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Newsletter: Vitamin D events of interest

Posted on: October 15, 2010   by  John Cannell, MD

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Is sarcoidosis another vitamin D deficiency disease?

Why do some people get heart disease from vitamin D deficiency, others get colon cancer, yet others get multiple sclerosis and some live to be 100? For the same reason some smokers get lung cancer, others get heart disease, others get bladder cancer, others die of emphysema, and some live to be 100. Each of us has genetic weaknesses, some of our organs are less resistant to disease than others and we tend to die from a disease in our genetically weakest organ. The genome project was supposed to let us all know which organ is our weakest one but such knowledge was never forthcoming and probably never will be. So far, the greatest discovery of the genome project is that epigenetics is important.

Sarcoidosis is a rare disease that has the external trappings of a vitamin D deficient disease: it is less common close to the equator; it is more frequently diagnosed in the winter; and it is more common in those with dark skin. In sarcoidosis, the body forms a granuloma, or protective shell, that protects the body from further disease, and allows the disease to protect itself from the body’s immune system. Now comes evidence that sarcoidosis is actually caused by a mycobacterium similar to TB.

Sarcoidosis is the most common of the granulomatous diseases to cause vitamin D hypersensitivity. Even the summer sun can trigger high blood calcium in sarcoid patients. The immune cells in and around the granuloma are furiously making activated vitamin D in an attempt to make more of the naturally occurring antibiotics, in this case cathelicidin. As an aside, the activated vitamin D increases serum calcium levels, which is the way sarcoidosis is often diagnosed in the first place.

In other words, the body may know exactly what it is doing by increasing activated vitamin D levels; it is trying to rid itself of infection. This research implies that sarcoid patients need vitamin D, but supplementation should proceed slowly and carefully. Once 25(OH)D levels are around 30 ng/mL (75 nmol/L), increase supplementation by only 100–200 IU at a time, measuring vitamin D, activated vitamin D levels, and serum calcium every month in order to give the body enough vitamin D substrate (calcitriol) to make activated vitamin D, but not enough to trigger dangerous hypercalcemia. I suspect the body may eventually rid itself of the sarcoid infection, if vitamin D supplementation is adequate and if the clinician can tolerate mild hypercalcemia in his patients.1

Vitamin D and Autism

Professor Michael Holick changes his book cover to remove autism as one of the diseases vitamin D “prevents and treats.”

If you bought a copy of Mike Holick’s new book, The Vitamin D Solution, when it first came out in April, your book cover prominently lists autism as one on the many diseases vitamin D “prevents and treats.” However, the latest printing of his book removed autism from the book cover. Which is just as well as the content of the book never contained anything of interest on autism and vitamin D.

Why did Holick remove it? What research was published in the last several months that indicated autism was not related to vitamin D? What discovery?

None, the New York Times insisted he remove it!

NYT: What bothers me about your research is the inflated claims you make for it. You say that one pill can prevent and treat everything from cancer to autism to depression. There has never been a medication that did all that.

Holick: I never said autism.

NYT: It’s on the cover of your book!

Holick: O.K. There has been an association between vitamin D deficiency and autism. More studies need to be done. What I recommend certainly is that autistic children receive vitamin D, because it improves muscle function.

Deborah Solomon. Questions for Dr. Michael Holick, Dr. Sunshine. NYT, March 19, 2010.

Autistic children have much lower vitamin D levels

Researchers from Egypt took the next step in discovering the relationship between vitamin D and autism. They simply measured vitamin D levels in autistic children and compared them to healthy children. The autistic children had much lower levels.2

Vitamin A

Dogs, cats, sheep, and vitamin D

Did you know that dogs and cats cannot make vitamin D in their skin? Predators rely on the vitamin D content of meat (which is substantial when prey animals live in the wild) and predators have developed an enzyme in their skin that degrades vitamin D’s building block, 7-dehydro-cholesterol.

Most grazing animals make vitamin D in their skin, including sheep, goats, pigs, cattle, horses, llamas, and alpacas. Entire flocks of sheep can get rickets, but it due to the flock being put on a crop in the winter that is high in vitamin A. In fact, to sheep farmers in New Zealand, vitamin A is known as the “rachitogenic” vitamin.

