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{{Short description|Autoimmune disorder that results in a reaction to gluten}}
{{Featured article}}
{{Use dmy dates|date=August 2018}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Use British English|date=April 2012}}
<!--
This article employs British spelling; please do not try to "correct" coeliac to celiac, diarrhoea to diarrhea, etc. See [[WP:ENGVAR]] for an explanation.
-->
{{Infobox medical condition (new)
| name            = Coeliac disease
| image           = Coeliac path.jpg
| caption         = Biopsy of [[small bowel]] showing coeliac disease manifested by blunting of [[intestinal villus|villi]], crypt [[hyperplasia]], and [[lymphocyte]] infiltration of crypts
| field           = [[Gastroenterology]], [[internal medicine]]
| pronounce       = {{IPAc-en|ˈ|s|iː|l|i|æ|k}} {{respell|SEE|lee|ak}}
| synonyms        = Coeliac sprue, nontropical sprue, endemic sprue, gluten enteropathy
| symptoms        = None or [[Non-specific symptoms|non-specific]], [[abdominal distention]], [[diarrhea|diarrhoea]], [[constipation]], [[malabsorption]], weight loss, [[dermatitis herpetiformis]]<ref name=Fasano2005Pediatric/><ref name=SymptomsCausesNIDDK>{{cite web |title=Symptoms & Causes of Celiac Disease {{!}} NIDDK |url=https://www.niddk.nih.gov/health-information/digestive-diseases/celiac-disease/symptoms-causes |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |access-date=24 April 2017 |date=June 2016 |url-status=live |archive-url=https://web.archive.org/web/20170424175500/https://www.niddk.nih.gov/health-information/digestive-diseases/celiac-disease/symptoms-causes |archive-date=24 April 2017}}</ref>
| complications   = [[Iron-deficiency anemia]], [[osteoporosis]], [[infertility]], [[cancer]]s, [[neurological disorder|neurological problem]]s, other [[autoimmune diseases]]<ref name=Leb2015/><ref name=Lund2015/><ref name=WGO2016/><ref name=Cic2015/><ref name=LionettiFrancavilla2010/>
| onset           = Any age<ref name=Fasano2005Pediatric/><ref name=ESPGHAN2012 />
| duration        = Lifelong<ref name=Cic2015 />
| causes          = Reaction to [[gluten]]<ref name=TovoliMasi2015/>
| risks           = [[Genetic predisposition]], [[type 1 diabetes]], [[autoimmune]] [[thyroid disease]], [[Down syndrome|Down]] and [[Turner syndrome]]
| diagnosis       = [[Family history (medicine)|Family history]], blood [[antibody]] tests, intestinal [[biopsy|biopsies]], [[genetic testing]], response to gluten withdrawal<ref name=NIH2015/><ref name=VivasVaquero2015 />
| differential    = [[Inflammatory bowel disease]], [[intestinal parasites]], [[irritable bowel syndrome]], [[cystic fibrosis]]<ref>{{cite book | vauthors = Ferri FF |title=Ferri's differential diagnosis : a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders |date=2010 |publisher=Elsevier/Mosby |location=Philadelphia, PA |isbn=978-0323076999 |page=Chapter C |edition=2nd}}</ref>
| prevention      = 
| treatment       = [[Gluten-free diet]]<ref name=SeeKaukinen2015/>
| medication      = 
| prognosis       = 
| frequency       = ~1 in 135<ref name=NEJM2012/>
| deaths          = 
}}

'''Coeliac disease''' ([[British English]]) or '''celiac disease''' ([[American English]]) is a long-term [[autoimmune disorder]], primarily affecting the [[small intestine]], where individuals develop [[hypersensitivity|intolerance]] to [[gluten]], present in foods such as [[wheat]], [[rye]] and [[barley]].<ref name="NIH2015" /> Classic symptoms include gastrointestinal problems such as chronic [[diarrhea|diarrhoea]], [[abdominal distention]], [[malabsorption]], [[Anorexia (symptom)|loss of appetite]], and among children [[failure to thrive|failure to grow normally]].<ref name=Fasano2005Pediatric/> Non-classic symptoms are more common, especially in people older than two years.<ref name=ESPGHAN2012 /><ref name=Newnham2017>{{cite journal |doi=10.1111/jgh.13704 |doi-access=free |pmid=28244672 |title=Coeliac disease in the 21st century: Paradigm shifts in the modern age |journal=Journal of Gastroenterology and Hepatology |volume=32 |pages=82–85 |year=2017 | vauthors = Newnham ED |s2cid=46285202 |quote=Presentation of CD with malabsorptive symptoms or malnutrition is now the exception rather than the rule.}}</ref><ref name=TonuttiBizzaro2014>{{cite journal |vauthors=Tonutti E, Bizzaro N |title=Diagnosis and classification of celiac disease and gluten sensitivity |journal=Autoimmun Rev |volume=13 |issue=4–5 |pages=472–6 |date=2014 |pmid=24440147 |doi=10.1016/j.autrev.2014.01.043}}</ref> There may be mild or absent gastrointestinal symptoms, a wide number of [[systemic disease|symptoms involving any part of the body]], or no obvious symptoms.<ref name=Fasano2005Pediatric /> Coeliac disease was first described in childhood;<ref name=Cic2015>{{cite journal |vauthors=Ciccocioppo R, Kruzliak P, Cangemi GC, Pohanka M, Betti E, Lauret E, Rodrigo L |title=The Spectrum of Differences between Childhood and Adulthood Celiac Disease |journal=Nutrients |volume=7 |issue=10 |pages=8733–51 |date=22 October 2015 |pmid=26506381 |pmc=4632446 |doi=10.3390/nu7105426 |type=Review |quote=Several additional studies in extensive series of coeliac patients have clearly shown that TG2A sensitivity varies depending on the severity of duodenal damage, and reaches almost 100% in the presence of complete villous atrophy (more common in children under three years), 70% for subtotal atrophy, and up to 30% when only an increase in IELs is present. ''(IELs: intraepithelial lymphocytes)'' |doi-access=free}}</ref><ref name=ESPGHAN2012>{{cite journal |vauthors=Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Mäki M, Ribes-Koninckx C, Ventura A, Zimmer KP,(( ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition)) |s2cid=15029283 |title=European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease |journal=J Pediatr Gastroenterol Nutr |volume=54 |issue=1 |pages=136–60 |date=January 2012 |pmid=22197856 |url=http://www.espghan.org/fileadmin/user_upload/guidelines_pdf/Guidelines_2404/European_Society_for_Pediatric_Gastroenterology_.28__1_.pdf |doi=10.1097/MPG.0b013e31821a23d0 |type=Practice Guideline |quote=Since 1990, the understanding of the pathological processes of CD has increased enormously, leading to a change in the clinical paradigm of CD from a chronic, gluten-dependent enteropathy of childhood to a systemic disease with chronic immune features affecting different organ systems. (...) atypical symptoms may be considerably more common than classic symptoms |url-status=dead |archive-url=https://web.archive.org/web/20160403065800/http://www.espghan.org/fileadmin/user_upload/guidelines_pdf/Guidelines_2404/European_Society_for_Pediatric_Gastroenterology_.28__1_.pdf |archive-date=3 April 2016 |access-date=19 March 2016}}</ref> however, it may develop at any age.<ref name=Fasano2005Pediatric>{{cite journal |vauthors=Fasano A |title=Clinical presentation of celiac disease in the pediatric population |journal=Gastroenterology |volume=128 |issue=4 Suppl 1 |pages=S68–73 |date=April 2005 |pmid=15825129 |doi=10.1053/j.gastro.2005.02.015 |type=Review}}</ref><ref name=ESPGHAN2012 /> It is associated with other [[autoimmune disease]]s, such as [[Type 1 diabetes mellitus]] and [[Hashimoto's thyroiditis]], among others.<ref name=Cic2015 />

Coeliac disease is caused by a reaction to gluten, a group of various proteins found in [[wheat]] and in other grains such as [[barley]] and [[rye]].<ref name=TovoliMasi2015>{{cite journal |vauthors=Tovoli F, Masi C, Guidetti E, Negrini G, Paterini P, Bolondi L |title=Clinical and diagnostic aspects of gluten related disorders |journal=World Journal of Clinical Cases |volume=3 |issue=3 |pages=275–84 |date=March 2015 |pmid=25789300 |pmc=4360499 |doi=10.12998/wjcc.v3.i3.275 |type=Review |doi-access=free }}</ref><ref name=PenaginiDilillo2013>{{cite journal |vauthors=Penagini F, Dilillo D, Meneghin F, Mameli C, Fabiano V, Zuccotti GV |title=Gluten-free diet in children: an approach to a nutritionally adequate and balanced diet |journal=Nutrients |volume=5 |issue=11 |pages=4553–65 |date=November 2013 |pmid=24253052 |pmc=3847748 |doi=10.3390/nu5114553 |type=Review |doi-access=free}}</ref><ref name=Lancet2009>{{cite journal |vauthors=Di Sabatino A, Corazza GR |s2cid=8415780 |title=Coeliac disease |journal=Lancet |volume=373 |issue=9673 |pages=1480–93 |date=April 2009 |pmid=19394538 |doi=10.1016/S0140-6736(09)60254-3}}</ref> Moderate quantities of [[oats]], free of contamination with other gluten-containing grains, are usually tolerated.<ref name=PenaginiDilillo2013 /><ref>{{cite journal |vauthors=Pinto-Sánchez MI, Causada-Calo N, Bercik P, Ford AC, Murray JA, Armstrong D, Semrad C, Kupfer SS, Alaedini A, Moayyedi P, Leffler DA, Verdú EF, Green P |title=Safety of Adding Oats to a Gluten-Free Diet for Patients With Celiac Disease: Systematic Review and Meta-analysis of Clinical and Observational Studies |journal=Gastroenterology |volume=153 |issue=2 |pages=395–409.e3 |date=August 2017 |pmid=28431885 |doi=10.1053/j.gastro.2017.04.009 |url=http://eprints.whiterose.ac.uk/115341/1/FordSafety%20of%20Adding%20Oats.pdf}}</ref> The occurrence of problems may depend on the [[cultivar|variety]] of oat.<ref name=PenaginiDilillo2013 /><ref name=CominoMoreno2015>{{cite journal |vauthors=Comino I, Moreno M, Sousa C |title=Role of oats in celiac disease |journal=World Journal of Gastroenterology |volume=21 |issue=41 |pages=11825–31 |date=November 2015 |pmid=26557006 |pmc=4631980 |doi=10.3748/wjg.v21.i41.11825 |quote=It is necessary to consider that oats include many varieties, containing various amino acid sequences and showing different immunoreactivities associated with toxic prolamins. As a result, several studies have shown that the immunogenicity of oats varies depending on the cultivar consumed. Thus, it is essential to thoroughly study the variety of oats used in a food ingredient before including it in a gluten-free diet. |doi-access=free }}</ref> It occurs more often in people who are [[Genetic predisposition|genetically predisposed]].<ref name="NIH2015">{{cite journal | vauthors = Lindfors K, Ciacci C, Kurppa K, Lundin KE, Makharia GK, Mearin ML, Murray JA, Verdu EF, Kaukinen K | title = Coeliac disease | journal = Nature Reviews. Disease Primers | volume = 5 | issue = 1 | pages = 3 | date = January 2019 | pmid = 30631077 | doi = 10.1038/s41572-018-0054-z | s2cid = 5088821 }}</ref> Upon exposure to gluten, an abnormal [[immune system|immune]] response may lead to the production of several different [[autoantibody|autoantibodies]] that can affect a number of different [[Organ (anatomy)|organs]].<ref name=Lund2015>{{cite journal |vauthors=Lundin KE, Wijmenga C |s2cid=24533103 |title=Coeliac disease and autoimmune disease-genetic overlap and screening |journal=Nature Reviews. Gastroenterology & Hepatology |volume=12 |issue=9 |pages=507–15 |date=September 2015 |pmid=26303674 |doi=10.1038/nrgastro.2015.136 |type=Review |quote=The abnormal immunological response elicited by gluten-derived proteins can lead to the production of several different autoantibodies, which affect different systems.}}</ref><ref name=NICEcoeliac>{{NICE|86|Recognition and assessment of coeliac disease|2015}}</ref> In the small bowel, this causes an [[inflammation|inflammatory reaction]] and may produce shortening of the [[Intestinal villus|villi]] lining the small intestine ([[villous atrophy]]).<ref name=NIH2015/><ref name=VivasVaquero2015>{{cite journal |vauthors=Vivas S, Vaquero L, Rodríguez-Martín L, Caminero A |title=Age-related differences in celiac disease: Specific characteristics of adult presentation |journal=World Journal of Gastrointestinal Pharmacology and Therapeutics |volume=6 |issue=4 |pages=207–12 |date=November 2015 |pmid=26558154 |pmc=4635160 |doi=10.4292/wjgpt.v6.i4.207 |type=Review |quote=In addition, the presence of intraepithelial lymphocytosis and/or villous atrophy and crypt hyperplasia of small-bowel mucosa, and clinical remission after withdrawal of gluten from the diet, are also used for diagnosis antitransglutaminase antibody (tTGA) titers and the degree of histological lesions inversely correlate with age. Thus, as the age of diagnosis increases antibody titers decrease and histological damage is less marked. It is common to find adults without villous atrophy showing only an inflammatory pattern in duodenal mucosa biopsies: Lymphocytic enteritis (Marsh I) or added crypt hyperplasia (Marsh II) |doi-access=free }}</ref> This affects the absorption of nutrients, frequently leading to [[anaemia]].<ref name=NIH2015/><ref name=Lancet2009/>

