Vitamin D has been associated with numerous health benefits, including cardiovascular and immune health, bone strength, and prevention of cancer. However, studies claim that most of us are deficient in vitamin D, and thereby unnecessarily vulnerable to increased heart disease, stroke, cancer, diabetes, osteoporosis, infection and autoimmune disorders. According to a review of recent studies in Natural News, there is a woldwide epidemic of vitamin D deficiency: 59% of the population is “vitamin D deficient”. The article goes onto to speculate that “What’s becoming increasingly clear from all the new research is that vitamin D deficiency may be the common denominator behind our most devastating modern degenerative diseases.”

Supplementation with vitamin D capsules is advocated even by “primal” advocate Mark Sisson, normally one to take inspiration from our paleolithic ancestors, shunning medication and embracing a lifestyle of eating whole foods and engaging in moderately stressful, playful exercise:

We can’t all bask in the midday sun.. For those of us unable to run shirtless and shoeless through a sun kissed meadow…our option is oral intake… food will help, but it won’t suffice. You need something stronger. ..take a good D3 supplement if you can’t get real sunlight. As long as you don’t go overboard on the dosage, you’re good to go. If it’s not in an oil-based capsule, just take it with a bit of fatty food (not a stretch for an Primal eater). It travels the same pathway and results in the same benefits. It’s always easier to just let nature take its course, but it’s not always realistic. A good general rule is 4000 IU per day.

Therefore, we should supplement with vitamin D. Right?

Not so fast. A closer examination shows that low vitamin D levels may be a consequence, not a cause, of poor health. And that supplementation with Vitamin D may actually be counterproductive. Let me explain.

Homeostatic regulation. First, I’d like to return briefly to a previous post I wrote. In The case against antioxidants, I presented evidence that supplementation with antioxidants is not only unhelpful, but may actually be counterproductive. In my article, I surveyed several meta-analyses of the antioxidant vitamins A, C, and E — demonstrating a lack of benefit from supplementation, and in some cases positive harm. At first, this result surprised me. How can one explain it? After all, we know that vitamin-rich fruits, vegetables and herbs are good for us. Extracts from these anti-oxidant-rich foods have been shown to neutralize reactive oxygen species (ROS) in the lab. Hence, it must be the case that fruits, vegetables and herbs are good for us because of their antioxidant content – right?

Wrong. As we all know, correlation does not always imply causation. And it turns out that fruits, vegetables and nuts may improve our resistance to oxidative damage for reasons other than their antioxidant content. A more likely reason is that these foods are rich in polyphenolic phytochemicals–such as bioflavanoids– that stimulate the cells in our bodies to turn on a transcription factor called Nrf2, which activates our “xenobiotic” defense system. This xenobiotic defense system or Antioxdiant Response Element turns on the production of a number of endogenous anti-oxidant enzymes–such as superoxide dismutase and glutathione peroxidase–that inactivate ROS species catalytically. That means that unlike the antioxidant chemicals in foods–which quickly get used up one-for-one when neutralizating oxidant molecules–the anti-oxidant enzymes turn over thousands of times, and are thus far more potent and sustainable defenses. In addition, these enzymes are produced in cells throughout the body, localized where they are needed most.

In short, empowering our in-born antioxidant defense system is much more effective than supplementing with chemical antioxidants.

But what is even more startling is that supplementing with endogenous antioxidants can actually suppress your body’s endogenous ARE defense system. Startling, but not too surprising once you realize that the ARE system is homeostatically regulated. That means that your metabolism compensates for external changes by making the appropriate internal changes in order to restore a rough balance. Just as body temperature, blood glucose, and countless other internal variables are regulated, our defenses against oxidative stress are regulated.

Homeostatic regulation, ubiquitous in biology, evolved to help us adjust to changing circumstances, and to conserve resources. If antioxidants are supplied from the outside, there is less need to spend energy and internal resources making our own anti-oxidant enzymes, so the organism turns town their production. In my earlier article, I surveyed studies showing that this is just what happens, concluding:

So it appears that, by consuming more antioxidants, we become dependent upon them and perversely reduce our innate ability to detoxify. With any let-up in the constant supply of external defenses, we become more vulnerable to oxidative and inflammatory attack. And the externally supplied antioxidants themselves are in any case much less effective than the endogenous ones.

