Two forms of vitamin D, differing in the structure of the side chain, are of fundamental importance:
• ergocalciferol (vitamin D2), naturally occurring in plant organisms / yeasts
• cholecalciferol (vitamin D3), naturally occurring in animal organisms
Vitamins D in the human body are traditionally included in vitamins, but they fulfill the function of prohormones, because as a result of metabolic transformations a biologically active form – 1α, 25-dihydroxycholecalciferol.
In pharmacotherapy, vitamin D is used primarily in the prophylaxis and treatment of rickets, osteomalacia and osteoporosis.
Biosynthesis and metabolism of vitamin D in humans
Both vitamin D2 and D3 have no biological activity. It is obtained by enzymatic hydroxylation with the same carbon atoms of their molecules. In humans, the biologically active form of vitamin D is 1α, 25-dihydroxyvitamin D (1.25 (OH) 2D).
Photoisomerisation of 7-dehydrocholesterol to prettamine D
Isomerisation of previtamin D to cholecalciferol (vitamin D3)
Hydroxylation of vitamin D3 to 1,25- (OH) 2D3 (calcitriol)
Pro-vitamin D2 is ergosterol, and D3 – cholesterol derivative 7-dehydrocholesterol. In the skin, primarily in the epidermis (mainly in keratinocytes of the reproductive layer), under the influence of sunlight, 7-dehydrocholesterol undergoes non-enzymatic photoisomerization to pre-vitamin D, which under the action of thermal body is converted into vitamin D3 within a few hours.
The transformation of provitamin D into pre-vitamin D occurs under the influence of UV radiation of 290-315 nm (UV-B range), and it has been experimentally determined that the most effective wavelength of light is 295-300 nm (with a maximum at 297 nm).
There is no danger of toxic amounts of vitamin D3 resulting from excessive exposure to sunlight, because in this situation, the excess of pre-vitamin and vitamin is broken down.
It is estimated that approximately 80-100% of the amount of vitamin D3 needed for the body comes from the biosynthesis in the skin, and only to a small extent it is supported by food sources. The production in the skin is influenced, among others season, cloudiness and air pollution, latitude, use of sunblock, pigmentation and aging of the skin. Skin production of vitamin D is often not sufficient to meet daily demand, especially in highly industrialized countries, because effective sun exposure depends on many factors, such as geographical location, season, weather, time of day, air pollution, exposure time, skin tone, the thickness of body fat, the surface of the body exposed to the sun’s rays.
Chole- and ergocalciferol in combination with the vitamin D-binding protein are transported to the liver, respectively: from the small intestine, where they are absorbed and from the skin, where cholecalciferol is produced. In the liver, the first stage of the biosynthesis of the active form of vitamin D occurs. After enzymatic hydroxylation at C-25, vitamin 25- (OH) D is formed. This reaction is probably catalyzed by the hydroxylase complex of cytochrome P450 (CYP27A1, CYP3A4 and CYP2R1). 25- (OH) D is also transmitted, also in combination with a vitamin D-binding protein, from the liver to the kidneys (as well as to some other tissues, e.g. skin and immune cells) where the action of the enzyme 1α-hydroxylase (CYP27B1) results in the formation of the active form of vitamin D – 1α, 25- (OH) 2D. Both active forms (1α, 25- (OH) 2D2 and 1α, 25- (OH) 2D3) have identical properties, however, due to their prevalence, 1α, 25-dihydroxyvolecalciferol (1.25- (OH) 2D3) is more commonly used. or calcitriol.
There are about 10 provitamins from which compounds with vitamin D activity are formed. The industrial production of vitamin D is limited mainly to these two.
An important metabolite of vitamin D is 24R, 25-dihydroxyvitamin D, which is formed on the alternative 25 (OH) hydroxylation pathway.
The main action of vitamin D lies in its influence on the regulation of calcium and phosphate homeostasis. The two main effector organs associated with this function, which are active metabolites of vitamin D, are primarily the intestines and bones, and to a lesser extent the kidneys. In the gut, calcium absorption increases, bone releases calcium and phosphates (in hypocalcaemia) in the kidneys, and interacts with parathyroid hormone in calcium reabsorption.
Active metabolites of vitamin D are characterized by wide and diverse biological activities. Vitamin D activity is exerted by genomic and non-genomic actions. Vitamin D in many tissues and cells connects to the nuclear receptor for vitamin D (VDR), and then forms a heterodimer with the 9-cis retinoic acid receptor (RXR) with the properties of a transcription factor, thereby initiating genomic actions. Vitamin D controls over 200 genes.
Non-genomic activities are mediated by a membrane-located cellular receptor that is distinct from the nuclear receptor and activates intracellular metabolic pathways that modulate gene-expression activities.
