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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 5  |  Issue : 1  |  Page : 30-37

The sunshine of life: Vitamin D


Department of Oral Medicine and Radiology, Bapuji Dental College and Hospital, Davangere, Karnataka, India

Date of Web Publication7-Dec-2015

Correspondence Address:
Kanad Chaudhuri
Department of Oral Medicine and Radiology, Bapuji Dental College and Hospital, Davangere - 577 004, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-6027.171171

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  Abstract 

"Life has a way of shining on people who stand in the sunshine of kind actions"–Bryant Mcgill. Sun does not shine for few but for the wide world's joy and health. It is true in the sense of Vitamin D, an essential element, an elixir of sunshine. The aim of this report is to review key aspects relating to Vitamin D functions, its importance in preventing systemic diseases, and deficiency manifestations and its management.

Keywords: Calcium, osteomalacia, rickets, Vitamin D


How to cite this article:
Chaudhuri K, Ashok L, Sujatha G P. The sunshine of life: Vitamin D. Int J Oral Health Sci 2015;5:30-7

How to cite this URL:
Chaudhuri K, Ashok L, Sujatha G P. The sunshine of life: Vitamin D. Int J Oral Health Sci [serial online] 2015 [cited 2019 Nov 20];5:30-7. Available from: http://www.ijohsjournal.org/text.asp?2015/5/1/30/171171


  Introduction Top


Vitamin D is a chemically a secostroid, fat-soluble prohormone, found in cod liver oil which was identified after Vitamins A, B, and C. Humans obtain Vitamin D through dietary intake and exposure to sunlight.[1] Vitamin D occurs in two forms namely Vitamin D2 (ergocalciferol) and D3 (cholecalciferol).[1],[2],[3],[4] Vitamin D plays an important role in calcium homeostasis and also found to have effect on wide range of biological system.[1],[2],[3],[4],[5],[6],[7] Without Vitamin D, only 10–15% of dietary calcium and about 60% of phosphorus are absorbed.[1] Recent literature has linked Vitamin D deficiency as a significant risk factor for osteoporosis, diabetes, cancer, ischemic heart disease, and autoimmune and infectious diseases.[1],[6],[7],[8]

The earliest cave paintings indicate that humans appreciated not only the warmth but also the life-giving properties of the sun. The first evidence of the importance of sunlight for human health began with the industrial revolution in Northern Europe in the 15th century. People began congregating in cities and living in dwellings that were built in close proximity to each other. The burning of coal and wood polluted the atmosphere and, as a result, children living in these industrialized cities had little direct exposure to sunlight.[4] Glissen, DeBoot, and Whistler recognized that children living in the inner cities throughout Europe demonstrated growth retardation and developed skeletal deformities, including bony projections along the rib cage (rachitic rosary) and either bowed legs or knocked knees; they called this disease, rickets.[1],[3],[4]

By 1900, the disease was so common and devastating that it was estimated that >90% of children in Leiden, the Netherlands, and 80% of children in Boston suffered from rickets. In 1822, Sniadecki published his clinical observations and hypothesized that it was lack of adequate sun exposure that was most responsible for the development of rickets among children.[2],[3],[4] In 1890, Palm [4] concluded that sunbathing could prevent rickets and that some type of sunshine recorder should be developed to measure the bone-healing properties of the sun.

Hess and Unger observed children in New York City, who were exposed to sunlight on the roof of the hospital for a period of several months were free from the symptoms of rickets. This led Steenbock [4] to introduce the concept of irradiating foods with ultraviolet (UV) radiation for the treatment and prevention of rickets. This led to the fortification of milk with synthetically produced Vitamin D, which essentially eradicated rickets in countries that adopted this practice. In the 1930s, Vitamin D was the new miracle vitamin, and many products were fortified with Vitamin D2 including peanut butter, hot dogs, soda pop, and bread. Europe also fortified dairy products with Vitamin D.[1],[2],[3],[4],[5],[6],[7]

Sources of Vitamin D

Vitamin D is obtained by cutaneous production and from foods or dietary supplements containing either Vitamin D2 or D3. Vitamin D3 is the only form produced cutaneously. Vitamin D2 is formed in plants by UV-B exposure of the plant steroid, ergosterol. A metabolite of Vitamin D, 25-hydroxyvitamin D, is present in animal products.[1],[2],[3],[4],[5],[6],[7]