I ended by recommending that we select foods and herbs not for their anti-oxidant content, but rather for their hormetic ability to stimulate our native ability to produce’s its own detoxifying antioxidant enzymes. At the top of that list are brightly colored and bitter foods and herbs, such as broccoli, blueberries, red peppers, curcumin, green tea and even chocolate.

The moral of the story: When possible, build your own capacity rather than relying on external supplies.

Now on to vitamin D. Not everyone realizes that this “vitamin” is actually a hormone — a secosteroid in the same family as other steroid hormones like testosterone and cortisol. As a hormone, the primary function of vitamin D is to regulate levels of calcium and phosphorus in the bloodstream, thereby promoting healthy bone formation. But vitamin D also regulates a number of other important processes in the body, such as activation of both the innate immune system and the adaptive immune system.

The diet can supply vitamin D as either D2 (ergocalciferol, from plants) or D3 (cholescalciferol, from animals), but it is most effectively synthesized in the skin by the action of UV-B rays in sunlight acting on 7-dehydroxycholesterol. (Yes, it all starts with cholesterol!). But neither D2 nor D3 — the molecules present in supplements or food — are biologically active forms of the vitamin. The diagram at right shows how vitamin D must first be converted by hydroxylation to calcidiol (usually designated as 25 (OH) D, or just “25-D”) in the liver and then further hydroxylated to calcitriol (1,25 (OH)2 D or just “1,25-D”) in the kidney. It is the 1,25-D form that is biologically active, binding to the vitamin D receptor (VDR) and activating a cascade of important biological functions, such as calcium absorption in the intestines. So a well-functioning liver and kidney are required in order for vitamin D to be effective.

Vitamin D studies. Nobody doubts the important role of vitamin D in the body. But are higher levels of a hormone like vitamin D–whether or not provided as a supplement– always a good thing? Well, that is far from clear. In a review of vitamin D studies in The End of Illness, David Agus, professor of medicine at University of Southern California, cites both positive and negative consequences of increased vitamin D levels. On the positive side, a 2009 study presented by the Intermountain Medical Center in Utah, following 27,686 men older than 50 years over the course of a decade, found that those with the lowest levels of vitamin D had:

90% higher incidence of heart failure

81% higher incidence of heart attack

51% higher incidence of stroke

Pretty impressive association! And yet Agus also cites two negative studies worthy of comment:

A 2010 double-blind, placebo-controlled study, published in the Journal of the American Medical Association, found that older women who received annual oral high-dose vitamin D had an increased risk for falls and fractures.

A 2008 study, published in the Journal of the National Cancer Institute, found that vitamin D does not reduce the risk of prostate cancer, and furthermore that higher circulating levels of 25-hydroxyvitamin D may be associated with an increased risk of more aggressive forms of prostate cancer.

Correlation vs. causation. Agus points out that most of the vitamin D studies are “observational studies” that show associations. They uncover a correlation bertween vitamin D levels and some other condition. But they don’t show cause and effect. The few mechanistic studies of vitamin D action were mostly carried out in cell culture, for example adding vitamin D to breast cancer cell cultures suppressed their growth. But in real humans, vitamin D is part of a homeostatic regulation system. Vitamin D doesn’t just do one thing, like promote bone growth. It is involved in as the regulation of as many as 2000 genes, turning up the expression of some, turning down the expression of others.

So how do we interpret these associations? As Agus points out, in regard to the Utah study:

An association, however, does not prove cause and effect. Another way of looking at this study is to say it’s quite possible that a heart condition lowers vitamin D levels, directly or indirectly— by keeping people with health challenges indoors and out of the sun. Also, obesity throws another wrench into the problem because excess fat absorbs and holds on to vitamin D so that it cannot be properly used in the body. Hence, is low vitamin D in this study just a marker for those who were obese? It’s the old chicken-and-egg conundrum. The same can be said for hundreds of other such studies that link the health (or lack thereof) of an individual to levels of vitamin D.

This is the key point: Low vitamin D levels may be a biomarker for other problems. It may be the consequence, rather than the cause, of certain conditions such as heart disease or obesity. For the same reason, high vitamin D levels may be a biomarker for good health. Agus quotes Dr. JoAn Manson, chief of preventive medicine at Brigham and Women’s Hospital:

People may have high vitamin D levels because they exercise a lot and are getting ultraviolet-light exposure from exercising outdoors. Or they may have high vitamin D because they are health conscious and take supplements. But they also have a healthy diet, don’t smoke, and do a lot of the other things that keep you healthy.