Vitamin D effects
Vitamin D exerts a significant influence on bone metabolism – it increases the RANKL expression in osteoblast, which in turn activates RANK in the precursor osteoclast, which leads to the formation of a mature osteoclast that releases calcium from the bone by the resorption. During development, it is important in the formation of bones and teeth. Vitamin D deficiency (hypovitaminosis, avitaminosis) in children leads to rickets, abnormal bone mineralization and bone mass loss, and in adults causes bone pain, osteomalacia and osteoporosis.
Vitamin D can help in the fight against caries by the immune system, because it activates defense proteins (eg cathelicidin).
Nervous and muscular system
Low levels of vitamin D in patients using statins correlated with the occurrence of myalgia.
There is a relationship between plasma vitamin D levels and sleep disorders. The level of vitamin D in the pregnant woman’s plasma may be associated with the risk of autistic disorders in her future child.
It has immunomodulatory and indirectly antibacterial effects. Vitamin D activates genes encoding anti-bacterial peptides (with natural antibiotics), cathelicidin and β-defensin 2. Catelicidin has biological activity against many bacteria, including tuberculosis bacteria, which may explain the efficacy of the “solar cure” recommended in the 19th century to treat this disease . The catelicidin is produced by immune cells on contact with bacterial cell walls, in the presence of a 25D vitamin D form.
In multiple sclerosis – In 2017, the FDA issued a statement that states that there is not enough evidence to establish a link between vitamin D intake and the risk of multiple sclerosis in healthy people. Vitamin D may be one of the factors causing seasonal relapses of MS symptoms.
It has anti-proliferative properties and prevents the formation of cancer cells, affects apoptosis and angiogenesis.
According to research conducted on 17 thousand. people with higher levels of vitamin D in the serum do not affect the total number of deaths from cancer, although people with a higher level have a lower risk of developing colon cancer.
Analysis of 18 research results, in which 57 thousand participated. people, showed that among those taking vitamin D, in the average dose of 528 IU, the mortality rate decreased by 7%.
Some studies indicate that vitamin D may reduce the risk of influenza. Seasonal variability of vitamin D content in the body (caused by the variability of sun exposure in different seasons) is also associated, according to these studies, with the seasonality of infections for this disease.
Scientific studies do not show a clear influence of Vitamin D on hypertension.
Supplementation with Vitamin D3 and calcium modulates inflammation in chronic heart failure.
Metabolic activities in many tissues
Vitamin D stimulates the ability to regenerate the liver. Through its anti-proliferative functions, intensifying differentiation and apoptosis as well as anti-angiogenic, it can have anticancer effects.
Sources of vitamin D
Under the influence of sunlight in the yeast and plants, ergocalciferol is formed.
The most cholecalciferol contains meat from some fish (salmon, cod, tuna, herring, mackerel, sardines, eel and others) and fish oil. Important sources of cholecalciferol are: liver, cheese, egg yolk and some fungi.
In order to prevent possible vitamin D deficiencies, some food products are enriched in it. In the USA: milk and yogurt, breakfast cereals, orange juice and margarine. In European countries, these are: margarine and breakfast cereals. Mandarine is enriched with vitamins A and D in Poland.
Biofotosynthesis in the skin
Establishing norms of daily demand for vitamin D is difficult because its important source (sometimes satisfying 100% of the demand) is cholecalciferol formed in the skin, but the amount of vitamin D thus formed largely depends on the weather and on how much of the skin and for how long it is exposed to the effects of sunlight. Various institutions recommend various daily norms for the oral consumption of vitamin D.
The Polish Institute of Food and Nutrition recommends the following standards:
• infants: the recommended standard is 20 μg, the safe level is 10 μg
• children (1-9 years of age): 15 μg, safe level 10 μg
• adolescents and people over 60 years of age: 10 μg, safe level of 5 μg
In the European Union, it is officially recommended to consume 5 μg of vitamin D per day.
The FDA recommends taking 10 μg (400 IU) of vitamin D daily for children over 4 years of age. and adults (with a diet containing 2,000 kcal) . Another American scientific institution (Institute of Medicine, Food and Nutrition Board) recommends consuming 5 μg daily until the age of 51, 10 μg at the age of 51-70 and 15 μg above 71 years of age.
For people over 60 years, the International Osteoporosis Foundation recommends a serum 25OHD level of 75 nmol / L (30 ng / ml) achieved by consuming 20-25 μg / day (800-1000 IU / day). Until these recommendations were announced in 2010, the effectiveness of higher doses in the prevention of falls and fractures has not been evaluated in clinical trials. In obese people, with osteoporosis, with limited sun exposure (bedridden patients, cripples), with malabsorption and in non-Europeans it may be necessary to increase consumption to 50 μg / day (2000 IU / day). In these at-risk individuals, the Foundation recommends measuring serum 25OHD and repeating the measurement after 3 months of supplementation in order to check that the vitamin D concentration has reached the desired level. 2.5 μg (100 IU) of added vitamin D will increase serum 25OHD by about 2.5 nmol / l (1.0 ng / ml.