The journal Nature had the earliest report, in 1953. The author simply discovered that vitamin A can induce rickets in rats, if the vitamin D intake is kept constant. This was perhaps the first paper to report that vitamin A interferes with the function of vitamin D.3

Talk about the wisdom of animals. If your vitamin D intake was low, would you know enough to instinctively seek the sun? Chameleons do; if their chow does not have enough vitamin D in it, they spend increased time basking in the sun.4

Multicenter, randomized, double-blind, placebo-controlled trial (RCT) shows a fat-soluble vitamin increases risk of cancer and death

One of the reasons so many good scientists are cynical about vitamin D is that they have been through this all before, with vitamin A. Vitamin A’s ability to increase (not decrease) cancer rates, to increase (not decrease) death from cancer, is so robust that a randomized controlled trial (RCT) had to be stopped early because the group assigned to the vitamin A arm had a 46% increased risk of dying from cancer. The dose of vitamin A used was not that that much; equivalent to a couple of tablespoonfuls of cod liver oil per day, but it was enough to kill some of the volunteers taking vitamin A.

One can argue that this risk was just from lung cancer, not all cancers, the study was in people at high risk of lung cancer, not in normal people, the treatment arm included beta-carotene along with retinol palmitate, not simply retinol palmitate, and that an epidemiological study found cod liver oil reduces the risk of lung cancer, not increases it. However, hovering over all of this is the fact that this study was a randomized controlled trial and it found that vitamin A is lethal.5

Keeping this study in mind, think about the dozens of epidemiological studies that measure a vitamin D blood level in blood stored since the 1980s and 90s, and then examine the medical records from the next 20 years to see who dies or develops cancer. Recently a series of papers seemed to show that vitamin D has no role in preventing less frequent cancers. However, where did the subjects in these studies get their vitamin D in the 80s and 90s? Certainly some from the sun; we can get an idea of how much came from the sun by comparing group winter and summer vitamin D levels, the difference, usually about 5–8 ng/mL (12.5–20 nmol/L), means that the average person in these studies got 500 to 800 IU of vitamin D from the sun in the summer, not enough to store for the winter.

If not the sun, how did people in the 1980s and 90s get physiological amounts of vitamin D? There are only three other possibilities, fish, multivitamins, or cod liver oil, as pure vitamin D supplements in meaningful doses were not available in the 1980s and 90s. Multivitamins of that time contained 5,000– 10,000 IU of retinol, together with a variable amount of vitamin D, usually 400 IU. Cod liver oil of that time had more vitamin D then modern cod liver oil and about the same amount of vitamin A as today; two tablespoonfuls may contain 25,000 IU of vitamin A, the same dose used in the fatal study.

Why am I spending all this time on vitamin A? It is called a confounding variable. If subjects in the vitamin D and cancer studies had higher vitamin D levels, and did not get their vitamin D from the sun — and the elderly are the most likely group to heed sun-phobic advice — then where did they get their vitamin D? From fish? Some, but I doubt very much. Without the sun and fish, that leaves only two possibilities, multivitamins and cod liver oil; there is simply no other possibility. And what did these folks get along with their vitamin D from multivitamins and cod liver oil? They got vitamin A, a known carcinogen, and lots of it. Total vitamin A intake is a confounder, an important confounder, and such vitamin D studies that do not measure total vitamin A intakes, from diet, multivitamins, and cod liver oil are flawed, fatally flawed.

Finally, a vitamin A expert at Cornell tells the truth about his favorite nutrient

In The Great Vitamin A Fiasco, Professor Michael Latham of the Division of Nutritional Sciences at Cornell University questions the wisdom of the academic elite of rich countries administering massive doses of vitamin A to the children of desperately poor countries and then congratulating themselves on “lives saved.”

In the 1990s, a small coterie of academics, mostly in the United States, became convinced that vitamin A is the antibiotic vitamin and would prevent infections if administered in massive doses to third world children. The United Nations (UN) got involved, along with drug companies that manufactured vitamin A capsules. That combination meant that the alternative approach, increased consumption of vitamin A-rich vegetables and fruit, had no chance.

It turns out that clinical evidence of vitamin A deficiencies (night blindness and eye lesions that lead to blindness) are now quite rare in third world countries who have never received vitamin A from the UN, probably due to the fact that these particular third world countries now consume more fruit and vegetables than they did in the 1960s and 70s. Remember, unlike vitamin D which is constantly being used up by the body and rapidly excreted, some vitamin A is recycled, especially in the retina where it is used again and again. The rate limiting step for the control of vitamin A in the body is an enzyme in the intestine that increases and decreases production of vitamin A from fruit and vegetables as the body requires.

After the drug companies had teamed up with the UN and the academic elite, nothing could stop the massive overdosing of third world children. Even two randomized controlled trials early this century and a subsequent meta-analysis — all showing massive doses of vitamin A increased, not decreased, infection — could not stop the juggernaut. This means that, in spite of evidence that these massive doses of vitamin A are actually killing some children in the third world, the administration of toxic doses of vitamin A to third-world kids will continue and the end of the “Great Vitamin A Fiasco,” is nowhere in sight.

