Vitamin D

Vitamin D is a group of fat-soluble secosteroids. In humans vitamin D is unique both because it functions as a prohormone and the body can synthesize it (as vitamin D3) when sun exposure is adequate. Measures of the serum levels reflect endogenous synthesis from sun exposure as well as intake from the diet and it is believed that synthesis may contribute generally to the maintenance of adequate serum concentrations. The evidence indicates that the synthesis of vitamin D from sun exposure works in a feedback loop that prevents toxicity but, because of uncertainty about the cancer risk from sunlight, no recommendations are issued by the Institute of Medicine for the amount of sun exposure required to meet vitamin D requirements. Accordingly the Dietary Reference Intakes for vitamin D assume that no synthesis occurs and that all of a person's vitamin D is from his or her diet.

When synthesized in the kidneys, calcitriol circulates as a hormone, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. Vitamin D prevents rickets in children and osteomalacia in adults, and, together with calcium, helps to protect older adults from osteoporosis. Vitamin D also affects neuromuscular function, inflammation, and influences the action of many genes that regulate the proliferation, differentiation and apoptosis of cells.

Forms
Several forms (vitamers) of vitamin D exist (see table). The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol, vitamin D without a subscript refers to either D2 or D3 or both. These are known collectively as calciferol. Vitamin D2 was chemically characterized in 1932. In 1936, the chemical structure of vitamin D3 was established and resulted from the ultraviolet irradiation of 7-dehydrocholesterol.

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 D3 (cholecalciferol) is produced by ultraviolet irradiation (UV) of its precursor 7-dehydrocholesterol. This molecule occurs naturally in the skin of animals and in milk. Vitamin D3 can be made by exposure of the skin to UV, or by exposing milk directly to UV (one commercial method).

Vitamin D2 is a derivative of ergosterol, a membrane sterol named for the ergot fungus, which is produced by some organisms of phytoplankton, invertebrates, and fungi. The vitamin ergocalciferol (D2) is produced in these organisms from ergosterol in response to UV irradiation. D2 is not produced by land plants or vertebrates, because they lack the precursor ergosterol. The biological fate for producing 25(OH)D from vitamin D2 is expected to be the same as for D3, although some controversy exists over whether or not D2 can fully substitute for vitamin D3 in the human diet.

Evolution
The photosynthesis of vitamin D evolved over an estimated 750 million years ago; the phytoplankton coccolithophore Emiliania huxleyi is an early example. Vitamin D played a critical role in the maintenance of a calcified skeleton in vertebrates as they left their calcium-rich ocean environment for land over an estimated 350 million years ago.

Vitamin D can be synthesized only via a photochemical process, so early vertebrates that ventured onto land either had to ingest foods that contained vitamin D or had to be exposed to sunlight to photosynthesize vitamin D in their skin to satisfy their body's vitamin D requirement.

Production in the skin


Vitamin D3 is made in the skin when 7-dehydrocholesterol reacts with ultraviolet light (UVB) at wavelengths between 270 and 300 nm, with peak synthesis occurring between 295 and 297 nm. These wavelengths are present in sunlight when the UV index is greater than three and also in the light emitted by the UV lamps in tanning beds. Tanning lamps produce ultraviolet primarily in the UVA spectrum, but typically produce 4% to 10% of the total UV emissions as UVB. 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, vitamin D3 can be made in the skin. Latitude does not consistently predict the average serum 25OHD level of a population. The assumption that vitamin D levels in the population follow a latitude gradient is especially questionable in view of surveys which have shown that UVB penetrating to the earth's surface over 24 hours during the summer months in northern Canada equals or exceeds UVB penetration at the equator. Accordingly, there is sufficient opportunity during the spring, summer, and fall months at high latitude for humans to form and store vitamin D3. Depending on the intensity of UVB rays and the minutes of exposure, an equilibrium can develop in the skin, and vitamin D degrades as fast as it is generated.

The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer, thinner epidermis. Thick epidermis in the soles and palms consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Vitamin D is produced in the two innermost strata, the stratum basale and stratum spinosum.

Cholecalciferol is produced photochemically in the skin from 7-dehydrocholesterol; 7-dehydrocholesterol is produced in relatively large quantities in the skin of most vertebrate animals, including humans. The naked mole rat appears to be naturally cholecalciferol deficient, as serum 25-OH vitamin D levels are undetectable. In some animals, the presence of fur or feathers blocks the UV rays from reaching the skin. In birds and fur-bearing mammals, vitamin D is generated from the oily secretions of the skin deposited onto the feathers or fur and is obtained orally during grooming.

