Vitamin D Resistance: Vitamin D, the superstar hormone we call a vitamin, is of particular interest in the wellness world because of the many ways it functions for our health. As interest in the benefits of vitamin D continues to grow, questions also arise about how much we really understand individual responses to supplementation. Specifically, why do some people easily reach optimal vitamin D levels with little intervention while others don’t even seem to respond to standard supplementation recommendations?

This article has been medically reviewed by Dr. Charles Penick, MD

In an article published in Frontiers in Immunology, researchers suggest there may be an acquired form of vitamin D resistance that explains why there is so much variation from person to person in their paper “Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol.”

Vitamin D foundations

Vitamin D can be obtained in small amounts from the food we eat. Still, sunshine is the best way to get vitamin D outside of supplementation. When sunlight interacts with receptors on our skin, we can make vitamin D2, the inactive form of D. The conversion of inactive to active forms of vitamin D involves two crucial steps, starting with the liver, where inactive calcidiol is made. Calcidiol is then transported for a second hydroxylation, primarily in the kidneys, where the active form calcitriol is created. Finally, this active form of vitamin D is sent throughout the body to the vitamin D receptors (VDR).

Vitamin D has many vital jobs in the body. While many are familiar with its role in bone health and calcium regulation, its impact on gene expression, immunity, and inflammation may be just as significant. Studies suggest that it may regulate the body’s inflammatory and immune signaling responses in both the adaptive and innate systems. Research also shows that low vitamin D levels are associated with several autoimmune diseases. Further, several essential genes in the immune system are expressed by VDR once vitamin D is activated.

The hypothesis of acquired vitamin D resistance

In this paper, Lemke et al. propose that varying responses to vitamin D supplementation may be due to an underlying resistance to vitamin D. Those with autoimmune diseases may, in fact, need higher than average doses to bring levels in the body up to optimal levels.

As part of the hypothesis for vitamin D resistance, Lemke et al. point to studies where even high doses of vitamin D made little difference in the subject’s serum markers, even with really high one-time doses.

One study attempted to examine biomarkers for identifying vitamin D responders and found that changes in the expression of several genes impacted the amount of circulating active Vitamin D. In that study, only 55 to 62 percent of the subjects were considered responders to vitamin D supplementation.

Similar results of varying responsiveness were also seen in a study on young adults who received vitamin D supplementation. Some were highly responsive to vitamin D supplementation, while others had very little response to the same amount.

With these results in mind, Lemke et al. suggest that some people (especially those with autoimmune conditions) may require larger supplemental doses to down-regulate the immune system because of this vitamin D resistance.

How do you acquire vitamin D resistance?

Lemke et al. propose that the same factors contributing to chronic health conditions may also lead to vitamin D resistance. Namely, genetic predispositions can make you more susceptible to polymorphisms (or changes to DNA) that can impact the vitamin D system. This, combined with the impact of environmental factors like decreased sunlight and exposure to toxins or pathogens as we age, can lead to resistance, according to this paper.

The polymorphisms of genes can impact the expression of different proteins within the vitamin D system, such as:

• The enzymes needed to convert inactive to active vitamin D.
• Transport proteins that take vitamin D where it needs to go.
• The receptors like VDR or others help the body to use and store vitamin D.

An alteration in any of these system parts can impact the ability to bring vitamin D levels up to optimal values. The authors note that some polymorphisms are also associated with autoimmune disease.

Lemke et al. state that VDR is “the most vulnerable part of the vitamin D metabolic system” as it is present in almost all of our cells, especially immune cells. This is also echoed by other research.

This paper suggests that polymorphisms associated with VDR can influence acquired vitamin D resistance in combination with lifestyle factors like stress. Chronic stress can play a role, as the authors point out, that VDR can be inhibited by long-term stress hormones.

The relationship to autoimmune disease

The connection between acquired vitamin D resistance and autoimmune disease deepens when researchers discuss VDR related to pathogens. Viruses have long been considered a potential trigger for several autoimmune conditions. Interestingly, this paper by Lemke et al. notes that VDR is also targeted by pathogens, disrupting vitamin D signaling.

As described in this paper, “The mechanisms of how pathogens disrupt vitamin D signaling may provide a missing link between the association of infections and autoimmune pathogenesis. Indeed, pathogen infections have been discussed as triggers of autoimmune diseases for longer.” The suggestion is that through VDR and vitamin D signaling, pathogens may alter the immune response and impact autoimmune disease, thus connecting vitamin D resistance to autoimmune disease development.

Can you measure vitamin D resistance?

Lemke et al. suggest that testing vitamin D levels is not enough if vitamin D resistance is suspected. Instead, they note that vitamin D resistance is accompanied by high parathyroid hormone (PTH) levels. Unlike some of the other biomarkers used in clinical studies, the authors suggest that measuring PTH is a viable and accessible way to measure resistance.

