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Supplementing For Low Vitamin D? Not So Fast…

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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.

Now what?

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.

CONSIDER OLMESARTAN

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.

Key points

  • 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-manginMeg 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.

Resources

References

Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflamm Res. Oct 2014;63(10):803-19.

Anderson G, Horvath J. The growing burden of chronic disease in America. Public Health Rep. 2004;119(3):263–70

Woolard MD, Frelinger JA. Outsmarting the host: bacteria modulating the immune response. Immunol Res. 2008;41(3):188-202.

Dermine JF, Desjardins M. Survival of intracellular pathogens within macrophages. Protop. 1999;210(1-2):11-24.

Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci. Sep 209;1173:384-90.

Rasmussen SB, Reinert LS, Paludan SR. Innate recognition of intracellular pathogens: detection and activation of the first line of defense. APMIS. May 2009(117(5-6)):323-37.

Lambert PW, Stern PH, Avioli RC, et al. Evidence for extrarenal production of 1 alpha ,25-dihydroxyvitamin D in man. J Clin Invest. Mar 1982;69(3):722-5.

Edfeldt K, Liu PT, Chun R, et al. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci U S A. Dec 2010;107(52):22593-8.

Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G. High levels of active 1,25-dihydroxyvitamin D despite low levels of the 25-hydroxyvitamin D precursor-implications of dysregulated vitamin D for diagnosis and treatment of chronic disease. In: Stolzt VD, ed. Vitamin D: New Research. New York, NY: Nova Science Publishers.

Carlberg C, Molnar F. Detailed Molecular Understanding of Agonistic and Antagonistic Vitamin D Receptor Ligands. Curr Top Med Chem. 2006;6(12):1243-53.

Kongsbak M, Levring TB, Geisler C, von Essen MR. The vitamin D receptor and T cell function. Front Immunol. Jun 2013;4:148.

 

 

42 Comments

  • Profile photo of admin2
    admin2

    “Take that post down!”
    “This is bad medicine.”
    “Are you crazy?”
    “You should be ashamed of yourself.”

    This vitamin D post hit a nerve!

    When we read something that doesn’t square with what we think and even more importantly, what we do and what we recommend to others, it bothers people a lot.

    The above comments were from medical doctors and they were not happy. (I encouraged them to post their comments on the site. I hope they will.)

    Like many others, I (Louise) have been supplementing with vitamin D at a dosage that far exceed recommended levels and I’ve been feeling virtuous about it. It’s all about getting to that magical 60 to 80 ng/ml level where I’m no longer vitamin D deficient. I’m changing my mind (see comment below).

    When I first saw Meg’s work, I had the same initial reaction. NO WAY! And the use of a pharmaceutical drug? UNACCEPTABLE! But I started to scratch a little beneath the surface of this issue of vitamin D deficiency and what I read intrigued me. I heard from people who admitted that certain symptoms resolved for them after they discontinued high dose supplementation. That’s interesting. I want to know more.

    Kelly Brogan, MD does not use this protocol in her practice but she supports the inquiry and conversation. If you scroll down and read her reply to one of the comments on this post, you will find a link to a powerful deck of slides on nutritional medicine prepared by Alan Gaby, MD, one of the leaders in nutrigenomics. Take a look!

    To be clear, we are not advocating this treatment protocol. Not yet anyway. But we are really curious about it. We believe people deserve to have access to information. In our opinion, (high dose) supplementation for low D on the basis of a single test for all people at all times is deserving of greater scrutiny. We are not saying that the body doesn’t need D. We are not saying anyone should stop doing anything after reading one article any more than we think that people should start or continue doing something just because everyone else is.

    A few people were quick to slam this piece as a plug for Pharma and to denigrate Meg’s participation on an NIH panel. Is every drug bad all the time? If we embrace clinicians who work outside the system, does this mean we must shun those who work within the system?

    We’d like to say a special word about conflicts of interest. We deplore the industry spokesman who fails to disclose his commercial ties and represents himself as “The Good Doctor” while proffering advice that promotes his corporate sponsors. Similarly, we would ask that clinicians in our community who are aligned with special interests, including supplement companies and organizations with close ties to supplement companies, disclose these ties.

    So this is Fearless Parent. We’re committed to exploring cutting edge ideas and unconventional practices. Our community does not accept orthodoxy reflexively, and this includes orthodoxy that comes from within our community. Whenever the response to our work is, “I’m too busy to explain, but you’re totally wrong.” then we know we’re onto something. Let’s share information and engage in respectful debate so we can help advance our knowledge and keep each other honest about the things we stand for.

    Louise Kuo Habakus
    Kelly Brogan, MD
    Cornelia Mazzan

  • kelly fincher

    grateful to Louise & crew on their mission of information…go social media!!

  • Sylvia F

    Fantastic summary of an issue/intervention that has previously been oversimplified. Louise, you are an endless source of well-researched, timely and vitally important info. Kudos to you and your crew.

  • Amy

    Thanks for the information. This is very helpful! Family members of mine were diagnosed with Vitamine D deficiency. Now I have to look at it from a whole different angle.

  • CS

    I wonder if this is what my daughter is going thru. What lab test is used to measure the levels of calcidiol/calcidriol in the body – what laboratory test is used to do this??

  • Meg Mangin

    The best way to diagnose the presence of an intracellular infection is via a secondary marker that indicates vitamin D metabolism dysregulation. That marker is calcitriol. You may have had a test for vitamin D but this would have been the inactive precursor (calcidiol). When it’s low, as we often see in chronic and inflammatory diseases, it’s due to a rapid, and uncontrolled, conversion to the active metabolite (which is high).
    Recommended vitamin D tests:

    25-hydroxyvitamin-D (also known as 25(OH)D or calcidiol)
    • This is the inactive form.
    • CPT code: 82306
    • This is the form of vitamin D that is commonly measured.
    • It is measured in ng/ml.

    1,25-dihydroxyvitamin-D (also known as 1,25(OH)2D or calcitriol)
    • This is the active form.
    • CPT code: 82652
    • This test is a delicate assay and the sample should be frozen for transport to avoid degradation due to agitation.
    • It may be expensive but it is usually covered by insurance.
    • ICD-9 diagnostic codes:
    o 780.9 Fatigue
    o 733.00 Osteoporosis, unspecified
    o 733.90 Osteopenia
    o 135 Sarcoidosis
    o 275.40 Unspecified disorders of calcium metabolism
    o 275.42 Hypercalcemia
    o 278.4 Hypervitaminosis D
    o E55.9 Vitamin D deficiency, unspecified (ICD-10-CM code)
    • It is measured in pg/ml.

    Both tests are necessary to assess the vitamin D endocrine system which can affect immune system function. Sometimes abnormal test results appear to be acceptable because calcitriol lab ranges have been skewed high. Chronic Illness Recovery offers a free professional analysis of vitamin D test results. Send a copy of lab report to info@chronicillnessrecovery.org.

  • DAVID AYOUB, MD

    I am enormously disappointed in this work. It shamefully inaccurate and misleading.

    Nurse Mangin relies on an online article written by “Catherine”, a nutritionist in Seattle. She characterizes Vitamin D supplementation as a dietary fad and deficiencies the result of secondary conditions such as malabsorption, increased turnover, etc. First, widespread deficiencies are being recognized all over the world. Perhaps this is too much to believe, but the data is overwhelming. I suggest the reason that discussion is so tiring to health paraprofessionals is that is is indeed an epidemic that affects so many people. Most vitamin D is obtained from direct sun exposure. There has been a gradual yet significant reversal is sun exposure policy over the last several decades. In the late 1920s the Children’s Bureau recommended that infants sunbathe 15 minuets a day (in diapers only) beginning at the end of the first week of life and increasing until daily exposures were 1-2 hours a day (depending on skin type) and also supplement with cod liver oil twice daily. Now sun is to be avoided unless wearing protective clothing and sunblock. Supplementation is critical to achieve normal and healthy vitamin D status yet use of adequate supplementation is abysmal. “Catherine” suggests a good calcium source instead but since fractional absorption of calcium from the gut is dependent upon vitamin D status, it is a poor advice without absolute assurance that serum 25 hydroxyvitamin D levels are maintained above 30 ng/ml.

    Back to the Mangin piece, it is, in my opinion, medical negligence to even suggest that supplementing for vitamin D deficiency is generally dangerous-in fact it is on eof the safest supplements in use. Toxicity reports are rare, requiring on average several 100,000’s IU of D2/D3 daily over extended periods of time. Deficiency is related to a vast spectrum of diseases, most of which are exploding along with vitamin D deficiency rates, such as diabetes, hypertension, cancers (breast, colorectal, prostate), fractures, falls, upper respiratory tract infections, strokes, autoimmune diseases, etc.
    Mangin’s emphasis on intracellular bacteria is perplexing. The advice to draw 1,25 dihydroxyvitamin D to test for intracellular bacteria is even more strikingly misguided as an array of conditions can elevate these levels, particularly inadequate calcium status. It would be assured that the vast majority of patients with elevated levels would not have bacterial infections.
    Olmesartin as a vitamin D analog? Is there even a single research study designed to evaluate this? Who is promoting this dangerous and controversial drug in replacement of safe and effective vitamin D3 or sunshine? In 2014 there are already over 20 publications describing enteropathy associated complications from this drug, comprising about 20% of all publications in this interval. Ironically, diarrhea states can result in serious nutritional deficiencies including calcium and vitamin D loss! The obvious question….Has Mangin or her organization received financial backing from pharma in exchange for promoting this dangerous pharmaceutical? How does she know the 2013 study dispelling cardiovascular risks with Olmesartin wasn’t in fact the erroneous study and the 2011 study finding cardiovascular side effects the correct one? I am always very concerned when later research dispels original concerns, it smacks of damage control funded and directed by the heavy hand of the drug cartel.

    In summary this is a column that should be discarded. It is filled with many unsubstantiated statements. I am ashamed that Dr. Brogan has endorsed this work. If you want to know the truth about vitamin D, subscribe to Dr Cannell’s “The Vitamin D Council” or Dr Mayer Eisenstein’s “Home First” mailing list.

    • Kelly Brogan, MD

      Thanks for your feedback. I have been investigating this since I sat in on a lecture (attached – slides 12-34) by one of the, if not THE, leaders in the field of nutrigenomics, Dr. Alan Gaby, and have monitored, with interest, the complexity of vitamin D physiology over the years of my clinical practice. I believe that your information falls into the dogmatic one-size-fits-all rubric that governs pharmaceutically-minded interventions and does not reflect the dialogue that my colleagues and I engage on this subject. I don’t use this protocol in my practice, but I believe the conversation is valid, and I’m sorry that you felt the need to use language like “I am ashamed that Dr Brogan…” as it is highly non-collegial. Fearless Parent is intended to be a platform that promotes inquiry and dialogue in unconventional thinking.

    • Meg Mangin

      The column “Supplementing For Low Vitamin D? Not So Fast…” was based on a peer-reviewed article recently published in Inflammation Research. [1] The link to a nutritionist’s column was simply meant to point out that many authorities are becoming concerned about the widespread use of vitamin D supplements. There are many common beliefs about vitamin D which are false. This brief summary addresses those that Dr. Ayoub has mentioned.

      In the U.S., the leading authority regarding medical research is the prestigious Institute of Medicine (IOM). The IOM defines vitamin D deficiency as a serum level of 25(OH)D less than 12 ng/mL. [2]

      The Endocrine Society definition of vitamin D deficiency is a level of 25(OH)D less than 20 ng/mL. [3] Following a review, the IOM discounted the Endocrine Society data and showed it was incorrectly analyzed. [4] In April, 2013 a paper published in Endocrine Connections reported concerns that the Endocrine Society’s Clinical Practice Guideline may lead to vitamin D toxicity.

      The way forward is the implementation of IOM recommendations, worldwide, especially given that the new specifications have increased two to threefold for children and young adults and increased by 33-50% for those over age 50 years compared with the last IOM report in 1997. [5]

      The Vitamin D Council definition of deficiency is worrisome because it is much higher; 25(OH)D less than 40 ng/mL. [6] The Vitamin D Council is the most vocal source of information urging the public to take more vitamin D. This organization markets vitamin D3 as a nutrient, sells books about vitamin D, as well as vitamin D supplements and vitamin D test kits. Dr. Len Lichtenfeld (Deputy Chief Medical Officer for the national office of the American Cancer Society) countered Vitamin D Council claims in his online blog with this statement,

      When we succumb to making every medical decision solely on the basis of the strongest advocate’s voice, we run the risk of moving medical practice back into an era similar to that from which we are trying to emerge. If the review and research studies confirm Dr. Cannell’s position, that will be welcome. But we need to once and for all establish the science-based evidence that will conclusively answer the question one way or the other, rather than relying on advocacy to establish dietary and medical practice recommendations for the world. [7]

      Rickets is caused by impaired metabolism of vitamin D, phosphorus, or calcium and low levels of vitamin D are associated with rickets. [8-10] Hypophosphatemia (low phosphorus) is the common denominator of all rickets; low calcium intake leads to hyperparathyroidism, which leads to high phosphorus excretion and, thus, phosphorus deficiency. [11] Adequate vitamin D is essential to prevent rickets, but adequate calcium is equally important; if either calcium or vitamin D is deficient, bone health suffers. [12] Rickets is rare in the developed world; [13] however, children in developing countries, who usually photosynthesize enough vitamin D from sunlight, develop rickets if poverty prevents them from eating enough calcium rich food. [14] Studies found rickets occurs in sunny countries due to poor calcium intake [15, 16] and is cured with increased calcium ingestion. [17, 18]

      High quality human studies of vitamin D are difficult to conduct because of the difficulty in eliminating the con-founding factor of photosynthesis. The IOM noted that most vitamin D studies are observational; few are randomized or well-controlled. Most are short-term and serum 25(OH)D is used as a surrogate marker (i.e., not a true health outcome). At the 15th European Congress of Endocrinology April 27 – May 1, 2013 in Copenhagen, Denmark, Mark Cooper, M.D., a leading expert in the field of vitamin D, noted that the supposed benefits of vitamin D are exclusively reported in observational studies and there is a huge sector of the scientific community which is “evangelical” in its pro–vitamin-D stance. He commented,

      We really need some robust evidence. Physicians have been here before, with many other nutrients that subsequently, in large intervention trials, turned out to have a null effect or even be harmful. In fact, there is already evidence of risks with supplements of vitamin D from randomized clinical trials, with no evidence of benefit. There have been lots of randomized controlled trials, different doses of vitamin D, different groups, all well-designed, all in major journals, and all negative. At least 1 in 20 of these studies should be positive just by chance, but we haven’t seen that yet. [19]

      Meta-analysis statistics studies have attempted to make sense of multiple vitamin D studies. An analysis was done in 2012 by Loyola University Chicago Stritch School of Medicine, in which researchers explored all-cause mortality rates, across the spectrum of 25(OH)D levels, over an eighteen-year follow-up, among adults with and without kidney disease. They concluded that while significantly higher mortality rates are noted with 25(OH)D levels less than 12 ng/mL, mortality rates are fairly similar across the range of 25(OH)D levels 20–40 ng/mL [20] In other words, they found no benefit to a higher level of 25(OH)D. A retrospective analysis of over 247,000 subjects in Denmark came to a similar conclusion; at the University of Copenhagen, scientists found the lowest mortality rate when 25(OH)D was 20 ng/mL. [21] A 2013 study found parallel results; 25(OH)D in the 20-36 ng/mL range was associated with the lowest risk for mortality and morbidity. [22]

      Most vitamin D is obtained from direct sun exposure. It takes relatively little sunlight exposure to acquire adequate stores of vitamin D. Ten to 15 minutes of sunlight or daylight exposure to a small area of skin (e.g., the forearm or face, etc.) twice a week (without sunscreen) supplies all the vitamin D necessary for health. [23]

      Autier et al. [24] point out that:
      • Observational studies report inverse associations between 25(OH)D concentrations and many non-skeletal diseases.
      • Intervention studies do not show a beneficial effect of vitamin D supplementation on disease occurrence.
      • The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health.

