Vitamin D

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Structural formula
Structural formula of cholecalciferol
General
Common name Vitamin D 3
other names
  • Colecalciferol ( INN )
  • Calciol
  • (3 β , 5 Z , 7 E ) -9,10-Secocholesta-5,7,10 (19) -trien-3-ol
  • IUPAC : 3- [2- [7-methyl-1- (6-methylheptan-2-yl) -2,3,3a, 5,6,7-hexahydro-1 H ] -indene-ylidene 4-ethylidene] - 4-methylidene-cyclohexan-1-ol
Molecular formula C 27 H 44 O
CAS number 67-97-0
PubChem 5280795
ATC code

A11 CC05

DrugBank DB00169
Brief description colorless solid
Occurrence non-vegetable eukaryotes
physiology
function Precursor of calcitriol , as such: regulation of the calcium balance, maturation of immune cells
Daily need about 20 µg (800 IU ) daily (sum of skin production and food intake)
Consequences in case of deficiency Rickets , osteomalacia
Overdose see hypervitaminosis D.
properties
Molar mass 384.64 g mol −1
Physical state firmly
Melting point

82-87 ° C

boiling point

decomposition

solubility fat-soluble, 50-80% protein-bound in the blood (to VDBP )
safety instructions
Please note the restricted labeling requirements for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling from  Regulation (EC) No. 1272/2008 (CLP) , expanded if necessary
06 - Toxic or very toxic 08 - Dangerous to health

danger

H and P phrases H: 330-311-301-372
P: 280-304 + 340-302 + 352-309 + 310
Toxicological data

42 mg kg −1 ( LD 50ratoral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Vitamin D is a group of fat-soluble vitamins that belong to the secosteroids and are known in physiology for their role in calcium metabolism . In the body, the physiologically most important representative cholecalciferol (= vitamin D 3 ) can also be formed from 7-dehydrocholesterol in the skin with the help of UV-B radiation ( Dorno radiation) . Therefore, the term vitamin according to the historical definition of vitamins is not entirely correct, because this definition rules out that such substances can be synthesized by the body itself in sufficient quantities.

It is found in food mainly in fatty fish or is added to food as a dietary supplement . It has the function of a prohormone in the body and is converted via an intermediate stage to the active steroid hormone calcitriol .

Vitamin D plays an essential role in regulating the calcium level in the blood and in building bones. A vitamin D deficiency leads in the medium term to rickets in children and osteomalacia in adults . Other possible health consequences of a vitamin D deficiency (such as osteoporosis ) are the subject of current scientific research.

For a sufficient supply of vitamin D, adequate exposure to sunlight or UV-B radiation or, otherwise, additional intake ( supplementation ) is necessary. In some states, certain foods are fortified with vitamin D for this purpose.

history

The discovery of vitamin D is linked to the search for a cure for rickets . In 1919 it was shown that rickets can be cured by irradiation with artificially generated UV light, and two years later this was also proven by irradiation with normal sunlight. Regardless of these findings, the British physician Edward Mellanby (1884–1955) was convinced that rickets was caused by a nutritional deficit, and was also able to show in experiments with dogs in 1919 that rickets could be cured with butter, milk and, in particular, cod liver oil . He then considered vitamin A, which had only recently been discovered in cod liver oil, to be the triggering factor. It was known that vitamin A is destroyed by oxidation . Cod liver oil therefore loses its ability to cure night blindness after oxidative treatment . Cod liver oil treated in this way was still able to cure rickets, however. The chemist Elmer Verner McCollum (in collaboration with the pediatrician John Howland ) concluded that another substance, independent of the well-known vitamin A, was responsible for this effect. As the fourth vitamin found (after vitamins A, B and C), it was named "vitamin D".

Mellanby's wife, a dentist, first used vitamin D in dentistry. In Bonn, rickets prophylaxis was used for the first time in schools for caries prophylaxis.

There is an initiative to declare November 2nd as Vitamin D Day and thus to point out how big the problem of vitamin D deficiency is worldwide .

physiology

Biosynthesis of vitamin D 3

Most vertebrates, including humans, get much of their vitamin D needs from sun exposure of their skin; this also occurs with certain types of plankton (phytoplankton coccolithophor Emiliania huxleyi ).

By definition, vitamins are substances that the body cannot produce itself, but are required for life and must therefore be supplied. The precursors of the so-called vitamin D are produced by the body itself. In addition to the provitamin 7-dehydrocholesterol present in the body (the starting substance for vitamin D synthesis), sunlight must then be added. Vitamin D 3 is therefore known as a vitamin for historical reasons. Due to its endogenous synthesis and the fact that its effect affects other tissues in addition to the site of synthesis, vitamin D 3 should be called a prohormone .

Ultraviolet Induced Synthesis

In the skin , the highest concentrations of 7-dehydrocholesterol are found in the stratum spinosum and stratum basale . In humans and most mammals, 7-dehydrocholesterol is abundantly available for vitamin D production (an exception are domestic cats, for example).

Metabolites of 7-dehydrocholesterol in the skin (simplified to and)
  1. If 7-dehydrocholesterol is irradiated with UV radiation with wavelengths in the range 280-315 nm ( UV-B radiation ) and at least 18 mJ / cm², a photochemically induced 6-electron conrotatory electrocyclic reaction of the B- Ring are broken: Previtamin D 3 is formed .
  2. Previtamin D 3 is thermodynamically unstable and experiences a (1-7) sigmatropic shift of a proton from C-19 to C-9 with subsequent isomerization: Vitamin D 3 is formed . Vitamin D 3 gets into the blood and is mainly bound to the vitamin D binding protein (DBP) transported to the liver, where it is further hydroxylated to 25 (OH) vitamin D 3 . In the test tube, 80% of the previtamin D 3 is isomerized to vitamin D 3 after three days , in the skin this happened after eight hours.

