First let me thank you all for your patience in waiting for this post and for your interest in the blog. I’ve lately been a bit busy with my day job. I also have duties managing various investments and being the building maintenance and IT guy for my wife’s dental practice, so there may be slow periods from time to time as a result.
You have no doubt also noticed that this is, so far, not one of those “here is what I ate today” blogs. Nothing wrong with that - I have a good camera - it’s just not my focus. The ratio of background reading and research per post is usually high and likely to stay that way.
I am very gratified by the positive response to the site. I first began this as a resource for patients and friends only 2 months ago. I don’t have one of those page-counter-gadgets displayed but the site has had over 7,000 unique visitors and about 35,000 page hits in that time. Your interest and intelligent questions help motivate me to learn more and keep blogging, so thank you all for that.
On to the topic.
Vitamin D is a prohormone or hormone precursor and not really a vitamin. Like cortisol and the sex hormones estrogen and testosterone, it is derived from cholesterol molecules. It is technically a secosteroid, as it is derived from cholesterol with the “3’ ring broken open.
Vitamin D is phylogenetically old, being found in simple organisms that have been around for as long as 700 million years. A molecule being preserved through that much evolutionary time is usually a clue that it could be important. Ultraviolet light (UV) is part of the spectrum of solar irradiation that has bathed the earth since before life began. (Before the air was poisoned by oxygen and the ozone layer formed, there was much more incident UV than now.) Vitamin D2 (ergocalciferol) is the more ancient plant and fungal version of D and is formed from cholesterol with UV light. D2 may have originally evolved as a kind of sunscreen in these simpler organisms. Animals evolved a chemically different form of D, called D3, which is formed via UV light and 7-dehydrocholesterol. Animals with feathers or fur create D3 photochemically within the oils on their feathers or fur, and then lick themselves to get their dose of D. Humans make D3 in the bottom two layers of their epidermis in a photochemical reaction driven by UV in a narrow band centered on about 297 nanometers wavelength – known as UVB. This opens the 3 ring in 7-dehydocholesterol and there follows a quick thermally driven isomerization:
This results in vitamin D3 or cholecalciferol, which goes to the liver and is converted to 25-hydroxycholeclaciferol or 25 (OH) D. 25 (OH)D is what we are most interested in clinically and nutritionally. It is the blood and tissue levels of 25 (OH) D that determine your Vit D status. 25 (OH) D is fat soluble and stored in adipose tissue and clinically these fat stores of D have a half life of about 2 months so it takes a few months of darkness to get deficient if you start out healthy, but it would be hard to still be stoked up after 6 months of a Wisconsin winter. When you replace D orally, you are usually taking D3 as Cholecalciferol – it is absorbed in the gut and carried into the blood in chylomicrons, makes its way to the liver and is then converted to 25 (OH)D.
The much more high-potency active form of Vit D has an extra hydroxyl group and is 1,25 (OH)D or calcitriol. Calcitriol is found in concentrations about 1000 times lower than 25 (OH) D in the serum. This is important as although 25 (OH)D has some end-organ effects, including on its own synthesis, the major hormonally active D is calcitriol. The kidney is one primary end organ mediating the classical effects of Vit D and it is here that 25 (OH)D is converted to calcitriol like this:
This calcitriol made in the kidney then circulates and acts on the classical target organs of the gut, the bones and the kidney itself. The effects on these organs center around calcium ion homeostasis. Calcium levels must be tightly controlled for proper cell functioning, so it is no surprise that calcitriol levels are tightly controlled regardless of 25 (OH)D levels. One can therefore be 25 (OH)D deficient and have normal serum calcitriol levels. That is why you must measure 25 (OH)D to assess Vitamin D status and not calcitriol. 25(OH)D in the serum is in equilibrium with tissue stores of 25 (OH)D and these levels are the ones that determine health or deficiency.
