Vitamin D

Vitamin D is a fascinating molecule with a fascinating story.  Historically, “vitamins” were defined as chemicals that humans required from their environment that were “vital” to human health.  These chemicals were needed only in very small amounts to prevent disease; an absence of a particular vitamin in the diet led to a specific deficiency disease: vitamin C, scurvy; thiamine, beri beri.  Other vitamin deficiencies were found to be a bit more complicated: vitamin B12 deficiency was found to cause a type of anemia, dementia, and spinal cord problems.

Because vitamins are required in such small amounts, and are often present in small amounts in foods, their discovery was an opportunity to prevent and cure several diseases.  One of these diseases was rickets.

Rickets was common in America and Northern Europe when vitamin D was discovered early in the 2oth century.  A series of fascinating experiments found that a fat-soluble substance present in cod-liver oil had the ability to prevent and cure rickets.  Environmental observations also found that children in the tropics were less likely to develop rickets than those in high northern latitudes, and sunlight seemed to prevent the disease.

This child's bowed legs are typical of rickets

It is nearly impossible to ingest sufficient vitamin D in a typical diet, and it is nearly absent from breast milk.  In areas where sunlight is scarce or where culture prevents sun exposure, rickets was more common. Rickets became rare in the U.S. once children’s parents began shoving them full of cod-liver oil, and once vitamin D was added to milk.

Vitamin D is more properly called a “hormone” rather than a vitamin.  It’s precursor is naturally produced in the body and is present in the skin in large amounts.  When it is exposed to ultraviolet B radiation, as from sunlight, this precursor is converted to another molecule that is absorbed into the blood stream.  It travels to the liver where it is converted into a “prohormone” (precursor to a hormone).  After leaving the liver, the prohormone can be converted in the kidneys to the hormone form of vitamin D on a (relatively) large scale to be distributed throughout the body, or it can be converted on a small scale in local tissues.

Vitamin D receptors are present in nearly every tissue in the human body.  Aside from its effects on bone growth, its various effects are only incompletely understood.   But is the prevention of severe vitamin D deficiency such as rickets all we need to know? Growing evidence is suggesting that vitamin D deficiency is more common that previously believed, and that vitamin D may play an important role in many common diseases such as heart disease and cancer.

In the early part of the century, scientists fed rats very limited diets, teasing out the effects of various foods and the micronutrients they contained, including vitamin D.  Such controlled experiments are, needless to say, problematic in humans.  Rickets was a common, even endemic, disease, and therefore not terribly difficult to study.  But other effects of vitamin D may be more subtle.  Attempts have been made to correlate other disease states with the relative deficiency in vitamin D that is still common in high latitudes.  Part of the difficulty in studying the effects of low vitamin D levels is in simply defining them.  Assays that measure vitamin D in the blood are not entirely reliable.  Still, we can try to correlate vitamin D levels with obvious deficiency diseases such as rickets, but the environmental studies that look at other possible effects are problematic.

Heart disease is one of our three biggest killers (along with cancer and stroke).  One of the better prospective studies done on vitamin D and heart disease followed subjects over time, measuring vitamin D levels and following them to see who developed a first incidence of heart attack.  They found that those with low vitamin D levels who also had high blood pressure (a well-recognized risk factor for heart disease) were more likely to develop a first heart attack than hypertensive patients with higher vitamin D levels.

These data are intriguing, but because low vitamin D levels and heart disease are both very common, and because this was not an interventional study, it is difficult to draw firm conclusions, other than more research is probably warranted.

Other studies of the effects of low vitamin D are more problematic. Vitamin D has been convincingly correlated with all-cause mortality, with certain cancers, and with multiple sclerosis.  But causation is very difficult to attribute in these cases.  Vitamin D deficiency is common in people with poor diets (including obese people) and in people who are relatively inactive.  These are independent risk factors for mortality, heart disease, and some cancers.  And while some cellular mechanisms have been discovered that may lend plausibility to a vitamin D hypothesis, there are as of yet no convincing data that allow us to draw conclusions about vitamin D and these diseases.

Low vitamin D levels are quite common, and it is nearly impossible to attain adequate levels with diet alone.  We know that vitamin D is necessary to prevent rickets, and that, combined with calcium, it is needed to prevent osteoporosis.  We do know that sun exposure will ensure an adequate level of vitamin D and because of a clever regulatory mechanism, will never result in excess vitamin D.  But we do not know what a “safe” level of sun exposure is.  We know that the relationship between sun exposure, photoaging of the skin, and skin cancers is dose-dependent, but we don’t know where to place the fulcrum in balancing the need for vitamin D and the risk of cancer.

