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BLOG: September 2009

 Vitamin D status: murky waters

Is abundant skin exposure to sunshine unreliable in securing good body vitamin D status, as the Binkley et al results imply? Is the nominal blood level of the primary vitamin D metabolite, 25[OH]D, by itself sufficiently accurate indicator of vitamin D status? These questions concern our very basic understanding of our needs for this important nutrient (or, more accurately, secosteroid hormone), necessary to preserve, or regain health.

As it is, the study result is not more than an indication. In addition to the main study weakness - insufficient control over the actual sun exposures of study participants, as well as other personal factors that may have interfered with the results, the usefulness of its results is seriously compromised by the fact that nominal values for vitamin D level vary, sometimes significantly, from one to another 25[OH]D assay type.

The HPLC assay used in this study indicated nearly 7ng/ml lower nominal level of 25[OH]D, on average, than the alternative Diasorin RIA assay it was tested against during the study. If the RIA assay has been chosen as the one that is representative, the percentage of participants below the nominal 30ng/ml mark for the minimum adequate vitamin D level

 would have been cut in half.

There are also other 25[OH]D assays in use, also varying in their measured nominal value around any given actual blood level of vitamin D metabolites. No specific assay has been officially set as the representative for measuring vitamin D status, so the researchers are free to use whichever they find most suitable.

This comparatively negative nominal bias of the 25[OH]D assay used in the study, combined with the above mentioned uncertainties related to the factors directly influencing the outcome (actual sun exposure, physiological, dietary, medical and lifestyle factors affecting vitamin D status), predisposes the study toward underestimating the level of sunshine-produced vitamin D.

The problem is that, even with all relevant factors strictly controlled, the results would only be comparable with standards and results based on this particular 25[OH]D assay.

Bottom line: we need

strictly controlled studies, and a standardized 25[OH]D assay

if we are to be able to meaningfully interpret and compare their results.

Another question is, whether a nominal 25[OH]D level by itself is sufficient determinant of one's vitamin D status? In other words, from the standpoint of satisfying body's needs, is there significant difference if a given 25[OH]D level results from metabolizing synthetic (D2), as opposed to natural (D3) vitamin's form? The official stand is that it is all the same. But the evidence we have suggest that any given 25[OH]D level is likely significantly more bioactive when originating from the natural D3 form.

That wouldn't be surprising, considering pretty solid evidence that vitamin D3 is, unit per unit, more efficient than D2.

As far back as 1930, Hass et all found that one unit of cod liver oil, containing natural D3 form, can be as effective in preventing rickets as four units of Viosterol (pharmacologically produced D2). A number of subsequent studies furnished inconclusive results, so that in 1949 the World Health Organization made the two formally equal in effectiveness. Yet, only a few years latter, it was established in Germany that D3 form is approximately four times more effective (Klinke et al, 1954). As a result, the most popular vitamin D supplement in Europe, Vigantiol oil, has been reformulated to use vitamin D3 instead of D2.

It should be noted that part of the reason for lower vitamin D2 efficiency is probably due to it being less stable than D3, hence likely to have smaller than declared effective dose in preparations and food items.

As the accepted functional indicator of vitamin D status, since 1997, became blood level of its first major body metabolite,

serum 25-hydroxyvitamin D, or 25[OH]D,

the research focused in that direction. Trang et al (1998) found vitamin D3 to be about twice, and Mastaglia et al (2006) about 2.5 times more effective than D2 in raising 25[OH]D blood level.

Armas et al (2004) took another perspective by examining the effect of a single 50,000 IU dose of the two vitamin D forms. While both forms produced similar rise in serum 25[OH]D level for the first three days, it quickly dropped back with the D2 form, reaching the initial level by day 14, and falling below it by the last, 28th day.

To the contrary, with vitamin D3 form, serum 25[OH]D level peaked at day 14, and was still above the initial level by day 28. Comparing the areas below the two curves indicates that vitamin D3 is over three times more effective in raising and maintaining serum 25[OH]D levels than D2.

However, the authors concluded that the overall difference is still greater: according to them, 2000 μg (50,000 IU) of D2 is comparable to anywhere from 375 to 125 μg of D3. That is

up to 16-fold difference!