Self-regulation of ultraviolet-induced synthesis

If a certain amount of 7-dehydrocholesterol is exposed to simulated equatorial solar radiation in a test tube experiment, approx. 20% of the initial amount is converted to previtamin D 3 after a few minutes . This amount of previtamin D 3 remains in equilibrium with further irradiation, because previtamin D 3 is also photolabile and is broken down into physiologically inactive lumisterol and tachysterol over the next eight hours by further UV-B irradiation , before it isomerizes to vitamin D 3 . During this time, the 7-dehydrocholesterol drops to about 30% of the initial amount. On the other hand, under unnatural narrow-spectrum UV-B irradiation with a wavelength of 290 to 300 nm, 65% of the original 7-dehydrocholesterol is converted into previtamin D 3 .

The vitamin D 3 produced from previtamin D 3 is also photolabile: If vitamin D 3 cannot be removed quickly enough in the blood, UV-B and UV-A radiation (up to 345 nm) produce at least three more ineffective ones Products: Suprasterol-1 and -2 and 5,6-Transvitamin D 3 .

Short exposure to sunlight (with a sufficiently high UV-B component) produces a similar amount of vitamin D 3 for a few minutes as a comparable exposure over a longer period of time. As a result, the body is briefly protected from vitamin D intoxication caused by too much radiation.

In the long term, there is protection against vitamin D intoxication through increased formation of melanin ( tanning , darker skin type in southern countries) in the skin, which absorbs ultraviolet light with a wavelength of 290-320 nm.

The 7-dehydrocholesterol content of the skin decreases with age. In addition, the ability of the skin to produce vitamin D 3 decreases with age by a factor of approximately 3 compared to a 20-year-old person.

For the pale skin of a fair-skinned, young, adult person, the minimum erythema dose (MED) (when the skin starts to turn red) is on a sunny summer afternoon at 42 ° latitude at sea level (corresponding to Boston, Barcelona or Rome) after 10 to 12 Minutes, a dark-skinned person needs 120 minutes accordingly. If the skin of these people is completely irradiated, it releases an amount comparable to 10,000 to 20,000 IU (250 µg to 500 µg) of vitamin D 3 from food to the blood within the next 24 hours  , a multiple of the recommended diet of 200 to 500 IU of vitamin D 3 daily. A strong formation of vitamin D 3 in the skin is therefore possible even with short but intense exposure to sunlight with a high UV-B content.

Since the bone density in dark-skinned people is not reduced despite the somewhat reduced vitamin D formation due to the lower permeability of the skin to UV rays, it is assumed that dark-skinned people have a lower concentration of the vitamin D-binding protein.

function

Vitamin D 3

25-hydroxylation of vitamin D 3

Vitamin D 3 , mainly bound to the vitamin D-binding protein , is transported to the liver via the blood. There it is hydroxylated by the enzyme cytochrome P450 2R1 in the microsomes to calcidiol (25 (OH) vitamin D 3 ). An earlier assumption that this reaction also takes place in the mitochondria has now been refuted.

Calcidiol (25 (OH) vitamin D 3 ) is bound to vitamin D-binding protein again in the liver and released into the blood. There it has a half-life of approx. 19 days.

This enzymatic reaction is probably not subject to any regulation worth mentioning, since the 25 (OH) vitamin D 3 level in the blood pretty much reflects the longer-term vitamin D 3 supply of the last three to four months, while the vitamin D 3 level shows the supply of the last hours to days.

25 (OH) vitamin D 3

25 (OH) vitamin D 3 (calcidiol) is a storage form of vitamin D 3 . There has to be one in order to be able to intercept the large peaks and pauses in the main vitamin D supply through light. The medium to long-term vitamin D supply of an organism can best be determined via the blood level of 25 (OH) vitamin D 3 (see below for details). Calcidiol is also deposited in the hair.

The 25 (OH) D 3 formed in this way now reaches its target tissues , mainly bound to the vitamin D-binding protein , for example to the kidneys, where it then becomes calcitriol (1α, 25 (OH) 2 vitamin D 3 ) is activated (see below). This is the main activating ligand for the vitamin D receptor . This last activation step is redundant on many levels and regulated differently from tissue to tissue in order to always be adapted to the current need of the body and the target tissue for the vitamin D effect.

25 (OH) vitamin D 3 can probably also activate the vitamin D receptor itself, but about a hundred times less than calcitriol. This comes into play in the event of poisoning with vitamin D 3 if the last regulation of the activation of vitamin D 3 is overlooked by excessive 25 (OH) vitamin D 3 levels.

Activation of 25 (OH) vitamin D 3 to form calcitriol

The vitamin D metabolites are transported as a complex together with the vitamin D-binding protein (VDBP) in the blood plasma. In the kidney corpuscles (glomeruli), this complex binds to cubilin molecules in the cell membrane of proximal tubular cells and is then transported into the cell with the help of megalin and released there. In the lysosomes the complex is separated again by peptidases , whereby 25 (OH) vitamin D 3 diffuses freely in the cytosol .

In the kidneys, the 25 (OH) vitamin D 3 can be further hydroxylated by 1α-hydroxylase on the mitochondrial plasma membrane of the cells of the proximal tubules to the biologically active 1,25 (OH) 2 vitamin D 3 ( calcitriol ) or by the oppositely regulated 24-hydroxylase to 24R, 25 (OH) 2 vitamin D 3 are inactivated or leave the kidney cells unchanged into the blood (to be bound again to VDBP there).

The formation of 1,25 (OH) 2 vitamin D 3 in the kidneys is finely regulated: the most important factors that directly promote its enzymatic formation via activation of 1α-hydroxylase are, independently of one another, an increased parathyroid hormone , a reduced calcium level and a low levels of phosphate in the blood. 1,25 (OH) 2 D 3 itself inhibits 1α-hydroxylase and activates 24-hydroxylase. Indirectly, mostly via the parathyroid hormone, calcium, estrogen , glucocorticoids , calcitonin , somatotropin and prolactin influence the formation of calcitriol. Glucocorticoids cause a deficiency in calcitriol. (Therefore, during systemic corticosteroid therapy, if vitamin D has to be taken, it is necessary to use vitamin D in active form as alfacalcidol (current (2008) drugs in Germany: "EinsAlpha", "Bondiol", "Doss"). ) All these regulations serve to synthesize just enough active vitamin D that the body can meet its calcium and phosphate requirements in its current situation. The regulation of 24R, 25 (OH) 2 D 3 formation is carried out by the same factors, but in the opposite direction.

