Vitamin d

The term vitamin D (vulgo: "sun vitamin") is to be understood as a collective term for a group of fat-soluble vitamins that regulate the calcium and phosphate balance, among other things. All steroid-like representatives of the vitamin D group (vitamin _D1, vitamin _D2, vitamin _D3) belong to the secosteroids and differ only in their side chains (see formulas of vitamins _D2/3). They are formed in the organism from unsaturated sterols, the various vitamin D precursors (D-provitamins). Vitamin D has complex hormone-like effects ("vitamin D hormone") with an influence on muscle strength, cardiovascular diseases, blood pressure and diabetes mellitus as well as immunoregulatory properties.

The individual representatives of the vitamin D group are only present in minimal quantities in food. In contrast, their precursors, the D-provitamins, are abundant in the animal and plant kingdoms.

Historically, "vitamin _D1 " is a reaction mixture of ergocalciferol and the biologically inactive lumisterol, which is formed when ergosterol is exposed to UV radiation.

Vitamin _D2 (ergocalciferol) can be formed by UV irradiation of ergosterol, primarily in fungi and yeasts; this also occurs - less frequently - in other eukaryotic microorganisms.

Vitamin _D3 is formed from provitamin _D3 (7-dehydrocholesterol), which is mainly found in animal tissue. 7-dehydrocholesterol is the most important representative of provitamin D. Under UV radiation, 1,25(OH)₂D₃, cholecalciferol, is formed. However, 7-dehydrocholesterol can also be produced renally by the body itself. Both D vitamins are therefore subject to the same metabolic process; they are mutually interchangeable.

The skin, especially the epidermis, plays a decisive role in vitamin D synthesis in the organism. As UV rays convert the photosensitive and photoreactive provitamins into metabolically active compounds (D vitamins), the organism stores the provitamins in the epithelial cells, as UVB rays (UV spectrum: 290-320 nm) are only effective there. This means that the highest concentrations of provitamin _D3 are found in the epidermis and there in the stratum spinosum and stratum basale. In the blood, these are bound to the vitamin _D3-binding protein (DBP, transcalciferin) and transported to the liver. Vitamin _D3 plays by far the most important role of the D vitamins.

Formation of 1,25(OH)₂D₃ (calcitriol): Cholecalciferol itself is functionally inactive and is only hydroxylated in a further enzymatic step in the liver to 25-hydroxycholecalciferol (calcidiol) or further in the kidney by 1α-hydroxylase to 1,25-dihydroxycholecalciferol (calcitriol). Calcidiol is the form circulating in the blood (and the main indicator of vitamin D status in the body). This derivative is still largely inactive as a pre-hormone or precursor. Only the second hydroxylation mentioned above leads to the highly effective 1,25(OH)₂D₃ (see also the importance of externally applied calcitriol in psoriasis therapy), the actual hormonally active form of vitamin D in the human organism (vitamin D hormone). This enzymatic step is regulated by calcium, phosphate and FGF23, among other things. A low phosphate level promotes calcitriol formation, a high phosphate level inhibits it. Calcitriol synthesis is significantly restricted in advanced renal insufficiency. Calcitriol is broken down by 24-hydroxylase to water-soluble calcitroic acid and excreted via the bile.

Extrarenal calcitriol: Calcitriol is also formed extrarenally in keratinocytes, monocytes, T and B lymphocytes and Langerhans cells. However, this extrarenally formed calcitriol is not released into the blood, but regulates various cell functions such as proliferation, differentiation, angiogenesis and apoptosis locally, in some cases also tissue-specifically (Reichrath J et al. 2018).

Calcitriol effect: Calcitriol acts like a steroid hormone. It reciprocally inhibits the enzyme 1α-hydroxylase, whereby calcitriol formation is controlled as required. It binds to an intracellular vitamin D receptor (VDR). This receptor has the systematic designation NR1I1 (NR = nuclear receptor, subfamily 1, group I, for member 1; see nuclear receptors below) and belongs to the superfamily of nuclear transcription factors (nuclear receptors) and here to subfamily 1 (thyroid hormone receptor-like). The coding gene for VDR in humans is located on chromosome 12, gene locus q13.11.