Cod liver oil and oily fish such as salmon, mackerel, and sardines are good sources. Eating oily fish at least 3–4 times/week will help to satisfy the requirement for adequate intake (AI). Some foods such as milk (100 IU/8 oz), orange juice (100 IU/8 oz), and some cereals and bread are fortified with Vitamin D.[7],[8],[9]

Dietary reference intake for Vitamin D

The 1997 Dietary Reference Intake (DRI) Committee identified AI of 5 µg (200 IU)/d for children more than 6 months onward up to 50 years. For pregnant and lactating women and adults from 51 to 70 years of age, 10 µg (400 IU)/day was established. The corresponding value for adults >70 years of age was 15 µg (600 IU)/day. The AI value was used instead of the more familiar recommended dietary allowance, derived from the estimated average requirement, because of uncertainties in sun exposure and body stores of the study participants and potential errors in food composition values.[9]

In 2010, the new DRI Committee on calcium and Vitamin D established a tolerable upper intake level (UL) for calcium of 2500 mg/day for children and for adults up to age 70, but a lower UL of 2000 mg/day for men and women over the age of 70. An upper level of 4000 IU was set for Vitamin D for children and adults in all age groups. ULs for both nutrients apply to total dietary intake.[10]

RDAs for calcium in boys and girls ages 9–18 are higher than for any other age group 1300 mg/day, which is the equivalent of about four glasses of milk per day. Recommendations for calcium in adults in the age range 19–50 are a little lower 1000 mg/day, which is the equivalent of about three glasses of milk per day.[10]

Metabolism of Vitamin D

Vitamin D3 (cholecalciferol) is taken in the diet (from fortified dairy products and fish oils) or is synthesized in the skin from 7-dehydrocholesterol by UV irradiation.[4],[7],[11] The Vitamin D produced by 7-dehydrocholesterol depends on the intensity of UV-B irradiation which varies with season and latitude.[1],[3],[12] Sunscreen and clothing have been reported to prevent the conversion of 7-dehydrocholesterol to Vitamin D3.[13],[14]

Vitamin D is transported in the blood by the Vitamin D binding protein (DBP, a specific binding protein for Vitamin D and its metabolites in serum) to the liver. In the liver, Vitamin D is hydroxylated at C-25 by one or more cytochrome P450 Vitamin D 25 hydroxylases. It has been suggested that CYP2R1 is the key enzyme required for 25 hydroxylation of Vitamin D since a homozygous mutation of the CYP2R1 gene was found in Vitamin D deficiency.[15]

25(OH) D3, the major circulating form of Vitamin D, is transported by the DBP to the kidney. In the proximal renal tubule, it is hydroxylated, resulting in the hormonally active form of Vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3), which is responsible for most of the biological actions of Vitamin D [Figure 1]. Renal production of (1,25(OH)2D3) is strongly influenced by parathormone (PTH). It is well known that this type of metabolic regulation is particularly important in physiologically maintaining plasma calcium homeostasis. 1,25(OH)2D3 sec reted into the blood is transported to the target organs of Vitamin D including intestine, bone, and kidney, and then easily penetrates the plasma membranes of the target cells to bind Vitamin D receptor (VDR).[1],[2],[3],[4],[7],[16],[17]
Figure 1: Vitamin D metabolic pathway

Click here to view


Vitamin D and its metabolites are excreted primarily via the biliary and renal routes. Vitamin D2 and D3 further get hydroxylated in the kidneys to Ergocalcitriol and cholecalcidiol and are excreted by the kidneys [Figure 1].[1],[2],[3],[4],[7],[16],[17]

Blood calcium concentrations remain in the normal range even when an animal is placed on a no-calcium diet or in the absence of intestinal calcium absorption. Vitamin D hormone stimulates osteoblasts to produce receptor activator nuclear factor kappa B ligand (RANKL). RANKL then stimulates osteoclasts for bone resorption. Therefore, the Vitamin D hormone plays an important role in allowing individuals to mobilize calcium from the bone when it is absent from the diet. It is very important to note, however, that in-vivo both Vitamin D and parathyroid hormone are required for this mobilization event.[17],[18]

