Let's begin.
Ted Hutchinson posted a link to Dr Reinhold Vieth's discussion of vitamin D. Dr Vieth is extremely knowledgeable about vitamin D and is looking for an hypothesis to explain the prostate/pancreatic cancer paradox.
Figure 1 sets out the paradox, which is observational in nature.
Under year round UV exposure conditions (low latitudes, broken line, "High UV") there is no association between 25(OH)D and either prostate or pancreatic cancer. At high latitudes (Solid line, "Low UV") there is a positive association between blood levels of 25(OH)D and these cancers. The average year round levels of 25(OH)D actually tend to be higher in northern latitudes, higher than those where there is year-round solar UVB.
Vieth explains that we know almost nothing about the enzymes controlling tissue 1,25(OH)2D levels and much of his discussion is extrapolated from renal enzyme activity.
Formation of 1,25(OH)2D is under the direct control of blood Vitamin D, the more Vitamin D, the more 1,25(OH)2D is formed. An increase in Vitamin D will immediately produce an increase in 1,25(OH)2D as the enzyme is just there and waiting for substrate. Eventually the production of the enzyme down regulates but by then there is plenty of 1,25(OH)2D. The degradation of 1,25(OH)2D is also under the control of blood Vitamin D. There is a lag in response of this enzyme so as blood Vitamin D rises there will eventually be increased breakdown of 1,25(OH)2D and all will be hunky dory with optimal tissue levels.
So there is no problem dealing with rising or steady state Vitamin D levels.
The bug bear is during periods of falling blood Vitamin D levels. Falling substrate produces falling production of 1,25(OH)2D but the degradation enzyme is still active and takes time to shut down in response to low blood Vitamin D levels.
The result is graph A in Figure 5.
I'll put the whole figure up with legend after the individual graphs. In northern latitudes (in my hemisphere!) there is sub optimal 1,25(OH)2D from just after the summer solstice until the UVB comes back in March. The fall is relatively slow and the rise is rapid due to the enzyme kinetic reasons detailed above. Grey hatching suggests sub optimal or pro-neoplasic levels of 1,25(OH)2D in tissues.
Vieth points out in graph C that the situation can be largely ameliorated by constantly supplementing the mean level of northern people from graph A's 40nmol/l to fluctuations around the mean level of 130nmol/l:
There are several implications from this hypothesis.
Short term studies at constant dose rates will mimic the up-swing of Spring in the northern hemisphere. They should produce optimal tissue 1,25(OH)2D concentrations. The supplementation would need to be sustained and long term benefits need long term supplementation.
Anything which produces a falling Vitamin D level will put you in to the unpleasant grey zone. Large intermittent doses are the worst case scenario and are illustrated in graph D.
Stopping your supplements or reducing your dose rate will also put you in to the grey zone.
The very simple message is, if you are going to supplement, supplement consistently and don't take more than a week off at any given time.
But life is never quite that simple. It's time to look at graph B.
Graph B is the pattern of those southerners who get a bit of all year round sun but never go over the top or under the bar for sun exposure and Vitamin D levels. The grey zones in graph B look as small as those in "supplemented" graph C to me. Ultimately it is variations in vitamin D levels which produce the grey zones.
Because the synthetic and degradation enzymes for 1,25(OH)2D adapt to blood Vitamin D levels, provided there is a basic minimum of Vitamin D, tissue levels should be OK.
I'll take a break here and come back to the implications, especially for us Glaswegians, of diet in addition to sunlight and supplementation.
Enjoy
Peter
Oh, here are the four graphs and legend all together:
15 comments:
The East African highlands where humans evolved has one of the most stable climates on Earth. UV levels area always very high to extreme (10+)for the entire year. So our earliest ancestors vitamin D levels would have had almost zero variation.
Peter,
This will be a curious study to review. Globally humans are suboptimal vitamin D levels and UVB exposure (gluten/ lectin/ fiber exposure, indoor living, etc).
I'm not sure what Vieth can surmise. It is like comparing BPs of 160/100 to 180/110. Both are obviously not optimal. He used 78 nmol/L as the upper limit on the first graph you posted. That is ~31 ng/ml and considered vitamin D insufficiency. At this low level and below, humans apparently can neither upregulate intestinal calcium nor add to adipose tissue vitamin D stores.
(also I bolus my vitamin D and I hope that is not bad!! my curves would have lots of 'grey 'areas' *ha* other than caffeien and etoh, I can't take drugs daily...)
The premise of all of this is that some associative studies find greater risk of these certain cancers with higher vitamin D levels, right?
I suspect that residual confounding is a better explanation. Here's why:
First, I had the exact opposite understanding from Blogblog... My understanding was that frequent and dramatic climate changes were the rule in east Africa over the past million years and that evolutionary biologists believe that humans are evolved for variability not stability.
Second, all confounding is very hard to tease out of associative studies, especially under-powered ones. I am sure that the obvious things are controlled for -- e.g., smoking, physical activity, wealth, race, gender, age, etc. However, the people with naturally high vitamin D levels are the people who don't avoid the sun - the same class of people who eat more fat - i.e., not the goody-goodies. Doesn't every reader (and author) of this blog believe that the existing associative studies fail to account for the residual confounding arising from years of bad fat press? What about years of bad sun press?
Although I am clearly not qualified to debate Vieth's mechanistic understanding of vitamin D, it just doesn't pass the smell test for me.
Also wanted to point out that, among vitamin D deficient people (in a polluted and poor province in China), higher vitamin D levels are significantly associated with higher rates of esophageal cancer. However in Italy higher vitamin D levels are significantly associated with lower rates of esophageal cancer.