In other tissues, the activation of 25 (OH) vitamin D 3 to 1α, 25 (OH) 2 vitamin D 3 is regulated by other factors: cytokines , growth factors , etc.

1.25 (OH) 2 D 3 is much lower in concentration than 25 (OH) D 3 and is mainly bound to VDBP in the blood. The concentration in particular of free 1,25 (OH) 2 D 3 (calcitriol) is strictly regulated and largely correlated with its activity. It is also largely independent of the concentration of its precursor 25-hydroxy-cholecalciferol (Calcidiol) or the VDBP .

Function of calcitriol

In the cells of the target organs, 1,25 (OH) 2 D 3 (calcitriol) acts like a steroid hormone : It is bound to an intracellular receptor protein , the vitamin D receptor (VDR), and transported into the cell nucleus . There the vitamin-receptor complex associates with the DNA and changes the transcription of various hormone-sensitive genes , which ultimately leads to changes in protein synthesis with corresponding biological effects.

Breakdown of vitamin D 3

1,25 (OH) 2 D 3 (calcitriol) is broken down by 24-hydroxylase to water-soluble calcitroic acid , which is excreted in the bile . The 24-hydroxylase is encoded by the gene CYP24A1.

Vitamin D metabolism in diseases

Patients with tuberculosis , sarcoid and other granulomatous diseases and occasionally cancer also activate the 25 (OH) vitamin D 3 z. B. in the macrophages stronger to 1,25 (OH) 2 vitamin D 3 and can functionally result in a vitamin D hypervitaminosis with hypercalcemia. This is based on an originally mostly sensible immunological mechanism (for more details see under Calcitriol ).

15% of patients with Williams-Beuren syndrome have hypercalcaemia. There have been many suspicions of a link to vitamin D metabolism, but the results of such observations have been contradicting.

In patients with Smith-Lemli-Opitz syndrome , the breakdown of the vitamin D precursor 7-dehydrocholesterol into cholesterol is disturbed by mutations in 7-dehydrocholesterol reductase . The 7-dehydrocholesterol builds up in your metabolism. Their skin is sometimes photosensitive and their vitamin D status is increased compared to the normal population, but without being toxic.

“Idiopathic infantile hypercalcemia” is caused by a mutation in the CYP24A1 gene , which inhibits the breakdown of vitamin D. Affected children have an increased sensitivity to vitamin D and, in the case of additional intake, an increased risk of hypercalcemia , which is characterized by growth retardation, vomiting, dehydration , fever attacks and nephrocalcemia . Subsequent research showed that the disorder persists into adulthood.

Formation in human skin from sunlight

The UV-B component in sunlight is responsible for the formation of vitamin D 3 through exposure to the sun. Various factors influence the light intensity and the resulting vitamin D 3 formation in the skin, such as: B. the position of the sun, the height above sea level, the nature of the earth's surface, the clouds, smog or the ozone . Window glass absorbs almost all UV-B components in sunlight, and sunscreen prevents vitamin D 3 production. A visit to the solarium is usually not beneficial, as the skin is usually irradiated with UV-A and not with UV-B light.

Under optimal conditions, a quarter of an hour's exposure of the face, hands and forearms to the sun is sufficient for the production of several thousand IU of vitamin D. However, whole-body radiation is more efficient. The exact length of exposure required depends on the skin type. A short and intensive exposure of one third to one half of the minimum erythema dose , i.e. the amount of sunlight above which the skin becomes red, is recommended . Prolonged sunbathing is pointless, since a similar amount of vitamin D 3 is formed as with comparable irradiation over a short period of time (see above). A skin cancer risk can thus be prevented.

Influence of the position of the sun

Among other factors, the altitude of the sun is crucial for vitamin D 3 formation. In the temperate latitudes, the formation of vitamin D in the skin increases with the height of the sun (see AM spectrum ) and is therefore largely dependent on the time of year and time of day. When the sun is low, with a predominantly UV-A component of the sunlight, the border area between a light dose sufficient for effective vitamin D formation in the skin and a sunburn is narrow or nonexistent. If the required UV-B dose is not reached all day long in otherwise good light conditions that vitamin D 3 can no longer be formed in the skin, this is known as “vitamin D winter”.

The basic requirement for a sufficient UV-B component in sunlight is that the angle of incidence of the sun's rays on the earth is not too small. According to this, in winter north of the 51st parallel (Cologne-Erfurt-Dresden), no vitamin D 3 can be formed in the skin even at lunchtime . South of the 37th parallel (San Francisco – Algarve – southern Sicily – Antalya), on the other hand, adequate vitamin D biosynthesis is possible throughout the year.

Influence of skin texture

The lighter the skin, the better UV-B radiation can be used for vitamin D production. People who emigrated from Africa to northern latitudes in the course of human expansion developed fair skin. The only exception are the Inuit , who have only lived in the Arctic for a relatively short time and meet their vitamin D requirements through food (fatty fish).

If people with dark skin now live at higher latitudes, their risk of vitamin D deficiency increases. The deficiency can arise especially during pregnancy . Vitamin D supplementation during pregnancy can be insufficient because of the high requirement. In a study, Lisa Bodnar and colleagues found a deficiency in 80 percent of African American women and almost half of white American women, even though nine out of ten of the total of 400 pregnant women were taking a vitamin supplement .

Despite a mean lower vitamin D level in African Americans , their bone density is on average higher and the risk of osteoporotic fractures lower than in Americans with European ancestry. In an American cohort study with over 2000 participants, half from both ethnic groups , the mean 25-OH vitamin D level was found to be 15.6 ng / ml in African Americans and 25.8 ng / ml in white Americans . The vitamin D binding protein (VDBP) was also significantly lower in African Americans with a mean of 168 µg / ml versus 337 µg / ml, while the free and bioavailable 25-OH vitamin D with 2.9 ng / ml versus 3.1 ng / ml was almost identical for both ethnic groups and the African American population had a significantly higher femoral neck bone density of a mean 1.05 g / cm² versus 0.94 g / cm². The three phenotypes of the VDBP, which are distributed very differently in the two ethnic groups, can explain almost 80% of the variations in the VDBP level and 9.9% of the variations in the vitamin D level, while the ethnic group accounts for a further 0.1% or 7.3% of the variations is responsible and the seasonal changes can explain a further 10.5% of the vitamin D variations. Thus, the specified limit values ​​can only be transferred to non-white ethnic groups to a limited extent.

