The Value of Vitamin D
When describing vitamin D, it is a common misconception to say "vitamin" when in fact it is a hormone. Vitamin D is produced from sterols in the body by the photolytic action of ultraviolet light on the skin. Sterols are naturally occurring unsaturated steroid alcohols, typically waxy solids and photolytic, as the name implies, is the decomposition or separation of molecules by the action of sunlight (irradiation). Consequently, appropriate exposure to the sun prevents vitamin D deficiency. It is commonly referred to as a vitamin because it is an essential molecule that we need to have in a sufficient amount for many essential biological functions. Vitamin D, otherwise expressed as 1, 25-OH-D, is critical to the growth and development of the human skeleton and for keeping other bodily functions running optimally throughout the life cycle. Vitamin D was first identified as an essential nutrient supplement in the early 20th century and classified as a vitamin because supplementary dietary intake is required in certain circumstances.
The most elucidated and apparent physiological function of vitamin D is the homeostasis (balance / regulation) of calcium and phosphorus. This is processed through a multi-hormonal system involved in the control and production of 1, 25-OH-D (Calcitriol when man-made), which functions in concert with parathyroid hormone and calcitonin. Vitamin D is biologically inert and must be converted to its active form.
The liver metabolizes it to 25-hydroxyvitamin D (25-OHD), which is the major storage and circulating form of the hormone. A hydroxy or hydroxyl group is the entity with the formula OH. It contains oxygen bonded to hydrogen. Regulation of the system occurs at the points of the intestinal absorption, renal excretion, and mobilization. The active metabolite, one 1,25-OHD, stimulates enteric absorption of calcium. Vitamin D promotes the resorption of both calcium and phosphorus in the kidney tubule.
Vitamin D allows the body to absorb calcium, and calcium is necessary for building strong, healthy bones. Without enough vitamin D or calcium, the parathyroid glands will compensate by producing too much of their hormone, creating a condition called hyperparathyroidism, which can lead to bone weakening and increased fracture risk. Vitamin D has also been found to affect other minerals such as zinc; zinc deficiency has been found to diminish 1,25-(OH)2-D3 response to low calcium intake. Iron deficiency is associated with low serum concentrations of Dihydroxycholecalciferol and 25-OH-D3.
This vitamin is rather unique as it is one of the few that can also be produced endogenously, that is to say, it can be produced internally, inside the body, so it doesn't quite meet a classic vitamin criterion, hence is why it is a hormone. Sufficient vitamin D can be made from the skin from what is known as 7-dehydrocholesterol, which is provitamin D3. This provitamin D3 is located in specific skin layers, such as the stratum Basale and stratum spinosum. Vitamin D3 is made from its precursor 7-dehydrocholesterol, made in human skin when the skin is exposed to the ultraviolet irradiation in sunlight. Vitamin D can be produced from the sun or obtained from food or supplements.
Vitamin D and calciferol are terms that refer collectively to the two primary nutritionally relevant chemical forms known as vitamin D2 (ergocalciferol) and vitamin D3 (Cholecalciferol). Vitamin D3 is produced in the skin of vertebrate animals when the skin is exposed to ultraviolet irradiation. Humans can synthesize vitamin D through a regulated multi-step process that begins in the skin's inner layers. Ergocalciferol (vitamin D2) and Cholecalciferol (Vitamin D3) make up 40% of the supplement form's vitamin D. Ergosterol is found mainly in plants, and it is the precursor for Ergocalciferol (D2).
Let’s break down how vitamin D is activated within your body to gain a fuller understanding of this hormone. Vitamin D is also classified as a Secosteroid because one of the rings breaks UVB/UVA exposure. It has core structure comprised of a carbon skeleton fused ring of A, B, C, and D, derived from the parent compound cholesterol. And that ring has conjugated double bonds. The B portion of the ring is responsible for absorbing ultraviolet B (UVB) light photons, which is 285-320nm (nanometer) in wavelength and is the amount of energy required to break open the B ring and produce provitamins D3, (Precalciferol). UVA gives a quick tan that lasts for days by oxidizing melanin that was already present and triggers the release of the melanin from melanocytes. UVB yields a tan that takes roughly 2 days to develop because it stimulates the body to produce more melanin – long lasting pigmentation. What's interesting with this process is that the amount of energy it takes to break the B ring, in doing so it prevents vitamin D toxicity when over-exposed to too much sunlight.
