndromes such as celiac disease, Crohn's disease, lactose intolerance, and intestinal damage

Hepatic or Kidney Failure

Anti-Seiziures or Anti-Viral medications

Several studies have reported opposite interaction among serum 25- (OH) D levels and the risk for a broad variety of conditions, including vascular disease [20], autoimmune disorder [21], type 2 diabetes mellitus [22], obesity [23], and cognitive impairment [24]. Numerous promising circumstances, including the persuade of confounders, may explain these associations. For example, vitamin D insufficiency may only act as a replacement indicator for an ill-health status as it reveals an inability to get outdoors for ultraviolet B exposure due to amplified body mass index, manifold co-morbid surroundings, or reduced exercise tolerance. [25]

LINKED TO CARDIOMETABOLIC: CONSEQUENCES:

Vitamin D Deficiency is associated with the advancement of many cardio-metabolic disorders such as hypertension, coronary artery disease (CAD) and diabetes. A rat model of vitamin D deficiency was initially accomplished to prove the association between cardiovascular homeostasis and vitamin D status. This study also established that any deficiency in vitamin D3 can cause intense variation in cardiovascular function, as well as producing the discriminating contractile effect of both cardiac and vascular smooth muscle, indicating that the normal cardiovascular function is well maintained by this vitamin [26]. Though numerous small studies perhaps didnot recognize an efficient role for vitamin D insufficiency in the pathophysiology of hypertension [27, 28], big studies such as the cross-sectional and the cohort and Health Study established a reverse association between serum levels of 25 (OH)D levels and blood pressure [29,30]. The General mechanism for Vitamin D Deficiency provoked cardiac damage has been reviewed in Figure 2

Fig 2: Hypovitaminosis D and CVD Risk

People residing at higher latitudes are at increased risk of hypertension and cardiovascular disease. Moreover, hypertension is also less frequent or less rigorous at elevated altitudes [31]. Frequency rates of vitamin D deficiency and cardiovascular disease amplify with distance from the equator, with elevated rates of ischemic heart disease prominent in nations with lower levels of ultraviolet B exposure [32]. Epidemiologic reviews [33,34] have described an inclination towards the higher occurrence of ischemic heart disease and hypertension with rising distance from the equator, and these higher rates are ascribed to the elevated rates of vitamin D insufficiency in places with less exposure to sunlight. Prior studies [35,36] have established relation exist between low vitamin D levels and augmented plasma renin activity, coronary artery calcification, blood pressure, and cardiovascular disease.

HYPOVITAMINOSIS D AND: ATHEROSCLEROSIS:

An inverse relationship exists between 25- (OH)D levels and subclinical atherosclerosis has been revealed, as calculated by the carotid thickness and computed tomography [37-39]. A survey from National Health and Nutrition Examination Survey (NHANES) [40] observed the relationship between vitamin D and atherosclerosis and described that Hypovitaminosis D was related to higher levels of peripheral arterial disorder. Low serum 25-(OH)D levels are also associated with reduced levels of HDL [41].

HYPOVITAMINOSIS D AND HYPERTENSION:

Numerous research studies [42, 43] have recommended that relationship exists between low 25-(OH)D levels and an advanced risk for hypertension. The proposed mechanism for the link between vitamin D and high blood pressure involves in the inhibition of the Renin AngiotensinAldosterone System by vitamin D. These data are mainly derived from in vitro and animal studies [44, 45]. Earlier studies have revealed an involvement of parathyroid hormone and hypertension. The pathogenesis for such link cannot be clearly emphasized, but current reports [46] propose that parathyroid hormone may augment arterial stiffness and stimulate atherosclerotic transformation by performing in the endothelial smooth-muscle cells.

HYPOVITAMINOSIS D AND HEART FAILURE:

The certainty that the deficiency of vitamin D stimulates the activation of the Renin Angiotensin Aldosterone System (RAAS) and the immune system led to the comprehension that this deficit can cause harmful effects in patients with heart failure. Research executed on patients with decompensated and compensated heart failure and the performance of systolic heart failure patients on the walk test about 6 minutes showed a constructive correlation between vitamin D deficiency and heart failure [47, 48]. To sum up, from the various studies the fact suggests that subjects with heart failure have reduced serum vitamin D levels.