Cardiovascular Issues

Vitamin D is effective treatment for the muscle injuries caused by statin drugs

The most common side-effect of statin drugs is muscle pain and muscle injury called myositis-myalgia or muscle injury pain. Such injuries account for 95% of the side-effects reported by statin users. Sometimes evidence of muscle injury [elevations in serum creatine kinase (CK)] is severe, with CK levels more than ten times the upper limit. To date, no treatment exists for statin induced myositismyalgia and nothing is known to prevent this side effect of statins.

Now, researchers from the Jewish Hospital of Cincinnati may have discovered both how to prevent it and how to treat it. First they found that higher vitamin D levels tended to protect you against myositismyalgia. Then they took 38 patients with both myositis-myalgia and vitamin D deficiency and gave them 50,000 IU of vitamin D2 every week for 12 weeks. In 92% of these patients the myositis-myalgia disappeared.

While this is not the double blind, randomized controlled trial that is needed, it is pretty strong evidence. So far, four studies have shown that statins increase vitamin D levels (Crestor, Lipitor, Zocor, and Mevacor) while one study (Pravacol) found it had no effect on vitamin D levels. It seems possible, even likely, that many of the good effects of statins are simply due to them increasing vitamin D levels. Think of it, an entire country on statin drugs, at the yearly cost of billions of dollars, due to double-blind randomized controlled trials showing statins reduce mortality, when a better reduction in mortality could be achieved by a little sunshine.6

Randomized controlled trial shows vitamin D reduces a known cardiac risk factor

One of the things that happen to most people, as they grow older, is that arteries designed to be thin elastic balloons turn into thick, stiff pipes. One can measure the stiffness of the artery — the stiffer it is, the less it is like a balloon and the greater the risk of cardiovascular disease. In a remarkable study from the University of Georgia, researchers discovered that even a low dose (2,000 IU/day) of vitamin D for a short period (4 months) began to reverse this process and made arteries more like balloons and less like pipes.7

This study was conducted in African American teenagers during the spring; 2,000 IU per day got the average teenager’s 25(OH)D up to 34 ng/mL (85 nmol/L), still deficient. That is, 50% of the teenagers had levels less than 34 ng/mL (85 nmol/L) after treatment with 2,000 IU/day and none had levels of 50 ng/mL (125 nmol/L), the minimum level the Vitamin D Council recommends for otherwise healthy people. The 2,000 IU/day had no effect on PTH levels, further evidence the dose was inadequate.

The evidence that vitamin D is a strong and independent risk factor for cardiovascular disease is now overwhelming. Mechanisms are multiple and include involvement in hypertension, diabetes, and abnormal lipids, as well as suppression of inflammation, suppression of epidermal growth factor in arterial muscles, induction of prostacyclin in vascular smooth muscle with subsequent prevention of thrombus formation, suppression of macrophages loaded with bad cholesterol lining the arteries (foam cells), and now reversal of stiffness in arteries.

This also makes the recent paper by Dr. William Davis more believable. Dr. Davis used a potpourri of drugs and supplements, most of which have been shown not to reverse atherosclerosis when used by themselves, to achieve improvements in coronary calcification scores. Now, we have independent evidence that one of the things Dr. Davis used, vitamin D, does reverse at least one aspect of the disease.8 If you have atherosclerosis, my advice is to take 10,000 IU/day of vitamin D3 along with vitamin K2. Some fish oil won’t hurt. I predict the vitamin D3 and K2 combination will slowly, but progressively, reverse atherosclerosis!

Evidence-Based Medicine

British Medical Journal publishes study crucial to understanding the place of randomized controlled trials

Evidence based medicine is the mantra for many of the fresh faces just out of medical schools. Everything doctors do should be based on good science they say. However, when queried, the evidence based religion begins to break down. For example, say you had an incurable autoimmune arthritic disease and your doctor, having kept up with the hundreds of vitamin D papers on the immune system, says to you, “we can’t try vitamin D because there are not enough randomized controlled trials.” Your doctor stays true to his religion while your joints head towards irreversible destruction.

With fatal diseases the evidence based system not only fails but runs foul of basic medical morals. I can’t find the quote but it goes something like this, “Physicians have lots of rights but one right they do not have is the right to take away hope.” For this reason, the experienced physician always has something else in their bag of tricks to try. Ethical physicians will never say, “nothing more can be done for you.”