Classical effects of Vitamin D
The classical effects of Vitamin D are the ones I was taught in medical school. They have been known for the longest and are well understood. The focus is on maintaining appropriate calcium levels, as multicellullar animals that have circulatory systems need a calcium ion concentration that is fairly constant, regardless of eating schedules, hydration status, etc., in order for cells to work properly. Vitamin D and parathyroid hormone (PTH, secreted by 4 or so ridiculously tiny glands behind the thyroid gland in your neck) work in concert to balance calcium absorption in the gut, filtration of calcium and phosphorus at the kidney, and turnover of hydroxyapatite in bone. Hydroxyapatite composed of calcium and phosphorus is the “concrete” of your bones, providing compressive strength. You can think of the collagen matrix in your bones as the “steel rebar”, providing tensile strength and elasticity. A tired metaphor, but it works for me.
Your body emphasizes staying alive first, so bone strength is secondary to calcium homeostasis when push comes to shove. You could say that when calcium is short in the bloodstream, PTH will view your endoskeleton as a big reservoir containing 1 kg of calcium. When you are a Paleolithic human, with minimal clothing and forced to spend time outside foraging, your D levels and calcium levels are concordant with the way the EM2 has selected us to function. When you are a Neolithic human (like, say, a radiologist working in a windowless room and living at 45 degrees north!) your 25(OH)D levels are suddenly chronically artificially low, and hey, not my design, but now you are absorbing 15% of your dietary calcium instead of 70%, and you are peeing out more in your urine. Your serum calcium levels come before your bone strength, so now PTH (in one of it’s actions) increases and acts to encourage specialized bone cells called osteoclasts to literally start dismantling the hydroxyapatite “concrete” in your bones in order to supply your blood with calcium.
Rickets and Osteomalacia
So if you are a Neolithic human that has just been weaned, and you live in the late nineteenth century in London, which is not only far north but has what little sun is there being screened by soot, your growing skeleton may be affected by Rickets – severe hypovitaminosis D in the skeletally immature- and you may end up bow-legged or knock-kneed. If you are an adult with a mature skeleton, there will not be the same deformity, but you may have osteomalacia - collagan matrix “rebar” is laid down but there is inadequate hydroxyapatite “concrete”. This can have a painful periostitis in addition to weakening of the bone.
Osteoporosis means lower than desirable bone density with increased fracture risk and is a condition endemic in older folks on a Neolithic diet. It is different from osteomalacia in that the ratio of collagen matrix “rebar” to hyroxyapatite “concrete” is correct, but the total bone mass and density is low. Neolithic osteoporosis is probably multifactorial, in my opinion mostly caused by excess grain consumption, inadequate consumption of animal products in general and animal fats in particular, and is likely most related to low vitamin D and low Vitamin K2. When the D deficiency is severe, there is secondary hyperparathyroidism and PTH is measurably elevated in response to low calcium levels. Vitamin K2, especially Menaquinone or M4, is a cofactor for osteocalcin (which helps make bone) and Matrix Gla protein (which helps remodel or remove it). Please see Stephan’s fascinating posts on the importance of K2 for proper maxillofacial development, bone and dental health and cardiovascular health. K2 is also important to blood clotting and also seems to be part of the atherosclerosis puzzle – it helps to prevent atherosclerotic vascular calcification and some animal studies suggest it may reverse vascular calcifications. So K2 is needed both to make bone and to remove bony or bone-like calcifications.
For osteoporosis treatment, trials in Japan suggest K2 supplementation is highly efficacious, with one trial showing 80% reduction in hip fractures with K2 supplementation. This is much more impressive than the rather modest improvements in fracture risk reported so far with Vitamin D supplementation, but to be fair, the doses used with D have been very small, in the 400 -800 iu/day range. More on doses later. Calcium supplements seem to be the least helpful for osteoporosis, which makes sense when you understand that absorption from the gut can be very poor without D and very high with adequate D levels. It is not logical that we should need calcium as a supplement at all as long as D3 and K2 are at Paleolithic levels and you are not binding up dietary calcium with phytates in cereal grains. (Yeah, I know, you can soak the grains overnight, but that does nothing to the gliadin proteins and wheat germ agglutinin. Exactly how many reasons do you need to not eat grains?)