Diagnosis is typically made by a combination of blood antibody tests and intestinal [[biopsy|biopsies]], helped by specific [[genetic testing]].<ref name=NIH2015/> Making the diagnosis is not always straightforward.<ref name=MatthiasPfeiffer2010 /> About 10% of the time, the autoantibodies in the blood are negative,<ref name=LewisScott2006>{{cite journal |vauthors=Lewis NR, Scott BB |title=Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests) |journal=Alimentary Pharmacology & Therapeutics |volume=24 |issue=1 |pages=47–54 |date=July 2006 |pmid=16803602 |doi=10.1111/j.1365-2036.2006.02967.x |s2cid=16823218 |doi-access=free}}</ref><ref name=AGA2006 /> and many people have only minor intestinal changes with normal villi.<ref name=MolinaInfanteSantolaria2015>{{cite journal |vauthors=Molina-Infante J, Santolaria S, Sanders DS, Fernández-Bañares F |title=Systematic review: noncoeliac gluten sensitivity |journal=Alimentary Pharmacology & Therapeutics |volume=41 |issue=9 |pages=807–20 |date=May 2015 |pmid=25753138 |doi=10.1111/apt.13155 |s2cid=207050854 |type=Review |quote=Furthermore, seronegativity is more common in coeliac disease patients without villous atrophy (Marsh 1-2 lesions), but these 'minor' forms of coeliac disease may have similar clinical manifestations to those with villous atrophy and may show similar clinical–histological remission with reversal of haematological or biochemical disturbances on a gluten-free diet (GFD). |doi-access=free}}</ref> People may have severe symptoms and they may be investigated for years before a diagnosis is achieved.<ref name=CichewiczMearns2019 /><ref name=LudvigssonCard2015>{{cite journal |vauthors=Ludvigsson JF, Card T, Ciclitira PJ, Swift GL, Nasr I, Sanders DS, Ciacci C |title=Support for patients with celiac disease: A literature review |journal=United European Gastroenterology Journal |volume=3 |issue=2 |pages=146–59 |date=April 2015 |pmid=25922674 |pmc=4406900 |doi=10.1177/2050640614562599 |type=Review}}</ref> As a result of [[Screening (medicine)|screening]], the diagnosis is increasingly being made in people who have [[asymptomatic|no symptoms]].<ref name="VanHeelWest">{{cite journal |vauthors=van Heel DA, West J |title=Recent advances in coeliac disease |journal=Gut |volume=55 |issue=7 |pages=1037–46 |date=July 2006 |pmid=16766754 |pmc=1856316 |doi=10.1136/gut.2005.075119 |type=Review}}</ref> Evidence regarding the effects of screening, however, is not sufficient to determine its usefulness.<ref name=USPSTF2017>{{cite journal |vauthors=Bibbins-Domingo K, Grossman DC, Curry SJ, Barry MJ, Davidson KW, Doubeni CA, Ebell M, Epling JW, Herzstein J, Kemper AR, Krist AH, Kurth AE, Landefeld CS, Mangione CM, Phipps MG, Silverstein M, Simon MA, Tseng CW |s2cid=205086614 |title=Screening for Celiac Disease: US Preventive Services Task Force Recommendation Statement |journal=JAMA |volume=317 |issue=12 |pages=1252–1257 |date=March 2017 |pmid=28350936 |doi=10.1001/jama.2017.1462}}</ref> While the disease is caused by a [[Food intolerance|permanent intolerance]] to gluten proteins,<ref name=NIH2015/> it is distinct from [[wheat allergy]], which is much more rare.<ref>{{cite journal | vauthors = Burkhardt JG, Chapa-Rodriguez A, Bahna SL | title = Gluten sensitivities and the allergist: Threshing the grain from the husks | journal = Allergy | volume = 73 | issue = 7 | pages = 1359–1368 | date = July 2018 | pmid = 29131356 | doi = 10.1111/all.13354 | doi-access = free }}</ref> <ref>Costantino A, Aversano GM, Lasagni G, Smania V, Doneda L, Vecchi M, Roncoroni L, Pastorello EA, Elli L. Diagnostic management of patients reporting symptoms after wheat ingestion. Front Nutr. 2022 Oct 6;9:1007007. doi: 10.3389/fnut.2022.1007007. PMID: 36276818; PMCID: PMC9582535.</ref>

The only known effective treatment is a strict lifelong [[gluten-free diet]], which leads to recovery of the intestinal lining ([[mucous membrane]]), improves symptoms, and reduces the risk of developing complications in most people.<ref name=SeeKaukinen2015>{{cite journal |vauthors=See JA, Kaukinen K, Makharia GK, Gibson PR, Murray JA |s2cid=20270743 |title=Practical insights into gluten-free diets |journal=Nature Reviews. Gastroenterology & Hepatology |volume=12 |issue=10 |pages=580–91 |date=October 2015 |pmid=26392070 |doi=10.1038/nrgastro.2015.156 |type=Review |quote=A lack of symptoms and/or negative serological markers are not reliable indicators of mucosal response to the diet. Furthermore, up to 30% of patients continue to have gastrointestinal symptoms despite a strict GFD.122,124 If adherence is questioned, a structured interview by a qualified dietitian can help to identify both intentional and inadvertent sources of gluten.}}</ref> If untreated, it may result in [[cancer]]s such as intestinal [[lymphoma]], and a slightly increased risk of early death.<ref name=Leb2015>{{cite journal |vauthors=Lebwohl B, Ludvigsson JF, Green PH |title=Celiac disease and non-celiac gluten sensitivity |journal=BMJ |volume=351 |pages=h4347 |date=October 2015 |pmid=26438584 |pmc=4596973 |doi=10.1136/bmj.h4347 |quote=Celiac disease occurs in about 1% of the population worldwide, although most people with the condition are undiagnosed. It can cause a wide variety of symptoms, both intestinal and extra-intestinal because it is a systemic autoimmune disease that is triggered by dietary gluten. Patients with coeliac disease are at increased risk of cancer, including a twofold to fourfold increased risk of non-Hodgkin's lymphoma and a more than 30-fold increased risk of small intestinal adenocarcinoma, and they have a 1.4-fold increased risk of death. |type=Review}}</ref> Rates vary between different regions of the world, from as few as 1 in 300 to as many as 1 in 40, with an average of between 1 in 100 and 1 in 170 people.<ref name=NEJM2012>{{cite journal |vauthors=Fasano A, Catassi C |title=Clinical practice. Celiac disease |journal=The New England Journal of Medicine |volume=367 |issue=25 |pages=2419–26 |date=December 2012 |pmid=23252527 |doi=10.1056/NEJMcp1113994 |type=Review}}</ref> It is estimated that 80% of cases remain undiagnosed, usually because of minimal or absent gastrointestinal complaints and lack of knowledge of symptoms and diagnostic criteria.<ref name=WGO2016 >{{cite web |url=http://www.worldgastroenterology.org/guidelines/global-guidelines/celiac-disease/celiac-disease-english |title=Celiac disease |date=July 2016 |publisher=[[World Gastroenterology Organisation]] Global Guidelines |access-date=23 April 2017 |url-status=live |archive-url=https://web.archive.org/web/20170317123604/http://www.worldgastroenterology.org/guidelines/global-guidelines/celiac-disease/celiac-disease-english |archive-date=17 March 2017}}</ref><ref name=CichewiczMearns2019>{{cite journal | vauthors = Cichewicz AB, Mearns ES, Taylor A, Boulanger T, Gerber M, Leffler DA, Drahos J, Sanders DS, Thomas Craig KJ, Lebwohl B | title = Diagnosis and Treatment Patterns in Celiac Disease | journal = Digestive Diseases and Sciences | volume = 64 | issue = 8 | pages = 2095–2106 | date = August 2019 | pmid = 30820708 | doi = 10.1007/s10620-019-05528-3 | type = Review | s2cid = 71143826 }}</ref><ref name=LionettiGatti2015>{{cite journal |vauthors=Lionetti E, Gatti S, Pulvirenti A, Catassi C |title=Celiac disease from a global perspective |journal=Best Practice & Research. Clinical Gastroenterology |volume=29 |issue=3 |pages=365–79 |date=June 2015 |pmid=26060103 |doi=10.1016/j.bpg.2015.05.004 |type=Review}}</ref> Coeliac disease is slightly more common in women than in men.<ref name=His2006>{{cite journal |vauthors=Hischenhuber C, Crevel R, Jarry B, Mäki M, Moneret-Vautrin DA, Romano A, Troncone R, Ward R |title=Review article: safe amounts of gluten for patients with wheat allergy or coeliac disease |journal=Alimentary Pharmacology & Therapeutics |volume=23 |issue=5 |pages=559–75 |date=March 2006 |pmid=16480395 |doi=10.1111/j.1365-2036.2006.02768.x |s2cid=9970042 |doi-access=free}}</ref>

{{TOC limit}}

==Signs and symptoms==
The classic symptoms of untreated coeliac disease include [[diarrhea]], [[steatorrhea|steatorrhoea]], [[iron-deficiency anemia]], and weight loss or failure to gain weight. Other common symptoms may be subtle or primarily occur in organs other than the bowel itself.<ref>{{cite journal |vauthors=Schuppan D, Zimmer KP |title=The diagnosis and treatment of celiac disease |journal=Deutsches Ärzteblatt International |volume=110 |issue=49 |pages=835–46 |date=December 2013 |pmid=24355936 |pmc=3884535 |doi=10.3238/arztebl.2013.0835}}</ref> It is also possible to have coeliac disease without any of the classic symptoms at all.<ref name=Lancet2009/> This has been shown to comprise at least 43% of presentations in children.<ref name=VriezingaSchweizer2015>{{cite journal |vauthors=Vriezinga SL, Schweizer JJ, Koning F, Mearin ML |s2cid=2023530 |title=Coeliac disease and gluten-related disorders in childhood |journal=Nature Reviews. Gastroenterology & Hepatology |volume=12 |issue=9 |pages=527–36 |date=September 2015 |pmid=26100369 |doi=10.1038/nrgastro.2015.98 |type=Review}}</ref> Further, many adults with subtle disease may only present with fatigue, [[anaemia]] or [[Osteopenia|low bone mass]].<ref name=VanHeelWest/> Many undiagnosed individuals who consider themselves asymptomatic are in fact not, but rather have become accustomed to living in a state of chronically compromised health. Indeed, after starting a gluten-free diet and subsequent improvement becomes evident, such individuals are often able to retrospectively recall and recognise prior symptoms of their untreated disease that they had mistakenly ignored.<ref name=WGO2016 /><ref name=LudvigssonCard2015 /><ref name=LionettiGatti2015 />

===Gastrointestinal===
[[diarrhea|Diarrhoea]] that is characteristic of coeliac disease is chronic, sometimes pale, of large volume, and abnormally foul in odor. [[Abdominal pain]], cramping, bloating with [[abdominal distension]] (thought to be the result of fermentative production of bowel gas), and [[mouth ulcer]]s<ref>{{cite journal | vauthors = Ferguson R, Basu MK, Asquith P, Cooke WT | title = Jejunal mucosal abnormalities in patients with recurrent aphthous ulceration | journal = British Medical Journal | volume = 1 | issue = 6000 | pages = 11–13 | date = January 1976 | pmid = 1247715 | pmc = 1638254 | doi = 10.1136/bmj.1.6000.11 }}</ref> may be present. As the bowel becomes more damaged, a degree of [[lactose intolerance]] may develop.<ref name=Lancet2009/> Frequently, the symptoms are ascribed to [[irritable bowel syndrome]] (IBS), only later to be recognised as coeliac disease. In populations of people with symptoms of IBS, a diagnosis of coeliac disease can be made in about 3.3% of cases, or four times more likely than in general.<ref name=AJ2017>{{cite journal | vauthors = Irvine AJ, Chey WD, Ford AC | title = Screening for Celiac Disease in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-analysis | journal = The American Journal of Gastroenterology | volume = 112 | issue = 1 | pages = 65–76 | date = January 2017 | pmid = 27753436 | doi = 10.1038/ajg.2016.466 | s2cid = 269053 | url = http://eprints.whiterose.ac.uk/106483/3/AJG-16-1318R1%20CLEAN.pdf }}</ref> Screening them for coeliac disease is recommended by the [[National Institute for Health and Clinical Excellence]] (NICE), the [[British Society of Gastroenterology]] and the [[American College of Gastroenterology]], but is of unclear benefit in North America.<ref name=AJ2017/><ref name=NICEIBS>{{NICE|61|Irritable bowel syndrome|2008}}</ref>

Coeliac disease leads to an increased risk of both [[adenocarcinoma]] and [[lymphoma]] of the small bowel ([[enteropathy-associated T-cell lymphoma]] (EATL) or other [[non-Hodgkin lymphoma]]s).<ref>{{cite journal | vauthors = Caio G, Volta U, Sapone A, Leffler DA, De Giorgio R, Catassi C, Fasano A | title = Celiac disease: a comprehensive current review | journal = BMC Medicine | volume = 17 | issue = 1 | pages = 142 | date = July 2019 | pmid = 31331324 | pmc = 6647104 | doi = 10.1186/s12916-019-1380-z | publisher = Springer Nature | doi-access = free }}</ref> This risk is also higher in first-degree relatives such as siblings, parents and children. Whether a gluten-free diet brings this risk back to baseline is not clear.<ref name=WJG2012>{{cite journal | vauthors = Gujral N, Freeman HJ, Thomson AB | title = Celiac disease: prevalence, diagnosis, pathogenesis and treatment | journal = World Journal of Gastroenterology | volume = 18 | issue = 42 | pages = 6036–6059 | date = November 2012 | pmid = 23155333 | pmc = 3496881 | doi = 10.3748/wjg.v18.i42.6036 | df = dmy-all | doi-access = free }}</ref> Long-standing and untreated disease may lead to other complications, such as [[Enteropathy-associated T-cell lymphoma#Ulcerative jejunitis|ulcerative jejunitis]] (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring with obstruction of the bowel).<ref name=AGA>{{cite journal | vauthors =  | title = American Gastroenterological Association medical position statement: Celiac Sprue | journal = Gastroenterology | volume = 120 | issue = 6 | pages = 1522–1525 | date = May 2001 | pmid = 11313323 | doi = 10.1053/gast.2001.24055 | s2cid = 28235994 | doi-access = free }}</ref>

===Malabsorption-related===
The changes in the bowel reduce its ability to [[Small intestine#Absorption|absorb]] nutrients, minerals, and the [[Vitamin#Classification|fat-soluble vitamins]] A, D, E, and K.<ref name=Lancet2009/><ref name=AFP>{{cite journal |vauthors=Presutti RJ, Cangemi JR, Cassidy HD, Hill DA |title=Celiac disease |journal=Am Fam Physician |volume=76 |issue=12 |pages=1795–802 |year=2007 |pmid=18217518 |url=http://www.aafp.org/afp/20071215/1795.html |access-date=13 December 2009 |archive-date=19 April 2021 |archive-url=https://web.archive.org/web/20210419111728/https://www.aafp.org/afp/2007/1215/p1795.html |url-status=dead}}</ref>

*[[Malabsorption]] of carbohydrates and fats may cause [[weight loss]] (or [[failure to thrive]] or [[stunted growth]] in children) and [[fatigue]] or lack of energy.
*[[Anaemia]] may develop in several ways: iron malabsorption may cause [[iron deficiency anaemia]], and [[folic acid]] and [[vitamin B12|vitamin B<sub>12</sub>]] malabsorption may give rise to [[megaloblastic anemia|megaloblastic anaemia]].
*[[Calcium in biology|Calcium]] and [[vitamin D]] malabsorption (and compensatory [[secondary hyperparathyroidism]]) may cause [[osteopenia]] (decreased mineral content of the bone) or [[osteoporosis]] (bone weakening and risk of fragility fractures).
*[[Selenium]] malabsorption in coeliac disease, combined with low selenium content in many gluten-free foods, confers a risk of [[selenium deficiency]].<ref name="pietzak_book">{{cite book |vauthors=Pietzak MM |chapter=Dietary supplements in celiac disease |veditors=Rampertab SD, Mullin GE |title=Celiac disease |isbn=978-1-4614-8559-9 |pages=137–59 |date=2014|publisher=Springer }}</ref>
*[[Copper deficiency|Copper]] and [[Zinc deficiency|zinc deficiencies]] have also been associated with coeliac disease.<ref name="pietzak_book" />
*A small proportion of people have abnormal [[coagulation]] because of [[vitamin K deficiency]] and are at a slight risk of abnormal bleeding.

===Miscellaneous===
Coeliac disease has been linked with many conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.