      Despite conflicting study results and the IOM recommendation, vitamin D proponents continue to oversell study findings and exhort people to take vitamin D supplements.
      Thankfully, some experts are advising caution regarding recommendations made based on observational studies. In his August 4, 2009 presentation “Weighing Scientific Evidence” at the IOM Information Gathering Workshop for Dietary Reference Intakes for Vitamin D and Calcium, Dr. Barry Kramer (Office of Disease Prevention, NIH) urged caution by quoting the Scottish philosopher David Hume (1711-1778) “A wise man proportions his belief to the evidence”. In a May 10, 2010 Chicago Tribune article Julie Deardorff quoted two other vitamin D experts. [25] Anastassios Pittas (endocrinologist at Tufts University Medical Center, Boston) stated, “It’s premature to go out and make a big deal out of vitamin D supplementation when we don’t have the evidence. We’ve been burned before on nutrition-based interventions.” Dr. Ethan Balk (Center for Clinical Evidence Synthesis) cautioned, “There’s a potentially large problem with leaping from observational studies to making decisions about interventions.” In a Journal of the National Cancer Institute editorial Davis and Dwyer concluded [26], “While vitamin D may well have multiple benefits beyond bone, health professionals and the public should not, in a rush to judgment, assume that vitamin D is a magic bullet and consume high amounts of vitamin D. More definitive data on both benefits and potential adverse effects of high doses are urgently needed.”

      More vitamin D experts are beginning to reconsider vitamin D supplementation among the general population. [27] In fact, excessive vitamin D can be toxic to humans and to animals. This is dramatically illustrated in the use of rodenticides with high vitamin D content (e.g., True Grit Rampage & Ortho Rat-B-Gone) and when livestock die following ingestion of plants that contain derivatives of vitamin D metabolites (e.g., cestrum diurnum and solanum malacoxylon). [28, 29] DeLuca et al. concluded that 25(OH)D is the metabolite responsible for vitamin D toxicity. [30] The immediate effects of significant vitamin D toxicity (hypervitaminosis-D) are hypercalcemia, hypercalciuria, bone resorption, and calcification of soft tissues. In humans, symptoms of hypervitaminosis-D depend on the patient’s condition and the level of excess vitamin D metabolites; people with high blood calcium or phosphorus levels, heart problems, kidney disease, sarcoidosis, and tuberculosis are at highest risk. [31] It is difficult to ingest too much vitamin D from food, and natural mechanisms regulate the amount of vitamin D3 photosynthesized from sunlight. [32] However, elevated 25(OH)D and hypervitaminosis-D can occur due to vitamin D supplementation. [33]

      Researchers are beginning to realize excessive vitamin D intake may cause problems. Muhammad Amer, M.D., an assistant professor at Johns Hopkins University School of Medicine, said “People taking vitamin D supplements need to be sure the supplements are necessary. Those pills could have unforeseen consequences to health even if they are not technically toxic.” [34] When cancer studies (breast and colorectal) from the Womens’ Health Initiative, showed no protective effects of vitamin D supplementation, the researchers suggested the dose of vitamin D might have been too low. However, the results of the studies actually showed trends toward potential harmful effects of high vitamin D intake. [35] Researchers like Dr. Anja Olsen are concerned that the discussion on potential negative effects of vitamin D supplementation (besides those of toxicity) is very limited. “…the past has shown us (with the history of β-carotene and lung cancer as the scariest lesson) that observational studies on micronutrient blood levels cannot always be extrapolated to positive effects of high-dose supplementation.” [36] Cases such as these remind us that some therapies which seemed to show promise for treating or preventing health problems ultimately did not work out and even caused harm. Emerging evidence about an intervention should be approached cautiously and with an open mind.

      Dr. Michael J. Glade believes 25(OH)D may appear to be low for reasons totally independent of sunlight exposure or vitamin D intake. He expresses concern that local tissue vitamin D intoxication may be present in individuals with much lower serum 25(OH)D concentrations than are currently appreciated and that prolonged routine consumption of megadoses of vitamin D may interfere with the regulation of phosphate homeostasis by fibroblast growth factor-23 (FGF23) and the Klotho gene product, with consequences that are detrimental to health. [37] This 1983 study sounded an early alarm,

      The requirement for vitamin D is normally met by its synthesis in the skin. In the United States, various foods are fortified with vitamin D to ensure that deficiencies do not occur. As a result, most individuals consume and synthesize more vitamin D than they require. As most individuals appear to be at risk of obtaining too much vitamin D rather than too little, we suggest that fortification of foods with vitamin D should be curtailed, preferably abolished, that excessive fortification of animal foods be reduced to the level required, and that the use of dietary supplements be restricted. Populations at risk could be monitored closely and counseled to prevent vitamin D deficiency. [38]

      A comprehensive review of observational studies and randomized clinical trials of vitamin-D status and health outcomes, published online December 2013 in Lancet Diabetes & Endocrinology, concluded that low concentrations of 25(OH)D are most likely an effect of health disorders and not a cause of illness. [39] Commenting on the findings in a press statement, Autier [24] explained that the observed discrepancy between observational and randomized trials suggests “that decreases in vitamin D levels are a marker of deteriorating health.” He added: “Ageing and inflammatory processes involved in disease occurrence and clinical course reduce vitamin D concentrations, which would explain why vitamin D deficiency is reported in a wide range of disorders.” The authors speculate that a key mechanism that causes lower 25(OH)D concentrations in people with illness is disease-related inflammation. “[W]e postulate that inflammation is the common factor between most non-skeletal health disorders and low 25(OH)D concentrations,” they write. “Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin-D status is reported in a wide range of disorders,” they state. “However, increases in 25(OH)D have no effect on inflammatory processes or on disorders at the origin of these processes.” They add that ongoing trials will provide more information, but in the meantime they advise against vitamin-D supplementation. A 2014 meta-analysis on the effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes concluded that vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. The authors stated that future trials with similar designs are unlikely to alter these conclusions. [40] In their 2014 analysis of vitamin D studies, Theodoratou et al. [41] concluded, “Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable”. In a second 2014 analysis also published in the BMJ, Chowdry et al. [42] noted that “in all randomized controlled trials combined, vitamin-D supplementation, when given alone, did not reduce overall mortality significantly among older adults.” In a BMJ editorial commenting on these papers, Dr. Helen Macdonald, PhD, professor of nutrition and musculoskeletal health at the University of Aberdeen, Scotland, and advisor to the United Kingdom’s National Osteoporosis Society (NOS) emphasized that she believed that 25(OH)D might not be the best marker for research anymore. She stated, “It used to be great for finding those who were deficient, but now that the deficiency threshold keeps moving upward and supplementation doses are much higher, other metabolites might be more important.”

      The IOM has shifted the paradigm from thinking about ‘more is better’ to a more risk-averse approach. [43] It has also challenged the notion that harm should be viewed in terms of vitamin D toxicity such as hypercalcemia, hypercalciuria, or metastatic calcification. It has advanced the concept of ‘harm’ in terms of chronic disease outcomes and mortality. [44] Because adverse effects of vitamin D supplementation may take decades to be realized, clinicians (mindful of the medical ethics precept “First, do no harm”) should err on the side of caution; follow the IOM guideline and wait for the results of long-term vitamin D studies.

      Blaney et al. [45] found elevated 1,25-dihydroxyvitamin-D in 85% of a cohort of 100 patients with autoimmune diseases without hypercalcemia. This provides evidence for unregulated production of extrarenal production which is, theoretically, stimulated by intracellular bacteria.

      in silico molecular modeling found evidence that angiotensin receptor blockers (ARBs) modulate the activation of the vitamin D receptor (VDR). In particular, the ARB olmesartan medoxomil (brand name Benicar®) was estimated to have a Ki value in the low nanomolar range, similar to the Ki values of the natural ligands. [46] In the clinical setting, olmesartan is being used off-label as a novel VDR ligand and it appears to function as a VDR agonist. [47] In patients with autoimmune and inflammatory disorders, olmesartan is noted to provoke inflammatory symptoms that suggest the expression of endogenous antimicrobials under VDR control. Olmesartan is the only ARB shown to lower angiotensin II (a peptide that’s implicated in the inflammatory process). [48] Data support the hypothesis that RAS is key mediator of inflammation. [49] The endogenous VDR ligand 1,25(OH)2D has a similar anti-inflammatory effect in that it represses renin gene expression to down-regulate the renin-angiotensin-aldosterone system (RAAS) and reduce inflammation via the Nuclear Factor-kappa ß (NFk-ß) pathway. [50] VDR and RAAS receptors are distributed in almost the same tissues. Shao et al. [51] found a link between RAAS activity and activation of the VDR:

      …the inappropriate stimulation of the RAS has been associated with the pathogenesis of hypertension, heart attack, stroke, and hypertrophy of both the left ventricle and vascular smooth muscle cells. Changes in RAS activity and activation of VDR seem to be inversely related, making it possible to speculate that both systems could have a feedback relationship. [The researchers conclude] the combination of RAS blockade and VDR stimulation appears to be more effective than each one used individually.

      This is what olmesartan appears to accomplish (blocking angiotensin II and stimulating the VDR) and is consistent with a theory of VDR incompetence. Hajishengallis et al. [52] concluded that a blockade of hijacked receptors may offer promising options to control infection and associated immunopathology. Although this use of olmesartan is off-label, its safety profile is well established. [53] The multiple beneficial effects of olmesartan, including the ability to correct imbalance in Th subsets, to treat cardiovascular and kidney disease, prevent migraines, and ameliorate ischemic cerebral brain damage, suggest it could play a key role in the resolution of chronic systemic inflammation. [54-58]

      Disclosure:
      Neither Meg Mangin, RN nor Chronic Illness Recovery has any financial arrangements or affiliations with a commercial entity.

      References

      1. Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflamm Res. Oct 2014;63(10):803-19.
      2. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C.: National Academy of Sciences; 2010. 0-309-16394-3.
      3. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab. Apr 2012;97(4):1153-8.
      4. Rosen CJ, Abrams SA, Aloia JF, et al. IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab. Apr 2012;97(4):1146-52.
      5. McKenna MJ, Murray BF. Vitamin D dose response is underestimated by Endocrine Society’s Clinical Practice Guideline. Endocr Connect. Apr 2013(2(2)):87-95.
      6. For health professionals: Position statement on supplementation, blood levels and sun exposure Vitamin D Council. Vitamin D Council. Jan 12, 2010. Available at: http://www.vitamindcouncil.org/further-topics/for-health-professionals-position-statement-on-supplementation-blood-levels-and-sun-exposure/.
      7. Lichtenfeld L. Maybe Vitamin D Isn’t The Answer After All. American Cancer Society. Oct 30, 2007. http://www.cancer.org/.
      8. Brown JE. Nutrition through the life cycle. Belmont, CA: Thomson/Wadsworth; 2008.
      9. Favus MJ. Nutritional and drug-induced rickets and osteomalacia. Primer on the metabolic bone diseases and disorders of mineral metabolism. 6th ed. Washington, D.C.: Rittenhouse; 2006.
      10. Zagar AH, Mithal A, Wanai AI, et al. Pseudovitamin D deficiency rickets—a report from the Indian subcontinent. Postgrad Med J. Jun 2000;76(896):369–72.
      11. Tiosano D, Hochberg Z. Hypophosphatemia: the common denominator of all rickets. J Bone Miner Metab. 2009;27(4):392-401.
      12. Aloia J, Bojadzievski T, Yusupov E, Shahzad G, Pollack S, Mikhail M, Yeh J. The relative influence of calcium intake and vitamin D status on serum parathyroid hormone and bone turnover biomarkers in a double-blind, placebo-controlled parallel group, longitudinal factorial design. J Clin Endocrinol Metab. 2010 Jul;95(7):3216-24.
      13. Rickets. MedlinePlus. Aug 1, 2012. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000344.htm. Accessed May 6, 2013.
      14. Lerch C, Meissner T. Interventions for the prevention of nutritional rickets in term born children. Cochrane Database Syst Rev. Oct 2007;(4):CD006164.
      15. Pettifor JM, Ross P, Wang J, Moodley G, Couper-Smith J. Rickets in children of rural origin in South Africa: is low dietary calcium a factor? J Pediatr. Feb 1978;92(2):320-4.
      16. Craviari T, Pettifor JM, Thacher TD, Meisner C, Arnaud J, Fischer PR. Rickets: an overview and future directions, with special reference to Bangladesh. A summary of the Rickets Convergence Group meeting, Dhaka, 26-27 January 2006. J Health Popul Nutr. Mar 2008;26(1):112-21.
      17. Oginni LM, Sharp CA, Badru OS, Risteli j, Davie MW, Worsfold M. Radiological and biochemical resolution of nutritional rickets with calcium. Arch Dis Child. Sep 2003;88(9):812-7.
      18. Pettifor JM. Nutritional rickets: deficiency of vitamin D, calcium, or both? Am J Clin Nutr. Dec 2004;80(6 Suppl):1725S-9S.
      19. Nainggolan L. To [Vitamin] D or Not to D? That Is the Question. Medscape Medical News. Apr 29, 2013. Available at: http://www.medscape.com/viewarticle/803275?nlid=30983_1049&src=wnl_edit_dail&uac=67391MX.
      20. Kramer H, Sempos C, Cao G, et al. Mortality rates across 25-hydroxyvitamin D (25[OH]D) levels among adults with and without estimated glomerular filtration rate PLoS One. 2012;7(10):e47458.
      21. Durup D, Jørgensen HL, Christensen J, Schwarz P, Heegaard AM, Lind B. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study. J Clin Endocrinol Metab. Aug 2012;97(8):2644-52.
      22. Dror Y, Giveon S, Hoshen M, Feldhamer I, Balicer F, Feldman B. Vitamin D Levels for Preventing Acute Coronary Syndrome and Mortality: Evidence of a Non-Linear Association. J Clin Endocrinol Metab. Mar 2013.
      23. Dietary Supplement Fact Sheet: Vitamin D. National Institutes of Health. Jan 24, 2011. Available at: http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/?print=1.
      24. Autier, P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. Jan 2014;2(1):76-89
      25. Deardorff J. Vitamin D shows promise; research still lagging. Mar 10, 2010. Available at: http://featuresblogs.chicagotribune.com/features_julieshealthclub/2010/03/vitamin-d-shows-promise.html.
      26. Davis CD, Dwyer JT. The “sunshine vitamin”: benefits beyond bone? J Natl Cancer Inst. Nov 2007;99(21):1563-5.
      27. Tseng L. Controversies in Vitamin D Supplementation. eScholarship. 2003. http://www.escholarship.org/uc/item/4m84d4fn#page-1.
      28. Krook L, Wasserman RH, McEntee K, Brokken TD, Teigland MB. Cestrum diurnum poisoning in Florida cattle. Cornell Vet. Oct 1975(65(4)):557-75.
      29. Boland RL. Solanum malacoxylon: a toxic plant which affects animal calcium metabolism. Biomed Environ Sci. Dec 1988;1(4):414-23.
      30. DeLuca HF, Prahl JM, Plum LA. 1,25-Dihydroxyvitamin D is not responsible for toxicity caused by vitamin D or 25-hydroxyvitamin D. Arch Biochem Biophys. Jan 2011;505(2):226-30.
      31. Vitamin D Overview. University of Maryland Medical Center. 2011. Available at: http://www.umm.edu/altmed/articles/vitamin-d-000340.htm. Accessed May 8, 2013.
      32. Holick MF. Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr. Mar 1995;61(3 Suppl):638S-645S.
      33. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. May 1999;69(5):842-56.
      34. Amer M, Qayyum R. Relation between serum 25-hydroxyvitamin D and C-reactive protein in asymptomatic adults (from the continuous National Health and Nutrition Examination Survey 2001 to 2006). Am J Cardiol. Jan 2012;109(2):226-30.
      35. Neuhouser ML, Manson JE, Millen A, et al. The influence of health and lifestyle characteristics on the relation of serum 25-hydroxyvitamin D with risk of colorectal and breast cancer in postmenopausal women. Am J Epidemiol. Apr 2012;175(7):673-84.
      36. Olsen A, Egeberg R, Tjønneland A. Re: Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer. Journal of the National Cancer Institute. May 6, 2009. http://jnci.oxfordjournals.org/content/early/2009/04/28/jnci.djp065.full.
      37. Glade MJ. Vitamin D: health panacea or false prophet? Nutrition. Jan 2013;29(1):37-41.
      38. Holmes RP, Kummerow FA. The relationship of adequate and excessive intake of vitamin D to health and disease. J Am Coll Nutr. 1983;2(2):173-99.
      39. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. Jan 2014;2(1):76-89.
      40. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. The Lancet Diabetes & Endocrinology. May 2014.
      41. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMG. Apr 2014;348:g2035.
      42. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. Apr 2014;348:g190.
      43. Ross AC, Manson JE, Abrams SA, et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know. J Clin Endocrinol Metab. Jan 2011;96(1):53–58.
      44. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C.: National Academy of Sciences; 2010. 0-309-16394-3.
      45. Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci. Sep 209;1173:384-90.
      46. Marshall TG, Lee RE, Marshall FE. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor Biol Med Model. Jan 2006;3:1.
      47. Proal AD, Albert PJ, Marshall TG, Blaney GP, Lindseth LA. Immunostimulation in the treatment for chronic fatigue syndrome/myalgic encephalomyelitis. Immunol Res. Apr 2013;[published online ahead of print April 11, 2013].
      48. Ichikawa S, Takayama Y. Long-term effects of olmesartan, an Ang II receptor antagonist, on blood pressure and the renin-angiotensin-aldosterone system in hypertensive patients. Hypertens Res. Nov 2001(24(6)):641-6.
      49. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol. Jun 2003;35(6):881-900.
      50. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. Jul 2002;110(2):229-38.
      51. Ferder M, Inserra F, Manucha W, Ferder L. The world pandemic of Vitamin D deficit could possibly be explained by cellular inflammatory response activity induced by the renin angiotensin system. Am J Physiol Cell Physiol. Jan 2013;[Epub ahead of print].
      52. Hajishengallis G, Lambris JD. Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol. Mar 2011(11(3)):187-200.
      53. Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol. May 2001(41(5)):515-527.
      54. Shao J1, Nangaku M, Miyata T, et al. Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury. Hypertension. Jul 2003;42(1):31-8.
      55. Ferrario C. Effect of angiotensin receptor blockade on endothelial function: focus on olmesartan medoxomil. Vasc Health Risk Manag. 2009;5(1):301-14.
      56. Yanagi M, Tamura K, Fujikawa T, et al. The angiotensin II type 1 receptor blocker olmesartan preferentially improves nocturnal hypertension and proteinuria in chronic kidney disease. Hypertens Res. Mar 2013;36(3):262-9.
      57. 4Charles LA, Jotkowitz S, Byrd LH. Prevention of migraine with olmesartan in patients with hypertension/prehypertension. Headache. Mar 1996;46(3):503-7.
      58. Takizawa S, Dan T, Uesugi T, et al. A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage. J Cereb Blood Flow Metab. Oct 2009;29(10):1665-72.

