Talk:Coeliac disease

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[edit] Refractory Disease

Refractory disease

A tiny minority of patients suffer from refractory disease, which means they do not improve on a gluten-free diet. This may be because the disease has been present for so long that the intestines are no longer able to heal on diet alone, or because the patient is not adhering to the diet, or because the patient is consuming foods that are inadvertently contaminated with gluten. If alternative causes have been eliminated, steroids or immunosuppressants (such as azathioprine) may be considered in this scenario.[6]

The above paragraph maybe considered misleading and opinionated. Refractory Celiac Disease can be broken down into groups RCD1 and RCD2. RCD1 is found in people who are DQ2 heterozygotes or DQ8 and are found in general is disease diagnosed over the age of 35. RCD2 is found in people who are DQ2/DQ2 (70%) and really has little to do with 'cheating on wheat' it is found in older onset cases. RCD2 generally appears with 3 years of diagnosis in patients generally over the age of 45, and is associated with precancerous tissues, it is generally untreatable with drugs (except bone marrow replacement and chemotherapy) and generally progresses to EATL. In many cases, at the time of diagnosis the precancerous tissue is already present. RCD2 is generally fatal within 5 years. Nor is it a condition of failure to heal, specifically, as a result of prolonged disease, but the constant stimulation by T-cells that are no longer require antigen, gliadin. If those cells are oblated the GI tract should heal. In RCD I there are markers that indicated some sort of cellular transformation, in RCD II there are typically clonal lymphocyte cell lines present and ussually spreading.

In addition recent studies show that DQ2.5/DQ2 individuals have more serious histological pathology and this corroborates with the finding of RCD2 (although the RCD2 study did not do SSP-PCR genotyping). The enhanced stimulation of homozygotes and the duration of the disease are likely major factors in whether T-cells will undergo transformation. Pdeitiker 04:04, 28 September 2007 (UTC)

This is based on the AGA position document. Go complain to them. Obviously compliance is a major issue. JFW | T@lk 15:03, 8 October 2007 (UTC)
Not complaining, I was made aware of a specific case in which a persons doctor continued to insist that the patient was cheating as her symptoms aggressively returned, she went about contacting and threatening food and drug companies. Despite the fact she had CD+ 6 children (i.e. very plausible DQ2 homozygote), after switching to a physician that was familiar with RCD, she is now being treated for RCD. RCD2 is an aggressive and life threatening disease and may flare up within 3 years on a gluten free diet, largely late onset in origin but in some cases can be earlier in onset, and has a very strong genetic component. user:pdeitiker) 18:38, 18 December 2007

[edit] Messing around with gliadin

Gianfrani et al report T-cell reactions, specifically affinity to DQ2, to gluten transamidated with an amine donor. doi:10.1053/j.gastro.2007.06.023... JFW | T@lk 15:15, 8 October 2007 (UTC)

[edit] More CD over time

The Finnish coeliac lot seem to think that a higher diagnostic level of suspicion does not explain the rise in incidence over time: doi:10.1111/j.1365-2036.2007.03502.x JFW | T@lk 11:36, 19 October 2007 (UTC)

[edit] Review

In this week's NEJM. May be interesting, for those with access :) Fvasconcellos (t·c) 22:42, 24 October 2007 (UTC)

[edit] Pathophysiology

I think the section for Pathophysiology needs to be reviewed since it makes too much mention to genetics specifically, perhaps a more clear, consise explanation should be given instead of genetics only. PLEASE!!! it's rather confusing!!!Chaotic rach 23:41, 4 November 2007 (UTC)

Genetics is a major issue in coeliac disease, and needs substantial coverage. What information do you think is presently lacking? JFW | T@lk

[edit] Liver

Review on liver in coeliac disease: doi:10.1002/hep.21949 JFW | T@lk 23:32, 5 November 2007 (UTC)

doi:10.1111/j.1365-2036.2007.03535.x - all about oral lesions. Many coeliacs have dental enamel problems and soft tissue lesions. JFW | T@lk 17:48, 25 November 2007 (UTC)

[edit] Indo-European

Where does the van Heel article say anything about Indo-Europeans. The data suggests that North-Americans and Europeans have a similar epidemiology (1%). The prevalence seems to be lower among non-Caucasians. Do you have a study about Iraninans or North-Indians?

See http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16564784&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

and also

http://www.consensus.nih.gov/2004/2004CeliacDisease118html.htm

They both mention studies in North America and Europe being similar. Whence the generalization to Indo-European (which, approrpriately or not, the present zeitgeist has relegated to Linguistics) 138.5.88.219 (talk) 02:35, 13 December 2007 (UTC)smorr

For genetic risk factors here are the frequencies of DQ2.5 and HLA-DQ8. DQ2.2 is higher in Iberia to central Asia. Reports coming from India some slight differences in genetic risk. DQ2.5 is not abundant in India, and associations with DQ2 are not as clear as in NW Europe. North American disease frequencies are comparable to British disease frequencies within the Caucasian population. The gene frequencies of DQ2 and DQ8 are comparable. Some areas of Europe have relatively low frequencies of disease, and parts of India have almost no genetic susceptibility.
In terms of disease genes here are the gene frequencies from north India [1]Pdeitiker (talk) 05:09, 25 December 2007 (UTC)
The geographical distribution of gene frequencies still wouldn't justify using Indo-European in this context in my personal opinion. Indo-European is a linguistic term, and as far as I can see, Wikipedia's own disambiguation page only lists linguistic definitions, although it does talk about 'Indo-European people'. Put it this way, is there anything to show that the gene frequency was not already present before the Indo-European language expansion? Maybe some other term should be used, or just a simple description of European, Central Asian and North Indian populations, if a geographical description is needed. Stevebritgimp (talk) 13:20, 18 May 2008 (UTC)
Or put another way while I think about it: 1) If this were so, Coeliac disease would be a strong indicator of the genetic unity of a very widespread linguistic group - itself probably news to historians and linguists. 2) If this is unproven it would be conclusion drawing, and basically contrary to WP:SYNTH (I think) - a synthesis would be made of geographical distribution and linguistic characteristics - that would need to be attested in a Reliable Source (hell, now I'm sounding like a WP rules lawyer - definitely not me!). Cheers. Stevebritgimp (talk) 13:24, 18 May 2008 (UTC)

[edit] Celiac Disease, T1D, RA linked to 4q27

Novel Association in Chromosome 4q27 Region with Rheumatoid Arthritis and Confirmation of Type 1 Diabetes Point to a General Risk Locus for Autoimmune Diseases. Zhernakova et al.

Recently, association of celiac disease with common single-nucleotide polymorphism (SNP) variants in an extensive linkage-disequilibrium block of 480 kb containing the KIAA1109, Tenr, IL2, and IL21 genes has been demonstrated in three independent populations (rs6822844 ). The KIAA1109/Tenr/IL2/IL21 block P p 1.3#10514 corresponds to the combined Idd3 locus in the nonobese diabetic mouse model of type 1 diabetes (T1D). This block was recently found to be associated with T1D in a genomewide association study, although this finding lacks unequivocal confirmation.We therefore aimed to investigate whether the KIAA1109/Tenr/IL2/IL21 region is involved in susceptibility to multiple autoimmune diseases. We tested SNP rs6822844 for association with disease in 350 T1D-affected and 1,047 rheumatoid arthritis (RA)–affected Dutch patients and in 929 controls. We replicated the association with T1D (P p .0006; OR 0.64 [95% CI 0.50–0.83]), and revealed a similar novel association with RA (P p .0002; OR 0.72 [95% CI 0.61–0.86]). Our results replicate and extend the association found in the KIAA1109/Tenr/IL2/IL21 gene region with autoimmune diseases, implying that this locus is a general risk factor for multiple autoimmune diseases.[End Abstract]

User:Pdeitiker 18:31, 18 December 2007 (UTC)

[edit] Cardiovascular disease

In contrast to the Cambridge study cited in Van Heel/West, there is now some linkage with cardiovascular disease doi:10.1111/j.1365-2036.2007.03594.x JFW | T@lk 09:06, 23 December 2007 (UTC)

good, its about time. The misconception of many physicians is that celiacs are underweight and are starving to death. Many celiacs have weight problems that can be attributed to partial maladsorption. I lost 25 lbs after going on a GF diet, largely because of increased adsorption of omega-3 fats and vitamin B. Celiacs can also be at risk because of secondary conditions such a rheumatoid arthritis or other debilitating conditions that result in lowered mobility. Other problems includes increased reliance on carbs as a result of protein/saturated fat intolerance and pancreatic insufficiency. This then sets up a condition if the person is not aware of the affects of fast carbs (starch) on saturated fat catabolism and cholesterol production, increased triglycerides and low density lipoprotein concentrations.Pdeitiker (talk) 04:59, 25 December 2007 (UTC)

Phil, are you certain you want to share personal experience with us? How certain are you about omega-3 and vitamin B absorption after starting a gluten-free diet? Did you get them checked? JFW | T@lk 07:49, 6 January 2008 (UTC)