*[[IgA deficiency]] is present in 2.3% of people with coeliac disease, and is itself associated with a tenfold increased risk of coeliac disease. Other features of this condition are an increased risk of infections and [[autoimmune disease]].<ref>{{cite journal |vauthors=Cunningham-Rundles C |s2cid=13285781 |title=Physiology of IgA and IgA deficiency |journal=J. Clin. Immunol. |volume=21 |issue=5 |pages=303–9 |date=September 2001 |pmid=11720003 |doi=10.1023/A:1012241117984}}</ref>
*[[Dermatitis herpetiformis]], an itchy cutaneous condition that has been linked to a transglutaminase enzyme in the skin, features small-bowel changes identical to those in coeliac disease and may respond to gluten withdrawal even if no gastrointestinal symptoms are present.<ref name=Marks>{{cite journal |vauthors=Marks J, Shuster S, Watson AJ |title=Small-bowel changes in dermatitis herpetiformis |journal=Lancet |volume=2 |issue=7476 |pages=1280–2 |year=1966 |pmid=4163419 |doi=10.1016/S0140-6736(66)91692-8}}</ref><ref>{{cite journal |vauthors=Nicolas ME, Krause PK, Gibson LE, Murray JA |title=Dermatitis herpetiformis |journal=Int. J. Dermatol. |volume=42 |issue=8 |pages=588–600 |date=August 2003 |pmid=12890100 |doi=10.1046/j.1365-4362.2003.01804.x |s2cid=42280769}}</ref>
*[[Growth failure]] and/or [[delayed puberty|pubertal delay]] in later childhood can occur even without obvious bowel symptoms or severe [[malnutrition]]. Evaluation of growth failure often includes coeliac screening.<ref name=Lancet2009/>
*[[Pregnancy complication]]s can occur if coeliac disease is [[pre-existing disease in pregnancy|pre-existing]] or later acquired, with significant outcomes including [[miscarriage]], [[intrauterine growth restriction]], [[low birthweight]] and [[preterm birth]].<ref name="TersigniCastellani2014">{{cite journal |vauthors=Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, Scambia G, Di Simone N |title=Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms |journal=Human Reproduction Update |volume=20 |issue=4 |pages=582–93 |year=2014 |pmid=24619876 |doi=10.1093/humupd/dmu007 |doi-access=free|hdl=10807/56796 |hdl-access=free }}</ref>
*[[Hyposplenism]] (a small and underactive [[spleen]])<ref name=Ferguson>{{cite journal |vauthors=Ferguson A, Hutton MM, Maxwell JD, Murray D |title=Adult coeliac disease in hyposplenic patients |journal=Lancet |volume=1 |issue=7639 |pages=163–4 |year=1970 |pmid=4189238 |doi=10.1016/S0140-6736(70)90405-8}}</ref> occurs in about a third of cases and may predispose to infection given the role of the spleen in protecting against harmful bacteria.<ref name=Lancet2009/>
*Abnormal [[liver function test]]s (randomly detected on blood tests) may be seen.<ref name=Lancet2009/>
*[[Depression (mood)|Depression]], [[anxiety]] and other mental health disorders<ref>{{cite journal | vauthors = Zingone F, Swift GL, Card TR, Sanders DS, Ludvigsson JF, Bai JC | title = Psychological morbidity of celiac disease: A review of the literature | journal = United European Gastroenterology Journal | volume = 3 | issue = 2 | pages = 136–145 | date = April 2015 | pmid = 25922673 | pmc = 4406898 | doi = 10.1177/2050640614560786 }}</ref>

Coeliac disease is associated with several other medical conditions, many of which are autoimmune disorders: [[diabetes mellitus type 1]], [[hypothyroidism]], [[primary biliary cholangitis]], [[microscopic colitis]], [[ataxia|gluten ataxia]], [[psoriasis]], [[vitiligo]], [[autoimmune hepatitis]], [[primary sclerosing cholangitis]], and more.<ref name=Lund2015 />

==Causes==
Coeliac disease is caused by an inflammatory reaction to [[gliadin]]s and [[glutenin]]s ([[gluten]] proteins)<ref name=KupferJabri2012>{{cite journal | vauthors = Kupfer SS, Jabri B | title = Pathophysiology of celiac disease | journal = Gastrointestinal Endoscopy Clinics of North America | volume = 22 | issue = 4 | pages = 639–660 | date = October 2012 | pmid = 23083984 | pmc = 3872820 | doi = 10.1016/j.giec.2012.07.003 | type = Review | quote = Gluten comprises two different protein types, gliadins and glutenins, capable of triggering disease. }}</ref> found in wheat and to similar proteins found in the crops of the [[tribe (biology)|tribe]] [[Triticeae]] (which includes other common grains such as [[barley]] and [[rye]])<ref name=Lancet2009/> and to the tribe [[Aveneae]] ([[oat]]s).<ref name=Biesiekierski2017>{{cite journal | vauthors = Biesiekierski JR | title = What is gluten? | journal = Journal of Gastroenterology and Hepatology | volume = 32 | issue = Suppl 1 | pages = 78–81 | date = March 2017 | pmid = 28244676 | doi = 10.1111/jgh.13703 | 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." Derivatives of these grains such as triticale and malt and other ancient wheat varieties such as spelt and kamut also contain gluten. The gluten found in all of these grains has been identified as the component capable of triggering the immune-mediated disorder, coeliac disease. | s2cid = 6493455 | doi-access = free }}</ref> Wheat subspecies (such as [[spelt]], [[durum]], and [[Kamut]]) and wheat hybrids (such as [[triticale]]) also cause symptoms of coeliac disease.<ref name=Biesiekierski2017 /><ref name=Kupper>{{cite journal | vauthors = Kupper C | title = Dietary guidelines and implementation for celiac disease | journal = Gastroenterology | volume = 128 | issue = 4 Suppl 1 | pages = S121–S127 | date = April 2005 | pmid = 15825119 | doi = 10.1053/j.gastro.2005.02.024 | doi-access = free }}</ref>

A small number of people with coeliac disease react to oats.<ref name=Lancet2009/> Oat toxicity in coeliac people depends on the oat [[cultivar]] consumed because the prolamin genes, protein amino acid sequences, and the [[immunoreactivity|immunoreactivities]] of toxic prolamins are different in different oat varieties.<ref name=CominoMoreno2015/><ref name=PenaginiDilillo>{{cite journal |vauthors=Penagini F, Dilillo D, Meneghin F, Mameli C, Fabiano V, Zuccotti GV |title=Gluten-free diet in children: an approach to a nutritionally adequate and balanced diet |journal=Nutrients |volume=5 |issue=11 |pages=4553–65 |date=18 November 2013 |pmid=24253052 |pmc=3847748 |doi=10.3390/nu5114553 |doi-access=free}}</ref> Also, oats are frequently cross-contaminated with other grains containing gluten.<ref name=CominoMoreno2015 /><ref name=PenaginiDilillo /><ref name=DeSouzaDeschenes2016>{{cite journal |vauthors=de Souza MC, Deschênes ME, Laurencelle S, Godet P, Roy CC, Djilali-Saiah I |title=Pure Oats as Part of the Canadian Gluten-Free Diet in Celiac Disease: The Need to Revisit the Issue. |journal=Can J Gastroenterol Hepatol |year=2016 |volume=2016 |pages=1–8 |pmid=27446824 |doi=10.1155/2016/1576360 |pmc=4904650 |type=Review |doi-access=free}}</ref> The term "pure oats" refers to oats uncontaminated with other gluten-containing cereals.<ref name=CominoMoreno2015 /> The long-term effects of pure oat consumption are still unclear,<ref name=HaboubiTaylor2006>{{cite journal |vauthors=Haboubi NY, Taylor S, Jones S |title=Coeliac disease and oats: a systematic review |journal=Postgrad Med J |volume=82 |issue=972 |pages=672–8 |date=October 2006 |pmid=17068278 |pmc=2653911 |doi=10.1136/pgmj.2006.045443 |type=Review}}</ref> and further studies identifying the cultivars used are needed before making final recommendations on their inclusion in a [[gluten-free diet]].<ref name=DeSouzaDeschenes2016 /> Coeliac people who choose to consume oats need a more rigorous lifelong follow-up, possibly including periodic [[coeliac disease#Endoscopy|intestinal biopsies]].<ref name=HaboubiTaylor2006 />

===Other grains===
Other cereals such as [[maize|corn]], [[millet]], [[sorghum]], [[teff]], [[rice]], and [[wild rice]] are safe for people with coeliac disease to consume, as well as non-cereals such as [[amaranth]], [[quinoa]], and [[buckwheat]].<ref name=Kupper/><ref>{{Cite book | vauthors = Gallagher E |title=Gluten-free Food Science and Technology |publisher=Published by John Wiley and Sons |year=2009 |page=320 |isbn=978-1-4051-5915-9 |url=http://eu.wiley.com/WileyCDA/WileyTitle/productCd-1405159154.html |url-status=live |archive-url=https://web.archive.org/web/20090617114337/http://eu.wiley.com/WileyCDA/WileyTitle/productCd-1405159154.html |archive-date=17 June 2009}}</ref> Noncereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.<ref name=Kupper/>

===Risk modifiers===
There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include surgery, pregnancy, infection and emotional stress.<ref name=Glutengovca>{{cite web |title=The Gluten Connection |url=https://www.canada.ca/en/health-canada/services/food-nutrition/reports-publications/food-safety/celiac-disease-gluten-connection-1.html |publisher=Health Canada |access-date=1 October 2013 |url-status=live |archive-url=https://web.archive.org/web/20170705183625/https://www.canada.ca/en/health-canada/services/food-nutrition/reports-publications/food-safety/celiac-disease-gluten-connection-1.html |archive-date=5 July 2017 |date=May 2009}}</ref>

The eating of gluten early in a baby's life does not appear to increase the risk of coeliac disease but later introduction after six months may increase it.<ref>{{cite journal |vauthors=Pinto-Sánchez MI, Verdu EF, Liu E, Bercik P, Green PH, Murray JA, Guandalini S, Moayyedi P |title=Gluten Introduction to Infant Feeding and Risk of Celiac Disease: Systematic Review and Meta-Analysis |journal=The Journal of Pediatrics |volume=168 |pages=132–43.e3 |date=January 2016 |pmid=26500108 |doi=10.1016/j.jpeds.2015.09.032 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Ierodiakonou D, Garcia-Larsen V, Logan A, Groome A, Cunha S, Chivinge J, Robinson Z, Geoghegan N, Jarrold K, Reeves T, Tagiyeva-Milne N, Nurmatov U, Trivella M, Leonardi-Bee J, Boyle RJ |title=Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease: A Systematic Review and Meta-analysis |journal=JAMA |volume=316 |issue=11 |pages=1181–1192 |date=September 2016 |pmid=27654604 |doi=10.1001/jama.2016.12623 |hdl=10044/1/40479 |s2cid=25694792 |url=http://jamanetwork.com/journals/jama/fullarticle/2553447 |hdl-access=free}}</ref> There is uncertainty whether being breastfed reduces risk. Prolonging [[breastfeeding]] until the introduction of gluten-containing grains into the diet appears to be associated with a 50% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear.<ref>{{cite journal |vauthors=Akobeng AK, Ramanan AV, Buchan I, Heller RF |title=Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies |journal=Archives of Disease in Childhood |volume=91 |issue=1 |pages=39–43 |date=January 2006 |pmid=16287899 |pmc=2083075 |doi=10.1136/adc.2005.082016}}</ref> These factors may just influence the timing of onset.<ref>{{cite journal |vauthors=Lionetti E, Castellaneta S, Francavilla R, Pulvirenti A, Tonutti E, Amarri S, Barbato M, Barbera C, Barera G, Bellantoni A, Castellano E, Guariso G, Limongelli MG, Pellegrino S, Polloni C, Ughi C, Zuin G, Fasano A, Catassi C |title=Introduction of gluten, HLA status, and the risk of celiac disease in children |journal=The New England Journal of Medicine |volume=371 |issue=14 |pages=1295–303 |date=October 2014 |pmid=25271602 |doi=10.1056/NEJMoa1400697 |type=comparative study |author-link18=Alessio Fasano |hdl=2318/155238 |doi-access=free |hdl-access=free }}</ref>

==Mechanism==
Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person.<ref name= pmid35125829>{{Cite journal |vauthors= Gnodi E, Meneveri R, Barisani D |title=Celiac disease: From genetics to epigenetics |journal=World J Gastroenterol |volume=28 |pages=449–463 |year= 2022 |issue=4 |doi=10.3748/wjg.v28.i4.449 |pmid=35125829|pmc=8790554 |doi-access=free }}</ref>

Almost all people (95%) with coeliac disease have either the variant [[HLA-DQ2]] [[allele]] or (less commonly) the [[HLA-DQ8]] [[allele]].<ref name=VanHeelWest/><ref>{{Cite book |title=Oxford handbook of Clinical Medicine | vauthors = Longmore M |publisher=Oxford University Press |year=2014 |isbn=9780199609628 |pages=280}}</ref> However, about 20–30% of people without coeliac disease have also inherited either of these alleles.<ref name="pmid17785484"/> This suggests that additional factors are needed for coeliac disease to develop; that is, the predisposing HLA risk allele is necessary but not sufficient to develop coeliac disease. Furthermore, around 5% of those people who do develop coeliac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles (see below).<ref name=VanHeelWest/>

===Genetics===
[[File:DQa2b5 da gliadin.JPG|thumb|DQ α<sup>5</sup>-β<sup>2</sup> -binding cleft with a deamidated gliadin peptide (yellow), modified from {{PDB|1S9V}}<ref>{{Cite journal |vauthors=Kim C, Quarsten H, Bergseng E, Khosla C, Sollid L |title=Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease |journal=Proc Natl Acad Sci USA |volume=101 |issue=12 |pages=4175–9 |year=2004 |pmid=15020763 |doi=10.1073/pnas.0306885101 |pmc=384714 |bibcode=2004PNAS..101.4175K |doi-access=free}}</ref>]]
The vast majority of people with coeliac have one of two types (out of seven) of the [[HLA-DQ]] protein.<ref name="pmid17785484">{{cite journal |vauthors=Hadithi M, von Blomberg BM, Crusius JB, Bloemena E, Kostense PJ, Meijer JW, Mulder CJ, Stehouwer CD, Peña AS |s2cid=24275278 |title=Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease |journal=Ann. Intern. Med. |volume=147 |issue=5 |pages=294–302 |year=2007 |pmid=17785484 |doi=10.7326/0003-4819-147-5-200709040-00003 |df=dmy-all}}</ref> {{citation needed span|HLA-DQ is part of the [[major histocompatibility complex|MHC class II antigen-presenting receptor]] (also called the [[human leukocyte antigen]]) system and distinguishes cells between self and non-self for the purposes of the [[immune system]]. The two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of [[chromosome 6]].|date=December 2022}}

There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of people with coeliac have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate [[T cell|T lymphocytes]] and initiate the autoimmune process.<ref name=VanHeelWest/>

