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[[Coeliac disease]] ([[American and British English spelling differences|American English]]: celiac) (CD) is one of the most common chronic, immune-mediated disorders, triggered by the eating of [[gluten]], a mixture of proteins found in [[wheat]], [[barley]], [[rye]], and derivatives.<ref name=Biesiekierski2017>{{cite journal| author=Biesiekierski JR| s2cid=6493455 | title=What is gluten? | journal=J Gastroenterol Hepatol | year= 2017 | volume= 32 | issue=Suppl 1 | pages= 78–81 | pmid=28244676 | doi=10.1111/jgh.13703 | type=Review | quote= Similar proteins to the gliadin found in wheat exist as secalin in rye, hordein in barley, and avenins in oats and are collectively referred to as “gluten.” The gluten found in all of these grains has been identified as the component capable of triggering the immune-mediated disorder, coeliac disease.| doi-access=free }}{{open access}}</ref><ref name=LebwoholLudvigsson /> Evidence has shown that this condition not only has an environmental component but a genetic one as well, due to strong associations of CD with the presence of HLA ([[Human leukocyte antigen]]) type II, specifically DQ2 and DQ8 alleles.<ref name=Denham>{{cite journal|last1=Denham|first1=JM|last2=Hill|first2=ID|title=Celiac disease and autoimmunity: review and controversies.|journal=Current Allergy and Asthma Reports|date=August 2013|volume=13|issue=4|pages=347–53|pmid=23681421|doi=10.1007/s11882-013-0352-1|pmc=3725235}}</ref> These alleles can stimulate a [[T cell]], mediated immune response against tissue [[transglutaminase]] (TTG), an enzyme in the extracellular matrix, leading to inflammation of the intestinal mucosa and eventually villous atrophy of the small intestine.<ref name=Pasha>{{cite journal|last1=Pasha|first1=I|last2=Saeed|first2=F|last3=Sultan|first3=MT|last4=Batool|first4=R|last5=Aziz|first5=M|last6=Ahmed|first6=W|s2cid=25585961|title=Wheat Allergy and Intolerence; Recent Updates and Perspectives.|journal=Critical Reviews in Food Science and Nutrition|date=2 January 2016|volume=56|issue=1|pages=13–24|pmid=24915366|doi=10.1080/10408398.2012.659818}}</ref> This is where the innate and adaptive immune response systems collide.
[[File:Inflammed mucous layer of the intestinal villi depicting Celiac disease.jpg|thumb|249x249px|Villous atrophy of the small intestine]]
CD is not only a gastrointestinal disease. It may involve several organs and cause an extensive variety of non-gastrointestinal symptoms. Most importantly, it may often be completely asymptomatic. Added difficulties for diagnosis are the fact that [[serological]] markers ([[Anti-transglutaminase antibodies#Anti-tissue transglutaminase|anti-tissue transglutaminase]] [TG2]) are not always present<ref name=NEJM2012>{{cite journal|last1=Fasano|first1=A|last2=Catassi|first2=C|title=Clinical practice. Celiac disease.|journal=The New England Journal of Medicine|date=December 20, 2012|volume=367|issue=25|pages=2419–26|pmid=23252527|doi=10.1056/NEJMcp1113994}}</ref> and many people may have minor mucosal lesions, without atrophy of the [[intestinal villi]].<ref name=BoldRostami>{{cite journal | vauthors = Bold J, Rostami K| title = Gluten tolerance; potential challenges in treatment strategies | journal = Gastroenterol Hepatol Bed Bench | volume = 4| issue = 2| pages = 53–7| date = 2011 | pmid = 24834157|pmc= 4017406}}</ref> Diagnosis of CD should be based on a combination of person's familial history, genetics (i.e. presence of HLA DQ2/DQ8) serology and intestinal histology.<ref name=ElliBranchi />
CD affects approximately 1–2% of general population all over the world,<ref name=LundinWijmenga2015>{{cite journal|vauthors=Lundin KE, Wijmenga C|s2cid=24533103|title=Coeliac disease and autoimmune disease-genetic overlap and screening|journal=Nat Rev Gastroenterol Hepatol|volume=12|issue=9|pages=507–15|date =September 2015|pmid=26303674|doi=10.1038/nrgastro.2015.136}}</ref> but most cases remain unrecognized, undiagnosed and untreated, and exposed to the risk of long-term complications.<ref name="ElliBranchi" /><ref name="Fasano2005Pediatric">{{cite journal |