I love the paper written about randomized controlled trials of the effectiveness of parachutes. You can download it in its entirety, thanks to the British Medical Journal.

Vitamin D Dosing

The average vitamin D scientist is now taking 5,000 IU/day

Martin Mittelstaedt deserves a Pulitzer Prize. No reporter, in any country, for any publication, has produced the quantity and quality of vitamin D articles as has Mr. Mittelstaedt for the Toronto Globe and Mail. His latest work was quite simple: Martin thought you would be interested in knowing how much vitamin D researchers take every day. In the article, Dr. Robert Heaney was quoted about a meeting a year ago at the CDC in which nine experts reported how much vitamin D they personally took. The doses ranged from 3,000 to 10,000 IU/day, with the average dose being 5,000 IU per day — exactly the amount the Vitamin D Council has recommended for the last six years.

The one holdout, Professor Roger Bouillon of the Catholic University of Leuven in Belgium, is still back in the last century with 800 IU/day advice. As time marches on, Professor Bouillon is being left further and further behind. One of the reason he recommends such a small amount (800 IU is only 20 micrograms), is because he disagrees that adequate 25(OH)D levels are at least 50 ng/mL (125 nmol/L). He doesn’t believe vitamin D blood levels should be 40 or even 30; he thinks a 25(OH)D level of 20 ng/mL (50 nmol/L) is just fine. One of the reasons he gave, in a 2007 letter to the editor of the NEJM, was that if 30, 40, or 50 ng/mL (75, 100, or 125 nmol/L) was the lower limit of good health, then everyone in Belgium is deficient. He can’t conceive that this could be the case, thus 20 ng/mL (50 nmol/L) must be okay.

Vitamin D nutritional policy needs a vision for the future

The same Professor Bouillon discussed above teamed up with Professor Tony Norman to produce a thought-provoking review article last month. First the authors reviewed the 37 organs that use vitamin D and tried to classify vitamin D’s action into six physiological systems (calcium homeostasis, immune function, pancreatic, cardiovascular, muscle, and brain systems).9

They also discuss toxicity, and predict that levels of 100–150 ng/mL (250–375 nmol/L) will eventually be found to be toxic for some individuals. They base this on mathematics: if 200 ng/mL (500 nmol/L) is toxic for some, then 100 ng/mL (250 nmol/L)will be toxic for a few, once hundreds of thousands of people obtain levels of 100 ng/mL (250 nmol/L). By toxic I assume they mean asymptomatic mild hypercalcemia.

The authors then considered four alternatives for the world. First, do nothing, which is bad they say, as rickets would continue to worsen. Second, fully implement current guidelines, which would be good they say, as it would eradicate rickets. Third, 1,000 IU per day, which would “be beneficial for all major human diseases (cancer plus cardiovascular, metabolic, and immune diseases),” Fourth, 2,000 IU per day, which would “favorably impact the disease states associated with vitamin D deficiency, such as autoimmune diseases…cardiovascular diseases and most cancers.” That is, they seem to recognize that 2,000 IU per day will save more lives than 1,000 IU/day.

However, the authors then recommend the 1,000 IU per day alternative, rejecting the 2,000 IU/day alternative because they say there is not enough science to support it — in particular, not enough randomized controlled trials. That is, these two scientists imply they have done a risk-benefit analysis and are not willing to recommend 2,000 IU/day until it has been proven safe. Time will tell who is right and who is wrong.

Influenza

Two more papers confirm I was right when I wrote Pascal’s Wager and Pandemic Influenza in 2005

In the summer of 2005, I called Professors Reinhold Vieth and Ed Giovannucci after I had noticed that very few of my hospital patients on vitamin D came down with viral respiratory infections during an influenza outbreak. A Science News article, entitled The antibiotic vitamin, subsequently documented my observations.

I remember Reinhold’s reaction the best, something like, “this can’t be true, you must have made up this data.” Ed’s reaction, while doubtful, was more interested in what and when and where and by how much? Next, I wrote the first paper in the medical literature about vitamin D and epidemic influenza, entitled Epidemic influenza and vitamin D, working with co-authors, being careful to credit the person I thought most responsible for the discovery, Edgar Hope-Simpson.

Now, what happened in my hospital in early 2005 seems like old news. For example, a recent paper from Yale University, a really good paper that is open access (you can read the entire paper for free) has only 2,300 views, and no comments, and that in PLoS One, a well-respected journal. The authors simply measured vitamin D levels and discovered that the people who maintained higher vitamin D levels throughout the winter [>38 ng/mL (97 nmol/L)] had a 2.7 times lower incidence of respiratory infection and 4.9 times fewer number of days ill.10 The authors did not credit me with the discovery, instead saying that vitamin D’s ability to prevent respiratory infection “has been suggested for many years.” They then proceeded to use many of the same citations I used in my 2005 paper.