90 to 95% of most people’s vitamin D requirement comes from casual sun exposure, and the amount of sunlight required to support adequate vitamin D status can substantially less than that. Michael F. Holick, adult endocrinologist, specializing in the field of vitamin D, has estimated that exposure of only 6-10% of body surface, making a median erythema - superficial reddening of the skin - with sunlight can be equivalent to consuming 600-1,000IU (international unit) of vitamin D. Vitamin D has been found to have a physiological half-life of about two months. This relatively long half-life likely reflects its partial sequestration in adipose tissue. Unlike other fat-soluble vitamins, vitamin D is not stored by the liver. It reaches the liver within a few hours after being absorbed across the gut or synthesized in the skin.
A factor that affects vitamin D stores and synthesis, is body fat. Since vitamin D is stored in hydrophobic lipid-rich areas in the body, adipocytes are an excellent place for vitamin D to be stored. Adipocytes are a storage site for vitamin D3, and with high intake, more vitamin D is stored in the body's adipose tissue (fatty) and then released as needed. Obese individuals sequester more vitamin D in the adipose tissue and thus have low 25-OH vitamin D status. Therefore, obesity has been associated with vitamin D insufficiency and secondary hyperparathyroidism. Research is uncovering that obese individuals have lower liver enzyme levels that convert vitamin D into 25-hydroxyvitamin D, which is the primary form in the blood. Low circulating levels of 25-hydroxyvitamin D are typical in obese individuals and has also been attributed to vitamin D sequestration in fat cells. Obese individuals tend to need more vitamin D than the average individual.
Now let’s examine Vitamin D, Calcitriol cancer and your immune system. Vitamin D as you have seen is multifaceted. It is converted to the biologically active form of vitamin D (calcitriol) in the kidneys before it is released into the circulation. Calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), mainly located in most cells' nuclei. Vitamin D receptors have been found, and 37 different tissues and approximately 300 genes are known to be regulated by calcitriol.
Vitamin D receptors are found in cells closely related to the maintenance of calcium homeostasis and immune, endocrine (hormone secreting gland), hematopoietic (blood formation), skin, and tumor cells. Vitamin D receptors play crucial roles in mediating the physiological function of vitamin D. In newborns, the vitamin D receptor is absent until weaning, being induced on the feeding of solid foods, by a process involving cortisol. Calcitriol Has been found to inhibit cancer cell proliferation. Certain cells have four phases of cell cycle that takes place in eukaryotic cell division. Calcitriol prevents the spread of cancer cells at the first, g₁ or Gap 1 phase, by inhibiting the G1 phase of the mitotic cell cycle through increased P53 and P21.
P53 is considered the Guardian of the Genome. In cases of DNA damage, there is triggering of expression of the P53 gene which increases the production of P53 proteins. These proteins prevent cells from entering the synthesis phase of cell cycle and allows time for DNA repair to take place. P21 is an inhibitor of the processes that allow cells to divide and can prevent eye-cancer. Vitamin D metabolites have been found to promote differentiation and inhibit proliferation, invasiveness, and metastasis and prostate cells. High vitamin D receptor expression has been associated with reducing the risk of initiation and progression of prostate cancer in young men. The vitamin D receptor activation upregulates the androgen receptor expression, which regulates the vitamin D receptor, suggesting that the anti-proliferative action of vitamin D is androgen dependent. Prostate cells contain a 25-OH-D3 hydroxylase activity which is suppressed in individuals with clinically detected prostate tumors.
