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, which enables normal mineralization of bone and prevents hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts.
• In the absence of vitamin K or with drugs (particularly blood thinners) that interfere with Vitamin K metabolism, Vitamin D can promote soft tissue calcification
• 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. Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis. However, sunlight exposure, to avoid deficiency, carries other risks, including skin cancer; this risk is avoided with dietary absorption, either through diet or as a dietary supplement.


Forms

Several forms (vitamers) of vitamin D have been discovered. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. These are known collectively as calciferol

• Vitamin D1: molecular compound of ergocalciferol with lumisterol, 1:1

• Vitamin D2: ergocalciferol (made from ergosterol)

• Vitamin D3: cholecalciferol (made from 7-dehydrocholesterol in the skin).

• Vitamin D4: 22-dihydroergocalciferol

• Vitamin D5: sitocalciferol (made from 7-dehydrositosterol)

Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken. 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 is not 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 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 after only 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 is
generated.

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.

Vitamin D as a Vitamin

Since Vitamin D is naturally produced by human body it only became a Vitamin because of cultural changes, related to civilization that reduced natural production due to less exposure of the human skin to the sun, caused by the use of more clothes and less time of outdoors exposition.

Nutrition

Only fish is naturally rich in vitamin D, so much vitamin D intake in the industrialized world is from fortified products including milk, soy milk and breakfast cereals or supplements.
A blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine vitamin D nutritional status. The optimal level of serum 25-hydroxyvitamin D is 35–55 ng/mL; with some debate among medical scientists for the slightly higher value. Supplementation of 100 IU (2.5 mcg) vitamin D3 raises circulating 25(OH)D by 2.5 nmol/l (1 ng/ml).
The 2005 Dietary Guidelines for Americans recommend that older adults, people with dark skin, and those exposed to insufficient ultraviolet radiation (i.e., sunlight) consume extra vitamin D from vitamin D-fortified foods and/or supplements. Individuals in these high-risk groups should consume 25 μg (1000 IU) of vitamin D daily to maintain adequate blood concentrations of 25-hydroxyvitamin D, the biomarker for vitamin D status.

Milk and cereal grains are often fortified with vitamin D.
The Canadian Pediatric Society recommends 2,000 IU daily for pregnant and breastfeeding women.

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 is 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.


Fatty fish, such as salmon, are natural sources of vitamin D.
Fortified foods represent the major dietary sources of vitamin D, as very few foods naturally contain significant amounts of vitamin D.

Natural sources of vitamin D include:

• Fish liver oils, such as cod liver oil, provides 1,360 IU (one IU equals 25 ng)
• Fatty fish species, such as:
o Herring,
o Catfish,
o Salmon,
o Mackerel, Sardines,
o Tuna,
o Eel,

Diseases caused by deficiency


Vitamin D deficiency is known to cause several bone diseases[24] 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.[25]
• 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.
Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases such as high blood pressure, tuberculosis, cancer, periodontal disease, multiple sclerosis, chronic pain, depression, schizophrenia, seasonal affective disorder, peripheral artery disease[26] and several autoimmune diseases including type 1 diabetes
There is an association between low vitamin D levels and Parkinson's disease, but whether Parkinson's causes low vitamin D levels, or whether low vitamin D levels have a role to play in the pathogenesis of Parkinson's disease is not currently established.
A deficiency of Vitamin D is mentioned as one of the possible causes of seasonal flu (refer to influenza).
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 70 ng/mL (80 to 175 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.

Some symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Vitamin D toxicity is known to be a cause of high blood pressure. 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. In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity. 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.

Role in immunomodulation


Cholecalciferol (D3)
The hormonally active form of vitamin D mediates immunological effects by binding to nuclear vitamin D receptors (VDR) which are present in most immune cell types including both innate and adaptive immune cells. The VDR is expressed constitutively in monocytes and in activated macrophages, dendritic cells, NK cells, T and B cells. In line with this observation, activation of the VDR has potent anti-proliferative, pro-differentiative, and immunomodulatory functions including both immune-enhancing and immunosuppressive effects.

Role in cancer prevention and recovery

The Canadian Cancer Society recommends that adults should consider supplementeing with 1,000 IU of vitamin D per day during the fall and winter. They base this recommendation on the growing evidence for a link between vitamin D and a reduced risk for colorectal, breast and prostate cancers.
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 is not fully understood, it is 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.

Role in cardiovascular disease prevention

Research indicates that vitamin D may play a role in preventing or reversing coronary disease. Vitamin D deficiency is associated with an increase in high blood pressure and cardiovascular risk. When 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
A report from the National Health and Nutrition Examination Survey (NHANES) found that low levels of vitamin D were associated with an increased risk of peripheral artery disease (PAD)..