Absorption through food

Vitamin D 3 is not a common food component. Only in the last 10 years has it been increasingly recognized which diseases of civilization (apart from rickets and osteomalacia ) are associated with the endemic lack of light in modern societies (see under Calcitriol ). Therefore, the publicly recommended daily requirement ( RDA ) of vitamin D 3 is lively discussed among scientists and those responsible for health care. The 2007 recommendations are viewed by researchers in the field as either irrelevant (for people sufficiently exposed to UV-B light) or inadequate (for the majority of the population in higher-latitude civilized societies).

The need for vitamin D through food increases the shorter the time a person spends in direct daylight or sunlight. The synthesis in the skin is not only dependent on the time it is exposed to the sun, but also, among other things, on the skin's content of the precursor 7-dehydrocholesterol. The increasing use of sun protection cream also reduces the synthesis of vitamin D when staying in the sun. Therefore, the argument that the intake of vitamin D is only of secondary importance in addition to self-production is not generally valid.

The German Nutrition Society (DGE) has given guide values ​​for the amount of vitamin D that should be covered "in the absence of endogenous synthesis", i.e. when no vitamin D can be formed through exposure to sunlight. It recommends 10 µg daily for babies in the first year of life and 20 µg (800 IU) of vitamin D 3 for other children and adults . In Germany, most infants are given one tablet with 12.5 µg vitamin D 3 (500 IU) every day in the first year of life and possibly even in the second winter to prevent rickets.

The European Food Safety Authority (EFSA) has set the appropriate intake level for all healthy people over the age of one (including pregnant and breastfeeding women) at 15 µg per day, for small children aged 7-11 months at 10 µg per day. The agency emphasizes that these values ​​were based on "the assumption of minimal solar radiation and, consequently, limited amounts of vitamin D produced by the body itself" and that this value decreases when one is exposed to solar radiation. It is also not a question of the recommendation to take in this amount of vitamin D through food supplements, but rather the total amount of vitamin D that should be available to the body daily through food, solar radiation and, if necessary, food supplements. EFSA also assumes that children up to one year of age are not expected to have any harmful effects from excessive intake of vitamin D if they do not ingest more than 25 µg of vitamin D per day. In children between 1 and 10 years of age they consider harmful effects at doses below 50 µg and in adolescents at doses below 100 µg to be unlikely.

Current guidelines in the US recommend 5 µg (200 IU) daily for children and younger adults, 10 µg (400 IU) for 50- to 70-year-olds, and 15 µg (600 IU) for over 70-year-olds. However, there are also more recent studies that criticize the excessive use of vitamin D in the USA and other countries. The claim that large parts of the North American population and that of other countries are vitamin D deficient is based on a misinterpretation that can have a negative impact on the health of patients.

In winter, only 500–1000 IU (12.5–25 µg) are required because the rest of the requirement for this is covered by the body's own stores.

It has been estimated that the daily intake of 1 IU of vitamin D 3 in adults increases the 25 (OH) vitamin D 3 level in the blood by approx. 0.007 ng / ml (depending on the vitamin D status). Adults weighing approx. 80 kg require approx. 114 µg (4600 IU) of vitamin D 3 daily to maintain a sufficient 25 (OH) vitamin D 3 level of 80 nmol / l = 32 ng / ml in the blood over the long term as long as there is no vitamin D formation from light.

If a nursing mother takes 100 µg (4000 IU) of vitamin D daily (if she is not exposed to UV-B light), enough vitamin D activity appears in her breast milk to prevent the infant from becoming vitamin D deficient Feed is safely protected. At 50 µg (2000 IU) this is not yet definitely the case (the number of women examined was small, however).

Food intake usually only covers 5 to 20% of the vitamin D 3 requirement. Direct exposure of the skin to sunlight is therefore essential for vitamin D 3 formation. On sunny summer days, this alone covers the daily requirement many times over. In the winter months, however, the formation through sun exposure is reduced because of the low UV-B content in sunlight and north of the 51st parallel it can even be temporarily absent. The vitamin D reserves built up in the body in summer and food are then the only natural sources. One study showed a decrease in the body's own vitamin D level after just one month without intake.

Vitamin D in breast milk

Breast milk contains few vitamin D components. Their amount is very dependent on the mother's vitamin D status. Already hydroxylated 25 (OH) vitamin D 3 accounts for the largest part of the antirachitic activity of breast milk. The vitamin D content in the higher-fat hind milk (which the infant drinks last) is greater than in the fore milk. If the mothers living in higher latitudes take 50 µg (2000 IU) of vitamin D 3 daily in winter, their breast milk reaches the antirachitic activity of unsupplemented mothers in summer, but the answer varies greatly from person to person.

If mothers have a (mild) vitamin D deficiency, which is subclinical for them (like most women in civilized societies far away from the equator in winter and especially in Islamic societies), the infants have a much higher risk of rapidly developing a relevant vitamin D deficiency. Develop D deficiency. A study recently carried out by the National Institute of Child Health and Human Development in the USA and published in The Archives of Pediatrics & Adolescent Medicine in June 2008 claims that up to 78% of people in the USA are breastfed with breast milk Babies may be vitamin D deficient in winter. Overall, however, the formation of vitamin D 3 in the skin also appears to be the most important natural protection against rickets for babies .

It is possible that the vitamin D 3 currently present in the mother's blood passes into breast milk much better (30–80%) than the already hydroxylated 25 (OH) vitamin D 3 (0.5%); whether this is the case is still being researched.

Vitamin D in foods

Under conditions that are not always and everywhere optimal (see above), the skin of a young adult can produce 10,000–20,000 IU (250–500 µg) of vitamin D daily. In contrast, only a few foods contain vitamin D 3 in comparable quantities. It is found mainly in fatty fish, offal, eggs and, to a limited extent, in dairy products.