[[File:HLA.svg|upright=0.9|thumb|HLA region of chromosome 6]]
Most people with coeliac bear a two-gene HLA-DQ2 [[haplotype]] referred to as [[HLA-DQ2#DQ2.5|DQ2.5 haplotype]]. This haplotype is composed of two adjacent gene [[allele]]s, DQA1*0501 and [[HLA-DQ2#DQB1*0201|DQB1*0201]], which encode the two subunits, DQ α<sup>5</sup> and DQ β<sup>2</sup>. In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents (DQ2.5cis). Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from ''both'' parents; the latter are especially at risk for coeliac disease as well as being more susceptible to severe complications.<ref name="pmid17190762">{{cite journal |vauthors=Jores RD, Frau F, Cucca F, Grazia Clemente M, Orrù S, Rais M, De Virgiliis S, Congia M |s2cid=7675714 |title=HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease |journal=Scand. J. Gastroenterol. |volume=42 |issue=1 |pages=48–53 |year=2007 |pmid=17190762 |doi=10.1080/00365520600789859}}</ref>

Some individuals inherit DQ2.5 from one parent and an additional portion of the haplotype (either DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent (DQ2.5trans) (called a trans-haplotype association), and these individuals are at similar risk for coeliac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, the disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 4% have the [[HLA-DQ2#DQ2.2 and gluten|DQ2.2]] isoform, and the remaining 2% lack DQ2 or DQ8.<ref name="pmid12651074">{{cite journal |vauthors=Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, Ciclitira PJ, Sollid LM, Partanen J |title=HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease |journal=Hum. Immunol. |volume=64 |issue=4 |pages=469–77 |year=2003 |pmid=12651074 |doi=10.1016/S0198-8859(03)00027-2}}</ref>

The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe ([[Basque Country (greater region)|Basque Country]] and Ireland<ref>{{cite journal |vauthors=Michalski JP, McCombs CC, Arai T, Elston RC, Cao T, McCarthy CF, Stevens FM |title=HLA-DR, DQ genotypes of celiac disease patients and healthy subjects from the West of Ireland |journal=Tissue Antigens |volume=47 |issue=2 |pages=127–33 |year=1996 |pmid=8851726 |doi=10.1111/j.1399-0039.1996.tb02525.x}}</ref> with highest frequencies) and portions of Africa and is associated with disease in India,<ref>{{cite journal |vauthors=Kaur G, Sarkar N, Bhatnagar S, Kumar S, Rapthap CC, Bhan MK, Mehra NK |title=Pediatric celiac disease in India is associated with multiple DR3-DQ2 haplotypes |journal=Hum. Immunol. |volume=63 |issue=8 |pages=677–82 |year=2002 |pmid=12121676 |doi=10.1016/S0198-8859(02)00413-5}}</ref> but it is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ2.5 and is particularly common in South and Central America; up to 90% of individuals in certain Amerindian populations carry DQ8 and thus may display the coeliac [[phenotype]].<ref>{{cite journal |vauthors=Layrisse Z, Guedez Y, Domínguez E, Paz N, Montagnani S, Matos M, Herrera F, Ogando V, Balbas O, Rodríguez-Larralde A |title=Extended HLA haplotypes in a Carib Amerindian population: the Yucpa of the Perija Range |journal=Hum Immunol |volume=62 |issue=9 |pages=992–1000 |year=2001 |pmid=11543901 |doi=10.1016/S0198-8859(01)00297-X}}</ref>

Other genetic factors have been repeatedly reported in coeliac disease; however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population.<ref name="Dubois2010">{{cite journal |vauthors=Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adány R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernández-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, MacMathuna P, Mäki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Núñez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA |title=Multiple common variants for celiac disease influencing immune gene expression |journal=Nature Genetics |volume=42 |issue=4 |pages=295–302 |year=2010 |pmid=20190752 |pmc=2847618 |doi=10.1038/ng.543}}</ref> Many of the loci detected have been found in association with other autoimmune diseases. One locus, the [[LPP (gene)|LPP]] or lipoma-preferred partner gene, is involved in the adhesion of extracellular matrix to the cell surface, and a minor variant ([[Single nucleotide polymorphism|SNP]]=rs1464510) increases the risk of disease by approximately 30%. This gene strongly associates with coeliac disease ([[Probability#Relation to randomness|p]] < 10<sup>−39</sup>) in samples taken from a broad area of Europe and the US.<ref name="Dubois2010"/>

The prevalence of coeliac disease genotypes in the modern population is not completely understood. Given the characteristics of the disease and its apparent strong heritability, it would normally be expected that the genotypes would undergo negative selection and to be absent in societies where agriculture has been practised the longest (compare with a similar condition, [[lactose intolerance]], which has been negatively selected so strongly that its prevalence went from ~100% in ancestral populations to less than 5% in some European countries). This expectation was first proposed by Simoons (1981).<ref>{{cite book |title=Food, nutrition, and evolution: food as an environmental factor in the genesis of human variability | vauthors = Walcher DN, Kretchmer N |pages=179–199 |publisher=Papers presented at the International Congress of the International Organization for the Study of Human Development, Masson Pub. USA |year=1981 |isbn=978-0-89352-158-5}}</ref> By now, however, it is apparent that this is not the case; on the contrary, there is evidence of ''positive'' selection in coeliac disease genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections.<ref>{{cite journal |title=Where Is Celiac Disease Coming From and Why? |vauthors=Catassi C |s2cid=12843113 |journal=[[Journal of Pediatric Gastroenterology & Nutrition]] |year=2005 |doi=10.1097/01.MPG.0000151650.03929.D5 |pmid=15735480 |volume=40 |issue=3 |pages=279–282|doi-access=free }}</ref><ref name="pmid20560212">{{cite journal |vauthors=Zhernakova A, Elbers CC, Ferwerda B, Romanos J, Trynka G, Dubois PC, de Kovel CG, Franke L, Oosting M, Barisani D, Bardella MT, Joosten LA, Saavalainen P, van Heel DA, Catassi C, Netea MG, Wijmenga C |title=Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection |journal=[[American Journal of Human Genetics]] |volume=86 |issue=6 |pages=970–7 |year=2010 |pmid=20560212 |pmc=3032060 |doi=10.1016/j.ajhg.2010.05.004}}</ref>

===Prolamins===
The majority of the proteins in food responsible for the immune reaction in coeliac disease are the [[prolamin]]s. These are storage proteins rich in [[proline]] (''prol-'') and [[glutamine]] (''-amin'') that dissolve in alcohols and are resistant to [[protease]]s and [[peptidase]]s of the gut.<ref name=VanHeelWest/><ref name="pmid17960014">{{cite journal |vauthors=Green PH, Cellier C |title=Celiac disease |journal=N. Engl. J. Med. |volume=357 |issue=17 |pages=1731–43 |year=2007 |pmid=17960014 |doi=10.1056/NEJMra071600}}</ref> Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley ([[hordein]]), rye ([[secalin]]) and [[oat]]s ([[avenin]]).<ref name=Biesiekierski2017 /> One region of [[Gliadin|α-gliadin]] stimulates membrane cells, [[enterocyte]]s, of the intestine to allow larger molecules around the sealant between cells. Disruption of [[tight junctions]] allow peptides larger than three [[amino acid]]s to enter the intestinal lining.<ref name="pmid18485912">{{cite journal |vauthors=Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A |title=Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3 |journal=Gastroenterology |volume=135 |issue=1 |pages=194–204.e3 |year=2008 |pmid=18485912 |pmc=2653457 |doi=10.1053/j.gastro.2008.03.023}}</ref>

[[File:A2-gliadin-33mer.png|thumb|upright=1.2|Illustration of deamidated α-2 gliadin's 33mer, amino acids 56–88, showing the overlapping of three varieties of T-cell epitope<ref name="pmid15265905">{{cite journal | vauthors = Qiao SW, Bergseng E, Molberg Ø, Xia J, Fleckenstein B, Khosla C, Sollid LM | title = Antigen presentation to celiac lesion-derived T cells of a 33-mer gliadin peptide naturally formed by gastrointestinal digestion | journal = Journal of Immunology | volume = 173 | issue = 3 | pages = 1757–1762 | date = August 2004 | pmid = 15265905 | doi = 10.4049/jimmunol.173.3.1757 | s2cid = 24910686 | doi-access = free }}</ref>]]
Membrane leaking permits peptides of gliadin that stimulate two levels of the immune response: the innate response, and the adaptive (T-helper cell-mediated) response. One protease-resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of [[interleukin-15]]. This [[Gluten immunochemistry#Innate immunity|innate response to gliadin]] results in immune-system signalling that attracts inflammatory cells and increases the release of inflammatory chemicals.<ref name=VanHeelWest/> The strongest and most common adaptive response to gliadin is directed toward an [[Gluten immunochemistry#A2-gliadin|α2-gliadin fragment]] of 33&nbsp;amino acids in length.<ref name=VanHeelWest/>

The response to the 33mer occurs in most coeliacs who have [[HLA-DQ2#DQ2.5 and gluten|a DQ2]] [[wikt:isoform|isoform]]. This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 isoform will bind, and stay bound to, peptide when recognised by T-cells.<ref name="pmid15265905"/> Gliadin in wheat is the best-understood member of this family, but other prolamins exist, and hordein (from barley), secalin (from rye), and avenin (from oats) may contribute to coeliac disease.<ref name=VanHeelWest/><ref name=Biesiekierski2017 /><ref name="pmid16212427">{{cite journal |vauthors=Shan L, Qiao SW, Arentz-Hansen H, Molberg Ø, Gray GM, Sollid LM, Khosla C |title=Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue |journal=J. Proteome Res. |volume=4 |issue=5 |pages=1732–41 |year=2005 |pmid=16212427 |pmc=1343496 |doi=10.1021/pr050173t}}</ref> Avenin's toxicity in people with coeliac disease depends on the oat [[cultivar]] consumed, as prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins vary among oat varieties.<ref name=CominoMoreno2015 />

===Tissue transglutaminase===
[[File:TG2 bound to gluten peptide mimic.png|thumb|upright=1.6|The active form of [[tissue transglutaminase]] (green) bound to a [[gluten]] peptide mimic (blue). {{PDB|3q3z}}]]
[[Anti-transglutaminase antibodies]] to the enzyme [[tissue transglutaminase]] (tTG) are found in the blood of the majority of people with classic symptoms and complete villous atrophy, but only in 70% of the cases with partial villous atrophy and 30% of the cases with minor mucosal lesions.<ref name=LewisScott2006 /> Tissue transglutaminase modifies gluten [[peptide]]s into a form that may stimulate the immune system more effectively.<ref name=VanHeelWest/> These peptides are modified by tTG in two ways, [[deamidation]] or [[transamidation]].<ref name=Skovbjerg>{{cite journal |vauthors=Skovbjerg H, Norén O, Anthonsen D, Moller J, Sjöström H |title=Gliadin is a good substrate of several transglutaminases: possible implication in the pathogenesis of coeliac disease |journal=Scand J Gastroenterol |volume=37 |issue=7 |pages=812–7 |year=2002 |pmid=12190095 |doi=10.1080/713786534}}</ref>

Deamidation is the reaction by which a glutamate residue is formed by cleavage of the epsilon-amino group of a glutamine side chain. Transamidation, which occurs three times more often than deamidation, is the cross-linking of a glutamine residue from the gliadin peptide to a lysine residue of tTg in a reaction that is catalysed by the transglutaminase. Crosslinking may occur either within or outside the active site of the enzyme. The latter case yields a permanently covalently linked complex between the gliadin and the tTg.<ref name=Fleckenstein>{{cite journal |vauthors=Fleckenstein B, Molberg Ø, Qiao SW, Schmid DG, von der Mülbe F, Elgstøen K, Jung G, Sollid LM |s2cid=7102008 |title=Gliadin T cell epitope selection by tissue transglutaminase in celiac disease. Role of enzyme specificity and pH influence on the transamidation versus deamidation process |journal=J Biol Chem |volume=277 |issue=37 |pages=34109–34116 |year=2002 |pmid=12093810 |doi=10.1074/jbc.M204521200 |doi-access=free}}</ref> This results in the formation of new epitopes believed to trigger the primary immune response by which the autoantibodies against tTg develop.<ref name="Dieterich-2003">{{cite journal |vauthors=Koning F, Schuppan D, Cerf-Bensussan N, Sollid LM |title=Pathomechanisms in celiac disease |journal=Best Practice & Research. Clinical Gastroenterology |volume=19 |issue=3 |pages=373–387 |date=June 2005 |pmid=15925843 |doi=10.1016/j.bpg.2005.02.003 |issn=1521-6918}}</ref><ref name=Mowat>{{cite journal |vauthors=Mowat AM |s2cid=10259661 |title=Coeliac disease – a meeting point for genetics, immunology, and protein chemistry |journal=Lancet |volume=361 |issue=9365 |pages=1290–1292 |year=2003 |pmid=12699968 |doi=10.1016/S0140-6736(03)12989-3}}</ref><ref name=Dewar>{{cite journal |vauthors=Dewar D, Pereira SP, Ciclitira PJ |title=The pathogenesis of coeliac disease |journal=Int J Biochem Cell Biol |volume=36 |issue=1 |pages=17–24 |year=2004 |pmid=14592529 |doi=10.1016/S1357-2725(03)00239-5}}</ref>

Stored biopsies from people with suspected coeliac disease have revealed that [[autoantibody]] deposits in the [[wikt:subclinical|subclinical]] coeliacs are detected prior to clinical disease. These deposits are also found in people who present with other autoimmune diseases, anaemia, or malabsorption phenomena at a much increased rate over the normal population.<ref name=Kaukinen>{{cite journal |vauthors=Kaukinen K, Peräaho M, Collin P, Partanen J, Woolley N, Kaartinen T, Nuutinen T, Halttunen T, Mäki M, Korponay-Szabo I |s2cid=27068601 |title=Small-bowel mucosal tranglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: A Prospective and radmonized clinical study |journal=Scand J Gastroenterol |volume=40 |issue=5 |pages=564–572 |year=2005 |pmid=16036509 |doi=10.1080/00365520510023422}}</ref> Endomysial components of antibodies (EMA) to tTG are believed to be directed toward cell-surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative people with coeliac tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms, including autoimmune disease.<ref name=EMAnegCD>{{cite journal |vauthors=Salmi TT, Collin P, Korponay-Szabó IR, Laurila K, Partanen J, Huhtala H, Király R, Lorand L, Reunala T, Mäki M, Kaukinen K |title=Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits |journal=Gut |volume=55 |issue=12 |pages=1746–53 |year=2006 |pmid=16571636 |pmc=1856451 |doi=10.1136/gut.2005.071514}}</ref> In this study, the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with work showing that gliadin has an innate response component,<ref name=InnateReview>{{cite journal |vauthors=Londei M, Ciacci C, Ricciardelli I, Vacca L, Quaratino S, Maiuri L |title=Gliadin as a stimulator of innate responses in celiac disease |journal=Mol Immunol |volume=42 |issue=8 |pages=913–918 |year=2005 |pmid=15829281 |doi=10.1016/j.molimm.2004.12.005}}</ref> suggest that gliadin may be more responsible for the primary manifestations of coeliac disease, whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of people with coeliac, the anti-tTG antibodies also recognise a [[rotavirus]] protein called VP7. These antibodies stimulate [[monocyte]] proliferation, and rotavirus infection might explain some early steps in the cascade of [[White blood cell|immune cell]] proliferation.<ref name="toll-like">{{cite journal |vauthors=Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S, Beri R, Dolcino M, Valletta E, Corrocher R, Puccetti A |title=In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes |journal=PLOS Med |volume=3 |issue=9 |pages=e358 |year=2006 |pmid=16984219 |pmc=1569884 |doi=10.1371/journal.pmed.0030358 |doi-access=free }}</ref>

