Note from Fearless Parent’s Medical Director, Kelly Brogan, MD: The moment that a substance is adopted by mainstream medicine and used “pharmaceutically” without attention to underlying drivers of deficiency, it’s time to expand our thinking. What follows is an exploration of a theoretical model supporting an alternative understanding about vitamin D deficiency in chronic illness and what it might represent. My Functional Medicine colleagues and I debate the role of vitamin D treatment and discuss this perspective with varied opinions on what the data and our clinical experience represent.
by Meg Mangin, RN
I am encouraged to see articles and messages cautioning use of vitamin D supplementation. Food is surely medicine and there’s a place for judicious remedies but there are times when this “fix it” message is overly simplistic. Chronic illness is complex and it follows that solutions must also be nuanced. We’re excited to be working closely with researchers, clinicians, and patients to offer an alternative framework for understanding vitamin D deficiency.
Vitamin D helps regulate the immune system
Inflammation occurs as a normal consequence of the innate immune system response to pathogens (e.g., bacteria, viruses, fungi) and molecules that the immune system perceives to be foreign and autoimmune. When the immune system eliminates the invader, inflammation stops. Inflammation that persists is thought to be the cause of many chronic illnesses.
What causes the immune system to continuously create low-grade inflammation? That’s the $64,000 question.
The immune system is modulated by a hormone we call vitamin D. Vitamin D was mistakenly named a vitamin when it was discovered in 1928. Vitamins are substances that the body cannot make; they must be ingested. Vitamin D is not simply a nutrient.
Vitamin D3 is produced in the skin when it is exposed to sunlight. This molecule is transported to the liver where it is used to produce calcidiol. This inactive form of vitamin D is transported to the kidneys where it is converted to the active form of vitamin D, called calcitriol. Calcitriol is a hormone that affects almost every cell in the body; it is the key to an effective immune system response to pathogenic invaders.
Doctors assess vitamin D status by measuring calcidiol, the inactive form. This is a simple and inexpensive lab test. Recently, studies have noted that people who are chronically ill often have a low level of calcidiol. This has led to the assumption that low calcidiol makes people ill and that healthy people with low calcidiol will become ill.
Supplementing for low vitamin D can be… harmful?
In healthy people, the level of calcidiol accurately reflects the level of the active form of vitamin D. What has not been generally recognized is that in sick people, low calcidiol indicates that this hormonal precursor is being rapidly converted into calcitriol, the active form. When doctors measure the calcitriol level of people who have a chronic illness, they often find that calcitriol is above the normal range. Too much calcitriol causes inflammatory symptoms and eventual tissue damage due to persistent inflammation.
In sick people, low calcidiol (often labeled as vitamin D deficiency) and high calcitriol are markers of a chronic inflammatory process. Low calcidiol is a consequence of a disease process, not a cause. Supplementing with vitamin D increases the level of calcidiol, making it easier for the body to produce excess calcitriol, which increases inflammatory symptoms.
The National Institutes of Health advises: “Ten to 15 minutes of sunlight or daylight exposure to a small area of skin (e.g., the forearm or face) twice a week (without sunscreen) supplies all the vitamin D necessary for health.” This is an achievable goal for most of the world’s population. [Ed.: the amount of sun needed varies by a number of factors; some people need much more]
Numerous studies have shown that people living in very sunny countries have levels of calcidiol that are being labeled as vitamin D deficient despite the fact that these people are healthy. This suggests that ‘low’ calcidiol is normal in healthy individuals. And studies of disease occurrence have not shown that taking vitamin D supplements to increase calcidiol has a beneficial effect.
Sometimes, vitamin D increases inflammation
Production of calcitriol in the kidneys is controlled by a feedback mechanism based on the level of calcium, phosphate and parathyroid hormone (PTH). This keeps calcitriol from becoming too high. When calcitriol is above the normal range the doctor will check calcium, phosphate and PTH levels. If they’re normal, this indicates that calcitriol is being produced by cells outside the kidneys (extra-renal).
At least 37 types of extra-renal cells (monocytes, macrophages, bone cells, keratinocytes, spleen, etc.) are capable of producing calcitriol. These cells are stimulated to produce calcitriol by inflammatory molecules (e.g., cytokines, lipopolysaccharides) but the production is not controlled by a feedback mechanism.
