Vitamin d

The term vitamin D (sun vitamin) is to be understood as a collective term for a group of fat-soluble vitamins which regulate, among other things, the calcium and phosphate balance. 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 formulae of vitamin D2/D3). They are formed in the organism from unsaturated sterols, the various vitamin D precursors (D-provitamins). Vitamin D possesses complex hormone-like effects (vitamin D hormone) with influence on muscle strength, cardiovascular diseases, blood pressure and diabetes mellitus and also immunoregulatory properties.

The individual members of the vitamin D group are present in the diet in minimal amounts only. In contrast, their precursors, the D-provitamins, are abundant in the animal and plant kingdom.

Vitamin D1 is a molecular compound of ergocalciferol and lumisterol and is an ineffective by-product of vitamin D2 synthesis. It does not occur naturally.

Vitamin D2 is formed from the provitamin D2 (ergosterol), which is mainly found in the plant kingdom, in the skin under UV irradiation Ergocalciferol, the vitamin D2.

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

The skin, especially the epidermis, plays a decisive role in the synthesis of vitamin D in the organism. Since UV rays convert the photosensitive provitamins into metabolically active compounds (D vitamins), the organism stores the provitamins in the epithelial cells, since only there are UVB rays (UV spectrum: 290-320nm) effective. This means that even the highest concentrations of provitamin D (7-dehydrocholesterol) are found in the epidermis and there in the stratum spinosum and stratum basale. In the epidermis the provitamins are converted into the vitamins of the D group. These are bound in the blood to the vitamin D3-binding protein (DBP, transcalciferin) and transported to the liver.

By far the most important biological role of the vitamin D group is played by vitamin D3, the 1,25(OH)2-D3 ( calcitriol) which is formed enzymatically from 7-dehydrocholesterol under UVB radiation.

Formation of 1,25 (OH)2-D3 (calcitriol): Colecalciferol itself is functionally inactive and is only hydroxylated to 25-OH-D3 (calcifediol, calcidiol) in a further enzymatic step in the liver or in the kidney at C-atom 25. Calcifediol is the form circulating in the blood. This derivative is also still largely inactive. The second hydroxylation to the highly effective 1,25 (OH)2-D3 (calcitriol), (see also importance of externally applied calcitriol in psoriasis therapy), the actual active form of vitamin D in the human organism (vitamin D hormone), occurs mainly in the kidney. This enzymatic step is regulated among others by the phosphate concentration. A low phosphate level promotes calcitriol formation, a high phosphate level inhibits it. In advanced renal insufficiency, calcitriol synthesis is significantly reduced. Calcitriol is degraded by 24-hydroxylase to the water-soluble calcitroic acid and excreted via bile.

Extrarenal calcitriol: Calcitriol (1,25(OH)2D3) 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 different cell functions such as proliferation, differentiation, angiogenesis, and apoptosis in a site-specific, and in some cases tissue-specific manner (Reichrath J et al. 2018).

Calcitriol action: Calcitriol (1,25(OH)2D3) acts like a steroid hormone. Thus, it reciprocally inhibits the enzyme 1α-hydroxylase thereby controlling calcitriol formation as needed. Calcitriol binds to an intracellular vitamin D receptor (VDR). This receptor bears the systematic designation NR1I1 (NR=nuclear receptor, 1 subfamily1, I for group I, 1 for member 1; see below nuclear receptors) and belongs to the superfamily of nuclear transcription factors (nuclear receptors) and here to subfamily 1 (thyroid hormone receptor-like). In humans, the coding gene for VDR 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, 1,25(OH)2D3 (calcitriol), is the ligand with by far the highest binding affinity. Thus, 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, enters the nucleus and binds as a heterodimer with retinoid X receptor alpha (RXR alpha) to its responsive elements in DNA. It alters the transcription of various genes with corresponding biological effects. Thus, 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 goal is to ensure that plasma calcium levels are kept stable within narrow limits and, together with PTH, to provide calcium for bone mineralization. Here, the small intestine as the site of enteric calcium and phosphorus absorption, the kidneys as the site of renal calcium and phosphorus excretion or reabsorption, 1,25(OH)2D3 biosynthesis, and the parathyroid gland as the site of formation of the most important regulatory hormone (besides 1,25(OH)2D3), PTH, play a decisive role. 1,25(OH)2D3 (calcitriol) in turn reciprocally inhibits parathyroid hormone secretion. Indirectly, estrogens, glucocorticoids, calcitonin, somatotropin, and prolactin, among others, influence 1,25(OH)2D3 formation. Glucocorticoids inhibit calcitriol formation (possible vitamin D deficiency under systemic corticosteroid therapy; substitution if necessary).