  • Anna Churchill

    Regarding getting Vitamin D from sunlight, I have heard that the sunlight reacts with skin oils which are then absorbed back into the body over a few days. Therefore showering or washing the area removes the oil and the vitamin D is not absorbed. Do you know if this is true?

  • Jennifer

    This is the first time I have seen this information outside of deep in a medical paper, or from highly specific research, about the relationship of D1,25 (v) vs d25 ( inactive, dietary) Vitamin D, and the dangers associated with a blanket assumption that low levels of d25 ( inactive, dietary) D automatically means to take D supplements.

    The granuloma diseases, one of which is Sarcoidosis, cause this exact scenario and for medial professionals to suggest supplements to a patient with low dietary D without testing for the reasons behind it ( such as the levels of d1,25 and calcium) is highly negligent. A person with a granuloma disease is harmed by dietary supplements and an inactive phase of the disease can be pushed into an active phase with increased dietary D.

    The body goes into protective mode if the calcium is too high. A PTH growth/problem can cause the calcium to rise, which in turn can cause the inactive D to lower. A patient with a granuloma disease can have high active d 1,25 because the granulomas produce this hormone. Again, the body goes into protective mode against high calcium ( high calcium is very dangerous) resulting in the lowered inactive D,25.

    I am not a medical professional, but I studied sarcoidosis and came across the not very well known, Marshall protocol. ( I see the author is listed in the list of research papers below) This was when I began understanding the link to bacteria and the danger of increasing dietary D in persons with a granuloma disease. But, this took me years of research. That is not acceptable. A medical professional should have some knowledge of this. Dr who is responsible for the published research of the wonders of health benefits of dietary d,25, had in his paper, buried within a paragraph, a couple of sentences addressing granuloma diseases and the danger of it. My research found a Dr in a city two hours away that was an expert in the disease, and he knew the link and immediately recommended stopping any d supplements. This was almost 10 years ago.

    I’m so glad to see this posted on Facebook. This needs to be more well known, since many medical professionals do not understand the relationship between the forms of D, and calcium, and the PTH. Many people with parathyroid tumors, and granuloma diseases can suffer needlessly when medical professionals that don’t understand this relationship correctly miss very important causes of the patients problems. Sometimes it is the patient that must take the responsibility and do research to ask the Dr to consider tests outside their norm. tests that could be highly important to the patient. Thankfully, the internet has been a highly valuable tool for patients that learn how to filter information, and balance information with the medical professional.

  • grant

    I was experiencing a constellation of symptoms of inflammatory disease but docs of various specialties were treating them as unrelated conditions. I asked for both vit.D tests and doc phoned to tell me they were normal. But I saw that the RATIO between the two was out of line. My body was making too much 1.25D compared to the level of 25D. Which has to raise the question, where is the extra coming from?

    Long-story-short, over the past decade of inflammation therapy I am healthier and feeling better than ever. No joint pains, NO nasal congestion and headaches, NO achy muscles, NO stabbing shoulder pains, NO distrubted sleep, NO snoring, NO C-pap, NO extra-sensitivity to sunlight, Weight reducing to normal (gradually took off 30 lbs), Normal chest X-ray, and a stable (no significance) RBBB.

    Inflammation therapy reversed a slow downward spiral and made it a slow UPWARD spiral and gave me my life back. Thanks to all those researchers and early adopters and open-minded doctors who made this possible.

  • Darlene Turner

    This is the best article I have read about Vitamin D. Most are too hard to understand! I am fortunate to have a doctor who understands, does not prescribe Vit. D and has worked with me for 6+ years to resolve my chronic inflammation. I feel better than I have in many, many years! Thank you Chronic Illness Recovery for all you do!

  • Meg Mangin, RN

    Anna,

    I’m not aware of any scientific evidence that removing skin oils prevents production of vitamin D3 following exposure to natural light. Do you have a reference you can refer me to? Photosynthesis is a complex process but humans appear to have evolved to efficiently produce vitamin D when sunlight is available and to store it when sunlight is not available.

  • Ann

    THANK YOU for this post. I have been researching low vitamin d, supplementation, autoimmune disease, demineralization, and parathyroid imbalance in depth for over a month now, and I had not yet come across this information or the articles cited. It has been over a year since things started to go awry, and my health care providers simply aren’t cutting it. Each one is interested in making one number change, and all of them are missing the overall picture. I don’t know how the thoughts contained herein may or may not fit into that picture, but I appreciate hearing another way to look at the incredibly complicated interactions involving vit d…especially for those who are working with long term issues. I appreciate learning about some new leads to investigate. Thank you Louise, Kelly, and Ms. Mangin.

  • Profile photo of admin2
    admin2

    Q: Ok, so bottom line this for me. How much vitamin D should I take?

    A: Disclaimer first: I’m not a doctor and this is not medical advice. Please research this issue and discuss it with a likeminded professional who’s familiar with your personal history and committed to staying up-to-date on this complex and important topic. With that said, this is what I’ve learned so far:

    1. Vitamin D deficiency is pervasive and people are suffering because of it. It’s tied to chronic and autoimmune diseases. Rickets remains a public health problem, even in the U.S..

    2. Sufficient UVB exposure (sunshine) is the best way for your body to make the D it needs.

    3. Even with lots of sun exposure, not all people can make enough D. Those who should pay extra attention are:

    * people with darker colored skin
    * the elderly
    * people who use sunscreen (8 SPF reduces D production by 95%)
    * those who live in latitudes around 40° north and 40° south from Nov-Mar (New Jersey is 40° north).

    4. Long-term high dose supplementation of vitamin D has not been proven beneficial or safe as a routine treatment. It can cause adverse effects. In animal studies, vitamin D supplementation (in doses that weren’t even that high) caused atherosclerosis.

    5. The ideal target level of 25(OH)D has been evolving and might be less than we have been thinking. There seems to be growing agreement for 40-ish ng/ml vs 60 to 80. This may not apply to your personal situation.

    Resources:

    * Nutritional Medicine by Alan Gaby, MD (2011) and youtube video clip
    * Linus Pauling Institute – Micronutrient Information Center (updated 2011)
    * Vitamin D as an accelerator of atherosclerotic calcification: Diabetologia. Dec 2010; 53(12): 2688.
    * Vitamin D: More May Not Be Better – Johns Hopkins (2013)

    • Meg Mangin

      In order to decide whether or not to take a vitamin D supplement, a little background information is helpful. Chemically, vitamin D is a steroid that functions as a hormone. Hormones are chemical messengers secreted by cells or glands. These messengers are sent out from one part of the body to affect cells in other parts of the body. Hormone signals play a major role in the control and regulation of the body’s internal environment. The active form of vitamin D (calcitriol) is the most potent steroid hormone in the human body. Calcitriol binds to the vitamin D receptor and mediates many biological effects. Classical effects include calcium transport and bone health. Non-classical, genomic effects include cell differentiation and immune system regulation.

      When a hormonal deficiency is diagnosed, your doctor may order a supplement. Insulin, testosterone, estrogen and thyroxine are examples of other hormones that are commonly supplemented. Vitamin D deficiency is diagnosed by assessing the level of the inactive form (calcidiol). The only function of calcidiol is to serve as the precursor to the active form. It is presumed that calcidiol reflects the level of the active hormone. In other words, if calcidiol is low then calcitriol must be low too. But in people with chronic illnesses, the level of calcidiol may be low while the level of calcitriol is elevated. It’s important to know if the active form is abnormally high because this indicates systemic inflammation which is thought to be a cause of many chronic diseases.

      Vitamin D supplementation increases the level of both the inactive and active forms of vitamin D. Increasing the level of calcidiol sometimes makes people with a chronic disease feel better. This is because calcidiol suppresses the immune system when the level is high. Calcidiol is converted to calcitriol which also suppresses the immune system when it is elevated. However, this effect is usually short-lived because suppressing the immune system may allow an underlying disease process (intracellular infection) to persist. Tissue damage, due to persist inflammation, continues and inflammatory symptoms eventually return.

      This is the probable reason why preventive studies of vitamin D supplementation have failed to show any significant benefit. The Institute of Medicine has shifted from thinking ‘more vitamin D is better’ to a more risk-averse approach. Because adverse effects of vitamin D supplementation may take decades to be realized, doctors and patients should err on the side of caution.

      In summary, it’s essential to assess both the inactive and active form of vitamin D to determine if vitamin D supplementation is necessary. If calcidiol is low but the active hormone is normal or high, then one should not be considered vitamin D deficient.

      References:

      DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. Dec 2004;80(6 Suppl):1689S-96S.

      Holick M, Schnoes H, Deluca H, Suda T, Cousins R. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochem. Jul 1971;10(14):2799-804.
      Sutton A, MacDonald P. Vitamin D: more than a “bone-a-fide” hormone. Mol Endocrinol. May 2003;17(5):777-91.

      Norman A. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology. Dec 2006;147(12):5542-8.

      Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci. Sep 209;1173:384-90.

      Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis. Sep 2007;66(9):1137-42.

      Zhang Y, Leung DY, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol. Mar 2012;188(5):2127-35.

      Lemire J. 1,25-Dihydroxyvitamin D3–a hormone with immunomodulatory properties. Z Rheumatol. 2000;59 Suppl 1:24-7.

      Onwuamaegbu ME, Belcher RA, Soare C. Cell wall-deficient bacteria as a cause of infections: a review of the clinical significance. J Int Med Res. Jan-Feb 2005;33(1):1-20.

      Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. The Lancet Diabetes & Endocrinology. May 2014.

      Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. Apr 2014;348:g2035.

      Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. Apr 2014;348:g190.

      Ross AC, Manson JE, Abrams SA, et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know. J Clin Endocrinol Metab. Jan 2011;96(1):53–58.

  • Meg Mangin

    Louise,

    You’ve mentioned several common misconceptions about vitamin D photosynthesis. These beliefs are often cited as reasons to take a vitamin D supplement.

    The concern about dark skin and vitamin D deficiency appears to be misplaced. In 2010, researchers at the Department of Dermatology in Copenhagen, Denmark measured the baseline serum calcidiol and total cholesterol levels of 182 fair-skinned and dark-skinned subjects; and studied the effect of ultraviolet radiation on their calcidiol levels. They found the amount of calcidiol produced was determined by the amount of cholesterol in the skin, not on skin pigmentation. Matsuoka et al. concluded that while racial pigmentation has a photo-protective effect, it does not prevent the generation of normal levels of active vitamin D metabolites. Most importantly, skin pigmentation doesn’t negatively affect vitamin D status. Persons with dark skin compensate for low calcidiol by rapidly converting it to the active vitamin D metabolite, thus allowing them to maintain adequate vitamin D status. For details and references, please see Vitamin D and Skin Pigmentation. https://www.chronicillnessrecovery.org/index.php?option=com_content&view=article&id=297%3Avitamin-d-photosynthesis-and-skin-pigmentation&catid=1%3Ageneral&Itemid=5

    As the skin ages, there is a decline in the cutaneous levels of 7-dehydrocholesterol, resulting in a marked reduction of the skin’s capacity to produce vitamin D3. However, Vanderschueren et al. concluded that renal capacity to synthesize calcitriol, in addition to calcidiol production in the skin in response to sunlight, may be relatively well conserved, even in elderly community-dwelling men. Despite the up to fourfold reduction in vitamin D3 production in a 70-year-old compared to a 20-year-old, the skin has such a high capacity to make vitamin D3, elders exposed to sunlight will produce an adequate amount of vitamin D3 to satisfy their vitamin D requirement.

    References

    MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. Oct 1985;76(4):1536-8.

    Vanderschueren D, Pye SR, O’Neill TW, et al. Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European Male Aging Study (EMAS). J Clin Endocrinol Metab. Mar 2013;98(3):995-1005.

    Chuck A, Todd J, Diffey B. Subliminal ultraviolet-B irradiation for the prevention of vitamin D deficiency in the elderly: a feasibility study. Photodermatol Photoimmunol Photomed. Aug 2001;17(4):168-71.

    Chel VG, Ooms ME, Popp-Snijders C, et al. Ultraviolet irradiation corrects vitamin D deficiency and suppresses secondary hyperparathyroidism in the elderly. J Bone Miner Res. Aug 1998;13(8):1238-42.

    The belief that sunscreen lotion blocks vitamin D production is based on a 1987 study funded by the ultraviolet foundation, which is supported by the tanning bed industry. Contradictory information was provided by a 2010 study which concluded that although sunscreens are effective, many may not actually be blocking UV-B rays because they are improperly or inadequately applied. Thus, sunscreen use may not actually diminish vitamin D synthesis in real world use. Although dermatologists express concern about UV radiation leading to skin cancer, the amount of sun exposure required to produce adequate vitamin D is unlikely to damage skin cells. For details and references, please see Vitamin D, Clothing and Sunscreens.
    https://www.chronicillnessrecovery.org/index.php?option=com_content&view=article&id=299%3Avitamin-d-photosynthesis-clothing-and-sunscreen&catid=1%3Ageneral&Itemid=5

    An early study done in Boston and Canada is often cited to support the conviction that latitude dramatically influences the amount of solar radiation available to synthesize vitamin D3. However, authorities who conducted recent studies refute this hypothesis. Blaney et al. found that vitamin D deficiency was not as common as speculated in Canadian adults living in the Pacific Northwest and was not found in the majority of patients with diseases previously associated with vitamin D deficiency. Kimlin concluded, “It may no longer be correct to assume that vitamin D levels in populations follow latitude gradients.” And Lubin stated, “Geophysical surveys have shown that UV-B penetration over 24 hours, during the summer months at Canadian north latitudes when there are many hours of sunlight, equals or exceeds UV-B penetration at the equator.”

    In addition, our bodies have mechanisms for preserving the vitamin D we acquire during the summer; which have evolved to stabilize and maintain serum levels of calcidiol in environments with variable vitamin D availability. The D binding protein (DBP) optimizes and stores calcidiol for later use; it also binds calcitriol, as well as the parental vitamin D itself. DBP sequesters vitamin D sterols in the serum, prolongs their serum half-lives, and provides a circulating store of vitamin D to meet transient periods of deficiency. A review by Ross et al. reports that ample opportunities exist to form vitamin D (and store it in the liver and fat) from exposure to sunlight during the spring, summer, and fall months even in the far north latitudes.

    References

    Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. Clin Endocrinol Metab. Aug 1988;67(2):373-8.

    Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci. Sep 209;1173:384-90.

    Kimlin MG, Olds WJ, Moore MR. Location and vitamin D synthesis: is the hypothesis validated by geophysical data? J Photochem Photobiol B. Mar 2007;86(3):234-9.