Fungi (e.g. yeasts ) contain the mycosterol ergosterol , which can be converted into biologically active ergocalciferol (vitamin D 2 ) if there is sufficient UV light exposure . In a study by the Freiburg University Clinic , it was demonstrated that mushrooms that were cultivated with UV-B radiation produced significant amounts of vitamin D 2 (491 μg or 19,640 IU per 100 g of mushrooms). The administration of the so-enriched pine mushrooms were vitamin D 2 - supplements equal. Similar results can also be achieved with shiitake , maitake , shimeji or other mushrooms. In the case of shiitake, values ​​of up to 267,000 IU per 100 g of shiitake mushrooms could be achieved after exposure to sunlight for 14 hours.

Some plants also contain traces of ergosterol.

The vitamin D 3 content of some selected foods shows that food plays a minor role in the vitamin D supply:

food µg or IU per 100 g (1 µg corresponds to 40 IU) reference
Cod liver oil 170 µg to 3,800 µg 6,800 IU to 152,000 IU
Herring herring , salted 27 µg 1,080 IU
Eel (smoked) 21 µg 840 IU
salmon 16 µg 640 IU
sardine 11 µg 440 IU
Veal ( free range ) 3.8 µg 152 IU
Chicken egg (free range) 2.9 µg 116 IU
industrially produced baby milk in Germany 1-2 µg / 100 kcal 40-80 IU / 100 kcal
Mushrooms 1.9 µg 76 IU
Liver ( free range beef ) 1.7 µg 68 IU
butter 1.2 µg 48 IU
Cream (cream) 1.1 µg 44 IU
Emmentaler 1.1 µg 44 IU
Gorgonzola 1 µg 40 IU
Edam 40% fat i. Tr. 0.29 µg 12 IU
Quark 40% fat i. Tr. 0.19 µg 8 IU
Whole milk at least 3.5% fat 0.088 µg 4 IU
Yoghurt at least 3.5% fat 0.062 µg 2 IU
Breast milk 0.01-0.12 µg 0.4-4.8 IU

When making the information, it must be taken into account that not all foods are consumed in the same amount. Cod liver oil is a rich source of vitamin D, but it is known that it is only consumed in extremely small quantities. On the basis of this data, in addition to high-fat fish, mushrooms, dairy products and fortified edible fats can also make a good contribution to vitamin D 3 supply.

Between 2003 and 2006, the EsKiMo study examined the eating habits of 2,500 children aged 6 to 11 throughout Germany. For the daily vitamin D 3 intake, the lowest value of all examined nutrients was measured in relation to the recommended value. Accordingly, the actual vitamin D 3 intake is only around 30% of the DGE recommendation . The authors conclude: "The intake of vitamin D is ... suboptimal and can quickly lead to a real deficiency situation with long-term negative consequences for bone health in children who are rarely outdoors." The DONALD nutrition study published in September 2008 by the research institute for child nutrition (FKE) confirmed the vitamin D 3 deficiency in children. In the 598 study participants aged 1 to 12 years, the evaluation according to individual protocols showed that eight out of ten children did not achieve the DGE recommendation for vitamin D.

So far, in addition to industrially produced baby milk, only margarine has been fortified with 2.5 µg vitamin D 3 per 100 g in order to ensure that the population is adequately supplied. In contrast, the fat-soluble vitamin is not available in ready-to-use multivitamin juices, but only in (effervescent) tablets.

The insufficient supply of vitamin D 3 is a hotly debated problem in many countries with moderate solar radiation, long winters and only moderate consumption of fatty fish. One solution is to consume foods containing vitamin D daily and to build up a reserve in the summer months through daily short and intensive sun exposure. In addition, the fortification of foods with vitamin D 3 is aimed at increasing the intake from food in many countries.

The daily dietary intake of vitamin D in different countries is approximately as follows (1 µg corresponds to 40 IU of vitamin D 3 ):

Population group daily vitamin D 3 intake of which supplemented vitamin D 3 reference
young white American men 8.1 µg 5.1 µg
young white American women 7.3 µg 3.1 µg
black American adults 6.2 µg 4.3 µg
british men 4.2 µg 1.4 µg
british women 3.7 µg 1.1 µg
japanese women 7.1 µg 0 µg
Norwegian men 6.8 µg 2.9 µg
Norwegian women 5.9 µg 2.9 µg
spanish men approx. 4 µg
spanish women approx. 3 µg
German men 2.9 µg 0 µg
German women 2.2 µg 0 µg
Italian households 3.0 µg

However, these average figures vary considerably within these population groups and between the studies evaluated.

In Germany, vitamin D 3 supplementation is not yet common among adults. The results of the 2008 national consumption study show that only around 3% of all women questioned and less than 2% of men questioned also take in 5 µg of vitamin D 3 per day.

In the USA and Canada, drinking milk is regularly supplemented with 10 µg vitamin D 3 per liter. In Great Britain, Ireland and Australia breakfast cereals and margarine can be supplemented with vitamin D 3 . In Norway and Japan, fatty fish consumption contributes to the supply of vitamin D through food. In Norway, cod liver oil is still very widespread as a dietary supplement. In most other countries hardly any vitamin D 3 is absorbed with food .

In the USA, industrially produced baby milk must be supplemented with 1 to 2.5 µg / 100 kcal. Infants who are breastfed or who drink less than 500 ml of this formula should receive 200 IU (5 µg) of vitamin D 3 daily .

Vitamin D ingested with food is quickly absorbed in the small intestine and enters the bloodstream together with the fats via the lymph . There it has a half-life of 19 to 25 hours. During this time it is either deposited in adipose tissue or hydroxylated to 25 (OH) vitamin D 3 in the liver .

Vitamin D 3 deficiency

According to a meta-analysis from 2016 regarding the pooled data from 55,844 Europeans from different countries, an insufficient supply was found in 13.0%, according to the defined limit of 25 (OH) D <30 nmol / l (<12 ng / ml) im Annual average. If the samples were taken from April to November, what was referred to as the extended summer in the study, this was the case in 8.3%, and if the samples were taken from October to March, the “extended” winter, 17.7% showed a deficiency .

In the opinion of the German Nutrition Society (DGE), it would not make sense to have one's own vitamin D level determined without a justified suspicion . On the other hand, if you belong to a risk group, because of the important functions of vitamin D 3 in the human metabolism, it may also be appropriate to take appropriate preparations in addition to food.

risk groups

Older people from 65 years of age belong to the risk groups, as the ability of the skin to synthesize vitamin D decreases significantly with age. In this way, a large amount of vitamin D can no longer be produced in a short time.

