Diabetes -- A systematic review of concluded that the available studies show no evidence of vitamin D3 supplementation having an effect on glucose homeostasis or diabetes prevention. Depression -- Clinical trials of vitamin D supplementation for depressive symptoms have generally been of low quality and show no overall effect, although subgroup analysis showed supplementation for participants with clinically significant depressive symptoms or depressive disorder had a moderate effect.
Cognition and dementia -- A systematic review of clinical studies found an association between low vitamin D levels with cognitive impairment and a higher risk of developing Alzheimer's disease. However, lower vitamin D concentrations are also associated with poor nutrition and spending less time outdoors. Therefore, alternative explanations for the increase in cognitive impairment exist and hence a direct causal relationship between vitamin D levels and cognition could not be established.
Pregnancy -- Low levels of vitamin D in pregnancy are associated with gestational diabetes , pre-eclampsia , and small for gestational age infants. Weight loss -- Though hypothesized that vitamin D supplementation may be an effective treatment for obesity apart from calorie restriction , one systematic review found no association of supplementation with body weight or fat mass. Governmental regulatory agencies stipulate for the food and dietary supplement industries certain health claims as allowable as statements on packaging.
European Food Safety Authority. US Food and Drug Administration. Other possible agencies with claim guidance: Various institutions have proposed different recommendations for the amount of daily intake of vitamin D. These vary according to precise definition, age, pregnancy or lactation, and the extent assumptions are made regarding skin synthesis of vitamin D. The dietary reference intake for vitamin D issued in by the Institute of Medicine renamed National Academy of Medicine in , superseded previous recommendations which were expressed in terms of Adequate Intake.
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, and assumes that calcium requirements are being met. Health Canada published recommended dietary allowances RDA and tolerable upper intake levels for vitamin D in [] based on the Institute of Medicine report. Australia and New Zealand published nutrient reference values including guidelines for dietary vitamin D intake in The European Food Safety Authority EFSA in [] reviewed the current evidence, finding the relationship between serum 25 OH D concentration and musculoskeletal health outcomes is widely variable.
The UK National Health Service recommends babies and young children aged six months to five years, pregnant or breastfeeding women, and sun-deprived elderly people should take daily vitamin supplements to ensure sufficient vitamin D intake. Non-government organisations in Europe have made their own recommendations. Although vitamin D is not present naturally in most foods, [2] [4] it is commonly added as a fortification in manufactured foods.
In some countries, staple foods are artificially fortified with vitamin D. In general, vitamin D 2 is found in fungi and vitamin D 3 is found in animals. The vitamin D 2 content in mushrooms and Cladina arbuscula , a lichen, increase with exposure to ultraviolet light. Manufactured foods fortified with Vitamin D include some fruit juices and fruit juice drinks, meal replacement energy bars , soy protein -based beverages, certain cheese and cheese products, flour products, infant formulas , many breakfast cereals , and milk.
While some studies have found that vitamin D 3 raises 25 OH D blood levels faster and remains active in the body longer, [] [] others contend that vitamin D 2 sources are equally bioavailable and effective as D 3 for raising and sustaining 25 OH D. Vitamin D content in typical foods is reduced variably by cooking. Recommendations on recommended 25 OH D serum levels vary across authorities, and vary based on factors like age.
The dietary reference intakes for vitamin D are chosen with a margin of safety and 'overshoot' the targeted serum value to ensure the specified levels of intake achieve the desired serum 25 OH D levels in almost all persons. No contributions to serum 25 OH D level are assumed from sun exposure and the recommendations are fully applicable to people with dark skin or negligible exposure to sunlight.
Vitamin D toxicity is rare. Pregnant or breastfeeding women should consult a doctor before taking a vitamin D supplement. In addition, for products intended for infants, the FDA recommends the dropper hold no more than IU. One thousand micrograms per day in infants has produced toxicity within one month. Calcitriol itself is auto-regulated in a negative feedback cycle, and is also affected by parathyroid hormone , fibroblast growth factor 23 , cytokines , calcium, and phosphate.
Vitamin D overdose causes hypercalcemia, which is a strong indication of vitamin D toxicity — this can be noted with an increase in urination and thirst. If hypercalcemia is not treated, it results in excess deposits of calcium in soft tissues and organs such as the kidneys, liver, and heart, resulting in pain and organ damage. The main symptoms of vitamin D overdose which are those of hypercalcemia including anorexia , nausea, and vomiting.