If the plasma calcium concentrations overshoot, then the C-cells of the thyroid gland secrete the 32-amino acid peptide calcitonin, which blocks bone calcium mobilization. Fibroblast growth factor (FGF23) protein, a bone-derived hormone, and calcitonin stimulates the renal 1 alpha-hydroxylase to provide the Vitamin D hormone for noncalcemic needs under normocalcemic conditions.[17],[18],[19],[20]

FGF23 inhibits 1,25(OH)2D3 production by the kidney; this feedback loop like that for PTH secretion maintains a balance in the levels of these important hormones. Inhibition of FGF23 secretion leads to hyperphosphatemia, increased 1,25(OH)2D3 and tumoral calcinosis.[20]

Apart from calcium homeostasis, Vitamin D also found to play a significant role in secretion of hormones such as insulin, regulation of immune function, and regulation of cellular proliferation and differentiation of keratinocytes.[1],[2],[3],[4],[5],[6],[7]

Literature data agree that Vitamin D is important to maintain a good bone health and reduce the risks of new fractures in clinical vertebral and nonvertebral fractured patients. Simonelli et al. proved that the 97% of patients with a history of falls and minimal trauma fractures had serum 25(OH)-D levels inferior to 30 ng/ml, and the 72.5% of them had levels even lower to 20 ng/ml.[2],[21],[22]

Functional markers of Vitamin D status

There is a general, current consensus that circulating 25(OH) D should be used to assess Vitamin D status. Circulating PTH appears to be a useful biomarker of Vitamin D status, when Vitamin D is given without calcium but not in its presence. Intestinal calcium absorption may respond to Vitamin D status and may be a novel functional status marker for Vitamin D.[23]

Vitamin D deficiency

Gauris et al.[24] suggested a threshold concentration of 25(OH) D be set at 30 ng/ml for "Vitamin D inadequacy," which can be divided into two groups: UVB-related deficiency and medical/physical condition-related deficiency.[1],[2],[3],[4],[5],[6],[7]

The elderly, due to the decreased presence of skin 7-dehydrocholesterol which is the precursor for UVB-mediated synthesis of Vitamin D, are particularly at risk of Vitamin D deficiency.[1],[2],[3],[4],[5],[6],[7],[25],[26],[27]

People with dark skin have great amounts of melanin in their epidermis. Melanin competes with 7-dehydrocholesterol for absorption of UVB photons. Therefore, people of color are less efficient in producing Vitamin D than are whites.[1],[28]

It has been established that the ozone layer can absorb UVB radiation above 290 nm which is responsible for generating pre-Vitamin D3. The thicker the ozone layer is, the fewer amounts of UVB photons can reach the earth, and thus few pre-Vitamin D3 can be produced. Sunscreens can efficiently absorb UVB radiation. This dramatically prevents the interaction of UVB with 7-dehydrocholesterol, the process of pre-Vitamin D3 generation.[1],[2],[3],[4],[5],[6],[7],[12]

Certain pathological conditions such as Crohn's disease, cystic fibrosis, celiac disease, surgical removal of part of the stomach, or intestines are associated with fat malabsorption and lead to Vitamin D deficiency.[29] It is well-recognized that long-term use of some antiepileptic drugs including phenobarbital, phenytoin, and carbamazepine, and the antimicrobial agent rifampicin can result in osteomalacia. The induction of the catabolism of 1,25-dihydroxyvitamin D by these drugs is thought to contribute to their deleterious side effects.[30],[31],[32],[33]

In patients with end-stage renal disease, due to direct effect in inhibiting parathyroid hormones expression result in inadequate Vitamin D.[34]

It is known for a long time that obese people are prone to be Vitamin D deficient since their subcutaneous fat, which is known to store Vitamin D, sequestered more of the cutaneous synthesized Vitamin D and lead to low 25-hydroxyvitamin D.[1],[35],[36]

Clinical manifestations of Vitamin D deficiency

Rickets

Vitamin D–dependent rickets type I, Vitamin D–dependent rickets type II, and hypophosphatemic Vitamin D resistant rickets represent the 3 distinct hereditary defects in Vitamin D metabolism.[37]

The classical manifestation of Vitamin D deficiency is nutritional rickets, which results from inadequate mineralization of growing bone. Consequently, rickets is a disease of children. Far from being eradicated, nutritional rickets continues to occur throughout the world, with reports from at least 60 countries in the past 20 years. Florid rickets manifests with leg deformities; enlargement of the growth plates of the wrists, ankles, and costochondral junctions; and rib cage deformities [Figure 2]. Subtle symptoms that should raise the clinical suspicion of rickets in children include bone pain in the legs, delayed age of standing or walking, frequent falling, and delayed growth. Hypocalcemic seizures in the 1st year of life may be the initial manifestation of rickets.[2],[4],[7],[37],[38]
Figure 2: Features of rickets