    Lubin D, Jensen EH, Gies HP. Global surface ultraviolet radiation climatology from TOMS and ERBE data. J Geo Res. 1998;103(D20):26061-91.

    Berg J. Vitamin D-binding protein prevents vitamin D deficiency and presents vitamin D for its renal activation. Eur J Endocrinol. Oct 1999;1(4):321-2.

    Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C.: National Academy of Sciences; 2010. 0-309-16394-3.

  • kelly fincher

    it’s hard to watch the autism community endorsing vitamin D…unless they mean to be using it for immune suppression I wouldn’t think you’d want to hamper antimicrobial peptide production or increase inflammation and hormone dysregulation (thyroid is especially affected)…four physicians prescribed my sons high-dose vitamin D and they became much sicker…i urge physicians, clinicians, and the public to be very cautious with this hormone from personal experience…get some sunshine but interestingly chronic disease sometimes makes you very light sensitive with one son having debilitating headaches and the other said the sun hurt his skin and loved cloudy weather…I’m grateful for Meg’s tireless unpaid full-time job to educate this important part of our immune system…and read labels, vit. D is in many drinks/foods…oh what a metabolic epigenetic costly mess this toxic world has given us…22 years and counting…

  • Alison

    But isn’t there a huge difference between high-dose vitamin D (which is usually in the form of ergocalciferol) and OTC cholecalciferol supplements? And aren’t most of the calcium-supplemented foods supplemented with D2 rather than D3?

    I think there must be a lot that remains unknown or not completely understood.

    And what about the elevated rates of autoimmune disorders in regions considered to be highest in vitamin D-deficiency rates, like the Pacific Northwest, the UK, etc?

    • Meg Mangin, RN

      Allison,

      Ergocalciferol is the chemical name of vitamin D2, the form of vitamin D formed by the action of ultraviolet light on ergosterol in plants. A 2011 clinical guideline considered vitamin D2 to be as effective at raising serum calcidiol as vitamin D3 (cholecalciferol) which is produced naturally by the skin when exposed to ultraviolet light. Conflicting evidence exists for how similarly D2 and D3 behave in the body and whether they are equally active or efficient in production of 1,25-hydroxyvitamin D (calcitriol), the active hormone. This is another reason to check both calcidiol and calcitriol levels to assess vitamin D status.

      Most vitamin D studies are observational; few are randomized or well-controlled. And very few assess the active form of vitamin D which is often found to be elevated in autoimmune diseases. No biological plausibility is given to explain study conclusions and often the evidence is ambiguous. Con-founding variables (e.g., health consciousness, sick people remain indoors, access to medical care, etc.) are often not taken into account. The studies only show a link between low calcidiol and illness; researchers and clinicians understand that correlation does not infer causation. In a widely studied example, numerous observational studies showed that women who were taking hormone replacement therapy (HRT) also had a lower-than-average incidence of coronary heart disease (CHD), leading doctors to propose that HRT was protective against CHD. But randomized controlled trials showed that HRT caused a small but statistically significant increase in risk of CHD. Re-analysis of the data from the epidemiological studies showed that women undertaking HRT were more likely to be from higher socio-economic groups, with better-than-average diet and exercise regimens. The use of HRT and decreased incidence of coronary heart disease were coincident effects of a common cause (i.e. the benefits associated with a higher socioeconomic status), rather than cause and effect, as had been supposed.

      References

      Holick, M. F., et al. (2011). “Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline”. Journal of Clinical Endocrinology & Metabolism 96 (7): 1911–1930.

      Abreu MT, Kantorovich V, Vasiliauskas EA, et al. Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn’s disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut. Aug 2004;53(8):1129-36.

      Mawer EB, Hayes ME, Still PE, et al. Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res. Jul 1991;6(7):733-9.

      Aldrich J. Correlations Genuine and Spurious in Pearson and Yule. Stat Scien. 1995;10(4):364-76.

      Lawler DA, Davey SG, Ebrahim S. Commentary: the hormone replacement-coronary heart disease conundrum: is this the death of observational epidemiology? Int J Epidemiol. Jun 2004;33(3):464-7.

  • kelly fincher

    Stanford’s Dr. Ioannidis says “evidence of a clear role of vitamin D (supplements) does not exist for any outcome”
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972415/

  • kelly fincher

    dig for conflicts of interest! vitamin d council’s John Cannell sells supplements…of course they & their commercial sponsors & studies they fund will recommend vitamin d

  • kelly fincher

    Vitamin D Council proves our point:
    It is the most important hormone in our body but NO study has proven D supplements cure disease.
    We say err on the side of caution with this potent hormone, immune-suppressing in high doses.
    It should be a red flag to the public when someone is selling the product they endorse.
    https://www.vitamindcouncil.org/health-conditions/
    There are no reported studies on the benefits of vitamin D for acne.
    There haven’t been many good quality experiments that would be able to show clearly whether low vitamin D levels cause Alzheimer’s disease.
    There are no reported studies indicating that vitamin D may be used to treat allergies or anaphylaxis.
    There are no reported studies of vitamin D preventing anemia.
    There is some research that shows that vitamin D can reduce the number of asthma attacks for children with asthma. It’s currently unknown if vitamin D can reduce the number of asthma attacks for adults, too. At this time, it is also unknown if vitamin D can improve the airways of people with asthma.
    These and other findings do not prove that vitamin D reduces the risk of autism.
    Researchers can’t say for sure whether low vitamin D levels cause breast cancer or lead to worse outcomes, and therefore whether or not vitamin D can help to prevent or treat breast cancer.
    Etc.

    • david ayoub, MD

      Here is my favorite musculoskeletal paper though because they reported: “Follow-up assessment confirmed the remarkable recovery of their muscle strength and resolution of their other musculoskeletal symptoms within three months….After many months of disability, wheelchair bound patients were ambulating independently.”

      I call this the tent revival study!

      Severe proximal myopathy with remarkable recovery after vitamin D treatment.
      Al-Said YA1, Al-Rached HS, Al-Qahtani HA, Jan MM.Can J Neurol Sci. 2009 May;36(3):336-9.

      Abstract
      BACKGROUND:
      Osteomalacia is an uncommon cause of muscle weakness. Our objectives were to describe features of myopathy associated with Vitamin D deficiency and examine the contributing factors leading to osteomalacic myopathy in our region.
      METHODS:
      Patients identified retrospectively for the six year period ending in December 2006 with the diagnosis of osteomalacia and/or Vitamin D deficiency associated proximal muscle weakness were included. They were followed in three major centers in western Saudi Arabia. Clinical, biochemical, radiological, and electrophysiological findings were collected before and after Vitamin D treatment by chart review.
      RESULTS:
      Forty seven female patients aged 13-46 years (mean 23.5, SD 4.5) were included. All were veiled and covered heavily when outside the house for social and cultural reasons. Only eight (17%) had adequate varied diet with daily milk ingestion. All patients presented with progressive proximal muscle weakness lasting 6-24 months (mean 14) prior to our evaluation. The weakness was severe in six (13%) patients leading to wheel chair bound states. Associated musculoskeletal pain involving the back, hips, or lower limbs was common (66%). Osteomalcia was the referral diagnosis in only 11 patients and the remaining 36 (77%) patients were misdiagnosed. All patients had metabolic and radiological profiles suggestive of osteomalacia. Remarkable recovery was documented in all patients following oral cholecalciferol and calcium supplementation.
      CONCLUSIONS:
      Vitamin D deficiency is an important treatable cause of osteomalacic myopathy in Saudi Arabia. The diagnosis is frequently delayed or missed. Screening for Vitamin D deficiency in patients with acquired myopathy is needed to identify this treatable disorder.

      I can personally attest to this, I have seen even dysphagia in elderly resolve with Vitamin D repletion.

      re Alzheimer’s and cognitive function, these abstracts can be found on Pubmed.com

      -Vitamin D deficiency predicts cognitive decline in older men and women: The Pro.V.A. Study. Toffanello ED, Coin A, Perissinotto E, Zambon S, Sarti S, Veronese N, De Rui M, Bolzetta F, Corti MC, Crepaldi G, Manzato E, Sergi G. Neurology. 2014 Nov 5.

      -Lower vitamin d is associated with white matter hyperintensity in elderly women with Alzheimer’s disease and amnestic mild cognitive impairment. Sakurai T, Ogama N, Toba K. J Am Geriatr Soc. 2014 Oct;62(10):1993-4

      -Vitamin D Levels and Cognition in Elderly Adults in China. Chei CL, Raman P, Yin ZX, Shi XM, Zeng Y, Matchar DB. J Am Geriatr Soc. 2014

      Readers interested in a review paper, I would suggest this recent one:

      J Intern Med. 2014 Jul 3. doi: 10.1111/joim.12279. [Epub ahead of print] ‘Vitamin D and cognition in older adults’: updated international recommendations. Annweiler C1, Dursun E, Féron F, Gezen-Ak D, Kalueff AV, Littlejohns T, Llewellyn DJ, Millet P, Scott T, Tucker KL, Yilmazer S, Beauchet O.

      BACKGROUND:
      Hypovitaminosis D, a condition that is highly prevalent in older adults aged 65 years and above, is associated with brain changes and dementia. Given the rapidly accumulating and complex contribution of the literature in the field of vitamin D and cognition, clear guidance is needed for researchers and clinicians.
      METHODS:
      International experts met at an invitational summit on ‘Vitamin D and Cognition in Older Adults’. Based on previous reports and expert opinion, the task force focused on key questions relating to the role of vitamin D in Alzheimer’s disease and related disorders. Each question was discussed and voted using a Delphi-like approach.
      RESULTS:
      The experts reached an agreement that hypovitaminosis D increases the risk of cognitive decline and dementia in older adults and may alter the clinical presentation as a consequence of related comorbidities; however, at present, vitamin D level should not be used as a diagnostic or prognostic biomarker of Alzheimer’s disease due to lack of specificity and insufficient evidence. This population should be screened for hypovitaminosis D because of its high prevalence and should receive supplementation, if necessary; but this advice was not specific to cognition. During the debate, the possibility of ‘critical periods’ during which vitamin D may have its greatest impact on the brain was addressed; whether hypovitaminosis D influences cognition actively through deleterious effects and/or passively by loss of neuroprotection was also considered.
      CONCLUSIONS:
      The international task force agreed on five overarching principles related to vitamin D and cognition in older adults. Several areas of uncertainty remain, and it will be necessary to revise the proposed recommendations as new findings become available.

      If readers who cannot get the full article, this single paragraph on treatment/prevention is insightful:

      “Vitamin D supplements and cognition: Few intervention studies have been conducted specifically to test the effect of vitamin D supplements on cognitive function. Of interest, observational studies have reported that a higher intake of vitamin D (whether from food, supplements orsun exposure) is associated with better cognitive function in older individuals [27]. For instance, consuming more than 800 IU of vitamin D per day resulted in a fivefold reduction in the risk of AD after 7 years of
      follow-up [52]. This neuroprotective effect has been further confirmed by before–after studies and quasiexperimental studies reporting cognitive improvement
      after vitaminDsupplementation in the general population of seniors [53] as well as in patients who already havesymptomsofADRDs[54]. The cognitive benefits of supplementation appear from 4 weeks [55] and seem to be particularly strong for
      executive function and processing speed [13]. Supraphysiological doses may not be necessary to exert a cognitive effect [54], and consensual supplementation, with the objective to raise the concentration of 25OHD above 30 ng mL1 (i.e., 75 nmol L1), appears to be sufficient [56].”

      Kelly F stated: “There are no reported studies of vitamin D preventing anemia”.
      Well, myelofibrosis is a well known disorder associated with rickets/VDD. Resolution with vitamin D often occurs along with resolution of rickets.

      Here is just one citation: Can Med Assoc J. 1966 Feb 19;94(8):392-5. Reversible myelofibrosis due to vitamin D deficiency rickets. Cooperberg AA, Singer OP.

      There are many studies linking Vitamin D to anemia. Classically in rickets, the anemia is Fe-deficient like. Of course secondary diseases like celiac share both VDD and anemia. Again, go to pubmed, many many papers for example:

      Low vitamin D levels increase anemia risk in Korean women. Shin JY1, Shim JY.Clin Chim Acta. 2013 Jun 5;421:177-80. doi: 10.1016/j.cca.2013.02.025. Epub 2013 Mar 4.

      Kelly F. stated: “It should be a red flag to the public when someone is selling the product they endorse.” response: if someone sells a product they don’t endorse, then this would be a red flag

      Kelly F., again it is very easy to rely on other critics and skeptics, but opinions should be based upon research studies and personal experience. I do not advocate sole reliance on reviews and meta analysis because if performed by a zealous critic or for the benefit of pharma, they can appear very authoritative and damning. I suggest you look deeply under the hood before judgement.

      • Meg Mangin

        Epidemiologic data may impress a naïve audience but it should be viewed as hypothesis-generating rather than definitive. At the 15th European Congress of Endocrinology April 27 – May 1, 2013 in Copenhagen, Denmark, Mark Cooper, M.D., from the University Hospital, Birmingham, UK, a leading expert in the field of vitamin D, noted that the supposed benefits of vitamin D are exclusively reported in observational studies and there is a huge sector of the scientific community which is “evangelical” in its pro–vitamin-D stance. He commented,

        We really need some robust evidence. Physicians have been here before, with many other nutrients that subsequently, in large intervention trials, turned out to have a null effect or even be harmful. In fact, there is already evidence of risks with supplements of vitamin D from randomized clinical trials, with no evidence of benefit. There have been lots of randomized controlled trials, different doses of vitamin D, different groups, all well-designed, all in major journals, and all negative. At least 1 in 20 of these studies should be positive just by chance, but we haven’t seen that yet.

        A growing body of evidence suggests that non-resolving, low-grade inflammation plays an integral part in the development and pathogenesis of many chronic diseases. Vitamin D proponents have failed to recognize the anti-inflammatory
        effect of elevated 25(OH)D in short-term studies of vitamin D supplementation that report resolution of symptoms. Vitamin D supplementation may suppress the immune system and reduce inflammation, clinical disease markers and symptoms of chronic disease but this doesn’t treat the underlying cause and relapse is common. Many patients have contacted me relating stories of feeling better for a while after taking vitamin D only to have symptoms eventually return much worse than before.

        Anemia of chronic disease is one of the most common syndromes in medicine. Chronic diseases of all types may impair hematopoiesis [the formation of blood cells] and lead to mild or moderate anemia, which is called the anemia of chronic disease. Anemia of chronic disease is not due to iron deficiency and will not be helped by iron supplements.

        Nainggolan L. To [Vitamin] D or Not to D? That Is the Question. Medscape Medical News. Apr 29, 2013. http://www.medscape.com/viewarticle/803275

        De Vita F, Lauretani F, Bauer J, et al. Relationship between vitamin D and inflammatory markers in older individuals. Age (Dordr). Aug 2014;36(4):9694.

        Kim HM, Chung MJ, Chung JB. Remission and relapse of autoimmune pancreatitis: focusing on corticosteroid treatment. Pancreas. Jul 2010;39(5):555-60.

        Iron Disorders Institute, Anemic of Chronic Disease. An HONCode website. http://www.irondisorders.org/anemia-of-chronic-disease

  • kelly fincher

    we thought gov health agencies had our best interest but industry bought them…now as Lisa Goes says Parents Do The Work…we trusted, we got burned & we can be burned again by opportunistic therapies preying on our vulnerable state…I’ve done many & spent much money on therapies that were ridiculous in hind sight…but I’ll try about anything when my babes’ health is on the line…and opportunistic folks know this

  • Meg Mangin

    Allison,

    Ergocalciferol is the chemical name of vitamin D2, the form of vitamin D formed by the action of ultraviolet light on ergosterol in plants. A 2011 clinical guideline considered vitamin D2 to be as effective at raising serum calcidiol as vitamin D3 (cholecalciferol) which is produced naturally by our skin when exposed to ultraviolet light. Conflicting evidence exists for how similarly D2 and D3 behave in the body and whether they are equally active or efficient in production of 1,25-hydroxyvitamin D (calcitriol), the active hormone. This is another reason to check both calcidiol and calcitriol levels to assess vitamin D status.

