[GFCFNN] Re: The Value of the IgA Stool Test and the Etiology of Celiac

<snip>

Actually this statement has nothing to do with Dr. Fine's test,
because it concerns anti-endomysial antibodies, whereas EnteroLab
diagnoses gluten intolerance based on fecal anti-gliadin antibodies.

==============
http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSz
uszS\
zcommonzSzdorlandszSzdorlandzSzdmd_e_08zPzhtm

endomysial (en·do·my·si·al) (en"do-mis´e-əl) pertaining to the
endomysium.

endomysium (en·do·mys·i·um) (en"do-mis´e-əm) [endo- + Gr. mys muscle]
[TA] the sheath of delicate reticular fibrils which surrounds each
muscle fiber.
==============

<snip>

That is an enormous leap in logic. Out of 17 patients with
biopsy-proven celiac, they merely mention a single one who had high
fecal anti-gliadin antibodies with normal serology. That doesn't mean
the test is more "sensitive" unless it can actually be used to tell
the celiacs from the non-celiacs when they haven't already been proven
celiac by intestinal biopsy.

Can it? No, it can't at all:

=================
With all salivary parameters and fecal IgA AGA, IgM AGA, IgA EMA and
IgG EMA, healthy volunteers and patients showed partially overlapping
results.
=================

Unfortunately I don't have access to the full text so I don't know to
what degree these parameters overlap, but they don't give figures
either for the negative predictive value or positive predictive value,
and they explicitly state that there was overlap. In other words, a
number of people exhibiting no pathology had just as high fecal
antibody levels as a number of people exhibiting pathology.

Moreover, they do not indicate the *incidence* of fecal anti-gliadin
antibodies. This is essentially what Entero Lab's test is: a test of
incidence. If you have any presence of these antibodies at all,
beyond a very low level that is apparently supposed to be cutting out
the "background noise," you are diagnosed as gluten intolerant. This
is not remotely supported whatsoever by either of these studies, which
found anti-gliadin fecal IgA in people with no apparent pathology.

(Again, although there could be gluten-induced non-celiac pathology
that is marked by the fecal anti-gliadin IgA, there remains, to my
knowledge, no evidence for this.)

<snip>

It relates because the entire subset tested positive for anti-gliadin
IgA, which is what Entero Lab uses for its diagnosis (although it
seems the subset was originally taken based on serum tests). The
reason I posted the study is because it not only could find no
relationship between serum or fecal anti-gliadin IgA and clinical
signs of enteropathy, but it found that 50% of those with anti-gliadin
IgA in one test did not have it in the next test, and that when fecal
and serum IgA in the same people were compared, there was no
relationship between the two.

You suggest above that the fecal IgA is more "sensitive" than serum
IgA. This means by definition that the latter has some predictive
power and the former has a greater power to predict the same thing.
If this is true, there should be a relationship -- if you have the
serum anti-gliadin IgA, you should have the more sensitive fecal IgA.
Yet there is no relationship whatsoever between the two, indicating
that one, the other, or both are either not useful measures of
anything or that they are measuring completely different things.

<snip>

Well I searched pubmed.com for "fecal IgA gluten" and I turned up 11
studies, none of which examined the association of fecal IgA with any
health problems besides celiac. If they exist, I'd love to see them.

In any case, these studies would not be particularly valuable unless
they ALSO tested fecal IgA to OTHER foods. Otherwise, the fecal
anti-gliadin IgA could just be a marker for elevated intestinal IgA
over all. This could be a marker for, for example, poor digestion in
general. (Or it could be a healthy development. We'd have to see
whether fecal anti-gliadin IgA was associated with good health or bad
health.)

You can only show a gluten-specific problem if you examine fecal IgA
to gluten AND to other food antigens to which antibodies may be
elevated, and show that gluten specifically is elevated where the
others are not.