VDRs are found in almost all cells of the body, but in varying distribution and density. For example, dendritic cells, macrophages, T and B cells express the vitamin D receptor and 1α-hydroxylase (CYP27B1).

Of the natural ligands of the VDR, calcitriol is by far the ligand with the highest binding affinity. Calcitriol binds 100-1000 times more strongly to the VDR than 25(OH)_D3 or 24,25(OH_)2D3. The vitamin D receptor activated via ligand binding is channeled into the cell nucleus and binds as a heterodimer with the retinoid X receptor alpha (RXR alpha) to its responsive elements in the DNA. It alters the transcription of various genes with corresponding biological effects. The activated vitamin D receptor regulates multiple cell effects such as proliferation, apoptosis, migration, invasion and differentiation.

Calcitriol and regulation of calcium homeostasis: The best known function of 1,25(OH)₂D₃ is its central role in the regulation of calcium homeostasis and bone metabolism ("calcemic effects"). The primary aim is to ensure that plasma calcium levels are kept stable within narrow limits and, together with PTH, to provide calcium for bone mineralization. The small intestine as the site of enteral calcium and phosphorus absorption, the kidneys as the sites of renal calcium and phosphorus excretion and reabsorption, 1,25(OH)₂D₃ biosynthesis and the parathyroid gland as the site of formation of the regulatory hormone PTH (which is the most important besides 1,25(OH)₂D₃) play a decisive role here. Calcitriol in turn reciprocally inhibits parathyroid hormone secretion in the parathyroid glands. Its formation is indirectly influenced by oestrogens, glucocorticoids, calcitonin, somatotropin and prolactin, among others. Glucocorticoids inhibit the formation of calcitriol (possible vitamin D deficiency under systemic corticosteroid therapy; substitution if necessary).

Vitamin D3 _function in lymphocytes: In addition to the classic role of the vitamin D3 _endocrine system, "non-classical" functions of vitamin _D3 have also been demonstrated. For example, a connection between vitamin D3 _deficiency and an increased prevalence of immunological disorders, malignant processes and metabolic and cardiovascular diseases is being discussed (Geldmeyer-Hilt K et al. 2011).

VDR activation by its natural ligand calcitriol induces antimicrobial proteins such as cathelicidin (LL-37) or β-defensin(DEFB4) in monocytes and macrophages. The induction of β-defensin is NF-κB- and IL-1β-dependent(Doss M et al. 2010). Calcitriol also inhibits the expression of proinflammatory cytokines such as TNF-α, IL-6 and IL-12 in monocytes (Zhang Y et al. (2012). Calcitriol also modulates the function of the adaptive immune system, such as TCR-dependent activation and differentiation of naive T cells as well as T cell proliferation (inhibition) and promotes the formation of regulatory CD4+ and CD25+ T cells. Calcitriol inhibits both B-cell proliferation and plasma cell differentiation. Calcitriol also inhibits IgE secretion. Activated T and B lymphocytes express the enzyme CYP27B1, which catalyzes the synthesis of the active form of vitamin _D3, calcitriol, from its precursor form, 25(OH)D (calcidiol). Therefore, endogenous calcitriol synthesis can also take place (non-genomically) autocrine.

UV-inducedformation of 1,25(OH)₂D₃: If the skin of a fair-skinned, non-UV-irradiated fair-skinned Caucasian is exposed to full-body irradiation, it produces 10,000 to 20,000 IU (250 µg to 500 µg) of vitamin _D3 within 24 hours. Sufficient vitamin D3 _production of the skin for one day is achieved after 15 minutes of sun exposure of the face, hands and forearms! In dark-skinned people, the high melanin content in the skin reduces successful vitamin D production. In northern latitudes, it is therefore not uncommon for migrants with dark skin to suffer from low vitamin D3 _levels(Powe CE et al. 2013).
The vitamin _D3 supplied through food or produced in the skin is bound to the _vitamin D3-binding protein (DBP, transcalciferin) in the blood and transported to the liver.

Calcitriol promotes the enteral absorption of calcium and phosphate via the induction of the calcium-binding protein in the mucosa cells of the small intestine and reduces renal calcium and phosphate excretion; bone mineralization is thus promoted. Calcitriol reciprocally inhibits parathyroid hormone secretion in the parathyroid glands.

