A Deeper Look at Physiology of Vitamin D & Its Long Term Effects

Vitamin D is a fat-soluble steroidal molecule that enters nuclei of cells and modulates genetic expression, it meas active vitamin D affects decisions on how our body uses about 1,000 of our genes.  In this way it is similar to other steroidal hormones – cortisol or sex hormones. In fact,  Vitamin D is referred to as “hormone D” by some researchers. It affects human physiology on a very deep level, its effects are long term and excess vitamin D is stored for later use.

Where does Vitamin D come from? 

Our bodies manufacture vitamin D3 in the skin from cholesterol when exposed to sunshine. The form made in the sun is slightly different from that in the supplements.  The sunshine vitamin d is sulfated, making it more water soluble and bio-available. The sulfated form also conveys more of the immune benefits compared to the “supplemental” D3 form.

Vitamin D is only made in the skin when the UV index is greater than 3, which is between 10am and 2pm in temperate regions during summer and spring. A number of other vitamin D related compounds are also made in the skin during sun exposure, including activated vitamin A – retinoic acid.

Regulation of Vitamin D 

Our bodies tightly regulate vitamin D production in the skin – after about 20 mins in the sun the skin stops making vitamin D to prevent overload. Children given higher doses of vitamin D supplements convert it into inactive form to prevent disruption of calcium and phosphate metabolism.

After taking high dose vitamin D for an extended period it can take anywhere between several months to 2 years to clear the stored Vitamin D out of the fatty tissues.

Vitamin D metabolism 

After we go in the sun or take a vitamin D supplement, vitamin D3 is transported into the liver where another hydroxyl group is added, generating 25-hydroxyl vitamin D3.  This is also called “storage” vitamin D. It circulates in the blood (with a half life of 2-3 weeks) and is stored in fatty tissues for later use (you are going to rely on those stores in the winter). It has low biological activity. This is the form of Vitamin D that is measured by a blood test.

The next step in vitamin D activation takes place in the kidneys where another hydroxyl group is attached, forming 1,25 hydroxyl vitamin D3, also called “active” Vitamin D. This is a very powerful hormone.  Its half-life is much shorter, only 4-6 hours.

Active vitamin D then enters cells, travels to the nucleus and binds to “vitamin D receptor” (also called VDR).

Activated Vitamin D requires presence of both adequate magnesium and retinoic acid (activated vitamin A or retinol) in order to be effective.   Both Magnesium and vitamin A are low in the modern diet.  Activation of vitamin A also requires sun exposure.

Biological effects of vitamin D – more is not better 

Most of us are familiar with vitamin D effects on calcium and phosphate metabolism.  Vitamin D increases calcium absorption in the gut and prevents calcium excretion via the kidneys thus increasing amount of available calcium in the body.  Extreme vitamin D deficiency in children leads to lack of mineralization of bones and bending of long bones, known as rickets.

Because of its calcium effects, vitamin D has long been used as a therapy for osteoporosis.  However, recent study from Canada shows an opposite effect (1) – dose dependent bone loss with supplementation beween 4,000 and 10,000 iu per day.  Low dose Vitamin D supplements (between 400-800iu) may be a better choice for bone density as the bone loss effect has not been observed at lower doses.

Vitamin D enhances innate/non-specific arm of the immune. Vitamin D supplements slightly reduce duration and frequency of the common cold. It also slightly reduces overall inflammation with activation of T-reg cells (these are cells that reduce specific immunity) and increases Th-2 immunity (antibody production).

Why is vitamin D so popular?  

When you check wikipedia research review on long term effects of Vitamin D supplementation you find there is suprisingly little scientific evidence of its long term benefits. (2) Vitamin D supplements affect calcium/phosphorus metabolism and only slightly reduce severity and frequency of colds.  There is no positive effect on cardiovascular disease, cancer, overall morbidity or extension of life span, contrary to popular opinion.

The only exception is supplementation in true vitamin D deficiency – Vitamin D supplements are undeniably beneficial in patients whose storage vitamin D3 is below 21ng/dL.

The main reason why vitamin D is so popular is because blood levels of  “storage” 25-hydroxyl Vitamin D3 levels are reduced in chronic inflammation.  Low “storage” vitamin D status is associated with all kinds of poor health outcomes, including cancer, cardiovascular disease, autoimmune disorders, and also Covid-19 complications. Thus many practitioners have reached the conclusion that when blood levels are low, supplementation will be beneficial, in spite of lack of scientific evidence.

Low storage D in these conditions is not a cause of the inflammation but rather its consequence.

In chronic illness there is increased activation of microbes living inside our bodies (yes, with improved detection methods scientists discovered microbiome in all of our organs).  Increased number and activity of this internal microbiome is found in most chronic inflammatory conditions, from cancer, to heart disease to autoimmune conditions.  The body responds to this stress by upregulating conversion of storage vitamin D to its active form in order to increase anti-microbial activity of the innate immune system, specifically little molecules called anti-microbial peptides.  Low level of storage vitamin D in patients with chronic inflammation is often accompanied by elevated levels of active 1,25 hydroxyl Vitamin D3.

It is easy to assume that when a patient suffers from a chronic condition and their storage Vitamin D3 is low, they would benefit from supplementation.  Scientific research does not support this practice, unless storage vitamin D3 is below 21ng/dL.