Moreover, fecal IgA in general tends to be polyreactive:

=================
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Ab
stra\
ctPlus&list_uids=10664845&query_hl=5&itool=pubmed_docsum

(from full text)

IgG1 [monoclonal antibodies -- mAbs] [to chicken egg lysozyme] bound
only to lysozymes, while IgA/IgM mAbs in the other groups showed
cross-reactivity with one or more of the antigens, including putative
environmental antigens in the gut [mouse food, denatured
single-stranded DNA and E. coli]. Thus, many of these IgA/IgM mAbs
can be considered to be polyreactive antibodies.
=================

So, in this study, they looked for intestinal IgA to a chicken egg
protein. Had they ONLY looked for IgA to chicken egg, then they would
have considered it anti-chicken egg antibody. Yet, these same
antibodies were ALSO antibodies to mouse food, denatured
single-stranded DNA, and E. coli. So, if you found the mice they
studied to have elevated chicken egg IgA and concluded that they must
have some kind of "IgA allergy" to chicken egg, you'd be failing to
rule out the presence of other food antigens, single-stranded DNA or
E. coli.

Thus, it's not only important to run multiple different antibody tests
because you could have *separate* antibodies elevated to gliadin and
many other food antigens, but because those very antibodies that are
elevated to gliadin might be polyreactive for many other antigens
despite also being able to bind to gliadin.

The reason that IgA in the gut might have such low specificity
compared to IgA elsewhere or to IgG in the gut may be that IgA is a
sort of general janitor of the intestines, mopping up any crap it kind
find to make sure it doesn't get where it shouldn't and cause a
problem:

=============
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Ab
stra\
ctPlus&list_uids=10664845&query_hl=5&itool=pubmed_docsum

(from full text)

The uptake of digested protein is considered to induce several
immunological responses. One of these responses in the gut is local
antibody production that is dominant in IgA antibodies against oral
antigens. These locally produced IgA/IgM antibodies are secreted into
the lumen of the intestine and may act as a mucosal barrier to prevent
further uptake of antigenic digested peptides that may cause
unfavorable immunological response such as food allergy.
==============

If so, this might explain why different researchers get wildly
different results for fecal IgA scores. Because not every
anti-gliadin antibody is the same. Some of them may be highly
specific and others may have relatively low specificity or be broadly
polyreactive and bind to gliadin along with a whole bunch of other
stuff. And it is primarily IgA in the GUT that has this low
specificity because of its specific function there.

For example, Dr. Fine found something like 30 or 35% of the general
population to have fecal anti-gliadin IgA, while study (4), which you
did not address, found only 1 of 20 children with celiac disease to
have elevated fecal anti-gliadin IgA, and only 1 of 64 control
children:

=============

http://www.pubmedcentral.nih.gov.silk.library.umass.edu:2048/articlerender.f
cgi?\
tool=pubmed&pubmedid=16377644

Faecal anti-gliadin antibodies were positive in one child with coeliac
disease and one control patient.
===============

That's 5% for celiac and less than 2% for general population, versus
Dr. Fine's 35% for general population (no numbers for celiac). And
the relationship to biopsy-assessed enteropathy?

None:

============
http://www.pubmedcentral.nih.gov.silk.library.umass.edu:2048/articlerender.f
cgi?\
tool=pubmed&pubmedid=16377644

The κ values between histology and stool test were 0.093 (-0.033
to0.219) for tissue transglutaminase antibodies and 0.062 (-0.027
to0.151) for anti-gliadin antibodies, indicating no agreement.
============

<snip>

Allright, if that's true, then by virtue of the lack of serum/fecal
association, IgA to gliadin in the gut has no predictive power
whatsoever to diagnose leaky gut. What, then, does it diagnose?

<snip>

Study (3) actually found that those with only IgA to gliadin in the
blood had a 0% rate of celiac disease, and 4.3 years later still had a
0% rate of celiac disease. Nevertheless, were it true that serum
anti-gliadin IgA tracked well with celiac disease, its lack of
relationship to fecal anti-gliadin IgA would suggest that fecal
anti-gliadin IgA has no value in predicting celiac. Again, what,
then, does it diagnose?

<snip>

Perhaps, as you said, because this is an indicator of leaky gut. I'm
sure there are other possibilities as well. One would get a much
better idea if serum IgA to *other* food proteins was assessed, and if
the polyreactivity of the anti-gliadin IgA was assessed.