Vitamin D3 function in lymphocytes: In addition to the classical role of the vitamin D3 endocrine system, "non-classical" functions of vitamin D3 have also been demonstrated. Thus, a connection between vitamin D3 deficiency and an increased prevalence of immunological disorders, furthermore of malignant porcesses as well as of metabolic and cardiovascular diseases is discussed (Geldmeyer-Hilt K et al. 2011).

VDR activation by its natural ligand calcitriol induces antimicrobial proteins in monocytes and macrophages, such as cathelicidin (LL-37) or β-defensin(DEFB4). The induction of β-defensin is NF-κB and IL-1β dependent (Doss M et al 2010). Calcitriol further inhibits the expression of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-12 in monocytes (Zhang Y et al. (2012). Furthermore, calcitriol modulates adaptive immune system function, such as TCR-dependent activation and differentiation of naive T cells, T cell proliferation (inhibition), and promotes the generation of regulatory CD4+ CD25+ T cells. Calcitriol inhibits both B-cell proliferation and plasma cell differentiation. In addition, calcitriol 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)-D3. Therefore, endogenous calcitriol synthesis may also be (non-genomic) autocrine.

UV-induced formation of 1,25(OH)2vitamin D3: When the skin of a fair-skinned non-UV-preirradiated light-skinned masticated male is exposed to total body irradiation, it produces 10,000 to 20,000 IU (250 µg to 500 µg) of vitamin D3 within 24 hours. Vitamin D3 production by the skin is sufficient for one day's exposure of the face, hands and forearms to the sun for 15 minutes!In dark-skinned people, the high content of melanin in the skin reduces successful vitamin D production. Therefore, in northern latitudes, migrants of dark skin type quite often suffer from low vitamin D3 levels (Powe CE et al. 2013).
Vitamin D3 supplied by the diet or produced in the skin is bound in the blood to the vitamin D3-binding protein (DBP, transcalciferin) and transported away to the liver.

Calcitriol (1,25(OH)2D3) promotes the enteric absorption of calcium and phosphate via the induction of 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.

Calcitriol in turn reciprocally inhibits the enzyme 1α-hydroxylase. This demand-driven control of calcitriol formation accounts for why calcitriol is accorded "hormone status" .

Indirectly, mostly via the parathyroid hormone, estrogens, glucocorticoids, calcitonin, somatotropin and prolactin, among others, influence calcitriol formation. Glucocorticoids inhibit calcitriol formation (this is why it is necessary to substitute vitamin D in active form in case of vitamin D deficiency occurring under systemic corticoid therapy).

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

Calcitriol (1,25(OH)2D3) is not exclusively produced in the kidney, but also extrarenally in keratinocytes, monocytes, T and B lymphocytes and Langerhans cells. However, this extrarenal calcitriol is not released into the blood, but regulates different cell functions such as proliferation, differentiation, angiogenesis and apoptosis in a site-specific, and in some cases tissue-specific manner (Reichrath J et al. 2018)

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

Rickets and osteomalacia: Rickets and osteomalacia are syndromes of vitamin D deficiency in growing or adult individuals. They are caused either by a lack of absorption or self-synthesis of vitamin D, by disorders in vitamin D metabolism, or by functional disorders in the receptor or transactivation area. In the absence of 1,25(OH)2D3 (calcitriol), this deficiency always leads to hypocalcaemia, because the enteral uptake and renal reabsorption of calcium are restricted. This in turn triggers increased PTH secretion. Serious disturbances in bone metabolism occur; on the one hand, due to calcium deficiency (or the disproportion of calcium and phosphate in plasma) and the resulting reduced mineralisation of the bone matrix, on the other hand, due to the misregulated matrix synthesis and the PTH-induced increased rate of bone resorption. The result is mechanical instability of the bone, which leads to severe clinical symptoms, especially on the growing skeleton, such as growth retardation, deformations especially of the long tubular bones and excessive matrix production at the epiphyseal joints, accompanied by bone pain, hypocalcemia and phosphatemia and secondary (reactive) hyperparathyroidism. In the adult organism there is mainly 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 calcitriol (1,25(OH)2 vitamin D3) 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 eosinophil infiltration and Th2 cytokine levels in bronchoalveolar lavage fluid (BALF) in ovalbumin-sensitized mice. Serum 25(OH) vitamin D3 levels were shown to correlate inversely with total IgE, but also with the frequency of eosinophils in peripheral blood. An increase of 10 ng/ml (25 nmol/L) serum 25(OH) vitamin D3 leads to a decrease of 25 I.U./ml in total IgE and of 29/mm3 in eosinophils in 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 induction of IL-10 in CD4+ regulatory T cells (Searing DA et al. 2010; Sutherland E R et al. 2010). Apparently, vitamin D3 supplementation also appears to reduce the risk of recurrent respiratory infections and the frequency of asthma attacks in children with asthma (Majak P et al. 2011). A further connection between vitamin D3 metabolism and the development of asthma is proven by various studies. VDR polymorphisms, which are associated with an increased risk for the occurrence of type I bronchial asthma.