There is also a study showing that high levels of stored iron in the liver are associated with low blood levels of storage Vitamin D and red blood cell magnesium.  Stored iron promotes growth of all microscopic forms of life, from viruses to bacteria to parasites and promotes inflammation and oxidative stress. So it may be that the people with low storage vitamin D, that have inflammation and microbial overgrowth also have high levels of iron that is feeding the bacteria. (3)

Are there any damaging effects of excess vitamin D? 

There are many research studies that have found negative effects of supplemental Vitamin D on human physiology. Many of these effects are indirect and manifest gradually over months or years, resulting in increased oxidative stress, calcification of soft tissues, mineral and electrolyte imbalance and epigenetic dysregulation. Oxidative stress is a ubiquitous process that causes us to rust, age and develop chronic degenerative diseases. Understanding these effects requires detailed understanding of biochemistry and human physiology, I credit Morley Robbins with uncovering the research studies below:

  1. Excess vitamin D supplementation can dysregulate calcium metabolism in the body with both increased calcification in soft tissues and blood vessels and loss of bone mass. Long term vitamin D supplementation can lead to hypertension and cardiovascular disease. This effect is well documented and can be offset by supplementing with vitamin K2.
  2. Vitamin D increases production of intracellular protein metallothionein. This in turn reduces copper bioavailability in the body leading dysregulation of iron metabolism and increased oxidative stress (long term supplementation with zinc has a similar effect). (4)
  3. Activated Vitamin D3 – calcitriol – inhibits expression of HIF-1 (hypoxia inducible factor 1) and VEGF (vascular endothelial growth factor).  The main function of hypoxia inducible factor is to balance oxidative stress and mitochondrial metabolism (it works like a see-saw, the more oxidative stress there is, the slower the metabolism).  This was originally a very exciting finding, leading many scientists to believe that vitamin D supplementation may prevent cancer. (This claim was disproved by more recent research findings. (5)Reduced HIF-1 expression also inhibits ceruloplamin and copper metabolism which in turn can lead to increased oxidative stress and iron dysregulation. Because of industrial agriculture and modern lifestyle  most Amercians are already copper deficient so further reducing copper metabolism may be the proverbial “straw that broke the camel’s back”.
  4. Vitamin D is stored in the fatty tissues, we need this reserve to get through the winter months. After long term supplementation with vitamin D  it can take anywhere from several months to 2 years before it is cleared out of the body (how fast it is detoxified depends on metabolic rate).
  5. Vitamin D supplements cause mineral dyregulation. Imbalances in sodium, potassium, magnesium and calcium ratios are routinely found in hair tissue mineral analysis.
  6. Vitamin D increases calcium absorption in the intestines and reduces magnesium absorption, thus aggravates magnesium deficiency (already present in 85% of U.S. population).
  7. Vitamin D increases renal potassium excretion which in turn leads to intracellular dehydration and increased activation of the sympathetic nervous system (i.e.stress). (6)
  8. Vitamin D increases iron absorption in the gut and reduces cellular ATP production and reduces kidney function (7). – ATP is the “energy” molecule in the cell, it is produced by the mitochondria and fuels all other chemical reactions requiring energy.  Reduced ATP production can cause fatigue, weight gain and host of other dysfunctions.
  9. Retinol (animal based Vitamin A) and Vitamin D3 have an antgonistic relationship and high doses of supplemental D block absorption of and action of retinol. (8)  

So what do we need to do in order to stay healthy?  

  1. Go outside – sun exposure is the best source of vitamin D (we also make endorphins and a variety of other vitamin D related chemicals with sunshine) and our body naturally stops vitamin D production when it has had enough
  2. Our skin will only make vitamin d when UV index is greater than 3, which in temperate regions occurs between 10am-2pm during the summer, late spring and early fall.
  3. 15-20 mins of sun exposure is all that is needed to make vitamin D, if your skin is darker it takes longer
  4. Our bodies store vitamin D so we do not have to supplement or sunbathe every day
  5. If you are going to supplement, have a blood test for both the “storage” 25-OH vitamin D and “active” 1,25-OH Vitamin D to determine if it is truly necessary
  6. If your vitamin D is testing low, address chronic inflammation
  7. Only supplement vitamin D is storage D (25-hydroxyl) D3 is below 21ng/dL AND active D (1,25 hydroxyl) D3 is not elevated
  8. Cod Liver Oil is the ideal supplement for Vitamin D – it has small amount of vitamin D to prevent deficiency and also contains retinol. Its health promoting qualities are well established – it has been used for over 200 years. It is a naturally occuring, non-synthetic food. It is important to use fresh, high quality cod liver oil and store it in the fridge and away from light as it is easily oxidized. I like Rosita and Dropi brands.
  9. Supplement magnesium at a dose of 300mg 2x/daily of either magnesium glycinate or magnesium malate, this along with vitamin A will ensure that your vitamin D be biologically activate
  10. If you are going to supplement with synthetic vitamin D use lower dose supplements, no greater than 1,000 i.u. of Vitamin D per day.

If you have any questions about Vitamin D feel free to contact me at marketabilkova@msn.com


  1. https://pubmed.ncbi.nlm.nih.gov/31454046/
  2. https://en.wikipedia.org/wiki/Vitamin_D
  3. https://www.sciencedirect.com/science/article/abs/pii/S0016508585800019
  4. https://jamanetwork.com/journals/jama/article-abstract/2613159
  5. https://dm5migu4zj3pb.cloudfront.net/manuscripts/104000/104583/JCI62104583.pdf
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866639/
  7. https://academic.oup.com/edrv/article/34/6/766/2354654
November 6, 2020