The required exposure to the sun is often not guaranteed for people who are immobile or bedridden for a long period of time and who do not spend enough time outdoors. Likewise, people who only go into daylight with their bodies completely covered belong to the risk groups.

In view of the widespread vitamin D deficiency in Europe, especially among people in nursing homes and among people of non-European origin, scientists recommend daily vitamin D supplementation for people belonging to a risk group.

Infants are also at risk because their sensitive skin and insufficient heat regulation mean that they should not be exposed to direct sun. Vitamin D deficiency is common among healthy babies, children and adolescents in Europe. Pediatric risk groups include:

  • breast-fed infants without the recommended vitamin D dose
  • dark-skinned children and adolescents in northern countries
  • Children and adolescents without adequate sun exposure and
  • obese children.

Chronic conditions such as liver disease and kidney disease are also seen as a barrier to vitamin D intake. As a result of exocrine pancreatic insufficiency , there may be a deficient absorption of vitamin D due to a reduced or absent production of digestive enzymes.

Symptoms

The symptoms of vitamin D deficiency or D-avitaminosis in adults include primarily diffuse bone and muscle pain and muscle weakness (myopathy); fractures (broken bones) are also possible.

Various studies attribute a wide variety of health problems to a vitamin D deficiency. The US health organization Institute of Medicine (IOM) has reviewed over 1,000 such studies and found that these studies did not provide sufficient evidence for almost any of these problems. The IOM sees an exception in bone disorders, for which, in its opinion, the evidence is clear.

The most impressive symptoms that are characteristic of disease are found in the human skeleton. In the first place are the skeletal pain and bones bent, which arise from damage to the diaphysis due to impaired bone mineralization. In addition, there are axial deviations caused by knee deformations and expansion or rupture of the metaphyseal growth plates . These changes in the skeletal system give rise to clinical pictures such as scoliosis , the bell chest , the rachitic rosary (circumscribed swelling of the ribs at the cartilage-bone boundary) or kyphosis . A significant influence of a vitamin D 3 deficiency on overload damage to the child's joint in the form of osteochondrosis dissecans could also be demonstrated. Here, the lack of vitamin D leads to an increased incorporation of calcium salt-free osteoid into growing bones.

The second set of symptoms is based on changes in the nervous system. A tendency to tetany , muscular hypotension and also a general motor development delay are observed here. In addition, patients with vitamin D deficiency can have epileptic seizures. Further symptoms are cardiac arrhythmias that can result from hypocalcemia , a generally increased susceptibility to infections and gum overgrowth, the so-called gingival hyperplasia .

consequences

Since the 1990s it has been shown that the vitamin D system in various other tissues has internal controlling ( autocrine ) functions in particular , which include cell differentiation , inhibition of cell proliferation , apoptosis , immunomodulation and the control of other hormonal systems. Therefore, intensive research was carried out in this area, with some of the studies coming to very different results. It is relatively undisputed that a good vitamin D status can prevent falls and broken bones. The other effects are still controversial despite many studies. It is noticeable that many studies looking for a connection between vitamin D concentration in the blood and diseases have usually found this connection. On the other hand, studies that looked at whether people who also took vitamin D were less likely to get the disease often came to the conclusion that there was no association. One possible explanation for this would be that it is not the low vitamin D level that leads to a disease, but that the inflammatory processes associated with many diseases lead to a low vitamin D level.

Baby Jesus in Albrecht Dürer's painting Madonna with the pear slice (1512, Kunsthistorisches Museum , Vienna ) has characteristics of a vitamin D deficiency on: prominence of forehead and crown cusps with Hinterhauptabflachung (caput quadratum), sagging abdomen, thorax deformation and swelling of the epiphyseal plates at Wrists and ankles.

Cardiovascular diseases

In 2011, the German Nutrition Society (DGE) assessed the study situation in such a way that there is probably no influence between vitamin D supplementation and blood pressure in healthy people. On the other hand, there are indications that an antihypertensive effect occurs with existing high blood pressure. The DGE assessed the study situation with regard to cardiovascular diseases as contradicting. Nevertheless, she rated a connection as "possible".

An overview study from 2018 also found that research to date has not yet led to unambiguous results that could justify recommendations regarding additional intake (supplementation) of vitamin D.

A meta-analysis published in 2019 of 21 studies with a total of 83,291 participants showed that vitamin D supplementation does not offer cardiovascular protection. There was no difference in either major cardiovascular events ( primary endpoint ) or myocardial infarction, stroke, cardiovascular mortality, or all-cause mortality ( secondary endpoints ) between the groups that received placebo or verum . The initial vitamin D level, gender of the participants, dose and formulation of the vitamin D supplements and the additional administration of calcium had no effect on the result.

Infections

The possible connection between vitamin D and virus infections is the subject of research. In the case of a vitamin D deficiency, the addition of vitamin D offers improved protection against infections of the respiratory tract.

Asthma and autoimmune diseases

It was investigated whether an undersupply of vitamin D could be a risk factor for the following diseases:

Diseases that are more common in the elderly

According to previous studies, an undersupply of vitamin D appears to be a risk factor for the following diseases:

Cancer and other diseases

In 2014, the German Cancer Research Center evaluated several European and US observational studies in a meta-study and came to the conclusion that "Vitamin D deficiency probably has no influence on the development of cancer", which is why the authors did not generally recommend using preventive ( prophylactic ) vitamin To take D supplements. At the same time, a low vitamin D level could have a negative effect on the course of an existing cancer. The results of a probably non-existent influence on cancer development were then confirmed in 2017 in an extensive analysis of genetic and epidemiological databases. For example, the data from over 70,000 cancer patients with seven different types of cancer did not show a causal relationship between the gene variants that influence the vitamin D level in the blood and the risk of the disease.