Vitamin D receptors (see below) are also found on skeletal muscle cells. Many fractures in the elderly may be related to muscle weakness contributing to more falls. It is speculated that in addition to age-related sarcopenia (loss of muscle mass with age) causing muscle weakness, there may be muscle weakness from lack of Vitamin D to properly stimulate muscle cells.
Vitamin D, grain avoidance and eating grass-fed butter and hard cheeses (for the K2) are my strong recommendations for avoiding osteoporosis. I doubt if bisphosphonate drugs work better, and there is no way they are safer than butter.
Non-classical effects of Vitamin D
It seems that this hormone does much more that “just” regulate calcium ion homeostatis. The vitamin D receptor, or VDR, is a nuclear receptor. Nuclear receptors are found within the cell, sometimes on the nucleus itself, and are bound by the signaling hormone when it enters the cell. The hormone-receptor complex attaches to a specific site adjacent to the location of a gene on your DNA inside the nucleus, inducing the DNA to be “read” and transcribed into a protein. The gene turned on and the protein produced will be specific to the cell type and this explains how a single hormone can cause mutiple effects in the body depending on the type of cell having the receptor.
In the case of Vitamin D, there are VDRs found in many cells besides the Kidney, small intestine, bone cells and parathyroid gland we discussed above.
VDRs are found on B and T lymphocytes and monocytes, all cells involved in immune function. D3’s effect on immune function improves resistance to infection by strengthening the innate immune system, for instance by supporting phagocytosis and destruction of invading organisms. D3 also modulates the adaptive immune response to better differentiate self from non-self. This latter effect, modulation of the adaptive immune response, appears to be involved in the ability of Vitamin D to decrease susceptibility to serious and common autoimmune disorders like Type I diabetes, rheumatoid arthritis and multiple sclerosis. Now, this does not mean these diseases are caused by hypovitaminosis D. In fact, Peter discusses how these are Neolithic diseases of molecular mimicry caused by other elements of Neolithic nutrition, namely interaction of a leaky gut from gluten grains and overgrowth of commensal organisms in our guts caused by starches and fiber in amounts that are not optimal. For now, you can search these diseases on Peter’s blog to learn more. I will post more of my thoughts on this phenomenon later.
I view Vitamin D deficiency as just one more Neolithic discordance with the EM2 that increases the likelihood of these autoimmune diseases of civilization, not as the primary cause.
Other elements of PaNu will interact synergistically with restoring Vitamin D to Paleolithic levels, including moderation of insulin levels and correction of the 6:3 ratio. All will conspire to improve immune function, both in terms of improving resistance to infection, decreasing promotion of common cancers, and reducing inappropriate immune responses directed against self-proteins (autoimmune diseases).
In addition to immune cells that may control cancer promotion, cells of tissues susceptible to cancer also express the VDR. Vitamin D binds to the VDR and new proteins are synthesized that control cell differentiation, proliferation and recognition of adjacent cells, all functions important in the development of cancer.
The evidence that hypovitaminosis D causes cancer is mostly epidemiologic, but is powerfully suggestive, and unlike, say, the diet/heart hypothesis (cholesterol or saturated fat causing heart disease), has the virtue of biological plausibility and support by laboratory science. The evidence can be summarized thusly:
A wealth of studies show that exposure to UV light (latitude) and in some cases vitamin D intake or serum levels, are inversely related to the risk of common cancers, including colon, breast, prostate, esophagus and non-Hodgkin lymphoma. African Americans are particularly likely to be D deficient and have higher rates of many cancers, especially when they live at higher latitudes. The same latitude epidemiology supports the effect of D on risk of MS diabetes and hypertension. One review suggested that supplementation with 1000 iu/day D3 would decrease colon cancer by as much as 50%. There is evidence both for reduced incidence (risk of getting cancer) and reduced mortality if you get it. Making sure my Vitamin D levels were high is the first thing I would do if I were diagnosed with cancer.
A trial from Creighton University investigating calcium and Vitamin D at 1100 iu/day for fracture prevention “accidentally” showed 60% lower cancer risk in women over a 4 year period.