CD with "classic symptoms", which include gastrointestinal manifestations such as chronic diarrhea and bloating, malabsorption of certain vitamins and minerals, loss of appetite, impaired growth and even bone pain, is currently the least common presentation form of the disease and affects predominantly to small children generally younger than two years of age.<ref name="Pasha" /><ref name=Fasano2005Pediatric /><ref name=LudvigssonCard />
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To date, the only available medically accepted treatment for people with coeliac disease is to follow a lifelong gluten-free diet.<ref name="ElliBranchi" /><ref name="LamacchiaCamarca2014">{{cite journal |vauthors=Lamacchia C, Camarca A, Picascia S, Di Luccia A, Gianfrani C |title=Cereal-based gluten-free food: how to reconcile nutritional and technological properties of wheat proteins with safety for celiac disease patients |journal=Nutrients |volume=6 |issue=2 |pages=575–90 |year=2014 |pmid=24481131 |pmc=3942718 |doi=10.3390/nu6020575 |type=Review|doi-access=free }}</ref><ref name="De Palma">{{cite journal |last1=Palma |first1=Giada De |last2=Nadal |first2=Inmaculada |last3=Collado |first3=Maria Carmen |last4=Sanz |first4=Yolanda |title=Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects |journal=British Journal of Nutrition |date=2009 |volume=102 |issue=8 |pages=1154–1160 |doi=10.1017/S0007114509371767 |pmid=19445821 |s2cid=4537912 |hdl=10261/15885 |hdl-access=free }}</ref>
With continuous mass [[Genetically modified organism|genetic modification]] of grain crops, for instance for drought resistance and pest repellence, the occurrence of diagnosed CD had increased by 400% in the past 50 years alone.<ref name="Fasano2005Pediatric" />
==== Dermatitis herpetiformis ====
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=== Non-celiac gluten sensitivity (NCGS) ===
{{Main|Non-celiac gluten sensitivity}}
Non-celiac gluten sensitivity (NCGS), or gluten
Gastrointestinal symptoms, which resemble those of [[irritable bowel syndrome]] (IBS),<ref name=ElliRoncorni /><ref name="CatassiBai2013">{{cite journal|vauthors=Catassi C, Bai J, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, Vécsei A, Volta U, Zevallos V, Sapone A, Fasano A|title=Non-celiac gluten sensitivity: the new frontier of gluten related disorders|journal=Nutrients|volume=5|issue=10|year=2013|pages=3839–3853|issn=2072-6643|doi=10.3390/nu5103839|pmid=24077239|type=Review|pmc=3820047|doi-access=free}}</ref> may include any of the following: [[abdominal pain]], [[bloating]], bowel habit abnormalities (either [[diarrhea]] or [[constipation]]),<ref name="CatassiBai2013" /><ref name=VoltaCaio2015>{{cite journal | vauthors = Volta U, Caio G, De Giorgio R, Henriksen C, Skodje G, Lundin KE| title = Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat-related disorders | journal = Best Pract Res Clin Gastroenterol | volume = 29| issue = 3| pages = 477–91| date = June 2015| pmid = 26060112 | doi = 10.1016/j.bpg.2015.04.006}}</ref> [[nausea]], [[aerophagia]], [[gastroesophageal reflux disease]], and [[aphthous stomatitis]].<ref name=FasanoSapone2015 /><ref name="CatassiBai2013" />
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=== Other conditions or risk factors ===
{{Primary sources|section|date=January 2015|reason=Updated secondary sources (e.g. review articles) are needed; also, the 1991 reference comes from a period when testing for subclinical CD was undeveloped.}}
[[Anti-gliadin antibodies|Antibodies to α-gliadin]] have been significantly increased in non-celiacs individuals with [[oral ulceration]].<ref name="pmid1753350">{{cite journal |vauthors=