Atopic dermatitis: Many publications have discussed the role and possible beneficial effects of vitamin D3 metabolism in atopic dermatitis (AD).

Psoriasis: The beneficial effects of calcitriol on psoriasis are well known. It has been shown that the biologically active form of vitamin D3, calcitriol, promotes keratinocyte differentiation and has a stimulating or even inhibitory effect on keratinocyte growth depending on calcitriol concentrations. Calcitriol induces the synthesis of growth factors from the PDGF family (plateletderived growth factor) and thus promotes wound healing. Furthermore, calcitriol increases TNF-α-dependent keratinocyte differentiation, decreases 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 between vitamin D deficiency and various autoimmunological diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis have been reported (Ao T et al. 2017; Langer-Gould A et al. 2018). Thus, various studies have shown that Studies have shown a negative correlation between serum 25(OH) vitamin D3 concentrations and the risk of MS. In addition, most of the MS patients investigated to date were vitamin D3-deficient. Supplementation of MS patients with high-dose 1,25(OH)2 vitamin D3 resulted in an increase in IL-10+ frequencies and a decrease in the ratio of IFN+/IL-4+ T cells. Furthermore, an association between a low serum 25(OH) vitamin D3 status and the occurrence of T1 diabetes mellitus has been demonstrated (Svoren BM et al. 2009). In rheumatoid arthritis (RA), a negative correlation between serum 25(OH) vitamin D3 concentrations and disease activity was observed in patients with RA.

Vitamin D and age: With age, the 7-dehydrocholesterol content of the epidermis decreases continuously. Furthermore, the skin's ability to produce vitamin D3 also decreases with age (by a factor of about 3 compared to a 20-year-old person). A simultaneous low UV exposure may provide indications for vitamin D substitution.

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

The German Society for Nutrition (DGE) has given guideline values for the amount of vitamin D in the absence of endogenous synthesis. It recommends 10 µg per day for infants in the first year of life and 20 µg (800 IU) vitamin D3 for toddlers and adults.

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

The International Vitamin D Standard is a 0.01% solution of irradiated ergosterol in olive oil. 1 IU is the amount of vitamin that has the antirachitic power of 1mg of this standard solution (=0.025ug of pure crystalline vitamin D3); 1mg of vitamin D3 is 40,000 IU.

Vitamin D3 supplementation during pregnancy but also in early childhood reduces the risk of T1DM (T1 diabetes mellitus). However, vitamin D3 supplementation studies in patients with established T1DM showed contradictory results.

The German Society for Nutrition (DGE) has given guideline values for the amount of vitamin D in the absence of endogenous synthesis. It recommends 10 µg per day for infants in the first year of life and 20 µg (800 IU) vitamin D3 for toddlers and adults.

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

The International Vitamin D Standard is a 0.01% solution of irradiated ergosterol in olive oil. 1 IU is the amount of vitamin that has the antirachitic power of 1mg of this standard solution (=0.025ug of pure crystalline vitamin D3); 1mg of vitamin D3 is 40,000 IU.

Further on the formation of colecalciferol (vitamin D3) in the skin under UV influence: The process of UV-induced formation of the D vitamin is also experimental. This can be demonstrated by the example of 7-dehydrocholesterol. When 7-dehydrocholesterol is exposed to natural sunlight, about 20% of the 7-dehydrocholesterol is converted into 1,25(OH)-D3 (colecalciferol) after a few minutes. With further irradiation, the concentration of colecalciferol remains constant in this experimental approach. Colecalciferol 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 radiation source, even 65% of the original 7-dehydrocholesterol is converted into colecalciferol (vitamin D3).

If the skin of a fair-skinned non-UV-irradiated fair-skinned Caucasian male is irradiated whole-body, it produces 10,000 to 20,000 IU (250 µg to 500 µg) of vitamin D3 within 24 hours. A vitamin D3 production of the skin sufficient for one day is sufficient after a 15-minute exposure of the face, hands and forearms to the sun! In dark-skinned people, the high content of melanin in the skin reduces the production of vitamin D. In northern latitudes, migrants with dark skin types therefore often suffer from low vitamin D3 levels (Powe CE et al.2013).

Other effective vitamin D3 derivatives: In the human body, not only the actually effective 1,25(OH)2D3 (calcitriol) and its known derivatives are produced and active, but also a number of other hydroxylated vitamin D3 and D2 compounds mediated by the cytochrome P 450 family, which are formed by deposits on the side chain of the original substance framework. These derivatives interact with different affinities not only with the vitamin D receptor (VDR) but also with other cell receptors.