<snip>

If they stop eating "gluten" that probably means they stop eating
wheat. If they stop eating wheat, they stop eating potential sources
of dietary opioids that might disrupt the nervous system (and I'm sure
cause other problems), they avoid a variety of different lectins,
peptides that have pharmacological properties and peptides that have
immunogenic peptides, and a variety of different food chemicals that
can be problematic. They also stop eating a food that is very
difficult to digest, and eating foods you can't digest tends to be
problematic regardless of which specific foods they are.

So, you could identify in this case that wheat was part of the
person's problem, but you're a long way from showing it is problematic
because of an immunological reaction rather than any of the other
possible reactions listed above, and you're certainly a long, long way
from showing that fecal anti-gliadin IgA can predict gluten-mediated
depression, or even that fecal anti-gliadin IgA correlates with
depression at all (since you're citing serum IgA).

You could make the enormous leap in logic to say that if serum
anti-gliadin IgA correlates with depression and more people have fecal
anti-gliadin IgA than have serum anti-gliadin IgA, then fecal
anti-gliadin IgA is a more "sensitive" marker of depression, but it
would clearly be false reasoning to do so. And I content we will get
farther in figuring these things out if we use sound logic.

<snip>

And he's been charging $300 and diagnosing people for 8 years while he
crunches his numbers. You don't need to number-crunch for a decade
before publishing preliminary data. Since there is nothing published
anywhere including his web site that substantiates the validity of the
test, other than the fallacious notion that if more people have the
fecal IgA than it must be more "sensitive," then it gives me little
comfort to know that he intends to publish data some day some
undefined length of time into the future.

<snip>

Really? So if I get an Entero Lab test and I test positive for fecal
anti-gliadin IgA to they tell me in the write up "It isn't really
clear what this means"? When I go to type in my credit card number
does it say "This test may have some predictive value for something or
other but we're not sure yet because we are in the process of
crunching numbers. Thank you for paying to be a crunched number."?

Usually people get paid, rather than pay, to be subjects in an experiment.

<snip>

What is this clear from? Fine apparnetly did a study on the general
population years ago that fueled his claim on the 2003 article on his
web site that 30-35% of the general population has elevated fecal
anti-gliadin IgA (apparently he's still crunching *those* numbers
too), but he gave no indication he was tracking how many of them gave
up gluten, or how many of those who tested negative gave up gluten.

In any case, many people who give up wheat will have improvements for
many different reasons. The fact that people who suspect they have a
problem with wheat get diagnosed by Entero Lab (as do most people who
get the test) with gluten intolerance and then improve when they
remove wheat does not give any indication that the mechanism by which
giving up wheat improved their health is by eliminating an immunologic
IgA reaction. And the fact that almost everyone who suspects they
have a problem with wheat gets a positive test makes it very difficult
to test the predictive power of that test.

<snip>

Again, I searched pubmed for "fecal IgA gluten" and got no results
indicating this. If you know of them, I'd like to see them.

<snip>

Based on the studies published on pubmed.com, they are not getting any
ground in showing that high fecal anti-gliadin IgA signifies anything
bad. Even if they were, it would not show anything gluten-specific or
even wheat-specific, and certainly not substantiate the highly
questionable idea that wheat problems are actively mediated by an IgA
reaction to gliadin.

<snip>

You've referred to "IgA allergies" and "IgA reactions" repeatedly, as
if they are the corresponding counterparts to "IgE allergies." IgE
"causes" allergies because the tail of an IgE molecule acts as a
receptor ligand for inflammatory cells and actively stimulates
inflammation. I am not aware of research showing that IgA has similar
or corresponding capabilities, although I'm aware of evidence it
protects against IgE allergies.

<snip>

High blood sugar *does* cause many of the problems in diabetes,
despite not being the first problem to occur. There is no evidence
that I am aware of, however, that intestinal anti-gliadin IgA is
responsible for the gut damage in celiac.

<snip>

There may be many things to learn about them, but we have a decent
understanding of how the IgE molecules stimulate inflammation. I'm
not aware of evidence that IgA molecules do anything similar.

<snip>

.

So far I see gluten-sensitive enteropathy and dermatitis herpetiformis
grouped under the "celiac" umbrella. These are usually attributed to
gluten because the etiology of the pathology is worked out decently
enough to clarify that gliadin-derived peptides are involved in the
pathological process. Like newer research is revealing roles for
peptides other than the well-studied 33-mer in this process, it's also
possible that the etiology of celiac will be recognized to extend
beyond gliadin-derived peptides.