HYPOVITAMINOSIS D AND CVD RISK:

Consequently, vitamin D deficiency was caught up in numerous types of vascular disease with myocardial infarction (MI), coronary heart disease (CHD), and Ischemic stroke. In an investigational study, about 454 men with cardiovascular disease were reported to have significantly lower levels of 25 (OH)D when compared with 900 matched controls without cardiovascular disease; even after the modification of other risk factors including family history, diabetes, hypertension, race/ethnicity, body mass index, and others, this deficit remained significant [49]. In yet another cross-sectional study it was found that patients with levels below 20 ng/mL had a higher prevalence of cardiovascular disease by measuring serum 25 (OH)D concentrations at a single outpatient visit of more than 400 diabetic patients [50]. A similar study, with 1739 subjects were assessed prospectively and established that vitamin D concentration below 15 ng/mL was found to be constantly linked with an augmented risk of cardiovascular events [51]. Thus, it can be securely mentioned that vitamin D deficiency acts as an independent risk factor for several cardiovascular diseases including MI and CHD.

HYPOVITAMINOSIS D AND DIABETES:

A study by Bayani et.al., [52] where about 120 DM patients selected as a study group and 120 healthy individuals as control group, wherein the results of the study showed that vitamin D concentration was significantly lower in diabetic patients than the healthy individuals. Therefore it was found that vitamin D deficiency has been found to have an inverse relationship with the occurrence of type-2 diabetes mellitus (DM).

In a study in Saudi Arabia, in a total of 340 patients, vitamin D deficiency has been concerned in reduced insulin secretion and augmented insulin resistance, and further currently with development of type 2 diabetes mellitus [53].

Another study suggested an inverse connection amid vitamin D status and A1C levels in the U.S. adult residents about 35–74 years of age and subjects who do not report a history of diabetes. This suggests a mechanistic connection between serum vitamin D concentrations and glucose homeostasis. [54].

Numerous reports suggest that there showed a reduced risk of a type of Diabetes-I on vitamin D supplementation. Even on increasing vitamin D intake during pregnancy lowers the expansion of islet autoantibodies in the progeny [55].

A study by Hypponen et.al. [56], children in Finland were given 2000 IU of vitamin D3 per day during their first year of life and were subsequently given for 31 years, however, it reduced the risk of type 1 diabetes by roughly about 80%. This proved the fact that the adequate vitamin D supplementation for neonates could help to oppose the rising trend in the occurrence of type 1 diabetes.

HYPOVITAMINOSIS D AND METABOLIC SYNDROME:

Current epidemiologic findings suggest that an increased risk of metabolic syndrome is observed in low serum 25-hydroxyvitamin D, an estimate of vitamin D status. A study by Ford, et.al. [57], suggested that the metabolic syndrome was found around 1 in 5 adults. Those patients with metabolic syndrome carried an average of 67.1 nmol/L of 25-hydroxyvitamin D levels which was considerably lower than that in subjects without metabolic syndrome, who had a mean concentration of 75.9 nmol/L.

An article [58] mentioning a study which included a group of healthy (n=126), glucose-tolerant subjects was the first to demonstrate the positive correlation between 25(OH) D concentration with insulin sensitivity index using a hyperglycemic clamp technique. The unpretentious result of vitamin D on insulin sensitivity in individual persons may interpret into a striking effect because of the towering frequency of hypovitaminosis D, which, in a large population, brings a characteristic risk for type 2 diabetes and the metabolic syndrome.

In yet another study by StefaniaMakario et.al [59], patients with metabolic syndrome have lesser 25(OH)Vit D levels compared with non-metabolic syndrome patients. Significantly, it was reported an inverse relationship between 25 (OH) Vit D serum levels and sdLDL-C (small dense), that could be possible through increased triglyceride levels.

