Vitamin D: the vital non-vitamin

Outline:

  • Recommendation
  • What it is
  • Its function
  • Recommended blood levels
  • The risk of too much
  • Common sources
  • Vitamin D and cancer
  • How it’s formed
  • Conclusion
  • Recommendation: As recommended by the Institute of Medicine and others, try to maintain blood levels of 25(OH)D above 20 ng/mL. Though 20 ng/mL may be enough to avoid disease, I’d rather have optimal levels, as with any test. 30-40 ng/mL seems to be a decent bet, and I certainly didn’t find research showing benefit over 50 ng/mL. Thus, my target range is 20-50 ng/mL (50-125 nmol/L).

    If you haven’t tested your blood level of vitamin D in the past 12 months, call your general physician to schedule a test. A common time for this is an annual physical, though a semi-annual or quarterly test may be warranted for awhile if your first result shows your vitamin D level is low. To raise your blood level of vitamin D, consider eating 2-3 servings of “oily” fish like tuna, salmon, or mackerel weekly, (if you’re not already). Also, make sure to get 15-30 minutes of sunlight each day as you begin to monitor this health metric. If these alone don’t raise your serum 25(OH)D levels, work with your doctor or nutritionist to determine if more sun or vitamin D3 supplementation is right for you. Note: you may need more sun if you live far from the equator or have a dark skin tone.

    Technically, what is vitamin D?

    The term “vitamin D” can refer to something different depending on context. Throughout this article, we’ll talk mainly about these three forms:

  • D3 also known as cholecaciferol
  • 25(OH)D also known as 25-hydroxyvitamin D, “calcidiol“, or “calcifediol“; the inactive forms measured in blood
  • calcitriol” also (usually) known as 1,25-dihydroxyvitamin D; the active form
  • To further complicate things, vitamin D can be classified as either a vitamin, hormone, or prehormone, depending on source and context.
    Vitamins are organic compounds vital to life that aren’t synthesized in adequate amounts.
    Hormones are able to be synthesized adequately, and they’re mostly active away from the location they’re made.
    Prehormones include inactive forms of hormones requiring some modification to become active.

    Though strong opinions exist for each, I don’t worry much about which is most accurate, as it won’t affect what I do to maintain healthy levels of vitamin D. What a blood test (currently) measures is a prehormone form, but I’d consider the active form a hormone since it is synthesized in adequate amounts and it’s active outside of the kidney, where it’s made. In any case, the Vitamin D category of molecules is important for health and we can get one or more of each form from either sunlight, food, or supplements.1

    What is calcitriol’s function?

    It seems there are many functions of the active forms of vitamin D. A 2014 Cell article states:

    “With the finding of the vitamin D receptor (VDR) in nearly every tissue and the more recent discovery of thousands of VDR binding sites throughout the genome controlling hundreds of genes, the interest in vitamin D and its impact on multiple biologic processes has accelerated tremendously as evidenced by the thousands of publications each year for the past several years.”2

    – From a 2013 review of published work:

    “The classical, hormonal actions of vitamin D are related to mineral metabolism and skeletal health. Vitamin D enhances intestinal calcium and phosphate absorption, stimulates osteoclast differentiation and calcium reabsorption from bone and promotes mineralization of the bone matrix. Over the last decade, the perspective on how vitamin D influences human health has changed dramatically based on the finding that the vitamin D receptor (VDR) and the vitamin D activating enzyme 1-α-hydroxylase (CYP27B1) are expressed in many cell types which are not involved in bone and mineral metabolism, such as intestine, pancreas, prostate and cells of the immune system. This suggests an important impact of vitamin D on a much wider aspect of human health than previously known. Especially in the field of human immunology, the extra-renal synthesis of calcitriol by immune cells and peripheral tissues has been proposed to have immunomodulatory properties similar to locally active cytokines.”3

    A thorough description of its functions would take too long, but here’s a brief summary:

    Bone health: Reduced fractures after age 65,4 proper intestinal absorption of calcium and phosphate, and parathyroid function (“reducing the risk for PTG hyperplasia and elevated PTH secretion”).5
    Skin health: In the skin, vitamin D helps with “inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, regulation of the hair follicle cycle, and suppression of tumor formation”.6
    Inhibition of cancer: Depending on cell type, several mechanisms of cancer-fighting ability have been seen including “stimulation of DNA damage repair, prevention of tumor angiogenesis, and inhibition of metastasis”.7

    Skip ahead to see more detail on this in the section “vitamin D and cancer”

    Cardiac health: Randomized controlled trial evidence is lacking, but vitamin D receptors are found throughout the cardiovascular system. In a Finnish study, low serum 25(OH)D in children indicated increased carotid artery thickness in adulthood.8 However, a 2015 JAMA publication showed no benefit of vitamin D supplementation on blood pressure in their comprehensive meta analysis.9 Still many studies I read note the growing interest (funded studies) in vitamin D and cardio health.
    Immune function: Vitamin D stimulates induction of cathelicidins (antimicrobial peptides which fight bacterial infections).10

    To summarize our current understanding of these major topics of interest:

    “[vitamin D and synthetic versions of it]…have been developed for the treatment of hyperproliferative skin diseases, hyperparathyroidism, and osteoporosis. But for many of the potential applications including the treatment/prevention of cancer, CVD, infections, and autoimmune diseases, solid data from randomized clinical trials are lacking despite promising epidemiologic data and animal studies.”11

    What are the recommended blood levels?