== Symptoms ==
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When enteropathy develops in early childhood, symptomatic disease is more rapidly evident. A survey of geriatrics with celiac disease in Finland revealed that the incidence of disease was much higher than the general population.<ref>{{cite journal |vauthors=Vilppula A, Collin P, Mäki M, etal |title=Undetected coeliac disease in the elderly: a biopsy-proven population-based study |journal=Dig Liver Dis |volume=40 |issue=10 |pages=809–13 | date=October 2008 |pmid=18467196 |doi=10.1016/j.dld.2008.03.013 |type=Research Support, Non-U.S. Gov't}}</ref> Allergic disease may rise or fall with age; certain evidence points to the increased or daily use of non-steroidal anti-inflammatory factors (aspirin, ibuprofen) as an increased risk factor for [[urticaria]] or [[anaphylaxis]], and the sensitizing dose may include low-dose aspirin therapy used in the treatment of heart disease. NCGS may be a late-onset condition: in a prospective study performed among adults of 18 to 80 years, the median age of disease onset was found to be 55 years, with a six times higher prevalence in females than in males.<ref name="VoltaCaioQuestions">{{cite journal |vauthors=Volta U, Caio G, Tovoli F, De Giorgio R |title=Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness |journal=Cellular & Molecular Immunology |volume=10 |issue=5 |pages=383–92 | date=September 2013 |pmid=23934026 |pmc=4003198 |doi=10.1038/cmi.2013.28 |type=Review}}</ref>
The pathogenesis of NCGS is not yet well understood. There is evidence that not only [[gliadin]] (the main cytotoxic antigen of gluten), but also other proteins named ATIs which are present in gluten-containing cereals ([[wheat]], [[rye]], [[barley]], and their derivatives) may have a role in the development of symptoms. ATIs are potent activators of the [[innate immune system]].<ref name="FasanoSapone2015">{{cite journal |vauthors=Fasano A, Sapone A, Zevallos V, Schuppan D|title=Nonceliac gluten sensitivity |journal=Gastroenterology |volume=148|issue=6|pages=1195–204|date=May 2015|pmid=25583468 |doi=10.1053/j.gastro.2014.12.049|type=Review|doi-access=free}}</ref><ref name=Verbeke2018 /> [[FODMAP]]s, especially [[fructans]], are present in small amounts in gluten-containing grains and have been identified as a possible cause of some gastrointestinal symptoms in persons with NCGS.<ref name=FasanoSapone2015 /><ref name="VoltaCaioQuestions" /><ref name=Verbeke2018 /><ref name=OntiverosHardy>{{cite journal |vauthors=Ontiveros N, Hardy MY, Cabrera-Chavez F |title=Assessing of Celiac Disease and Nonceliac Gluten Sensitivity |journal=Gastroenterology Research and Practice |volume=2015 |pages=1–13 |year=2015 |pmid=26064097 |pmc=4429206 |doi=10.1155/2015/723954 |type=Review |doi-access=free }}</ref> As of 2019, reviews have concluded that although FODMAPs may play a role in NCGS, they only explain certain gastrointestinal symptoms, such as [[bloating]], but not the [[#Extraintestinal|extra-digestive symptoms]] that people with NCGS may develop, such as [[neurological disorder]]s, [[fibromyalgia]], psychological disturbances, and [[dermatitis]].<ref name=Verbeke2018 /><ref name=VoltaDeGiorgio2019 /><ref name="FasanoSapone2015" />
=== Immunochemistry of glutens ===
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== Treatment ==
{{Main|Gluten-free diet}}
For people with celiac disease, a lifelong strict gluten-free diet is the only effective treatment to date;<ref name="LamacchiaCamarca2014" /><ref name="Czaja-Bulsa-2014-table2">{{cite journal |author=Czaja-Bulsa G |title=Non coeliac gluten sensitivity
For people diagnosed with non-celiac gluten sensitivity, there are still open questions concerning for example the duration of such a diet. The results of a 2017 study suggest that non-celiac gluten sensitivity may be a chronic disorder, as is the case with celiac disease.<ref name=VoltaDeGiorgio2019 />