These may be followed by polyuria , polydipsia , weakness, insomnia, nervousness, pruritus and ultimately renal failure. Furthermore, 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. The concentrations of vitamin D precursors produced in the skin reach an equilibrium , and any further vitamin D produced is degraded.
Synthesis of vitamin D in nature is dependent on the presence of UV radiation and subsequent activation in liver and in kidney. Many animals synthesize vitamin D 3 from 7-dehydrocholesterol , and many fungi synthesize vitamin D 2 from ergosterol. Click on icon in lower right corner to open. Click on genes, proteins and metabolites below to link to respective articles. The transformation that converts 7-dehydrocholesterol to vitamin D 3 occurs in two steps. The process is faster in white button mushrooms.
Vitamin D 3 is produced photochemically from 7-dehydrocholesterol in the skin of most vertebrate animals, including humans. Exposure to light through windows is insufficient because glass almost completely blocks UVB light. The darker the skin, and the weaker the sunlight, the more minutes of exposure are needed. Vitamin D overdose is impossible from UV exposure; the skin reaches an equilibrium where the vitamin degrades as fast as it is created. Sunscreen absorbs or reflects ultraviolet light and prevents much of it from reaching the skin.
The skin consists of two primary layers: Vitamin D is produced in the keratinocytes [] of two innermost strata, the stratum basale and stratum spinosum. Vitamin D can be synthesized only by a photochemical process. Phytoplankton in the ocean such as coccolithophore and Emiliania huxleyi have been photosynthesizing vitamin D for more than million years. Primitive vertebrates in the ocean could absorb calcium from the ocean into their skeletons and eat plankton rich in vitamin D. Land vertebrates required another source of vitamin D other than plants for their calcified skeletons.
They had to either ingest it or be exposed to sunlight to photosynthesize it in their skin. In birds and fur-bearing mammals, fur or feathers block UV rays from reaching the skin. Instead, vitamin D is created from oily secretions of the skin deposited onto the feathers or fur, and is obtained orally during grooming. Vitamin D 3 cholecalciferol is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification.
Vitamin D 2 ergocalciferol is produced in a similar way using ergosterol from yeast or mushrooms as a starting material. Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcifediol. Circulating calcifediol may then be converted into calcitriol , the biologically active form of vitamin D, in the kidneys. Whether it is made in the skin or ingested, Vitamin D is hydroxylated in the liver at position 25 upper right of the molecule to form hydroxycholecalciferol calcifediol or 25 OH D.
The conversion of calcifediol to calcitriol is catalyzed by the enzyme hydroxyvitamin D 3 1-alpha-hydroxylase , which is the product of the CYP27B1 human gene. The activity of CYP27B1 is increased by parathyroid hormone , and also by low calcium or phosphate.
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Following the final converting step in the kidney, calcitriol is released into the circulation. By binding to vitamin D-binding protein, calcitriol is transported throughout the body, including to the classical target organs of intestine, kidney and bone. In addition to the kidneys, calcitriol is also synthesized by certain other cells including monocyte - macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine , modulating body defenses against microbial invaders by stimulating the innate immune system.
The activity of calcifediol and calcitriol can be reduced by hydroxylation at position 24 by vitamin D3 hydroxylase , forming secalciferol and calcitetrol respecively. American researchers Elmer McCollum and Marguerite Davis in [9] 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 , Elmer McCollum tested modified cod liver oil in which the vitamin A had been destroyed.
He called it vitamin D because it was the fourth vitamin to be named. In , [9] it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced now known as D 3. Alfred Fabian Hess stated: A meeting took place with J.
Bernal , and Dorothy Crowfoot to discuss possible structures, which contributed to bringing a team together. X-ray crystallography demonstrated the sterol molecules were flat, not as proposed by the German team led by Windaus. In , Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids which found immediate acceptance. In the s, Windaus clarified further the chemical structure of vitamin D. In , American biochemist Harry Steenbock at the University of Wisconsin demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials.