Supplementation is effective in raising vitamin D levels, but we do not yet know what an “optimum” level of vitamin D is, and we don’t know what the long-term effects of supplementation may be.  Other fat soluble vitamins have been found to actually increase the risk of cancer if supplemented too aggressively.

The vitamin D story is fascinating, and despite over a century of study, it is still playing out.  While we can draw some pretty safe conclusions about the prevention and treatment of some common bone diseases, it is too early to form any useful conclusions about other diseases such as cancer, influenza, or multiple sclerosis.  Given our limited knowledge, recommendations on screening and treatment for vitamin D deficiency in reasonably healthy people are neither clear nor final.  We have a set of plausible and interesting hypotheses to work with, and now we need some randomized controlled trials to give us data we can really use.

Selected References

Wang, T., Pencina, M., Booth, S., Jacques, P., Ingelsson, E., Lanier, K., Benjamin, E., D’Agostino, R., Wolf, M., & Vasan, R. (2008). Vitamin D Deficiency and Risk of Cardiovascular Disease Circulation, 117 (4), 503-511 DOI: 10.1161/CIRCULATIONAHA.107.706127

Holick, M. (2007). Vitamin D Deficiency New England Journal of Medicine, 357 (3), 266-281 DOI: 10.1056/NEJMra070553

IARC. Vitamin D and Cancer. IARC Working Group Reports Vol.5, International Agency for research on Cancer, Lyon, 25 November 2008 (pdf)

Rajakumar, K. (2003). Vitamin D, Cod-Liver Oil, Sunlight, and Rickets: A Historical Perspective PEDIATRICS, 112 (2) DOI: 10.1542/peds.112.2.e132

Brannon PM, Yetley EA, Bailey RL, & Picciano MF (2008). Overview of the conference “Vitamin D and Health in the 21st Century: an Update”. The American journal of clinical nutrition, 88 (2) PMID: 18689388

19 Comments

  1. JM_Shep

     /  August 18, 2010

    This example of the complexity of ONE vitamin just goes to show that the high vitamin doses recommended by quacks cannot be the panacea they claim to be. These vitamins and minerals all evolved together, making the web they weave particularly hard to untangle.

  2. While you have it in your head to look at vitamin D, check to see any studies done for vitamin D and depression, especially the Seasonal Affective Disorder (SAD), which has been treated in the past by exposing people to full-spectrum lighting (read EXPENSIVE).
    My thoughts were. all the lights were doing was getting enough UVB on folkes skins to do the magicks of making their own vitamin D as shown in the article.

    P

  3. Nathan Myers

     /  August 18, 2010

    Other fat soluble vitamins have been found to actually increase the risk of cancer if supplemented too aggressively.

    Would that “found to” refer to trials of synthetic DL-alpha-tocopherol acetate? I don’t think DL mixtures, or isolated alpha-tocopherol, occur in nature. It leads me to wonder whether the effect of “aggressively supplemented” vitamin E was being tested, or L- isomers and relative deficits of the other forms of tocopherol and tocotrienol.

  4. I was thinking more of beta-carotenes. But the concept stands, whether found “naturally” or not. What I’m speaking of here, and perhaps I wasn’t making it clear, was exogenous supplementation rather than sun exposure. It is nearly impossible to get enough vitamin d from a typical diet.

  5. Nathan Myers

     /  August 19, 2010

    Similar remarks apply to beta-carotenes, of course. In nature they are never found all of one type. (Unlike, e.g., ascorbic acid.) When you say “the concept stands”, does that mean you assume that the results of any trial of one mix of chemicals would match that of any other mix that happens to share the same shelf label?

  6. Perhaps you could de-saladify that question?

  7. Nathan Myers

     /  August 19, 2010

    I’m asking what you mean by “the concept stands”. You seem to be implying that if someone conducted a similar trial, but supplemented with tocopherols and tocotrienols in forms and proportions that occur in dietary sources, the increased mortality found with isolated D,L-alpha-tocopherol acetate alone would be expected. Does any evidence lead you to this conclusion, or are you simply assuming it, or have I misunderstood your intention?

  8. No, I mean that just because it may sound plausible that supraphysiologic supplements of fat soluble vitamins may do something good doesn’t mean that it will be found to be a correct supposition when studied in depth.

  9. Nathan Myers

     /  August 19, 2010

    You seem to be suggesting that supplements of fat-soluble vitamins were found not to do something good. Approximate analogs of vitamins were so found, but we still don’t know about the actual vitamins. This is not to say that your final statement is, technically, incorrect, but the published trial results don’t seem to serve as an example of it unless you relax, a little too conveniently, the definition of “vitamin”. It’s only after a non-dietary analog has been shown to perform as well as the real thing, in every way, that it can defensibly be called a vitamin. That’s not necessarily easy, but nobody said it was.

