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Everything You Don’t Know About Vitamin D That You Must Know

Functional Nutrition

This may not be the easiest blog to read. It is technical and complex to understand, but if you finish it, you will have ridden on a bull named Fu Manchu for way more than 2.7 seconds, and you will understand just how critical it is to  properly assess and treat Vitamin D deficiency, especially if you have osteoporosis or an autoimmune condition. Much of this article is derived, either directly or indirectly from the groundbreaking study titled “Vitamin D Resistance as a Possible Cause of Autoimmune Diseases”1

The first thing very few people know is that Vitamin D3 (cholecalciferol) is actually a pro-hormone (hormone precursor) secosteroid (it is made from cholesterol). It is converted by various tissues to multiple active forms, the most important being 1,25(OH)2D3 (Calcitriol), which has numerous effects throughout the body, including regulation of the immune system. It has been estimated that Vitamin D may affect up to 2000 genes in the body. It does much more than strengthen bone. 

The second concept even fewer people are aware of is that one can have Vitamin D resistance. Should this be you, especially if you have an autoimmune disease (or osteoporosis), you may require much larger amounts of Vitamin D. This may occur due to genetic mutations (called single nucleotide polymorphisms or SNP’s). There are multiple genes that affect absorption and utilization of Vitamin D, and SNP’s are common. (More on this later). Since Vitamin D is a fat-soluble vitamin, its absorption depends on proper GI function. Lack of bile, liver conditions such as fatty liver, lack of pancreatic and brush border enzymes, steatosis (excess fat in the stool), dysbiosis, rapid transit time, etc. can all reduce Vitamin D absorption. In addition pathogen infections can block the Vitamin D Receptor (VDR). Vitamin A deficiency may cause the VDR to fail to function properly. Excess steroids such as cortisol and prednisone decrease VDR expression. If you have low cholesterol, as is seen with people taking statin drugs, you may not be able to make your own Vitamin D.

The VDR is what is called a transcription factor. Calcitriol binds to the VDR on the cell surface. This VDR-Calcitol complex then further binds to the retinoid-X-receptor, which requires Vitamin A to function properly. This entire complex moves to the cell nucleus and binds to a specific spot of DNA called the Vitamin D response element (VDRE). This binding initiates DNA transcription (the process of converting DNA to RNA, which in turn creates many specific gene products; proteins, enzymes, hormones, etc). The VDR is found on almost all cells of the body, and especially immune cells. Among many other things it regulates gene expression of absorption and transport of calcium and other minerals.

Under optimal conditions, Vitamin D may be produced in the skin, via interactions between 7-Dehydrocholesterol and ultraviolet light (UVB), creating Pre-Vitamin D3. Body heat then converts, Pre-Vitamin D3 to Vitamin D3. In the liver, two enzymes (CYP2R1, and CYP27A1) metabolize Vitamin D3 to 25-hydroxyvitamin D (25OHD). The final step in the process occurs in the kidneys, where the enzyme 1-alpha-hydroxylase makes the active hormone 1,25(OH)2D3

Further complicating the issue is the fact that another enzyme found in mitochondria called CYP11A1 can convert D3 into several other forms, called 20-hydroxyvitamin D3,.These forms of D3 also have hormonal activity, and play a role in regulating immune activity, especially the part of the immune system related to autoimmunity, called Th17. This part of the immune system produces a chemical called interleukin 17 (IL17), which is involved with autoimmune disorders, including psoriasis and multiple sclerosis. Here is the punchline. Both the 20 and 25 forms of D3 bind to two other types of receptors that are found on the inflammatory Th17 cells, inhibiting the production of IL17, which may protect, reduce, or eliminate autoimmune symptoms. So now you see? But wait, there is more!

You say, yeah, yeah, I have had my Vitamin D levels checked and they are in the normal range. Have you really? What is the “normal range? If you have  asked your doctor, or less likely, if you doctor took the initiative to order a Vitamin D level, odds are 99% that a 25OHD level was ordered. But you already know that this is not the primary active form, which is 1,25(OH)2D3. So what you ask? Well, everyone knows that Vitamin D increases absorption of calcium from the intestines, but very few realize that it is specifically Calcitriol that does so. When serum ionized calcium levels (another test that is rarely done) are low, parathyroid hormone (PTH) is released from the parathyroid glands. This first stimulates the kidney to convert more 25OHD into Calcitriol, and then tells cells located in bone called osteoclasts to break down bone to increase serum calcium levels, which if not maintained within a narrow range, may lead to death. Additionally, osteoclasts are created from immune cells called macrophages, so note the immune system connection to bone.

To summarize, low serum calcium and ionized calcium levels stimulates release of PTH, which are in turn increases Calcitriol levels, leading to increased calcium absorption. So PTH provides a direct feedback mechanism in Vitamin D metabolism. Normal levels of Calcitriol should suppress PTH levels, so when Calcitriol is high, PTH should be low, and vice versa. The standard Vitamin D test, measuring serum 25OHD, is totally inadequate. One must measure serum calcium, serum ionized calcium, PTH, 25OHD, and Calcitriol for a complete, accurate analysis. So have you really had your Vitamin D levels checked?

Let’s talk about “normal range”. The reference range for 25OHD at both LabCorp and Quest is between 30-100ng/ml. The difference between the low and high “normal” is 333%, a significant difference. In Functional Medicine 80ng/ml is often considered optimal. But does any of this matter if Calcitriol levels are low? Lab normals vary but range from 18-84 pg/ml (a picogram is 1/1000 of a nanogram). How will you know if it is low, if you don’t test for it?

What could cause Calcitriol levels to be low? Kidney disease, chronic or acute, is common. In fact, a large percentage of people are in Stage 2 and Stage 3 and are unaware of the potential consequences. (See chart below2). 