Discovery
American researchers Elmer McCollum and Marguerite Davis in 1913 discovered a substance in cod liver oil which later was called "vitamin A". British doctor Edward Mellanby noticed dogs that were fed cod liver oil did not develop rickets and concluded vitamin A, or a closely associated factor, could prevent the disease. In 1921, Elmer McCollum tested modified cod liver oil in which the vitamin A had been destroyed. The modified oil cured the sick dogs, so McCollum concluded the factor in cod liver oil which cured rickets was distinct from vitamin A. He called it vitamin D because it was the fourth vitamin to be named. It was not initially realized that, unlike other vitamins, vitamin D can be synthesised by humans through exposure to UV light.

In 1923, it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced (now known as D3). Alfred Fabian Hess showed "light equals vitamin D." Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928, for his work on the constitution of sterols and their connection with vitamins. In the 1930s he clarified further the chemical structure of vitamin D.

In 1923, Harry Steenbock at the University of Wisconsin demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials. After irradiating rodent food, Steenbock discovered the rodents were cured of rickets. A vitamin D deficiency is a known cause of rickets. Using $300 of his own money, Steenbock patented his invention. His irradiation technique was used for foodstuffs, most memorably for milk. By the expiration of his patent in 1945, rickets had been all but eliminated in the US.

Industrial production
Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification. The 7-dehydrocholesterol is a natural substance in wool grease (lanolin) from sheep or other woolly animals. Vitamin D2 (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.

Mechanism of action
Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcidiol. Circulating calcidiol may then be converted into calcitriol, the biologically active form of vitamin D, either in the kidneys or by monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, defending the body against microbial invaders. Following the final converting step in the kidney, calcitriol (the physiologically active form of vitamin D) is released into the circulation. By binding to vitamin D-binding protein (VDBP), a carrier protein in the plasma, calcitriol is transported to various target organs.

Calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine.

The vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDRs are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.

Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. It also is involved in the biosynthesis of neurotrophic factors, synthesis of nitric oxide synthase, and increased glutathione levels.

The VDR is known to be involved in cell proliferation and differentiation. Vitamin D also affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B cells.

Apart from VDR activation, various alternative mechanisms of action are known. An important one of these is its role as a natural inhibitor of signal transduction by hedgehog (a hormone involved in morphogenesis).

Vitamin D and health outcomes
The Institute of Medicine report Dietary Reference Intakes for Calcium and Vitamin D was requested by the U.S. and Canadian governments. The report was the work of an ad hoc consensus committee of 14 scientists with "expertise in the areas of vitamin D and calcium or a related topic area, with specific expertise related to pregnancy and reproductive nutrition, pediatrics and infant nutrition, minority health and health disparities, cellular metabolism, toxicology and risk assessment, dermatology, immunology, endocrinology, skeletal health, oncology, cardiovascular health, epidemiology; nutrition monitoring, and biostatistics". The report examined literature identified by the committee and incorporated systematic evidence-based reviews from the Agency for Healthcare Research and Quality to assess indicators of chronic and non-chronic disease outcomes. The Institute of Medicine's report provides the most objective scientifically based information about what is adequate or excess intake of vitamin D and the role of vitamin D in human health.

Outcomes related to cancer/neoplasms, cardiovascular disease and hypertension, diabetes and metabolic syndrome, falls and physical performance, immune functioning and autoimmune disorders, infections, neuropsychological functioning, and preeclampsia could not be linked reliably with calcium or vitamin D intake and were often conflicting.

According to the report: "Despite the many claims of benefit surrounding vitamin D in particular, the evidence did not support a basis for a causal relationship between vitamin D and many of the numerous health outcomes purported to be affected by vitamin D intake. Although the current interest in vitamin D as a nutrient with broad and expanded benefits is understandable, it is not supported by the available evidence. The established function of vitamin D remains that of ensuring bone health, for which causal evidence across the life stages exists and has grown since the 1997 DRIs were established (IOM, 1997). The conclusion that there is not sufficient evidence to establish a relationship between vitamin D and health outcomes other than bone health does not mean that future research will not reveal a compelling relationship between vitamin D and another health outcome. The question is open as to whether other relationships may be revealed in the future."