The reason for this apparent discrepancy between the efficacy in raising serum 25[OH]D and overall efficacy is in the molecular forms of these two forms of vitamin D being not quite identical, which extends to their primary - 25[OH]D3 and 25[OH]D2 - and secondary metabolites. Both, human and animal studies indicate that vitamin D3 has higher affinity for the liver enzyme (25-hydroxylase) converting 25[OH]D to its active form (Holmberg et al, 1986), as well as for vitamin-D-binding proteins, channeling its metabolism, and for vitamin D cellular receptors.

Such metabolic inferiority of vitamin D2 would be consistent with its markedly greater toxicity.

Now, extrapolating from over three times better efficiency in maintaining 25[OH]D levels, and 5-16 times greater overall efficiency, it seems appropriate to conclude that study authors estimate about

2-5 times higher efficiency of vitamin D3
for given 25[OH]D level!

Here we come to the question: "Which form of vitamin D is predominant in the body?". Your actual status may be very different if it is the natural D3 form - which is likely to be the case in persons exposed to abundant sunshine - as opposed to the synthetic D2, for those relaying mainly on this supplemental form of the vitamin.

In other words, a nominally "insufficient" level of, say, 20 ng/ml of mainly vitamin D3 originating 25[OH]D should be similar in effect to 2-5 times higher - formally optimal or even excessive according to some criteria - level of mainly vitamin D2 originating 25[OH]D. On the other hand, 20 ng/ml of vitamin D2 originating 25[OH]D could be effectively a severe deficiency. And all this is, of course, subject to individual variations in the actual level needed for optimum health.

Since the official recommendations and standards for vitamin D intake ignore this - by all indications significant - difference in potency between metabolites of the two main forms of vitamin D, it is impossible to meaningfully interpret these recommendations, or find a sound basis for their criteria. So, how do you figure out whether your vitamin D status is satisfactory or not, or what are your actual needs for it?

The only working answer seems to be: make it reasonable sure you get enough of it. That, in the first place, means

sufficient sunlight exposure when it is available.

And it doesn't take a lot. According to Engelsen and Webb, mid-day exposure of face, neck, hands, arms and legs needed to generate enough sunshine for 400 IU of vitamin D varies, for light skin, from 0.9 to 1.6 minutes in the peak of summer, and from 1.1 minute to 10 hours in the mid-winter, from zero to 60° latitude, respectively.

For 80° latitude, the respective times are 6 minutes in mid-summer, and never in the winter. For dark skin, depending on the level of pigment, required time can be up to several times longer.

In order to generate 4,000 IU - which seems to be an average daily use by healthy men (Heaney et al, 2003) - by exposing only face, neck and hands, which makes less than 12% of the total skin area - skin type 5 (dark) needs from 1.4 to 3 hours in mid-summer, and 1.8 hours to never in mid-winter, from zero to 60° latitude, respectively (already at 25° latitude it requires 12 hours). Again, for lighter skin the required times would be up to several times shorter.

Obviously, at higher latitudes, where winters are cold, limited skin exposure is the only available option for most people, and it does not generate significant vitamin D production. That makes

sunlight exposure within the rest of 9 months -

especially the summer - even more important, for it is then when the body stores the excess vitamin D for rainy/snowy days.

These numbers help estimate your approximate vitamin D gains from sunlight exposure. The differential to 4,000 IU per day should be obtained through supplementation, preferably vitamin D3 form. Even taking 4,000 IU daily seems to be perfectly safe considering body's ability to produce up to five time as much in a single day. Several studies have demonstrated that daily doses of 10,000 IU for up to 16 weeks and 50,000 IU for up to 8 weeks do not produce any signs of toxicity.

For children below 6 years of age, it is advisable to be cautious and not to exceed 1,000 IU of vitamin D supplementation, unless they are severely deficient and/or sun deprived.

According to Heaney (The Vitamin D requirement in health and disease, 2005), continuous daily dose of 10,000 IU produces mean 25[OH]D level similar to that after extensive summer sunlight exposure at mid latitudes (nearly 50 ng/ml, Barger-Lux and Heaney, 2002). Depending on the source, this nominal level is regarded either as near-optimal, or sub-optimal, but generally sufficient.

Of course, this intake level is much above the official safety limit of 2,000 IU/d for vitamin D supplementation. But how much can we relay on the opinion that still uses 60+ years old criterion for the recommended daily vitamin D intake - 200 IU daily up to 50 years of age - based on the observation that this level of intake prevents rickets?