Studies have also demonstrated that vitamin D3 can attenuate the growth of rapidly dividing colonic tumor cells. One study found that 50% of colon cancer incidence could be prevented by maintaining a serum 25-OH vitamin D level of less than 34 ng/mL (nanogram/milliliter). High vitamin D receptor expression has been associated with a more favorable prognosis for Colorectal cancer patients. The same study found that 50% of breast cancer incidence could be prevented by maintaining serum 25-OH vitamin D levels of more than 52 ng/mL. Vitamin D has also been shown to play a role in the prevention of type two diabetes. Vitamin D helps protect pancreatic beta cells from inflammatory damage. Vitamin D treatment has also been found to reduce rejection of allografts of the heart, kidney, liver, pancreatic islets, small intestines, and skin. Vitamin D has also been effective in reducing signs of a TH1 induced inflammatory bowel disease. Calcitriol plays a vital role in the regulation of blood pressure. It suppresses the renin gene expression, thereby diminishing the production of angiotensin II to lower blood pressure.
Vitamin D plays many immune regulating roles and genomic roles, most notably its effects on telomere length. Many studies have found that individuals with vitamin D deficiency have shorter telomeres. Telomeres are the caps at the end of chromosomes; they protect the chromosomes from deterioration and effusion during cell division; telomeres are progressively eroded with the successive amounts of cell division and attrition. Shorter telomere length is associated with age-related diseases, including cardiovascular disease, hypertension, diabetes, and all-cause mortality. Vitamin D status has been found to affect the maintenance of telomere length or its effects on mechanisms including inflammation and the rate of cell proliferation. Epidemiological studies have found that higher vitamin D associations measured by circulating 25 hydroxyvitamin D are associated with a lower risk of all-cause mortality. A meta-analysis of 18 independent randomized controlled trials showed that participants randomized to vitamin D supplementation at 400 to 800 IUs had a statistically significant, 7% reduction in mortality from any cause.
Finally, we’ll talk about the significance of suntans! Many factors affect vitamin D synthesis, the first one being skin tone. The epidermal pigment, melanin, efficiently absorbs UVB, for which reason darker skin tone individuals require more sunlight exposure than lighter skin tone individuals. Melanin can be regarded as a natural sunscreen because it protects against sunburn and, in some instances, skin cancer. Dark skin tone Individuals that live closer to the equator typically do better for comparable vitamin D biosynthesis and regulation in regards to sunburn compared to a person with the type of skin that is easily sunburned and never tans, an individual with dark type fiber types of skin that never burns and always tans can require 5 to 10 times as much sun exposure to produce the same amount of vitamin D3.
Another factor that affects vitamin D synthesis is sunscreen. SPF 15 reduces the capacity of the skin to produce vitamin D3 by 90% and 95%. SPF 50 sunscreen has been found to decrease cutaneous vitamin D production significantly. Other factors that affect vitamin D synthesis include age, air pollution, skin thickness, and latitude. High levels of atmospheric pollution can reduce ground levels of UVB significantly. Many studies show that individuals in highly polluted areas have lower levels of vitamin D. Air pollution is a chief factor in determining the extent of solar UVB that reaches the earth's surface. This is also true for areas that have high ozone pollution. UVB photons must pass through the ozone layer at an oblique angle, causing many photons to be absorbed by the ozone, which can scatter the UVB photons. More UVB photons penetrate the ozone layer in the spring, summer, and fall months because the sun is directly overhead. The other factor is latitude; many people believe that if they go out and sit in the sun at any time of the day, vitamin D synthesis is induced, but that is not the case. The sun has to be at its highest points, which is when the UVB rays are the most intense; this also means it is where an individual needs less sun exposure. Many studies show that the body is most efficient at producing vitamin D at noon. In general, reliable vitamin D synthesis to meet individual needs can be achieved at the equator and up to 40° north and south.
Because dark skin toned individuals have to remain in the sun a bit longer for the UV energy to make it past the melanin layer, this concept also provides some insight about vitamin D testing and misdiagnosing of vitamin D deficiency in African Americans. The current blood test for vitamin D renders many African Americans deficient. However, the problem is with the test and not the individual. Many studies show that African Americans have the circulating form of vitamin D, which is what matters, keeping it ever present so that cells can use it. This low vitamin D paradox has been a cause for concern. Genetically, Black people have low 25-hydroxyvitamin D (25(OH)D) levels but paradoxically higher bone density and lower bone fracture risk.