    NOTE: U.S. labs generally report 25(OH)D levels as ng/mL. Other countries often use nmol/L. Multiply ng/mL by 2.5 to convert to nmol/L.

    Serum Vitamin D guidelines. Image from mollysfund.org.
    Serum Vitamin D guidelines. Image from mollysfund.org.

    The recommended range for serum vitamin D changes based on whom you ask. A 2011 report from the Institute of Medicine found the ideal range to be 20-50 ng/mL.12 They expand on this, noting:

    Based on this committee’s deliberations, the vitamin D–related bone health needs of approximately one-half of the population may be expected to be met at serum 25OHD concentrations between 30 and 40 nmol/L (12 and 16 ng/mL); most of the remaining members of the population are likely to have vitamin D needs met when serum concentrations between 40 and 50 nmol/L (16 and 20 ng/mL) are achieved. Failure to achieve such serum concentrations place persons at greater risk for less than desirable bone health as manifested by, depending upon age, increased rates of bone accretion, bone mineral density, and fractures.

    A 2013 review of published controlled trials concluded 20 ng/mL was the evidence-based minimum for maintaining bone health.13 ,14 Remember, blood tests measure inactive forms of vitamin D. Thus, your test results are useful for estimating effective levels only if you assume normal kidney function, since kidneys turn inactive D into its active form.

    What’s the risk of too much vitamin D?

    Though rare, Vitamin D toxicity was associated with these issues by the Institute of Medicine in a 2011 review:

    -Intoxication and related hypercalcemia and hypercalciuria
    -Measures in infants: retarded growth, hypercalcemia
    -Emerging evidence for all-cause mortality, cancer, cardiovascular risk, falls and fractures

    From one 2013 review:

    “…there are many mechanisms to protect against vitamin D excess and few against vitamin D deficiency. This is also reflected in the rarity of vitamin D toxicity in humans because only access to large pharmacological doses of vitamin D leads to vitamin D toxicity.”15

    What are common sources of vitamin D?

    Food: fish, meat, offal, egg, and dairy. “The published data show that the highest values of vitamin D are found in fish and especially in fish liver, but offal also provides considerable amounts of vitamin D. The content in muscle meat is generally much lower. Vitamin D concentrations in egg yolks range between the values for 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. However, as recommendations for vitamin D intake have recently been increased considerably, it is difficult to cover the requirements solely by foodstuffs.”16

    Sunlight: UV light from the sun is a major source of vitamin D. If you’re trying to determine how much sun to get in order to raise blood levels of vitamin D, it depends on several factors. Different amounts of light reach us depending on weather, altitude, our latitude, and season. Furthermore, genetic and epigenetic differences in each person will play a role in how much vitamin D we make from any amount of UV light. A study from 2013 found that deliberate sunlight exposure could “usefully enhance” serum levels of vitamin D. The methods: “15–90 min unshaded noontime summer sunlight at 53.5°N (Manchester, United Kingdom), 3 times/wk for 6 wk, while wearing casual clothes that revealed a 35% skin area”. Two major caveats of this study: the subjects were South Asian with Fitzpatrick skin type 5. This scale measures the darkness of a person’s skin, thus risk of sunburn. These subjects are in the 5th out of 6 categories, so any effect of sunlight on vitamin D would be greater among lighter-skinned individuals. Second, the study found a mean rise of 8.7 ± 5.7 ng/mL. That range, while obviously a good thing, is wide and supports the idea of a genetic/epigenetic effect unique to each person.17

    Supplement: Supplements of D3 are known to raise serum levels of calcidiol (25(OH)D). Obviously, this is helpful for people who have limited access to sunlight, foods rich in vitamin D, and issues with absorption or conversion in their body. In a 2012 study, both 20 000 and 40 000 IU weekly vitamin D3 supplementation over a 6-week period elevated serum 25[OH]D concentrations above 50 nmol/l among healthy athletes.18 Another 2012 study compared D2 and D3 supplementation among 18-50s with mean baseline serum vitamin D levels of 80 nmol/l (32 ng/mL). After 25 weeks of daily 1000 IU supplementation, those taking D3 maintained their serum levels, while D2-takers lost 21 nmol/l (8 ng/mL) of 25(OH)D.19