1. Ao T et al (2017) Update on recent progress in vitamin D research. The effects of vitamin D in autoinflammatory diseases. Clin Calcium 27:1551-1559.
2. Aranda A et al (1998) Nuclear hormone receptors and gene expression. Physiol Rev 2001. 81: 1269-1304.
3. Baughman RP et al (2017) Current concepts regarding calcium metabolism and bone health in sarcoidosis. Curr Opin Pulm Med 23:476-https://www.ncbi.nlm.nih.gov/pubmed/28598871
4. Baudino T A et al (1998) Isolation and characterization of a novel coactivator protein, NCoA-62, involved in vitamin D-mediated transcription. J Biol Chem 273: 16434-16441.
5. Bjelakovic G et al (2017) Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev 11:CD011564.
6. Black PN et al (2005) Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 128: 3792-3798.
7. Doss M et al (2010) Human defensins and LL37 in mucosal immunity. J Leukoc Biol 87: 79-92.
8. González-Castro TB et al (2019) Association of vitamin D receptor polymorphisms and nephrolithiasis: A meta-analysis.genes 711:143936. https://www.ncbi.nlm.nih.gov/pubmed/31212049
9. Fukuoka M et al (1998) RANTES expression in psoriatic skin, and regulation of RANTES and IL-8 production in cultured epidermal keratinocytes by active vitamin D3 (tacalcitol). Br J Dermatol 138: 63-70.
10. Geldmeyer-Hilt K et all. (2011) 1,25-dihydroxyvitamin D3 impairs NF-kappaB activation in human naïve B cells. Biochem Biophys Res Commun 407: 699-702.
11. Gregoriou E et al (2017) The Effects of Vitamin D Supplementation in Newly Diagnosed Type 1 Diabetes Patients: Systematic Review of Randomized Controlled Trials. Rev Diabet Stud 14:260-268.
12. Haussler MR et al.(2008) Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev 66: 98-112.
13. Hollams EM et al (2011) Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study. Eur Respir J 38: 1320-1327.
14. Issa L et al (1998) J. A., Molecular mechanism of vitamin D receptor action. Inflamm Res 1998. 47: 451-475.
15. Jamali N et al (2017) Vitamin D and regulation of vascular cell function. Am J Physiol Heart Circ Physiol doi: 10.1152/ajpheart.00319.2017.
16. Langer-Gould A et al (2018) Vitamin D-binding protein polymorphisms, 25-hydroxyvitamin D, Sunshine and Multiple Sclerosis. Nutrients doi: 10.3390/nu10020184.
17. Mayak P et al (2011) Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol 127: 1294-1296.
18. Makishima M (2017) Update on recent progress in vitamin D research. Vitamin D receptor and the nuclear receptor superfamily. Clin Calcium 27:1533-1541.
19. Norman AW (1998) Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral components of the vitamin D endocrine system. At J Clin Nutr 67: 1108-1110.
20. Powe CE et al (2013) Vitamin D Binding Protein and Vitamin D Status of Black Americans and White Americans. New England Journal of Medicine 369: 1991-2000
21. Prufer K et al (2000) Dimerization with retinoid X receptors promotes nuclear localization and subnuclear targeting of vitamin D receptors. J Biol Chem 2000. 275: 41114-41123.
22. Reichrath J et al (2018) Die Haut als Hormonfabrik: a short overview of vitamin D supply in Germany. Act Dermatol 44: 53-61
23. Rigby WF et al (1984) Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest 74: 1451-1455.
24. Rosen C J et al (2012) The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev 33: 456-492.
25. Searing DA et al (2010) Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol125: 995-1000.
26. Shallis RM et al (2018) Mechanisms of Hypercalcemia in Non-Hodgkin Lymphoma and Associated Outcomes: A Retrospective Review. Clin Lymphoma Myeloma Leuk 18: e123-e129.
27. Shirakawa AK et al (2008) 1,25-dihydroxyvitamin D3 induces CCR10 expression in terminally differentiating human B cells. J Immunol180: 2786-2795.
28. Sutherland E R et al (2010) Vitamin D levels, lung function, and steroid response in adult asthma. At J Respir Crit Care Med181: 699-704.
29. Svoren BM et al (2009) Significant Vitamin D Deficiency in Youth with Type 1 Diabetes Mellitus. Journal of Pediatrics 154: 132-134.
30. Veldman C M et al (2000) Expression of 1,25dihydroxyvitamin D (3) receptor in the immune system. Arch Biochem Biophys 374: 334-338.
31. von Essen MR et al (2010) Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol11: 344-349.
32. Zhang Y et al (2012) Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1 J Immunol 188: 2127-2135.