One is never sure about sharing personal experiences, lol. There is chronic fatique and depression association with celiac disease. Some of this is attributed to the maladsoption of essential fatty acids. In addition sources of foods that are rich in certain vitamins tend also to be rich in protein, which can be the source of secondary allergic conditions (eggs, fish, etc). Gluten-sensitive_enteropathy_associated_conditions#Deficiencies links. Several CD specific conditions, such as localized epileptic seizures are attributed to folic acid deficiency that a recent paper (I will have to look up) claims is a secondary consequence of vitamine B12 decline, increasing B12 results in a rise of folic acid without additional folic acid treatment. Why B12 falls off in celiac disease is unclear, but omega-3s, B6, B12 and secondarily folic Acid all appear to have linked behavior. Not to give details but I do have a folic-deficiency related condition. These alone can explain at least some of the chronic fatique association. I should note however, starting last summer I moved away from processed grains to a complete whole grains-starch source diet, since then I have no general need for vit b supplimentation, but still maintain relative high O-3 intake. Many celiacs I have corresponded with complain of an addiction 'cravings' to fast carbs, I certainly can concur with this state given that 4 years ago I could eat very little protein because of the allergic responses, the body develops cravings for these things and these remain on a gluten free diet (at least for the year one is sorting out allergies). I still have difficulty maintaining certain species, e.g. cholesterol runs well below normal which means that HDL is usually a high percentage of TSC. Not sure why this is.
Given that late onset disease diagnosis is on the rise, I think the medical community has to face at least the fact: If the disease rate is not increasing then symptomatic disease is on the rise. Since my area of specialization is autoimmune disease it is relatively clear and certain that autoimmune diseases are rising in frequency and westernization of diet (increased saturated fats, increased processed foods, increased fast carbohydrates, affluence). The case for HLA-DQ and diet appears to be strengthening and does not appear to be restricted to DQ2 and DQ8. Part of the current 'Health Crisis' of the west is the genetic incompatibility of subpopulations within European derived peoples, or near entire groups incompatibility with the common western diet. The genetic factors within this overlap with HLA mediated and other immunological diseases. Or to put it more simply, some of us should be very carefully selected what we eat of a western diet. A recent paper by John Hawks and company (PNAS) shows that a large percentage of variable sites in the human genome have undergone _regional_ selection in the last 5000 years, a previous paper showed that a high percentage of these genes are in the immunological and digestion/metabolism area. So that my unabashed personal experiences reflect something that is becoming more widely established in the anthropology circles, we are not all alike.
Therefore it is not surprising that we are seeing a flip between very severe late onset cases that are starving, in which factors triggering symptomacy may have been enteric infections (rotavirus, enterovirus, influenza virus) are also associated with weight loss - situations that may have been identified back in the early half of the 20th century . . . .but now a class of symptomatic patients is emerging where the damaging agents might be an excess of certain chemicals in the diet which include spikes in glucose as a result of starch metabolism. Other factors include aspirin, NSAIDS, MSG, sodium benzoate, that damage or weaken the lining of the GI tract, things people consume more of relative to 50 years ago. Instead of seeing these patients in a emaciated moribund state they are being identified in the clinics much earlier.Pdeitiker (talk) 15:32, 2 February 2008 (UTC)
No sooner said. Arch Pediatr Adolesc Med. 2008 Feb;162(2):164-8. Emerging new clinical patterns in the presentation of celiac disease. Telega G, Bennet TR, Werlin S.
"...The number of patients diagnosed with celiac disease increased from 1 in 1986 to 93 in 2003. The mean age at diagnosis increased from 5.32 years for patients diagnosed before 1995 to 8.70 years for patients diagnosed after 1995. Gastrointestinal symptoms dominated in children younger than 3 years, whereas in children older than 3 years, the majority presented with non-gastrointestinal indications. The percentage of patients presenting with gastrointestinal symptoms alone decreased during the study period; 11.2% of patients diagnosed with celiac disease were overweight (body mass index > 90). CONCLUSIONS: Our study provides a unique longitudinal follow-up of clinical practice over a 17-year period. Currently, patients with celiac disease usually do not present with classic symptoms; they are more likely to be asymptomatic school-aged children who belong to a high-risk group...."Pdeitiker (talk) 00:50, 16 February 2008 (UTC)

[edit] Males in DQ2/DQ8 negativity

doi:10.1111/j.1572-0241.2007.01716.x finds (in a smallish series) that CD is more common in women, that there is an usually high rate of DQ2/8 negativity in the male group, and that transmission of DQ2/DQ8 genotype from fathers to daughters posed a relatively high risk. Imprinting? JFW | T@lk 07:49, 6 January 2008 (UTC)

[edit] Here we go again...

doi:10.1111/j.1365-2036.2008.03609.x - if tTG antibody is >30 units/mL (10 the upper limit of normal) - which is the case in 50% of the cases - duodenal biopsy may be unnecessary because of the very high sensitivity and specificity of the test at this level. JFW | T@lk 21:25, 13 January 2008 (UTC)

Why 'here we go again', I would think this is common sense. I am waiting for the paper to come out that looks at tTG deposits and concludes that peroral biopsy as a stand alone diagnostic measure is obsolete and inaccurate.Pdeitiker (talk) 17:20, 3 February 2008 (UTC)

I wrote "here we go again", because guidelines presently demand a duodenal biopsy at least once in the disease course, and it is my personal opinion that neglecting to do so will lead to important comorbidities being missed, such as giardiasis or Whipple's. JFW | T@lk 09:43, 24 February 2008 (UTC)

hmmmm, what do you do about docs that, in the new health care restricted system, do not want to do biopsy. I would have loved to have had a biopsy, when I told my assigned PCP I thought I had CD he told me it was a fatal disease of small children and laughed. The first time I got to see a GI phys was for GERD 3 years after the fact. I work in a medical school. I was extremely fortunate that I know how to do DNA and Antibody work. I was trying to save my job and stay alive, I couldn't wait until MDs figured it was time to do the right thing.
I picked up someone in my screening work that was a suspicious of CD because of genetic and other known CD risk factors, in September this individual ask GI physician (after having gone through a GI crisis, treated for anti-biotics, including one specifically designed to treat GI yeast infections) for an ATA-IgA/IgG test and it was not given. After a query about what I thought it was and how it was treated I gave her some papers and against my recommendation, this individual went on the GF diet and saw immediate improvement. It will be lucky at this point if the individual gets the ATA test done and interpretation may be compromised. If I have my numbers correct the individual has been to see the PCP or GI about 7 times since September for the same issues. You tell us what to do, the individual works in a medical environment and still has no ability to convince the health care system to establish a probability-recommended course of action. Is there a button that the patient can push that gets MDs to start acting like scientist, start reading papers when patients present relevant information??? Nare judge a man 'till you walk 5 miles in his shoes. Pdeitiker (talk) 14:41, 20 March 2008 (UTC)

[edit] Wheat allergy vs gluten intolerance

This article does not distinguish between the two concepts, which although related, are not the same. Socrates2008 (Talk) 23:45, 1 February 2008 (UTC)

See Wheat allergies page. You can find the criteria for 3 wheat related diseases on Gluten sensitivity
Comparative pathophysiology of Gluten Sensitivities.
Gluten Sensitive Enteropathy (Major:Coeliac disease) is a subset of gluten sensitivities. It is defined by a number of phenomena in addition to allergic responses: Defined T-helper cell response, anti-Host-autoantibody presence, distinct pathology. One recent paper claims that CD in its advanced phases suppresses allergic responses even to gluten, and it has been observed that many chronic late onset cases lack anti-gliadin antibodies. It is therefore possible to have gluten allergy and not have celiac disease, and to have coeliac disease and not have anti-gliadin antibodies or gluten allergy (Noting that these studies have yet to stand of to the scrutiny of wheat hydrolysate testing). Pdeitiker (talk) 14:45, 2 February 2008 (UTC)
You sound like specialist in this area - would you mind updating the article to clarify? i.e. expand the intro to explain where this article on Coelic disease fits into the wider background of gluten-related sensitivities. Socrates2008 (Talk) 21:21, 2 February 2008 (UTC)
The complaint is that the GS article needs some 'de jargonization' but at the moment I am not sure how. What is considered jargon here is the 'lingua franca' elsewhere.Pdeitiker (talk) 03:19, 3 February 2008 (UTC)
I agree that a clear distinction needs to be made, and I have added this in the intro. I don't think any space should be devoted to the differences in pathophysiology, because that is something the wheat allergy page (presently a stupid laundry list) should do.
I don't know if I would call it a 'stupid laundry list', I agree, there is clearly enough information on this page, and until either gluten allergy or idiopathic gluten-sensitive neuropathy can be linked more specifically to GSE they should not be discussed here. However the differences in Pathophysiology need to be on the Gluten sensitivity page, if you place them on the allergy page you have the same conflict as placing them on the Coeliac disease page. PD (talk)
I see the problem, two pages, will merge the two articles under wiki-consistent name. BTW, when are you going to fix that table that has two rows with the same labels? PD (talk)
I have created a temporary page that I intend to replace the 'stupid laundry list' page others have stubbed for Wheat allergy.Proposed replacement of wheat allergy If this is acceptable I will replace the current page and redirect Wheat allergies to wheat allergy. From a naming convention point of view I would argue that there is no single wheat allergen but that allergic responses to different proteins can affect different systems, so it might be correct to call them wheat allergies instead of wheat allergy. Any thoughts? Pdeitiker (talk) 05:20, 11 February 2008 (UTC)
You should be having this discussion on the talk:Wheat allergy page, not here. Also, wheat allergy and wheat allergies need to be merged. Socrates2008 (Talk) 07:31, 11 February 2008 (UTC)
Pdeitiker, you are the principal author of a whole raft of articles (gluten sensitivity, gluten-sensitive enteropathy associated conditions, gluten-sensitive idiopathic neuropathies) that are chock-a-block with jargon that I have not encountered anywhere else in the literature. I have so far resisted having them merged or cleaned up, but I really wish you could try to improve the readability of your handiwork. JFW | T@lk 12:31, 10 February 2008 (UTC)
That is the reason I did not want to do them at all. I was asked by a few lay people because they get results from their MDs and they do not know whether they have allergy or intolerance or how the two can differ, and then finally, and most heinous, a certain third-party testing lab who uses this 'jargonistic' information about very rare idiopathic disorders to convince those that are tested that they have a gluten sensitivity. So prevalent was this diagnostics and belief that something needed to be done. The wheat allergy page is justified, but the 'idiopathic gluten sensitivity' falls into what I consider to be on the level of '..Spears current events'. . . . .
This is fairly important issue and I welcome critiques. However should we really discuss this on this page?
There are several issues on those pages that after having new literature and reread old literature I want to change. For example, on the wheat allergy page all psuedoallergies group and redirected off page. When the page was written there was not a page on anti-yeast allergies. However, I would like to go over all the literature at a sitting to see how it best be represented. At the time the page was written the issue of Atopia and wheat sensitive exercise induced anaphylaxis was not properly discussed on either the Atopia or the EIA page and there was a battle between authors of the Urticaria and EIA page going on, if you link to a page where the explanation is equally bad . . . . . You will noticed I changed the name of the page, even though gluten allergy is specifically mentioned in several papers, it is becoming evident that allergies cannot and should not be defined in the same way gluten intolerance is defined.PD (talk)