Serum 25-Hydroxyvitamin D
The Institute of Medicine committee concluded that a serum 25-hydroxyvitamin D level of 20 ng/mL is desirable for bone and overall health. The Dietary Reference Intakes for vitamin D are chosen with a margin of safety and 'overshoot' the targeted serum value to ensure that the specified levels of intake achieve the desired serum 25-hydroxyvitamin D levels in almost all persons. It is assumed there are no contributions to serum 25-hydroxyvitamin D level from sun exposure and the recommendations are fully applicable to people with dark skin or negligible exposure to sunlight.

The Institute of Medicine found that serum 25-hydroxyvitamin D concentrations above 30 ng/mL are "not consistently associated with increased benefit". Serum 25-hydroxyvitamin D levels above 50 ng/mL may be cause for concern.

Dietary reference intakes
The Dietary Reference Intake for vitamin D issued by the Institute of Medicine in 2010 superseded a previous recommendation which had Adequate Intake status. The recommendations were formed assuming the individual has no skin synthesis of vitamin D because of inadequate sun exposure. The reference intake for vitamin D refers to total intake from food, beverages and supplements, is intended for the North American population, and assumes that calcium requirements are being met.

The new reference intakes for vitamin D are:
 * 1–70 years of age: 600 IU/day (15 μg equivalent)
 * 71+ years of age: 800 IU/day
 * Pregnant/lactating: 600 IU/day

The reference AI for infants remains at:
 * 0–12 months: 400 IU/day

Potential for adverse effects from excess vitamin D
Vitamin D toxicity has never been reported from ultraviolet B light alone. The Institute of Medicine used a risk assessment framework in reviewing all available data related to vitamin D intake and various health outcomes. The aim was not to prove that certain levels of intake certainly cause harm, but rather to decide whether the emerging evidence warranted caution relative to vitamin D intakes and associated serum 25-hydroxyvitamin D concentrations less than those associated with acute toxicity but still associated with adverse effects that may occur as a result of chronic intake.

Tolerable upper intake levels
The Tolerable Upper Intake Level is defined as "the highest average daily intake of a nutrient that is likely to pose no risk of adverse health effects for nearly all persons in the general population". Although tolerable upper intake levels are believed to be safe, information on the long term effects is incomplete and these levels of intake are not recommended :
 * 0–6 months of age: 1,000 IU
 * 6–12 months of age: 1,500 IU
 * 1–3 years of age: 2,500 IU
 * 4–8 years of age: 3,000 IU
 * 9-71+ years of age: 4,000 IU
 * Pregnant/lactating: 4,000 IU

Dissenting opinions on vitamin D levels
One school of thought maintains that human physiology is fine tuned to an intake of 4000 — 12,000 IU/day with concomitant serum 25-hydroxyvitamin D levels of 40 to 80 ng/mL and that this is required for optimal health. The proponents of this view contend that the Institute of Medicine's warning about serum concentrations above 50 ng/mL lacks biological plausibility.

Dietary sources
In some countries, staple foods are artificially fortified with vitamin D. Dietary sources of vitamin D include:
 * Fatty fish species, such as:
 * Catfish, 85 g (3 oz) provides 425 IU (5 IU/g)
 * Salmon, cooked, 100 g (3.5 oz) provides 360 IU (3.6 IU/g)
 * Mackerel, cooked, 100 g (3.5 oz), 345 IU (3.45 IU/g)
 * Sardines, canned in oil, drained, 50 g (1.75 oz), 250 IU (5 IU/g)
 * Tuna, canned in oil, 100 g (3.5 oz), 235 IU (2.35 IU/g)
 * Eel, cooked, 100 g (3.5 oz), 200 IU (2.00 IU/g)
 * A whole egg provides 20 IU if egg weighs 60 g (0.33 IU/g)
 * Beef liver, cooked, 100 g (3.5 oz), provides 15 IU (0.15 IU/g)
 * Fish liver oils, such as cod liver oil, 1 Tbs. (15 ml) provides 1360 IU (90.6 IU/ml)
 * UV-irradiated mushrooms and yeast are the only known vegan significant sources of vitamin D from food sources. Exposure of portabella mushrooms to UV provides an increase of vitamin D content in an 100-g portion (grilled) from about 14 IU (0.14 IU/g non-exposed) to about 500 IU (5 IU/g exposed to UV light).

European Union's recommended daily amounts
The recommended daily amount for vitamin D in the European Union is 5 µg. 1 µg = 40 IU and 0.025 µg = 1 IU.

Australia and New Zealand
Australia and New Zealand have established average intakes for vitamin D, as follows.