Click here to view


Radiography of the long bones at the knees and the wrists is necessary to confirm the diagnosis of rickets. Radiography demonstrates impaired mineralization of the growth plates, evident by widening of the growth plate and fraying of the margin of the metaphyses. Biochemical features most consistently include hypophosphatemia and an elevated alkaline phosphatase level. As a result of Vitamin D deficiency, serum concentrations of 25(OH) D are very low in patients with rickets, usually <5 ng/mL. However, concentrations of 25(OH) D may not be markedly reduced if rickets results from calcium deficiency or if the child has recently received Vitamin D or sun exposure. In some tropical countries, where sun exposure is plentiful, calcium deficiency is more important than Vitamin D deficiency as a cause of rickets.[2],[4],[7],[37],[38]

Osteomalacia

The term osteomalacia is generally used to describe the bone disease caused by Vitamin D deficiency in adults, who no longer have growing bones. Bone pain is a characteristic feature of osteomalacia, and it can be confused with arthritis or fibromyalgia. The clinical manifestations of these 2 conditions are different. Proximal muscle weakness and gait instability are often present. Because the growth plates have closed in adults, the radiographic features differ from those typical of rickets. Radiography may reveal pseudofractures

of the pelvis, femurs, metatarsals, or lateral margins of the scapulae. The biochemical features of osteomalacia are similar to those of rickets, with increased serum alkaline phosphatase and PTH values, and low calcium, phosphorus, and 25(OH) D values in most cases.[32],[33],[38]

Management of Vitamin D deficiency

Due to concern about skin cancer, many patients and clinicians are cautious regarding sun exposure recommendations. Exposure of arms and legs for 5–30 min between the hours of 10 am and 3 pm twice a week can be adequate to prevent Vitamin D deficiency.[21]

Patients with chronic kidney disease are recommended to have 1000 IU of Vitamin D daily. Over-the-counter, multivitamin supplements frequently contain 400 IU of Vitamins D1, D2, and D3. To prevent Vitamin D deficiency in healthy patients, the 1997 institute of medicine recommendations suggested a daily Vitamin D intake of 200 IU for children and adults up to 50 years of age, 400 IU for adults 51–70 years of age, and 600 IU for adults 71 years or older.[21]

Vitamin D intoxication

Vitamin D intoxication may result from supplementation rarely, but it has been reported more frequently in recent years. When the calcium concentration exceeds 14 mg/dl, emergency intervention is necessary because of the adverse effects of hypercalcemia on cardiac, central nervous system (CNS), renal, and gastrointestinal functions.[39]

Vitamin D and systemic diseases

The VDR are ubiquitously expressed in almost all body cells, such as immune, vascular, or myocardial cells, suggest an involvement of Vitamin D-mediated effects in several other systems apart from musculoskeletal tissues.

This has led to extensive research on Vitamin D as a potential influencing factor in the pathogenesis of several chronic nonskeletal diseases, such as infectious or autoimmune diseases, cancer, or cardiovascular diseases.[40],[41],[42],[43],[44],[45],[46],[47]

Vitamin D and total mortality

Vitamin D may be a determinant of mortality because of its anti-inflammatory and immune-modulating effects. Some effects mediated through the activation of the VDR such as inhibition of cellular proliferation and activation of cellular differentiation could reduce aggressiveness of cancerous processes and expansion of atheromatous lesions. Low serum Vitamin D levels are also related to increased mortality in most patients with chronic kidney disease before dialysis.[40],[41],[42],[43],[44],[45],[46],[47]

Vitamin D and diabetes

Meta-analysis of the results of observational studies suggest that the risk of type 1 diabetes is significantly reduced in those who were supplemented in childhood with Vitamin D compared to those who were not supplemented,[42] which is likely to be through the prevention of hypovitaminosis D. There is evidence for a physiological role of Vitamin D in the immune system and also for a protective effect of the vitamin from cytokine-induced beta cell dysfunction.[43]