If vitamin D level in the blood is merely a biomarker, a consequence of good or bad health, then adding vitamin D to the diet will not necessarily improve your health. To really know whether vitamin D supplementation is beneficial, we need to look at interventional studies, where supplements are provided, and the outcomes are compared with those of control subjects who don’t get the supplement. In fact the two above-cited studies on the effects of supplementation on bone fractures in older women, and prostrate cancer in older men are two such interventional studies. And they showed that vitamin D supplementation was harmful in both cases. And note that the positive Utah study I cited above–showing a correlation between low vitamin D levels and elevated incidence of cardiovascular disease and stroke–was an observational study, not an interventional one. The men in that study with the higher vitamin D blood levels and lower incidence of heart disease were not given supplements.

Vitamin D levels are homeostatically regulated in our bodies, and this process varies with your genetics and health. As one examlple of this, people with lighter skin color and less melanin in the skin evolved to make higher vitamin D levels even with reduced sun exposure; the converse is true of those with darker skin. (This may explain why African Americans are at much higher risk for vitamin D “deficiency”, particularly if they live in higher latitudes and work indoors). People vary widely in the level at which they regulate vitamin D levels in their blood — it tends to be homeostatically controlled in a given individual, but the “normal” level may vary between 8 and 80 ng/ml, or even more widely than that. Vitamin D levels are are genetically controlled by 3 or 4 genes, and are under control of the vitamin D receptor. (This homeostatic regulation of vitamin D levels will sound familiar to those who read my previous post, “Change your receptors, change your set point“). As Agus notes,

When your cells are deluged with vitamin D…they will pull back on their sensitivity to vitamin D by reducing their number of receptors for vitamin D. But if there’s a perceived shortfall of vitamin D in the bloodstream, your cells will up-regulate— create more receptors for vitamin D— to become more sensitive to every vitamin D molecule that passes by. What happens, then, when we consume lots of vitamin D from unnatural sources such as supplements? (I use the term unnatural to imply that it’s not coming from the sun, which is a source of vitamin D that has built-in regulatory mechanisms.) No doubt our bodies are adept at adjusting using their feedback loops as I just described, and the constant surplus of vitamin D means our cells are constantly down-regulating. If we took the supplemental vitamin D away, our cells would up-regulate to make up the difference. Vitamin D has multiple downstream signaling molecules, for the vitamin D receptor signals several reactions.

So if you take vitamin D supplements, and vitamin D is regulated homeostatically, your body will turn down its endogenous production of vitamin D. If you believe that vitamin D is a “biomarker” of good health, do you really want to turn down the upstream processes that synthesize vitamin D? Think about that before you pop a vitamin D capsule.

Unintended consequences. Even worse, taking vitamin D supplements may actually suppress the immune system. This “alternative hypothesis” of vitamin D has been put forward by Trevor Marshall and Paul Albert. Supplementation with vitamin D will tend to increase levels of the inactive form of vitamin D–that is, 25-D. Conversion of inactive 25-D to active 1,25-D in the kidneys is not immediate, and may not be efficient, particular if kidney function is less than optimal. Now here is the problem: While both the inactive 25-D and active 1,25 bind to the vitamin D receptor (VDR), only the 1,25-D turns on the VDR, allowing it to perform its beneficial functions; the inactive 25-D actually inhibits the VDR. This is a problem because the VDR is the “gate-keeper” of the innate immune system, regulating over a thousand genes. So elevated levels of 25-D can result in immunosuppressive effects. As Albert writes in Vitamin D: the alternative hypothesis:

Indeed, the secosteroid 25-D may exert palliation on the innate immune system not unlike the way corticosteroids exert palliation on the adaptive immune system. So is it possible then that supplemental vitamin D is now perceived as a wonder substance simply because it effectively palliates the inflammation associated with diseases across the board? If so, this would certainly explain why its effects are most noticeable in the short-term and why efficacy often diminishes in the long-term.

And we need to also take into account the regulation of vitamin D levels through homeostatic feedback processes. Consider that it is typically the 25-D form of vitamin D–not the biologically active 1,25-D– that is measured in blood tests. And there is very little correlation between the active and inactive forms, as shown in the the figure below, from a 2009 study by Blaney et al., published in the Annals of the New York Academy of Sciences in a sample of 100 Canadian patients. As the authors note, while many of the subjects had very low levels of 25-D–the type reported in most blood tests–most of them had levels of 1,25-D elevated above the normal range. Can those subjects with low levels of 25-D but elevated levels of the biologically active 1,25-D truly be considered vitamin D deficient?