If the stimulation is persistent, the cells will continue to produce calcitriol. This will deplete the level of calcidiol (the inactive precursor) and cause inflammatory symptoms.
It’s about bacteria
Bacteria exist that are smaller than viruses and can enter human cells because they don’t have cell walls. They are called L-forms (after the Lister Institute). L-forms have been found multiplying within the cells of the immune system; the very cells that are supposed to kill them. The natural response of the immune cell is to produce calcitriol because this hormone binds to a receptor within the cell (called the vitamin D receptor) and initiates production of the body’s natural ‘antibiotics,’ called antimicrobial peptides (AMPs).
In order for the L-form bacteria to remain undetected within the cell, they have devised a strategy to ‘block’ the vitamin D receptor (VDR). The cell is stimulated by the L-form bacteria to produce calcitriol (an inflammatory molecule) to begin the process of eliminating the intracellular bacteria, but the effort is futile because the VDR is blocked. The result is inflammation that doesn’t end and causes inflammatory disease symptoms. L-form bacteria may also stimulate an adaptive immune system response which produces antibodies that cross-react and attack human proteins (auto-antibodies), as well as attacking the target: intracellular bacteria.
MEASURE CALCIDIOL AND CALCITRIOL
The presence of bacteria within the cells stimulates an active but ineffective immune system response that causes abnormal vitamin D metabolism (over-production of calcitriol). This can be diagnosed indirectly by assessing both calcidiol (it will be low) and calcitriol (it will be high). Effective immune system function can be restored by eliminating the intracellular bacteria that trigger the immune system’s non-resolving inflammatory response.
The key to resolving persist inflammation is to stop the L-form bacteria inside the cells from blocking the vitamin D receptor. A prescription medication called olmesartan (brand name Benicar®) has demonstrated the ability to dock into the vitamin D receptor (like calcitriol does) and initiate the production of AMPs (the body’s natural antibiotics).
In this way the cells of the immune system can, once again, effectively kill bacterial invaders; both intracellular and extracellular infections. Bacteria are cleared from extra-renal cells so they are no longer stimulated to produce excess calcitriol. The kidneys regain control of calcitriol production via the feedback mechanism; calcitriol returns to normal and inflammatory symptoms are reduced.
IS OLMESARTAN SAFE?
In 2002 the FDA approved olmesartan for the treatment of hypertension. Study subjects experienced no significant side effects and subjects who took the placebo experienced similar mild side effects. Concerns about cardiac side effects raised by a 2011 study were dispelled by a study done in 2013. The sprue-like enteropathy recently associated with olmesartan involves severe and protracted diarrhea. This puzzling syndrome has been experienced by only a tiny subset of millions of olmesartan users. It has not been seen in any of the thousands of patients taking olmesartan as part of a treatment plan which activates the immune system.
- Vitamin D is a steroid hormone which regulates immune system function.
- Low calcidiol is seen in healthy individuals exposed to abundant sunlight.
- Supplementing for low vitamin D to increase calcidiol has not shown any clear benefit.
- Low calcidiol and high calcitriol are markers of an inflammatory process.
- Vitamin D supplementation may increase calcitriol and inflammatory symptoms.
- In sick people, calcidiol may not accurately reflect the level of the active form of vitamin D (calcitriol).
- Accurate assessment of vitamin D status depends on measuring both calcidiol and calcitriol.
- Intracellular bacteria appear to cause ineffective immune system function by blocking the vitamin D receptor.
- Olmesartan stimulates the vitamin D receptor which enables the immune system to kill the intracellular bacteria; inflammation and symptoms are resolved.
Meg Mangin, RN is Executive Director of Chronic Illness Recovery. She has served on a National Institutes of Health State of the Science panel and an NIH Data, Safety and Monitoring Board. Meg has presented at numerous conferences; including Days of Molecular Medicine, the 6th International Conference on Autoimmunity the American Society of Hypertension Annual Meeting, Enabling Future Pharma, Perspective in Rheumatic Diseases and Immunology Summit. She contributed to the medical textbook Vitamin D: New Research and is the lead author of Inflammation and Vitamin D: the Infection Connection, which appeared in the peer-reviewed journal Inflammation Research.
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