Franz Mesmer was a German born physician that had interest related to human and animal behavior.  He contended that through ‘animal magnetism’, significant physical results could be realized.  His name is the basis for the word Mesmerized.  It has been an unfortunate occurrence in vitamin D science that the medical professionals and the general population have been hypnotized like chickens with a line drawn in the dirt. (We did this as kids – check it out Chicken Hypnotized) We all need a nudge to wake up from this surreal dream.  The following is not for the faint of heart or for those that do not have the curiosity to pursue a deeper understanding.  If not curious, then just watch the chicken video and have a good day.

Epimerization is simply the difference in the positioning or bond angle of the OH group in the Carbon 3 position of the vitamin D compound.  What do we know about how much difference a bond angle will make?  It seems that this bond angle is of significance in genetic expression, so let’s explore.  Check out this example for the sugar glucose: Epimers

It came to my attention several years ago that one of the local hospitals that was attached to a state university was doing vitamin D testing only on D2 and its metabolites.  The reasoning was that the clinicians wanted only to know the level of the drug, vitamin D2, because this is what had been prescribed.  The logic was that the level of the hormonal metabolites of natural vitamin D3 were so low that it was of no consequence.  After all, there had been a great job done for the last fifty years of scaring people out of the sun.  Or maybe, this was not exactly the logic, but I am sure this is close.  So the mixture of treating D3 and D2 as equals and ignoring the total effect of the metabolites of these pre-hormones has done the practice of medicine and the population as a whole a great disservice.  It is only through the separation of these two compounds and not allowing peer reviewed papers to be published without designating what is being used that we can achieve our goal of being reconnected to the sun.

I had always thought that the complications of not having accurate serum vitamin D levels or 25(OH)D was a matter of the different test methods not giving either totals of the two or only values for one or the other  –  25(OH)D₂ or 25(OH)D₃.  In the later case I was right as is suggested by what was being done at one of our university hospitals.  But it turns out that it is a lot more complicated.  Consider the recent release by the American Chemical Society – “New Standard for vitamin D testing to assure accurate test results”, January 25, 2012.  The paper describes the storage metabolites of vitamin D:  “The researchers developed four versions of the standard, with different levels of the vitamin D metabolites 25(OH)D₂ and 25(OH)D₃ in human serum. They also determined the levels of 3-epi-25(OH)D in the adult human serum samples. Surprisingly, they found that this metabolite — previously thought to only exist in the blood of infants — was present in adult serum. “This reference material provides a mechanism to ensure measurement accuracy and comparability and represents a first step toward standardization of 25(OH)D measurements,” say the researchers.”  It seems that these epi-metabolites have a less effect on calcium.  In order of effect on increasing hypercalcemia, it is 3-epi-25(OH)D_3, 25(OH)D₃, 3-epi-25(OH)D₂, and 25(OH)D₂ (and don’t forget the toxisterols that can be made during manufacture of D₂ from over irradiation of fungus).  It also seems that the epi-compounds are just as effective as the original.  Did I get this correct?  Here is a starting place for you to begin your consideration. 1α,25(OH)₂-3-Epi-Vitamin D₃, a Natural Physiological Metabolite of Vitamin D₃: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor  This is an open access to the full paper.  Do you begin to see the need for the separation of D2 and D3 and metabolites?

Now does this really get us to a better place in the understanding of our natural hormone D?  Consider the recent attention on cholesterol sulfate and the resulting compounds of hormones that are made from cholesterol sulfate, in particular vitamin D3 sulfate.  So now are we looking at eight storage metabolites instead of four?  How confusing can it get?  Consider what the writers of this paper:  HPLC Method for 25-Hydroxyvitamin D Measurement: Comparison with Contemporary Assays, March 2006, had to say: “According to Shimada et al., nearly equal amounts of 25(OH)D₃ sulfate and 25(OH)D₃ are usually present in patient sera.”  The Shimada paper: Shimada K, Mitamura K, Higashi T. Determination of vitamin D₃ metabolites using high-performance liquid chromatography or immunoaffinity chromatography. J Chin Chem Soc 2000;47:285-228.  

Only after the clinical outcomes related to the levels of the eight compounds, 3-epi-25(OH)D_3, 25(OH)D₃, 3-epi-25(OH)D₂, 25(OH)D_2, 3-epi-25(OH)D₃ sulfate_, 25(OH)D₃ sulfate, 3-epi-25(OH)D₂ sulfate, and 25(OH)D₂ sulfate are determined will we be able to accurately assess the health benefits  of vitamin D. 

Just think of the confusion of test methods to determine the amounts of the various vitamin D compounds and correlating clinical outcomes with one thing that we call 25(OH)D.  Researchers and reviewers, it is really up to you.  If you fail in allowing papers to be published without making the necessary distinctions, then, the population will continue to suffer at your ineptness. Kathleen Sebelius, Secretary HHS   –  Carolyn M. Clancy, M.D., Director Agency for Healthcare Research and Quality, are you listening?  Okay, all you chickens, GET UP!

If you really were not curious and you made it this far anyway, then may God bless you and go spend some time in the sun.  – Pandemic Survivor