Vitamin D replacement improves insulin sensitivity, beta cell function (ability to secrete insulin) and hypertension. Interestingly, these are all effects that counter elements of metabolic syndrome. Vitamin D can be thought of as an anti-metabolic syndrome hormone. How much of Neolithic disease is due to hypovitaminosis D? It certainly seems to be an element. My suspicion is that, like fructose avoidance and maybe lack of excess linoleic acid, high D levels may be one of those things that increase our tolerance for carbohydrates – think of the Kitavans with their high carbohydrate diet but no evidence of metabolic syndrome and preserved glucose homeostasis.
Replacement, Not Supplementation
OK, so now I sound like all the other bloggers. I don’t really believe in supplementation, but......
I have talked previously about my view of the distinction between supplementation, compensatory supplementation and replacement. Supplementation is the belief that there is something magic that was not present in Paleolithic life that can give us “supranormal” health. The belief in dietary antioxidants or novel drugs or eating lots of some unusual particular food is supplementation. It is generally not biologically plausible that there is some completely novel element that can improve health.
What are the sources of Vitamin D? Even in the deficient population, 80% or more of serum 25(OH)D is attributable to sunlight. Sunlight is effectively the only natural source of significance. You can get some D from fish, beef liver, irradiated mushrooms (D2), etc. Once you are taking cod liver oil (over 1000 iu./15 ml), which is hardly a consistent Paleolithic source, you are replacing at dietary levels which are artificial.
As a source of Vitamin D3, whole body UV between 10 am and 1 pm for 20 minutes will give a D3 equivalent to oral dosing with 10,000 iu vitamin D3 (cholecalciferol). This is a rough estimate - it assumes you are outside only between March and October if north of 37 degrees latitude, and that you are unclothed and have average skin pigmentation where your minimal erythemal dose (MED) is 20 minutes. Black persons may need 5-6 times the exposure for the same dose. There is simply no natural food source that can compare to sunlight.
How much do you need and what is deficient?
Referencing the classical effects of D we might define insufficiency at less than 20 ng/ml and severe deficiency at 10 ng/ml. Current RDAs of 400 iu/day are based on avoiding rickets and were made before there was recognition of the other important effects of D. The dose-response curve for serum levels is highly non-linear, with each 5 ng/ml increment in serum levels requiring a larger increase in daily intake. Even 400 iu/day has been shown to be ineffective in treating osteoporosis. The non-classical effects of D seem to require larger levels to ensure health. Using a few facts we can come up with a more modern recommendation that is safe and reflects a more complete understanding of the importance of vitamin D.
1) The level of 25(OH)D at which most dietary calcium intake is adequate (absorption is maximized) is 50 ng/ml
2) The level of 25(OH)D that optimizes fracture prevention is about 40 ng/ml
3) The level that causes PTH levels to plateau at a minimum (ensures no secondary hyperparathyroidism) is 40 ng/ml
4) The level of oral D3 intake required to ensure a level of 40 ng/ml in most people is 4000 iu/day
5) The highest reported level of oral intake that has never been associated with a case of hypercalcemia due to hypervitaminosis D is 10,000 iu/day
NOTE: The following section has been updated as of February 2011
Using the above numbers most of us who are not lifeguards would have D3 insufficiency, if not deficiency by the end of winter. I find that implausible and despite the epidemiology I believe megadosing with Vit D orally is unproven and unnatural.
I think it is reasonable to get some sun exposure up to but not exceeding the minimal erythemal doseIf you can get adequate sunlight at midday, say, sitting outside at lunchtime with 25% of your skin exposed for a half hourr, and your latitude and the season allow enough UV, you can use that as your source. Am I concerned about skin cancer or wrinkles? I think some sunning without burning is fine. I suspect what really trashes your skin are PUFAs and cigarettes, not the sun. If you worry about wrinkling, wear a broad-brimmed hat and get the sun on your arms and shoulders.
Finally, don’t forget plenty of grass-fed butter or hard cheeses to get your K2.
NOTE: My standard disclaimer that this is not individualized medical advice applies here, only more so. If you take warfarin or other medications, or are otherwise not healthy, always consult your personal physician before taking any drug or dietary supplement.