Calcitriol reciprocally inhibits the enzyme 1α-hydroxylase. This needs-based control of calcitriol formation explains why calcitriol is recognized as having "hormone status".

As a steroid hormone, the substance binds to an intracellular vitamin D receptor (VDR). It can thus be channeled into the cell nucleus. There, the vitamin D receptor complex binds to the DNA and changes the transcription of various genes with corresponding biological effects. It has been found that vitamin D improves the induction of cathelicidin from monocytes. Furthermore, the formation of defensins is stimulated.

Degradation of calcitriol: Calcitriol is degraded by 24-hydroxylase to water-soluble calcitroic acid and excreted via the bile.

Rickets and osteomalacia: Rickets and osteomalacia are vitamin D deficiency syndromes in adolescents and adults respectively. They are caused either by inadequate absorption or synthesis of vitamin D, by disorders in vitamin D metabolism, or by functional disorders in the area of the receptor or transactivation. If 1,25(OH)₂D₃ (calcitriol) is missing, this deficiency always leads to hypocalcemia because enteral absorption and renal reabsorption of calcium are restricted. This in turn triggers increased PTH secretion. This leads to serious disturbances in bone metabolism: on the one hand due to the calcium deficiency (or the imbalance of calcium and phosphate in the plasma) and the resulting reduced mineralization of the bone matrix; on the other hand due to the dysregulated matrix synthesis and the PTH-induced increased bone resorption rate. The result is mechanical instability of the bone, which leads to severe clinical symptoms such as growth retardation, deformation, especially of the long tubular bones and excessive matrix production at the epiphyseal joints, accompanied by bone pain, hypocalcemia and hypophosphatemia as well as secondary (reactive) hyperparathyroidism, particularly in the growing skeleton. In the adult organism, there is above all an increased susceptibility to fractures and a radiographically detectable reduction in bone mineral density.
Granulomatous diseases: Patients with tuberculosis, sarcoidosis and other granulomatous diseases produce increased amounts of 1,25(OH)₂D₃ in macrophages. This can lead to vitamin D hypervitaminosis with consecutive hypercalcemia (E83.58) (Baughman RP et al. 2017).

Vitamin D3_in atopic diseases: Vitamin _D3 promotes immunological tolerance in most immune cells associated with asthma. For example, vitamin _D3 inhibits the production of IgE in B cells and the maturation and differentiation of mast cells. In dendritic cells, it induces a tolerogenic phenotype and generates CD4+ CD25+ T cells with regulatory properties. In a mouse model of allergic asthma, vitamin _D3 application reduces the infiltration of eosinophils and the amount of Th2 cytokines in bronchoalveolar lavage fluid (BALF) in ovalbumin-sensitized mice. Serum 25(OH)-vitamin D3 levels were shown to be inversely correlated with total IgE, but also with the frequency of eosinophils in peripheral blood. An increase of 10 ng/ml (25 nmol/L) 25(OH)-vitamin D3 in serum leads to a decrease of 25 I.U./ml in total IgE and of 29 in eosinophils per mm3ⁱⁿ peripheral blood. Furthermore, studies have shown that vitamin D3 status was negatively associated with total IgE and the number of circulating eosinophils, basophils and neutrophils (Hollams EM et al. 2011; Black PN et al. 2005).

Bronchial asthma: It has been shown that vitamin _D3 uptake in asthma patients with glucocorticoid resistance leads to an improved response to dexamethasone and an induction of IL-10 in CD4+ regulatory T cells (Searing DA et al. 2010; Sutherland E R et al. 2010). Vitamin D3 _{supplementation} in children with asthma also appears to reduce the risk of recurrent respiratory tract infections and the frequency of asthma attacks (Majak P et al. 2011). A further link between vitamin D3 _metabolism and the development of asthma is demonstrated by various VDRpolymorphisms, which are associated with an increased risk of developing type I bronchial asthma.

Atopic dermatitis: The role and possible positive effects of vitamin D3_on atopic dermatitis (AD) have been discussed in many publications.