As proof for their “many years” statement, they go on to imply that the long-known association between rickets and respiratory infections was long thought to be due to the antimicrobial effects of vitamin D. This could not be further from the truth. The association of rickets and respiratory infections was explained 50 years ago; it was simple: rib cages weakened by rickets prevented the lungs from defending themselves. No one thought differently, no one at Yale, no one in Bangladesh, no one at Harvard, no one at all; if anyone did question the conventional thinking, they never wrote about it. I challenge Dr. Sabetta of Yale University School of Medicine to produce any paper, written in any language, from any time, that questioned conventional thinking and concluded the alternative hypothesis that I first wrote about in 2005: vitamin D has independent anti-viral actions that explain the increased rate of infections in rachitic children and increased infections in rachitic children are not dependent on weakened rib cages.

By comparison, Dr. Mitsuyoshi Urashima and his Japanese colleagues who recently wrote in their randomized controlled trial that proved vitamin D prevents influenza: “Seasonal oscillation of influenza is prominent, its epidemic is explosive, and it ends abruptly. To explain this peculiar pattern, Cannell et al hypothesized that the seasonal oscillation of serum vitamin D concentrations, which was recently discovered to up-regulate innate immunity, may affect the epidemic pattern of influenza.”11

Invitation Rescinded

Dear Dr Cannell: I have the pleasure of inviting you to participate in the National Institutes of Health meeting entitled “Impact of Micronutrients on Respiratory Infections” in May of 2010. The overall purpose is to examine the role of selected micronutrients in the host responses to respiratory infections and to discuss the feasibility of nutritional supplementation as an adjuvant therapy.

This invitation is an acknowledgement of your overall expertise in this research area. We anticipate that this should be an opportunity to identify challenges, gaps, discuss the complex interrelationships, and how advances in Immunology and genomics (and other “omics”) can shape our current thinking.

Please respond to the following at your earliest convenience:

  1. Your availability for the following dates in 2010 (May, 10–11, June 7–8, or May 17–18, May 24–25); these are listed in priority order
  2. Your recommendation for other speakers
  3. Your recommendation for topics to be considered
  4. Any general comments or concerns

John Doe, MD National Institutes of Health

Dear Dr. Doe: Thank you for the invitation, it is an honor. I accept. As of now, the dates look fine but I don’t have my calendar with me. Sincerely, John Cannell, MD

Dear Dr Cannell: I must rescind my invitation for you to speak. We have had a number of exchanges with the Office of Dietary Supplements and other micronutrient experts at the NIH and, they made some recommendations of speakers and useful suggestions. In that the ODS is sponsoring the meeting, in part, I have had to accommodate their suggestions.

John Doe, MD National Institutes of Health

At first I thought this rescinded invitation was due to the intervention of Paul Coates, PhD, Director of the NIH’s Office of Dietary Supplements. About eight years ago I happened to mention publicly that I thought Dr. Coates was killing thousands of Americans due to his ignorance of vitamin D. Eight years later, I still believe it.

However, Paul Coates was not alone in rescinding my invitation. I have learned that a number of academics, including some invited to speak at the same conference, find it embarrassing that a psychiatrist working at a state mental hospital discovered that vitamin D plays a key role in viral respiratory infections. They objected to having me speak on the same platform as they were going to speak, so they requested that my invitation be rescinded.

Anyway, what a difference a half a decade makes:

  • Everyone now knows, and has known for a long time, that vitamin D helps prevent viral respiratory infections.
  • Everyone now knows, and has known for a long time, that rickets predisposes to viral respiratory infections because vitamin D has antiviral effects.
  • Everyone now knows, and has known for a long time, that influenza occurs in the winter because of low vitamin D levels.
  • Everyone now knows, and has long known, that only professors make important discoveries.

I’m not proud to say that this rescinded invitation upset me terribly. In case you wondered why I didn’t write anything for three months this spring; that was the reason. However, it was nothing but an arrow into my vanity. A friend asked me after he noticed I was still upset two months after the NIH rejection, “Did you do this vitamin D stuff to be famous or to help people?”

“I have come to the conclusion that my subjective account of my motivation is largely mythical on almost all occasions. I don’t know why I do things.” J. B. S. Haldane British geneticist & scientist (1892–1964)

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