I just don't think that these few studies are enough to believe that there is a W shaped dose response curve for vitamin D (rather than U shaped). It's possible, but residual confounding should be the presumption until proven otherwise.
Peter, if high serum 25(OH)D levels are the problem and not ingestion of vitamin D itself, would it be safe to conclude that less is better, as opposed to more? According to the paper, as long as the input is constant, everything's alright. They don't mention an optimal amount of D, though I assume you have to have some.
This also doesn't take into account those of us who've taken out grains. Cordain claims grains are responsible for blocking D production.
Gunther,
Vieth does not claim high serum D is a problem. In fact, he advocates for it. This paper is merely his attempt to explain the strange findings that higher (but still low) levels of serum D are associated with greater incidence of certain cancers. His theory is that DECLINING serum levels cause problems, not higher levels. Indeed, I believe that Vieth argues that we should supplement (regularly) with sufficient D3 to get levels over 100nmol/L.
Daniel:
"First, I had the exact opposite understanding from Blogblog... My understanding was that frequent and dramatic climate changes were the rule in east Africa over the past million years and that evolutionary biologists believe that humans are evolved for variability not stability."
The climate in many places would vary more in a single week than East Africa has over the past million years. The "drastic" climate changes of East Africa involve nothing more than variations in rainfall and modest temperature changes.
The climate of the East African highlands has so little seasonal variation (2-3C) that it is like living in an air-conditioned room. The only thing that changes is the amount of rain.
The East African highlands are both elevated and equatorial. This means that UV levels will always be extremely high.
This lack of temperature variation in our evolutionary past explains humans poor tolerance of heat and cold compared with many other mammal species. A cat having evolved in the desert can handle a much wider temperature range. My cats were just as willing to go outside whether it was 5C or 40C.
Daniel. Sorry I meant 1,25(OH)2D. This is what you don't want high amounts of in the blood. I understand this will adjust upward to D intake, but does not adjust downward fast enough if you stop D intake.
With this in mind, it seems D just has to be constant and relatively high. From what I can see here, superdoses of 10,000 IU per day may not be necessary as long as your intake is adequate and CONSTANT.
Gunther, got it. Sorry to misunderstand you.
Blogblog, I see your point, but think that small differences in rain could be important, especially if the habit changed back and forth from jungle canopy to grassland. One would expect that humans evolved to experience some vitamin d droughts -- after all, we evolved to store vitamin D in our fat...
Vieth in a 2005 presentation says that humans have not genetically altered in 100,000 years.
Here's Dr. Vieth on human evolution
"Humans are optimized through
evolution to be a tropical species. Annual cycles of fluctuating 25(OH)D concentrations are not physiologic.(!)
Natural selection has certainly not stood still for the hundreds of generations that modern humans have been in Europe; they are adapted to the annual UVB-less period.
Formation of 1,25(OH)2D is under the direct control of blood Vitamin D, the more Vitamin D, the more 1,25(OH)2D is formed. An increase in Vitamin D will immediately produce an increase in 1,25(OH)2D as the enzyme is just there and waiting for substrate. Eventually the production of the enzyme down regulates but by then there is plenty of 1,25(OH)2D. The degradation of 1,25(OH)2D is also under the control of blood Vitamin D. There is a lag in response of this enzyme so as blood Vitamin D rises there will eventually be increased breakdown of 1,25(OH)2D and all will be hunky dory with optimal tissue levels
"Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose".(Merck Manual)
So there is no problem dealing with rising or steady state Vitamin D levels
Vitamin D and aging.
"Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40-60 nmol/L for the lowest cancer risk".
Premature aging in vitamin D receptor mutant mice.
"Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts.[...] Unlike the wildtype controls, VDR KO mice lose their ability to swim after 6 months of age.[...] our study suggests that VDR genetic ablation promotes premature aging in mice, and that vitamin D(3) homeostasis regulates physiological aging"
Here's some discussion about Vieth:
http://gimpyblog.wordpress.com/2009/02/19/anh-undermine-public-health-care-efforts/
Mainly between Gimpy and Damien Downing.
Mark.
And a long lecture by Vieth:
http://www.vitamind-veith.ms-diet.org/
About an hour long.
Mark.
There is a significant error in your consideration that I think you need to consider.
You have two sources of 1,25D production:
a) the kidneys
b) extrarenal production in several tissues, mainly as consequence of immflamation
The production under a) is tighly regulated by the Kidneys itself and there is no "proportionality" with 25D.
only the production under b) is proportional to the substrate and this is only a small part of the complete picture, at some point of time higher 25D will lead to falling 1,25D values. There is (as always) not a strict proportionality.This is an area that has little research.
The "U" Shaped curve for Colon and Pancreas cancer was already discovered and published by researches, I can you send the link.
Best regards,
Alex
Hi Mark, not managed the Vieth link but Gimpyblog was thought provoking.
Alex, thanks for your input, that is particularly reasonable. There does appear to be an acute anti inflammatory effect of a mega dose of D, as there does of C. I keep drifting back to keeping my fats saturated and avoiding inflammatory triggers as far as I can!
The papers would be nice (email is on my profile). I view prostate cancer as metabolic syndrome, so am more concerned about insulin than vitamin D, though D does appear to improve insulin sensitivity.... I might have a little more to say on pancreatic cancer when I get to blog about non alcoholic pancreatic disease and its parallels to non alcoholic liver disease....
Peter
I used to take 9K IU/day of D3 (1K in multi and 2 x 4K Carlson Solar Gems). My level was 77 ng/ml. I recently switched to 50K/week.
Like Dr. B G I wonder about the gray areas, ha.
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