Indeed, earlier studies of rotavirus damage in the gut showed this causes villous atrophy.<ref>{{cite journal |vauthors=Salim AF, Phillips AD, Farthing MJ |title=Pathogenesis of gut virus infection |journal=Baillière's Clinical Gastroenterology |volume=4 |issue=3 |pages=593–607 |year=1990 |pmid=1962725 |doi=10.1016/0950-3528(90)90051-H |pmc=7172617}}</ref> {{citation needed span|This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a second source of crossreactive antibodies.|date=December 2022}}

Other intestinal disorders may have [[biopsy]] that look like coeliac disease including lesions caused by Candida.<ref>{{cite journal |title=Celiac disease: A review |journal=BCMJ |date=September 2001 |volume=43 |issue=7 |pages=390–395 |url=http://www.bcmj.org/article/celiac-disease-review#Abstract |url-status=dead |archive-url=https://web.archive.org/web/20140222160458/http://www.bcmj.org/article/celiac-disease-review#Abstract |archive-date=22 February 2014 |access-date=15 February 2014 |df=dmy-all}}</ref>

===Villous atrophy and malabsorption===
{{citation needed span|The inflammatory process, mediated by [[T cell]]s, leads to disruption of the structure and function of the small bowel's mucosal lining and causes malabsorption as it impairs the body's ability to absorb [[nutrient]]s, minerals, and fat-soluble [[vitamin]]s A, D, E, and K from food. Lactose intolerance may be present due to the decreased bowel surface and reduced production of [[lactase]] but typically resolves once the condition is treated.|date=December 2022}}

Alternative causes of this tissue damage have been proposed and involve the release of [[interleukin 15]] and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of [[enterocyte]]s by lymphocytes in the [[epithelium]].<ref name=VanHeelWest/> The villous atrophy seen on biopsy may also be due to unrelated causes, such as [[tropical sprue]], [[giardiasis]] and [[radiation enteritis]]. While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to the diet may require these alternative diagnoses to be considered.<ref name=AGA/>

==Diagnosis==
[[Medical diagnosis|Diagnosis]] is often difficult and as of 2019, there continues to be a lack of awareness among physicians about the variability of presentations of coeliac disease and the diagnostic criteria, such that most cases are diagnosed with great delay.<ref name=CichewiczMearns2019 /><ref name=MatthiasPfeiffer2010>{{cite journal |vauthors=Matthias T, Pfeiffer S, Selmi C, Eric Gershwin M |s2cid=33661098 |title=Diagnostic challenges in celiac disease and the role of the tissue transglutaminase-neo-epitope |journal=Clin Rev Allergy Immunol |volume=38 |issue=2–3 |pages=298–301 |date=April 2010 |pmid=19629760 |doi=10.1007/s12016-009-8160-z |type=Review}}</ref> It can take up to 12 years to receive a diagnosis from the onset of symptoms and the majority of those affected in most countries never receive it.<ref name=CichewiczMearns2019 />

Several tests can be used. The level of [[symptom]]s may determine the order of the tests, but ''all'' tests lose their usefulness if the person is already eating a [[gluten-free diet]]. [[Small intestine|Intestinal]] damage begins to heal within weeks of gluten being removed from the diet, and [[antibody]] levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a [[gluten challenge test|rechallenge]] with some gluten-containing food in one meal a day over six weeks before repeating the investigations.<ref name="NICEcoeliac"/>

===Blood tests===
[[File:ENDOMYSIAL ANTIBODIES.jpg|thumb|[[Immunofluorescence]] staining pattern of endomysial antibodies on a monkey oesophagus tissue sample]]
[[Serology|Serological]] blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Its sensitivity correlates with the degree of histological lesions. People who present with minor damage to the small intestine may have seronegative findings so many patients with coeliac disease often are missed. In patients with villous atrophy, anti-[[endomysium|endomysial]] (EMA) antibodies of the [[immunoglobulin A]] (IgA) type can detect coeliac disease with a [[sensitivity and specificity]] of 90% and 99%, respectively.<ref name="pmid20442390">{{cite journal |vauthors=van der Windt DA, Jellema P, Mulder CJ, Kneepkens CM, van der Horst HE |title=Diagnostic testing for celiac disease among patients with abdominal symptoms: a systematic review |journal=[[JAMA (journal)|JAMA]] |volume=303 |issue=17 |pages=1738–46 |year=2010 |pmid=20442390 |doi=10.1001/jama.2010.549 |quote=Most studies used similar histological criteria for diagnosing celiac disease (Marsh grade ≥III), but the level of damage may vary across populations. Only 4 studies presented the proportion of patients in whom only partial villous atrophy was found (Marsh grade of IIIA), which ranged from 4% to 100%. The presence of positive serum antibodies has been shown to correlate with the degree of villous atrophy, and patients with celiac disease who have less severe histological damage may have seronegative findings. This could be important, especially in primary care, in which levels of mucosal damage may be lower, and consequently, more patients with celiac disease may be missed. |doi-access=free}}</ref> [[Serology]] for [[anti-transglutaminase antibodies]] (anti-tTG) was initially reported to have a higher [[sensitivity and specificity|sensitivity]] (99%) and [[sensitivity and specificity|specificity]] (>90%). However, it is now thought to have similar characteristics to anti-endomysial antibodies.<ref name="pmid20442390"/> Both anti-transglutaminase and anti-endomysial antibodies have high sensitivity to diagnose people with classic symptoms and complete villous atrophy, but they are only found in 30–89% of the cases with partial villous atrophy and in less than 50% of the people who have minor mucosal lesions ([[duodenal lymphocytosis]]) with normal villi.<ref name=LewisScott2006 /><ref name=AGA2006 />

[[Tissue transglutaminase]] (abbreviated as tTG or TG2) modifies gluten [[peptide]]s into a form that may stimulate the immune system more effectively.<ref name=VanHeelWest/> These peptides are modified by tTG in two ways, deamidation or transamidation.<ref name="Skovbjerg"/> Modern anti-tTG assays rely on a human [[recombinant DNA|recombinant protein]] as an [[antigen]].<ref>{{cite journal |vauthors=Sblattero D, Berti I, Trevisiol C, Marzari R, Tommasini A, Bradbury A, Fasano A, Ventura A, Not T |title=Human recombinant tissue transglutaminase ELISA: an innovative diagnostic assay for celiac disease |journal=[[The American Journal of Gastroenterology|Am. J. Gastroenterol.]] |volume=95 |issue=5 |pages=1253–57 |year=2000 |doi=10.1111/j.1572-0241.2000.02018.x |pmid=10811336 |s2cid=11018740}}</ref> tTG testing should be done first as it is an easier test to perform. An equivocal result on tTG testing should be followed by anti-endomysial antibodies.<ref name=NICEcoeliac/>

Guidelines recommend that a total serum IgA level is checked in parallel, as people with coeliac with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those people, IgG antibodies against transglutaminase (IgG-tTG) may be diagnostic.<ref name="NICEcoeliac"/><ref>{{cite journal |vauthors=Korponay-Szabó IR, Dahlbom I, Laurila K, Koskinen S, Woolley N, Partanen J, Kovács JB, Mäki M, Hansson T |title=Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency |journal=Gut |volume=52 |issue=11 |pages=1567–71 |year=2003 |pmid=14570724 |pmc=1773847 |doi=10.1136/gut.52.11.1567}}</ref>

If all these antibodies are negative, then anti-DGP antibodies (antibodies against deamidated gliadin peptides) should be determined. IgG class anti-DGP antibodies may be useful in people with IgA deficiency. In children younger than two years, anti-DGP antibodies perform better than anti-endomysial and anti-transglutaminase antibodies tests.<ref name=ESPGHAN2012 />

Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive [[blood test]] is still followed by an [[endoscopy]]/[[esophagogastroduodenoscopy|gastroscopy]] and [[biopsy]]. A negative serology test may still be followed by a recommendation for endoscopy and [[duodenum|duodenal]] biopsy if clinical suspicion remains high.<ref name="NICEcoeliac"/><ref name=AGA/><ref name="NASPGHAN">{{cite journal |vauthors=Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, Hoffenberg EJ, Horvath K, Murray JA, Pivor M, Seidman EG |s2cid=14805217 |title=Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition |journal=[[Journal of Pediatric Gastroenterology and Nutrition|J. Pediatr. Gastroenterol. Nutr.]] |volume=40 |issue=1 |pages=1–19 |year=2005 |pmid=15625418 |doi=10.1097/00005176-200501000-00001|doi-access=free }}</ref>

Historically three other antibodies were measured: anti-[[reticular fiber|reticulin]] (ARA), anti-[[gliadin]] ([[Anti-gliadin antibodies|AGA]]) and anti-endomysial (EMA) antibodies.<ref name="HillNIH"/> ARA testing, however, is not accurate enough for routine diagnostic use.<ref name="pmid23365209">{{cite journal |vauthors=Nandiwada SL, Tebo AE |title=Testing for antireticulin antibodies in patients with celiac disease is obsolete: a review of recommendations for serologic screening and the literature |journal=[[Clinical and Vaccine Immunology|Clin. Vaccine Immunol.]] |volume=20 |issue=4 |pages=447–51 |date=April 2013 |pmid=23365209 |pmc=3623418 |doi=10.1128/CVI.00568-12}}</ref> Serology may be unreliable in young children, with anti-[[gliadin]] performing somewhat better than other tests in children under five.<ref name="HillNIH">{{cite journal |vauthors=Hill ID |title=What are the sensitivity and specificity of serologic tests for celiac disease? Do sensitivity and specificity vary in different populations? |journal=[[Gastroenterology (journal)|Gastroenterology]] |volume=128 |issue=4 Suppl 1 |pages=S25–32 |date=April 2005 |pmid=15825123 |doi=10.1053/j.gastro.2005.02.012 |url=http://consensus.nih.gov/2004/2004CeliacDisease118Program.pdf |url-status=live |archive-url=https://web.archive.org/web/20070414230731/http://consensus.nih.gov/2004/2004CeliacDisease118Program.pdf |archive-date=14 April 2007}}</ref> Serology tests are based on [[immunofluorescence|indirect immunofluorescence]] (reticulin, gliadin and endomysium) or [[ELISA]] (gliadin or tissue [[transglutaminase]], tTG).<ref>{{cite journal |vauthors=Wong RC, Steele RH, Reeves GE, Wilson RJ, Pink A, Adelstein S |title=Antibody and genetic testing in coeliac disease |journal=Pathology |volume=35 |issue=4 |pages=285–304 |year=2003 |pmid=12959764 |doi=10.1080/00313020307527}}</ref>

Other antibodies such as [[Anti–Saccharomyces cerevisiae antibody|anti–Saccharomyces cerevisiae antibodies]] occur in some people with coeliac disease but also occur in other autoimmune disorders and about 5% of those who donate blood.<ref>{{cite journal |vauthors=Fagoonee S, De Luca L, De Angelis C, Castelli A, Rizzetto M, Pellicano R |title=Anti-Saccharomyces cerevisiae as unusual antibodies in autoimmune hepatitis |journal=Minerva Gastroenterologica e Dietologica |volume=55 |issue=1 |pages=37–40 |date=March 2009 |pmid=19212306}}</ref>

Antibody testing may be combined with [[Human leukocyte antigen|HLA]] testing if the diagnosis is unclear. TGA and EMA testing are the most sensitive serum antibody tests, but as a negative HLA-DQ type excludes the diagnosis of coeliac disease, testing also for HLA-DQ2 or DQ8 maximises sensitivity and negative predictive values.<ref name="pmid17785484"/> In the United Kingdom, the [[National Institute for Health and Clinical Excellence]] (NICE) does not (as of 2015) recommend the use of HLA typing to rule out coeliac disease outside of a specialist setting, for example, in children who are not having a biopsy, or in patients who already have limited gluten ingestion and opt not to have a gluten challenge.<ref name="NICEcoeliac"/>

===Endoscopy===
[[File:Celiac endo.JPG|thumb|[[Endoscopy|Endoscopic]] still of [[duodenum]] of a person with coeliac disease showing scalloping of folds and "cracked-mud" appearance to mucosa]]
[[File:Coeliac Disease.png|thumb|upright=2.4|Schematic of the Marsh classification of upper [[jejunum|jejunal]] pathology in coeliac disease{{image reference needed|date=December 2022}}]]
An [[esophagogastroduodenoscopy|upper endoscopy]] with [[biopsy]] of the [[duodenum]] (beyond the [[duodenal bulb]]) or [[jejunum]] is performed to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative.<ref name="AGA"/> Even in the same bioptic fragment, different degrees of
damage may be present.<ref name=TonuttiBizzaro2014 />

Most people with coeliac disease have a [[small intestine]] that appears to be normal on endoscopy before the biopsies are examined. However, five findings have been associated with high specificity for coeliac disease: scalloping of the small bowel folds (''pictured''), paucity in the folds, a [[mosaic]] pattern to the [[mucous membrane|mucosa]] (described as a "cracked-mud" appearance), prominence of the [[submucosa]] [[blood vessel]]s, and a nodular pattern to the mucosa.<ref>{{cite journal |vauthors=Niveloni S, Fiorini A, Dezi R, Pedreira S, Smecuol E, Vazquez H, Cabanne A, Boerr LA, Valero J, Kogan Z, Mauriño E, Bai JC |title=Usefulness of videoduodenoscopy and vital dye staining as indicators of mucosal atrophy of celiac disease: assessment of interobserver agreement |journal=Gastrointestinal Endoscopy |volume=47 |issue=3 |pages=223–29 |year=1998 |pmid=9580349 |doi=10.1016/S0016-5107(98)70317-7}}</ref>

European guidelines suggest that in children and adolescents with symptoms compatible with coeliac disease, the diagnosis can be made without the need for intestinal biopsy if [[Coeliac disease#Blood tests|anti-tTG antibodies]] titres are very high (10 times the upper limit of normal).<ref name=ESPGHAN2012 />

Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After [[x-ray]] verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. Often-utilised capsule systems were the [[Watson capsule]] and the [[Crosby–Kugler capsule]]. This method has now been largely replaced by [[optical fiber|fibre-optic]] endoscopy, which carries a higher sensitivity and a lower frequency of errors.<ref>{{cite journal |vauthors=Mee AS, Burke M, Vallon AG, Newman J, Cotton PB |title=Small bowel biopsy for malabsorption: comparison of the diagnostic adequacy of endoscopic forceps and capsule biopsy specimens |journal=[[BMJ|The BMJ]] |volume=291 |issue=6498 |pages=769–72 |year=1985 |pmid=3929934 |pmc=1417146 |doi=10.1136/bmj.291.6498.769}}</ref>