[edit] Monosodium glutamate/Glutamic acid

Are there any issues for people with gluten sensitivity to monosodium glutamate and glutamic acid (both of these are highly processed forms of gluten)? Either way, might be worth a mention. Socrates2008 (Talk) 12:20, 10 February 2008 (UTC)

I don't know. Is that your personal theory? MSG and glutamic acid are amino acids, and it is unusual to have immune-mediated reactions against amino acids. The only possibility would be contamination with gliadin peptides. How about you Google it and let us know? JFW | T@lk 12:35, 10 February 2008 (UTC)
No, I don't have a theory. However have read about hidden gluten as an additive in some foods such as ice-cream, so was wondering if these were an issue too. Socrates2008 (Talk) 13:12, 10 February 2008 (UTC)

As a non-scientist, non-physician member of the celiac community for over twenty-five years I would like to interject a simple answer to this question: 1)Beware of anecdotal "information" bandied about by fellow celiac sufferers. Too often it is not supported by fact. 2) Certain substances (e.g. Monosodium Glutamate) are simply irritating to the unhealed tissues of a recently diagnosed celiac. These items are best avoided in the diets of children anyway and in both children and adults may be introduced in small quantities later. Remember just because you have a hammer, everything isn't a nail.

There have been inferences made about Aspirin, MSG, Sodium benzoate, FD&C yellow, NSAIDS. I believe based upon what I have read that microperforations of the GI tract may have more to do with allergies and inflamatory bowel illnesses than Coeliac disease, specifically. Aspirin and Exercise have both been implicated in Uticaria and Exercise Induced Anaphylaxis and it has been reported that in the case of EIA that these agents allow gliadin peptides to enter the blood stream from the GI tract. The modality of glutamate and benzoate action is not clear. Allergic disorders can aggrevate autoimmunity, as appears to be the case with rheumatoid arthritis, and entering of digested peptides into the blood may be a factor in several disorders. With regard to Coeliac disease these may be involved in triggering disease, but once disease is triggered it seems unlikely they play a maintenance role and the damage induced is relatively minor compared to other agents. PD

Peptides in the bloodstream? That is a highly controversial theory. JFW | T@lk 09:39, 24 February 2008 (UTC)

[edit] Haptoglobin variants, Maladsorption and CD

Clin Chem. 2008 Feb 7. Haptoglobin Polymorphism: A Novel Genetic Risk Factor for Celiac Disease Development and Its Clinical Manifestations. " . . .RESULTS: Hp2-1 was associated with a significant risk for celiac disease (P = 0.0006, odds ratio [OR] 1.54, 95% CI 1.20-1.98; prevalence 56.9% in patients vs 46.1% in controls). It was also overrepresented among patients with mild symptoms (69.2%) or silent disease (72.5%). Hp2-2 was less frequent in patients than in controls (P = 0.0023), but patients having this phenotype were at an increased risk for severe malabsorption (OR 2.21, 95% CI 1.60-3.07) and accounted for 45.3% of all malabsorption cases. Celiac and dermatitis herpetiformis patients showed similar haptoglobin phenotype distributions. . . . "

Not sure what to make of thisPdeitiker (talk) 00:23, 16 February 2008 (UTC)

Perhaps this needs to await further studies. What role does haptoglobin have in immunomodulation? JFW | T@lk 09:39, 24 February 2008 (UTC)

[edit] Gluten-free diet is protective against subsequent (secondary) autoimmune diseases

Clin Gastroenterol Hepatol. 2008 Feb 5 Incidence of Autoimmune Diseases in Celiac Disease: Protective Effect of the Gluten-Free Diet.

"... The cumulative risk of subsequent autoimmune disease was lower in patients compliant to a gluten-free diet versus noncompliant patients (at 10 years, 6% +/- 2% vs 15.6% +/- 5.9%, respectively; P = .02). The incidence of autoimmune diseases was 5.4 per 1000 patient-years during adherence to a gluten-free diet versus 11.3 per 1000 patient-years during nonadherence to the diet (P = .002). Results were similar in both the pediatric and the adult populations. CONCLUSIONS: Celiac patients most at risk for autoimmune disease are those diagnosed early in life and having a family history of autoimmunity. The gluten-free diet has a protective effect."

This is one of my pet 'harps' that the importance of secondary diseases, many of them rare in celiacs, are increased for celiac disease. The statistics of the problem is one that I deal with, there are many rare diseases that are at ever so slightly increased risk in celiac disease, many of these are autoimmune diseases that are 'discounted' in association. While risk of individual disease is rare the number or these rare diseases that are associated is high, therefore overall the risk of celiacs acquiring a secondary disease is high, it is simply impossible to predict which one. Celiacs often contain a second allele (either DRB1 or DQB1) that can increase the risk of the secondary disease.

According to this study going on a gluten-free diet decreases the risk to almost 1/3rd which for many disease is approximately normal risk. While it may appear that GF diet solves the problem, other factors, allergens in particular, may elevate risk for diseases like thrombosis or arthritis and therefore simply excluding gluten is not the solution to the problem of autoimmune disease triggered by inflammatory disease.Pdeitiker (talk) 00:36, 16 February 2008 (UTC)

That sounds controversial and not ready for prime time. JFW | T@lk 09:39, 24 February 2008 (UTC)


[edit] BBC news article

Socrates2008 (talk · contribs) added an external link to a BBC article about a patient with coeliac disease. I generally find that external links to news resources are a bad idea. If the topic of the news article is relevant, this should be integrated with the article and footnoted to the news article.

In this particular instance, the article is about a patient with coeliac disease. Much of his disease course is typical (diagnosis was on the basis of atypical symptoms) and he needs characteristic treatment with a diet. The article has several inaccuracies that make it less suitable still: it suggests that colon cancer risk is raised in untreated CD (small bowel lymphoma and carcinoma was undoubtedly intended, but these are different diseases), red blood cells are not "malformed" in B12 deficiency (they are enlarged and have hypersegmented nuclei) and B12 is not absorbed in the upper part of the gut (it is absorbed in the terminal ileum), gluten might be present in oats but oats are not necessarily a problem in coeliac disease... The concern about his 4-year old daughter could be alleviated if she was tested for HLA-DQ2 and coeliac serology. JFW | T@lk 12:55, 24 February 2008 (UTC)

Comment: I added the link because:

  • The Wiki article is currently presented from a medical point of view - the link adds the missing patient perspective.
  • I could not see any easy way to integrate the story in the current article without upsetting someone (although I seem to have succeeded on that score anyway)
  • The linked article is from a reliable source, the BBC - an organisation that is cited widely by Wikipedia.
  • The linked article fits under the guidelines of What should be linked - i.e. "Sites with other meaningful, relevant content that is not suitable for inclusion in an article, such as reviews and interviews."
  • The linked article covers the correct subject matter, Coeliac disease
  • The linked article is easy for lay readers to read and understand.
  • The linked article includes information that is not present in this article, e.g. problems faced trying to follow a gluten-free diet for the first time.