    Most vitamin D studies are observational; few are randomized or well-controlled. And very few assess the active form of vitamin D which is often found to be elevated in autoimmune diseases. No biological plausibility is given to explain study conclusions and often the evidence is ambiguous. Con-founding variables (e.g., health consciousness, sick people remain indoors, access to medical care, etc.) are often not taken into account. The studies only show a link between low calcidiol and illness; researchers and clinicians understand that correlation does not infer causation. In a widely studied example, numerous observational studies showed that women who were taking hormone replacement therapy (HRT) also had a lower-than-average incidence of coronary heart disease (CHD), leading doctors to propose that HRT was protective against CHD. But randomized controlled trials showed that HRT caused a small but statistically significant increase in risk of CHD. Re-analysis of the data from the epidemiological studies showed that women undertaking HRT were more likely to be from higher socio-economic groups, with better-than-average diet and exercise regimens. The use of HRT and decreased incidence of coronary heart disease were coincident effects of a common cause (i.e. the benefits associated with a higher socioeconomic status), rather than cause and effect, as had been supposed.

    References

    Holick, M. F., et al. (2011). “Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline”. Journal of Clinical Endocrinology & Metabolism 96 (7): 1911–1930.

    Abreu MT, Kantorovich V, Vasiliauskas EA, et al. Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn’s disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut. Aug 2004;53(8):1129-36.

    Mawer EB, Hayes ME, Still PE, et al. Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res. Jul 1991;6(7):733-9.

    Aldrich J. Correlations Genuine and Spurious in Pearson and Yule. Stat Scien. 1995;10(4):364-76.

    Lawler DA, Davey SG, Ebrahim S. Commentary: the hormone replacement-coronary heart disease conundrum: is this the death of observational epidemiology? Int J Epidemiol. Jun 2004;33(3):464-7.

    • david ayoub, MD

      The original posting by Meg Magnin was NOT directed at the concern of supplementation of vitamin D deficient autistic patients or those with chronic inflammatory disorders. Perhaps that was her intention, but that was not the clear message most would perceive. Her opinions were directed at the larger, general population, healthy or otherwise, and my original comments were provided in that light. Not that those with complex illnesses shouldn’t deserve individualised treatment-they do. I do not wish to address the perceived controversy of vitamin D repletion in small subsets, but rather the population at large.

      Magnin’s follow-up posts have failed to address one of my main concerns, that of promoting Olmesartin (Benicar) as a Vit D analog, a topic which occupied about 15% of the word count in her original letter. My concerns about data on efficacy and safety remain inadequately addressed. Let me be crystal clear, Magnin stated “Consider Olmesartin”. The lead author (Schwocho) of the 2001 paper Magnin cites as evidence of drug safety worked for Sankyo Pharma Development (the makers of Olmesartin) at the time this research was published. Am I the only one who believe this represents an enormous conflict of interest? Reliance on this 13 year-old study as reassurance of drug safety is disturbing.

      So, what did the Schwocho study actually show? It was a small study comprised of 4 study groups. A total of 104 previously healthy male individuals were dosed with Olmesartin and a small number served as controls receiving placebo. (Why male? I will get to that later). The results:

      – 44% or previously health male subjects receiving the drug showed new, clinically relevant adverse events which the authors dismissed because, well, 40% of healthy male receiving placebo coincidentally showed nearly identical rates of adverse reactions. That placebo had one heck of a kick! (This reminds me of the HPV vaccine trials comparing vaccinated subjects to those receiving an aluminum adjuvant, surprisingly, no difference in outcomes there either. After all, drug companies share from the same bag of tricks). Other adverse events reported in healthy males receiving the drug and seen more commonly in the treatment group were:

      -hypertension (<90mmHg systolic) 18%
      -tachycardia (13%)
      -dizzy 12%
      -asthenia (feeling lousy) 8%
      -musculoskeletal pain-11%

      So why did placebo recipients get so sick? This is the magic that pharma brings to the table! One will have to look closer at the IRB since the paper did not detail exactly what constituted a “placebo” (perhaps they were run-over by a truck). One IRB used according to the paper was Harris Laboratories from Lincoln Nebraska. From their website:

      AgSource Laboratories – Harris, the oldest and most experienced independent soil-testing laboratory, provides a full-range of turf-testing services. AgSource Laboratories – Harris has been conducting testing services for all 50 states and 38 foreign countries since 1958. Attention to quality results and quick turnaround are the reasons that AgSource Laboratories – Harris became the first accredited soil testing laboratory and the first to introduce electronic data transfer over 17 years ago

      Ok, now we know more- the placebo must have been Round-Up! The second IRB approval for this work came from Research Consultants’ Review Committee, now known as SalusIRB in Austin. At least they had a website, but still no University affiliation, and it certainly shows. Their turn-around time after application varied from “same-day” to 48 hours. (clearly not shackled with the red tape delay that accompanies so many medical school IRBs)

      Ok, maybe I am being too harsh on this safety study lead by a researcher whose pension might have depended upon study outcome. Let’s judge the tree by its fruit. Did subsequent (post-2001) studies on Olmesartin confirm drug safety? Since I don’t have time to review all 13 year of research, let’s go back just 2 years. Here are 29 recent papers that warn of a major side effect of this drug:

      [A new spruelike disease as a cause of severe diarrhea]. Halevy D, Teeuwen U, Kohlhof P.
      Dtsch Med Wochenschr. 2014 Nov;139(45):2290-3. doi: 10.1055/s-0034-1387342. Epub 2014 Oct 28.

      Olmesartan-related sprue-like enteropathy. Bhat N, Anupama NK, Yelsangikar A, Vizhi K.
      Indian J Gastroenterol. 2014 Oct 12. [Epub ahead of print]

      Editorial: sprue-like enteropathy due to olmesartan and other angiotensin receptor blockers – the plot thickens. Lebwohl B, Ludvigsson JF.
      Aliment Pharmacol Ther. 2014 Nov;40(10):1245-6. doi: 10.1111/apt.12960.

      Olmesartan-associated enteropathy: results of a national survey. Marthey L, Cadiot G, Seksik P, et al l
      Aliment Pharmacol Ther. 2014 Nov;40(9):1103-9. doi: 10.1111/apt.12937. Epub 2014

      [Enteropathy by olmesartan.] Téllez Villajos L, Crespo Pérez L, Cano Ruiz A, Moreira Vicente V. Med Clin (Barc). 2014 Sep 3. pii: S0025-7753(14)00507-7.

      Spruelike enteropathy related to olmesartán treatment. Trigás-Ferrín M, Ferreira-González L, Gómez-Buela I, Pastor-Rubín-de-Celis E. Rev Clin Esp. 2014 Jul 26. pii: S0014-2565(14)00285-9. doi:

      Olmesartan, other antihypertensives, and chronic diarrhea among patients undergoing endoscopic procedures: a case-control study. Greywoode R, Braunstein ED, Arguelles-Grande C, Green PH, Lebwohl B. Mayo Clin Proc. 2014 Sep;89(9):1239-43. doi: 10.1016/j.mayocp.

      [Sprue-like enteropathy due to olmesartan: A case report.] Agudo Fernández S. Gastroenterol Hepatol. 2014 Jun 20. pii: S0210-5705(14)00164-2. doi: 10.1016/j.gastrohep.2014.05.006. [Epub ahead of print] Spanish.

      "Triple Phase" Budesonide Capsules for the Treatment of Olmesartan-Induced Enteropathy. Hartranft ME, Regal RE.Ann Pharmacother. 2014 Jun 23;48(9):1234-1237. [Epub ahead of print]

      [Enteropathy associated with chronic use of olmesartan.] Téllez A, Pellicé M, Llobell A, Milisenda JC.
      Med Clin (Barc). 2014 Jun 12.
      .
      Olmesartan: sprue-like enteropathy. Prescrire Int. 2014 Apr;23(148):102.

      Severe spruelike enteropathy due to olmesartan. Fiorucci G, Puxeddu E, Colella R, Paolo Reboldi G, Villanacci V, Bassotti G. Rev Esp Enferm Dig. 2014 Feb;106(2):142-4.

      Systematic review: Sprue-like enteropathy associated with olmesartan. Ianiro G, Bibbò S, Montalto M, Ricci R, Gasbarrini A, Cammarota G. Aliment Pharmacol Ther. 2014 Jul;40(1):16-23.

      [Diarrhoea and malabsorption due to olmesartan use]. van Beurden YH, Nijeboer P, Janssen J, Verbeek W, Mulder CJ. Ned Tijdschr Geneeskd. 2014;158:A7370. Dutch.

      Olmesartan associated sprue-like enteropathy and colon perforation. Abdelghany M, Gonzalez L 3rd, Slater J, Begley C. Case Rep Gastrointest Med. 2014;2014:494098.

      A Review of Current Evidence of Olmesartan Medoxomil Mimicking Symptoms of Celiac Disease.
      Sanford ML, Nagel AK. J Pharm Pract. 2014 Mar 28.

      Olmesartan-induced enteropathy resembling celiac disease. Khan AS, Peter S, Wilcox CM. Endoscopy. 2014;46 Suppl 1

      Olmesartan and drug-induced enteropathy. Tran TH, Li H.P T. 2014 Jan;39(1):47-50.

      Comparative effectiveness of olmesartan and other angiotensin receptor blockers in diabetes mellitus: retrospective cohort study. Padwal R, Lin M, Etminan M, Eurich DT. Hypertension. 2014 May;63(5):977-83.

      Five cases of sprue-like enteropathy in patients treated by olmesartan. Théophile H, David XR, Miremont-Salamé G, Haramburu F. Dig Liver Dis. 2014 May;46(5):465-9.

      Chronic diarrhea and weight loss. Gaur V, Albeldawi M, Weber L. Gastroenterology. 2014 Feb;146(2):347,591.

      [Severe enteropathy with villous atrophy olmesartan medoxomil-associated]. Nunge D, Eoche M, Fumery M, Nguyen-Khac E, Gras V, Andréjak M. Therapie. 2013 Nov-Dec;68(6):419-21. doi: 10.2515/therapie/2013057. Epub 2013 Nov 11.

      Angiotensin-II inhibitor (olmesartan)-induced collagenous sprue with resolution following discontinuation of drug. Nielsen JA, Steephen A, Lewin M. World J Gastroenterol. 2013 Oct 28;19(40):6928-30.

      Medication-associated lesions of the GI tract. Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Gastrointest Endosc. 2014 Jan;79(1):140-50.

      Olmesartan-associated sprue-like enteropathy. Stanich PP, Yearsley M, Meyer MM. J Clin Gastroenterol. 2013 Nov-Dec;47(10):894-5.

      Anti-inflammatory and anti-oxidant activities of olmesartan medoxomil ameliorate experimental colitis in rats. Nagib MM, Tadros MG, ElSayed MI, Khalifa AE.
      Toxicol Appl Pharmacol. 2013 Aug 15;271(1):106-13.

      Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma.
      DeGaetani M, Tennyson CA, Lebwohl B, Lewis SK, Abu Daya H, Arguelles-Grande C, Bhagat G, Green PH. Am J Gastroenterol. 2013 May;108(5):647-53.

      Spruelike enteropathy associated with olmesartan: an unusual case of severe diarrhea. Dreifuss SE, Tomizawa Y, Farber NJ, Davison JM, Sohnen AE. Case Rep Gastrointest Med. 2013;2013:618071. doi: 10.1155/2013/618071. Epub 2013 Mar 13.

      Severe spruelike enteropathy associated with olmesartan. Rubio-Tapia A, Herman ML, Ludvigsson JF, Kelly DG, Mangan TF, Wu TT, Murray JA. Mayo Clin Proc. 2012 Aug;87(8):732-8.

      To conclude that this drug has a tract record of safety would be an enormous blind leap of faith and an even greater understatement. It is simply disingenuous for this drug to be offered up on this blog as a safe alternative to sunshine and oral vitamin D3 supplementation. Is there a single study assessing its efficacy and safety as a vitamin D analog? Please do tell! This drug appears to have generated more papers on adverse effects in just 2 years than Vitamin D has in decades of experience. Why were only males evaluated in the Schwocho study? Mothers reading the FearlessParenting blog should certainly be made aware that the Olmesartin package insert warns of fetal toxicity and recommends immediate discontinuation if pregnant, the very group that, above most all others, particularly requires sufficient vitamin D levels. It would be tragic if one pregnant mother were to request this medication as a vitamin D analog from their clinician based upon this blog.

      In conclusion to my concerns of the promotion of Olmesartin as a vitamin D analog, I must firmly disagree with Magnin’s statement that “its safety profile is well established.” It certainly puts in perspective Magnin’s call for better studies on vitamin D supplements. Kettle, meet the pot.

      The second main contention I have is regarding Magnin’s statement: “And studies of disease occurrence have not shown that taking vitamin D supplements to increase calcidiol has a beneficial effect.”

      This is a sweeping conclusion with no citations. It is not based upon a comprehensive review on this subject. Since this is a blog called “Fearless Parent,” and parenting begins in-utero, let’s look at the narrow scope of vitamin D status in pregnancy. One can record health measures in deficient vs. sufficient mothers, or can look at outcomes based upon interventions, i.e., hi-dose supplementation vs placebo or low dose supplementation. Both methods are valid. Treatment studies suffer from the uncertainty of not knowing exactly how long therapy is required in order to overcome the biological results of a chronic deficiency. For example, is three months of supplementation in treatment studies long enough to reverse the mechanisms that result in an increased risk for preterm labor in vitamin D deficient women? No one knows this answer. Treatment studies also suffer from under-dosing and failing to correlate achievable blood levels with intakes. It cannot be assumed that a subject receiving 4,000 IU of D3 daily will actually absorb that and will have higher blood levels than an individual taking 2,000 IU. The uncertainties in VDR and VDBP are among many other factors impossible to control.

      Magnin also states: “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” What? Really? This is an absurd statement. Can subclinical disease exist in deficient individuals? Can cancer, hypertension, diabetes, osteomalacia/rickets exist in apparently healthy subjects? Does an apparently healthy, vitamin D deficient individual have the same long-term health outcome than an apparently healthy, replete one? ! Do you ignore anemia because the patient feels just fine?

      Magnin initially posted that “Supplementing for low vitamin D to increase calcidiol has not shown any clear benefit.” That depends upon your definition of “clear”. You cite a study by Loyola researchers showing “significantly higher mortality rates are noted with 25(OH)D levels less than 12 ng/mL”. Many readers will find this dichotomy confusing. Let’s see, i can wait for a double blind study on death rates vs supplementation OR I can take an inexpensive, safe supplement (or free sunshine) and hope it is not too late to benefit by not dying young. Hmmmm. I think I will get in the long line.

      Much of the conflict in outcomes assessment lies with the perceived significance of prospective repletion trials vs observational studies when health outcomes are correlated with measured vitamin D status. The results of observational studies are impressive over a diverse array of illnesses. Lower vitamin D status correlates with numerous adverse skeletal and non-skeletal conditions. Why then isn’t this enough? Do we really need double blind treatment studies when observational studies are so stunning? The answer is a resounding “No”! In drug intervention studies, groups have to be created and compared, for example- a subject on dose A vs a subject on dose B vs a placebo group. No one in the general population would have blood levels of drug X, so you cannot merely compare health measures with blood levels of drug X in the population. You need a treatment study. With studies assess health outcomes vs measurements of endogenous biologicals (25-hydroxyvitamin D or 25-OHD) whose status depends upon lifestyle exposures (dietary and solar), the general population already provides us with a diverse study group with varying blood levels. Why go to the expense of a double-blinded control study when much of the groups are already created naturally by human diversity? Few other than Pharma can afford to design, fund and perform such studies and thus it is the advocates of pharmacological based treatments that are usually clamouring the loudest for placebo controlled studies.

      That being said, what have observational studies shown us about vitamin D status and health? Let’s narrow the scope to pregnancy since this is posted to a mothering blog: pregnant women! Studies, usually multiple, have demonstrated positive outcomes with higher levels of 25-OHD and lower prevalence of: preeclampsia/hypertension, bacterial vaginosis, prolonged labor, C-section, preterm labor, depression, gingivitis, and maternal weight gain. Fetal and neonatal benefits reported include a variety of fetal measurements (bone length, fontanel size, weight gain), risk of neonatal rickets/hypocalcemia, bone mineralization/strength in offspring, respiratory tract infections, speech development, just to name a few. It is true that controlled studies have not been robust, but there are many reasons for that. First, we simply do not know how long a chronic deficiency needs to be reversed before a positive affect is seen. How long must mother be replete before there is a significant reduction in preterm labor risk? Three months? Three years? Secondly, defining treatment groups by administered dose dose not guarantee that this is the absorbed dose or the functional dose. Do dosing classes differ enough to see a measured benefit?

      Let me give you an example of the problematic interpretations of vitamin D and health. Since this is a mom friendly blog, lets look at something we all as parents fear: severe respiratory illness

      Vitamin D deficiency in young children with severe acute lower respiratory infection. McNally JD1, Leis K, Matheson LA, Karuananyake C, Sankaran K, Rosenberg AM. Pediatr Pulmonol. 2009 Oct;44(10):981-8.

