Vitamin D

Vitamin D, also known as calciferol, is a fat-soluble vitamin/prohormone that plays a pivotal role in calcium and phosphorus homeostasis, and bone metabolism.

It also has a pivotal role in the proper functioning of various organ systems- musculoskeletal, immune, nervous, and cardiovascular.

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A unique property of vitamin D as a nutrient is that apart from its dietary obtainment, it can also be synthesized by the body, through the action of sunlight.

These dual sources of vitamin D often make it challenging to develop dietary reference intake values.

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Low levels of vitamin D are strongly correlated with decreased calcium levels, which in turn lead to inadequate mineralization of teeth and bones with subsequent development of rickets in children and osteoporosis in adult populations.

This results not only in bone deformation, but also high susceptibility to falls and bone fractures.

Vitamin D deficiency is one of the most common nutritional deficiencies among individuals worldwide.

The recent introduction of diets based on highly processed food, an indoor lifestyle, and sun avoidance have all contributed to the development of a global vitamin D deficiency epidemic.

The fortification of milk with vitamin D in the 1930s proved effective in eradicating rickets and osteoporosis in some countries, such as the U.S.A. and Canada.

Despite that, subclinical vitamin D deficiencies are still widely prevalent in both developed and developing countries with a worldwide prevalence of up to 1 billion [1].

This widespread subclinical vitamin-D deficiency is associated with osteoporosis, osteomalacia, increased risk of falls, and fragility fractures.

Additionally, recent studies indicate an association between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune disease, and depression [2].

Proper vitamin D supplementation according to recent standards seems to be essential for the maintenance of human health and body homeostasis [3456].

Forms of Vitamin D

Vitamin D comprises a group of fat-soluble seco-sterols.

The two major forms are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol).

Vitamin D2 (ergocalciferol) is largely human-made and added to foods, whereas vitamin D3 (cholecalciferol) is synthesized in the skin of humans from 7-dehydrocholesterol, and is also obtained via diet through the consumption of animal-based foods, such as mackerel, salmon, salmon roe, herring, sardines, tuna, egg yolks, organ meats (offal).

Both vitamin D3 and vitamin D2 are commercially synthesized and found in dietary supplements or fortified foods.

The D2 and D3 forms differ only in their side-chain structure.

The differences do not affect metabolism (i.e., activation), and both forms function as prohormones (precursor substances that the body converts to active hormones).

When activated, the D2 and D3 forms have been reported to exhibit identical responses in the body, and the potency concerning their ability to cure vitamin D–deficiency rickets is the same (Jones et al., 1998Jurutka et al., 2001) [2021].

Experimental animal studies show that vitamin D2 is less toxic than vitamin D3, but this has not been demonstrated in humans.

Vitamin D, in either the D2 or D3 form, is considered biologically inactive until it undergoes two enzymatic hydroxylation reactions (hydroxylation- chemical process that introduces a hydroxyl group (-OH) into an organic compound).

The first takes place in the liver, mediated by the 25-hydroxylase (most likely cytochrome P-450 2R1 [CYP2R1]), which forms 25-hydroxy vitamin D (also referred to as 25OHD- the most common marker used in blood tests).

The second reaction takes place in the kidney, mediated by 1α-hydroxylase (CYP27B1), which converts 25OHD to the biologically active hormone, calcitriol (1,25-dihydroxy vitamin D).

The 1α-hydroxylase gene that encodes the action of 1α-hydroxylase (CYP27B1) in the kidneys is also expressed in several extra-renal tissues, but its contribution to calcitriol formation in these tissues remains unknown.

25OHD (also referred to as calcidiol or calcifediol), the precursor to calcitriol (1,25-dihydroxy vitamin D), is the major circulating form of vitamin D; it circulates bound to a specific plasma carrier protein, called vitamin D binding protein (DBP).

Vitamin D binding protein (DBP) can bind the various forms of vitamin D including ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), the 25-hydroxylated forms (calcifediol), and the active hormonal product, 1,25-dihydroxy vitamin D (calcitriol).