A vitamin D deficiency is a known cause of rickets. His irradiation technique was used for foodstuffs, most memorably for milk. By the expiration of his patent in , rickets had been all but eliminated in the US. In , after studying nuclear fragments of intestinal cells, a specific binding protein for Vitamin D called the Vitamin D Receptor was identified by Mark Haussler and Tony Norman. In the liver, vitamin D was found to be converted to calcifediol. Calcifediol is then converted by the kidneys to calcitriol, the biologically active form of vitamin D.
The vitamin D metabolites, calcifediol and calcitriol, were identified by competing teams led by Michael F. There is considerable research activity looking at effects of vitamin D and its metabolites in animal models, cell systems, gene expression studies, epidemiology and clinical therapeutics. These different types of studies can produce conflicting evidence as to the benefits of interventions with vitamin D.
Vitamin D: What’s the “right” level? - Harvard Health Blog - Harvard Health Publishing
They suggest, for some people, reducing the risk of preventable disease requires a higher level of vitamin D than that recommended by the IOM. Until such trials are conducted, the implications of the available evidence for public health and patient care will be debated". Some preliminary studies link low vitamin D levels with disease later in life. Vitamin D deficiency is widespread in the European population. Apart from VDR activation, various alternative mechanisms of action are under study, such as inhibition of signal transduction by hedgehog , a hormone involved in morphogenesis.
From Wikipedia, the free encyclopedia. For other uses, see Vitamin D disambiguation. The American Journal of Clinical Nutrition. The Journal of Nutrition. Retrieved 6 June American Association for Clinical Chemistry. Retrieved June 23, A metabolite of vitamin D active in intestine". Vitamin D and cardiometabolic outcomes". Annals of Internal Medicine. University of California, Riverside. Retrieved January 24, Molecular vitamin D mediated mechanisms". Journal of Cellular Biochemistry. Canadian Journal of Physiology and Pharmacology.
Retrieved July 9, The New England Journal of Medicine. The British Journal of Nutrition.
Nutrition Through the Life Cycle. The Cochrane Database of Systematic Reviews 4: Calcified Tissue International Review. Journal of Tropical Pediatrics.
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Archived from the original on June 8, Retrieved August 24, The Nutrition Desk Reference. Melanie 1 February How Milk Became America's Drink. A systematic review and meta-analysis". Therapeutic Advances in Musculoskeletal Disease. Progress in Cardiovascular Diseases. The Cochrane Database of Systematic Reviews. Preventive Services Task Force". A Systematic Review and Meta-analysis". American Journal of Epidemiology Review.
The Journal of Clinical Endocrinology and Metabolism. Vitamin D Summary of the role of vitamin D in human metabolic processes Overview of the role of vitamin D Populations at risk for vitamin D deficiency Evidence used for estimating recommended vitamin D intake Considerations in viewing recommended intakes for vitamin D Summary of the RNIs for vitamin D by age group Vitamin D toxicity Future research References Summary of the role of vitamin D in human metabolic processes Vitamin D is required to maintain normal blood levels of calcium and phosphate, that are in turn needed for the normal mineralisation of bone, muscle contraction, nerve conduction, and general cellular function in all cells of the body.
Vitamin D achieves this after its conversion to the active form 1,dihydroxyvitamin D [1, OH 2 D], or calcitriol. This active form regulates the transcription of a number of vitamin D-dependent genes coding for calcium-transporting proteins and bone matrix proteins. Vitamin D also modulates the transcription of cell cycle proteins, that decrease cell proliferation and increase cell differentiation of a number of specialised cells of the body e.
This property may explain the actions of vitamin D in bone resorption, intestinal calcium transport, and skin. Vitamin D also possesses immuno-modulatory properties that may alter responses to infections in vivo. The cell differentiating and immuno-modulatory properties underlie the reason why vitamin D derivatives are now used successfully in the treatment of psoriasis and other skin disorders. For the purposes of this document, 1, OH 2 D and OH-D will be used to refer to calcitriol and calcidiol, respectively.
Overview of the role of vitamin D Vitamin D, a seco-steroid, can either be made in the skin from a cholesterol-like precursor 7-dehydrocholesterol by exposure to sunlight or can be provided pre-formed in the diet 1. The version made in the skin is referred to as vitamin D 3 whereas the dietary form can be vitamin D 3 or a closely related molecule of plant origin known as vitamin D 2. Because vitamin D can be made in the skin, it should not strictly be called a vitamin, and some nutritional texts refer to the substance as a prohormone and to the two forms as cholecalciferol D 3 or ergocalciferol D 2.