      PATIENTS AND METHODS:
      Participants with a diagnosis of bronchiolitis or pneumonia (n = 55 or 50, respectively), as well as control subjects without respiratory symptoms (n = 92), were recruited at the Royal University Hospital, Saskatoon, Saskatchewan, Canada from November 2007 to May 2008. 25(OH)D levels were measured in patient serum

      RESULTS:
      The mean vitamin D level for the ALRI subjects admitted to the pediatric intensive care unit (49 +/- 24 nmol/L) was significantly lower than that observed for both control (83 +/- 30 nmol/L) and ALRI subjects admitted to the general pediatrics ward (87 +/- 39 nmol/L). Vitamin D deficiency remained statistically related to pediatric intensive care unit admission in the multivariate analysis.

      CONCLUSION: significantly more children admitted to the pediatric intensive care unit with ALRI were vitamin D deficient. These findings suggest that the immunomodulatory properties of vitamin D might influence ALRI disease severity.

      Ok, so how do we know that intervening with repletion helps? Do we need a double-blind intervention study? How large of a study would it need to dose a large population kids THEN sit back and wait to see who gets pneumonia? Nature has already done this. There is a diverse and large population of vitamin D levels already, just study them. Would you expect to treat them and get a rapid response? Unlikely. Nutrition establishes long term immune competence, not usually acute. The results of this study are bolstered by mountains of data indicating vitamin D role in immune competence. Vitamin D is cheap and inexpensive. Why would anyone not want to replete their kids! Unless of course you sell antibiotics for a livelihood.

      In regards to the Institute of Medicine’s (IOM) role in assessment of vitamin D status, their involvement in covering up the vaccine-autism connection in 2001-04 is well documented. That Magnin would characterise this organization as “prestigious” is a language I am all too familiar and a huge red flag, because it smacks of PR spin. Here is a quick Google hit result:

      About 15,200,000 results (0.82 seconds) 
      Showing results for the prestigious IOM

      If I only had a patent of the acronym PIOM, I would make a fortune. Whenever prestigious is used in front of any authoritative term (like journal, researcher, IOM, etc) , I cannot help but think the user of that term is attempting to snowball the audience. For example, here this same language was used by a “journalist” covering Dr. Paul (Pr)Offit’s book Deadly Choices.

      “In 2001, thimerosal was removed from all vaccines, and then in 2004, an independent committee appointed by the prestigious US Institute of Medicine concluded “the body of epidemiological evidence favors rejection of a causal relationship between the MMR vaccine and autism.”

      Point made. I prefer to base judgement of a tree by its fruits. And I have seen the fruits of Marie McCormick and the IOM and their botchery by their vaccine safety committee. As Mark Twain might have said, “If you have not read an IOM report, you are uninformed, but if you have read one, you are more likely misinformed”. To the point of IOM’s embarrassing work on the vitamin D guidelines, I leave you with the published opinions of Drs Holick and Heaney (note: I did not call them prestigious)

      Why the IOM recommendations for vitamin D are deficient†
      Robert P Heaney and Michael F Holick

      ABSTRACT: The IOM recommendations for vitamin D fail in a major way on logic, on science, and on effective public health guidance. Moreover, by failing to use a physiological referent, the IOM approach constitutes precisely the wrong model for development of nutritional policy. © 2011 American Society for Bone and Mineral Research.

      Introduction
      In the past two years, vitamin D supplement sales to consumers have increased by more than 100% per year.1 Now, following publication of the report2 on Dietary Reference Intakes (DRIs) for calcium and vitamin D by the Institute of Medicine (IOM), many physicians report that they are decreasing their vitamin D recommendations to patients. This change was explicitly proposed by members of the IOM panel in their various media statements. While a small fraction of consumers may well have all the vitamin D they need, on balance, we consider a general downward trend to be harmful to the health of the public.

      Both the authors of this Perspective served as members of the panel that drafted the 1997 report of the IOM on the DRIs for calcium and vitamin D. That report was the first issued by the IOM under the then-new evidence-based guidelines for evaluating studies and making recommendations. We are thus familiar with the process and, most important, with vitamin D itself. On the basis of this experience, we respectfully dissent from many of the findings and recommendations in the current report, and we set forth here a small fraction of the reasons for that dissent.

      The IOM report (and its presentation to the media) stressed that its recommendations for vitamin D were based primarily on the intake (and serum 25-hydroxyvitamin D concentration) needed to ensure skeletal health and that, in the panel's judgment, there was insufficient evidence to make any recommendations with respect to nonskeletal benefits, if any. Second, the report concluded that a serum level for 25-hydroxyvitamin D [25(OH)D] of 20 ng/mL was sufficient to ensure bone health. And third, the panel concluded that since the bulk of the American public had 25(OH)D values that were above 20 ng/mL, most individuals were getting all the vitamin D they needed and had no reason for further supplementation. These conclusions fail on three grounds: logic, science, and guidance.

      First, logic. Since the panel, in its judgment, concluded that it did not know whether there might be nonskeletal benefits (or at what blood level they could be ensured), then it is patently incorrect to say that they know that people are getting enough. The most the panel could have said logically was, “Here's what you need for bone; most people get that much; we do not know whether more would confer possible nonskeletal benefits.” That, at least, would have been an honest communication of the state of the issue as the panel apparently understands it. However, to state publicly that the general public does not need more goes well beyond what the panel admits it knows.

      Second, science. The statement that skeletal health can be ensured at serum 25(OH)D levels of 20 ng/mL is simply incorrect. Without going into an exhaustive recital of all the evidence pointing to a skeletal need for higher levels, we cite here three illustrative observations that, in our collective judgment, indicate that instead of 20 ng/mL, a serum level of 30 ng/mL is closer to the bottom end of the acceptable range for skeletal health. First, there is the large randomized, controlled trial in the United Kingdom that raised serum 25(OH)D level from 21 to 29 ng/mL and produced a 33% reduction in all major osteoporotic fractures combined.3 The fact that other trials, with less good compliance, failed to reproduce that effect does not negate the evidence of a well-conducted trial. Second, there are the many meta-analyses of Bischoff-Ferrari and colleagues4, 5 demonstrating that, taken overall, fracture reduction with vitamin D does not occur reproducibly below serum 25(OH)D levels of 30 ng/mL and for some fractures even 40 ng/mL. Finally, there is the demonstration, in a large German autopsy series (strangely misinterpreted by the panel), that osteoid seam width—the histologic hallmark of vitamin D deficiency—does not reach fully normal values until serum 25(OH)D levels are above 30 ng/mL.6 [N.B.: Of 33 patients with 25(OH)D values between 20 and 30 ng/mL, more than half (18) had elevated osteoid volume. A Recommended Daily Allowance (RDA), by definition, meets the need of 97.5% of the population.] In a closely related finding, investigators from South Australia7 showed seasonal variation in osteoid seam width and mineral appositional rate, reflecting variations in serum 25(OH)D precisely within the 20 to 30 ng/mL range, that is, above the IOM panel's “adequate” level.
      Additionally, there is an apparent inconsistency between the recommended intake (600 IU/day for all individuals up through age 70) and the bottom end of the acceptable 25(OH)D serum concentration range (let alone higher values). As virtually universal experience with vitamin D supplementation demonstrates, 600 IU/day, if the body's sole input of vitamin D, would not be enough to produce a value of even 10 ng/mL, let alone 20 ng/mL or above. There is a generally recognized “rule of thumb” to the effect that each additional 100 IU of vitamin D per day raises serum 25(OH)D concentration by approximately 1 ng/mL. That is, in fact, a “rounding up” for convenience of calculation. Several studies indicate that the response increment is closer to 0.7 ng/mL/100 IU.8, 9 Either way, 600 IU/day will not suffice without appreciable solar and dietary input. Furthermore, as is also widely recognized, 600 IU/day produces barely perceptible changes in individuals who are overweight or obese (now better than 50% of the US adult population). Hence the increase from the 1997 DRIs, while welcome, and certainly in the right direction, is simply inconsistent with current professional experience. It not only is inadequate, by itself, to meet even the panel's recommended serum levels, but this internal inconsistency detracts from the credibility of the whole report inasmuch as it flies in the face of the everyday experience of clinicians who recommend supplements to their patients and measure the resulting responses.

      Finally, guidance. At already noted, the panel indicated that it was uncertain about extraskeletal benefits—benefits that might accrue at intakes above the new intake recommendations. At the same time, the panel raised the upper-level intake “TUIL” to 4000 IU/day. (The report acknowledges that intakes up to 10,000 IU/day are probably safe for everyone and applied an uncertainty factor10 to that 10,000-IU figure to generate the 4000-IU TUIL. It is important to stress that the TUIL is not a limit but instead constitutes an assurance of safety for such an intake.) One should have thought that even a very simplistic game-theory approach would have led to a guidance statement such as the following: “We do not know whether taking more vitamin D than we are currently recommending will help you, but it could, and we can assure you that supplemental intakes up to at least 4000 IU/day are safe.” Such a statement, couched, perhaps, in less straightforward language, nevertheless would provide guidance that both the public and governmental agencies could find useful. Instead, we now have only a confused public.

      Beyond these errors and inconsistencies, though, serious as they are, lies a much deeper flaw in the approach taken by the panel, exemplified by a quote from one of the panel members to the New York Times at the time of release of the report.11 The statement was simply that the “onus” (ie, burden of proof) fell on anyone who claimed benefits for intakes higher than the panel's current recommendations. This is an approach that is correct for drugs, which are foreign chemicals and which do carry an appropriately heavy requirement for proof. For drugs, the position of privilege is given to the placebo. And in the current IOM report, the privilege is given to a serum 25(OH)D level that is effectively the status quo. We judge that this is exactly backward for nutrients. The privilege instead must be given to the intake that prevailed during the evolution of human physiology, the intake to which, presumably, that physiology is fine-tuned. So far as can be judged from numerous studies documenting the magnitude of the effect of sun exposure,12, 13 the primitive intake would have been at least 4000 IU/day and probably two to three times that level, with corresponding serum 25(OH)D levels ranging from 40 to 80 ng/mL. The fact that primitive levels would have been higher than current IOM recommendations does not, of course, prove their necessity today. But such intakes should be given the presumption of correctness, and the burden of proof must be placed on those who propose that lower intakes (and lower serum levels) are without risk of preventable dysfunction or disease. The IOM, in its report, has utterly failed to recognize or meet that standard.

      Finally, we commend the IOM panel for their concern about safety, certainly an appropriate posture for a body crafting public policy. However, the standards adopted by the panel for taking into evidence papers indicating possible risk were, we note, far lower than those the panel required to indicate benefit. Additionally, many of the purported risks were, on their face, implausible and inconsistent with the experience of population subgroups that routinely have serum levels in the range mentioned by the panel as possibly risky (eg, approximately 50 ng/mL). We note that one of the widely accepted Hill14 criteria for acceptance of observational data is precisely biologic plausibility. Furthermore, we consider it highly implausible that serum levels such as prevailed during hominid evolution could carry more risk than benefit for the populations concerned. Had that been the case, one should have expected that natural selection would have eliminated those prone to such risks.

      In this Perspective, we have deliberately avoided a mind-numbing laundry list of the vast number of factual inaccuracies and misinterpretations in the report. We are informed that there is a request, through the Freedom of Information Act, to obtain the external review comments submitted to the IOM in response to a prepublication draft. When those materials become available, those interested can review the many problems with the IOM report in detail. For now, our recommendation to the American public is that the IOM report should be taken with a grain of salt (another nutrient the IOM finds risky).

      REFERENCES

      1 [2010] Supplement Business Report, Nutrition Business Journal, September 28, 2010. 

      2 Institute of Medicine (IOM). Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press, 2011.
      3 Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomized, double-blind, controlled trial. BMJ. 2003; 326: 469–474.
      4 Bischoff-Ferrari HA, Willett WC, et al. Fracture prevention with vitamin D supplementation. JAMA. 2005; 293: 2257–2264.
      5 Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency. Arch Intern Med. 2009; 169: 551–561.
      6 Priemel M, von Domarus C, Klatte TO, et al. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res. 2010; 25: 305–312.
      7 Need AG, Horowitz M, Morris HA, Moore R, Nordin C. Seasonal change in osteoid thickness and mineralization lag time in ambulant patients. J Bone Miner Res. 2007; 22: 757–761. 

      8 Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxy-cholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003; 77: 204–210.
      9 Heaney RP, Armas LAG, Recker RR, Grote J, Horst RL. Vitamin D3 is more potent than vitamin D2 in humans. J Clin Endocrinol Metab. 2011; DOI: 10.1210/jc.2010-2230 [Epub ahead of print].
      10 Hathcock JN, Shao A, Vieth R, Heaney RP. Risk assessment for vitamin D. Am J Clin Nutr. 2007; 85: 6–18.
      11 Kolata G. Report questions need for 2 diet supplements. New York Times, November 29, 2010. Available at http://www.nytimes.com/2010/11/30/health/30vitamin.html?
      12 Holick MF. Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr. 1995; 62 (Suppl): 638–645S.
      13 Armas LAG, Dowell S, Akhter M, et al. Ultraviolet-B radiation increases serum 25-hydroxyvitamin D levels: the effect of UVB dose and skin color. J Am Acad Dermatol. 2007; 57: 588–893.
      14 Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965; 58: 295–300.

      While I fell short of proclaiming Mangin to be a Pharma Shill, like others have, on my first response to her column, I won’t miss this opportunity in this follow-up. I rarely respond to blogs but I have read many, particularly those related to the evidence and suppression of vaccine injury. I know that pharma interests use PR agencies to appear as the general public or even as journalists, researchers, clinicians and organizations, particularly web-based blogs. Nothing is off limits when it comes to protecting pharma. No one is above scrutiny. Magnin indeed has an interesting track record. She has “presented at numerous conferences; including “Enabling Future Pharma, Perspective in Rheumatic Diseases and Immunology Summit.” (Pardon me, but de we really need to enable Pharma even more?) She has also served on an NIH panel. I am sorry, but from someone who has seen a steady dose of lies from those protecting the vaccine industry including anyone under the umbrella of the NAS and the HHS, buyer beware.

      She advocates very clearly that vitamin D supplementation is to be questioned, and in fact, is unsupported. This is a tremendous injustice. We have a new generation of people who are facing unprecedented deprivation of sunlight through use of sunblock and sun avoidance, in addition to the little known fact of global dimming and decreased UVB hitting the earth’s surface. Widespread use of antacids deplete the acid necessary to make calcium soluble and absorbable. Along with common occurrence of dairy avoidance through use of alternative drinks and lactose intolerance, all serve to decrease calcium status and enhance depletion of vitamin D stores. There need not be an epidemic of intracellular bacterial infections that account for secondary hypovitaminosis. Policy makes and industry have created an environment in which billions are facing inadequate vitamin D levels and the consequences of this are just beginning to be seen. Researches at Mayo (Thacher 2013) have reported a dramatic rise in rickets since about the same time the AAP officially recommended sun exposure reduction measures for young infants. One thing for sure, their seems to be nothing new under the sun, pun intended. Clinicians in integrative medicine are a step closer to the truth than most MDs, but can still be fooled by the spin machine that operates daily to keep the status quo afloat. They want us to be “burned out” with the vitamin D story and will use whatever means to achieve this, even if they have to deploy PR firms to do so. Bloggers beware.

      And Kelly, I am sorry you will also find this non-collegial. I don’t know how to pleasantly tell you that I believe what you are doing is a giant disservice to those seeking health advise by posting what you are posting. I can’t possibly be more clear on this. Your follow-up posts are even a greater concern to me. I am beginning to wonder if you drank the Kool-aid or are actually serving it. And I will address them as professionally as I can.

      • Profile photo of admin2
        admin2

        David, thank you for sharing your concerns. Our blog is meant to be a collegial forum to discuss these kinds of issues. This type of back and forth among knowledgeable, engaged, passionate people is what we hope for. It’s not for everyone but it is precisely what our community wants.

        This discussion does apply to the “larger, general population” you reference. One in 2 Americans is chronically ill (including children) and 1 in 4 has two or more chronic health conditions. Seven of the top 10 causes of death are chronic diseases. Chronic illness is, by definition, complex. The main narrative is no longer about health. It’s about sick.

        Whatever we’re doing, we’re not doing it right. And people are increasingly taking more responsibility for their choices, of providers and treatment options. It’s hard to select the former without better understanding their positions on the latter. That’s where we come in.

        ps. I thought your research on aluminum in vaccines was brilliant, pioneering, and shattering. You know too well how challenging it is to raise new ideas about practices that are embedded in orthodoxy.