Outside of the naturally occurring, biological forms of vitamin D, more than 3000 synthetic analogs have been developed by various pharmaceutical companies and academic research groups based on the vitamin D structure, in order to advance the biological properties of the natural compound for applications in the therapy of hyperproliferative diseases, such as different types of cancer, psoriasis [22], and bone disorders, such as osteoporosis [23].

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Synthetic vitamin D analogs are not dietary or biosynthesized compounds; rather, they are designed for specific applications in research or clinical treatment.

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Some examples of synthetic vitamin D3 analogs that have gained importance in clinical medicine, and have made it to the commercial market are calcipotriol (brand name- Daivonex, Dovonex, Sorilux), doxercalciferol (brand name- Hectoral), alfacalcidol (brand name- Alphadol, AlphaD, One-Alpha), tacalcitol (brand name- Bonalfa, Curatoderm, Ticlapsor, Vellutan, Alfatacacil), paricalcitol (brand name- Aricitol, Caltopar, Deparic, Paridev, Porontazin, Rextol), maxacalcitol (brand name- Oxarol), falecalcitriol (brand name- Fulstan, Hornel), and eldecalcitol (brand name- Edirol). 

Vitamin D Biosynthesis

The renal synthesis of calcitriol (1,25-dihydroxy vitamin D) is tightly regulated by two counter-acting hormones- parathyroid hormone (PTH) and fibroblast-like growth factor-23 (FGF23).

Parathyroid hormone (PTH) up-regulates renal synthesis of calcitriol (1,25-dihydroxy vitamin D), while fibroblast-like growth factor-23 (FGF23) down-regulates it (Galitzer et al., 2008Bergwitz and Juppner, 2010) [2425].

Low serum phosphorus levels stimulate calcitriol synthesis, whereas high serum phosphorus levels inhibit it.

Following its synthesis in the kidney, calcitriol binds to vitamin D binding protein (DBP) to be transported to target organs.

The biological effects of calcitriol, involve regulation of gene expression at the transcriptional level, and are mediated through binding to a vitamin D receptor (VDR), located primarily in the nuclei of target cells (Jones et al., 1998Jurutka et al., 2001) [2021].

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Additional hydroxylation reactions, such as that mediated by CYP24A1 enzymes (member of the cytochrome P-450 superfamily of enzymes), result in more polar metabolites with greatly reduced or no apparent biological activity.

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The classical actions of vitamin D—which by itself is inactive—are due to the functions of the active metabolite, calcitriol (1,25-dihydroxy vitamin D), which include the regulation of serum calcium and phosphate homeostasis and, in turn, the development and maintenance of bone health (DeLuca, 1988Reichel et al., 1989Jones et al., 1998) [262720].

Non-classical functions of calcitriol are not yet well clarified.

Vitamin D receptors (VDRs) are found fairly ubiquitously throughout the body in tissues not involved with calcium and phosphate homeostasis, and their presence in these tissues implies that calcitriol may play a more general role, or that ligands (substances that form complexes with other biomolecules to serve a biological purpose) other than calcitriol can activate vitamin D receptors (VDRs).

Additionally, DNA sequences found in the promoter region of vitamin D regulated genes (known as vitamin D–responsive elements- VDREs) are also present in a large number of human genes involved in a wide range of classical and non-classical roles, such as the regulation of cell proliferation, cell differentiation, and apoptosis.

It has also been suggested that calcitriol exerts immunomodulatory and anti-proliferative effects through autocrine and paracrine pathways [28].

These wide-ranging actions of calcitriol have been further hypothesized to play a potential role in preventive or therapeutic actions against cancer [29] and chronic conditions, such as auto-immune diseases (including type 1 diabetes), cardiovascular disease, and infections [3031].

Vitamin D is Technically a Pro-Hormone, not a Vitamin

Prohormones are inactive precursors of hormones that are converted to active forms with the help of biochemical catalysts, called enzymes.