In recent times, the importance of vitamin D status as a risk factor in the advancement of metabolic syndrome has been the focal point of numerous studies [60].

HYPOVITAMINOSIS D AND CANCER:

People living at higher latitudes is at increased risk for different types of cancer. A prospective study of vitamin D ingestion and the threat of colorectal cancer in 1954 men showed a direct relationship [1]. A study by Suda et.al [61] showed that leukemic mouse survived longer with the treatment of vitamin D analogues. However, in the human trials, the results are still disappointing. Some in-vitro studies have shown that the anti-proliferative effect of the vitamin D in the form of 1,25 (OH)₂ D exhibited a better response on breast, prostate, and colon cancer cells, osteosarcomas, and melanomas. Numerous epidemiological reports have shown that elevated 25 (OH)D levels are connected with decreased cancer occurrence and reduced cancer-related mortality. (62-67) Addition to this information, there are numerous retrospective and prospective research showed that when serum 25 (OH) D levels are greater than 20 ng/mL (50 nmol/L) have reported decreasing 50% or greater in risk of large bowel cancer and prostate cancer.[63,66,68-72]. Related results have been analyzed for breast cancer. In a study, where women with elevated concentration of 1,25 (OH)₂ D had only one-fifth risk of acquiring breast cancer than those subjects without it [73]. Tuohimaa et al. [74]carried out longitudinal case-control study occurrence of prostate cancer in Scandinavian countries along with vitamin D status.

VITAMIN D AND MULTIPLE SCLEROSIS:

As with preceding epidemiological fact reporting a latitudinal risk inclined for cancer and cardiovascular disease a similar risk exists for developing multiple sclerosis. Patients who stayed below 35°N latitude during their first decade had reduced overall lifetime risks of developing multiple sclerosis [1,75,76]. A double-blinded randomized control trials illustrated that subjects who were given vitamin D supplementation had improved serum transforming growth factor β1 levels than those subjects who did not receive supplementation [77]. Similar two observational studies observed from Nurses' Health Study (I and II) stated that increased intake of vitamin D was associated with a lower risk of developing multiple sclerosis [78].

VITAMIN D AND PSORIASIS:

The huge achievement of vitamin D remedy for treating an extra-skeletal disease is in the management of psoriasis.The proliferation of Human keratinocytes is inhibited by 1,25 (OH)₂D₃ reported in a study by Smith et.al., [79]. Therefore, the recommended therapy for increased proliferative skin diseases such as psoriasis is proved to be 1,25 (OH)₂D₃. Even the vitamin D topical treatments exhibited a great development in decreasing the lesions and wounds. Vitamin D analogues comprising calcipotriene, are the first-line therapy used for psoriasis. [80-83].

HYPOVITAMINOSIS D AND INFLAMMATORY BOWEL DISEASE:

The two clinically distinct forms of inflammatory bowel disease (IBD), includes Crohn’s disease and ulcerative colitis (UC), wherein reports suggested that there is a number of environmental factors to the pathogenesis of IBD, mainly of UC [84]. Vitamin D deficiency might be one of those factors [85,86] and as a consequence of hypovitaminosis D, reduced local production of 1,25-(OH)₂D₃ causes inhibition of enhanced T helper cell reaction, which are characteristically connected with chronic enterocolitis [87]. The significance of the vitamin D for the continuance of normal immune responses in the gut is emphasized by the current observation that a deficit of expression of the vitamin D receptor intensifies the symptoms in colitis models [88]. A study by Cantorna et al. [89] exhibited that the active metabolite of vitamin D₃ inhibits the symptoms of IBD in an experimental mouse model.

