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 about 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 a new 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, the best way to get vitamin D outside of supplementation is through sunshine. 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 play a role in regulating the body’s inflammatory and immune signaling responses in both the adaptive and innate systems. Research also that low vitamin D levels are associated with several autoimmune diseases. Further, several essential genes involved 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.4
How do you acquire vitamin D resistance?
Lemke et al. propose that the same factors that can contribute 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.4
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 parts of the system can impact the ability to bring vitamin D levels up to optimal values. The authors note that some of these 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.
In this paper, it is suggested 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 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 a longer time.” 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?
If vitamin D resistance is suspected, Lemke et al. suggest that simply testing vitamin D levels is not enough. 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.
Vitamin D resistance: 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 make-up, we can better understand the individual response. As Lemke et al. note, 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), and this should be overseen by a medical professional.
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Medical Disclaimer: This article is based upon the opinions of Dr. Daniel Pompa. The information on this website is not intended to replace a one-on-one relationship with a qualified health care professional and is not intended as medical advice. It is intended as a sharing of knowledge and information from the research and experience of Dr. Pompa and his associates. This article has been medically reviewed by Dr. Charles Penick, MD for accuracy of the information provided, but Dr. Pompa encourages you to make your own health care decisions based upon your research and in partnership with a qualified health care professional.
- 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.
- 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.
- 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.
- 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.
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- 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.
- 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.
- 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.
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