In fact, unlike other vitamins, only about 10 percent of the needed vitamin D is obtained from food (such as oily fish); the rest 90% is made from the body itself.

For that reason, researchers consider calcitriol (1,25-dihydroxy vitamin D) to be a steroid hormone and believe that it functions in the same way as other steroid hormones—by interacting with its cognate vitamin D receptors (VDR) being present throughout the body [34].

Vitamin D Receptors

Vitamin D receptors (VDRs) are the only proteins expressed by the human genome that can bind with the biologically active forms of vitamin D- calcitriol (1,25-dihydroxy vitamin D) and its analogs, at subnanomolar concentrations [32].

All physiological functions of vitamin D compounds are mediated by the vitamin D receptor (VDR) and its target genes [33].

The vitamin D receptor (VDR) gene is expressed most prominently in the intestines, kidneys, and bone, but some VDR expression is also found in most of the other 400 human tissues and cell types [35].

This means that not only tissues related to calcium homeostasis and bone formation, but also immune cells, respond to vitamin D [36].

Vitamin D receptors (VDRs) are endocrine receptors and members of the superfamily of nuclear receptors, which means that their mechanism of action is comparable to glucocorticoid and estrogen receptors [37].

Tissues with Vitamin D receptors

AdiposeMuscle, embryonic 
Adrenal Muscle, smooth 
Bone Osteoblast 
Bone marrowOvary 
BrainPancreas β cells 
Breast Parathyroid 
Cancer cells Parotid 
Colon Placenta 
Eggshell gland Prostate 
Epididymis Retina
Hair follicle Skin 
Intestine Stomach 
Kidney Testis 
Liver (fetal) Thymus 
Lung Thyroid 
Lymphocytes (B & T) Uterus 
Muscle, cardiac Yolk sac (bird) 
Tissues that express the vitamin D receptor for the steroid hormone 1α, 25-dihydroxyvitamin D3

Immune System Modulation Effects

Vitamin D inhibits proliferation and induces differentiation of cells of different lineages, and is essential for the regeneration of the epithelial gut barrier, as well as the maturation of immune cells.

For example, lymphocytes, neutrophils, monocytes, and dendritic cells not only express vitamin D receptors (VDR) and are direct targets for calcitriol (1,25 dihydroxy vitamin D), but also activate circulating calcifediol (25-hydroxyvitamin D3) through the CYP27B1 gene.

CYP27B1 facilitates the production of the enzyme 1-alpha-hydroxylase (1α-hydroxylase), also known as cytochrome p-450 27B1, which catalyzes the conversion of calcifediol to calcitriol (the bioactive form of Vitamin D) [16].

The immunomodulatory effects of calcitriol (1,25 dihydroxy vitamin D) include switching between cell-mediated response (Th1) and humoral immunity (Th2).

Vitamin D activates macrophages and the production of antimicrobial peptides (AMPs) by epithelial and immune cells, which could be essential in the eradication of bacterial or viral infections.

It is not surprising that the occurrence of sessional infections, such as influenza, is often linked to vitamin D deficiency.

Taking into consideration the various effects of vitamin D on the immune response, Gruber-Bzura [17] examined the potential role of vitamin D in influenza prevention and treatment.

It has to be emphasized that the impact of vitamin D on the immune system is usually based on the immune cell type, tissue, or organ.

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For instance, it was recently suggested that vitamin D could be useful in the prevention and treatment of autoimmune diseases, such as multiple sclerosis, type 1 diabetes mellitus, rheumatoid arthritis, or systemic lupus erythematosus (SLE).

The consequence of vitamin D deficiency in the development and progression of lupus was reviewed by Mak [18].

Strikingly, exposure to UV light is a major contributor to lupus flare-up, but at the same time, sun avoidance behavior only aggravates vitamin D deficiency in lupus patients.

On the other hand, a few recent clinical studies proposed not only a correlation of vitamin D deficiency with the severity of lupus, but also that proper supplementation may inhibit the production of autoantibodies, decrease the Th1/Th17 and memory B cells fractions, and reduce fatigue [18].

