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Medical Forum / General / Laboratory / April 2004

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current lab ranges for 25-Hydroxyvitamin D

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Michael Rawlins - 30 Mar 2004 14:29 GMT
Most of the information I've found on the web indicates a healthy
range for 25-Hydroxyvitamin D of 25-50 mg/mL.  In a review article
just published, Holick (2004) argues for a normal range of 30-50
ng/mL.

The lab range for the test I just had indicated 8-38 ng/mL.  A person
with a 25-Hydroxyvitamin D level of 20 ng/mL, therefore, would be
presummed to have sufficient vitamin D stores, based on a peek at the
lab results.  Latest research suggests otherwise.

Cheers,
Mike

REFERENCE:  MF Holick, "Vitamin D: importance in prevention of
cancers, type 1 diabetes, heart disease, and osteoporosis". Am J Clin
Nutr, 2004, 79:362-371
Robert - 30 Mar 2004 20:21 GMT
> Most of the information I've found on the web indicates a healthy
> range for 25-Hydroxyvitamin D of 25-50 mg/mL.  In a review article
[quoted text clipped - 12 lines]
> cancers, type 1 diabetes, heart disease, and osteoporosis". Am J Clin
> Nutr, 2004, 79:362-371

It would depend on the method used for performing the assay. The individuals
used to collect reference range data. Of equal importance is the ROC data
incorporating normal and abnormal individuals. This is where you combine the
actual test with the population of normal and abnormal people. This
methodology is not standardized so do not expect to see one single range.
You should never take a number and apply it to all these different methods.
You need to review the chart to see if a clear separation exists between the
two groups and set that as the lower limit and upper limit. In real life
there is overlap between the two. The question then becomes does one want to
include the range where "all" normal people are found, then a broader range
is used. Keep in mind you increase your false negatives with some disease
individuals being called normal with this expanded range. If your intent is
on picking up "only" diseased individuals then you use a narrow  range. The
problem here is that you increase your chances of missing people with
disease.
Each test and each disease has it's own graph in which clinical cut-offs are
being used. They are not uniform.
You have to be careful with research where statistical differences are often
used. The mean of the disease group is compared to the mean of the non
disease group.  This is different than looking at a clinical cut-off range
where it is used for individual use and not the group.
This explains the different ranges. If you look up ARUP, you will see a
range of 20-57 ng/ml. You can even have ranges within ranges. You can have a
range for rickets and each of the many conditions associated with
alterations in vit 25 hydroxy.
Don't forget the biological and analytical variability that is also there
when trying to interpret results. There is a seasonal variation with the
test.
Robert - 30 Mar 2004 22:54 GMT
"Robert" <Robert@hotmail.com> wrote in message

I read the summary abstract on that and have a few comments about that, keep
in mind I did not read the entire article.
I think some people, doctors included, might want to extrapolate lab results
to an unproven or unwarranted point. Studies were made on the assays with
clinical samples as required by the FDA. Based on those studies, the
cut-offs were made. If the test is not able to separate disease from
non-disease, then that is a problem with that test. Simply put it may not be
a very good test and another with more sensitivity or specificity needs to
be found or done. If you raise the lower limit to detect more people who are
deficient then you also increase the rate with those who are normal that you
will now call abnormal. When it comes to laboratory work the determining
factors are clinical relevance. If you pick up one true abnormal patient but
get 20 normal ones within this raised range, you are left with a costly
work-up.
If the ratio were reversed, then you have a very poor test that needs to be
replaced with something else.
I am very leery of arguments concerning raising or lowering limits to detect
occult disease. The way to go is to develop better tests for what you are
looking for, which is the route that cardiac markers has taken. I recall a
non productive exchange with the so called hypothyroid NG concerning TSH.
The wanted to do the same thing, lower TSH limit so they can call takes meds
for it. They feel better, sure and they might even loose some weight, but so
does taking amphetamines.
Lastly, it is the clinical judgment that has the final say on all of this.
Some people want the lab to have the final say on what is deficient so they
want to have the range changed.
Michael Rawlins - 31 Mar 2004 14:38 GMT
> "Robert" <Robert@hotmail.com> wrote in message
>
[quoted text clipped - 24 lines]
> Some people want the lab to have the final say on what is deficient so they
> want to have the range changed.

Hi Robert,

Thanks for the excellent summary of pros/cons of raising/lowering lab
ranges.  In regards to ARUP's range of 20-57 ng/ml, I'm wondering if
methodological differences can account for the discrepancy between
that range and the one reported for my test, 8-38 ng/ml.  ARUP web
site mentions Chemiluminescent Immunoassay as the method.  If the lab
my physician used also performed Chemiluminescent Immunoassay, then
why the difference?  Could the lab have adjusted the range downward
with the knowledge that seasonal 25 OH D levels tend to drop in
winter?  That would make no sense, since optimal calcium absorption
(to my knowledge) does not "adjust" seasonally.