[[Capsule endoscopy]] (CE) allows identification of typical mucosal changes observed in coeliac disease but has a lower sensitivity compared to regular endoscopy and histology. CE is therefore not the primary diagnostic tool for coeliac disease. However, CE can be used for diagnosing T-cell lymphoma, ulcerative jejunoileitis, and adenocarcinoma in refractory or complicated coeliac disease.<ref>{{cite journal |vauthors=Redondo-Cerezo E, Sánchez-Capilla AD, De La Torre-Rubio P, De Teresa J |title=Wireless capsule endoscopy: Perspectives beyond gastrointestinal bleeding |journal=[[World Journal of Gastroenterology|World J. Gastroenterol.]] |volume=20 |issue=42 |pages=15664–73 |date=November 2014 |pmid=25400450 |pmc=4229531 |doi=10.3748/wjg.v20.i42.15664 |doi-access=free }}</ref>

===Pathology===
The classic pathology changes of coeliac disease in the small bowel are categorised by the "[[Michael Newton Marsh|Marsh]] classification":<ref>{{cite journal |vauthors=Marsh MN |title=Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue') |journal=Gastroenterology |volume=102 |issue=1 |pages=330–54 |year=1992 |pmid=1727768 |doi=10.1016/0016-5085(92)91819-p|doi-access=free }}</ref>
*Marsh stage 0: normal mucosa
*Marsh stage 1: increased number of intra-epithelial [[lymphocyte]]s (IELs), usually exceeding 20 per 100 [[enterocyte]]s
*Marsh stage 2: a proliferation of the [[intestinal gland|crypts of Lieberkühn]]
*Marsh stage 3: partial or complete [[intestinal villus|villous]] [[atrophy]] and crypt hyperplasia<ref>{{cite journal | vauthors = Villanacci V, Vanoli A, Leoncini G, Arpa G, Salviato T, Bonetti LR, Baronchelli C, Saragoni L, Parente P | title = Celiac disease: histology-differential diagnosis-complications. A practical approach | journal = Pathologica | volume = 112 | issue = 3 | pages = 186–196 | date = September 2020 | pmid = 33179621 | pmc = 7931573 | doi = 10.32074/1591-951X-157 }}</ref>
*Marsh stage 4: [[hypoplasia]] of the [[small intestine]] architecture

Marsh's classification, introduced in 1992, was subsequently modified in 1999 to six stages, where the previous stage 3 was split in three substages.<ref>{{cite journal |vauthors=Oberhuber G, Granditsch G, Vogelsang H |title=The histopathology of coeliac disease: time for a standardized report scheme for pathologists |journal=[[European Journal of Gastroenterology & Hepatology|Eur. J. Gastroenterol. Hepatol.]] |volume=11 |issue=10 |pages=1185–94 |date=October 1999 |pmid=10524652 |doi=10.1097/00042737-199910000-00019}}</ref> Further studies demonstrated that this system was not always reliable and that the changes observed in coeliac disease could be described in one of three stages:<ref name=Lancet2009/><ref>{{cite journal |vauthors=Corazza GR, Villanacci V, Zambelli C, Milione M, Luinetti O, Vindigni C, Chioda C, Albarello L, Bartolini D, Donato F |title=Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease |journal=[[Clinical Gastroenterology and Hepatology|Clin. Gastroenterol. Hepatol.]] |volume=5 |issue=7 |pages=838–43 |year=2007 |pmid=17544877 |doi=10.1016/j.cgh.2007.03.019}}</ref>
*A representing lymphocytic infiltration with normal villous appearance;
*B1 describing partial villous atrophy; and
*B2 describing complete villous atrophy.

The changes classically improve or reverse after [[gluten]] is removed from the diet. However, most guidelines do not recommend a repeat biopsy unless there is no improvement in the symptoms on diet.<ref name="AGA"/><ref name="NASPGHAN"/> In some cases, a deliberate gluten challenge, followed by a biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicates the diagnosis may have been incorrect.<ref name="AGA"/>

In untreated coeliac disease, villous atrophy is more common in children younger than three years, but in older children and adults, it is common to find minor intestinal lesions ([[duodenal lymphocytosis]]) with normal [[intestinal villi]].<ref name=VivasVaquero2015 /><ref name=MolinaInfanteSantolaria2015 />

===Other diagnostic tests===
At the time of diagnosis, further investigations may be performed to identify complications, such as [[iron deficiency]] (by [[complete blood count|full blood count]] and iron studies), [[Folate deficiency|folic acid]] and [[Vitamin B12 deficiency|vitamin B<sub>12</sub> deficiency]] and [[hypocalcaemia]] (low calcium levels, often due to decreased [[vitamin D]] levels). [[Thyroid function tests]] may be requested during blood tests to identify [[hypothyroidism]], which is more common in people with coeliac disease.<ref name="AFP"/>

[[Osteopenia]] and [[osteoporosis]], mildly and severely reduced bone mineral density, are often present in people with coeliac disease, and investigations to measure bone density may be performed at diagnosis, such as [[dual-energy X-ray absorptiometry]] (DXA) scanning, to identify the risk of fracture and need for bone protection medication.<ref name="AGA"/><ref name="AFP"/>

===Gluten withdrawal===
Although blood antibody tests, biopsies, and genetic tests usually provide a clear diagnosis,<ref name=AGA2006 /><ref name="pmid20442390" /> occasionally the response to gluten withdrawal on a [[gluten-free diet]] is needed to support the diagnosis. Currently, [[Gluten challenge test|gluten challenge]] is no longer required to confirm the diagnosis in patients with intestinal lesions compatible with coeliac disease and a positive response to a gluten-free diet.<ref name=AGA2006 /> Nevertheless, in some cases, a gluten challenge with a subsequent biopsy may be useful to support the diagnosis, for example in people with a high suspicion for coeliac disease, without a biopsy confirmation, who have negative blood antibodies and are already on a gluten-free diet.<ref name=AGA2006 /> Gluten challenge is discouraged before the age of 5 years and during [[puberty|pubertal]] growth.<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> The alternative diagnosis of [[non-celiac gluten sensitivity|non-coeliac gluten sensitivity]] may be made where there is only symptomatic evidence of gluten sensitivity.<ref name=GenuisLobo2014>{{cite journal |vauthors=Genuis SJ, Lobo RA |title=Gluten sensitivity presenting as a neuropsychiatric disorder |journal=Gastroenterol Res Pract |volume=2014 |page=293206 |date=2014 |pmid=24693281 |pmc=3944951 |doi=10.1155/2014/293206 |type=Review |doi-access=free}}</ref> Gastrointestinal and extraintestinal symptoms of people with non-coeliac gluten sensitivity can be similar to those of coeliac disease,<ref name=TonuttiBizzaro2014 /> and improve when gluten is removed from the diet,<ref name="pmid22345659">{{cite journal |vauthors=Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C |title=The Oslo definitions for coeliac disease and related terms |journal=Gut |volume=62 |issue=1 |pages=43–52 |date=January 2013 |pmid=22345659 |pmc=3440559 |doi=10.1136/gutjnl-2011-301346}}</ref><ref name=ElliRoncorni>{{cite journal |vauthors=Elli L, Roncoroni L, Bardella MT |title=Non-celiac gluten sensitivity: Time for sifting the grain |journal=World J Gastroenterol |volume=21 |issue=27 |pages=8221–6 |date=July 2015 |pmid=26217073 |pmc=4507091 |doi=10.3748/wjg.v21.i27.8221 |type=Review |doi-access=free }}</ref> after coeliac disease and [[wheat allergy]] are reasonably excluded.<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>

Up to 30% of people often continue having or redeveloping symptoms after starting a gluten-free diet.<ref name=SeeKaukinen2015 /> A careful interpretation of the symptomatic response is needed, as a lack of response in a person with coeliac disease may be due to continued ingestion of small amounts of gluten, either voluntary or inadvertent,<ref name=VivasVaquero2015 /> or be due to other commonly associated conditions such as [[small intestinal bacterial overgrowth]] (SIBO), [[lactose intolerance]], [[fructose malabsorption|fructose]],<ref name=CastilloTheethira2015>{{cite journal |vauthors=Castillo NE, Theethira TG, Leffler DA |title=The present and the future in the diagnosis and management of celiac disease |journal=Gastroenterology Report |volume=3 |issue=1 |pages=3–11 |date=February 2015 |pmid=25326000 |pmc=4324867 |doi=10.1093/gastro/gou065 |type=Review}}</ref> [[sucrase#Physiology|sucrose]],<ref name=LevyBernstein2014>{{cite journal |vauthors=Levy J, Bernstein L, Silber N |title=Celiac disease: an immune dysregulation syndrome |journal=Current Problems in Pediatric and Adolescent Health Care |volume=44 |issue=11 |pages=324–7 |date=December 2014 |pmid=25499458 |doi=10.1016/j.cppeds.2014.10.002 |type=Review |quote=Initially, reduced levels of lactase and sucrase activities might necessitate further dietary restrictions until the villi have healed and those sugars are better tolerated.}}</ref> and [[sorbitol#Adverse medical effects|sorbitol]]<ref name=MontaltoGallo2013>{{cite journal |vauthors=Montalto M, Gallo A, Ojetti V, Gasbarrini A |title=Fructose, trehalose and sorbitol malabsorption |journal=European Review for Medical and Pharmacological Sciences |volume=17 |issue=Suppl 2 |pages=26–9 |date=2013 |pmid=24443064 |url=http://www.europeanreview.org/wp/wp-content/uploads/026-0291.pdf |type=Review |archive-url=https://web.archive.org/web/20160412035313/http://www.europeanreview.org/wp/wp-content/uploads/026-0291.pdf |df=dmy-all |url-status=live |archive-date=12 April 2016}}</ref> malabsorption, [[exocrine pancreatic insufficiency]],<ref name=LefflerGreen2015>{{cite journal |vauthors=Leffler DA, Green PH, Fasano A |s2cid=15561525 |title=Extraintestinal manifestations of coeliac disease |journal=Nature Reviews. Gastroenterology & Hepatology |volume=12 |issue=10 |pages=561–71 |date=October 2015 |pmid=26260366 |doi=10.1038/nrgastro.2015.131 |type=Review}}</ref><ref name=Wood2016>{{cite journal |vauthors=Woodward J |title=Improving outcomes of refractory celiac disease - current and emerging treatment strategies |journal=Clinical and Experimental Gastroenterology |volume=9 |pages=225–36 |date=3 August 2016 |pmid=27536154 |pmc=4976763 |doi=10.2147/ceg.s87200 |type=Review |doi-access=free }}</ref> and [[microscopic colitis]],<ref name=Wood2016 /> among others. In untreated coeliac disease, these are often transient conditions derived from the intestinal damage.<ref name=LevyBernstein2014 /><ref name=MontaltoGallo2013 /><ref name=BerniCananiPezzella2016>{{cite journal |vauthors=Berni Canani R, Pezzella V, Amoroso A, Cozzolino T, Di Scala C, Passariello A |title=Diagnosing and Treating Intolerance to Carbohydrates in Children |journal=Nutrients |volume=8 |issue=3 |pages=157 |date=March 2016 |pmid=26978392 |pmc=4808885 |doi=10.3390/nu8030157 |doi-access=free}}</ref><ref name=GarciaManzanaresLucendo2011>{{cite journal |vauthors=García-Manzanares A, Lucendo AJ |title=Nutritional and dietary aspects of celiac disease |journal=Nutrition in Clinical Practice |volume=26 |issue=2 |pages=163–73 |date=April 2011 |pmid=21447770 |doi=10.1177/0884533611399773 |type=Review}}</ref><ref name=GreenJabri2003>{{cite journal |vauthors=Green PH, Jabri B |s2cid=39188931 |title=Coeliac disease |journal=Lancet |volume=362 |issue=9381 |pages=383–91 |date=August 2003 |pmid=12907013 |doi=10.1016/S0140-6736(03)14027-5 |type=Review}}</ref> They normally revert or improve several months after starting a gluten-free diet, but may need temporary interventions such as supplementation with [[digestive enzyme|pancreatic enzymes]],<ref name=GarciaManzanaresLucendo2011 /><ref name=GreenJabri2003 /> dietary restrictions of lactose, fructose, sucrose or sorbitol containing foods,<ref name=LevyBernstein2014 /><ref name=BerniCananiPezzella2016 /> or treatment with oral antibiotics in the case of associated bacterial overgrowth.<ref name=GreenJabri2003 /> In addition to gluten withdrawal, some people need to follow a low-[[FODMAP]]s diet or avoid consumption of commercial gluten-free products, which are usually rich in [[preservative]]s and [[food additive|additives]] (such as [[sulfite]]s, [[glutamic acid|glutamates]], [[nitrate]]s and [[benzoic acid|benzoates]]) and might have a role in triggering functional gastrointestinal symptoms.<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>

==Screening==
There is debate as to the benefits of screening. As of 2017, the [[United States Preventive Services Task Force]] found insufficient evidence to make a recommendation among those without symptoms.<ref name=USPSTF2017/> In the United Kingdom, the [[National Institute for Health and Clinical Excellence]] (NICE) recommend testing for coeliac disease in first-degree relatives of those with the disease already confirmed, in people with persistent fatigue, abdominal or gastrointestinal symptoms, faltering growth, unexplained weight loss or iron, vitamin B<sub>12</sub> or folate deficiency, severe mouth ulcers, and with diagnoses of type 1 diabetes, [[Autoimmune thyroiditis|autoimmune thyroid disease]],<ref name=NICEcoeliac/> and with newly diagnosed [[chronic fatigue syndrome]]<ref>{{NICE|53|Chronic fatigue syndrome/myalgic encephalomyelitis|2007}}</ref> and [[irritable bowel syndrome]].<ref name=NICEIBS/> [[Dermatitis herpetiformis]] is included in other recommendations.<ref>{{cite journal |vauthors=Murch S, Jenkins H, Auth M, Bremner R, Butt A, France S, Furman M, Gillett P, Kiparissi F, Lawson M, McLain B, Morris MA, Sleet S, Thorpe M |s2cid=30417933 |title=Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children |journal=Archives of Disease in Childhood |volume=98 |issue=10 |pages=806–11 |date=October 2013 |pmid=23986560 |doi=10.1136/archdischild-2013-303996 |doi-access=free}}</ref> The NICE also recommend offering serological testing for coeliac disease in people with [[metabolic bone disease]] (reduced bone mineral density or [[osteomalacia]]), unexplained neurological disorders (such as [[peripheral neuropathy]] and [[ataxia]]), fertility problems or recurrent [[miscarriage]], persistently raised liver enzymes with unknown cause, dental enamel defects and with diagnose of [[Down syndrome]] or [[Turner syndrome]].<ref name=NICEcoeliac/>