From a nutritional perspective, the two forms are metabolised similarly in humans, are equal in potency, and can be considered equivalent. It is now firmly established that vitamin D 3 is metabolised first in the liver to hydroxyvitamin-D OH-D or calcidiol 2 and subsequently in the kidneys to 1, OH 2 D 3 to produce a biologically active hormone.
The 1, OH 2 D, like all vitamin D metabolites, is present in the blood complexed to vitamin D binding protein, a specific a-globulin. The 1, OH 2 D is believed to act on target cells similarly to the way a steroid hormone would act. Free hormone crosses the plasma membrane and interacts with a specific nuclear receptor known as the vitamin D receptor, a DNA-binding, zinc-finger protein with a molecular weight of 55, 4.
This ligand-receptor complex binds to a specific vitamin D-responsive element and, with associated transcription factors e. As a result of these processes ,1, OH 2 D stimulates intestinal absorption of calcium and phosphate and mobilises calcium and phosphate by stimulating bone resorption 6. These functions serve the common purpose of restoring blood levels of calcium and phosphate to normal when concentrations of the two ions are low. Lately, interest has focused on other cellular actions of 1, OH 2 D.
With the discovery of 1, OH 2 D receptors in many classical non-target tissues such as brain, various bone marrow-derived cells, skin, thymus, etc. This effect has been widely interpreted to mean that the natural role of 1, OH 2 D is to induce osteoclastogenesis from colony forming units-granulatory monocytes in the bone marrow. The 1, OH 2 D also suppresses interleukin 2 production in activated T lymphocytes 10, 11 , an effect which suggests the hormone might play a role in immuno-modulation in vivo.
The pharmacologic effects of 1, OH 2 D are profound and have resulted in the development of vitamin D analogues, that are approved for use in hyper-proliferative conditions such as psoriasis In calcium homeostasis 1, OH 2 D works in conjunction with parathyroid hormone PTH to produce its beneficial effects on the plasma levels of ionised calcium and phosphate 5, The physiologic loop Figure 10 starts with calcium sensing by the calcium receptor of the parathyroid gland When the level of ionised calcium in plasma falls, PTH is secreted by the parathyroid gland and stimulates the tightly regulated renal enzyme OH-Daa-hydroxylase to make more 1, OH 2 D from the large circulating pool of OH-D.
The resulting increase in 1, OH 2 D with the rise in PTH causes an increase in calcium transport within the intestine, bone, and kidney. All these events raise plasma calcium levels back to normal, that in turn is sensed by the calcium receptor of the parathyroid gland. The further secretion of PTH is turned off not only by the feedback action of calcium, but also by a short feedback loop involving 1, OH 2 D directly suppressing PTH synthesis in the parathyroid gland not shown in figure.
Adapted from Jones et al. Although this model oversimplifies the events involved in calcium homeostasis it is easy to see from it that sufficient OH-D must be available to provide adequate 1, OH 2 D synthesis and hence an adequate level of plasma calcium and that vitamin D deficiency will result in inadequate OH-D and 1, OH 2 D synthesis, inadequate calcium homeostasis, and a constantly elevated PTH level termed: It becomes evident from this method of presentation of the role of vitamin D that the nutritionist can focus on the plasma levels of OH-D and PTH to gain an insight into vitamin D status.
Not shown but also important is the endpoint of the physiologic action of vitamin D, namely adequate plasma calcium and phosphate ions, that provide the raw materials for bone mineralisation. Populations at risk for vitamin D deficiency Infants Infants constitute a population at risk for vitamin D deficiency because of relatively large vitamin D needs brought about by their high rate of skeletal growth.
At birth, infants have acquired in utero the vitamin D stores that must carry them through the first months of life. Breast-fed infants are particularly at risk because of the low concentrations of vitamin D in human milk This problem is further compounded in some infants fed human milk by a restriction in exposure to ultraviolet UV light for seasonal, latitudinal, cultural, or social reasons. Infants born in the autumn months at extremes of latitude are particularly at risk because they spend the first 6 months of their life indoors and therefore have little opportunity to synthesise vitamin D in their skin during this period.
Consequently, although vitamin D deficiency is rare in developed countries, sporadic cases of rickets are still being reported in many northern cities but almost always in infants fed human milk These amounts of dietary vitamin D are sufficient to prevent rickets.