Lastly, the reasons given by Jfdwolff for removing this link amount to WP:OR. I note too that my edit has been reverted for a second time BEFORE consensus has been reached here. (Kindly refrain from reverting again until this issue is settled here.) I shall be happy to accept the consensus of other editors about the inclusion or exclusion of this link - so please indicate your preference below. Thank you. Socrates2008 (Talk) 09:31, 25 February 2008 (UTC)

A problem with "the patient perspective" is that everyone is different. There simply isn't room to discuss (or link to) all the different ways coeliac disease may affect someone's life. The patient charity web sites are better at this, and may include personal stories. These are already linked-to by this article. I'd also trust those websites to check their facts better than some journalist. The story shouldn't be integrated as the person involved is utterly non-notable. The BBC is a reliable source for news, not medical facts. JFW has indicated the article's shortcomings in this regard. Much of the article reports what the interviewee said about his medical story, and it appears the journalist hasn't checked to see if this was imprecise/incorrect, or whether she has misunderstood what she was told.
See Wikipedia:BOLD, revert, discuss cycle for why JFW's revert was acceptable practise and your revert of his revert was not. -- Colin°Talk 14:00, 25 February 2008 (UTC)
Colin, thanks for the feedback. I wouldn't exactly call my edit bold. On the contrary, it was a single external link that didn't change anything in the substance of the article. Socrates2008 (Talk) 14:17, 25 February 2008 (UTC)
You're right, but that's the name of the essay (it isn't even a guideline). See Wikipedia:External links for more guidance (though I suspect you already have). I think you made a good-faith addition, but on balance we already have plenty patient-friendly links for sites that are far more comprehensive than one short news story. If everyone added a useful/interesting link, the article would be nothing but links. So JFW's edit was mainly to keep to a sensible number of really good links. For example, if this disease was extremely rare, then the BBC interview might well be useful, due to the paucity of coverage by any media. Colin°Talk 14:27, 25 February 2008 (UTC)

Socrates2008 - I sometimes remove links without reviewing them closely, but in this case I gave the BBC article a close look before I removed it on the grounds mentioned above. Do you disagree that the interview is full of errors?

I disagree that every medical article needs something from "the patient's perspective". A good medical article discusses this as part of its content, and if you feel this is lacking from this article then please make content changes to that effect. The article already states that the diet can be cumbersome and that quality of life may be decreased even while on GFD. Is that not sufficiently aimed at the patient's perspective? JFW | T@lk 20:41, 25 February 2008 (UTC)

[edit] Patient perspectives

With regard to coeliac disease and the very high late onset misdiagnosis rate, one could argue the late onset disease is an assortment of patient perspectives. Since some people enter the process with a secondary autoimmune condition the quality of life may decrease on GFD, but if they do not abstain, quality of life may decrease with the next secondary condition. And, with regard to that RCD2 and EATL can markedly decrease the quality of a markedly shortened life. There are very few instances of late onset disease where the symptoms between patients match exactly, there are a few that are frequent such as abdominal inflammation, chronic fatique, "brain fog". Even with these the path to diagnosis may begin with autoimmune thyroiditis, dermatitis herpetiformis, or some other condition.

One of the problems with Coeliac disease page is that it focuses on the most common symptoms but if fails to detail higher frequency than normal symptoms and conditions seen in celiac disease. When all these are combined they are more common than the most common preclinical symptoms. These collections of symptoms are the patients perspective and clinical ignorance of these lessor symptoms is a major reason for the high misdiagnosis rate and is also part of the patient perspective on the process. Pdeitiker (talk) 12:42, 12 March 2008 (UTC)

With respect, I think you are completely wrong. The article makes it abundantly clear that presentation may be subtle and relating to nonspecific symptoms. It also cites recent UK guidance about screening for coeliac disease in typical "dustbin syndromes" where one would find many cases of CD, such as IBS and chronic fatigue.
Do you have a reliable source that sensibly enumerates the "higher frequency of symptoms and conditions"? JFW | T@lk 08:13, 7 May 2008 (UTC)

[edit] NICE guideline

The new NICE guideline National Institute for Health and Clinical Excellence. Clinical guideline CG61: {{{2}}}. London, {{{3}}}. advises coeliac serology in newly diagnosed irritable bowel syndome. It also advises screening in chronic fatigue syndrome. Torrent of new diagnoses? JFW | T@lk 07:32, 29 February 2008 (UTC)

[edit] Name (celiac not coeliac)

The more common name for celiac disease is "celiac" not "coeliac". I don't know why wikipedia has it spelled this way but I think that the name should be changed. The vast majority of website name the disease "celiac" not "coeliac". Bobje (talk) 22:46, 17 March 2008 (UTC)

It depends which part of the world you are in. The spelling coeliac is used in British and Commonwealth English. We have been through this before, see this discussion. On the English Wikipedia, once a page has been created under the British spelling it is not usually moved to the American spelling or vice versa. JFW | T@lk 01:13, 25 March 2008 (UTC)
How do we pronounce coeliac? OptimistBen (talk) 06:38, 16 April 2008 (UTC)
Different spelling, same pronunciation - like see-li-ac, emphasis on the first syllable.Trishm (talk) 11:21, 10 May 2008 (UTC)

[edit] LFTs

The following was added in "signs and symptoms":

An unexplained elevation in liver function tests may be the presenting sign of celiac disease in some children.

Firstly, this is not a sign or symptom but a laboratory abnormality. Secondly, while I have seen this mentioned in many publications, I am not sure whether it ever develops in the complete absence of any further symptoms nor am I convinced that this has been particularly well studied. JFW | T@lk 01:13, 25 March 2008 (UTC)

[edit] History

Full text at PMC: 1838854 is another historical resource (BMJ 1988). JFW | T@lk 11:27, 31 March 2008 (UTC)

[edit] Neurocoeliac

Another neurologist who doesn't believe all those papers associating coeliac with certain neurological presentations. Lovely rant about EBM: doi::10.1136/jnnp.2007.139717 JFW | T@lk 22:07, 9 April 2008 (UTC)

[edit] Main Page?

Apparently, May is celiac disease awareness month in the U.S. This fine article hasn't been on the Main Page yet—how about putting it in the queue when there's an opening? Fvasconcellos (t·c) 23:30, 9 April 2008 (UTC)

Will do. JFW | T@lk 11:26, 11 April 2008 (UTC)
Is on TFAR for 22 May: diff. JFW | T@lk 08:05, 7 May 2008 (UTC)

[edit] Genetics - more

PMID 18311140 is a genome-wide study from Nat Genet. Sounds like we will need to cover this, but I have no access to the journal. JFW | T@lk 11:22, 11 April 2008 (UTC)

I have the paper, coincidentally DLed it this morning, I will need to go over it with a fine toothed comb. Basically, the authors argue that all sites identified are already associated with autoimmune disease. The question is whether any of these associations might be secondary to celiacs or are they shared associations. Pdeitiker 15 April 2008 (UTC)
Given that you seem to have the paper, could you work its conclusions into the article in a brief, clear and comprehensive way? The level of detail in the below subsections is not really possible I'm afraid. JFW | T@lk 08:05, 7 May 2008 (UTC)
I am hesitant to do that with this paper. I am concerned that the study is biased by the diagnoses that leads eventually to the coeliac diagnosis. I do not see that they have picked the study subjects from assymptomatic population.Pdeitiker (talk) 13:55, 20 May 2008 (UTC)
Subpage for genetics?Pdeitiker (talk) 13:28, 21 May 2008 (UTC)


[edit] The paper

Hunt et al. Newly identified generic risk variants for celiac diease is relate to the immune response. Nature Genetics 40:395-402Pdeitiker (talk) 02:00, 16 April 2008 (UTC)

[edit] The case for 1q31 (putative RGS1)

The putative locus is the regulator of G-protein signaling 1 - rs2816316 location. Corroborrating Evidence -

  • Increased B-cell translocation in mice
  • Chemokine stimulated dendritic cell activity
  • localized in small intestinal biopsies
  • mouse intraepithelial cells.

With regard to this rs2816316, the authors give an overall P of 2.58 x 10e-11. The odds ratio is 0.71, although the allele frequency in CD of major and minor alleles is not apparent in the paper. There appears to be a marginal Type 1 diabetes association with this locus at p = 0.03. Confusing was the WTCCC table given that shows CD (referring to Crohn's not celiac disease. In the WTCCC table two alleles A and G were given, in the supplimentary material of A and C were given as major and minor variants (Celiacs = 0.1362-"C" and Normals 0.1741), therefore the minor allele is less common in celiacs. In T1D assuming that there is just a typographical error there is a similar decrease in the minor allele "C". If the information is correct then the distribution of homozygotes of A/A should be higher in celiacs.

[edit] The case for 2p21-22 (putative IL18)

The statistical case for this allele is much stronger. Crohn's disease is modestly associated with the same locus. IL18 induces T-cells to produce inteferon. The alleles are rs13015714 and rs917997 for genome wide markers.

  • IL18RAP is expressed in natural killer cells (what kills the epithelial cells?)
  • expressed in intestinal biopsies
  • IL18 is expressed in mucosa of active, treated and latent celiac disease but not healthy controls.

The WTCCC (Nature 447: 661-678) found the allele B ("T") to be associated with Crohn's disease (p=0.0008) and examining their data I came to a similar conclusion. There is a marginal risk for a type II diabetes association. rs917997 in celiac disease paper is given as A1 (minor allele) as "A" and major allele as "G". These rs markers generally only recognize one SNP so which is correct C/T (102508428) or A/G (102437000). These differences appear to be the result of a slight shift in SNP used by 71400 nt (or not). 102508428 is a physical map location. Therefore it seems to me there are errors in this paper that the authors have overlooked. The minor allele in which is higher in celiacs is also higher in crohn's disease.Pdeitiker (talk) 22:35, 15 April 2008 (UTC)

[edit] The case for 3q25-26, 28 (Putative IL12 and LPP)

rs17810546 and rs9811792 is a large linkage disequilibrated block may show an association with celiac disease. The region is proximal to IL-12 A locus (IL12A) IL-12A produces one subunit of a heterodimer that forms IL12p70.

  • broad range activities on T and natural killer cells.
  • induces T-helper cells. T-helper cells recognizing gliadin/HLA-DQ2.5(or DQ8) bearing APCs are a hallmark of celiac disease.
  • an LPP gene exists also the region. LPP is expressed in the small intestine.