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== Research ==
Research has attempted to discern, by [[double-blind placebo-controlled trial]]s, between a "fad component" to the recent popularity of the [[gluten-free diet]] and an actual sensitivity to gluten or other components of wheat.<ref name=FasanoSapone2015 /><ref name="CatassiBai2013" /><ref>{{cite journal |vauthors=Di Sabatino A, Volta U, Salvatore C, Biancheri P, Caio G, De Giorgio R, Di Stefano M, Corazza GR |title=Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial |journal=Clinical Gastroenterology and Hepatology |volume=13 |issue=9 |pages=1604–12 |year=2015 |doi=10.1016/j.cgh.2015.01.029 |pmid=25701700|hdl=11392/2375087 |url=https://www.cghjournal.org/article/S1542-3565(15)00153-6/fulltext |doi-access=free |hdl-access=free }}</ref>
In a 2013 [[blind experiment#Double-blind trials|double-blind]], [[placebo-controlled study|placebo-controlled]] challenge (DBPC) by Biesiekierski ''et al.'' in a few people with [[irritable bowel syndrome]], the authors found no difference between gluten or placebo groups and the concept of NCGS as a syndrome was questioned. Nevertheless, this study had design errors and an incorrect selection of participants, and probably the reintroduction of both gluten and [[whey]] protein had a [[nocebo]] effect similar in all people, and this could have masked the true effect of gluten/wheat reintroduction.<ref name=ElliBranchi /><ref name="AzizHadjivassiliou2015" />
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In a 2015 double-blind placebo cross-over trial, small amounts of purified wheat gluten triggered gastrointestinal symptoms (such as abdominal bloating and pain) and extra-intestinal manifestations (such as foggy mind, depression and aphthous stomatitis) in self-reported NCGS. Nevertheless, it remains elusive whether these findings specifically implicate gluten or proteins present in gluten-containing cereals.<ref name="AzizHadjivassiliou2015" />
A 2016 review of the recent research advancements in understanding diet's role in attenuating IBS patient's symptoms concluded that gluten was a common trigger. However, because on the different compounds responsible for symptoms, many patients that could be inaccurately labelled non-coeliac gluten sensitive; and it may be more appropriate to use nomenclature such as "non-coeliac wheat sensitive" (NCWS), "non-coeliac wheat protein sensitive" (NCWPS), or even FODMAP sensitive when referring to these patients.<ref>{{cite journal |last1=Giorgio |first1=Roberto De |last2=Volta |first2=Umberto |last3=Gibson |first3=Peter R. |title=Sensitivity to wheat, gluten and FODMAPs in IBS: facts or fiction? |journal=Gut |date=1 January 2016 |volume=65 |issue=1 |pages=169–178 |doi=10.1136/gutjnl-2015-309757 |s2cid=6012463 |pmid=26078292 |doi-access=free |hdl=11392/2375077 |hdl-access=free }}</ref>
In a 2018 double-blind, crossover research study on 59 persons on a gluten-free diet with challenges of [[gluten]], [[fructans]] or [[placebo]], intestinal symptoms (specifically [[bloating]]) were borderline significantly higher after challenge with fructans, in comparison with gluten proteins (P=0.049).<ref name="Verbeke2018" /><ref name="VoltaDeGiorgio2019" /> Although the differences between the three interventions was very small, the authors concluded that fructans (the specific type of FODMAP found in wheat) are more likely to be the cause of NCGS gastrointestinal symptoms, rather than gluten.<ref name="Verbeke2018" /> In addition, fructans used in the study were extracted from chicory root, so it remains to be seen whether the wheat fructans produce the same effect.<ref name="VoltaDeGiorgio2019" />
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