I think there are three questions here: The first is questioning whether there is a benchmark for measuring and assessing Vit D levels: The second one is whether the levels differ significantly from country to country ( and what other factors may be of importance) and perhaps is asking should there be one baseline level or should the baseline level vary from country to country. It s an excellent question which needs to be answered by laboratory scientists coupled with an epidemiological interpretation. The third question is: How relevant is Vit D. What is the true clinical significance of any given Vit D level? The answer here would lie in a systematic review of the evidence under the different topics mentioned in the question.

It has become a kind of fashion to study and relate vitamin D to various pathologies! However, I think we need more studies; both epidemiological and mechanistic ones in order to draw a firm conclusion. The other thing, I don't think that a certain level of Vit D is applicable to all countries and ethnicities. In Turkey, most of the values measured are below normal limits set by laboratories! And some endocrinologists think that the "normal" levels by the labs may be higher than the realistic levels. So, I think we need to do more before a logic conclusion.

I thank you indeed Dermot for your excellent rephrasing of my questions, Yes indeed we need to find answers to the questions because the rates of deficiency based on one normal range is very high indeed.

Dear respected Dr.

The vitamin-D deficiency is highly prevalent worldwide.

Vitamin-D level could be affected by age, sex, season, smoking status, iron

deficiency, and body mass index.

It is important to be precise with the language used in such a question. When you say vitamin -D I presume you mean the measurement of 25 Hydroxy vitamin D  (25(OH)D) as an indicator of vitamin D status. There are other metabolites in the vitamin D pathway that have importance (1,25 dihydroxy vitamin D and 24,25 dihydroxyvitamin D) and these  may need to be measured to fully evaluate an individuals vitamin D status. The role of free 25 OHD may be important particularly in certain nationalities and a measurement of vitamin D binding protein by an appropriate method may be required. The "optimal" circulating concentration for certain diseases and conditions has still to be worked out and although many associations exist evidence on causation or effect of vitamin D supplementation in many diseases/conditions has still to be provided and substantiated. If I remember correctly the seasonal variation in UAE of 25 OHD is different from the Northern hemisphere and so you will need to collect a large number of samples over the seasons to fully establish a reference range.

 Thank you indeed william for your advise. Will be considered for sure.

Rgds

 Na il

The level of normal vitamin D is such controversial as cholesterol one.

The consequences are verry different according to genetic inheritage, nutritional habits but also commercial interests of pharmaceutical companies

I agree with the sentiments above. If your fundamental research question is to generate a normal range for vitamin D in your region then ethnicity, adiposity, diet, sun exposure and latitude are extremely important. There are many informative studies in this area who have attempted to do exactly what you are doing in different populations and different regions of the world. I would use these as a guide.

• Thank you Alexander

Hello Nabil,

no, we probably can't. New research shows that our method of measuring Vitamin D may not be adequate.

It is not the total Vitamin D that is essential, but the bioavailable Vitamin D. Furthermore even that is not reliable, as several genetic variants influence how well Vitamin D can activate the Vitamin D Receptor.

Bioavailable Vitamin D

Most of 25-OH-D is bound to DBP.  In that form, it can only enter the kidneys via Megalin, but not cells - only unbound 25-OH-Vitamin D can enter cells (and unmetabolized Vitamin D3 itself).

So it follows that the bioavailable Vitamin D is also a function of DBP-levels. It has for example been shown, that "black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D-binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. " (study attached)

Dr Hollis and others are now considering that 25-OH-D may not be that relevant at all, but it is rather the level of unmetabolized Vitamin D itself, that is the most critical factor.

The weakness in arguing that blacks may need lower levels is that traditionally living Massai have levels around 40 ng/ml and that is the best indicator we have for natural levels of blacks. It would then rather follow that levels in whites should be much higher.

As mentioned above there is much research needed in different regions to establish normal levels.