Children Adults
 * 5.0 μg /day
 * 19–50 yr 5.0 μg/day
 * 51–70 yr 10.0 μg/day
 * >70 yr 15.0 μg/day

Deficiency
Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun. Deficiency results in impaired bone mineralization, and leads to bone softening diseases including:
 * Rickets, a childhood disease characterized by impeded growth and deformity of the long bones, can be caused by calcium or phosphorus deficiency as well as a lack of vitamin D; today it is largely found in low income countries in Africa, Asia or the Middle East and in those with genetic disorders such as pseudovitamin D deficiency rickets. Rickets was first described in 1650, by Francis Glisson who said it had first appeared about 30 years previously in the counties of Dorset and Somerset. In 1857, John Snow suggested the rickets then widespread in Britain was being caused by the adulteration of bakers bread with alum. The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920. Nutritional rickets exists in countries with intense year round sunlight such as Nigeria and can occur without vitamin D deficiency.  Although rickets and osteomalacia are now rare in Britain there have been outbreaks in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing. Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish and eggs, and low intakes of high-extraction cereals.  The dietary risk factors for rickets include abstaining from animal foods. Vitamin D deficiency remains the main cause of rickets among young infants in most countries, because breast milk is low in vitamin D and social customs and climatic conditions can prevent adequate UVB exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh where the disease occurs among older toddlers and children it has been attributed to low dietary calcium intakes, which are characteristic of cereal-based diets with limited access to dairy products. Rickets was formerly a major public health problem among the US population; in Denver where ultraviolet rays are approximately 20% stronger than at sea level on the same latitude almost two thirds of 500 children had mild rickets in the late 1920s. An increase in the proportion of animal protein in the 20th century American diet coupled with increased consumption of milk  fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases.
 * Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility. The effects of osteomalacia are thought to contribute to chronic musculoskeletal pain, there is no persuasive evidence of lower vitamin D status in chronic pain sufferers.

Adequate vitamin D may also be associated with healthy hair follicle growth cycles. There are also associations between low 25(OH)D levels and peripheral vascular disease, certain cancers, multiple sclerosis, rheumatoid arthritis, juvenile diabetes, Parkinson's and Alzheimer's disease. However these associations were found in observational studies and vitamin D vitamin supplements have not been demonstrated to reduce the risks of these diseases.

Research shows that dark-skinned people living in temperate climates have lower vitamin D levels. It has been suggested that dark-skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis, however a recent study has found novel evidence that low vitamin D levels among Africans may be due to other reasons. Recent evidence implicates parathyroid hormone in adverse cardiovascular outcomes, black women have an increase in serum PTH at a lower 25(OH)D level than white women. A large scale association study of the genetic determinants of vitamin D insufficiency in Caucasians found no links to pigmentation.

The Director General of Research and Development and Chief Scientific Adviser for the UK Department of Health and NHS said that children aged six months to five years should be given vitamin D supplements—particularly during the winter. However, people who get enough vitamin D from their diet and from sunlight are not recommended for vitamin D supplements.

With an emphasis on recommending treatment and intake levels for patients at risk of deficiency listed below, a panel of experts issued a clinical guideline in 2011, stating that vitamin D2 and D3 sources are equivalent.


 * infants and children aged 0–1 year (400 IU)
 * adults aged 19–70 years (600 IU)
 * adults aged 70+ years (800 IU)
 * pregnant and lactating women (600 IU)
 * obese children and adults (2-3 times more than for their respective age groups)
 * tolerable upper intake levels as 1,000 IU for infants up to 6 months, 1,500 IU for ages 6 months to 1 year, 2,500 IU for children aged 1–3 years, 3,000 IU for children aged 4–8 years, and 4,000 IU for everyone aged over 8 years

Measuring vitamin D status
The serum concentration of 25-hydroxy-vitamin D is typically used to determine vitamin D status. It reflects vitamin D produced in the skin as well as that acquired from the diet, and has a fairly long circulating half-life of 15 days. It does not, however, reveal the amount of vitamin D stored in other body tissues. The level of serum 1,25-dihydroxy-vitamin D is not usually used to determine vitamin D status because it has a short half-life of 15 hours and is tightly regulated by parathyroid hormone, calcium, and phosphate, such that it does not decrease significantly until vitamin D deficiency is already well advanced.

One study found that vitamin D3 raised 25-hydroxy-vitamin D blood levels more than did vitamin D2, but this difference has been adequately disproved to allow reasonable assumption that D2 and D3 are equal for maintaining 25-hydroxy-vitamin D status.