The WTCCC showed no disease association with common autoimmune diseases. The rs9811792 shows an almost balanced frequency of two alleles in the population, rs17810546 has a minor allele that is 4% higher in the celiac population than in normals. Homozygotes of the minor allele are expected to be twice as frequent in celiacs compared to normals, but they would make a minor subset of the total celiac population. p-values for markers in the region of these two markers are low with minima in the 10E-9 range. The entire region appears to be linked or in strong long range linkage disequilibrium.Pdeitiker (talk) 22:34, 15 April 2008 (UTC)

[edit] The case for 3q21 (CCR cluster)

The marker rs6441921 is within the Cytokine receptor gene cluster (CCR1, CCR2, CCR3, CCRL2, CCR3, CCR5 and XCR1). It has been previously linked to Type 1 diabetes in the WTCCC study at p=10E-5 range. There is a pretty hefty increase in the homozygotes of the minor allele in T1D, which is something that molecular geneticists really like to see. For coeliac disease the minor allele is about 5% higher in the population than normals, with a p value of <10E-6 when all studies are combined. T1D and coeliac disease share about the same risk. The minor allele is increased by 14% in celiacs, and homozygotes (rare-11% in celiacs) by 30%. There is a potential, at least, for this to be an important marker in individuals who have both CD and type 1 diabetes. Pdeitiker (talk) 22:34, 15 April 2008 (UTC)

[edit] The case for 4q27

The authors have reported on 4q27 and the results have been integrated into the main page. Since that time the locus has found to be associated with Graves, T1D and Rheumatoid arthritis. The WTCCC gives a relatively strong association with RA. The genes located in the region are IL2 and IL21.Pdeitiker (talk) 22:41, 15 April 2008 (UTC)

[edit] The case for 6q25

The HLA locus is found on the p-arm, this locus, rs1738074, is on the q-arm, and for all intents and purposes segregates independently of HLA-DQ. In the WTCCC there is a marginally increased risk for Crohns, Rheumatoid arthritis and Type 1 diabetes. The SNP is found within a long segment of DNA under linkage disequilibrium. The marker was found in nearly balanced frequencies indicating selection is either balancing, variable, or neutral at the site. Since the neither allele frequency is low homozygote differences on either side represent only modest differences. The authors speculate on the TAGAP gene and product.

[edit] The case for 12q24

This locus has a surprisingly high association with type 1 diabetes for the marker SNP rs653178. The markers map to the region of SH2B3 (LNK) and ATXN2 with linkage disequilibrium over a region of 1 Mb (In comparison Super b8 which contains HLA-DQ2.5 in europeans) maps to almost 2.5 Mb. The link to T1D is relatively strong at 10E-13 in the WTCCC study, with homozygotes "C/C" about 50% more frequent in T1D. The case is less strong in celiac disease, with less than 10% change in the minor allele frequency. Also linked to this locus marginally are rhuematoid arthritis and crohns disease.Pdeitiker (talk) 01:39, 16 April 2008 (UTC)

[edit] Previously described loci and other loci

"CELIAC2 (5q31-q33 - IBD5 locus), CELIAC3 (2q33 - CTLA4 locus), CELIAC4 (19q13.1 - MYOIXB locus), have been linked to coeliac disease. The CTLA4 and myosin IXB genes have been found to be linked to coeliac disease and other autoimmune diseases.[37][38] Two additional loci on chromosome 4, 4q27 (IL2 or IL21 locus) and 4q14, have been found to be linked to coeliac disease.[39][40]". With the exception of 4q27 (added by the same authors) none of the other loci were recognized in this study. Therefore these studies appear to be largely at odds with each other. The only agreement that is universally found is for the HLA-D locus (DQ2 and DQ8 with the lions share of risk for DQ2.5cis haplotype). In addition to these studies, there are 2 ongoing studies that are looking at specific family related disease risk in Finland (15q11-q13) and other parts of Scandinavia (5q31-33). In the case of the Finnish study some speculation can be made that the disease may be traced to a single individual in the 16th century. Other studies have shown risk specific for Spain and Italy. The northern European population, particularly the Irish have very high levels of HLA-DQ2.5, 1/3rd of all Irish have DQ2.5cis and in certain western Irish counties that rate may be as high as 50%, up until recently the consumption of Triticum sp. was relatively low compared to other parts of Europe. There is a continuity of genetic relationship between the Irish, Western England, Scotland and Scandinavia which represents, probably, the retention of pre-Neolithic traits as a result of the northern extent of Triticum cultivation up to the bronze age. As a result these studies may be picking up genetic risk common to people of relatively common ancestry to the early holocene. Admixture within these data sets may be diluting risk factors evident in other data sets. Examination of the Irish in this set showed many associations did not hold up, indicating the opposite, that admixture (Nordic/islandic into continental) may be increasing risk in UK and dutch populations. For example, 1q31, 2q11, 3p21, 3p28, and 12q24 showed no association in the Irish, whereas 4q27, 3q25, 6p21 (p<10E-80) showed strong association and other sites, chr3 (rs1021701), chr7 (rs269243), chr9 (rs1952461), chr11 (rs10501723, rs6483061, rs7479104), Chr12 (rs2078178).

What we need to keep in mind is that the odds ratios are very close to 1 for the 'celiac' allele in these studies. This indicates highly contingent associations with other genes, environmental factors, or study biases. Following these traits in families may be more enlightening since as in the case of 3p21-28 linkage disequilibration could hold a nest of associated traits for historically relevant generations.Pdeitiker (talk) 02:43, 16 April 2008 (UTC)

[edit] Some thoughts

One of the enigmatic questions of coeliac disease is if coeliac is primary to autoimmune diseases then those autoimmune diseases should undergo remission on a gluten-free diet. The risk associated with gluten consumption and celiac disease is a bit of a rarity in that removal of gluten generally causes the decline anti-transglutaminase activity. It should be expected if tTG is involved in the presentation of other self proteins, then the severity of other autoimmune diseases should abate, however abatement seldomly occurs. One plausible answer to this question is that other autoimmune diseases occur in CD with tTG assistance, but in these instances there are other promotors of disease, such as genetic risk factors. In this way, once a certain threshold is crossed these other autoimmune diseases have sufficient other factors to maintain themselves. We can also flip the argument, some of these markers, with the direction of allele association similar to CD, may be apparent in this data set because the second autoimmune disease was detected first and lead to the detection of CD. Since most CD goes undetected, having a secondary disease that has its own associations brings those associations into the CD genetic association. To remove this bias, CD needs to be selected from a population of randomly screened individuals for CD. The paper (Hunt et al. Newly identified generic risk variants for celiac diease is relate to the immune response. Nature genetics 40:395) was extremely difficult to comb through the data, there were many dangling abbreviations in the supplimentary information, its going to take some time to digest completely their methods before I would be willing to alter the genetics section. One problem of course is what to do with the other, older, studies.Pdeitiker (talk) 01:54, 16 April 2008 (UTC)

[edit] Pathophysiology section

" Almost all coeliac patients have an abnormal HLA DQ2 allele.[1] However, about 20–30% of people without coeliac disease have inherited an abnormal HLA-DQ2 allele.[24] This suggests additional factors are needed for coeliac disease to develop. Furthermore, about 5% of those people who do develop coeliac disease do not have the DQ2 gene.[1] "

I don't mean to be nitpicky, but there is ___no___ evidence that DQ2 is abnormal, in fact in certain parts of Africa it is the predominant allele. The statement above, IMHO, infers an ethnocultural bias that alleles or genes that are reactive to western foods are some how defective or abnormal. DQ2 frequency in certain parts of Europe is around 45% far higher than any other alleles in those regions. This high rate of gene frequency can be attributed to past positive selection, particularly in the pre-Neolithic period in Europe.

DQ8 reaches a gene frequency of ~80% in some populations. This is the highest gene frequency for any DQ type seen in any other people in the world. It strongly indicates positive selection. Both DQ8 and DQ2.5 are acid peptide presenters, and both have been found in regions of the world were shellfish consumption (as identified by the archaeological record) was quite common. IOW these may have been positive adaptations for a different kind of diet.Pdeitiker (talk) 12:48, 22 April 2008 (UTC)

I know that you have elaborate theories about this, but all this comment does is cite a reliable source. I am against changing this in favour of some paleogenetic inference. JFW | T@lk 08:05, 7 May 2008 (UTC)
See ......Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20753-8. Epub 2007 Dec 17. Recent acceleration of human adaptive evolution. Hawks J, Wang ET, Cochran GM, Harpending HC, Moyzis RK.