Vitamin D has recently been associated with several of the contributing factors known to be linked to the development of type 2 diabetes mellitus including defects in pancreatic beta-cell function, insulin sensitivity, and systemic inflammation.[7],[43],[44]

Vitamin D and osteoporosis

A low Vitamin D level is an established risk factor for osteoporosis. Although combination of calcium and Vitamin D supplementation is associated with higher bone mineral density and decreased incidence of hip fractures, the evidence for Vitamin D supplementation alone is less clear.[2],[24],[26],[44]

Vitamin D and cardiovascular disease

VDRs are present in vascular smooth muscle, endothelium, and cardiomyocytes, which may have an impact on cardiovascular disease. Observational studies have shown a relationship between low Vitamin D levels and blood pressure, coronary artery calcification, and existing cardiovascular disease. There are several plausible mechanisms of how Vitamin D may modify risk of cardiometabolic outcomes. Vitamin D regulates the rennin-angiotensin system, suppresses proliferation of vascular cell smooth muscle, ameliorates insulin resistance, improves endothelial cell-dependent vasodilation, inhibits anticoagulant activity, and myocardial cell hypertrophy and may modulate macrophage activity and cytokine generation. Vitamin D remains a promising, though unproven, new element in the prevention and management of cardiovascular disease.[45],[46],[47],[48],[49]

Vitamin D and cancer

By the late 1990's, the mechanisms whereby Vitamin D reduces the risk of cancer were fairly known and induce facilitation of calcium absorption (colon cancer), increased cell differentiation and apoptosis and reduction of both metastasis and angiogenesis.

The expression of VDR was found to be significantly increased in precancerous and oral squamous cell carcinoma compared with normal tissue.[50] VDR knockdown significantly enhanced oral keratinocyte differentiation and proliferation that occur due to disrupted calcium and 1,25(OH)2D3-induced pathway, emphasizing the anti-proliferative and pro-differentiation effects of Vitamin D in intraoral keratinocytes.[51] In a case–control study, it has been found that VDR pleomorphism was associated with the incidence of oral squamous cell carcinoma.[49],[50],[51],[52],[53]

Vitamin D and nervous system

In addition to its influence on neurotrophin synthesis, 1,25(OH)2D3 could mediate its neuroprotective effects via the modulation of neuronal Ca 2+ homeostasis and has also been reported to inhibit the synthesis of inducible nitric oxide synthase, an enzyme induced in CNS neurons and nonneuronal cells during various insults or diseases such as ischemia, Alzheimer's disease, and

Parkinson's disease.[1],[3],[7],[54]

Vitamin D and tuberculosis

Tuberculosis (TB) is a disease for which Vitamin D can strengthen the immune system by enhancing the macrophage phagocytosis of Mycobacterium tuberculosis.[2] The significance of an association between Vitamin D deficiency and TB is thought to be due to low levels predispose to other Vitamin D deficient states.[1],[2],[4],[55]

Potential antimicrobial implications of Vitamin D

Vitamin D may reduce the risk of infection through multiple mechanisms. Vitamin D boosts innate immunity by modulating production of anti-microbial peptides and cytokine response. The ability to regulate local immune and inflammatory responses offers exciting potential for understanding and treating chronic inflammatory dermatitis. Vitamin D may reduce susceptibility to infection in patients with atopic dermatitis, vitiligo, acne.[56] In recent years, several papers have discussed how cathelicidin and defensins reduce the risk of dental caries through attacking oral bacteria linked to dental caries. These polypeptides reduce the risk of several other types of bacterial infections such as TB, pneumonia, and severe sepsis. High Vitamin D content of food can do much to diminish the incidence of caries if the vitamin is given during the development of teeth.[57] Vitamin D may be of benefit in the treatment of periodontitis, not only because of its direct effects on bone metabolism, but also because it may have antibiotic effects on periodontal pathogens and inhibit inflammatory mediators that contribute to periodontal destruction.[58]

Vitamin D constitutes as an inexpensive prophylactic option and also a possible therapeutic approach, either by itself or as a synergistic agent to traditional antimicrobial agents.[59]


  Conclusion Top


In recent years, Vitamin D deficiency has been linked with the pathogenesis and/or progression of several disorders including cancer, hypertension, multiple sclerosis, and diabetes. Hence, it is necessary to focus on the potential use of Vitamin D for optimal health and its influence on reduced risks associated with many systemic diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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