There has been variability in results of laboratory analyses of the level of 25-hydroxy-vitamin D. Falsely low or high values have been obtained depending on the particular test or laboratory used. Beginning in July 2009 a standard reference material became available which should allow laboratories to standardise their procedures.

There is some disagreement concerning the exact levels of 25-hydroxy-vitamin D needed for good health. A level lower than 10 ng/mL (25 nmol/L) is associated with the most severe deficiency diseases: rickets in infants and children, and osteomalacia in adults. A concentration above 15 ng/ml (37.5 nmol/L) is generally considered adequate for those in good health. Levels above 30 ng/ml (75 nmol/L) are proposed by some as desirable for achieving optimum health, but there is not yet enough evidence to support this.

Levels of 25-hydroxy-vitamin D that are consistently above 200 ng/mL (500 nmol/L) are thought to be potentially toxic, although data from humans are sparse. In animal studies levels up to 400 ng/mL (1,000 nmol/L) were not associated with toxicity. Vitamin D toxicity usually results from taking supplements in excess. Hypercalcemia is typically the cause of symptoms, and levels of 25-hydroxy-vitamin D above 150 ng/mL (375 nmol/L) are usually found, although in some cases 25-hydroxy-vitamin D levels may appear to be normal. It is recommended to periodically measure serum calcium in individuals receiving large doses of vitamin D.

In overweight persons increased fat mass is inversely associated with 25(OH)D levels. This association may confound the reported relationships between low vitamin D status and conditions which occur more commonly in obesity as the circulating 25(OH)D underestimates their total body stores. However, as vitamin D is fat-soluble, excess amounts can be stored in fat tissue and used during winter months, when sun exposure is limited.

A study of highly sun exposed (tanned) healthy young skateboarders and surfers in Hawaii found levels below the proposed higher minimum of 30 ng/ml in 51% of the subjects. The highest 25(OH)D concentration was around 60 ng/ml (150nmol/L). A similar study in Hawaii found a range of (11–71 ng/mL) in a population with prolonged extensive skin exposure while as part of the same study Wisconsin breastfeeding mothers were given supplements. The range of circulating 25(OH)D levels in women in the supplementated group was from 12–77 ng/mL. It is noteworthy that the levels in the supplemented population in Wisconsin were higher than the sun exposed group in Hawaii (which again included surfers because it was the same data set).

Another study of African Americans found that blood levels of 25(OH)D decreased linearly with increasing African ancestry, the decrease being 2.5-2.75 nmol/L per 10% increase in African ancestry. Sunlight and diet were 46% less effective in raising these levels among subjects with high African ancestry than among those with low/medium African ancestry. It could be possible that vitamin-D metabolism differs by ethnicity. Further, Dr. Peter Frost (2009) concluded that vitamin-D deficiency is being diagnosed in non-European individuals who are, in fact, perfectly normal. This is particularly true for African Americans, nearly half of whom are classified as vitamin-D deficient, even though few show signs of calcium deficiency—which would be a logical outcome. Indeed, this population has less osteoporosis, fewer fractures, and a higher bone mineral density than do Euro-Americans, who generally produce and ingest more vitamin D. "What will be the outcome of raising vitamin-D levels in these populations? Keep in mind that we are really talking about a hormone, not a vitamin. This hormone interacts with the chromosomes and gradually shortens their telomeres if concentrations are either too low or too high. Tuohimaa (2009) argues that optimal levels may lie in the range of 40-60 nmol/L. In non-European populations the range is probably lower. It may also be narrower in those of tropical origin, since their bodies have not adapted to the wide seasonal variation of non-tropical humans.

If this optimal range is continually exceeded, the long-term effects may look like those of aging.."

Overdose by ingestion
In healthy adults, sustained intake of more than 1250 micrograms/day (50,000 IU) can produce overt toxicity after several months; those with certain medical conditions such as primary hyperparathyroidism are far more sensitive to vitamin D and develop hypercalcemia in response to any increase in vitamin D nutrition, while maternal hypercalcemia during pregnancy may increase fetal sensitivity to effects of vitamin D and lead to a syndrome of mental retardation and facial deformities. Pregnant or breastfeeding women should consult a doctor before taking a vitamin D supplement. For infants (birth to 12 months), the tolerable upper limit (maximum amount that can be tolerated without harm) is set at 25 micrograms/day (1000 IU). One thousand micrograms (40,000 IU) per day in infants has produced toxicity within one month. After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM), has increased the tolerable upper limit (UL) to 2500 IU per day for ages 1–3 years, 3000 IU per day for ages 4–8 years and 4000 IU per day for ages 9–71+ years (including pregnant or lactating women). Vitamin D overdose causes hypercalcemia, and the main symptoms of vitamin D overdose are those of hypercalcemia: anorexia, nausea, and vomiting can occur, frequently followed by polyuria, polydipsia, weakness, nervousness, pruritus, and, ultimately, renal failure. Proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop. Vitamin D toxicity is treated by discontinuing vitamin D supplementation and restricting calcium intake. Kidney damage may be irreversible.

Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity. Within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin), the concentrations of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded. According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day. According to Holick, "the skin has a large capacity to produce cholecalciferol"; his experiments indicate "[W]hole-body exposure to one minimal erythemal dose [a dose that would just begin to produce sunburn in a given individual] of simulated solar ultraviolet radiation is comparable with taking an oral dose of between 250 and 625 micrograms (10 000 and 25 000 IU) vitamin D."

Based on the non-observation of toxicity at daily intakes of up to 50,000 IU per day, leading to calcidiol levels of more than 600 nmol/L, and the similar effect of supplementation and whole body exposure to one erythemal dose, some researchers argued in 2007 that 250 micrograms/day (10,000 IU) in healthy adults was guaranteed to be safe and can thus be adopted as the tolerable upper limit. Published cases of toxicity involving hypercalcemia in which the vitamin D dose and the 25-hydroxy-vitamin D levels are known all involve an intake of ≥40,000IU (1000 mcg) per day. Supplements and skin synthesis have a different effect on serum 25(OH)D concentrations; endogenously synthesized vitamin D3 travels in plasma almost exclusively on vitamin D-binding protein (VDBP), providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol. Orally administered vitamin D produces swift hepatic delivery and increases in plasma 25-hydroxycholecalciferol. The richest food source of vitamin D — wild salmon — would require 35 ounces a day to provide 10,000IU. Recommending supplementation, when those supposedly in need of it are labeled healthy, has proved contentious, and doubt exists concerning long term effects of attaining and maintaining serum 25(OH)D of at least 80nmol/L by supplementation.

A Toronto study concluded, "skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D." The uniform occurrence of low serum 25(OH)D in Indians living in India and Chinese in China, does not support the hypothesis that the low levels seen in the more pigmented are due to lack of synthesis from the sun at higher latitudes; the leader of the study has urged dark-skinned immigrants to take vitamin D supplements nonetheless, saying, "I see no risk, no downside, there's only a potential benefit." Whether the toxicity of oral intake of vitamin D is due to that route being unnatural, as suggested by Fraser, is not known, but there is evidence to suggest dietary vitamin D may be carried by lipoprotein particles into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages. These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk.

Bone health
One of the most important roles of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestines, promoting bone resorption by increasing osteoclast number, maintaining calcium and phosphate levels for bone formation, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels. Vitamin D deficiency can result in lower bone mineral density and an increased risk of bone loss (osteoporosis) or bone fracture because a lack of vitamin D alters mineral metabolism in the body. Vitamin D has been studied as a potential treatment for osteoporosis, but since treatment of vitamin D deficiency is associated with an increase of mineralization of osteoid, it remains unclear whether vitamin D has any effect on osteoporotic bone. In cross-sectional studies there was a positive relationship between vitamin D and bone mineral density in the hip. Lips (2001) reported that bone mineral deficit in osteomalacia was larger than that in milder degrees of vitamin D deficiency.

There is also a relationship between low bone mineral density and sedentary life style. This is evident in frail, elderly subjects because they are often vitamin D deficient and lead an inactive lifestyle. Lips (2001) also reported that mild vitamin D deficiency was not associated with an increased risk for hip fracture. A study done in Norway consisted of 246 patients with hip fractures who were studied for risk factors. Results showed that a vitamin D intake lower than 100 IU/day was associated with an increased risk for hip fracture. Vitamin D supplements may also increase bone mineral density in other parts of the skeleton. A study showed that a supplement of 800 IU per day of vitamin D increased the bone mineral density of the lumbar spine in postmenopausal women in comparison with the control group. Persons over the age of 50 years need higher levels of vitamin D. In a study discussed in LoPiccolo et al. (2010), adults who consumed a daily supplementation with 482–770 IU of vitamin D had reduced fracture rates of 20% for non-vertebral fractures. However, there was no reported reduction in fracture risk for persons who had 400 IU or less of vitamin D daily.