      • Meg Mangin

        Despite vitamin D supplementation chronic diseases have increased. More foods than ever before are fortified with vitamin D; the Nutrition Business Journal reported sales of vitamin D supplements have skyrocketed to $425 million in 2009 from just $40 million in 2001. Vitamin D supplement proponents promised double digit declines in chronic disease yet, between 2000 and 2010, the percentage of adults aged 45-64 (and 65+) with two or more (of nine selected) chronic conditions, increased for both men and women, all racial and ethnic groups examined, and most income groups.

        Recently, I’ve seen a dramatic increase in the number of patients taking a vitamin D supplement and reporting alarmingly elevated calcitriol (e.g., 123 to 190 pg/mL). Quest lists the normal lab range as 18-72 pg/mL for adults. Chronic illnesses develop slowly and may be subclinical (without symptoms) for years before diagnosis. Checking the level of calcitriol (the bio-active hormone) when calcidiol (the inert prehormone) is low is an assessment tool that can diagnose a vitamin D endocrine system problem. In fact, the new diagnosis codes (ICD-10-CM) used to justify ordering the lab test for calcitriol includes “E55.9 Vitamin D deficiency, unspecified”.

        In 2002, following seven placebo-controlled studies, the U.S. Food and Drug Administration (FDA) approved olmesartan (brand name Benicar®) for the use of hypertension in adults. In 2010 the FDA approved the use of olmesartan to treat hypertension in children and adolescents 6 to 16 years of age. Following a safety review in 2014, the FDA noted that olmesartan has proven no real danger since it went on the market in 2002. They advised “Do not stop your treatment with Benicar unless told to do so by your healthcare professional.” Recent reports of a sprue-like enteropathy associated with olmesartan use involve a tiny subset of the millions of people who are taking Benicar. In fact, the work of Nagib et al., which was listed in the previous post, indicates olmesartan may relieve gastrointestinal symptoms through its anti-inflammatory and antioxidant effects.

        The off-label use of olmesartan to reduce elevated calcitriol and up-regulate the immune system (as described in our peer-reviewed paper that was recently published in the journal Inflammation Research) is an option many people might want to discuss with their doctor, if their calcitriol is elevated.

        Sometimes drugs are necessary to treat a medical condition and all medication (even supplements available over-the-counter) carries some risk. Doctors who treat patients understand this and consider the risk versus benefit ratio when recommending any medication (including supplements).

        Kumar et al. found that plasma calcitriol levels are elevated in early pregnancy and continue to increase throughout pregnancy. Thus, pregnant woman whose calcidiol is low should have calcitriol (the active form of vitamin D) measured to determine vitamin D status. If a woman has an adequate level of calcitriol, she is not vitamin D deficient, no matter how low the calcidiol.

        Observational studies cannot provide definitive evidence to determine the safety of vitamin D supplementation. And those that fail to measure the active metabolite (calcitriol) do not provide an accurate picture of vitamin D status. Benefits of vitamin D supplementation in pregnant women can be attributed to immune system suppression because studies have shown that vitamin D is primarily immunosuppressive. The risks of suppressing the immune system with vitamin D supplementation (infections can persist) may outweigh the benefits (temporary symptom reduction).

        It’s difficult to know who to trust but I believe the Institute of Medicine (IOM) has far more credibility regarding vitamin D than vitamin D supplement proponents. The IOM is an independent, non-government, non-profit organization with over 1700 volunteer members who provide evidence-based information on science, medicine, and health. IOM committees are carefully composed to assure expertise, avoid bias or conflict of interest, and their reports are reviewed by external experts. The 2010 IOM consensus report on vitamin D was endorsed by many organizations such as the American Society for Bone and Mineral Research. Hector DeLuca, one of the most respected vitamin D researchers in the world and a member the National Academy of Scientists, agrees with the IOM guidelines.

        I am not impressed with statements about vitamin D made by Dr. Heaney or Dr. Holick. Dr. Heaney has authored vitamin D studies funded by Smith/Kline/Glaxo, spoken on behalf of Proctor & Gamble, and sat on the board of a dairy association. Some of Dr. Holick’s research was supported by the ultraviolet (UV) foundation which is funded by the tanning bed industry.

        I am a health care professional (and mother) who was inspired to research vitamin D because of a diagnosis of sarcoidosis. I have no ties to any pharmaceutical industry and my motive is altruistic; to help patients recover their health as I have. My message is simple. Statements about vitamin D deficiency and the need for vitamin D supplementation should not be based on the results of studies that fail to adequately assess vitamin D status by measuring both calcidiol and calcitriol. Because adverse effects of vitamin D supplementation may take decades to be realized, clinicians (mindful of the medical ethics precept “First, do no harm”) should err on the side of caution; test calcitriol when calcidiol is low, before ordering vitamin D supplementation.

        References

        The vitamin D dilemma. ConsumerReports.org. May 2011. Available at: http://www.consumerreports.org/cro/2012/04/the-vitamin-d-dilemma/index.htm.

        Fried VM, Bernstein AB, Bush MA. Multiple Chronic Conditions Among Adults Aged 45 and Over: Trends Over the Past 10 Years. Centers for Disease Control and Prevention. Jul 2012. http://www.cdc.gov/nchs/data/databriefs/db100.htm.

        Anderson G. Chronic Care: Making the Case for Ongoing Care. Robert Wood Johnson Foundation. Jan 1, 2010. http://www.rwjf.org/content/dam/farm/reports/reports/2010/rwjf54583.

        Mattke S, Klautzer L, Mengistu T, Hu J, Wu H. Health and Well-Being in the Home: A Global Analysis of Needs, Expectations, and Priorities for Home Health care Technology. Rand Corporation. 2010. http://www.rand.org/pubs/occasional_papers/OP323.html.
        Beaubien J. National Public Radio. Shots-Health Reports from NPR. Sep 4, 2013;:Chronic Illnesses Outpace Infections As Big Killers Worldwide. Available at: http://www.npr.org/blogs/health/2013/09/04/218873813/chronic-illnesses-outpace-infections-as-big-killers-worldwide.

        Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflamm Res. Oct 2014;63(10):803-19.

        R Kumar, W R Cohen, P Silva, F H Epstein. Elevated 1,25-dihydroxyvitamin D plasma levels in normal human pregnancy and lactation. J Clin Invest. Feb 1979; 63(2): 342–344.

        • DAVID AYOUB, MD

          1) you cannot blame vitamin D supplementation on chronic disease without data. This is merely an observation. I could blame chronic illness on the Green Bay packers beating the Bears the last 5 years, since both chronic disease and Bears losses occur simultaneously

          2) More foods supplements? What data do you have? I have read the exact opposite.

          3) Who exactly promised double digit declines in illness when we supplement the population? Really? How about increase uptake of vaccines as accuse of chronic illness? Does increased supplementation mean increased sufficiency rates. Bodnar in Pittsburgh reported 90% pregnant women were on recommended does of supplementation and only 1 in 10 black babies, 1 in 3 which babies were born with normal D levels, non toxic!

          4) 25 OHD is NOT inert. By saying so makes me conclude you have no expertise in this topic whatsoever. These comments are reckless.

          5) 1,25 ODH should never ever be used as a marker for Vit D status even in pregnancy, even the labs will tell you this. This is scientific fact, There are biological reasons why 1,25 is elevated in pregnancy, it is in no way a method to determine status in pregnancy.

          6) FDA sais Vioxx was safe, that did not turn out too well. Are the 29 papers I cited all conspiring to destroy the drug makers?

          7) elevated 1,25 OHD has a differential diagnosis. It is nearly always elevated in cases of healing rickets even without supplementation. It is usually NOT elevated in Vit D toxicity and when it is, will be associated with elevated calcium and 25 OHD. Its elevation after vit D therapy is a normal thing and a sign of recovery from deficiency.

          Relative value of 25(OH)D and 1,25(OH)2D measurements. Lips P.
          J Bone Miner Res. 2007 Nov;22(11):1668-71.

          “In case of severe vitamin D deficiency, vitamin D therapy may cause an increase of serum 1,25(OH)2D.(19,32) The threshold serum 25(OH)D where vitamin D therapy still may increase 1,25(OH)2D may be identified by repeated measurements of serum 1,25(OH)2D. This may play a role in the establishment of the minimally required serum level of 25(OH)D.”

          Ann Intern Med. 1995 Apr 1;122(7):511-3.
          Serum levels of free 1,25-dihydroxyvitamin D in vitamin D toxicity.
          Pettifor JM1, Bikle DD, Cavaleros M, Zachen D, Kamdar MC, Ross FP.
          Author information

          Abstract
          OBJECTIVE:
          To determine the serum level of free 1,25-dihydroxyvitamin D [1,25-(OH)2D] in patients with vitamin D toxicity and to assess the in vitro effect of differing concentrations of vitamin D metabolites on the free serum levels of 1,25-(OH)2D.
          DESIGN:
          1) A case study of patients hospitalized with vitamin D toxicity after accidentally ingesting a veterinary vitamin D concentrate and 2) an in vitro experiment in which vitamin D metabolites in various concentrations were added to normal serum and their effect was noted on percentage offree 1,25-(OH)2D.
          PATIENTS:
          11 patients (age range, 8 to 69 years) were studied 10 to 40 days after hospitalization for hypercalcemia.
          MEASUREMENTS:
          Serum total 25-hydroxyvitamin D (25-OHD) and 1,25-(OH)2D levels were measured by radioreceptor assays. The percentage offree 1,25-(OH)2D was measured by centrifugal ultrafiltration isodialysis and was used to calculate actual free 1,25-(OH)2D levels. In the in vitro studies, vitamin D metabolites [25-OHD; 24,25-(OH)2D; 25,26-(OH)2D; and 25-OHD-26,23 lactone] were added to normal serum in concentrations expected to occur with vitamin D toxicity. The percentage of free 1,25-(OH)2D was measured by isodialysis.
          RESULTS:
          All patients presented with marked hypercalcemia (mean calcium level, 3.99 +/- 0.33 mmol/L). Serum 25-OHD levels ranged from 847 to 1652 nmol/L, and total 1,25-(OH)2D levels (mean, 106 +/- 86 pmol/L) were elevated in only three patients. The percentage of free 1,25-(OH)2D (mean, 1.023% +/- 0.366%) was elevated in all nine patients in whom it was measured. Actual free 1,25-(OH)2D levels (mean, 856 +/- 600 fmol/L) were elevated in six of the nine patients. Total 1,25-(OH)2D levels were correlated with 25-OHD levels (r = 0.66; P = 0.03), whereas total and free1,25-(OH)2D levels were highly correlated (r = 0.957; P < 0.001). In the in vitro studies, the percentage of free 1,25-(OH)2D increased after 25-OHD or 24,25-(OH)2D was added.
          CONCLUSIONS:
          Although the patients had normal or near-normal total 1,25-(OH)2D values, most patients had elevated free 1,25-(OH)2D levels. These findings suggest that elevated free 1,25-(OH)2D levels might play a role in the pathogenesis of hypercalcemia in vitamin D toxicity.

          8) Holick and Heaney's opinion is echoed by many many vitamin D experts. Apparently when you cite pharma Rx, conflicts don't count. There opinions are supported by published science. Your opinions are hypothetical and speculative.

          9) Now I understand your opinions. Sarcoid is about the only condition where Vit D supplements are controversial. I get that, but you are proposing to throw out the baby with the bath water and this is reckless. You are totally missing the big picture. Here is Dr Mercola's take on this:
          by Dr. Mercola http://articles.mercola.com/sites/articles/archive/2009/03/14/clearing-up-confusion-on-vitamin-d–why-i-dont-recommend-the-marshall-protocol.aspx

          Ever since I started promoting the benefits of vitamin D there has been a small but vocal minority of advocates of what is referred to as the “Marshall Protocol”.

          As much as I would like to ignore it due to its lack of validity, I can no longer do so, because so many people are using this information and at the very least, they are placing their health at great risk and in many cases they are damaging their health.

          Therefore, to remain silent would be irresponsible, so I am going to address this issue once and then put it to rest.

          I felt it was important to share my views on what I perceive is a dangerous view of vitamin D physiology. It has been my common strategy for as long as I have been in medicine to be open to new ideas and concepts and I have carefully evaluated Dr. Marshall’s protocol and even attended one of his lectures in Chicago nearly ten years ago.

          It was somewhat comical to attend his seminar as most of the people attending were wearing very large, wrap around UVB blocking glasses typically worn after cataract surgery. I knew at that point that the operating premise was seriously flawed. The belief that ANY exposure to the sun was dangerous and needed to be avoided gravely concerned me.

          “Dr.” Marshall is Not a Physician

          For those of you who are not familiar with the protocol recommended by Trevor Marshall, I will briefly summarize its basic tenets, as I understand them, before going on.

          First it is important to note that Dr. Marshall is not a medical doctor but has his PhD in Biomedical Engineering.

          Marshall is an Australian electrical engineer who developed an interest in biomedical engineering out of a desire to cure his own sarcoidosis, which he developed in the 1970s[i]. He has no medical degree. His theories come from mathematical molecular models, not clinical studies.

          Sarcoidosis is Only Disease Where Vitamin D Levels Are an Engima

          Sarcoidosis is an inflammatory condition that produces tiny lumps of cells called granulomas in various organs of the body. These granulomas clump together into large or small groups, resulting in organ damage. They most commonly occur in the lungs, lymph nodes, skin and eyes, and symptoms can wax and wane over many years.

          Symptoms can vary from very minimal to life threatening. Some medical experts believe sarcoidosis is an autoimmune process, and others believe some substance or pathogen has triggered the inflammation. There is no agreement yet about the cause of this illness.

          Marshall states the treatment he developed has cured his disease and claims that his protocol, the Marshall Protocol (aka MP) will cure a long list of chronic inflammatory and autoimmune diseases. According to one of his most vocal advocates, Amy Proal[ii], the MP cures sarcoidosis, Chronic Fatigue Syndrome (CFS), fibromyalgia, Crohn’s disease, and rheumatoid arthritis (RA), and many others.

          Marshall proposes the following:

          All chronic diseases are the result of infection by certain bacteria that hide out and proliferate inside the cytoplasm of the cells they infect. These cells include macrophages, the very cells of the immune system the body uses to kill invading pathogens. Once inside these cells, they generate the release of inflammatory cytokines, which cause the person pain and/or fatigue.

          The infected cells sustain themselves by congregating into communities called biofilms, which produce a protective matrix that allows them to more effectively evade the immune system and resist antibiotics.
          The reason these bacteria are able to proliferate in this way is directly related to vitamin D. Marshall argues that vitamin D is immunosuppressive—it effectively shuts down your body’s immune system. Therefore, he states, the lower your vitamin D is, the better, because vitamin D from any source (food, supplements, or sunlight) in any amount drives the disease process.
          The low vitamin D levels [meaning serum 25(OH)D] found in many people with chronic diseases are a result of the disease, rather than the cause. Marshall explains this by saying that the disease process causes 1,25-D to rise to an unnaturally high level. This in turn causes a cascade of reactions leading to a drop in 25(OH)D, leading to the low blood levels we observe in blood tests.
          Given these premises, his treatment plan consists of the following:

          Avoid sunlight and vitamin D as if they were the plague. He restricts people from eating foods high in vitamin D, as well as having them hole-up inside for months on end. If they go outside, they cover up completely, including wearing special sunglasses.
          Patients take a medication called Benicar (olmesartan), which is an angiotensin II receptor blocker (ARB). This is supposed to reactivate the immune system by opening up the VDRs (vitamin D receptors), allowing the body to once again manage the infections.
          Patients concurrently take pulsed, low-dose antibiotics to further combat the infection.
          The protocol is continued for 3-5 years. Before patients begin to feel better, they can expect to feel much worse due to the “Herx” reaction (Jarisch-Herxheimer reaction). Herx is the effect of bacterial dye-off, releasing toxins into the bloodstream, stimulating the production of inflammatory cytokines, which make the patient feel bad.

          So, Marshall believes, if you don’t feel bad, it’s not working.

          Why One Size Doesn’t Fit All

          Probably because Marshall is an engineer and not a physician, his approach reveals a lack of appreciation of the complexity and variation of the human system. Your body is not a piece of electronics that can be predicted to act a certain way every time. A radio is a radio is a radio, but not so with the human body. It is more than a sum of its parts, making medical science as much an art as it is a science.

          This is precisely why clinical trials are necessary before conclusions about causation can be drawn. There are simply too many variables.