The inverse correlation between 25 OH vitamin D and parathyroid
hormone levels has been well established in the literature.  My
primary symptoms/complaints which have arisen in late winter the past
three years, are classic of an elevated parathyroid hormone level.
Interestingly, the ARUP page says that 25 OH D levels can be normal in
hyperparathyroidism.

So I have a strong seasonal cycle to my symptoms, 25 OH D levels vary
strongly by season, 25 OH D and PTH are inversely correlated, and my D
level is borderline low, based on ARUP's Chemiluminescent Immunoassay
reference range. The reveiw article by Holick paints of clear picture
that current ranges for 25 OH D are too low.  A look at my chart would
support that.

I will find out today what methodology was used testing lab for my
sample.
I also plan to ask for a PTH test.  Wonder if the lab range for that
test varies widely between lab/methods (rhetorical question)?

Cheers,
Mike
Robert - 31 Mar 2004 20:03 GMT
"Michael Rawlins" <rawlins02@yahoo.com> wrote in message > Thanks for the
excellent summary of pros/cons of raising/lowering lab
> ranges.  In regards to ARUP's range of 20-57 ng/ml, I'm wondering if
> methodological differences can account for the discrepancy between
> that range and the one reported for my test, 8-38 ng/ml.  ARUP web

Michael,
You can see the many factors that one has to take into account in
establishing a reference range. It is best to have a regional reference
range which is often done even with the same instruments and methodology.
The range should be set for the group of people you are testing and not a
national range.  Cholesterol is the only nationally standardized assay. Even
with cholesterol you will have different LDL cholestrol level goals ie
reference goals if you have one, two, or three risk factor for coronary
heart disease. AThese are treatment goals.
Getting back to Vit D above, the 8-38, indeed sounds as though it is a
different methodology.

> site mentions Chemiluminescent Immunoassay as the method.  If the lab
> my physician used also performed Chemiluminescent Immunoassay, then
> why the difference?  Could the lab have adjusted the range downward
> with the knowledge that seasonal 25 OH D levels tend to drop in
> winter?  That would make no sense, since optimal calcium absorption
> (to my knowledge) does not "adjust" seasonally.

No direct info on that.

> The inverse correlation between 25 OH vitamin D and parathyroid
> hormone levels has been well established in the literature.
No secret there as PTH is involved in calcium metabolism. It is also related
to magnesium also among other things.

 My
> primary symptoms/complaints which have arisen in late winter the past
> three years, are classic of an elevated parathyroid hormone level.
[quoted text clipped - 7 lines]
> that current ranges for 25 OH D are too low.  A look at my chart would
> support that.

It is easy to establish if many cases of confirmed deficiency are below the
stated lower limit then it should be published. An adjustment will be made,
but implied deficiency or borderline deficiency are not valid. He may be
stating a target value as a treatment goal.

> I will find out today what methodology was used testing lab for my
> sample.
[quoted text clipped - 3 lines]
> Cheers,
> Mike

All tests may vary be lab even with the same equipment, some slightly,
others more so. Some vary based on their population.
If it is a renal clinic then they will only see renal patients with
secondary hyperparathyroidism. The general reference range may be the same
but they may use a more clinically useful or disease specific range or
target range.
Michael Rawlins - 31 Mar 2004 18:54 GMT
> "Robert" <Robert@hotmail.com> wrote in message
>
[quoted text clipped - 14 lines]
> If the ratio were reversed, then you have a very poor test that needs to be
> replaced with something else.

What do you think about a reference range based on 100 subjects living
in Minnesota?  Seems to be a rather small sample, at a rather high
latitude.  This lab is in the process of evaluating their 25 OH D
reference range, having held a meeting on it this week.  It is clearly
outdated, especially when one of the top vitamin D researchers in the
world stands behind optimal levels of 30-50 ng/ml (1).  There's too
much inertia in medicine these days.  But I do agree that test results
should be clinically evaluated.

REFERENCE:
MF Holick, "Vitamin D deficiency: What a pain it is", Mayo Clinic
Proceedings, 78 (12), Dec 2003.
 

