Vitamin D Totally Explained

Everything about Vitamin D totally explained

Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D₂ (or ergocalciferol) and vitamin D₃ (or cholecalciferol). The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D₃ is produced in skin exposed to sunlight, specifically ultraviolet B radiation.
Vitamin D plays an important role in the maintenance of organ systems.

Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys.
It promotes bone formation and mineralization and is essential in the development of an intact and strong skeleton. However, at very high levels it'll promote the resorption of bone.
It inhibits parathyroid hormone secretion from the parathyroid gland.
Vitamin D affects the immune system by promoting phagocytosis, anti-tumor activity, and immunomodulatory functions.

Vitamin D deficiency can result from inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders. The structural difference between vitamin D₂ and vitamin D₃ is in their side chains. The side chain of D₂ contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.
Vitamin D₂ is derived from fungal and plant sources, and isn't produced by the human body. Vitamin D₃ is derived from animal sources and is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–300 nm, with peak synthesis occurring between 295-297 nm. These wavelengths are present in sunlight at sea level when the sun is more than 45° above the horizon, or when the UV index is greater than 3. At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D₃ can be made in the skin only after ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and the vitamin simply degrades as fast as it's generated. However, in some species, such as rats, vitamin D₂ is more effective than D₃. Both vitamin D₂ and D₃ are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene.

Biochemistry

Vitamin D is a prohormone, meaning that it has no hormone activity itself, but is converted to the active hormone 1,25-D through a tightly regulated synthesis mechanism. Production of vitamin D in nature always appears to require the presence of some UV light; even vitamin D in foodstuffs is ultimately derived from organisms, from mushrooms to animals, which are not able to synthesize it except through the action of sunlight at some point in the synthetic chain. For example, fish contain vitamin D only because they ultimately exist on calories from ocean algae which synthesize vitamin D in shallow waters from the action of solar UV.

Production in the skin

The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer thinner epidermis. The epidermis consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.
Vitamin D₃ is produced photochemically in the skin from 7-dehydrocholesterol. The highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum. The two most important factors that govern the generation of pre-vitamin D₃ are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum. Thus, individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. As noted below, the amount of time an individual requires to produce a given amount of Vitamin D may also depend upon the person's distance from the equator and on the season of the year.

Synthesis mechanism (form 3)

1. Vitamin D₃ is synthesized from 7-dehydrocholesterol, a derivative of cholesterol, which is then photolyzed by ultraviolet light in 6-electron conrotatory electrocyclic reaction. The product is pre-vitamin D₃.
2. Pre-vitamin D₃ then spontaneously isomerizes to Vitamin D₃ in a antarafacial hydride [1,7]Sigmatropic shift.
3. Whether it's made in the skin or ingested, vitamin D₃ (cholecalciferol) is then hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D₃ or calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes, and stored until it's needed. 25-hydroxycholecalciferol is further hydroxylated in the kidneys by the enzyme 1α-hydroxylase, into two dihydroxylated metabolites, the main biologically active hormone 1,25-dihydroxycholecalciferol (1,25(OH)2D₃ or calcitriol) and 24R,25(OH)2D₃. This conversion occurs in a tightly regulated fashion. Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower ring at right, hydroxylated Carbon 25 is at the upper right end).

Mechanism of action

Once vitamin D is produced in the skin or consumed in food, it's converted in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)₂D) the physiologically active form of vitamin D (when "D" is used without a subscript it refers to either D₂ or D₃). Following this conversion, the hormonally active form of vitamin D is released into the circulation, and by binding to a carrier protein in the plasma, vitamin D binding protein (VDBP), it's transported to various target organs.
The VDR is known to be involved in cell proliferation, differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells. Adequate intake increases to 10 micrograms/day (400 IU/day) for men and women aged 51–70 and up to 15 micrograms/day (600 IU/day) past the age of 70. These dose rates will be too low during winter months above 30° latitude. In the absence of sun exposure, 1000 IU of cholecalciferol is required daily for children. 4000 IU of vitamin D may be required for adults absent summer UVB.