          What Marshall has done is take conclusions from his research for a cure for his own condition (sarcoidosis), and then applying it to everything from soapsuds to unicorns. The error in logic would not be so disturbing were it not for the fact that he is doing a lot of harm to people who desperately seek help for their pain.

          Our Ancient Ancestors Had Constant Sun Exposure

          First, let me address the most basic premise here—that vitamin D and sunshine promote disease. Besides being contrary to current research, this goes against our evolutionary history.

          Our ancient ancestors had regular and consistent sun exposure as they were from sub tropical environments and did not spend nearly all day indoors like most of us do when we work. We’ve spent thousands of years hunting and gathering outdoors, particularly in equatorial regions, and most of that time we certainly wore far less clothing than we wear today. It makes no sense that we would have developed the need to avoid sunlight altogether.

          Nature has designed a system in which humans go into the sun, make thousands of units of cholecalciferol, which the liver then converts to 25(OH)D. Our organs then make a steroid hormone, 1,25-D, which helps to regulate genes in every organ of the body[iii].

          As Dr. John Cannell, Executive Director of the Vitamin D Council, says, “We assume nature created this for a good reason.”

          Inflammation Requires Holistic Approach

          I can agree with Marshall on the idea that inflammation is a major underlying factor in many chronic diseases. However, ,inflammation must be addressed with a holistic approach that includes diet and nutritional type, exercise, sleep, stress, psychological factors, environmental toxins, and many other things. None of these is mentioned, that I can find, in the Marshall Protocol.

          And it is my firm belief that medication should rarely if ever be the first avenue of treatment for anything. Most healing can be achieved by supporting your body’s own ability to heal itself by strengthening your immune system.

          The Antibiotic Issue

          Taking antibiotics for years, as directed by the MP, is just ludicrous and is an invitation for disaster.

          There are certainly times when antibiotics are necessary, but they are widely overused. For every time they are used appropriately in traditional medicine, there are at least 10 to 20 times when they are inappropriately used, and this is what has resulted in antibiotic-resistant bacteria.

          Marshall claims that, by “pulsing” several different antibiotics, antibiotic resistance is avoided. However, there is evidence to the contrary in the literature.

          Mark London, of MIT, has written a very detailed, comprehensive analysis of the MP[iv]. He states that overuse of macrolides (Zithromax, clindomycin, and others) is known to result in resistant bacteria, and the risk is even higher when macrolides are combined. There is also cross-resistance between macrolides. Therefore, Marshall’s claim that his protocol prevents antibiotic resistance is false.

          In the past I have used antibiotics for rheumatoid arthritis when I was applying Dr. Thomas Brown’s protocol. Even though Dr. Brown clearly helped many thousands of patients with this, after using it for many years I realized that even better results could be achieved without the use of antibiotics.

          If infectious agents do underlie disease, which is certainly possible but remains to be proven, antibiotics are not the answer. There are many natural choices for anti-infectives that are much safer and have fewer side effects than antibiotics.

          For example, for thousands of years, Chinese medicine has been curing infections with herbs, mushrooms, bark, and other natural agents.

          If you have an infection, your best strategy is to get your immune system into shape by addressing the things I mentioned above, none of which are addressed by the Marshall Protocol.

          “Herx” Reactions, or Something More Ominous?

          Jarisch-Herxheimer reactions are a major part of what patients are told to expect once they begin the MP.

          The MP teaches that, in order to know that you have one of these infections, you go onto the MP, and if you have a Herx reaction (which they basically define as feeling bad in any number of ways), you can conclude you’re on the right path. By the same token, they say, if you don’t “Herx,” then you don’t have an infection.

          However, Herx reactions are known to occur only with certain types of infections such as Lyme and syphilis. They normally occur only early in treatment and typically last a few days or weeks, not months or years, and only in some people—not in all people3[v][vi].

          Therefore, any test that is based on whether or not a Herx reaction occurs is meaningless, since the lack of a reaction doesn’t rule out the presence of an infection. Similarly, an increase in your symptoms doesn’t necessarily mean you’re having a Herx reaction.

          So-called Herx reactions can be explained by well-documented medication side effects. For example, Minocycline has been known to cause dizziness and nausea in some people. Benicar has many documented side effects at much smaller doses than what the MP calls for, including headaches, chest pain, muscle pain, and coughing.

          How do you know that your “Herxing” isn’t just a reaction to the Benicar?

          Also, the MP can cause an elevated PTH level (Parathyroid Hormone), which in itself can cause symptoms of fatigue, poor concentration, irritability, depression, insomnia, headaches, and palpitations[vii].

          To say that everyone who has any increase in symptoms while on the MP is just having a “Herx reaction” is simply ignorant and foolhardy, as well as negligent as it causes the patient to ignore potentially dangerous signals that something else could be wrong!

          This is just what happened to a man by the name of Steve Carroll. Mr. Carroll is someone who tried the MP and nearly died of Addison’s disease, as a direct result of the Marshall Protocol. His symptoms were of a growing adrenal crisis. However, the MP advisors told him that he was simply “herxing.”

          When he consulted his own physician, who took him off the protocol and saved his life, Mr. Carroll contacted the MP “forum” advisors[viii]. He was met with nothing but resistance and denial, and told that his own physician was wrong. The Marshall forum advisors refused to even consider the possibility they might be wrong, and that using Benicar with people who have weak adrenal function (namely low cortisol and aldosterone production) is very dangerous and can lead to an adrenal crisis.

          A documentation of the dialog between Mr. Carroll and the MP folks is quite telling and has been posted verbatim online[ix].

          As Mr. London writes:

          “Giving a medicine to see if a person will get better from it, and then continuing that medicine due to the fact that a positive benefit occurred, is of course extremely common. However, giving a medicine specifically to see if a person will get worse from it, and then continuing that medicine because this occurred, is quite rare.

          While it’s true that many medicines will first cause side effects before the positive benefits occur from it, these side effects are almost never considered to be a sign that the medicine is the proper medicine to use to treat a person.”

          Measuring 1,25-D is Like Herding Cats

          Marshall states that 1,25-D levels are elevated in people with chronic infectious diseases. [Remember, 1,25-D is the active form of vitamin D, once it’s been converted from 25(OH)D.]

          He relies on 1,25-D levels as indicators of the disease process. However, 1,25-D values can fluctuate tremendously up and down for many reasons, other than disease processes. 1,25-D is influenced by calcium, phosphate, and PTH, just to name a few, which makes it meaningless to use it as a marker for dysfunctional vitamin D production or regulation.

          In fact, some studies show little to no correlation between 1,25-D and 25(OH)D levels[x][xi]. Many body tissues have the ability to generate 1,25-D themselves, as a way to self-regulate, rather than solely relying on serum 25(OH)D.

          This is why the standard used by the medical community for assessing health is serum 25(OH)D, which is not subject to these variables and fluctuations. This test has been standardized, recognized and used by every vitamin D expert in the world. I have talked to many of the leading vitamin D researchers and not one of them had anything favorable to say about the misinformation Marshall is promoting.

          What about the Cancer Studies Cited by MP Advocates?

          On her website called Bacteriality, Amy Proal mentions a number of cancer studies that reportedly demonstrate that vitamin D does not decrease cancer risk. Upon close inspection, however, several of those studies involve people supplementing with very low doses of vitamin D, lower than what is considered effective by most vitamin D experts. The supplementation levels are 600-800 IU per day, which is too little to prevent much of anything.

          Dr. John Cannell, one of the foremost experts on vitamin D today, scripted a response to the MP, which he sent out in his newsletter[xii]. He makes the point:

          If Marshall’s hypothesis is correct, that low vitamin D levels are the result of disease, then he is saying that cancer causes low vitamin D levels, not the other way around. The problem is that Professor Joanne Lappe directly disproved that theory in a randomized controlled trial[xiii] when she found that baseline vitamin D levels were strong and independent predictors of who would get cancer in the future.

          The lower your levels, the higher your risk. Furthermore, increasing baseline levels from 31 to 38 ng/ml reduced incident cancers by more than 60% over a four-year period. Therefore, advising patients to become vitamin D deficient as the MP clearly does, could cause some patients to die from cancer.

          It is worth noting that the amount of vitamin D subjects in the Lappe study received was 1,100 IU per day, higher than any of studies cited as negative toward vitamin D, and this study was of longer duration.

          Can Any Value Be Found in Marshall’s Work?

          Marshall arrived at most of his theories from his personal battle with sarcoidosis, and he certainly can’t be faulted for taking an aggressive approach to finding a solution for what is traditionally viewed as an incurable disease. After all, many serendipitous discoveries in history came about in unusual ways.

          I strongly believe his efforts have gone astray, however, in assuming all those other chronic diseases fit the same model.

          Sarcoidosis is a condition marked by abnormal immune responses, one of the many unique features of that condition. For example, according to Dr. Cannell, in sarcoidosis, the body can’t regulate activated vitamin D production, resulting in hypercalcemia12. But these immune responses are not found in all of the other inflammatory conditions, so any treatment effective against sarcoidosis is thus treating a rather unique condition and may not necessarily be as effective for other conditions.

          If the MP does indeed help some people with sarcoidosis and various other conditions as it seems to, based on some people’s reported experiences on the web, there is no guarantee it is working in the way Marshall assumes it is.

          For example, Benicar and the various antibiotics all have various effects, both positive and negative, on various conditions, which could be one explanation for why some folks feel better. Benicar has been shown to have some anti-inflammatory properties, among others. Some antibiotics have anti-inflammatory and analgesic effects themselves (minocycline, for example).

          It could be this effect that makes patients feel as if they are getting better. If so, patients might experience a recurrence of symptoms once the meds are discontinued.

          What About Melatonin?

          Since light suppresses melatonin, it would be expected that melatonin levels would rise when you avoid light. Melatonin has significant effects on your immune system. In fact, in 2006, a study showed that melatonin was a safe and effective treatment for sarcoidosis![xiv] Melatonin has also been shown to help other conditions, including CFS, fibromyalgia and colitis.

          How does anyone know it isn’t the melatonin that is causing some people to feel better? If so, there are much better ways to increase your melatonin level than by sacrificing sunlight and valuable vitamin D!

          The point is, there are many other factors that could explain why the MP could seem to help sufferers of sarcoidosis, besides the one he claims. To really determine what is causing what, a series of controlled studies would have to be done. He has drawn a lot of conclusions without the clinical studies to separate out the variables.

          I believe that Marshall is placing people’s health at risk by having them participate in a clinical trial via the Internet–and a badly designed one at that—with inadequate details and precautions about what the health consequences might be.

          My Recommendation

          Stick to what you know works, and if there is merit to any of Marshall’s theories, studies will bear that out in time. It would seem that the only indication for MP would be sarcoidosis. I believe it would be unwise to use it for other conditions, but even for sarcoidosis there are a number of effective non-drug approaches to address it.

          I would have to agree with Dr. Cannell that you would be hard-pressed to find any reputable person in the vitamin D field who takes Marshall’s theories seriously. They are poorly substantiated and lack corroborating evidence.

          Go with what you know. Health comes from getting back to the basics…nutrition, exercise, restorative sleep–and yes, appropriate exposure to sufficient sunshine to normalize your vitamin D levels.

        • Kelly

          Shame on you Meg. You know that many, many people were harmed by the Marshall Protocol — some of them almost lost their lives — and Marshall himself harassed very ill patients who disagreed with him.

          You KNOW many patients who got a lot worse using this protocol for non-sarc patients, but you say nothing about that. Shameful.

          1,25 D can be high due to low calcium levels. It’s not always about infection.

  • kim

    I am glad to see finaly there is some information on possible concerns with vit D supplementation. I have searched the internet for this kind of information and was not able to find it. On doing a google search of concerns with vit D supplemention, the ONLY thing I was able to find was regarding toxic overdose.

  • Free spirit

    I am really unclear now
    What about people who cannot go in the sun because they are housebound (disabled, elderly…)?
    Surely if not getting sunlight are not making vit d and need supplement, or am I missing something?

    I have m.e. (Aka chronic fatigue) and don’t get out much. my teeth were in a terrible state, crumbling and getting decayed. I took vit d and they are much better.
    I wonder also about people who work long hours indoors, and those who wear clothes that cover them completely.

    • Kelly Fincher

      CIR (100% volunteer nonprofit counseling service for physicians) suggest if you are sick have doc check the bioactive form of D called 1,25-dihydroxyvitamin-D3 
      also called:
      1,25(OH)2 D3
      1,25-D or calcitriol
      CPT code: 82652
      science is a work in progress
      if you have questions call Meg 888.846.2474

    • Kelly Fincher

      millions of research dollars are spent trying to find analogs for calcitriol that won’t raise calcium dangerously high; they know this metabolism is critical for good health BUT they also know it is a hormone precursor and too much is very bad as Dr. Henry DeLuca, THE vit D guy, says in this short video; not too long ago it wasn’t sold over the counter TinyURL.com/DeLucaD

    • Meg Mangin, RN

      Vitamin D deficiency or insufficiency can occur in certain situations. Genetic defects in the vitamin D receptor may result in vitamin D deficiency. Rare disorders that limit vitamin D absorption and conditions that impair conversion of vitamin D into active metabolites (e.g., certain liver, kidney & hereditary disorders) may cause deficiency. Sick or elderly people who rarely go outdoors and have poor diets are also at risk. Age is a factor, in that synthesis of vitamin D declines with increasing age, due in part to a fall in 7-dehydrocholesterol levels and due in part to alterations in skin morphology. Vitamin D supplementation may be appropriate in these special conditions but the evidence indicates it’s not appropriate to supplement the general population.

      The requirement for vitamin D is normally met by its synthesis in the skin. In the United States, various foods are fortified with vitamin D to ensure that deficiencies do not occur. As a result, most individuals consume and synthesize more vitamin D than they require.

      Clothing is a barrier to ultraviolet radiation but this is an issue only for people who cover themselves from head to toe (e.g., woman who wear a burka may not be exposed to sufficient sunlight). [1] It takes relatively little sunlight exposure to acquire adequate stores of vitamin D and few people wear enough clothes to prevent that from happening. Ten to 15 minutes of sunlight or daylight exposure to a small area of skin (e.g., the forearm or face, etc.) twice a week (without sunscreen) supplies all the vitamin D necessary for health. [2]

      Our bodies have mechanisms for preserving the vitamin D we acquire during the summer; which have evolved to stabilize and maintain serum levels of 25(OH)D in environments with variable vitamin D availability.

      The best way to get an accurate assessment of your vitamin D status is to measure both 25(OH)D and 1,25(OH)2D. The Institute of Medicine advises that almost all people get sufficient vitamin D when their 25(OH)D level is at or above 20 ng/mL (50 pmol/ml). If 1,25(OH)2D is within (or above) the normal range, you are not vitamin D deficient because this is the bio-active form of vitamin D. In one who is chronically ill, low 25(OH)D is a marker of a disease process, not a cause. It suggests rapid conversion of this hormonal precursor into the active metabolite. Supplementation could increase chronic inflammation. [3]

      References

      1. Matsuoka LY, Wortsman J, Dannenberg MJ, Holis BW, Lu Z, Holick MF. Clothing prevents ultraviolet-B radiation-dependent photosynthesis of vitamin D3. J Clin Endocrinol Metab. Oct 1992;75(4):1099-103.
      2. Dietary Supplement Fact Sheet: Vitamin D. National Institutes of Health. Jan 24, 2011. Available at: http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/?print=1.
      3. Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflamm Res. Oct 2014;63(10):803-19.

  • Lisa DeMarco

    Hi,
    I am looking for referrals for my 14 year old daughter. GI issues began in July. Blood work was normal except for very low vitamin D levels and iron in the low side of normal. Colonoscopy/endoscopy normal but significant inflammation in stomach. Symptoms: cramping, frequent bowel movements, sometimes diarrhea and touches of blood in stool occasionally although not found in stool sample. Looking for some balance between east and west. Dr is calling it irritable bowel syndrome. She is a devoted vegetarian.
    Considering Dr Furhman, Dr Menache or Dr Conti at this point. They are all out of my cigna plan so I can’t visit all and then decide. I am sure you all know people who specialize in this stuff and may be of help. Any suggestions? We live in scotch Plains,NJ
    Thanks,
    Lisa D. (FP has my email address)

  • Dr Danny Connaughton

    It may be too late to post now but a NATURAL solution which addresses the issue seems to be a good compromise i.e. NOT the drug which nurse Mangin suggested. If so, which natural treatment would be proposed for the bacteria identified – would it be as for leaky gut/parasites such as bone broth and probiotics such as kefir and sauerkraut?

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