HYPOVITAMINOSIS D AND RHEUMATOID ARTHRITIS:

A prospective cohort study by Linda A et.al. showed that an inverse association exists between vitamin D and RA risk. This report also stated that vitamin D deficit may be involved in the pathogenesis of rheumatoid arthritis. There are considerable facts from reports with animal models of rheumatoid arthritis that the advantageous consequence of vitamin D on the development of the disease results from its specific immunomodulatory effects. [90]

HYPOVITAMINOSIS D AND SKELETAL DISORDER:

Undoubtedly there is no requirement to highlight the significant role of vitamin D in the prevention of bone disorders such as rickets and osteomalacia. The stimulatory effect of 1,25-(OH) 2D3 has been recognized mostly for the effect of absorption of calcium and phosphate in the intestine. As realistically shown by Owen et al. [91], the fat hormone synchronizes the progression of osteoblast growth by specific VDR-mediated effects on the gene expression and helps in the production of several osteoblast proteins. The inadequacy of vitamin D status therefore not only causes rickets and osteomalacia but is also a significant risk factor for osteoporosis, which is usually caused by an inadequate rate of bone development. Furthermore, hypovitaminosis D could be connected with osteoporosis since, a decrease in serum 25-(OH) D levels augments secondary hyperparathyroidism and, accordingly, elevates osteoclastic bone resorption. [92,93]

CONCLUSION:

Hypovitaminosis D is a universal problem, as measured by 25-hydroxyvitamin D, which is referred as the biomarker for vitamin D status. Risk factors for hypovitaminosis D comprise of deficit exposure to adequate sunlight, inadequate nutritional intake and supplementation, and other causes, including adiposity, age, drug use, sunscreen use, clothing, and pigmentation of the skin. As most of the cell express vitamin D receptors, the functions of different organs are affected by changes in the activity of 25-(OH)D-1α-hydroxylase. Henceforth we put forward that this kind of changes is likely to occur under the conditions of hypovitaminosis D. Thereby we provide an elucidation on a molecular level from many epidemiological reports that important relationship exists between hypovitaminosis D and the pathogenesis of frequent chronic diseases. We hope that this assumption will further stimulate the discussion on the importance of vitamin D replacement or still supplementation, for preventive and clinical medicine, as this review gives a more insight into the pathogenic consequences of the deficit vitamin D condition.

REFERENCES:

1 M. F. Holick, “Medical progress: vitamin D deficiency,” The New England Journal of Medicine, 2007; vol. 357 (3): pp. 266–281.

2 Holick, M.F. Vitamin D status: Measurement, interpretation, and clinical application. Ann. Epidemiol. 2009;19:73–78.

3 Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J ClinNutr. 2004;80 (6):1678S-1688S.

4 Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol. 2009;6:621-630.

5 D. D. Bikle, “Vitamin D: newly discovered actions require reconsideration of physiologic requirements,” Trends in Endocrinology and Metabolism, 2010;21 (6):375–384.

6 Armin Zittermann. Vitamin D and disease prevention with special reference to cardiovascular disease. Progress in Biophysics and Molecular Biology 2006;92:39–48.

7 Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest 2006; 116:2062-2072.

8 Bouillon R. Vitamin D: from photosynthesis, metabolism, and action to clinical applications. In: DeGroot LJ, Jameson JL, eds. Endocrinology. Philadelphia: W.B. Saunders, 2001:1009-28. 3. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J ClinNutr 2004;80:1689S- 1696S.

9 B. Dawson-Hughes, A. Mithal, J. P. Bonjour et al., “IOF position statement: vitamin D recommendations for older adults,” Osteoporosis International, 2010;21 (7): 1151–1154.

10 R. Zhang and D. P. Naughton, “Vitamin D in health and disease: current perspectives,” Nutrition Journal 2010;9 (1): 65

11 A. G. Need, H. A. Morris, M. Horowitz, and B. E. C. Nordin, “Effects of skin thickness, age, body fat, and sunlight on serum 25-hydroxyvitamin D,” The American Journal of Clinical Nutrition, 1993;58(6):882–885.

12 T. L. Clemens, J. S. Adams, S. L. Henderson, and M. F. Holick, “Increased skin pigment reduces the capacity of skin to synthesisevitamin D₃,” The Lancet. 1982;1 (8263):74–76.

13 L. Y. Matsuoka, L. Ide, J.Wortsman, J. A. MacLaughlin, and M. F. Holick, “Sunscreens suppress cutaneous vitamin D3 synthesis,” Journal of Clinical Endocrinology and Metabolism, 1987;64(6):1165–1168.