Immune system
Vitamin D receptor ligands have been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages. Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi. Suggestions of a link between vitamin D deficiency and the onset of multiple sclerosis posited that this is due to the immune-response suppression properties of Vitamin D and that vitamin D is required to activate a histocompatibility gene (HLA-DRB1*1501) necessary for differentiating between self and foreign proteins in a subgroup of individuals genetically predisposed to MS. Whether vitamin D supplements during pregnancy can lessen the likelihood of the child developing MS later in life is not known; however, vitamin D fortification has been suggested to have caused a pandemic of allergic disease and an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life has been found. The average daily intake from fortified foods (less than 400 IU) should change the serum level only slightly, an additional 12 nmol/L for very deficient people, down to < 2 nmol/L increase for D sufficient persons. Veteran vitamin D researcher Hector DeLuca has cast doubt on whether vitamin D affects MS.

Tuberculosis
Historically, vitamin D3 was used to treat tuberculosis patients, but has not been adequately investigated in controlled clinical trials. The hormonally active form of vitamin D3, 1,25-dihydroxycholecalciferol (1,25(OH)2D), has been shown to have antimycobacterial activity in vitro, but the applicability of this effect to clinical situations has not been shown.

One study found that vitamin D metabolites regulate the expression of cathelicidin which is an antimicrobial peptide with activity against Mycobacterium tuberculosis, and that the prevalence of vitamin D insufficiency (serium 25(OH)D concentration < 30 ng/mL) in patients with active tuberculosis was 86%.

Vitamin D3 supplementations have not shown any improvement in treating tuberculosis except in a small subset of patients with the tt genotype of the TaqI vitamin D receptor polymorphism. Several studies have shown an association between low serum levels of 25-hydroxycholecalciferol (25(OH)D) and increased risk for both active tuberculosis disease progression and susceptibility. More prospective studies will be required to ascertain the potential role of vitamin D supplementation in treating patients with tuberculosis.

HIV
Vitamin D3 has also shown some anti-HIV-1 effects in vitro, including the induction of autophagy. The potential effect in humans has not been investigated. Lower levels of 1,25(OH)2D in HIV infected patients are correlated with significantly lower CD4+ T cell counts and higher tumor necrosis factor levels, which normally decrease in number with progression to AIDS, although no causative association has been shown. In an epidemiological study of HIV positive women in Tanzania, there appeared to be a correlation between reduced levels of vitamin D and speed of HIV disease progression. These results will need to be confirmed in a blinded clinical trial before dietary recommendations can be made.

Influenza
Lack of vitamin D synthesis during the winter is a possible explanation for high rates of influenza infection during winter; however, see flu season for the factors apart from vitamin D that are also hypothesized to influence rates of infection during winter. For viral infections, other implicated factors include low relative humidities produced by indoor heating and cold temperatures that favor virus spread during winter.

Cancer
The molecular basis for thinking that vitamin D has the potential to prevent cancer lies in its role in a wide range of cellular mechanisms central to the development of cancer. These effects may be mediated through vitamin D receptors expressed in cancer cells. Polymorphisms of the vitamin D receptor (VDR) gene have been associated with an increased risk of breast cancer. Women with mutations in the VDR gene had an increased risk of breast cancer.

A 2006 study using data on over 4 million cancer patients from 13 different countries showed a marked increase in some cancer risks in countries with less sun and another metastudy found correlations between vitamin D levels and cancer. The authors suggested 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%. Low levels of vitamin D in serum have been correlated with breast cancer disease progression and bone metastases. However, the vitamin D levels of a population do not depend on the solar irradiance to which they are exposed. Moreover, there are genetic factors involved with cancer incidence and mortality which are more common in northern latitudes.

A 2006 study 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. However, in male smokers a 3-fold increased risk for pancreatic cancer in the highest compared to lowest quintile of serum 25-hydroxyvitamin D concentration has been found.

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). The study was criticized on several grounds including lack of reported data, use of statistical techniques and comparison with a self-selected (i.e. non-randomized) observational study that found long term convergence of breast cancer incidence (i.e. the cancer occurrence had merely been delayed) The author's response provided the requested data, explained their statistical usage and commented that even if the vitamin D merely delayed the appearance of cancer (which they did not believe, based on other studies), that this was still a considerable benefit.

