John
You won't get flamed by me. I largely agree with
your subtext.
So here is my answer:
a) Where do the "ranges" come from?:
They are based primarily on the idea of PTH
elevation as a surrogate for Vitamin D deficiency
(at least on a group basis).
If you plot population PTH against 25D you (sort of) get
a plateau where beyond some certain level PTH
doesn't decline much more. This plateau starts at
around 60 or 80nmol/L
Likewise if you intervene with a modest dose of D,
PTH tends (on average) to decrease if
starting D is below around 60-80nmol/L but does
not respond much above that.
See attached slides which illustrate these two
concepts (note differing units)
Add to this some evolutionary evidence that God
designed us to have far higher Vitamin D than we
have, and some pretty weak fracture evidence, it
is possible to create an argument that at least in
a physiological sense 25(OH)D below 80nmol/L or so
is in some sense "suboptimal".
To put this into perspective the median 25(OH)D in
UK adults is around 45nmol/L, so depending on your
definitions anywhere between 40% and 80% of the
population are "suboptimal".
b) How we report stuff.....?
The above is all very important, and I think
should find a place in our reports. However I
think the dropping of traditional reference ranges
is a real problem. In my view we should not misuse
the term reference range to mean something very
different from its usual usage. Our users and
ourselves end up losing all perspective of "how
often that low", "how unusual is this", and are
also liable to misunderstand when deficiency is
really really profound (say 12nmol/L).
It also misleads decision making. What we have is
the typical scenario here:
- Patient attends GP with severe myalgia and
proximal weakness.
- GP does 25(OH)D and gets a report at 35nmol/L
which says "Insufficient D"
- The result actually does not contribute to the
diagnosis of Vitamin D deficiency induced mylagia
at all, and in fact probably makes it far less
likely than before the test. However, Hey presto,
in the mind of the GP we now have a diagnosis.
I'll probably be shot down in flames if I suggest
that we have done the same thing with cholesterol
- producing reports that fail to convey that (at
least in terms of unusualness) Cholesterol of
5.5mmol/L is really not high at all.
Aubrey
OJD>
OJD>
OJD> Dear collective neurone
OJD>
OJD> At the risk of being shot down in flames but
OJD> wishing to stimulate some debate. We are
OJD> finding our requests for Vit D2 and D3 have
OJD> tripled in the last 6 months. I am sure we
OJD> are not alone in this. Clearly this has been
OJD> in response to a much greater awareness of
OJD> Vit D deficiency. However, there is also a
OJD> significant increase in repeat requests,
OJD> largely due to the fact that about 75% of the
OJD> results we are reporting are sub optimal i.e.
OJD> total Vit D (D2+D3) are less than 75 nmol/l
OJD>
OJD> I have been trying to ascertain the source
OJD> of the reference range and its method of derivation.
OJD>
OJD> There is an excellent review of Vit D by
OJD> Michal Hollick in N Engl J Med 2007;357:266-81.
OJD>
OJD> This review cites the work of
OJD>
OJD> Heaney RP, Dowell MS, Hale CA, Bendich
OJD>
OJD> A. Calcium absorption varies within
OJD>
OJD> the reference range for serum 25-hydroxyvitamin
OJD>
OJD> D. J Am Coll Nutr 2003;22:142-6.
OJD>
OJD> As the main reference that seems to be the
OJD> origin of the ranges being quoted by referral
OJD> labs in my local neck of the woods.
OJD>
OJD> This is a very interesting paper that can be
OJD> accessed through this link
OJD>
OJD> http://www.jacn.org/cgi/reprint/22/2/142
OJD>
OJD> The authors use a method based on the
OJD> concept of “threshold behaviour of nutrients”
OJD>
OJD> This is explained in the discussion section
OJD> of the paper copied verbatim below
OJD>
OJD> “Many nutrients exhibit what has been termed “threshold
OJD>
OJD> behavior,” that is, the values for the
OJD> physiological response
OJD>
OJD> change directly with intake up to some
OJD> threshold value, above
OJD>
OJD> which the response does not change with further increases in
OJD>
OJD> intake. Calcium, iron and ascorbic acid are well recognized
OJD>
OJD> examples. Vitamin D is usually considered to exhibit similar
OJD>
OJD> behavior, and the limited evidence available is consistent with
OJD>
OJD> that interpretation. Threshold behavior in this instance would
OJD>
OJD> mean that, in a state of vitamin D
OJD> sufficiency, variations in
OJD>
OJD> vitamin D intake within the physiological range would not alter
OJD>
OJD> calcium absorption efficiency, while absorption would vary
OJD>
OJD> with intake at subthreshold values for vitamin D status.”
OJD>
OJD> The authors go on to state.
OJD>
OJD> We have recently shown that a drop in serum 25OHD from
OJD>
OJD> 122 to 74 nmol/L did not produce a
OJD> significant difference in
OJD>
OJD> calcium absorption
OJD>
OJD> and finally conclude
OJD>
OJD> Since calcium absorption is critical to the ability to maintain
OJD>
OJD> calcium balance, it follows that reduced
OJD> absorptive performance
OJD>
OJD> at 25OHD levels between _50 and _80 nmol/L must be
OJD>
OJD> considered suboptimal, and, accordingly, 25OHD values in that
OJD>
OJD> range ought to be considered subnormal. While the precise
OJD>
OJD> location of the threshold remains uncertain,
OJD> the evidence presented
OJD>
OJD> here points to a value closer to 80 or 90 nmol/L,
OJD>
OJD> consistent with the studies of PTH
OJD> concentration [2–4]. In any
OJD>
OJD> event, it seems more certain now that the lower boundaries of
OJD>
OJD> the reference ranges (i.e., 37.5 to 50
OJD> nmol/L) are incorrect, i.e.,
OJD>
OJD> such levels of serum 25 hydroxyvitamin D are associated with
OJD>
OJD> suboptimal calcium absorption, thereby
OJD> exacerbating the negative
OJD>
OJD> effects of the low calcium intakes that are today found
OJD>
OJD> across most population segments.
OJD>
OJD> The logic of the method of assigning a
OJD> reference range in this way is interesting. I
OJD> guess the problem I am having with applying
OJD> these recommended ranges is that the authors
OJD> exclusively used post menopausal women in their study.
OJD>
OJD> I am guessing here that many of these
OJD> subjects would have been total body calcium
OJD> deficient in which case looking at the
OJD> concentration of Vit D that would optimise
OJD> Calcium absorption would seem a reasonable thing to study.
OJD>
OJD> But we are getting literally hundreds of
OJD> requests on younger woman and men who have
OJD> completely normal calcium levels, totally
OJD> normal Alk Phos and PTH levels. And about
OJD> 75% of the total Vit D levels are < 75.
OJD>
OJD> Intuitively this seems wrong to me, but I
OJD> quite happy to be called and idiot and
OJD> persuaded by a good logical argument.
OJD>
OJD> Replies to mailbase and not to me personally.
OJD>
OJD> Bw John
OJD>
OJD>
OJD>
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Regards
Aubrey Blumsohn
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community working in clinical biochemistry.
Please note, archived messages are public and can be viewed
via the internet. Views expressed are those of the individual and
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