Some evidence has found that early detection may decrease the risk of developing health complications, such as osteoporosis, anaemia, and certain types of cancer, neurological disorders, [[cardiovascular disease]]s, and reproductive problems.<ref name="LionettiFrancavilla2010">{{cite journal |vauthors=Lionetti E, Francavilla R, Pavone P, Pavone L, Francavilla T, Pulvirenti A, Giugno R, Ruggieri M |title=The neurology of coeliac disease in childhood: what is the evidence? A systematic review and meta-analysis |journal=Developmental Medicine and Child Neurology |volume=52 |issue=8 |pages=700–7 |date=August 2010 |pmid=20345955 |doi=10.1111/j.1469-8749.2010.03647.x |doi-access=free}}</ref><ref name=VanHeelWest/><ref name="TersigniCastellani2014" /><ref name="HanChen2015">{{cite journal |vauthors=Han Y, Chen W, Li P, Ye J |title=Association Between Coeliac Disease and Risk of Any Malignancy and Gastrointestinal Malignancy: A Meta-Analysis. |journal=Medicine (Baltimore) |year=2015 |volume=94 |issue=38 |pages=e1612 |pmid=26402826 |doi=10.1097/MD.0000000000001612 |pmc=4635766 |type=Meta-Analysis}}</ref><ref name="CiaccioLewis2017">{{cite journal |vauthors=Ciaccio EJ, Lewis SK, Biviano AB, Iyer V, Garan H, Green PH |title=Cardiovascular involvement in celiac disease. |journal=World J Cardiol |year=2017 |volume=9 |issue=8 |pages=652–666 |pmid=28932354 |doi=10.4330/wjc.v9.i8.652 |pmc=5583538 |type=Review |doi-access=free }}</ref> They thus recommend screening in people with certain health problems.<ref name="CiaccioLewis2017"/>

[[Serology]] has been proposed as a [[Screening (medicine)|screening]] measure, because the presence of antibodies would detect some previously undiagnosed cases of coeliac disease and prevent its complications in those people. However, serologic tests have high sensitivity only in people with total villous atrophy and have a very low ability to detect cases with partial villous atrophy or minor intestinal lesions.<ref name=AGA2006>{{cite journal |vauthors=Rostom A, Murray JA, Kagnoff MF |title=American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease |journal=Gastroenterology |volume=131 |issue=6 |pages=1981–2002 |date=December 2006 |pmid=17087937 |url=http://www.gastrojournal.org/article/S0016-5085%2806%2902227-X/fulltext |doi=10.1053/j.gastro.2006.10.004 |type=Review|doi-access=free }}</ref><!-- Multiple studies have shown that the sensitivity of EMA, tTGA, or AGA is related to the grade of histologic damage in celiac disease.15, 16 This has been observed both at the initial diagnosis and in the setting of monitoring for adherence to a GFD with serologic testing. The identified studies outlined earlier in this report were consistent in demonstrating a high sensitivity of the serologic tests in patients with total villous atrophy, with a subsequent decrease in sensitivity as less severe histologic grades of coeliac disease were considered.12 The sensitivity of IgA EMA or tTG in patients with partial villous atrophy ranged from 89% to as low as 30%, while the sensitivity in patients with Marsh grade II lesions was less than 50%.12 --> Testing for coeliac disease may be offered to those with commonly associated conditions.<ref name=Lancet2009/><ref name=NICEcoeliac/>

==Treatment==

===Diet===
{{Main|Gluten-free diet}}
At present, the only effective treatment is a lifelong [[gluten-free diet]].<ref name=Kupper/> No medication exists that prevents damage or prevents the body from attacking the gut when gluten is present. Strict adherence to the diet helps the intestines heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer and in some cases sterility.<ref>{{cite journal |vauthors=Treem WR |s2cid=20221260 |title=Emerging concepts in celiac disease |journal=Curr Opin Pediatr |volume=16 |issue=5 |pages=552–9 |year=2004 |pmid=15367850 |doi=10.1097/01.mop.0000142347.74135.73}}</ref> Compliance to a strict gluten-free diet is difficult for the patient, but evidence has accumulated that a strict gluten-free diet can result in resolution of diarrhea, weight gain and normalization of nutrient malabsorption, with normalization of biopsies in 6 months to 2 years on a gluten-free diet.<ref>{{cite journal |vauthors=Freeman HJ |s2cid= 4387710|title=Dietary compliance in celiac disease |journal=World J Gastroenterol |volume=23 |issue=15 |pages=2635–2639 |year=2017 |pmid=15367850 |doi=10.3748/wjg.v23.i15.2635|doi-access= free}}</ref>

[[Dietitian]] input is generally requested to ensure the person is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries, gluten-free products are available on [[Medical prescription|prescription]] and may be reimbursed by [[health insurance]] plans. Gluten-free products are usually more expensive and harder to find than common gluten-containing foods.<ref name="economicburden">{{cite journal |year=2007 |title=Economic burden of a gluten-free diet |url=https://celiacdiseasecenter.columbia.edu/sites/default/files/2007-Economic-Burden-of-a-Gluten-Free-Diet.pdf |journal=J Hum Nutr Diet |volume=20 |issue=5 |pages=423–30 |doi=10.1111/j.1365-277X.2007.00763.x |pmid=17845376 |vauthors=Lee AR, Ng DL, Zivin J, Green PH |citeseerx=10.1.1.662.8399 |access-date=9 February 2018 |archive-url=https://web.archive.org/web/20150624043919/http://www.celiacdiseasecenter.columbia.edu/sites/default/files/2007-Economic-Burden-of-a-Gluten-Free-Diet.pdf |archive-date=24 June 2015 |url-status=dead |df=dmy-all}}</ref> Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.<ref name=Troncone2008>{{cite journal |vauthors=Troncone R, Ivarsson A, Szajewska H, Mearin ML |title=Review article: future research on coeliac disease – a position report from the European multistakeholder platform on coeliac disease (CDEUSSA) |journal=Aliment. Pharmacol. Ther. |volume=27 |issue=11 |pages=1030–43 |year=2008 |pmid=18315588 |doi=10.1111/j.1365-2036.2008.03668.x |s2cid=30241867}}</ref>

The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence.<ref name=Akobeng2008>{{cite journal |vauthors=Akobeng AK, Thomas AG |title=Systematic review: tolerable amount of gluten for people with coeliac disease |journal=Aliment. Pharmacol. Ther. |volume=27 |issue=11 |pages=1044–52 |date=June 2008 |pmid=18315587 |doi=10.1111/j.1365-2036.2008.03669.x |s2cid=20539463 |doi-access=free}}</ref> The exact level at which gluten is harmless is uncertain and controversial. A recent [[systematic review]] tentatively concluded that consumption of less than 10&nbsp;mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done.<ref name=Akobeng2008/> Regulation of the label "gluten-free" varies. In the European Union, the [[European Commission]] issued regulations in 2009 limiting the use of "gluten-free" labels for food products to those with less than 20&nbsp;mg/kg of gluten, and "very low gluten" labels for those with less than 100&nbsp;mg/kg.<ref>{{cite web |title=Gluten-free food |publisher=[[Directorate-General for Health and Consumers]] |access-date=25 July 2015 |url=http://ec.europa.eu/food/safety/labelling_nutrition/special_groups_food/gluten/index_en.htm |url-status=live |archive-url=https://web.archive.org/web/20150723135842/http://ec.europa.eu/food/safety/labelling_nutrition/special_groups_food/gluten/index_en.htm |archive-date=23 July 2015}}</ref> In the United States, the [[Food and Drug Administration|FDA]] issued regulations in 2013 limiting the use of "gluten-free" labels for food products to those with less than 20&nbsp;[[parts per million|ppm]] of gluten.<ref name="fda2013-08">{{cite web |url=https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm363069.htm |title=What is Gluten-Free? FDA Has an Answer |date=2 August 2013 |publisher=[[Food and Drug Administration]] |access-date=2 August 2013 |quote=As one of the criteria for using the claim 'gluten-free,' FDA is setting a gluten limit of less than 20 ppm (parts per million) in foods that carry this label. This is the lowest level that can be consistently detected in foods using valid scientific analytical tools. Also, most people with celiac disease can tolerate foods with very small amounts of gluten. This level is consistent with those set by other countries and international bodies that set food safety standards. |url-status=live |archive-url=https://web.archive.org/web/20130804202647/https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm363069.htm |archive-date=4 August 2013 |df=dmy-all}}</ref><ref>Section 206 of the Food Allergen Labeling and Consumer Protection Act of 2004, Title II of {{USStatute |108|282|118|891 |2004|08|02}}</ref><ref>{{USFR|78|47154}} (5 August 2013). Codified at {{USCFR|21|101|91}}.</ref> The current international [[Codex Alimentarius]] standard allows for 20&nbsp;ppm of gluten in so-called "gluten-free" foods.<ref name=CodexOfficial>{{cite web |publisher=FAO/WHO |title=Current Official Standards |url=http://www.codexalimentarius.net/web/standard_list.jsp |archive-url=https://web.archive.org/web/20110604194807/http://www.codexalimentarius.net/web/standard_list.jsp |archive-date=4 June 2011}}</ref>

Gluten-free diet improves [[Quality of life (healthcare)|healthcare-related quality of life]], and strict adherence to the diet gives more benefit than incomplete adherence. Nevertheless, gluten-free diet does not completely normalise the quality of life.<ref>{{cite journal |vauthors=Burger JP, de Brouwer B, IntHout J, Wahab PJ, Tummers M, Drenth JP |title=Systematic review with meta-analysis: Dietary adherence influences normalization of health-related quality of life in coeliac disease |journal=Clinical Nutrition |volume=36 |issue=2 |pages=399–406 |date=April 2017 |pmid=27179800 |doi=10.1016/j.clnu.2016.04.021}}</ref>

===Vaccination===

Even though it is unclear if coeliac patients have a generally increased risk of infectious diseases, they should generally be encouraged to receive all common vaccines against [[Vaccine-preventable diseases|vaccine preventable diseases]] (VPDs) as the general population. Moreover, some pathogens could be harmful to coeliac patients. According to the European Society for the Study of Celiac Disease (ESsCD), coeliac disease can be associated with hyposplenism or functional asplenia, which could result in impaired immunity to encapsulated bacteria, with an increased risk of such infections. For this reason, patients who are known to be hyposplenic should be administered at least the pneumococcal vaccine.<ref name="Al-Toma, A. 2019">Al-Toma, A.; Volta, U.; Auricchio, R.; Castillejo, G.; Sanders, D.S.; Cellier, C.; Mulder, C.J.; Lundin, K.E.A. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur. Gastroenterol. J. 2019, 7, 583–613</ref> However, the ESsCD states that it is not clear whether vaccination with the conjugated vaccine is preferable in this setting and whether additional vaccination against [[Haemophilus influenzae|Haemophilus]], [[Neisseria meningitidis|meningococcus]], and [[influenza]] should be considered if not previously given.<ref name="Al-Toma, A. 2019"/> However, Mårild et al. suggested considering additional vaccination against influenza because of an observed increased risk of hospital admission for this infection in celiac patients.<ref>Mårild, K.; Fredlund, H.; Ludvigsson, J.F. Increased risk of hospital admission for influenza in patients with celiac disease: A nationwide cohort study in Sweden. Am. J. Gastroenterol. 2010, 105, 2465–2473.</ref>

===Refractory disease===
Between 0.3% and 10% of affected people have refractory disease, which means that they have persistent villous atrophy on a gluten-free diet despite the lack of gluten exposure for more than 12 months.<ref name=Wood2016 /> Nevertheless, inadvertent exposure to gluten is the main cause of persistent villous atrophy, and must be ruled out before a diagnosis of refractory disease is made.<ref name=Wood2016/> People with poor basic education and understanding of gluten-free diet often believe that they are strictly following the diet, but are making regular errors.<ref name="SeeKaukinen2015"/><ref name=Wood2016 /><ref name=MulderWanrooij>{{cite journal |vauthors=Mulder CJ, van Wanrooij RL, Bakker SF, Wierdsma N, Bouma G |s2cid=14124370 |title=Gluten-free diet in gluten-related disorders |journal=Dig. Dis. |volume=31 |issue=1 |pages=57–62 |date=2013 |pmid=23797124 |doi=10.1159/000347180 |type=Review}}</ref> Also, a lack of symptoms is not a reliable indicator of intestinal recuperation.<ref name=Wood2016 />

If alternative causes of villous atrophy have been eliminated, [[glucocorticoid|steroids]] or [[Immunosuppressive drug|immunosuppressants]] (such as [[azathioprine]]) may be considered in this scenario.<ref name=AGA/>

Refractory coeliac disease should not be confused with the persistence of symptoms despite gluten withdrawal<ref name=Wood2016 /> caused by transient conditions derived from the intestinal damage,<ref name=LevyBernstein2014 /><ref name=MontaltoGallo2013 /><ref name=BerniCananiPezzella2016 /> which generally revert or improve several months after starting a gluten-free diet,<ref name=GarciaManzanaresLucendo2011 /><ref name=GreenJabri2003 /> such as [[small intestinal bacterial overgrowth]], [[lactose intolerance]], [[fructose malabsorption|fructose]],<ref name=CastilloTheethira2015 /> [[sucrase#Physiology|sucrose]],<ref name=LevyBernstein2014 /> and [[sorbitol#Adverse medical effects|sorbitol]]<ref name=MontaltoGallo2013 /> malabsorption, [[exocrine pancreatic insufficiency]],<ref name=LefflerGreen2015 /><ref name=Wood2016 /> and microscopic colitis<ref name=Wood2016 /> among others.