In 2017 the large randomized placebo- controlled intervention study VITAL on preventive supplementation with vitamin D in the general population ended. The results were published in November 2018. 25,871 healthy men and women with an average age of 67 were examined; they took either 2,000 IU of vitamin D or placebo daily. Compared to placebo, the risk of developing cancer or cardiovascular disease was not reduced by taking vitamin D after a median of 5.3 years. Vitamin D administration to prevent these diseases proved to be unsuitable.

The meta-analysis of six randomized controlled trials on seriously ill patients in intensive care showed no relief of symptoms in a vitamin D supplementation. High daily doses of more than 300,000 IU did not reduce mortality either.

However, according to previous studies, an undersupply of vitamin D could be a risk factor for the following diseases:

Vitamin D determination

The determination of the vitamin D 3 level in the blood serum only reflects the vitamin D absorption with food or the self-synthesis in the skin during the last hours or days. For an investigation of the long-term vitamin D status , it makes more sense to determine the 25 (OH) vitamin D 3 level in the blood, into which vitamin D 3 is quickly converted in the liver (see above). The half-life of 25 (OH) vitamin D 3 in the blood circulation is 1–2 months, depending on the overall vitamin D status. It takes up to four months until a new steady state with a stable serum value is established after a change in the daily vitamin D intake.

The 25 (OH) D 3 has been determined since the early 1980s and enabled a more detailed understanding of the physiology of vitamin D 3 . The measured values ​​are given either in weight or molar concentration units, with 1 ng / ml corresponding to around 2.5 nmol / l.

The analytical measurement of the 25 (OH) vitamin D 3 level in the serum can be carried out after HPLC separation by means of mass spectrometric detection (MS). The "gold standard" is the radioreceptor assay (RRA) using a 3 H -labeled tracer , which is hardly ever used in Germany. Automated, routine immunological methods are less complex, but are considered prone to failure. The rapid tests available in pharmacies are ascribed greater measurement uncertainty, as there is no reliable quality control for such tests.

Assessment of the 25 (OH) vitamin D 3 level

IUD from sufficient vitamin D supply to clinically manifest rickets (after)

People from southern countries who are heavily exposed to the sun and do not completely cover their skin often have serum concentrations of 50 to 90 ng / ml. A mean 25 (OH) vitamin D 3 level of 46 ng / ml was measured in the Maasai and Hadza , who were still originally living .

From a serum concentration of less than 30 ng / ml, the body compensates for a lack of vitamin D effects on the calcium balance with an increased parathyroid hormone (see below). Calcium absorption in the intestine is essentially influenced by the active form 1α, 25 (OH) 2 vitamin D 3 and independent of the 25 (OH) vitamin D 3 level. Older studies had assumed that calcium absorption in the intestine is slowed down from a 25 (OH) vitamin D 3 level below 30 ng / ml.

The definition of vitamin D deficiency based on the 25-OH vitamin D level continues to be controversial, and the American Institute of Medicine continues to name the lower limit value 20 ng / ml. Others assume the following assessment of the serum concentration for 25 (OH) D 3 :

  • Values below 11 ng / ml mean a serious risk of rickets for small children and infants and a risk of osteomalacat for adults.
  • Values below 20 ng / ml indicate a long-term relevant vitamin D deficiency (even if manifest rickets or osteomalacia do not necessarily occur).
  • Values ​​between 20 and 30 ng / ml indicate a relative deficiency (“insufficiency”).
  • Values ​​between 30 and 60 ng / ml mean a physiologically safe sufficient supply.
  • Values above 88 ng / ml can mean an oversupply of vitamin D.
  • Values above 150 ng / ml mean vitamin D intoxication .
  • Values above 280 ng / ml lead to serious disturbances in calcium homeostasis.

The literature data differ with regard to these standard values. In the sixth edition of the book Labor und Diagnose , the following reference ranges for vitamin D 25 OH are given: Age up to 50 years: 50 to 175 nmol / l (20 to 70 ng / ml), age from 50 years: 63 to 175 nmol / l (26 to 70 ng / ml). Values ​​between 50 and 100 ng / ml are considered good.

The blood level is maintained in a range of 30 to 88 ng / ml over a wide dose range of daily vitamin D intake from 20 µg (800 IU) to 250–500 µg (10,000–20,000 IU) in adults and only increases at higher levels Feed on. This upper limit (20,000 IU) corresponds to the maximum daily production of vitamin D 3 in the skin.

Frequency of low 25 (OH) vitamin D 3 levels

Depending on the season, geographical latitude, food habits, population group and lifestyle, the 25 (OH) vitamin D 3 level falls into areas in which one must assume a vitamin D deficiency. Low vitamin D levels are an independent and long-term risk factor for a number of diseases (cancer, autoimmune diseases, susceptibility to infections, more fragile bones). Since (as explained above) a low vitamin D level is due to civilization, it is often normal, but not yet healthy. The following values ​​were found in various studies:

place geogr.
width
Group, dude Summer / Autumn
(ng / ml ± SD)
Winter / spring
(ng / ml ± SD)
Ref.
Miami (Florida) 26 ° over 18 years 26.8 ± 10.3 (men)
25.0 ± 9.4 (women)
23.3 ± 8.4
Boston, Massachusetts 43 ° white women 20–40 Lj. 34.2 ± 13.2 24.0 ± 8.6
Boston, Massachusetts 43 ° black women 20–40 Lj. 16.4 ± 6.6 12.1 ± 7.9
Paris 49 ° male adolescents 23.4 ± 8.0 8.2 ± 2.8
Calgary, Alberta 51 ° 27.-89. Lj. 28.6 ± 9.4 22.9 ± 8.5

Paris was included in the table as the representative of Central European conditions in terms of geographical latitude, dietary habits and supplementation. The extremely low value in winter is particularly noticeable here. However, it should be borne in mind that a. the reduction of UV radiation through smog.
The effect of different skin pigmentation becomes clear from the example from Boston.

Additional intake as a balance or supplement

If there is a vitamin D deficiency, a supplementary dose of 10–25 µg (400–1000 IU) per day can be given.

During pregnancy

With regard to the intake of vitamin D during pregnancy, the study situation is not clear. The Federal Institute for Risk Assessment points out, however, that an overdose of vitamin D during pregnancy can have serious consequences. It could e.g. B. "to physical and mental retardation , supravalvular aortic stenosis and retinopathy of the child". Therefore, pregnant women should “only take daily doses of over 12.5 μg (500 IU) / day if strictly indicated”.