14 C. McGreevy and D. Williams, “New insights about vitamin D and cardiovascular disease,” Annals of Internal Medicine, 2011;155:820–826.

15 A. M. Pack and M. J. Morrell, “Epilepsy and bone health in adults,” Epilepsy and Behavior. 2004;5 (2):S24–S29.

16 S.C. Shah, R. K. Sharma, Hemangini, and A. R. Chitle, “Rifampicin induced osteomalacia,” Tubercle,1981;62 (3):207–209.

17 C. J. P. Van Den Bout-Van Den Beukel, L. Fievez, M. Michels et al., “Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy,” AIDS Research and Human Retroviruses. 2008;24 (11):1375– 1382.

18 Y. Liel, E. Ulmer, J. Shary, B. W. Hollis, and N. H. Bell, “Low circulating vitamin D in obesity,” Calcified Tissue International, 1988;43 (4):199–201.

19 L. Hyldstrup, T. Andersen, P. McNair, L. Breum, and I. Transbol, “Bone metabolism in obesity: changes related to severe overweight and dietary weight reduction,” ActaEndocrinologica, 1993;129 (5):393–398.

20 Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D improves endothelial function in patients with type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008;25:320-325.

21 Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J ClinNutr. 2004; 80:1678S-1688S.

22 Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2006;29:722-724.

23 Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bio-availability of vitamin D in obesity. Am J ClinNutr. 2000;72:690-693.

24 Llewellyn DJ, Lang IA, Langa KM, Muniz-Terrera G, Phillips CL, Cherubini A, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med. 2010;170:1135-1141.

25 Grey A, Bolland M. Vitamin D: a place in the sun? [Editorial]. Arch Intern Med. 2010;170:1099-1100.

26 R. E. Weishaar and R. U. Simpson, “Vitamin D3 and cardiovascular function in rats,” The Journal of Clinical Investigation. 1987;79:1706–1712.

27 D. Duprez, M. De Buyzere, T. De Backer, and D. Clement, “Relationship between vitamin D3 and the peripheral circulation in moderate arterial primary hypertension,” Blood Pressure, 1994;3(6):389–393.

28 R. Scragg, I. Holdaway, V. Singh, P. Metcalf, J. Baker, and E. Dryson, “Serum 25-hydroxycholecalciferol concentration in newly detected hypertension,” American Journal of Hypertension. 1995;8 (4):429–432.

29 R. Scragg, M. F. Sowers, and C. Bell, “Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the third national health and nutrition examination survey,” American Journal of Hypertension. 2007;20 (7):713–719.

30 J. P. Forman, E. Giovannucci, M. D. Holmes et al., “Plasma 25- hydroxyvitamin D levels and risk of incident hypertension,” Hypertension. 2007;49 (5):1063–1069.

31 Hultgren HN Reduction of systemic arterial blood pressure at high altitude. AdvCardiol.1970;5:49–55.

32 Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005;94:483-492.

33 Grimes DS, Hindle E, Dyer T. Sunlight, cholesterol and coronary heart disease. QJM. 1996;89:579-589.

34 Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension. 1997;30:150-156.

35 Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J PhysiolEndocrinolMetab. 2005;288:E125-132.

36 Martins D, Wolf M, Pan D, Zadshir A, Tareen N, Thadhani R, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2007;167:1159-1165.

37 Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M, et al. Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. ClinEndocrinol (Oxf). 2006;65:593-597.

38 De Boer IH, Kestenbaum B, Shoben AB, Michos ED, Sarnak MJ, Siscovick DS. 25-hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification. J Am Soc Nephrol. 2009;20:1805-1812.

39 Carrelli AL, Walker MD, Lowe H, McMahon DJ, Rundek T, Sacco RL, et al. Vitamin D deficiency is associated with subclinical carotid atherosclerosis: the Northern Manhattan study. Stroke. 2011;42:2240-2245.