In 2007, the Canadian Cancer Society recommended that adults living in Canada should consider taking vitamin D supplementation of 1,000 international units (IU) a day during the fall and winter. A US National Cancer Institute study analyzed data from the third national Health and Nutrition Examination Survey to examine the relationship between levels of circulating vitamin D in the blood and cancer mortality in a group of 16,818 participants aged 17 and older. It found no support for an association between 25(OH)D and total cancer mortality. However, the study did find that "[c]olorectal cancer mortality was inversely related to serum 25(OH)D level, with levels 80 nmol/L or higher associated with a 72% risk reduction (95% confidence interval = 32% to 89%) compared with lower than 50 nmol/L, Ptrend= .02." Unlike other studies, this one was carried out prospectively— meaning that participants were followed looking forward — and the researchers used actual blood tests to measure the amount of vitamin D in blood, rather than trying to infer vitamin D levels from potentially inaccurate predictive models.

A meta-study published in the International Journal of Cancer in May 2010 analyzed 35 independent studies of vitamin D and cancer. The researchers determined that a 10 nanogram/milliliter increase in serum vitamin D is associated with a 15% lower risk of colon cancer. The analysis also found an 11% lower risk for breast cancer, although the authors report that due to case study methodology that this finding is ultimately insignificant.

A 2011 study done at the University of Rochester Medical Center found that low vitamin D levels among women with breast cancer correlate with more aggressive tumors and poorer prognosis. The study associated sub-optimal vitamin D levels with poor scores on every major biological marker that helps physicians predict a patient’s breast cancer outcome. The lead researcher stated, “Based on these results, doctors should strongly consider monitoring vitamin D levels among breast cancer patients and correcting them as needed.”

Cardiovascular disease
A report from the National Health and Nutrition Examination Survey (NHANES) involving nearly 5,000 participants found that low levels of vitamin D were associated with an increased risk of peripheral artery disease (PAD). The incidence of PAD was 80% higher in participants with the lowest vitamin D levels (<17.8 ng/mL). Cholesterol levels were found to be reduced in gardeners in the UK during the summer months. Low levels of vitamin D are associated with an increase in high blood pressure and cardiovascular risk. Numerous observational studies show this link, but of two systemic reviews one found only weak evidence of benefit from supplements and the other found no evidence of a beneficial effect whatsoever.

There is a certain amount of evidence to suggest that dietary vitamin D may be carried by lipoprotein particles into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages. These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Calcifediol (25-hydroxy-vitamin D) is implicated in the etiology of atherosclerosis, especially in non-Caucasians. Freedman et al. (2010) found that serum vitamin D correlates with calcified atheroscleratic plaque (CP) in African Americans, but not in Euro-Americans, "Higher levels of 25-hydroxyvitamin D seem to be positively associated with aorta and carotid CP in African Americans but not with coronary CP. These results contradict what is observed in individuals of European descent." One study found an elevated risk of ischaemic heart disease in Southern India in individuals whose vitamin D levels were above 89 ng/mL. A review of vitamin D status in India concluded that studies uniformly point to low 25(OH)D levels in Indians despite abundant sunshine, and suggested a public health need to fortify Indian foods with vitamin D might exist. The levels found in India are consistent with many other studies of tropical populations which have found that even an extreme amount of sun exposure, such as incurred by rural Indians, does not raise 25(OH)D levels to the levels typically found in Europeans.

Mortality
Using information from the National Health and Nutrition Examination Survey a large scale study concluded that having low levels of vitamin D (<17.8 ng/ml) was independently associated with an increase in all-cause mortality in the general population. However it has been pointed out that increased mortality was also found in those with higher concentrations, (above 50 ng/ml). A sophisticated August 2010 study of plasma vitamin D and mortality in older men concluded that both high (>39 ng/ml) and low (<18 ng/ml) concentrations of plasma 25(OH)D are associated with elevated risks of overall and cancer mortality compared with intermediate concentrations. These boundaries were less than suggested by the Melamed et al. study of National Health and Nutrition Examination Survey data but the immunoassay used by National Health and Nutrition Examination Survey tended to overestimate vitamin D values.

Overall, excess or deficiency in the calciferol system appear to cause abnormal functioning and premature aging. The data suggest a U-shaped shaped risk curve between serum 25OHD level and all-cause mortality; increases in risk with high levels appear at a lower threshold for the black population.

Complex regulatory mechanisms control metabolism and recent epidemiological evidence suggests that there is a narrow range of vitamin D blood levels in which metabolic functions are optimized. Levels above or below this natural homeostasis of vitamin D are associated with increased mortality.