Vitamin D: an atypical and unsung vitamin

In this article, we will highlight the contrast between the importance of Vitamin D and the ease with which we can become depleted. We will also underline the fact that the knowledge on Vitamin D progresses steadily and by no means has reached a consensus in the interpretation of its blood levels.

The specific problem of Vitamin D’s availability

Contrary to other vitamines, which are exclusively available through food intake, Vitamin D is mainly produced in the body by the exposure of the skin to sun light, more specifically UtraViolet B rays. And similarly to humans, animals synthesize Vitamin D3 on their skin (fish), fur or feathers.

  • The animal version of Vitamin D, D3 (cholecalciferol) is mainly present in standard animal foods such as eggs and cheese etc., but at insufficient levels for the body’s needs, unlike polar bear liver (++ !!), or cod liver (also overloaded with Vitamin A). Natural commercial Vitamin D3 is actually extracted from sheep lanolin (non-vegan).
  • The vegetal version of vitamin D, D2 (ergocalciferol), can be obtained from eating mushrooms which have been exposed to UV light, but an intake of D2 does not fulfil the same role within the body as D3, and even seems to decrease the level  of active vitamin D in the blood (1). Therefore D2 intake alone is not sufficient.

As a result, if this liposoluble vitamin is not produced and stored in sufficient quantities during sunny days, a deficiency can occur in winter from reduced UVB exposure.

Other physical characteristics may aggravate this reduced exposure. Aged skin synthesizes less Vitamin D as does dark skin, and being overweight limits the availability of vitamin D. So the scenario where an overweight, or dark-skinned or elderly individual lives in a Nordic country is conducive to a vitamin D deficiency.
 

Out of all the vitamins, Vitamin D is the only one that cannot be obtained from food alone (animal rather than vegetal). It therefore needs to be supplemented when the access to sun is limited,  even within a naturopathic approach which traditionally avoids supplements.

 

 

The bad Vitamin D deal for Europeans compared to Northern Americans

The latitude of European cities is much higher than for those of North America. For instance, Madrid and Naples share the same latitude with New York, and Toronto has the same latitude as Nice on the Mediterranean sea.

This can come as a surprise to many of us, as we assume that Canada, a country with famously cold winters, must all be at a higher latitude than the UK.  We forget that our climate is kept unusually mild for its latitude by the gulf stream.

As a result, U.S. citizens are exposed to more UV light than their European counterparts  and might be less affected by Vitamin D Deficiency.

Therefore, any US Public health recommendations on Vitamin D intake can be taken with a pinch of salt by Europeans.

Vitamin D Public health policy in France

In France, pregnant mothers and infants up to five years old are systematically given megadoses called UVEDOSES: 100 000 UI of Vitamin D per ampoule, every three months. This equates roughly to 1000 IU per day.

This national public health policy has been implemented by paediatricians since the sixties, for all French children and expectant mothers.

So far, over a 60-year period, there have been no reports of health issues resulting from these megadoses of vitamin D (which does not mean that there are not). It should be noted, however, that small regular doses of Vitamin D3 are reported to be more effective than megadoses [5].

Lack of Vitamin D Public Policy in the UK

In the UK, unlike France, no such Public Health Policy exists. This led to tragic consequences for some Afro-Caribbean couples who were convicted of « shaken baby syndrome ». But it turned out that their infants’ Vitamin D levels were so low that they had advanced rickets and would fracture easily. One successful court case appeal led to the release of all the other wrongly convicted couples.

https://www.standard.co.uk/news/shaken-babies-suffering-from-vitamin-d-deficiency-7311950.html

The UK NHS has since become more aware of the rampant vitamin D deficiency.

Calibration of skin synthesis of vitamin D

The University of Manchester and the Norwegian Institute of Air Research have together created an algorithm to measure the UV exposure needed to supply enough Vitamin D according to several parameters (but not including “age”):

https://fastrt.nilu.no/VitD-ez_quartMEDandMED_v2.html

According to this website, an individual in London with Mediterranean skin will synthesize zero vitamin D from sun exposure during winter months, no matter how much daily exposure they receive .