Furthermore, increased immune activity, including the production of specific antibodies, is the most important factor in graft-versus-host disease (a condition where the donated bone marrow or peripheral blood stem cells view the recipient’s body as foreign, and the donated cells/bone marrow attack the recipient’s body) in recipients of allogeneic hematopoietic stem cell transplantation.

Thus, the immunomodulatory role of vitamin D may decrease the adverse effects of graft-versus-host disease [16].

Vitamin D and Cancer

Low levels of vitamin D are associated with an increased risk for all types of cancer and a decreased survival rate, mainly due to the worsening of the severity of symptoms and increased metastatic potential of malignancies [19].

Very promising clinical studies analyzed by Medrano [16] suggested that vitamin D supplementation is significantly associated with an increase in overall survival and lower risk of relapse of myeloid, but not lymphoid malignancies in transplant recipients.

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The possible link between vitamin D and immune regulation of the tumor microenvironment has also been discussed by Liu et al. [19].

It is well established that vitamin D modulates the immune response through the inactivation of the nuclear factor-kappa B (NF-κB) pathway.

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In the tumor stroma (connective tissue, blood vessels, and inflammatory cells interposed between malignant cells and normal host tissues), the secretion of cytokines and prostaglandins are essential for the propagation of cancer cells, but vitamin D, through the downregulation of nuclear factor-kappa B (NF-κB) and cyclooxygenase 2 (COX-2), can attenuate their secretion.

On the other hand, Pawlik and co-workers [38] observed that vitamin D and its analogs (PRI-2191 and PRI-2205) modulate the prevalence of certain types of lymphocytes- they increase the number of T helper lymphocytes (Th2), regulatory T (Treg), granulocytes, and B lymphocytes, but reduce the fraction of TCD4+, TCD4+, CD25+, and TCD8+ cells in the 4T1 mouse mammary gland cancer model (clinical model, in which mouse breast cancer cells of the 4T1 cell line are transplanted into the mammary fat pad to establish primary tumor nodules).

This immunoregulatory effect of vitamin D was accompanied by the modulation of levels of pro-tumorogenic cytokines in the serum.

Additionally, cancer metastasis is the most significant problem in the treatment of any type of cancer.

For instance, in melanoma, metastasis dramatically decreases the survival rate of patients [39].

Many recent studies have proposed that vitamin D and its analogs can be used in adjuvant radiotherapy (radiotherapy that is given in addition to the primary or initial cancer therapy) [40].

In a recent issue of the International Journal of Molecular Sciences (IJMS), Podgórska et al. [41] documented that treatment with either calcitriol (1,25-dihydroxy vitamin D) or calcifediol/calcidiol (25-hydroxy vitamin D) sensitized human (SKMEL-188) and Bomirski’s hamster melanoma cells to low doses of proton beam radiation (a type of cancer radiation therapy).

Interestingly, vitamin D is now being considered a potential therapeutic factor in the management of benign tumors, such as uterine fibroids, derived from smooth muscle cells of the uterus.

As reviewed by Ciebiera and co-workers [42], a few clinical studies have shown that low serum levels of vitamin D (25OHD3) or the presence of specific single nucleotide polymorphisms (SNPs) of genes related to vitamin D metabolism and activity, correlate with the occurrence of uterine fibroids.

Taking into consideration the anti-proliferative and anti-fibrotic properties of vitamin D, the authors suggested its potential beneficial role not only in the prevention but also the treatment of uterine fibroids [42].

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Vitamin D Sources


The dietary sources of vitamin D include food and dietary supplements; therefore, “total vitamin D intake” reflects the combined dietary contribution from foods and supplements.

Vitamin D levels in the diet—from foods and supplements—are expressed in International Units (IU), but in some products, it is shown as micrograms (μg).

The biological activity of 1 μg of vitamin D is equivalent to 40 IU.

Natural Sources

There are a only few naturally occurring food sources of vitamin D.

These include fatty fish (especially fish liver), egg yolks, and offal (organ meats).