40 Melamed ML, Muntner P, Michos ED, Uribarri J, Weber C, Sharma J, et al. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004. Arterioscler Thromb Vasc Biol. 2008;28:1179-1185.

41 Auwerx J, Bouillon R, Kesteloot H. Relation between 25-hydroxyvitamin D3, apolipoprotein A-I, and high density lipoprotein cholesterol. ArteriosclerThromb. 1992;12:671-674.

42 Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007;49:1063-1069.

43 Burgaz A, Byberg L, Rautiainen S, Orsini N, Håkansson N, Arnlo¨v J, et al. Confirmed hypertension and plasma 25 (OH)D concentrations amongst elderly men. J Intern Med. 2011;269:211-218.

44 Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab. 2005;288:E125-132.

45 Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25 (OH) 2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int. 2008;74:170-179.

46 Fitzpatrick LA, Bilezikian JP, Silverberg SJ. Parathyroid hormone and the cardiovascular system. CurrOsteoporos Rep. 2008;6:77-83.

47 S. P. Laguardia, B. K. Dockery, S. K. Bhattacharya, M. D. Nelson, L. D. Carbone, and K. T. Weber, “Secondary hyperparathyroidism and hypovitaminosis D in African-Americans with decompensated heart failure,” American Journal of the Medical Sciences. 2006;332 (3):112–118.

48 A. Zittermann, S. S. Schleithoff, G. Tenderich, H. K. Berthold, R. Korfer, and P. Stehle, “Low vitamin D status: a contributing ¨ factor in the pathogenesis of congestive heart failure?” Journal of the American College of Cardiology. 2003;41 (1):105–112.

49 E. Giovannucci, Y. Liu, B. W. Hollis, and E. B. Rimm, “25- Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study,” Archives of Internal Medicine, 2008;168 (11):1174–1180.

50 M. Cigolini, M. P. Iagulli, V. Miconi, M. Galiotto, S. Lombardi, and G. Targher, “Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients,” Diabetes Care. 2006;29(3):722–724.

51 T. J. Wang, M. J. Pencina, S. L. Booth et al., “Vitamin D deficiency and risk of cardiovascular disease,” Circulation. 2008;117 (4):503–511.

52 Bayani MA, Banasaz B, Saeedi F. Status of Vitamin-D in diabetic patients and compared it with healthy individuals. Caspian J Intern Med. 2014; 5 (1): 40-42.

53 Mohammed Alhumaidi, Adnan Agha, and Mohamed Dewish.Vitamin D Deficiency in Patients with Type-2 Diabetes Mellitus in Southern Region of Saudi Arabia. Maedica (Buchar). 2013;8 (3):231–236.

54 Kositsawat J, Freeman V, Gebber B, Geraci S. Association of A1c levels with vitamin D status in U.S.Adults. Diabetes Care. 2010;33:1236–1238.

55 Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and β cell dysfunction. Am J ClinNutr2004;79:820-825.

56 Hypponen E, Laara E, Reunanen A, Jarvelin M-R, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500-1503.

57 Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care. 2005;28:1228–1230.

58 Chiu, K. C., et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J ClinNutr2004;79 (5):820-825.

59 Stefania Makariou, EvangelosLiberopoulos, Matilda Florentin, Konstantinos Lagos, Irene Gazi, Anna Challa, Moses Elisaf. The relationship of vitamin D with non-traditional risk factors for cardiovascular disease in subjects with metabolic syndrome. Arch Med Sci. 2012;3:437-443.

60 Martini, L. A., and R. J. Wood Vitamin D status and the metabolic syndrome. Nutr Rev. 2006;64(11):479-486.

61 Suda T, Abe E, Miyaura C, et al. Induction of differentiation of human myeloid leukemia cells by 1α,25-dihydroxyvitamin D3 . In: Norman AW, Schaefer K, Herrath DV, Grigdeit HG, eds. Vitamin D, Chemical, Biochemical, and Clinical Endocrinology of Calcium Metabolism: Proceedings of the Fifth Workshop on Vitamin D, Williamsburg, VA, USA, February 1982;59–64.