But I don't see where any such pathological process for this broad
category of "gluten senstiivity" is worked out. I've seen research
substantiating the opioid theory of autism, but this doesn't belong
under "gluten sensitivity" because the process does not share the
immunological nature of celiac (although celiac might get expanded
beyond the immnological framework as it gets expanded beyond the
33-mer peptide as well), and because it isn't any more
gluten-sensitive as it is casein-sensitive, and these are simply the
most common foods containing potential opioids, not the only foods.

I see quite clearly a lot of anecdotal evidence that removing wheat
from the diet can improve many people's symptoms, but from this list I
see hardly anyone resolving their symptoms *only* by removing wheat,
and an awful lot of people who have very similar reactions to wheat
that they have to dairy, which to me raises the opioid flag.

What I *don't* see at all is any evidence whatsoever that Entero Lab's
test can actually carry a valid diagnosis for any of these problems,
which is the topic of this thread.

<snip>

I'm aware of the argument -- after all, I own a copy of _Dangerous
Grains_, have perused Fine's web site, and have been on this list for
quite a while -- but I am concerned about where the evidence for it
is.

<snip>

And there is:

-- No evidence that gluten mediates pathology by inducing anti-gliadin IgA.
-- No evidence documenting the reproducibility of the fecal
anti-gliadin IgA test.
-- No evidence documenting the agreement between different laboratory
tests for fecal anti-gliadin IgA test.
-- No evidence that fecal anti-gliadin IgA is a stable phenomenon,
such that there is actually a distinct subset of the population who
has it and a distinct subset who does not.
-- No evidence, that I am aware of, substantiating the specificity of
any particular lab's anti-gliadin IgA test for gliadin.
-- No evidence of the power of the fecal anti-gliadin IgA test to
predict celiac.
-- No evidence of the power of the fecal anti-gliadin IgA test to
predict the ill defined "gluten intolerance" or its 200 associated
diseases.

<snip>

Obviously they never stuck with this test and to whatever extent they
did, it seems it would have been a poor choice, since the study (3) I
posted earlier found a 0% rate of celiac among those who had serum
anti-gliadin IgA only at baseline and 0% rate of celiac among those
same people 4.3 years later. Moreover, this is serum IgA to gliadin,
which is *different* than fecal IgA to gliadin, and which study (3)
showed to have no realtionship to fecal IgA to gliadin, which in turn
was shown in study (4) to have no relationship to celiac.

<snip>

And they continue to use it because it actually works.

<snip>

Who noticed? Published where? And who connected the serum IgA to
fecal IgA, which the the only study I found on the subject showed to
have no connection at all?

<snip>

Well, only 0.2% of the population is considered IgA deficient (though
2-3% of the celiac population), but some people could be subclinically
IgA-deficient.

<snip>

Where does this figure come from? Shouldn't someone need to make a
valid definition of and diagnosis for "gluten-intolerance" in order to
derive this statistic?

<snip>

Well if it's actually true, it would mean that IgA-deficiency is 50
times higher in gluten intolerant folks than the general population,
which would strongly suggest that insufficient gut IgA contributes to
gluten intolerance.

<snip>

I have no qualms with the concept that removing wheat from the diet of
most people would improve their health. Wheat is difficult to digest,
contains proteins that can be maldigested into opioids, receptor
ligands that stimulate zonulin release, innate immune system
activation, cell-mediated immune system activation, growth factor
signaling, and so on, possibly calcium-binding peptides, lectins that
bind to sugar residues, starch that many people would have problems
with, and I believe it also contains various food chemicals or can
stimulate the endogenous release of some of them (I'll have to check
for specifics on this).

The question is, how does one determine WHY removing wheat from the
diet helps? If the problem is a particular wheat-derived antigen that
stimulates a gluten-specific IgA reaction, you'd only have to avoid
wheat. If the problem is opioids or lectins or food chemicals you
might have to avoid other foods, and knowing which type of reaction
you have will help you figure out which foods. Moreover, you might be
able to tolerate small amounts of wheat or other grains if they are
processed in certain ways.

Of course, the subject of this thread is whether the fecal
anti-gliadin IgA is a valuable test. If it is, where is the evidence?

Chris