The vitamin D content in muscle meat is generally much lower.

Egg yolks typically include concentrations ranging between the values found in meat and offal.

If milk and dairy products are not fortified, they are normally low in vitamin D, with the exception of butter, because of its high-fat content.

Since the recommendations for vitamin D intake have been substantially increased the recent years, it is often difficult to cover these requirements solely through diet.

For that reason, in most countries many foods are now fortified with vitamin D.

However, there are still several countries in which foods are not regularly fortified with vitamin D, which means that the aforementioned foods are the primary dietary sources of the nutrient. 

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Fortified Foods

After the recognition of vitamin D’s role in the prevention of rickets in the 1920s (Steenbock and Black, 1924), vitamin D fortification of specific foods has been voluntarily initiated.

In the United States, fluid milk is voluntarily fortified with 400 IU per quart (or 385 IU/L) of vitamin D, although U.S. regulations do not specify the form of added vitamin D.

In Canada, under the Food and Drug Regulation, fortification of fluid milk and margarine is also mandatory; fluid milk must contain 35–45 IU of vitamin D per 100 mL and margarine 530 IU per 100 g.

Additionally, fortified plant-based beverages must also contain vitamin D in equivalent amounts to fluid milk.

In the last decades, the list of vitamin D fortified foods has greatly expanded; manufacturers in the United States and other countries have proceeded to the synthetic addition of vitamin D to a wide variety of food products, with increased rates of commercial advertisements and promotion [43].

Based on data from the U.S. Food and Drug Administration (FDA), Yetley, (2008) reported that in the U.S. market, almost 100% of fluid milks, 75% of breakfast cereals, <50% of milk substitutes, 25% of yogurts, and 8-14% of cheeses, juices, and spreads, are vitamin D fortified.

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Many product labels included in the survey also clarified that the added form of vitamin D was vitamin D3.

However, some milk substitutes are fortified with vitamin D2, which is less bio-available than D3 [44].

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Cereal labels, in particular, did not specify the form of added vitamin D. In general, the levels of synthetically added vitamin D ranged from 40 IU per regulatory serving for cereals and cheeses, to 60 IU per regulatory serving for spreads, and 100 IU per regulatory serving for fluid milk.

Human Breast Milk

Serum levels of vitamin D and calcifediol/calcidiol (25-hydroxy vitamin D) have low penetrance into human breast milk, together comprising 40 to 50 IU of total vitamin D per liter, most of which is contributed by calcifediol/calcidiol (25-hydroxy vitamin D) (Leerbeck and Sondergaard, 1980Hollis et al., 1981Reeve et al., 1982Specker et al., 1985) [45, 464748].

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Data from the USDA report that the vitamin D content of human breast milk is 4.3 IU/100 kcal.

However, the biological activity of vitamin D in it may be higher than the analyzed values, as human breast milk contains small amounts of calcifediol/calcidiol (25-hydroxy vitamin D), in addition to vitamin D3 (Reeve et al., 1982).

Furthermore, the biological activity of 25-hydroxycholecalciferol is approximately 50% higher than that of vitamin D (25-hydroxy vitamin D) [49].

Infant Formulas

The FDA has established that infant formulas must contain 40 to 100 IU of vitamin D per 100 kcal.

In the U.S.A, commercial infant formulas contain approximately 60 IU of vitamin D per 100 kcal, as estimated by the USDA food composition database.

Yetley (2008) reported that commercial milk-based infant formulas collected and examined between the years of 2003 and 2006, contained 87-184% of the label declarations.

Similarly, in Canada, infant formulas are required by regulation to contain 40-80 IU of vitamin D per 100 kcal.

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Dietary Supplements

The use of vitamin D supplements to prevent and treat a wide range of illnesses has increased substantially over the last decade.

The primary forms of vitamin D used in supplement form are either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol), however, most manufacturers are slowly switching from vitamin D2 to vitamin D3, while others are also increasing the vitamin D content of their products.

In the past, most dietary vitamin D supplements contained about 400 IU per daily dose, while today the dose typically ranges from 1,000 to 5,000 IU per dose.