With adequate sun exposure, the amount of vitamin D, which is produced in the skin, is sufficient enough that you do not need to get it additionally from food sources (so it is not a completely vitamin). The amount of vitamin D produced in humans is subject to seasonal fluctuations and usually decreases, the farther north or south of the equatorial zone the area is located. In the temperate climate zone, the amount of sunlight delivered for about half a year is too small for the human skin to be able to produce enough of this vitamin.
Vitamin D circulates in the body mainly in the form of 25 (OH) D3. The most biologically active form is 1.25 (OH) 2D3, whose level is regulated hormonally . For this reason, it is more reliable to determine the level 25 (OH) D3. In moderate vitamin D deficiency, and also during treatment, 1.25 (OH) 2D3 levels may be false high and misleading, and in the case of overdose remain within the norm.
According to the American National Institutes of Health, the correct level of vitamin D is ≥20 ng / ml, values below 12 ng / ml lead to rickets and osteomalacia. Values persistently above 50 ng / ml are considered potentially toxic, however, this value is based on a small amount of data.
At the request of the US and Canadian Governments Institute of Medicne (IOM), after a literature review, in 2010 it recommended the same level of at least 20 ng / ml. It is available with a daily intake of 600 IU. (15 μg) and 800 IU. (20 μg) in the elderly. IOM found no evidence of the role of vitamin D in diseases other than bone disease . These recommendations have been criticized, including due to the fact that in one of the studies on which IOM was based, among people with levels of at least 20 ng / ml, 8.5% of people had poorly mineralized bones. The American Society of Endocrinology found the level below 30 ng / ml as insufficient, and the level 40-60 ng / ml, requiring daily intake of 37.5-50 μg of vitamin D, as ideal for the health of non-osseous systems.
Determination of the level of vitamin D
The concentration of 25-OH-vitamin D in blood serum is most often for practical reasons for laboratory diagnostics. This is the combined concentration of 25-OH-D2 and 25-OH-D3. It is believed that this study best assesses the metabolic state of vitamin D resources. In laboratory diagnostics, the following methods are used to determine vitamin D and its metabolites:
• high-pressure gas chromatography
Commercial tests used by laboratories may significantly differ in the degree of affinity for the metabolites being tested, which sometimes leads to a lowering of the vitamin D concentration in the blood.
The effects of scarcity
The reasons for the shortage are: low intake in combination with low sun exposure (UVB) and various disorders, including rarely hereditary, such as malabsorption disorders, diseases interfering with the metabolism of vitamin D in the liver and kidneys, into its biologically active metabolites.
Awitaminosis threatens with rickets in children and adolescents, osteomalacia and osteoporosis in adults, fractures, skewing and degeneration of the skeletal system, deformities of the body, poor functioning of the nervous and muscular system, conjunctivitis, inflammation of the skin, weakness of the body and diminished immunity, deterioration hearing loss, weakening and loss of teeth and an increased risk of autoimmune diseases, especially type 1 diabetes, Crohn’s disease, bladder cancer, breast, colon, colon and ovary. People with Parkinson’s disease and multiple sclerosis have lower serum vitamin D levels.
Skin with dark complexion produces vitamin D about six times slower, due to the absorption of UV radiation by melanin. The result is that black people usually have a half lower concentration of vitamin D in their blood than whites.
The daily dose of vitamin D in a light-skinned person is created during a 5-15 minute exposure between 10 and 15 hours. An adult woman (with a light complexion) during tanning in a bikini, produces about 10,000. IU within 15-20 minutes.
Currently, studies are under way to verify the recommended daily intake of vitamin D.
The effects of excess
It is not possible to cause hypervitaminosis with normal diet or intensive exposure to ultraviolet radiation. Excessive amount of UV rays breaks down vitamin D to suprasterol, preventing overproduction. For overdose of vitamin D administered orally, it is rare because it requires chronically high doses of this vitamin – about 50 thousand. IU daily or more. In some diseases, eg sarcoidosis, tuberculosis or idiopathic hypercalcaemia, much lower doses slightly exceeding the therapeutic doses (eg above 1000 IU per day) may already cause symptoms of poisoning. The level of vitamin D exceeding 200 ng / ml (500 nmol / L) is considered to be potentially toxic leading to hypercalcemia and hyperphosphatemia.
A tolerable higher level of vitamin D intake has been determined at 4,000 IU. (100μg)
The symptoms are associated with hypercalcemia – nausea and vomiting, lack of appetite, constipation, weakness and easy fatigue, excessive thirst, increased urination, pruritus, headaches. With accompanying hypercalciuria, there may be kidney deposits (kidney stones), as well as calcifications (nephrocalcinosis), followed by renal failure. Calcium deposits can appear in the tissues: eg, arteries, heart, lungs. In children, delays in psychomotor development can be observed.