Conversion of 25OHD into Calcitriol occurs primarily in the kidneys, only via the enzyme 1-alpha-hydroxylase ( a.k.a. CP27B1). This enzyme, like other Vitamin D-related ones, suffers from SNP’s or polymorphisms. These are caused by mutations at single amino acids caused by single point mutations in DNA, and can affect enzyme function. Theoretically, a mutation can occur at any spot in any molecule made from your genes. Many are known, many currently not known. In one research study four of five SNP’s tested reduced enzyme activity. At least two studies postulate that decreased Calcitriol levels caused by SNP’s may increase susceptibility to colon cancer3,4.

Show me the proof, you ask. Three different studies showed that individuals within study groups who were given either a large singe dose of Vitamin D (up to 80,000IU), or daily doses up to 3200IU/day responded differently. The researchers tested twelve genes regulated by Vitamin D, and that even at 3200IU/day doses, about 25% of the people tested did not show an adequate response to Vitamin D supplementation5,6,7, and may therefore be considered Vitamin D resistant. Higher doses would be needed for such individuals to achieve a complete response. 

A study of 148 outpatients with heart failure showed a clear relationship between death from any and all causes, and PTH levels. The higher the PTH, the greater the risk of death. They concluded “PTH and vitamin D were independently associated with all cause and cardiovascular mortality in patients with HF. This was independent of other known risk factors such as eGFR, LVEF, NT-proBNP, and age8.

With Vitamin D resistance from any cause, an elevated PTH will lead to an increased level of Calcitriol, and probably a low 25-OHD level. 

The Vitamin D receptor is the most likely part of the system to fail. Remember that it requires Vitamin A to function. Its importance is underscored by a study that showed that the VDR regulated 1204 genes in a human monocyte cell line9 . Several VDR SNP’s  have been associated with a variety of autoimmune conditions. Treatment of a variety of inflammatory conditions with steroids, long-term stress that chronically elevates cortisol levels, and Type II diabetes in which cortisol secretion is elevated, may all down regulate VDR function, leading to Vitamin D resistance and its consequences. 

VDR function may also be negatively affected by bacterial Lipopolysaccharides as seen in dysbiosis, GI infection, and Leaky Gut Syndrome10 . A variety of infections may down regulate the VDR, including: A. salmonicida, Legionella pneumophilia, Yersinia, Borrelia burgdorferi (Lyme Disease), Epstein Barr virus (mononucleosis) and Cytomegalovirus (CMV). Infection with CMV has been shown to reduce VDR expression by up to 88%11 . In addition, lack of sunlight; decreased Vitamin D absorption and skin production , and hydroxylation of 25OHD associated with normal aging; altered fat absorption; environmental toxins; and altered estrogen and thyroid levels affect VDR sensitivity.

When VDR function is adversely affected by SNP’s, infections, stress, or other causes, an increased Calcitriol is needed to maintain normal VDR signaling. Since PTH converts 25OHD into Calcitriol, an elevated PTH level can result from Vitamin D resistance, caused by lowered VDR signaling. Because elevated PTH is the primary cause of elevated Calcitriol, it is a sensitive surrogate marker for Vitamin D resistance. In other words, when PTH is high or in the upper “normal” range, Vitamin D resistance is probable. Ideally, PTH should be in the lower third of the normal range1. 

At a minimum, to accurately assess Vitamin D status the following tests need to be performed: 

  • 25-Hydroxy Vitamin D 
  • 1,25-Dihydroxy Vitamin D
  • Serum Calcium
  • Ionized Serum Calcium
  • Parathyroid Hormone
  • Serum Vitamin A

A comprehensive assessment includes a 24-hour cortisol rhythm panel, a comprehensive digestive stool analysis, to evaluate for dysbiosis and poor fat digestion, liver enzymes (ALT, AST, and GGT), kidney function tests, a full assessment of estrogen and thyroid hormones, and genetic testing for Vitamin D SNP’s.

REFERENCES

  1. 2) Chronic kidney disease, Hemodialysis. https://www.slideshare.net/ShumaylaAslam/chronic-kidney-disease-hemodialysis.
  2. Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis      Confirmed by a Therapeutic High-Dose Vitamin D Protocol. Front Immunol. 2021; 12: 655739.
  3. Single Nucleotide Polymorphisms in 25-Hydroxyvitamin D3 1-Alpha-   Hydroxylase(CYP27B1) Gene: The Risk of Malignant Tumors and Other Chronic Diseases.
  4. CYP24A1 and CYP27B1 Polymorphisms Modulate Vitamin D Metabolism in Colon Cancer Cells.
  5. The concept of the personal vitamin D response index. J Steroid Biochem Mol  Biol (2018) 175:12–7. 10.1016/j.jsbmb.2016.12.011.
  6. Dissecting high from low responders in a vitamin D3 intervention study. J Steroid Biochem Mol Biol (2015) 148:275–82.
  7. Molecular evaluation of vitamin D responsiveness of healthy young adults. J Steroid Biochem Mol Biol (2017) 174:314–21.
  8. Parathyroid hormone and vitamin D—markers for cardiovascular and all cause mortality in heart failure. Eur J Heart Fail (2011) 13:626–32.
  9. Epigenome-wide effects of Vitamin D and their impact on the transcriptome of human monocytes involve CTCF. Nucleic Acids Res (2016) 44:4090–104.
  10. Lipopolysaccharide negatively modulates vitamin D action by down-regulating expression of vitamin D-induced VDR in human monocytic THP-1 cells. Cell Immunol (2004)232:137–43.
  11. Human cytomegalovirus infection downregulates vitamin-D receptor in mammalian cells. J Steroid Biochem Mol Biol (2017) 165:356–62.