Also, if we rely solely on the skin to provide us with our Vitamin D needs, we can also end up being deficient due to washing, as the vitamin D created on the skin can easily be flushed down the drain due to the use of soaps and detergents during showers or baths.

There is a similar issue with sun creams: by blocking UVBs, they will prevent the skin from producing Vitamin D. This is the eternal subject of discordance between dermatologists and endocrinologists.

The long cascade of conversion for the synthesis and activation of vitamin D.

Actually, it is possible to live in a dark cave and still have good levels of vitamin D3 if it is taken orally (cholecalciferol).

 

 

However, in order to assimilate Vitamin D, vitamin A and Magnesium are needed as co-factors.

 

 

Vitamin D is transported in blood, bound to vitamin D–binding protein, and the activity of vitamin D–binding protein is also a magnesium-dependent process.

Furthermore, the enzymatic activity of both hepatic 25-hydroxylase and renal 1α-hydroxylase is a magnesium-dependent process.

  • Vitamin D3 (Cholecalciferol) is synthesized in the skin upon UVB exposure,
  • Vitamin D3 is transported to the liver where it is hydroxylated into calcifediol (25OHD3 ) which is the molecule tested in blood tests.
  • The 25OHD3 is hydroxylated a second time in the kidneys to the active metabolite calcitriol : 1,25(OH)2D3
  • Calcitriol  travels into each cell nucleus and binds to the vitamin D receptor (VDR) in the cell nucleus. The VDR is expressed in numerous tissues and for instance highly expressed in the small intestine and colon. Once calcitriol binds to the VDR, the Vitamin A (retinol) receptor (RXRA and RXRB) is involved in activation of the VDR targets.

Magnesium is involved in both activation and inactivation of vitamin D.

 

 

Possible roles of magnesium in vitamin D synthesis, Figure extracted from [2].

Abbreviations:

Ergocalciferol, D2                  vitamin D2 (from non animal sources);    

CholecalciferolD3                   vitamin D3 (from animal sources);
25(OH)D,                                calcifediol (inactive form from liver);
1,25(OH)2D,                           calcitriol (biologically active form from kidneys);
24,25(OH)2D,                         24,25-Dihydroxyvitamin D;
DBP                                       vitamin D–binding protein;
Mg                                           magnesium;
VDR                                        vitamin D receptors.

 

The broad spectrum action of active Vitamin D (calcitriol)

All the cascades of vitamin D conversion, from the synthesis of the skin to the secretions of the kidneys ultimately result in the active form of vitamin D : the CALCITRIOL. It is in fact a steroid hormone, unlike all the others. vitamins A, B, CE, K, etc. This hormone has long been recognized for its role in regulating the levels of calcium and phosphorus in the blood. But recently, it has become apparent that its VDRs (Vitamin D Receptors) are present in a wide variety of cells, which allows Calcitriol to have many biological effects other than controlling mineral metabolism:

BONES

The role of calcitriol begins in the intestine, where it plays an essential role for calcium absorption. Therefore it is involved with bone mineralization, by regulating the blood levels of calcium. This is why vitamin D blood dosages must be precisely adjusted, as too high a level can lead to calcium deposits and its collateral damage.For the same reason, Vitamin D intake can be associated with Vitamin K intake.

IMMUNE SYSTEM

Calcitriol has also been shown to act on T and B lymphocytes, and antibody-producing function of lymphocytes. It can alter the cells of the immune system to suppress autoimmunity, the reaction of the body against itself. Therefore it might improve conditions such as Diabetes type 1, Hashimoto thyroiditis, Vitiligo, Celiac disease, etc….

There is a great deal of evidence to support the claim that adequate levels of vitamin D are essential for preventing the flu. In 2017, a meta-analysis of a total of 11,321 participants in 25 randomized controlled trials concluded that vitamin D supplementation was safe and generally protected against acute respiratory infection. Patients who were severely vitamin D deficient and who received small, regular doses instead of one large dose at a time (UV dose) experienced the best improvements. The doses used in the daily dose studies ranged from 300 to 4000 IU / day (7.5 to 100 µg / day) [5].