PTH is downregulated by active vitamin D and upregulated by inactive vitamin D. It helps stimulate the production of more vitamin D. If someone is vitamin D resistant, the authors argue that PTH may be elevated, even if inactive forms are normal, as the normal conversion process isn’t happening. They suggest that a high PTH value indicates vitamin D resistance, assuming the person follows a normal, balanced diet and other disease states have been ruled out.

Summary

This paper provides a fascinating and compelling explanation behind the variation between individual responses to vitamin D supplementation. The connection between vitamin D deficiency and autoimmune conditions is also explained.

As we learn more about epigenetics, or how we are susceptible – but not resigned – to health concerns based on our genetic makeup, we can better understand the individual response. Lemke et al. note that the best intervention for vitamin D deficiency based on resistance is high-dose vitamin D therapy (based on a specific protocol named after its inventor Dr. Cicero Coimbra), which should be overseen by a medical professional.

You might be vitamin D resistant, OR you might just be taking the wrong supplement. The truth is that most supplements won’t do a thing to raise your vitamin D levels —no matter how much you take. That’s because most store-bought pills and tinctures contain fillers and low-quality nutrients.

CytoD+K2, on the other hand, is up to 2X the potency of normal vitamin D. Plus, it contains the ideal ratio of vitamin D to vitamin K2 for optimal nutrient absorption and calcium balance. The best part? You don’t need to down 2-3 pills to get your daily dose.

With just a dropper full per day, you can strengthen immunity, restore sleep, increase energy, improve skin health, and SO much more.

Medical Disclaimer: This article is based on the opinions of The Cell Health team. The information on this website is not intended to replace a one-on-one relationship with a qualified healthcare professional and is not intended as medical advice. It is intended to share knowledge and information from the research and experience of the Cell Health team. This article has been medically reviewed by Dr. Charles Penick, MD, for the accuracy of the information provided. Still, we encourage you to make your own healthcare decisions based on your research and in partnership with a qualified healthcare professional.

References

1. Jones, Glenville, David E. Prosser, and Martin Kaufmann. “Cytochrome P450-Mediated Metabolism of Vitamin D.” Journal of Lipid Research 55, no. 1 (January 1, 2014): 13–31. https://doi.org/10.1194/jlr.R031534.
2. Murdaca, Giuseppe, Alessandro Tonacci, Simone Negrini, Monica Greco, Matteo Borro, Francesco Puppo, and Sebastiano Gangemi. “Emerging Role of Vitamin D in Autoimmune Diseases: An Update on Evidence and Therapeutic Implications.” Autoimmunity Reviews 18, no. 9 (September 1, 2019): 102350. https://doi.org/10.1016/j.autrev.2019.102350.
3. Koivisto, Oona, Andrea Hanel, and Carsten Carlberg. “Key Vitamin D Target Genes with Functions in the Immune System.” Nutrients 12, no. 4 (April 2020): 1140. https://doi.org/10.3390/nu12041140.
4. Lemke, Dirk, Rainer Johannes Klement, Felix Schweiger, Beatrix Schweiger, and Jörg Spitz. “Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol.” Frontiers in Immunology 12 (2021). https://doi.org/10.3389/fimmu.2021.655739.
5. Saksa, Noora, Antonio Neme, Jussi Ryynänen, Matti Uusitupa, Vanessa D. F. de Mello, Sari Voutilainen, Tarja Nurmi, Jyrki K. Virtanen, Tomi-Pekka Tuomainen, and Carsten Carlberg. “Dissecting High from Low Responders in a Vitamin D3 Intervention Study.” The Journal of Steroid Biochemistry and Molecular Biology, 17th Vitamin D Workshop, 148 (April 1, 2015): 275–82. https://doi.org/10.1016/j.jsbmb.2014.11.012.
6. Seuter, Sabine, Jyrki K. Virtanen, Tarja Nurmi, Jussi Pihlajamäki, Jaakko Mursu, Sari Voutilainen, Tomi-Pekka Tuomainen, Antonio Neme, and Carsten Carlberg. “Molecular Evaluation of Vitamin D Responsiveness of Healthy Young Adults.” The Journal of Steroid Biochemistry and Molecular Biology 174 (November 1, 2017): 314–21. https://doi.org/10.1016/j.jsbmb.2016.06.003.
7. Bizzaro, Giorgia, Antonio Antico, Antonio Fortunato, and Nicola Bizzaro. “Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit?” The Israel Medical Association Journal: IMAJ 19, no. 7 (July 2017): 438–43.
8. Smatti, Maria K., Farhan S. Cyprian, Gheyath K. Nasrallah, Asmaa A. Al Thani, Ruba O. Almishal, and Hadi M. Yassine. “Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms.” Viruses 11, no. 8 (August 19, 2019). https://doi.org/10.3390/v11080762.
9. coimbraprotocol. “The Coimbra Protocol.” Accessed April 16, 2021. https://www.coimbraprotocol.com/the-protocol-1.