25-Dihydroxyvitamin D, also known as diyhydroxyvitamin D3, 24, 25 or 24-hydroxycalcidiol, belongs to the class of organic compounds known as vitamin D and its derivatives. The current vitamin D tests looks for vitamin D concentration in blood as having normal to optimal ranges of 25(OH)D. The reference range of the total 25(OH)D level is 20-100 ng/mL (nanogram/milliliter). The World Health Organization defines vitamin D insufficiency as 25(OH)D levels below 20 ng/ml. The standard for White people is 40-60 ng/mL.
People of color tend to have only a quarter to a third as much vitamin D binding protein that White people have. Because of the lower levels of vitamin D binding protein, the vitamin D test shows that people of color do not meet sufficient vitamin D levels when compared to whites. Early humans did not need to store vitamin D reserves, so they didn't need as much binding protein, which is in place so that vitamin D could be used for later. Many who came out of Africa had the ancestral genotype associated with lower vitamin-D-binding proteins (VDBP). However, when humans moved to areas with less sunlight, a different genotype evolved. The further north people moved, the need for vitamin D reserves increased, so VDBP also increased. Researchers have realized that VDBP is genetically different for people of color. The blood test for the 25(OH)D is misleading because even with lower 25-hydroxy levels, people of color still have enough bioavailable vitamin D.
In light of the clear effect of low vitamin D status and stimulating mobilization of calcium from bone, many African Americans’ situation would seem paradoxical. Their lower circulating levels of 25OHD3 would suggest an increased risk of fractures relative to White people. The reverse is true. Studies have shown that the prevalence of bone hip fracture and osteoporosis in African Americans is about the half of White Americans. This has been explored based on multiple characteristics. African Americans tend to have greater peak bone mass, greater muscle mass, and lower bone turnover rates. African Americans also have better enteric calcium absorption and renal calcium conservation than Whites. Further, African American adults have higher parathyroid hormone levels without associated bone loss, indicating skeletal resistance to parathyroid hormone. These advantages diminish with age, which is evident because elderly African Americans with elevated parathyroid hormone show bone loss due to other group factors.
Black people and whites have similar bioavailable vitamin D levels despite disparate Levels of 25(OH)D(15). As alternate mechanisms, Black individuals have higher circulating concentrations of 1,25-dihydroxyvitamin D, which is the form that counts. There is a vitamin D test in the patent process that considers the genetic VDBP differences; in the meantime, doctors should be running other tests like calcium, bone mineral density, and parathyroid test to more accurately assess if darker skin tone individuals are vitamin D deficient.
Combs, G. F., & McClung, J. P. (2017). The vitamins: Fundamental aspects in nutrition and health. Amsterdam: Academic Press.
Khan, Q., & Fabian, C. (2010, March). How I treat vitamin d deficiency. Retrieved October 04, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835491/
Knox, R. (2013, November 20). How A Vitamin D Test Misdiagnosed African-Americans. Retrieved October 04, 2020, from https://www.npr.org/sections/health-shots/2013/11/20/246393329/how-a-vitamin-d-test-misdiagnosed-african-americans
Stipanuk, M. H., & Caudill, M. A. (2019). Biochemical, physiological, and molecular aspects of human nutrition. St. Louis, MO: Elsevier.
Wortsman, J., Matsuoka, L., Chen, T., Lu, Z., & Holick, M. (2000, September 01). Decreased bioavailability of vitamin D in obesity. Retrieved October 04, 2020, from https://academic.oup.com/ajcn/article/72/3/690/4729361
Zheng, Y., Zhu, J., Zhou, M., Cui, L., Yao, W., & Liu, Y. (2013, December 3). Meta-analysis of long-term vitamin D supplementation on overall mortality. Retrieved October 04, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857784/
Zhu, H., Guo, D., Li, K., Pedersen-White, J., Stallmann-Jorgensen, I., Huang, Y., . . . Dong, Y. (2012, June). Increased telomerase activity and vitamin D supplementation in overweight African Americans. Retrieved October 04, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826782/