In addition, a preliminary study suggests that vitamin D would be very effective in avoiding intensive care for hospitalized covid-19 patients [6]. In fact, in this pilot study, only 2% of Covid-19 patients hospitalized on calcifediol had to be admitted to ICU instead of 50% of Covid-19 hospitalized patients not supplemented with calcifediol.

CANCER

Calcitriol slows the growth of cancer cells isolated from breast, prostate, and colon, and kills cancer cells in-vitro. But there is not enough evidence yet  that it can slow or even kill cancer cells in humans.

CARDIOVASCULAR

In animals studies, calcitriol has been shown to lower blood pressure, amongst other ways, by relaxing blood vessels and it can decrease the risk of an enlarged heart.

NEUROLOGICAL

NGF (nerve growth factor) is enhanced by activation of the VDR receptor in contrast to ß-amyloid plaque which inhibits NGF and leads to Alzheimer disease of the brain.

THE MOOD

Calcitriol is involved in the synthesis of serotonin in the brain. A Calcitriol deficiency may participate in the onset of depression, and supplementing with Vitamin D3 might help lift mood back from depression. The “winter blues syndrome” might be alleviated by taking Vitamin D3 during less sunny months.

 

Wrong tracks ? : Vitamin D in vegetables belonging to the solanacea family

It is currently not clear whether metabolites of Vitamin D3 are present in the edible fruits of the Solanaceae, although vegetal and not animal, but they are certainly present in their leaves [3],[4].

The nightshade leaves are considered as “calcinogenic »; they cause calcinosis, a toxic calcification of soft tissues when eaten by animals. This happens because they contain calcitriol (1,25-dihydroxy vitamin D), the most active form of vitamin D.

The level of calcitriol found in cell cultures varies according to the origin of the culture, i.e., stem > leaf > fruit. However, vitamin D-like activity could not been found in tomatoes.

Therefore, calcitriol does not seem to be present in fruits eaten by human, only leaves eaten by herbivores, but this fact has not been researched extensively.

 

To be followed : the dysregulation of the VDR with chronic and auto-immune disease

Some scientists believe that a low blood level of Vitamin D (calcifediol) is not necessarily linked to a low level of active vitamin D (calcitriol), on the contrary. In chronic illness, the body may try to downregulate the production of calcifediol when calcitriol is already in excess. Therefore, routine vitamin D3 supplementation of all patients based on their calcifediol blood test may be inaccurate. Blood levels should be tested for calcitriol rather than calcifediol but this test is not a standardized blood test. More to come in next episode

 

Resources :

[1] Ulrike Lehmann, Frank Hirche, Gabriele I. Stangl, Katja Hinz, Sabine Westphal, Jutta Dierkes. Bioavailability of Vitamin D2 and D3 in Healthy Volunteers, a randomised placebo-controlled trial. JCEM jc.2012-4287.

[2] Anne Marie Uwitonze, BDT, MS; Mohammed S. Razzaque, MBBS, PhD (2018) Review : Role of Magnesium in Vitamin D Activation and Function. The Journal of the American Osteopathic Association, March 2018, Vol. 118, 181-189. doi:https://doi.org/10.7556/jaoa.2018.037

[3] Talal Aburjaia, Suleiman Al-Khalila and Mustafa Abuirjeieb.(1998),″Vitamin D3 and its metabolites in tomato, potato, egg plant and zucchini leaves » , Phytochemistry Volume 49, Issue 8, 20 December 1998, Pages 2497-2499,

[4] Jäpelt R. B., Silvestro D., Smedsgaard J., Jensen P. E., Jakobsen J. (2012). Quantification of vitamin D3 and its hydroxylated metabolites in waxy leaf nightshade (Solanum glaucophyllum Desf.), tomato (Solanum lycopersicum L.) and bell pepper (Capsicum annuum L.). Food Chemistry. 138, 1206–1211 10.1016/j.foodchem.2012.11.064

[5] Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. “Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. “,Health Technol Assess. 2019 Jan;23(2):1-44.

[6] M.E. Castillo et al.(2020), “ Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”, Journal of Steroid Biochemistry and Molecular Biology