Because low levels of 25-D are often associated with inflammatory conditions such as cardiovascular disease and autoimmune disease, people jump to the conclusion that low 25-D levels are a cause of the inflammatory condition. On this point, listen again to Albert:

Yet, the alternative hypothesis must be considered – that the low levels of 25-D observed in patients with chronic disease could just as easily be a result rather than a cause of the inflammatory disease process. Our research suggests that this is the case. Indeed we have found that 1,25-D tends to rise in patients with chronic disease and that these high levels of 1,25-D are able to downregulate through the PXR nuclear receptor the amount of pre-vitamin D converted into 25-D, leading to lower levels of 25-D. I describe this finding further in my paper. So are we really facing an epidemic of vitamin D “deficiencey” or are we simply beginning to note more signs of an imminent epidemic of chronic disease – an epidenmic which would be exacerbated by increasing the amount of vitamin D added to our food supply?

So the body is making enough active vitamin D to deal with inflammation–maybe even too much, leading to downregulation of the inactive 25-D precursor. Trevor Marshall has also pointed out that elevated levels of 1,25-D may result from impaired activity of the VDR, which is essential for innate immunity. The excess 1,25-D can cause problems with other secosteroid receptors in the body, such as the thyroid receptor. But adding more 25-D, beyond what is needed, will tend to only further inhibit the VDR, interfering with its beneficial anti-inflammatory actions, and impairing innate immunity. In other words, well-intended supplementation with Vitamin D3 may actual backfire. Something to think about!

Marshall is currently conducting studies with a protocol involving restriction of vitamin D and use of an agonist drug that binds to the VDR receptor, upregulating it, and acting as an immuno-stimulant to treat immune disorders like arthritis and multiple sclerosis. Marshall’s protocol is controversial, because it flies in the face of the orthodoxy about Vitamin D. He acknowledges that vitamin D supplementation can indeed deliver some short term benefits because it acts as an immuno-suppressant–in much the same was as corticosteroids like prednisone. But just as prednisone is useful for acute treatments, yet is harmful if taken chronically, the immune-suppresant effects of vitamin D on the VDR may be detrimental.

One need not go to the extent of restricting or avoiding vitamin D to exercise some caution about actively supplementing it. If supplementation has risks, is there anything you can do to ensure adequate levels of the active form of vitamin D? Certainly, it is important to have at least an adequate level of D3 entering the liver, by eating foods rich in vitamin D, and through biosynthesis from adequate exposure to sunlight. But you also want to make sure that the conversion processes to 25-D in the liver and 1,25-D in the kidneys are functioning well. Which means eating a low-inflammatory diet — that is, one that is low in sugars, processed omega-6 vegetable oils and other pro-inflammatory compounds.

Here is the takeaway from this vitamin D story, together with my earlier post about antioxidants: Inflammatory conditions, such as heart disease, infection or autoimmune disease are often associated with reduced levels of certain biomarkers in the blood, such as antioxidant vitamins or hormones. Our natural instinct is to conclude that these are “deficiencies” that need to be corrected. While that may sometimes be the case, particularly in extreme cases, you should keep in mind the direct supplementation with additional vitamin or hormone may actually be counterproductive–by shutting down or impairing your body’s own ability to mount it’s own defense against oxidative stress and inflammation.

Rather than taking hormone and vitamin supplements, it is more effective to stimulate your body to strengthen its own defense and detoxification systems. I’m not against all supplementation — for example, I believe that ingestion of phytochemical-rich vegetables and herbs is useful as a hormetic stimulus. But I think we have to overcome the simplistic notion that if X is a good thing, we should consume more of X.

The body is more than a repository for chemicals — it is a self-regulating organism with hundreds of complex and dynamic feedback loops, evolved to enable us to adapt to changing circumstances and meet many challenges. We should take care that what we ingest is used to build up our natural capacities, not subvert them.

February 11, 2013 update: For suggestions on how you might be able to get the benefits of vitamin D supplementation without the possible downsides, see the more recent post: An alternative to vitamin D supplements?

December 7, 2013 update: A comprehensive review of 290 vitamin D interventional studies and 172 randomized trials, published in this month’s Lancet, adds further support my thesis that vitamin D levels are a consequence, not a cause, of health status

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70165-7/abstract

Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. 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. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

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