The general recommendation for pregnant women to take additional vitamin D as compensation is also called into question by a large-scale study of 3,960 mother-child couples, in which the maternal calciferol level had almost no influence on the child's bone density.

Two systematic reviews from 2017 and 2018 found no association between the vitamin D status during pregnancy and subsequent allergies or asthma in the child.

General population

A statistical connection between low vitamin D values ​​and reduced life expectancy has been found in a very large number of studies. So far (as of 2019) it has not been possible to clarify to what extent low vitamin D values ​​contribute to an earlier death or to what extent a poorer state of health leads to lower vitamin D values. The relationship between cause and effect remained unclear. However, a concrete possibility to clarify this question is emerging. It consists of extensive genetic studies of the Mendelian randomization type . The first results of such studies are already available. They do not yet permit firm conclusions, but they do show that such conclusions are likely to be possible in the near future.

The lowering of the risk factor vitamin D deficiency by taking vitamin D preparations ( supplementation ) in the event of a significant vitamin D deficiency suggests a decrease in the death rate ( mortality ) overall.

In countries such as the USA, Canada, Sweden and Finland, certain foods have been supplemented with vitamin D for years. In many countries, due to the new findings in recent years, supplementation is being considered through regulations, e.g. B. even in equatorial India.

In a randomized, controlled study in almost 400 people over 70 years of age, no increase in bone density could be observed after taking vitamin D. You had taken 24,000 or 48,000 IU of vitamin D per month for over a year.

The Institute for Quality and Efficiency in Health Care (IQWiG) published the following conclusion regarding osteoporosis on its continuously updated online platform Gesundheitsinformation.de (as of March 2019):

"However, according to current research results, dietary supplements with vitamin D have no use."

DA-CH reference values ​​of the DGE, ÖGE, SGE / SVE

The German Nutrition Society considers the vitamin D supply in Germany to be inadequate overall , despite the comparatively low assumed reference values (2017). In the existing recommendation from 2012, it still advises against taking vitamin D supplements without a specific reason. Supplementation is only recommended if “insufficient supply has been proven and if a targeted improvement in supply cannot be achieved through either diet or the body's own vitamin D formation through exposure to the sun.” As a rule, this is done in Germany Measures ensure adequate supply. In the absence of endogenous synthesis, i.e. when people live permanently without sun exposure, the DGE recommends consuming the following amounts of vitamin D through food and vitamin D preparations: It now gives these as “estimates for an appropriate intake in the absence of endogenous synthesis " on; the “intake recommendations” valid until 2012 were made without taking the self-synthesis into account and were on average four times lower. In 2012 the following values ​​were published:

Infants (0 to under 12 months): 10 µg / 400 IU per day (estimate)
Children (1 year to under 15 years): 20 µg / 800 IU per day
Adolescents and adults (15 years to under 65 years): 20 µg / 800 IU per day
Adults aged 65 and over: 20 µg / 800 IU per day
pregnant woman: 20 µg / 800 IU per day
breastfeeding women: 20 µg / 800 IU per day

In summary: all persons 20 µg / 800 IU, infants up to 1 year old, half of this dose; 1 µg = 40 international units (IU); 1 IU = 0.025 µg

Institute of Medicine

Between 2008 and 2010, the US health organization Institute of Medicine (IOM) examined the data available to date on vitamin D and its consequences for human health. The aim of the study was to provide specific recommendations regarding vitamin D based on scientific studies. The study found that health benefits beyond bone health for vitamin D levels higher than 20 μg / L are scientifically controversial. The daily requirement of vitamin D was thus set at around 15 µg / 600 IU, with the maximum daily dose ( Tolerable Upper Intake Level ) being increased to 100 µg / 4,000 IU. The recommendation is based on the study of more than 1000 publications on vitamin D, making it the largest vitamin D study in the last decade.

Tolerable upper intake level

The European Food Safety Authority names the following tolerable upper intake levels :

  • Infants (0 to under 12 months): 25 µg / day (1,000 IU)
  • 1-10 years: 50 µg / day (2,000 IU)
  • 11-17 years: 100 µg / day (4,000 IU)
  • 17+: 100 µg / day (4,000 IU)
  • pregnant, lactating woman: 100 µg / day (4,000 IU)

Vitamin D overdose and toxicity

Acute or chronic vitamin D overdose can lead to vitamin D hypervitaminosis. The Scientific Committee on Food of the European Commission issued the following opinion on the safety of vitamin D 3 in 2002 :

A maximum daily dose of 50 µg (2000 IU) for adolescents and adults (including pregnant women and nursing mothers) and 25 µg (1000 IU) for children in the first ten years of life can be taken long-term by healthy people without the risk of side effects, even without medical supervision.
This information is cautious, at least for adults, and has a safety factor of 2, which means that side effects were only observed at doses more than twice as high. Measured against the usual vitamin D doses, this opinion seems to leave sufficient leeway for adults. This safety area is lower for small children.

Most authors consider a daily intake of up to 100 µg (4000 IU) of vitamin D 3 for adults for six months as safe, i.e. without any verifiable side effects such as increased calcium excretion in the urine. In postmenopausal women, daily supplementation of 10 µg (400 IU; together with 1000 mg calcium) has been shown to be associated with a 17 percent increase in the risk of kidney stones over a period of seven years. In contrast, a study that was carried out over a period from 2011 to 2018, in which no additional calcium was administered, showed that much higher doses of vitamin D 3 can be administered (5000 IU to 50,000 IU) without any negative effects on kidney health.

A serum concentration of vitamin D 3 of over 500 nmol / l (this corresponds to over 200 ng / ml) is considered to be potentially toxic. Occasionally life-threatening complications occurred when this value was exceeded.

The package inserts of pharmacy-only vitamin D preparations, on the other hand, indicate an overdose threshold between 40,000 and 100,000 IU (equivalent to 1000 to 2500 µg) per day for one to two months for adults with normal function of the parathyroid glands. Infants and small children can be sensitive to much lower doses.

See also

literature

Web links

Wikibooks: Vitamin D Metabolism  - Learning and Teaching Materials

Individual evidence

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