It’s worth mentioning that megadoses of < 2,000 IU per serving exhibit less bio-availability and suboptimal intestinal absorption, compared to smaller and more frequents intakes of 800-2,000 IU per fat-containing meal.

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Vitamin D Content of Various Foods

FoodVitamin D content in International Units (IUs) per serving
Cod liver oil, 1 tablespoon1360
Swordfish, cooked, 3 ounces566
Salmon (sockeye) cooked, 3 ounces447
Tuna, canned in water, drained, 3 ounces154
Orange juice fortified with vitamin D, 1 cup137
Milk, vitamin-fortified, 1 cup115-124
Yogurt, fortified with 20% of the daily value of vitamin D, 6 ounces80
Sardines, canned in oil, drained, 2 sardines46
Liver, beef, cooked, 3 ounces42
Egg yolk, 1 large41
Cereal, fortified with 10% of the daily value of vitamin D, 1 cup40
Cheese, Swiss, 1 ounce6
Source: Vitamin D. Health Professionals. Dietary Supplement Fact Sheet. National Institutes of Health. Office of Dietary Supplements. August 7, 2019.


The efficient absorption of vitamin D is dependent upon the presence of fat in the gut, which triggers the release of bile acids and pancreatic lipase [53].

Bile acids initiate the emulsification of lipids, pancreatic lipase hydrolyzes the triglycerides into monoglycerides and free fatty acids, and bile acids support the formation of lipid-containing micelles, which diffuse into enterocytes (intestinal cells).

Early studies demonstrated that radiolabeled vitamin D3 appeared almost exclusively in the lymphatics and chylomicron fraction of plasma; as well, subjects with impaired bile acid release or pancreatic insufficiency both demonstrated significantly reduced absorption of vitamin D (Thompson et al., 1966Blomstrand and Forsgren, 1967Compston et al., 1981) [545556].

Subsequently, other clinical and experimental animal studies confirmed that vitamin D is most efficiently absorbed when consumed with foods containing fat (Weber, 1981Johnson et al., 2005Mulligan and Licata, 2010) [535758] and, conversely, that a weight-loss agent that blocks fat absorption impairs the absorption of vitamin D (James et al., 1997McDuffie et al., 2002) [5960].

The optimal amount of fat required for maximal absorption of vitamin D has not been determined.

Within the intestinal wall, vitamin D, cholesterol, triglycerides, lipoproteins, and other lipids are packaged together into chylomicrons (ultra low-density lipoproteins that consist of triglycerides, phospholipids, cholesterol, and proteins).

Interestingly, while a fraction of newly absorbed intestinal vitamin D is transported along with amino acids and carbohydrates into the portal system to reach the liver directly, the main pathway of vitamin D uptake is its incorporation into chylomicrons that reach the systemic circulation via the lymphatics.

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Chylomicron lipids are metabolized in peripheral tissues that express lipoprotein lipase (enzyme that degrades triglycerides), but particularly in adipose tissue and skeletal muscle, which are very rich in this enzyme.

During the hydrolysis of chylomicron triglycerides, a fraction of the vitamin D contained in the chylomicron can be taken up by these tissues.

Uptake into adipose tissue and skeletal muscle accounts for the rapid post-prandial (after eating) disappearance of vitamin D from plasma, and probably also explains why increased adiposity causes sequestering of vitamin D, and is associated with lower Vitamin D (25OHD) levels (Jones, 2008) [61].

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What remains of the original chylomicron after lipolysis is a chylomicron remnant, a cholesterol-enriched, triglyceride-depleted particle that still contains a fraction of its vitamin D content.

Skin Synthesis

Vitamin D3 is synthesized in the human skin from 7-dehydrocholesterol following exposure to ultraviolet B (UV-B) radiation with wavelength 290 to 320 nm.

The production of vitamin D3 in the skin is dictated by the amount of UV-B radiation reaching the dermis (the layer of skin that lies beneath the epidermis and above the subcutaneous layer), as well as the availability of 7-dehydrocholesterol.