In food

Season, geographic latitude, time of day, cloud cover, smog, and sunscreen affect UV ray exposure and vitamin D synthesis in the skin, and it's important for individuals with limited sun exposure to include good sources of vitamin D in their diet.
In some countries, foods such as milk, yogurt, margarine, oil spreads, breakfast cereal, pastries, and bread are fortified with vitamin D₂ and/or vitamin D₃, to minimize the risk of vitamin D deficiency. In the United States and Canada, for example, fortified milk typically provides 100 IU per glass, or one quarter of the estimated adequate intake for adults over the age of 50. this is one of a few natural food-based sources of vitamin D for vegans.

One whole egg, 20 IU

Deficiency

Vitamin D deficiency can result from: inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders. In 1921 Elmer McCollum identified an anti-rachitic substance found in certain fats could prevent rickets. Because the newly discovered substance was the fourth vitamin identified, it was called vitamin D. including:

Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones. The earliest sign of subclinical vitamin D deficiency is Craniotabes, abnormal softening or thinning of the skull.

Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility.

Osteoporosis, a condition characterized by reduced bone mineral density and increased bone fragility. Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States, milk has been fortified with 10 micrograms (400 IU) of vitamin D per quart since the 1930s, leading to a dramatic decline in the number of rickets cases. and several autoimmune diseases including type 1 diabetes (see role in immunomodulation).

Groups at greater risk of deficiency

Vitamin D requirements increase with age, while the ability of skin to convert 7-dehydrocholesterol to pre-vitamin D₃ decreases. In addition the ability of the kidneys to convert calcidiol to its active form also decreases with age, prompting the need for increased vitamin D supplementation in elderly individuals. One consensus concluded that for optimal prevention of osteoporotic fracture the blood calcidiol concentration should be higher than 30 ng/mL, which is equal to 75 nmol/L. One billion people in the world are currently Vitamin D deficient, if 75 nmol/L is used as cutoff value for insufficiency.
The American Pediatric Association advises vitamin D supplementation of 200 IU/day (5μg/d) from birth onwards. Health Canada recommends 400IU/day (10μg/d). While infant formula is generally fortified with vitamin D, breast milk doesn't contain significant levels of vitamin D, and parents are usually advised to avoid exposing babies to prolonged sunlight. Therefore, infants who are exclusively breastfed are likely to require vitamin D supplementation beyond early infancy, especially at northern latitudes. Patients with chronic liver disease or intestinal malabsorption disorders may also require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily). The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more than 95% of vitamin D production in the skin. Recent studies showed that, following the successful "Slip-Slop-Slap" health campaign encouraging Australians to cover up when exposed to sunlight to prevent skin cancer, an increased number of Australians and New Zealanders became vitamin D deficient. To avoid vitamin D deficiency dermatologists recommend supplementation along with sunscreen use.
The reduced pigmentation of light-skinned individuals tends to allow more sunlight to be absorbed even at higher latitudes, thereby reducing the risk of vitamin D deficiency. At latitudes below 30° where sunlight and day-length are more consistent, vitamin D supplementation may not be required.

Overdose

Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large volume of distribution and a long half-life (about 20 to 29 days). Although normal food and pill vitamin D concentration levels are too low to be toxic in adults, because of the high vitamin A content in codliver oil, it's possible to reach toxic levels of vitamin A (but not vitamin D) via this route, if taken in multiples of the normal dose in an attempt to increase the intake of vitamin D. Most historical cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.
   Exposure to sunlight for extended periods of time doesn't cause vitamin D toxicity. Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day. The Nutrition Desk Reference states "The threshold for toxicity is 500 to 600 micrograms [vitaminD] per kilogram body weight per day." The US EPA published an oral LD50 of 619 mg/kg for female rats.
   Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 32 to 69 ng/mL (82 to 176 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose. Gastrointestinal symptoms of vitamin D toxicity can include anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop. Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.
   Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible.
   Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of regulatory T cells, as well as effects on cytokine secretion patterns. VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression.
   VDR ligands have also been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages. Vitamin D deficiency tends to increase the risk of infections, such as influenza and tuberculosis. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets.
   These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of; inflammatory diseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis) and in preventing organ transplant rejection. A 2006 study published in the Journal of the American Medical Association, reported evidence of a link between Vitamin D deficiency and the onset of Multiple Sclerosis; the authors posit that this is due to the immune-response suppression properties of Vitamin D.