" (iii) an implausibly high number of adaptive substitutions [in these disequilibrated regions] between humans and chimpanzees, and (iv) nearly 100 times the observed number of high-frequency linkage disequilibrium blocks. Larger populations generate more new selected mutations, and we show the consistency of the observed data with the historical pattern of human population growth. We consider human demographic growth to be linked with past changes in human cultures and ecologies. Both processes have contributed to the extraordinarily rapid recent genetic evolution of our species. "

There are a number of papers on HLA that have stated that DQ2.5 was under positive selection in the past, but is under balancing selection, now, in some populations. It is called the European Ancestral Haplotype. If you need a body of references to change this opinion I can provide them. In the Hawks paper, the super B8 haplotype is longer than the longest haplotype they were capable of identifying, without selection would be 100s of years in age, but in fact by its distribution appears to be 1000s or 10s of 10000s of years in age. In theory all high frequency HLA should be under balancing selection but DQ2.5 is the only hap that has a measurable decline, most probably because of coeliac disease. Pdeitiker (talk) 13:04, 20 May 2008 (UTC)

Here is a review on the matter: doi: 10.1111/j.1744-313X.2008.00765.x International Journal of Immunogenetics 35, 179–192 179 Human MHC architecture and evolution: implications for disease association studies. J. A. Traherne

" Recent global studies using long-range haplotype (LRH) and extended haplotype homozygosity (EHH) tests support the hypothesis that signatures of positive selection are present in the MHC (The International HapMap Consortium, 2005, 2007; de Bakker et al., 2006b; Voight et al., 2006; Sabeti et al., 2007). " " Two of the most frequent long-range MHC haplotypes in Northern Europeans are the HLA haplotypes HLA-A1-HLA-B8-C7-DR3-DQ2 (also termed AH 8.1) and HLA-A3-B7-C7-DR15-DQ6 (the so-called ancestral DR2 haplotype). The frequencies of these haplotypes in European Caucasians are in the order of 10%, which is substantially higher than expected (< 0.5%) based on the frequencies of individual alleles on the haplotypes. The high sequence similarity of long-range haplotypes suggests that their prevalence is likely due to significant expansions in relatively recent times. Indeed, the AH 8.1 haplotype has been estimated to have diverged from a single common ancestor about 23,500 years ago (Smith et al., 2006). "

I agree about the timing, but if the timing is correct, then the AH 8.1 (alias super B8) was either singly expansive or under stringent positive selection after expansion. Linkage disequilibrium of the haplotype is very high for a haplotype of 23 kya. I have also a recent paper on Type 1 diabetes that shows linkage in some instances can be extended to 6 million nucleotides (1 Mbp generally = 1 centimorgan, with expected equilibration times in 100s of years). The only way selection is not involved in AH 8.1 disequilibrium is if AH 8.1 was the only haplotype in western europe for 15 to 20ky. And yet other haplotypes in Europe also show similar disequilibrium and long term presence. AH8.1 LD factors into population spread as wide from the Irish to the Basque to the Swiss to the Scandinavians with no evidence of recent immigration of AH8.1. There is a "cassette" of 4 types with stable ratios between the ancestral types: AH8.1, A3-B7-DR15-DQ6.2, A2-Cw5-B44, and A2-B7-DR15-DQ6 (AH 8.1 and A3..DQ6.2 is modal in W. Ireland, A2-B44 is nodal in the Cornish, A2-B7 is nodal in the Swiss). This indicates a cline created in the post-meoslithic period from 4 ancestral types introgressed by a large number of haplotypes of Mediterranean and Black Sea origin. An anti-node is reached in the Paris basin in which AH8.1 is 1/5th as frequent as found in the Western Irish. AH8.1 had declined as a result of negative selection in the post-neolithic although it was a dominant and stable feature of NW Europeans prior to the Neolithic. This does not indicate an genetic abnormality.

" The estimated ages of some common long-range haplotypes typically fall within range of the human migration out of Africa and expansion into Europe. This has led to theories of selective factors that acted to expand these haplotypes, which in general relate to adaptation to new environments, changes in nutrition, or resistance to infection during migrations (Distante et al., 2004; Moalem et al., 2005). "

Indeed, and in the regions of Europe where AH8.1 is high now, and in which there is an archaeological presence there is a consistent appearance of shellfish within the diet. Despite the large presence of bovids and reindeer within Europe from the LGM until the mesolithic, at only a few sites are bone fragments found. All but one site shows the presence of shellfish, and human bones show a strong carbon isotope ration consistent with marine nutrient dependence. The mesolithic in western Europe extend from 6500 bp(average) to the ~10,000 years ago. The only reason one does not see more dependence on shellfish is that today sea levels are 120 meters higher than at the holocene boundary did not begin to reach current levels until 8000 years ago, and as a result most sites are underwater. [AH8.1 in Europe is the parent haplotype of DQ2.5] One reason why DQ2.5 may be so high in Ireland is that the full neolithic package such as found in LBK culture of loess belt was not viable in Ireland, cattle pastoralism and barley cultivation did take root, but so did millet cultivation. Barley is the least related grain to wheat and preserves few pathogenic epitopes, it was malted and fermented, lowering its toxicity even more.

" Any past survival benefits of common long-range haplotypes have come at a cost since many predispose to inflammatory diseases prevalent in Westernized society, such as type I diabetes and multiple sclerosis. "

Many recent papers strongly agree with this conclusion. The results of the human genome project and the HapMap are parsimonious with this as a general background for the increases in autoimmune diseases as people transit from indigeonous cultures into westernized cultures. This does not infer that previous traits are abnormalities, since they confer selective advantages in specific regions. This in and of itself warrants a change in how the section is worded. In fact, given that that AH8.1 is ~ 23,000 years in age and the neolithic did not reach the node of AH8.1 (W. Europe) until a few thousand years ago (Liberally: Thracia 10 kya, Balkans 8.5 kya, Italy 8 to 9 kya, Iberia & Austria 7.5 kya, Germany, Netherland, Paris basin 7 kya, S. England 6.9 kya, Ireland 4.3 kya), there is no reason to believe that AH8.1 was disgenic when it formed or spread in Europe.Pdeitiker (talk) 19:04, 23 May 2008 (UTC)

[edit] Tartrazine

This article is missing any reference to the theory that those with celiac disease also have an intolerance to Tartrazine (Yellow food dye 5). I'm not sure if the intolerance to gluten and tartrazine are caused by the same bodily reaction, but every person I know with celiac (Several dozen) disease has a bad reaction to tartrazine so I assume they are linked. - 99.251.77.247 (talk) 01:10, 26 April 2008 (UTC)

There are a number of suspected damaging agents that could potentially trigger conversion to pathology or symptomacy in celiac disease. The list of suspected agents is long, for example rotavirus, enterovirus, influenza virus, aspirin, NSAIDS, MSG, sodium benzoate, certain food colorings, heliobactor pylori. With respect to the chemical agents it is known that aspirin and NSAIDs can 'pock' the small intestine and stomach with lesions which under appropriate conditions can allow food peptides (partial digests) to enter the blood stream thereby causing peripheral allergic responses. Such responses are seen in Urticaria, Schleroderma and are similar to exercise induced anaphylaxis in which, for wheat, the antigen, omega-gliadin, has been determined and the response pathway involves Mast cells, eosinophils and IgE. The chemicals may play a role in idiopathic gluten sensitivity, such as gluten sensitive idiopathic neuropathy or gluten sensitive autism. I have CD but I show no special reactivity to FD&C yellow#5, however I have a relative with strong wheat allergy (not CD) who does. OTOH, while I show no particular reactivity to aspirin or NSAIDs I choose to avoid taking these substances because of the potential risks that are elevated in celiacs.
One particular facet of celiacs is they frequently have intense wheat allergies as well as intolerance particularly after entering a GF diet. Allergies can be distinguished from CD because of the reactivities to HMW glutelins, omega-gliadin, and non-glutinous proteins. Some who have not been diagnoses and claim to have CD actually have a wheat allergy, others have both.Pdeitiker (talk) 13:20, 27 April 2008 (UTC)
I think 99.251 was looking for a reference. The University of Chicago website is quite clear that tartrazine is safe.[1] Pubmed gives no results for "tartrazine celiac". I think this concludes the matter - an assumption of linkage would be WP:NOR. JFW | T@lk 08:05, 7 May 2008 (UTC)
The health effects of Tartrazine are pertinent to CD and many celiacs have spoken of sensitivity to this. Not that it warrants lengthening this page, however it might be worthwhile addition to one of the subpages. The problem I have with the tartrazine issue is classification, because it is unclear whether it is a specific factor in CD versus allergic diseases. Or to put this in another light, in a very few people tartrazine may increase risk for CD, CD symptoms after latent disease, in others allergies, or in others sensitivities and intolerances. Finding triggers for autoimmune diseases is like picking a needle from a haystack, can chemical "E102" be the trigger, or does the sensitivity show up after the disease is present WP:NOR?Pdeitiker (talk) 13:27, 21 May 2008 (UTC)

[edit] Some APT papers

  1. Level of gluten consumption tolerated is highly variable, but <10mg/24h is unlikely to lead to symptoms although some develop mucosal abnormalities on amounts just slightly higher than this - systematic review doi:10.1111/j.1365-2036.2008.03669.x
  2. European stakeholder research agenda doi:10.1111/j.1365-2036.2008.03668.x
  3. Serology is so good that endoscopy is a waste of time (yes, still controversial) - doi:10.1111/j.1365-2036.2008.03609.x
  4. Dermatitis herpetiformis may cause villous atrophy, but is not associated with osteopenia, fracture or malignancy. At the same time, it seems to protect against breast cancer (and coeliac disease does too!) doi:10.1111/j.1365-2036.2008.03660.x}

I'm not sure if all of them need inclusion, but 1. perhaps should. JFW | T@lk 08:05, 7 May 2008 (UTC)

Before anyone asks, the DOIs are not activated yet (Blackwell being slow). Simply google for the DOI, and it will show up. JFW | T@lk 08:20, 7 May 2008 (UTC)


[edit] Autoimmune

Coeliac disease isn't an autoimmune disorder. Autoimmunity is an inappropreate response to self - I think it's fairly from the effect of diet, the antibodies produced and experiments from mice that the response isn't to self, it's to the contents of the gut, specifically wheat products. It's probably better to say it's an Immune-mediated disease Kantokano (talk) 17:08, 18 May 2008 (UTC)