Psoriasis: The positive effects of calcitriol on psoriasis are well known. It has been shown that the biologically active form of vitamin D3_promotes keratinocyte differentiation and has a stimulatory or inhibitory effect on keratinocyte growth depending on calcitriol concentrations. Calcitriol induces the synthesis of growth factors from the PDGF family (platelet derived growth factor) and thus promotes wound healing. In addition, calcitriol enhances TNF-α-dependent keratinocyte differentiation, reduces the synthesis of IL-1α, IL-6, CCL5 chemokine (RANTES) and reduces inflammation in epidermal keratinocytes (Fukuoka M et al. 1998).

Vitamin D and autoimmune diseases: Various immune cells, such as dendritic cells, macrophages, T and B cells, express the vitamin D receptor and 1α-hydroxylase (CYP27B1). Furthermore, associations of vitamin D deficiency with various autoimmunological diseases, e.g. rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, have been reported (Ao T et al. 2017; Langer-Gould A et al. 2018). Various studies have shown a negative correlation between serum 25(OH) vitamin D3 concentrations and the risk of MS. In addition, most MS patients studied to date were vitamin _D3-deficient. Supplementation of MS patients with high-dose 1,25(OH)₂D₃ resulted in an increase in the frequencies of IL-10+ and a reduction in the ratio of IFN+/IL-4+ T cells. An association between a low serum 25(OH) vitamin _D3 status and the occurrence of type I diabetes has also been confirmed (Svoren BM et al. 2009). In rheumatoid arthritis, a negative correlation was observed between serum 25(OH) vitamin D3 _{concentrations} and disease activity.

Vitamin D and age: The 7-dehydrocholesterol content of the epidermis decreases continuously with age. Furthermore, the ability of the skin to produce vitamin D3 also decreases with age (by a factor of about 3 compared to a 20-year-old person). If UV exposure is low at the same time, there may be indications for vitamin D supplementation.

Other: Vitamin D is often communicated as an "all-purpose weapon" against depression, cancer, diabetes and cardiovascular diseases. Vitamin D supplements can be found in large numbers on supermarket and drugstore shelves. However, according to RKI statistics, a relevant vitamin D deficiency (< 12.5 ng/ml) is rather rare, as the healthy organism is able to store sufficient vitamin D.

The German Nutrition Society (DGE) has specified guideline values for the vitamin D dose to be supplemented in the absence of endogenous synthesis. It recommends 10 µg daily for infants in the first year of life and 20 µg (800 IU) of vitamin _D3 for infants and adults.

Overdoses of vitamin D lead to hypervitaminosis with disturbed calcium and phosphate metabolism and a withdrawal of calcium from the bones. This is deposited in blood vessels and in the kidneys.

The international vitamin D standard is a 0.01% solution of irradiated ergosterol in olive oil. One IU corresponds to the amount of vitamin that has the antirachitic power of 1 mg of this standard solution (= 0.025 μg of pure crystalline vitamin _D3); 1 mg of pure vitamin D3_{corresponds to} 40,000 IU.

Vitamin D3 _{supplementation} during pregnancy, but also in early childhood, reduces the risk of developing type I diabetes mellitus. However, vitamin D3 _{supplementation} studies in patients with pre-existing type I diabetes have shown contradictory results.

Further information on the formation of cholecalciferol (vitamin _D3)in the skin under theinfluenceof UV: The process of UV-induced formation of the D vitamin can also be demonstrated experimentally. This can be shown using the example of 7-dehydrocholesterol. If 7-dehydrocholesterol is exposed to natural sunlight, about 20 % of it is converted to 1,25(OH)_-D3 (cholecalciferol) after a few minutes. With further irradiation, the concentration of cholecalciferol remains constant in this experimental approach. Cholecalciferol itself is also photolabile and is degraded to physiologically inactive products (lumisterol and tachysterol) by further UV-B irradiation. If a narrow-spectrum UV-B light source (UV spectrum: 290 to 300 nm) is used as the irradiation source, as much as 65 % of the original 7-dehydrocholesterol is converted into cholecalciferol.

Other active vitamin _D3 derivatives: In the human body, not only the actually active 1,25(OH)₂D₃ (calcitriol) and its known derivatives are produced, but also a number of other hydroxylated _vitamin D3 and _D2 compounds mediated via the cytochrome P450 family. They are formed by attachments to the side chain of the original substance scaffold. These derivatives interact with different affinities not only with the vitamin D receptor (VDR), but also with other cell receptors.

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