  10. Dianne

     /  August 19, 2010

    Folic acid, a water soluble vitamin, may be problematic in some cancers as well. (See, eg here

  11. Nathan, it’s not that I don’t agree with you, it’s just that, in this case, you’re not even wrong.

  12. leigh

     /  August 19, 2010

    solid writing, as usual Pal.

    there are a handful of clinical trials out there, but they are small, their controls are questionable, etc. i think it would be very useful to have any kind of baseline to leap from here, as opposed to the lack of footing that most people handwave around when they recommend astronomical levels of supplementation.

    we don’t know if low vitamin D levels are causative, if they’re associated with a causative factor but not causative on their own, if they’re a symptom of something else gone wrong, if they’re an adaptive response to something else gone wrong, etc. to simply state “low vitamin D causes cancer” does not reflect the current state of knowledge. we are nowhere near that certain.

  13. Nathan Myers

     /  August 19, 2010

    I don’t ask you to agree with me. I only ask that you try to be scrupulous about the truth.

  14. If you are going to accuse me of being untruthful it might be reasonable to demand of you something more than non-sensical word salad.

  15. Vitamin D deficiency could potentially a big problem here in Norway with the little sun get, but we have a solid tradition of supplementing with cod liver oil (everyday folk lore says it “makes you strong” just like Popeye’s spinach :P), and of baking ourselves in the sun at absolutely every single possible occasion. (Which, naturally, results in elevated skin cancer rates – especially since Norwegians are so desperate to get a tan that they don’t use sunscreen much.) And, of course, the lack of sun is causing problems for those immigrants that are significantly darker-skinned than us Norwegians, so some types of milk is fortified with extra vitamin D, and vitamin D drops are free for children of non-western immigrants. Fairly big studies show that low vitamin D levels is common in people of Pakistani descent here in Norway, but that it didn’t affect the incidence of osteoporosis as much as it would in those of ethnic Norwegian descent. (But then, we are a brittle sort… :P)

    Tl;dr – vitamin D is interesting. Thanks for the post 🙂

  16. I enjoyed your post on KevinMDs blog regarding placebo and I subsequently found my way to your site. Having the placebo effect fresh in my mind, I wanted to offer a simple case study related to vitamin D. I had the most horrific hip pain several years ago. I suffered and did nothing to get it checked out. A bit of denial I suppose. I was having a regular visit with my endocrinologist and he suggested I check my vitamin D level because my mother was severely deficient and he thought that was enough to warrent a blood level check. At that time, I did not connect vitamin D with my hip pain. Of course, it turned out I was extremely deficient and was started on 1000mg vit D daily. It barely raised my level to the bottom of the normal range. But after two weeks of supplement, my hip pain was completely gone! After reviewing everything I had done, it was only adding vit D that was different. I now swear it was the vit D that cured my pain. And I am quite thankful for the relief! Bottom line, sometimes listening to our patients and starting with case studies is what leads to great research studies. So listen to your patients, the clues are all there.
    LauraNP

  17. Kevan Gelling

     /  August 24, 2010

    I don’t think that there is any question now, that vitamin D deficiency is linked to a number of diseases. The question is, as you say, does low vitamin D cause morbidity or is it caused by morbidity?

    There is a heap of epidemiologic studies that link latitude, season and skin colour to increased morbidity risk (e.g. increased cancer risk at latitude, better cancer survival rates in summer, increased cardiovascular disease with increased skin pigmentation). All affect the amount of UVB light available to make vitamin D in the skin – the prime source of vitamin D. Combined, the studies suggest that less vitamin D production = more disease. If vitamin D was ‘bad’ then lower latitude, summer season and light skin would be associated with increased morbidity not the reverse.

    It’s worth noting that the laboratory (in-vivo) and animal (in-vitro) experiments that show vitamin D’s effect on key parts of animal physiology, an increasing number of small RCTs showing efficacy and a 4 year RCT found that vitamin D plus calcium supplementation lead to a 60% reduction in cancer risk (1).

    The science is almost there. It just needs a couple more intervention RCTs to win over the doubters. A new 5 year trial sponsored by NIH started this year which should help.

    References

    1) Lappe, J. M., Travers-Gustafson, D., Davies, K. M., Recker, R. R. & Heaney, R. P. Vitamin d and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85, 1586-1591 (2007). URL http://www.ajcn.org/content/85/6/1586.abstract.

  18. gnuma

     /  August 29, 2010

    Thanks for picking this up, nice post. My mom was put on a high D dose for a bit, and my doc recommended a D supplement for me as well. Given that we don’t know what the optimum level of D should be, can you explain why docs are suggesting supplementation?

  19. While we don’t have perfect evidence, there is a good deal of circumstantial evidence and plausibility as to how to assess and treat Vitamin D deficiency, but we need a lot more data.

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