Anti-gliadin T-cells recognize human-tissue-transglutaminase covelantly linked to gliadin (wheat) peptides. The T-cells stimulate human transglutaminase specific B-cells. This results in producing anti-tTG antibodies. The allows the targeting of connective tissue by eosinophiles (Eosinophilic gastrointeritis is a common finding in CD) and the targeting of surface tTG on epithelial cells by natural killer cells which results in the destruction of the villi. This causes villous atrophy. Therefore CD is an autoimmune disease. Pdeitiker (talk) 13:10, 20 May 2008 (UTC)
I agree with Phil that coeliac disease has all the features of an autoimmune disorder, except the precipitant for molecular mimicry is actually well understood (as opposed to many other autoimmune disorders). There is evidence of an autoimmune diathesis in coeliac disease. JFW | T@lk 06:09, 23 May 2008 (UTC)

[edit] Vegiac

I have asked Mrsleep99 (talk · contribs) to justify the inclusion of the long paragraph on vegetarianism. The reference provided is from a low-impact journal, and on PubMed there is no research on the gluten-free diet in vegetarians. I'm sure the problem exists, but in the absence of reliable sources there is little we can do. Discussion about Vegiacs and its coinage seem to be WP:WEIGHT - this is about one website. JFW | T@lk 06:11, 23 May 2008 (UTC)

[edit] Source worth including

doi:10.1136/jcp.2005.035345 is a recent (2006) update for pathologists. Given that it is free (J Clin Pathol) we might be able to include it preferentially. JFW | T@lk 08:59, 3 June 2008 (UTC)

[edit] A-2 Gliadin 57-89 "33mer" studies

There are two recent papers, Moron et al. 2008(PLOS one) and Moron et al. 2008(Am J. Clin. Nut).

The 33mer of gliadin, which the authors paint as being quintessential T-cell epitope in gliadin, is used to develope 2 monoclonal antibodies(Mabs). The Mabs are then used to probe the level of wheat levels. The Mabs do recognize gliadin but recognize deaminidated gliadin a > 1 magnitude lower, in both cases. Monoclona1 antibody A1 recognizes also the innate peptide region "19mer". While the antibodies do recognize the major cluster of T-cell epitopes (Coeliac disease is a T-cell mediated autoimmune disease) that cause celiac disease, they appear not to recognize the same structures as T-cell receptor/HLA DQ2.5 complex. So that these antibodies can not be seen as equal to this complex recognition. The basic outline of the first paper is that by having tools that can detect the two most important sites of gliadin, that they have effective tools for diagnosing disease or therapeutic methods.

Having said that the antibodies recognize and discriminated binding of rye secalins and barley hordeins with high affinity with at least one of the Mabs, protein to protein in some cases higher than gliadin. Both antibodies to oats appear to shadow the wheat A1-G12 differences suggesting that this reaction could be due to contamination of wheat with oats. Recognition of oat avenin is 2 magnitudes lower consistent with other studies. They constructed peptides corresponding to sites in gliadin, secalin, hordein, and avenin. The monoclonal antibody to A1, based figure 5E does not appear to have a significant response to oats given assay point variance. This indicates an apparent advantage of using synthetic peptides over native proteins that can be contaminated from their source. One could argue that there is not enough sequence information from oats or they used sequence from a non-CD causing oat strain.

They tested the effectiveness of these antibodies on digesting whole wheat bread in synthetic stomach acid for 1 hour using 2 therapeutic enzymes pepsin with EP-B2 and SC PEP (neither of which are defined in the paper) but apparently cut at prolines and glutamines. They show that either alone will only reduce the 33mer. The problem here is that some stomach fluid will leak out an one hour and the bread (1 gram - a real meal!) was premixed with the enzyme before addition to the stomach acid.Pdeitiker (talk) 01:54, 10 June 2008 (UTC)

I just wanted to add that I read the materials and methods of both papers, and they gave no mention in either paper of having drawn an especially selected batch of oats that was wheat, barley and rye free. The assumption is that these are off the shelf or out of the bin oats. Here is an instance where it is preferential to use the synthetic peptide data over the protein digests because the later is at greater risk of contamination.Pdeitiker (talk) 03:22, 10 June 2008 (UTC)

[edit] Dietary guidelines . .

For a paper written in 2005 it gives a surpisingly balanced perspective on diet. This paper has been referenced up the page- - Kupper. Gastroenterology 2005: 128, S121-S127.

[edit] Oats

Oats are single-handedly set aside from wheat(spelt, semolina,durum), rye, barley, triticale and kamut in this review as they are controversial. As part of that they come to no opinion about oats other than the results, as of 2005, were premature. As I mentioned two papers provide 5 year followup on children and adults who eat oats, no disease was seen in the patients which did not intially react with oats, although the reason why 2 patients in the study dropped out was unclear. They stated that contamination varied, a common observation, from <1.5 ppm to >400 ppm. Here is what kupper says:

"Research supports that oats may be acceptable for the majority but not all patients with CD. Ludlin at al. also suggests that there may be a subset of CD patients who have an exaggerated sensitivity to oats, not related to CD"(Kupper, 2005, gastroenterology 128, S122)

In essense we are in complete agreement. I have seen figures thrown out that oat intolerance represents 10 to 20% of CD, and others suggesting 1 to 5%. It is clear that a subset of celiacs are completely tolerant of GF oats, however not enough studies have been done, the currents studies lack, technically, statistical power. She goes on to say:

"At this time, there are no large-scale studies available to assess the potential contamination of commercial oats"(Kupper, 2005, gastroenterology 128, S122)

See:Oat contaminants in Europe Canada and US

The reward may outweigh the risk.

"Storsrud found that the use of oats increased the patients intake of iron, dietary fiber, thiamin, and zinc"(Kupper, 2005, gastroenterology 128, S122)

Pdeitiker (talk) 01:54, 10 June 2008 (UTC)

[edit] Wheat Starch

One of the key issues of the paper is wheat starch. For a bit of background information it was found in 1952 that the starch fraction of wheat could not maintain disease in children, whereas the protein fraction did cause coelaic disease. This was the critical breakthrough in gluten-sensitive enteropathy, since previously it was believed that cereals did cause coeliac disease. The guidelines point out that wheat starch, when properly purified to standards contained only trace amounts of gluten, and in fact the protein estimate is a high end estimate of gliadin since it is certain contaminated with other endosperm proteins.Pdeitiker (talk) 16:48, 11 June 2008 (UTC)

[edit] Anti-yeast antibodies (ASCA)

A new paper has been published in the J. clinical immunology. doi:10.1007/s10875-008-9200-9 The authors examine 242 suspected celiacs for presence of antibodies to yeast, Baceroides caccae ounter memberane protein, and Psuedomonas fluorescens I2 sequence. What they found is that of the 242 suspected 134 were confirmed of these 62 (47%) has ASCA, whereas of the non-CD in the suspected group only 15% showed ASCA. The reactions with either B. cacae Omp W or P. floursescents I2 sequence were not significantly different between the CD and non-CD within the suspected cohort, although the reaction with I2 was slightly higher. The presence of ASCA, anti-OmpW or anti-I2 was higher in the suspected group even if no CD diagnostic was made relative to control. This suggests that some sensitivity to wheat in the form of breads and other risen foods is due to inflammation caused by ASCA. ASCA has been associated with Crohn's disease and a form of microscopic colitis, people with ASCA may have decreased lectin binding proteins, and the site of inflammation is typically the ileum and ascending colon. Both diseases are a form of inflammatory bowel disease. Pdeitiker (talk) 21:27, 10 June 2008 (UTC)

[edit] Celiac disease in the Elderly

There is a recent article from Finland outlining the incidence of coeliac disease specifically in the elderly group doi:10.1016/j.dld.2008.03.013. There are some interesting finds in this paper. One find is that the group born before 1930 had the lowest risk of celiac disease 1.48% at age ~80 ya. The younger groups (~70, ~60)had 2.4% incidence of celiac disease. Of the 2815 people screened 25 had appeared positive at or before the onset of the study and 6 presented with DH, 4 became positive after the study began, all classified were Marsh grade III. 49 of 2815 had ATA IgA, 44 were EMA positive. A total of 60 patients together showed clinical signs. 2 additional subjects who did not undergo biopsy were included as positive, bringing the overall frequency to 2.45%. This frequency is much higher than the 1% frequency often cited for the general population. Of 38 seropositives all had DQ2 or DQ8. Of the 35 detected in the screening, 20 (57%) had no gaastrointestinal symptoms. The primary symptoms in those picked up by screening were abdominal pain & distention, flatus and infrequently diarrhoea or loose stools. Whereas those detected clinically diarrhoea and maladsorption were the most common symptoms. 2 of 60 had EATL that appeared without refractory celiac disease (called 'de novo' WS- EATL ). In one case, the individual had CD for 27 years. Of those picked up in the screening 25% had autoimmune thyroid disease, 3 had psoriasis, one had type 1 diabetes, and 1 had pernecious anemia. 28 of 32 who went on GFD reported improvements in symptoms, 6 reported marked improvement. 87% had a significant reduction of Marsh score, the median being Marsh grade I and serological scores of 31 showed only 2 with positive scores. These criteria indicate that there was an increase in CD incidence with aging, this was shown by biopsy, serology, genetic testing, and the restoration to normality on the GFD. The results suggest that lifelong risk of celiac disease is higher than 1% frequently given, if the DQ2:DQ8 ratio in CD remains constant with age, then it is likely that a significant fraction, ~12-20%, of DQ2.5 positive individuals will have gluten sensitive enteropathy within their lifetime.Pdeitiker (talk) 22:40, 10 June 2008 (UTC)

[edit] Oat contaminants in Europe, Canada and US

This paper I mentioned above, it is fairly complicated, as I have read it now 3 times, somewhat grasp what they are trying to prove. Most current tests for gluten look for gluten - by definition gluten is the sticky proteins in wheat that form the gluten aspect of bread making. In reality, this generally includes all glutinous proteins but for gluten free diet it refers to glutinous proteins in wheat, barley and rye. Based on immunochemical understanding, once disease is present, all members of Triticeae are likely to restimulate CD. Therefore testing for wheat gluten, only, in oats is not thorough. The paper Hernando et al. PubMed looks at 134 oat sources, they use an R5 sandwich assay that detects wheat, barley and rye. The authors do not state, nor should the reader assume that the R5 ELISA is a measure of T-cell immunoreactivity, only that the assay has detected glutinous material from three species. The second approach that they use is Q-PCR to determine whether barley, rye or wheat DNA is present. Western blot is also used as well as Maldi-TOF Mass spectroscopy.