    Vitamin D and cancer

    I was unable to find conclusive reports of vitamin D’s role in cancer prevention. However, many studies–even meta analyses–do report a benefit of either high serum levels or supplementation. Therefore, it’s unclear whether low serum vitamin D is a cause or a result of illness, including cancers. A 2014 review found that, “high 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer”.20 A promising 2016 pooled report of two studies (combined N=2334) found that women (over 55) with 25(OH)D concentrations ≥40 ng/ml “had a 67% lower risk of (all) cancer than women with concentrations <20 ng/ml".21
    Furthermore, among some studies which have found a cancer-preventative role of vitamin D, certain mechanisms have been hypothesized. For example, skin cancer–even though it’s caused by the same UVB radiation we use to make vitamin D–can be mitigated by vitamin D via “inhibition of proliferation, stimulation of differentiation, immune regulation, and DNA repair.”22 A 2009 review specifically attempted to find a relationship between melanoma and mutations of the vitamin D receptor gene. They found a “small but potentially important role in melanoma susceptibility” and progression. Two single nucleotide polymorphisms were identified. An increased risk was found among carriers of the “FokI T” allele, and a reduced risk among carriers of the “BsmI A” allele.23

    How it’s formed

    Step 1: In the skin, a molecule called 7-dehydrocholesterol is hit by UVB light. UVB is powerful enough to break a bond in one part of this molecule. Once that break occurs, the molecule is called previtamin D3.
    Step 2: Within about 3 days, body heat causes previtamin D3 to change structure to become vitamin D3, or “cholecalciferol”.
    Step 3: This inactive D3 is picked up by vitamin D binding protein and they enter the blood together, on the way to the liver. This is also where vitamin D from diet/supplements enters the process.

    First 3 steps in synthesis of vit D in the skin.
    First 3 steps in synthesis of vit D in the skin.

    Step 4: In the liver, certain enzymes add an OH group to the 25th carbon of cholecalciferol. This turns it into 25(OH)D3 (pronounced “25 hydroxy vitamin D3”). A.k.a “calcidiol” or “calcifediol”, this is the inactive form of vitamin D tested in blood. It won’t become active (able to attach to a vitamin D receptor) until it’s changed by the kidney.
    Step 5: The kidney contains an enzyme which adds an OH group to 25(OH)D3. This makes our most common active form of vitamin D3, known as 1,25(OH)2D3 (pronounced “1 25 di-hydroxy vitamin D3”). A.k.a. “calcitriol”, this molecule is able to bind to vitamin D receptors throughout the body. Other forms have been seen, and are biologically active, but are considered less important, currently.

    Steps 4 & 5: Two OH groups are added to make calcitriol (one at each end.
    Steps 4 & 5: Two OH groups are added to make calcitriol (one at each end).

    In Conclusion

    We know this vitamin/hormone/prehormone is a crucial nutrient, though we have yet to elucidate its full range of effects. So, eat a variety of D-containing whole foods and get a bit of sunlight each day. Consider getting a 25(OH)D test quarterly, semi-annually, or at least as part of your annual physical. These combined efforts should provide effective first steps toward maintaining optimal levels of vitamin D throughout life.


    1. Vitamin D: beyond bone (2013) 

    2. Vitamin D Metabolism, Mechanism of Action, and Clinical Applications (2014) 

    3. Vitamin D and Immune Function (2013) 

    4. Prevention of Nonvertebral Fractures With Oral Vitamin D and Dose Dependency (2009) 

    5. Vitamin D Metabolism, Mechanism of Action, and Clinical Applications (2014) 

    6. Vitamin D and the skin: Physiology and pathophysiology (2012) 

    7. Vitamin D Metabolism, Mechanism of Action, and Clinical Applications (2014) 

    8. Childhood 25-OH Vitamin D Levels and Carotid Intima-Media Thickness in Adulthood: The Cardiovascular Risk in Young Finns Study (2014) 

    9. Effect of Vitamin D Supplementation on Blood Pressure (2015) 

    10. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3 (2005) 

    11. Vitamin D Metabolism, Mechanism of Action, and Clinical Applications (2014) 

    12. DRI DIETARY REFERENCE INTAKES Calcium Vitamin D (2011) 

    13. Optimal Vitamin D Status: A Critical Analysis on the Basis of Evidence-Based Medicine (2013) 

    14. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes (2014) 

    15. Optimal Vitamin D Status: A Critical Analysis on the Basis of Evidence-Based Medicine (2013) 

    16. Natural Vitamin D Content in Animal Products (2013) 

    17. Efficacy of a dose range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure (2013) 

    18. The effects of vitamin D3 supplementation on serum total 25[OH]D concentration and physical performance: a randomised dose–response study (2012) 

    19. Long-term vitamin D3 supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months (2012) 

    20. Vitamin D status and ill health: a systematic review (2014) 

    21. Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study (2016) 

    22. Protective role of vitamin D signaling in skin cancer formation (2013) 

    23. Vitamin D receptor gene polymorphisms, serum 25-hydroxyvitamin D levels, and melanoma: UK case–control comparisons and a meta-analysis of published VDR data (2009)