The level of synthesis is influenced by several factors, including season of the year, skin pigmentation, latitude, use of sunscreen, clothing, and amount of skin exposed.

Age is also a factor, in that synthesis of vitamin D declines with increasing age, due in part to a fall in 7-dehydrocholesterol levels, and also due to alterations in skin morphology (MacLaughlin and Holick, 1985) [50].

Toxic levels of vitamin D do not occur from prolonged sun exposure.

Thermal activation of previtamin D3 in the skin gives rise to multiple non–vitamin D forms, such as lumisterol, tachysterol, and others (Holick et al., 1981Webb et al., 1989) [5152], which limits the formation of vitamin D3 itself.

Vitamin D3 can also be converted to non-active forms.

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The absolute percentage of circulating calcifediol/calcidiol (25-hydroxy vitamin D) that arises from cutaneous (skin) synthesis versus oral intake of vitamin D in the free-living North American population cannot be clearly specified.

Individuals living at Earth’s poles during winter months and submariner crew members with very limited or no measurable UV-B exposure have indeed detectable levels of vitamin in the blood, arising from dietary sources, and likely from previously synthesized and stored vitamin D.

Vitamin D Deficiency


Low vitamin D levels are considered a global public health issue.

About 1 billion people worldwide suffer from vitamin D deficiency, while 50% of the population exhibit vitamin D hypovitaminosis [7].

The prevalence of vitamin D deficiency is highest in the elderly, obese patients, nursing home residents, and hospitalized patients.

The prevalence of vitamin D deficiency is 35% higher in obese subjects irrespective of latitude and age [8].

In the United States, about 50% to 60% of nursing home residents and hospitalized patients exhibit vitamin D deficiency [910].

The rates of Vitamin D deficiency may be higher in populations who have a higher skin melanin content and who use extensive skin coverage, particularly in Middle Eastern countries (i.e., burka, abaya, jilbāb).

In the United States, 47% of African American infants and 56% of Caucasian infants exhibit vitamin D deficiency, while over 90% of infants in Iran, Turkey, and India present vitamin D deficiency.

In the adult population, 35% of adults in the United States are vitamin D deficient, whereas over 80% of adults in Pakistan, India, and Bangladesh are Vitamin D deficient.

In the United States, 61% of the elderly population is vitamin D deficient, whereas 90% in Turkey, 96% in India, 72% in Pakistan, and 67% in Iran are found to be vitamin D deficient [11].

Causes of Vitamin D Deficiency

Dermal synthesis and dietary intake (fatty fish, egg yolks, organ meats, fortified foods) are the major sources of ergocalciferol (D2) and cholecalciferol (D3), both of which are converted to 25-hydroxy-vitamin D2 (25-OH-D2) and 25-hydroxy-vitamin D3 (25-OH-D3), respectively, in the liver by the enzyme 25–hydroxylase.

Both D2 and D3 are then converted to the most active form of vitamin D- calcitriol (1,25 dihydroxy vitamin D) by the enzyme 1-alpha-hydroxylase in the kidneys.

This active calcitriol (1,25 dihydroxy vitamin D) increases intestinal absorption of calcium and bone resorption, and decreases renal excretion of calcium and phosphate.

Vitamin D deficiency can result from several causes.

1. Decreased Dietary Intake and/or Absorption.

Certain malabsorption syndromes, such as celiac disease, short bowel syndrome, gastric bypass, inflammatory bowel disease (IBD), chronic pancreatic insufficiency, and cystic fibrosis may lead to vitamin D deficiency.

Lower dietary intakes of vitamin D are more prevalent in elder populations [12].

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2. Decreased Sun Exposure

About 50% to 90% of vitamin D is absorbed through the skin via sunlight exposure, while the rest comes from the diet.

Twenty minutes of daily sunshine with over 40% of skin exposed is the minimum requirement to prevent vitamin D deficiency [13].

Skin synthesis of vitamin D declines with age.