As suspected many oat varieties (supplied by various hospitals) showed up with contaminants. In this paper finding out the source of contamination requires some work. For each source, say V12-from the US, there are several samples (e.g. 11 for V12). Some of the samples were oat berries, the oat berries were covered with dust, and the dust could be removed with an alcohol wash. The dust on 3 samples was the source of the contamination. The pure oat strains did not show western blot reactions with R5 antibody. The problem in examining the blots is that few of the patterns, obviously contaminants, match reliably wheat, barley or rye patterns in the control. In the US, the Q-PCR reveals that wheat, then barley are the primary contaminants. One sample, 106 from Finland had abundant contamination (I estimated 22%). The DNA suggested that barley was the primary contaminant, and by MS-maldi one can see barley proteins comparable in abundance to avenins, the level of barley contamination suggested this grain was a mixture of oats and barley. 97% of the contamination of this was barley and the barley pattern was apparent on the western blot.

The paper goes on to discuss the medical-political situation with celiac disease. The fact that US and Canada have not recommended oats in diet is something they concur, that oats are not safe for celiac consumption until the sources of Triticeae within the potential contaminants can be measured. They recommend their test-method, but also suggest that the method alone is not sufficient, that western blot, and PCR should be performed or maldi-MS to look for evidence of contamination. We also see, that with many papers that give immunochemical reactions to oats may not have carefully looked at all sources of contamination from Triticeae cultivars and wild grasses. They go on to say "It may, however, take some time before gluten-free oat-based foods are totally accepted and oats are removed from the list of toxic cereals". Pdeitiker (talk) 05:02, 11 June 2008 (UTC)

[edit] Summary of Oats Issue

Starting from the 2005 guideline

The use of oats may be acceptable, provided

  • More studies with more participants are done.
  • The source of contaminants is studied and resolved.

Findings since 2005

1. Studies have looked at situation in adults and children and found oats can be used because:

  • the majority of celiacs are completely tolerant of uncontaminated oats

but:

  • The actual frequency and nature of oat intolerance in CD has not been resolved.
  • Oats strains may induce T-cell responses, and other studies contradict these findings (contamination or differences in oat intolerances?), GF-Oats (widely available) have not been tested for celiac or "oat-intolerant" celiacs.

confusing the issue:

  • Triticeae contamination(TC) in most 'oat intolerance' studies still an issue.
  • Increases in IEL freqeuncy in oat-eating celiacs, but no increased atrophy. TC?.
  • In a study that identifies the pathogenic "33mer" the 'triticeae' cultivars are separated (increase sensitivity) from avenins by 2 orders of magnitude. Synthetic peptides of oat homologs to "33mer" failed to show significant binding to mAbs. TC?
  • Gluten is what? - Strictly - glaidins and glutenins. From barley and rye, comparisons are rough to wheat and contraditions in quantitation exists (see contamination paper), they seek to define an immunochemical gluten. Are glutinous proteins in oats to be considered gluten? What is the comparison based on, pathogenic epitopes between these species. Not done. Gluten is the glutinous proteins in wheat, but to 95% of coeliacs they are the glutinous proteins within the edible culitvars in Triticeae. What is gluten to an oat intolerant person? Too many different definitions of gluten creates trouble. Trouble is that gluten is a baking definition not a medical definition.

2. TC remains the key problem within the US, Canada and Europe.

  • Testing had generally been for wheat only. Studies recommend R5-ELISA (barley sensitive) tests for barley, rye and wheat. Additional, preferred, test resolve the species that contaminate.
  • Greater government oversight needed in cereal industries, standards of purity are low.
  • Additional testing needs to reflect regional TC threats.
  • In US, assuming equal contamination of wheat and barley in oats - seed:seed total TC range from 0 to 11%, estimated, >50% had "unacceptable" contamination by the old Codex standard. Study flaw - No label information provided. Codex standard-current: >200 PPM gluten is "unacceptabl"e.
  • One forth oat sources were negative for TC by one assay. No brands or lots given for these sources.
  • GF Oats
    • Too many standards - Some dated, many based on obsolete information, and contradictions in standards. The current Codex standard excludes oats and has a maximum of 200 ppm gluten contamination. The proposed Codex standard (proposed) tolerates oats if gluten content of 20 ppm in natural products (includes oats).
    • Testing - Paraphrasing the University of Nebraska FARRP testing discloses.

r-biopharm Inc. Kits "is a sandwich enzyme immunoassay for the quantitative analysis of gliadins from wheat and corresponding prolamines from rye and barley in food". Ridascreen Fast Gliadin (R7002), detection limit is 10 ppm and "Note: In addition to wheat gluten, the Fast Gliadin kit is 100% cross-reactive to rye and barley." This test may give results off by a factor of 2 if species information is not provided. Ridascreen Fast Gliadin (R7002) According to the product literature one can detect down to 2 ppm but quantiation below 10 ppm is questionable. They do use the R5 sandwich assay mentioned in the previous paper. Products that test below 10 PPM can be considered "safe" since Codex recommends contamination less that 20 PPM.

Currently BRM (shelf) and GFO (internet) brands of GF-oats use the R5-ELISA assay, by the proposed Codex standards these products are to be considered gluten-free (based on my internet search). Pdeitiker (talk) 16:38, 11 June 2008 (UTC)

I think my points are bolstered with regards to the importance of guidelines. You have basically shown that many coeliacs will tolerate oats but you can't predict which ones, and how safe the oats are with respect to wheat flour contamination. I really do not think this page should suggest that the guidelines are to be violated.
For the clinician and obviously the patient, these uncertainties are major issues. In the consulting room, a physician cannot - on the basis of the information you provided above - recommend to his patient what to do.
Now, Phil, what changes need to be made in the article? JFW | T@lk 20:34, 11 June 2008 (UTC)
Not at the point of diagnosis, certainly. There is a bit of an ethical issue in terms of physician recommendations. If the physician recommends the patient try oats, again after the 1 year abstinence period, that physician will also have to insist that the patient agree to followup procedures (serology, biopsy) which may incur additional cost for the patient. From the patient side, they should be aware of what refractory disease and the consequences. If the section is to be changed it should be done judiciously, however I think the position of the 2 canadian (NGO and agricultural agency) organization could be added to the page. There is an inevitability where this science is going, oats will need to be handled, at some point, in its own sub-section.
The flip-side of the ethical issue, is the nutrition and fiber brought by oats. Again, using my own personal anecdote, my form of disease requires a large amount of daily fiber. This makes it difficult to pack a lunch, and in my case a dry lunch, oats give me the ability to make dry baked goods comparable to wheat, with 12% fiber, and as the principle binding agent for other materials (such as sunflower seed butter). One can argue that there is an ethical issue if the physician does not provide an alternative that improves the quality of life (This is generally in the first paragraph in most oat studies). Whole oats provide slow carbs (studies indicated celiacs eat too much fast carbs), fiber (studies indicate that celiacs often don't get enough fiber), iron (arthritic celiacs may not be getting enough iron), and vitamins. People have to work and otherwise have an active life, in your medical school or office, what is the availability of GF foods. Here, the contracted provider has said that their food is not gluten free, at most you can eat a green salad and boiled eggs. People who have CD and work need to have options.
Fiber foods.
- Oats-Rolled 12% - Can be served as a hot cereal or baked into cookies, or made into flour.
- Buckwheat 12%, a frequent allergen, almost as bad as wheat in Asia.
- Brown rice 8 - 12%, must be cooked until soft to be edible.
- Polenta 8% (Corn grits) - Generally limited to a breakfast dish.
- Whole stone ground tortillas, 8% - Diminishing market, can be used for lunch.
- Hominy w/germ - 8% For soups, etc.
- Quinoa 8% - flour-bitter contains soponins, seeds washed, generally for soups. Pdeitiker (talk) 19:49, 12 June 2008 (UTC)
I wanted to know your ideas for the article, not your personal experiences. Will you please focus on the issues? JFW | T@lk 21:47, 12 June 2008 (UTC)
I think the conversation has devolved into rhetoric. I have created a section in gluten sensitivity on "the oat controversy"Pdeitiker (talk) 03:44, 13 June 2008 (UTC). It does not make a recommendation but it addressed the issues from all sides. Should you desire you can link to it within the article.