> I am very leery of arguments concerning raising or lowering limits to detect
> occult disease. The way to go is to develop better tests for what you are
[quoted text clipped - 6 lines]
> Some people want the lab to have the final say on what is deficient so they
> want to have the range changed.
Robert - 31 Mar 2004 20:24 GMT
"Michael Rawlins" <rawlins02@yahoo.com> wrote in message > What do you think
about a reference range based on 100 subjects living
> in Minnesota?  Seems to be a rather small sample, at a rather high
> latitude.  This lab is in the process of evaluating their 25 OH D
> reference range, having held a meeting on it this week.  It is clearly
> outdated, especially when one of the top vitamin D researchers in the
> world stands behind optimal levels of 30-50 ng/ml (1).
It is OK if their only subjects are from Minnsota. Very few places perform
Vit D testing. It is very specialized and low volumn. We in San Diego send
out ours to ARUP so it would be inappropiate for them to have such a small
local geographic sample. It should include sample from where ever they get
specimens from.
I also noticed the wording stating "optimal levels" at 30-50 ng/ml. It means
that once established as deficient one should shoot for that range. It does
not say to have it as a diagnostic cut-off for establishing deficiency. A 25
value may or may not be deficient, but it is out of the target treatment
range. There is a difference between diagnostic range and treatment range
and reference range. The same exists for all hormone deficiencies or excess.

 There's too
> much inertia in medicine these days.  But I do agree that test results
> should be clinically evaluated.

There's a lot not known about diseases let alone pre disease.
It is easy to cling to a number and the tendency is to over interpret it.
Michael Rawlins - 02 Apr 2004 16:02 GMT
> "Michael Rawlins" <rawlins02@yahoo.com> wrote in message > What do you think
> about a reference range based on 100 subjects living
[quoted text clipped - 3 lines]
> > outdated, especially when one of the top vitamin D researchers in the
> > world stands behind optimal levels of 30-50 ng/ml (1).

> It is OK if their only subjects are from Minnsota. Very few places perform
> Vit D testing. It is very specialized and low volumn. We in San Diego send
[quoted text clipped - 7 lines]
> range. There is a difference between diagnostic range and treatment range
> and reference range. The same exists for all hormone deficiencies or excess.

Since I am at the same latitude as Rochester, MN, maybe that's why the
sample was sent there, rather than to ARUP.  But since vitamin D
testing is so "specialized", I doubt that anyone thought that through.

Now, I'm no MD, but I'd like to think that samples should be evaluated
and compared against what is known about the bodies ability to absorb
calcium.  If the body's ability to absorb calcium is severely impared
at < 15 ng/ml, then that value should be listed as such on a reference
range: DEFICIENT.  If marginal imparement occurs at less than 30, then
list as such.  Since there's likely a non-linear relationship between
vit D level and calcium absorption, and each person's body acts
differently, this all becomes rather difficult.  I agree with many of
your arguments in that regard.

But if there's a wealth of data suggesting higher mortality rates for
a number of diseases at higher latitudes (may or may not be true, MF
Holick review says there is), and vitamin D levels are known to be
lower at higher latitudes, then it would seem obvious that reference
ranges should not be different based on location.

Cheers,
Mike
Robert - 03 Apr 2004 10:07 GMT
"Michael Rawlins" <rawlins02@yahoo.com> wrote in message > Since I am at the
same latitude as Rochester, MN, maybe that's why the
> sample was sent there, rather than to ARUP.  But since vitamin D
> testing is so "specialized", I doubt that anyone thought that through.
[quoted text clipped - 4 lines]
> at < 15 ng/ml, then that value should be listed as such on a reference
> range: DEFICIENT.

You are now getting more complicated with calcium absorption which is
multifactoral. The PTH hormone level is always measured as low, normal or
high in relation to ionized calcium and not Vit D.
Very few vitamine assays are in clinical use for various reasons. Acute
injection one day may render a normal or high level whereas a person may
have a chronic low level otherwise. The half-life of the analyte is
important in evaluating status. It may might be more valuable to measure
precursor metabolites rather than the vitamine itself. With B12 it was found
that backed up precursor intermediates are more sensitive in picking up B12
deficiency than the actual measurement of B12. Other Biochemical markers of
deficiency are valid in evaluating one another. If Vit D is below the
reference range then it is evaluated to determine if other markers are
present indicating deficiency. If it is grossly in the abnormal range then
obvious clinical signs and symptoms would be present.
If marginal imparement occurs at less than 30, then
> list as such.

Unfortunately only gross abnormalities correlate more closely with clinical
symptoms in any disease. Borderline values with non specific symptoms makes
for poor science. The answer is to find a better test with less borerline
values or to include a battery of test in which they are taken as a whole
for proper interpretation.

Since there's likely a non-linear relationship between
> vit D level and calcium absorption, and each person's body acts
> differently, this all becomes rather difficult.  I agree with many of
[quoted text clipped - 5 lines]
> lower at higher latitudes, then it would seem obvious that reference
> ranges should not be different based on location.

I agree with you there about ranges. The problem though is evaluating your
single result and how it relates to others in your cohort. Taking vitamins
are not without complications so it's not a simple answer for everyone.
Granted if you live in the higher latitudes then it goes without saying. The
russians even put their children under UV.

> Cheers,
> Mike
 
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