Role in cancer prevention and recovery

The vitamin D hormone, calcitriol, has been found to induce death of cancer cells in vitro and in vivo. Although the anti-cancer activity of vitamin D isn't fully understood, it's thought that these effects are mediated through vitamin D receptors expressed in cancer cells, and may be related to its immunomodulatory abilities. The anti-cancer activity of vitamin D observed in the laboratory has prompted some to propose that vitamin D supplementation might be beneficial in the treatment or prevention of some types of cancer. In 2005, scientists released a metastudy which demonstrated a beneficial correlation between vitamin D intake and prevention of cancer. Drawing from a meta-analysis of 63 published reports, the authors showed that intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancer risk by 50%, and breast and ovarian cancer risks by 30%. Research has also shown a beneficial effect of high levels of calcitriol on patients with advanced prostate cancer. A randomized intervention study involving 1,200 women, published in June 2007, reports that vitamin D supplementation (1,100 international units (IU)/day) resulted in a 60% reduction in cancer incidence, during a four-year clinical trial, rising to a 77% reduction for cancers diagnosed after the first year (and therefore excluding those cancers more likely to have originated prior to the vitamin D intervention). In 2006, a study at Northwestern University found that taking the U.S. RDA of vitamin D (400 IU per day) cut the risk of pancreatic cancer by 43% in a sample of more than 120,000 people from two long-term health surveys.
A 2006 study using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk between countries classified as sunny and countries classified as less–sunny for a number of different cancers. Research has also suggested that cancer patients who have surgery or treatment in the summer — and therefore make more endogenous vitamin D — have a better chance of surviving their cancer than those who undergo treatment in the winter when they're exposed to less sunlight.
However, a large scientific review undertaken by the National Cancer Institute found no link between baseline vitamin D status and overall cancer mortality. They did find that vitamin D was beneficial in preventing colorectal cancer, which showed an inverse relationship with blood levels "80 nmol/L or higher associated with a 72% risk reduction".

Role in coronary disease prevention

Research indicates that vitamin D may play a role in preventing or reversing coronary disease. As with cancer incidence, a qualitative inverse correlations was found between coronary disease incidence and serum vitamin D levels of 32.0 versus 35.5 ng/mL. Cholesterol levels were found to be reduced in gardeners in the UK during the summer months. Heart attacks peak in winter and decline in summer in temperate but not tropical latitudes. The issue of vitamin D in heart health hasn't yet been settled. Exercise may account for some of the benefit attributed to vitamin D, since vitamin D levels are higher in physically active persons. Moreover, there may be an upper limit after which cardiac benefits decline. One study found an elevated risk of ischaemic heart disease in Southern India in individuals whose vitamin D levels were above 89 ng/mL. These sun-living groups results don't generalize to sun-deprived urban dwellers. Among a group with heavy sun exposure, taking supplemental vitamin D may result in blood levels over the ideal range, while urban dwellers not taking supplemental vitamin D may fall under the levels recognized as ideal, and being above or below the preferable levels may cause adverse affects on the health of each group.
Researchers at the Harvard Medical School in Boston reported in Circulation, the Journal of the American Heart Association, January 2008 that vitamin D deficiency is associated with an increase in high blood pressure and cardiovascular risk. Researchers monitored the vitamin D levels, blood pressure and other cardiovascular risk factors of 1739 people, of an average age of 59 years for 5 years. They found that those people with low levels of vitamin D had a 62% higher risk of a cardiovascular event than those with normal vitamin D levels.

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