62 Zhao XY, Feldman D. The role of vitamin D in prostate cancer. Steroids. 2001;66:293-300.

63 Polek TC, Weigel NL. Vitamin D and prostate cancer. J Androl. 2002;23:9-17

64 Holick MF. Vitamin D: a millenium perspective. J Cell Biochem. 2003;88:296-307.

65 DeLuca H. Overview of general physiologic features and functions of vitamin D. Am J ClinNutr. 2004;80 (6):1689S-1696S.

66 Chen TC, Holick MF. Vitamin D and prostate cancer prevention and treatment. Trends EndocrinolMetab. 2003;14:423-430.

67 John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk: the NHANES I epidemiologic follow-up study, 1971-1975 to 1992: National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev. 1999;8:399-406.

68 Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health: a review. Altern Med Rev. 2005;10:94-111.

69 Tangrea J, Helzlsouer K, Pietinen P, et al. Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control. 1997;8:615-625.

70 Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control. 2000;11:847-852.

71 Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet. 1985;1:307-309.

72 Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet. 1989;2:1176-1178.

73 Janowsky EC, Lester GE, Weinberg CR, et al. Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk. Public Health Nutr. 1999;2:283-291.

74 Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer 2004;108:104–108.

75 Ponsonby AL, McMichael A, van der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology. 2002;181-182:71-78.

76 Embry AF, Snowdon LR, Vieth R. Vitamin D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis [letter]. Ann Neurol. 2000;48:271-272.

77 Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT. Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J Neuroimmunol. 2003;134:128-132.

78 Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62:60-65.

79 Smith EL, Walworth NC, Holick MF. Effect of 1α,25- dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. J Invest Dermatol. 1986;86:709-714.

80 Smith EL, Pincus SH, Donovan L, Holick MF. A novel approach for the evaluation and treatment of psoriasis: oral or topical use of 1,25-dihydroxyvitamin D3 can be a safe and effective therapy for psoriasis. J Am AcadDermatol. 1988;19:516-528.

81 Holick MF. Clinical efficacy of 1,25-dihydroxyvitamin D3 and its analogues in the treatment of psoriasis. Retinoids1998;14:12-17.

82 Guenther L, Cambazard F, Van De Kerkhof PCM, et al. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol. 2002;147:316-323

83 Perez A, Chen TC, Turner A, et al. Efficacy and safety of topical calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis. Br J Dermatol. 1996;134:238-246.

84 Farrell RJ, Peppercorn MA. Ulcerative colitis. Lancet 2002;359:331–40.

85 Sonnenberg A, McCarty DJ, Jacobsen SJ. Geographic variation of inflammatory bowel disease within the United States. Gastroenterology 1991;100:143–9.

86 Podolsky DK. Inflammatory bowel disease. N Engl J Med 1991;325:928–1016.

87 Targan SR, Murphy LK. Clarifying the causes of Crohn’s. Nat Med 1995;1:1241–1243.

88 Froicu M, Weaver V, Wynn TA, McDowell MA, Welsh JE, Cantorna MT. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. MolEndocrinol 2003;17:2386–2392.

89 Cantorna MT, Munsick C, Bemiss C, Mahon BD. 1,25- Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J Nutr2000;130:2648–2652.

90 Merlino L, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis. Results from the Iowa Women’s Health Study. Arthr Rheumat 2004;50:72–77.

91 Colston KW, Hansen CM. Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. EndocrRelat Cancer 2002;9:45–59.

92 Dawson-Hughes B, Harris SS, Dallal GE. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J ClinNutr 1997;65:67–71.

93 Pasco JA, Henry MJ, Kotowicz MA, Sanders KM, Seeman E, Pasco JR et al. Seasonal periodicity of serum vitamin D and parathyroid hormone, bone resorption, and fractures: the Geelong Osteoporosis Study. J Bone Miner Res 2004;19:752–758.

Received on 22.12.2017 Modified on 27.01.2018

Research J. Pharm. and Tech 2018; 11(6): 2659-2666.

DOI: 10.5958/0974-360X.2018.00493.6