Adolescents Another period of rapid growth of the skeleton occurs at puberty and increases the need not for the vitamin D itself, but for the active form 1, OH 2 D. Furthermore, unlike infants, adolescents are usually outdoors and therefore usually are exposed to UV light sufficient for synthesising vitamin D for their needs. Excess production of vitamin D in the summer and early fall months is stored mainly in the adipose tissue 22 and is available to sustain high growth rates in the winter months that follow.
Insufficient vitamin D stores during these periods of increased growth can lead to vitamin D insufficiency Elderly Over the past 20 years, clinical research studies of the basic biochemical machinery handling vitamin D have suggested an age-related decline in many key steps of vitamin D action 24 including rate of skin synthesis, rate of hydroxylation leading to activation to the hormonal form, and response of target tissues e. Not surprisingly a number of independent studies from around the world have shown that there appears to be vitamin D deficiency in a subset of the elderly population, as characterised by low blood levels of OH-D coupled with elevations of plasma PTH and alkaline phosphatase There is evidence that this vitamin D deficiency contributes to declining bone mass and increases the incidence of hip fractures Although some of these studies may exaggerate the extent of the problem by focusing on institutionalised individuals or in-patients with decreased sun exposures, in general they have forced health professionals to re-address the intakes of this segment of society and look at potential solutions to correct the problem.
These findings have led agencies and researchers to suggest an increase in recommended vitamin D intakes for the elderly from the suggested 2. The increased requirements are justified mainly on the grounds of the reduction in skin synthesis of vitamin D, a linear reduction occurring in both men and women, that begins with the thinning of the skin at age 20 years Pregnancy and lactation Elucidation of the changes in calciotropic hormones occurring during pregnancy and lactation has revealed a role for vitamin D in the former but probably not the latter.
Even in pregnancy, the changes in vitamin D metabolism which occur, namely an increase in the maternal plasma levels of 1, OH 2 D 34 due to a putative placental synthesis of the hormone 35 , do not seem to impinge greatly on the maternal vitamin D requirements. The concern that modest vitamin D supplementation might be deleterious to the foetus is not justified.
In lactating women there appears to be no direct role for vitamin D because increased calcium needs are regulated by PTH-related peptide 36, 37 , and recent studies have failed to show any change in vitamin D metabolites during lactation 38, As stated above, the vitamin D content of human milk is low Consequently, there is no great drain on maternal vitamin D reserves either to regulate calcium homeostasis or to supply the need of human milk. Because human milk is a poor source of vitamin D, rare cases of nutritional rickets are still found, but these are almost always in breast-fed babies deprived of sunlight exposure Furthermore, there is little evidence that increasing calcium or vitamin D supplements to lactating mothers results in an increased transfer of calcium or vitamin D in milk Thus, the current thinking, based on a clearer understanding of the role of vitamin D in lactation, is that there is little purpose in recommending additional vitamin D for lactating women.
The goal for mothers who breast-feed their infants seems to be merely to ensure good nutrition and sunshine exposure in order to ensure normal vitamin D status during the perinatal period. Adapted with permission from Shearer Evidence used for estimating recommended vitamin D intake Lack of accuracy in estimating dietary intake and skin synthesis The unique problem of estimating total intake of a substance that can be provided in the diet or made in the skin by exposure to sunlight makes it difficult to estimate adequate total intakes of vitamin D for the general population.
Accurate food composition data are not available for vitamin D, accentuating the difficulty for estimating dietary intakes. A recent study of elderly women by Kinyamu et al. Skin synthesis is equally difficult to estimate, being affected by such imponderables as age, season, latitude, time of day, skin exposure, sun screen use, etc. Use of plasma OH-D as a measure of vitamin D status Numerous recent studies have used plasma OH-D as a measure of vitamin D status, and there is a strong presumptive relationship of this variable with bone status.
Thus, it is not surprising that several nutritional committees e. This dietary intake of vitamin D for each population group was rounded to the nearest 50 IU 1. They termed this amount adequate intake AI and used it in place of recommended dietary allowance RDA , that had been used by US agencies since We are recommending the use of those figures here as recommended nutrient intakes RNIs because it is an entirely logical approach to estimating the vitamin D needs for the whole population.
Frequency distribution of serum or plasma OH-D. Values for all ages, ethnicity groups, both sexes.