Vitamin D Action

Even with similar levels of any form of Vitamin D, Vitamin D action can differ a lot, due to several genetic variants that influence the VDR or the hydroxylases. Dr Coimbra for example has shown that in MS patients Vitamin D action is very low, even with 25-OH-D-levels above 100 ng/ml. He thinks that MS is a form of vitamin-d-resistance and has remarkable results.

What he does is measuring PTH while patients are on a low-calcium diet. He can that tailor the Vitamin D dose and level to the effect on PTH-suppression. He reports that doses differ vastly. (all unpublished, but search for "Coimbra-Protocol" - biggest breakthrough in vitamin d research in my opinion)

So probably we need to measure more than just 25-OH-D. A combination of several metabolites and PTH might be a good approach, even though PTH is only reliable under controlled Calcium intake.

Article Vitamin D and DBP: The free hormone hypothesis revisited

Article The Role of the Parent Compound Vitamin D with Respect to Me...

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Article Quantifying the vitamin D economy

When evaluating patients with low 25(OH)D levels, we should now consider the possibility that there are factors affecting DBP, which may alter the interpretation of total plasma 25(OH)D levels.  This possibility should encourage clinician to consider races, the various clinical situations and may necessitate the need for measuring or calculating free 25(OH)D or iPTH with corresponding calcium levels if free 25(OH)D is not available. 

I think for many analyte including Vit D, we need locally established normal values. There are some exception called common reference values (e.g. plasma glucose). In case of Vit D many geographical parameters affect its level and therefore should be taken into account. 

Thank you all indeed for your valuable advise

There is a true (traceable) measurement of Vitamin D set by reference methods like mass spectrometry, and the better assays can be shown to be measuring accurately by a well conducted Vitamin D proficiency testing / external quality assurance program.

There are still however many problems with Vitamin D (25OH) measurement, for example; the high levels of Vitamin D binding protein levels in pregnancy, or the higher affinity of some inherited forms of Vitamin D binding protein which cause problems in many assays that try to strip Vitamin D off its binding protein for immunoassay measurement.

Vitamin D deficiency clearly 'causes' Rickets and osteomalacia. While there is considerable debate around the 'association' of low vitamin D levels with many (all?) diseases (metabolic syndrome, diabetes, renal disease, autoimmunity, cancer etc etc), I think it is fair to say that vitamin D deficiency does not CAUSE these diseases, but seems to statistically accentuate their progression. Is this worth worrying about? I think it is. For example, a major concern is that according to meta-analysis (eg Nutrients 2013, 5, 3551-3562), vitamin D supplementation may decrease the development of type 1 diabetes in siblings of type 1 diabetics by 30% - ie 70% still get diabetes   - but shouldn't try and do everything to reduce the incidence of the lifelong disease? In contrast, imagining that we could tackle obesity/metabolic syndrome with vitamin D deficiency would seriously neglect the underlying dietary causes of this disease.

In my view, the biggest problem with interpreting Vitamin D levels and limits is considering 'nature'; It could be argued that 'nature' meant us to have vitamin D levels that are higher in the summer than in the winter, and that having tonically high levels (eg >100 nmol/L) may be as 'unnatural' as having a tonically low level (< 50 nmol/L). My guide (regardless of where in the world you live) is that Vitamin D should be above 75 nmol/L... at some time of the year, so that in the winter (or in the wet season in the tropics), Vitamin D levels will not drop below 50 nmol/L for too long. Finally, the circannual fluctuations in sunlight in different places on earth may not be as important as the social behaviours (eg staying indoors in air conditioned comfort in the summertime, clothing and sun protection).

Thank you indeed Ken for your comprehensive response, very informative, I am grateful for your time.

N Jassil et al. Vitamin D Binding Protein and 25-Hydroxyvitamin D Levels: Emerging Clinical Applications.  Endocr Pract. 2017 Jan 17. doi: 10.4158/EP161604.RA. [Epub ahead of print]). PMID: 28095044