Also, dark-skinned people, due to higher amounts of the skin pigment melanin, have less cutaneous vitamin D synthesis.

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Decreased exposure to the sun, as observed in individuals who are institutionalized, or have prolonged hospitalizations, can also lead to vitamin D deficiency [14].

Effective sun exposure is also lower in individuals who use sunscreens and wear consistently. 

3. Decreased Endogenous Synthesis

Individuals with chronic liver disease, such as cirrhosis, can have defective liver 25-hydroxylation activity, leading to deficiency of active vitamin D.

Defects in 1-alpha 25-hydroxylation can be observed in hyperparathyroidism (oversecretion of parathyroid hormones), kidney failure, and 1-alpha hydroxylase deficiency. 

4. Increased Hepatic Catabolism

Medications, such as phenobarbital, carbamazepine, dexamethasone, nifedipine, spironolactone, clotrimazole, and rifampin stimulate the activity of hepatic p-450 enzymes, which induce vitamin D degradation [15].

5. End Organ Resistance

End organ resistance to vitamin D can be observed in hereditary vitamin D resistant rickets.

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Vitamin D plays a crucial role in calcium and phosphorus homeostasis, and bone metabolism.

With chronic and/or severe vitamin D deficiency, a decline in intestinal calcium and phosphorus absorption leads to hypocalcemia, leading to secondary hyperparathyroidism (condition in which one or more of the parathyroid glands become overactive and secrete too much parathyroid hormone).

This secondary hyperparathyroidism then leads to phosphaturia (excessive amounts of phosphorus in the urine) and accelerated bone demineralization.

This can further result in osteomalacia and osteoporosis in adults, and osteomalacia and rickets in children.

Other symptoms of vitamin D deficiency include muscle weakness [62], pain [63], fatigue, and depression [64].


Vitamin D is a fat-soluble vitamin that acts as a prohormone.

It plays a pivotal role in calcium and phosphorus homeostasis, therefore regulating bone and teeth mineralization.

A subclinical vitamin-D deficiency is associated with osteoporosis, osteomalacia, increased risk of falls, and fragility fractures.

Epidemiologic evidence links vitamin D deficiency to autoimmune disease, cancer, cardiovascular disease, depression, dementia, infectious diseases, musculoskeletal decline, and more.

The two major forms of vitamin D are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol).

Vitamin D2 (ergocalciferol) is largely human-made and added to foods, whereas vitamin D3 (cholecalciferol) is synthesized in the skin of humans from 7-dehydrocholesterol, and is also obtained via diet through the consumption of a few animal-based foods, such as mackerel, salmon, herring, sardines, tuna, egg yolks, some organ meats.

The differences between these two forms do not affect metabolism (i.e., activation), and both forms function as prohormones (precursor substances that the body converts to actives hormones).

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Both vitamin D3 and vitamin D2 are synthesized commercially and found in dietary supplements or fortified foods.

All physiological functions of vitamin D, no matter its form, are mediated by vitamin D receptors found mainly in the nuclei of cells throughout the body (nuclear receptors).

The sources of Vitamin D are dualistic: dietary (animal-based products, such as fatty fish) and non-dietary (sun exposure).

The primary side-effects of vitamin D deficiency include a decline in intestinal calcium and phosphorus absorption, which leads to hypocalcemia, and subsequently hyperparathyroidism and phosphaturia (increased excretion of phosphorus through urine).

Eventually, this manifests as osteoporosis in adults, and osteomalacia and rickets in children.

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Other symptoms of vitamin D deficiency include muscle weakness, pain, fatigue, and depression.

The main causes of vitamin D deficiency include: 1) Decreased dietary intake and/or absorption 2) Decreased sun exposure 3) Decreased endogenous synthesis 4) Increased hepatic catabolism 5) End-organ resistance.

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About George Kelly

George Kelly M.Sc is a Sports Nutritionist, Functional Nutritional Therapy Practitioner (FNTP), and Metabolic Type expert. He is the CEO and lead author of Metabolic Body.