Refractory celiac disease can be divided in type I and II. A recent studied compared patients with type I and II. Refractory celiac disease type I more frequently exhibits diarrhea, anemia, hypoalbuminemia, parenteral nutrition need, ulcerative jejuno-ileitis, and extended small intestinal atrophy. Among patients with refractory celiac disease type II is more common to develope lymphoma. Among these patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality.
<ref>Elli L, Soru P, Roncoroni L, Rossi FG, Ferla V, Baldini L, Nandi N, Scaramella L, Scricciolo A, Rimondi A, Fusco N, Croci GA, Gianelli U, Cro L, Barbieri M, Lombardo V, Costantino A, Vaira V, Ferrero S, Tontini GE, Barigelletti G, Fabiano S, Doneda L, Vecchi M. Clinical features of type 1 and 2 refractory celiac disease: Results from a large cohort over a decade. Dig Liver Dis. 2023 Feb;55(2):235-242. doi: 10.1016/j.dld.2022.08.022. Epub 2022 Sep 10. PMID: 36096991.</ref>

==Epidemiology==
Globally coeliac disease affects between 1 in 100 and 1 in 170 people.<ref name="NEJM2012"/><ref name=BMJ2015>{{cite journal |vauthors=Lebwohl B, Ludvigsson JF, Green PH |title=Celiac disease and non-celiac gluten sensitivity |journal=BMJ |volume=351 |pages=h4347 |date=October 2015 |pmid=26438584 |pmc=4596973 |doi=10.1136/bmj.h4347}}</ref> Rates, however, vary between different regions of the world from as few as 1 in 300 to as many as 1 in 40.<ref name=NEJM2012/> In the United States it is thought to affect between 1 in 1750 (defined as clinical disease including dermatitis herpetiformis with limited digestive tract symptoms) to 1 in 105 (defined by presence of IgA TG in blood donors).<ref name="nih_epi">{{cite journal |vauthors=Rewers M |title=Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? |journal=Gastroenterology |volume=128 |issue=4 Suppl 1 |pages=S47–51 |date=April 2005 |pmid=15825126 |doi=10.1053/j.gastro.2005.02.030 |url=http://consensus.nih.gov/2004/2004CeliacDisease118Program.pdf#page=40 |archive-url=https://web.archive.org/web/20070414230731/http://consensus.nih.gov/2004/2004CeliacDisease118Program.pdf#page=40 |df=dmy-all |url-status=live |archive-date=14 April 2007}}</ref> Due to variable signs and symptoms it is believed that about 85% of people affected are undiagnosed.<ref>{{cite journal |vauthors=Guandalini S, Assiri A |title=Celiac disease: a review |journal=JAMA Pediatrics |volume=168 |issue=3 |pages=272–8 |date=March 2014 |pmid=24395055 |doi=10.1001/jamapediatrics.2013.3858}}</ref> The percentage of people with clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the percentage of people with the disease may be between 0.33 and 1.06% in children (but 5.66% in one study of children of the predisposed [[Sahrawi people]]<ref name="Catassi1999">{{cite journal |vauthors=Catassi C, Rätsch IM, Gandolfi L, Pratesi R, Fabiani E, El Asmar R, Frijia M, Bearzi I, Vizzoni L |s2cid=9242679 |title=Why is coeliac disease endemic in the people of the Sahara? |journal=Lancet |volume=354 |issue=9179 |pages=647–8 |date=August 1999 |pmid=10466670 |doi=10.1016/S0140-6736(99)02609-4}}</ref>) and 0.18–1.2% in adults.<ref name=VanHeelWest/> Among those in primary care populations who report gastrointestinal symptoms, the rate of coeliac disease is about 3%.<ref name="pmid20442390"/> In Australia, approximately 1 in 70 people have the disease.<ref>{{Cite web |url=https://www.coeliac.org.au/coeliac-disease/#Coeliac3 |title=Coeliac Disease - Coeliac Australia |website=www.coeliac.org.au |access-date=2019-05-08}}</ref> The rate amongst adult blood donors in Iran, Israel, Syria and Turkey is 0.60%, 0.64%, 1.61% and 1.15%, respectively.<ref name=WJG2012/>

People of African, Japanese and Chinese descent are rarely diagnosed;<ref>{{cite journal |vauthors=Houlston RS, Ford D |title=Genetics of coeliac disease |journal=QJM |volume=89 |issue=10 |pages=737–43 |year=1996 |pmid=8944229 |doi=10.1093/qjmed/89.10.737 |doi-access=free}}</ref> this reflects a much lower prevalence of the genetic [[risk factors]], such as [[HLA-B8]].<ref>{{Cite book |vauthors=Buchanan N |year=1987 |title=Child and Adolescent Health for Practitioners |publisher=Williams & Wilkins |isbn=978-0-86433-015-4 |page=164}}</ref> People of Indian ancestry seem to have a similar risk to those of Western Caucasian ancestry.<ref name=WJG2012/> Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due, in part, to many clinicians being unfamiliar with the condition and also due to the fact it can be asymptomatic.<ref>{{cite journal |vauthors=Zipser RD, Farid M, Baisch D, Patel B, Patel D |title=Physician awareness of celiac disease: a need for further education |journal=J Gen Intern Med |volume=20 |issue=7 |pages=644–6 |year=2005 |pmid=16050861 |pmc=1490146 |doi=10.1007/s11606-005-0111-7}}</ref> Coeliac disease is slightly more common in women than in men.<ref name="His2006"/> A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic people, 2.6% in second-degree relatives (like grandparents, aunt or uncle, grandchildren, etc.) of a person with coeliac disease and 4.5% in first-degree relatives (siblings, parents or children).<ref name=WJG2012/> This profile is similar to the prevalence in Europe.<ref name=WJG2012/> Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with [[Down syndrome|Down]] and [[Turner syndrome]]s, [[type 1 diabetes]], and autoimmune thyroid disease, including both [[hyperthyroidism]] (overactive [[thyroid]]) and [[hypothyroidism]] (underactive thyroid).<ref name=Barker>{{cite journal |vauthors=Barker JM, Liu E |title=Celiac disease: pathophysiology, clinical manifestations, and associated autoimmune conditions |journal=Adv Pediatr |volume=55 |pages=349–65 |year=2008 |pmid=19048738 |pmc=2775561 |doi=10.1016/j.yapd.2008.07.001}}</ref>

Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%.<ref name=Barker/> The reason for the recent increases in the number of reported cases is unclear.<ref name=BMJ2015/> It may be at least in part due to changes in diagnostic practice.<ref>{{cite journal | vauthors = Leeds JS, Hopper AD, Sanders DS | title = Coeliac disease | journal = British Medical Bulletin | volume = 88 | issue = 1 | pages = 157–170 | year = 2008 | pmid = 19073695 | doi = 10.1093/bmb/ldn044 | doi-access = free }}</ref> There also appears to be an approximately 4.5 fold true increase that may be due to less exposure to bacteria and other pathogens in Western environments.<ref name=BMJ2015/> In the United States, the median age at diagnosis is 38 years.<ref name=Oxentenko>{{cite journal | vauthors = Oxentenko AS, Rubio-Tapia A | title = Celiac Disease | journal = Mayo Clinic Proceedings | volume = 94 | issue = 12 | pages = 2556–2571 | date = December 2019 | pmid = 31806106 | doi = 10.1016/j.mayocp.2019.02.019 | doi-access = free }}</ref> Roughly 20 percent of individuals with coeliac disease are diagnosed after 60 years of age.<ref name=Oxentenko />

==History==
The term ''coeliac'' comes from Greek κοιλιακός ({{Transliteration|el|koiliakós}}) 'abdominal' and was introduced in the 19th century in a translation of what is generally regarded as an [[Ancient Greek]] description of the disease by [[Aretaeus of Cappadocia]].<ref name="Aretaeus">{{Cite book |author=Aretaeus, the Cappadocian |author-link=Aretaeus of Cappadocia |translator=Francis Adams |translator-link=Francis Adams (translator) |title=The extant works of Aretaeus, The Cappadocian |url=https://books.google.com/books?id=v4gIAAAAIAAJ&pg=PT1 |chapter=On The Cœliac Affection |pages=350–1|chapter-url=https://books.google.com/books?id=v4gIAAAAIAAJ&pg=PA350 |access-date=12 December 2009 |year=1856 |publisher=Sydenham Society |location=London}}</ref><ref name="Losowsky">{{cite journal |vauthors=Losowsky MS |s2cid=10062937 |title=A history of coeliac disease |journal=Digestive Diseases |volume=26 |issue=2 |pages=112–20 |year=2008 |pmid=18431060 |doi=10.1159/000116768}}</ref>

Humans first started to cultivate grains in the [[Neolithic]] period (beginning about 9500&nbsp;BCE) in the [[Fertile Crescent]] in Western Asia, and, likely, coeliac disease did not occur before this time. [[Aretaeus of Cappadocia]], living in the second century in the same area, recorded a malabsorptive syndrome with chronic diarrhoea, causing a debilitation of the whole body.<ref name="Aretaeus"/> His "Cœliac Affection" gained the attention of Western medicine when [[Francis Adams (translator)|Francis Adams]] presented a translation of Aretaeus's work at the Sydenham Society in 1856. The patient described in Aretaeus' work had stomach pain and was atrophied, pale, feeble, and incapable of work. The diarrhoea manifested as loose stools that were white, malodorous, and flatulent, and the disease was intractable and liable to periodic return. The problem, Aretaeus believed, was a lack of heat in the stomach necessary to digest the food and a reduced ability to distribute the digestive products throughout the body, this incomplete digestion resulting in diarrhoea. He regarded this as an affliction of the old and more commonly affecting women, explicitly excluding children. The cause, according to Aretaeus, was sometimes either another chronic disease or even consuming "a copious draught of cold water."<ref name="Aretaeus"/><ref name=Losowsky/>

The [[pediatrics|paediatrician]] [[Samuel Gee]] gave the first modern-day description of the condition in children in a lecture at [[Great Ormond Street Hospital|Hospital for Sick Children, Great Ormond Street]], London, in 1887. Gee acknowledged earlier descriptions and terms for the disease and adopted the same term as Aretaeus (coeliac disease). He perceptively stated: "If the patient can be cured at all, it must be by means of diet." Gee recognised that milk intolerance is a problem with coeliac children and that highly starched foods should be avoided. However, he forbade rice, sago, fruit, and vegetables, which all would have been safe to eat, and he recommended raw meat as well as thin slices of toasted bread. Gee highlighted particular success with a child "who was fed upon a quart of the best Dutch [[mussel]]s daily." However, the child could not bear this diet for more than one season.<ref name=Losowsky/><ref>{{Cite journal | vauthors = Gee SJ |year=1888 |title=On the coeliac affection |journal=St Bartholomew's Hospital Report |volume=24 |pages=17–20 |url=http://web2.bium.univ-paris5.fr/livanc/?cote=epo0466&p=1&do=page |url-status=dead |archive-url=https://web.archive.org/web/20070926231536/http://web2.bium.univ-paris5.fr/livanc/?cote=epo0466&p=1&do=page |archive-date=26 September 2007 |df=dmy-all |access-date=20 March 2007}}</ref>

[[Christian Archibald Herter (physician)|Christian Archibald Herter]], an American physician, wrote a book in 1908 on children with coeliac disease, which he called "intestinal [[infantilism (disorder)|infantilism]]". He noted their growth was retarded and that fat was better tolerated than carbohydrate. The [[eponym]] ''Gee-Herter disease'' was sometimes used to acknowledge both contributions.<ref name=Herter1908>{{Cite book | vauthors = Herter CA |year=1908 |title=On infantilism from chronic intestinal infection; characterized by the overgrowth and persistence of flora in the nursing period |url=https://archive.org/details/oninfantilismfr01hertgoog |publisher=Macmillan & Co |location=New York}} as cited by WhoNamedIt</ref><ref name=whoNamedItHerter>{{cite web |url=http://www.whonamedit.com/doctor.cfm/1490.html |title=Christian Archibald Herter |access-date=20 March 2007 |vauthors=Enersen OD |publisher=Who Named It? |url-status=live |archive-url=https://web.archive.org/web/20061231203644/http://www.whonamedit.com/doctor.cfm/1490.html |archive-date=31 December 2006 |df=dmy-all}}</ref> [[Sidney V. Haas]], an American paediatrician, reported positive effects of [[Specific Carbohydrate Diet|a diet of bananas]] in 1924.<ref>{{Cite journal |vauthors=Haas SV |year=1924 |title=The value of the banana in the treatment of coeliac disease |doi=10.1001/archpedi.1924.04120220017004 |journal=Am J Dis Child |volume=24 |pages=421–37 |issue=4}}</ref> This diet remained in vogue until the actual cause of coeliac disease was determined.<ref name=Losowsky/>

While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Dr [[Willem Karel Dicke]].<ref>{{cite journal |vauthors=van Berge-Henegouwen GP, Mulder CJ |title=Pioneer in the gluten free diet: Willem-Karel Dicke 1905–1962, over 50 years of gluten free diet |journal=Gut |volume=34 |issue=11 |pages=1473–5 |year=1993 |pmid=8244125 |pmc=1374403 |doi=10.1136/gut.34.11.1473}}</ref> It is likely that clinical improvement of his patients during the [[Dutch famine of 1944]] (during which flour was scarce) may have contributed to his discovery.<ref>{{Cite book |vauthors=Dicke WK |title=Coeliakie: een onderzoek naar de nadelige invloed van sommige graansoorten op de lijder aan coeliakie, PhD thesis |language=nl |location=Utrecht, the Netherlands |publisher=University of Utrecht |year=1950}}</ref> Dicke noticed that the shortage of bread led to a significant drop in the death rate among children affected by coeliac disease from greater than 35% to essentially zero. He also reported that once wheat was again available after the conflict, the mortality rate soared to previous levels.<ref>{{Cite journal |vauthors=Fasano A |title=Celiac Disease Insights: Clues to Solving Autoimmunity |journal=Scientific American |issue=August |year=2009 |pages=49–57 |url=http://www.scientificamerican.com/article.cfm?id=celiac-disease-insights |url-status=live |archive-url=https://web.archive.org/web/20100208120817/http://www.scientificamerican.com/article.cfm?id=celiac-disease-insights |archive-date=8 February 2010 |df=dmy-all}}</ref> The link with the gluten component of wheat was made in 1952 by a team from [[Birmingham]], England.<ref>{{cite journal |vauthors=Anderson CM, French JM, Sammons HG, Frazer AC, Gerrard JW, Smellie JM |title=Coeliac disease; gastrointestinal studies and the effect of dietary wheat flour |journal=Lancet |volume=1 |issue=17 |pages=836–42 |year=1952 |pmid=14918439 |doi=10.1016/S0140-6736(52)90795-2}}</ref> Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery.<ref>{{cite journal |vauthors=Paulley JW |title=Observation on the aetiology of idiopathic steatorrhoea; jejunal and lymph-node biopsies |journal=Br Med J |volume=2 |issue=4900 |pages=1318–21 |year=1954 |pmid=13209109 |pmc=2080246 |doi=10.1136/bmj.2.4900.1318}}</ref> This paved the way for biopsy samples taken by endoscopy.<ref name=Losowsky/>

Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965.<ref>{{cite journal |vauthors=Macdonald WC, Dobbins WO, Rubin CE |title=Studies of the familial nature of celiac sprue using biopsy of the small intestine |journal=N Engl J Med |volume=272 |issue=9 |pages=448–56 |year=1965 |pmid=14242522 |doi=10.1056/NEJM196503042720903}}</ref> In 1966, dermatitis herpetiformis was linked to [[gluten sensitivity]].<ref name=Losowsky/><ref name=Marks/>

==Society and culture==
{{See also|List of people diagnosed with coeliac disease}}
May has been designated as "Coeliac Awareness Month" by several coeliac organisations.<ref>{{Cite news |date=11 May 2010 |title=Buy Me Some Gluten-Free Peanuts, Cracker Jacks |periodical=QSR Magazine |publisher=Journalistic |url=http://www.qsrmagazine.com/news/buy-me-some-gluten-free-peanuts-cracker-jacks |access-date=30 December 2010 |url-status=live |archive-url=https://web.archive.org/web/20111204091018/http://www.qsrmagazine.com/news/buy-me-some-gluten-free-peanuts-cracker-jacks |archive-date=4 December 2011 |df=dmy-all}}</ref><ref>{{Cite news | vauthors = Hillson B |date=9 January 2008 |title=May as Celiac Awareness Month |periodical=Celiac Disease Foundation |url=http://www.celiac.org/index.php?option=com_content&view=article&id=86&Itemid=119 |archive-url=https://web.archive.org/web/20100224094719/http://www.celiac.org/index.php?option=com_content&view=article&id=86&Itemid=119 |archive-date=24 February 2010 |access-date=1 July 2011}}</ref>

===Christian churches and the Eucharist===
Speaking generally, the various denominations of Christians celebrate a [[Eucharist]] in which a wafer or small piece of [[sacramental bread]] from wheat bread is blessed and then eaten. A typical wafer weighs about half a gram.<ref>{{cite web | url = http://www.eden.co.uk/shop/peoples-alter-breads-single-cross-sealed-edge-white-125972.html | title = One on-line site sells 1200 wafers weighing a total of 523 g | archive-url = https://web.archive.org/web/20110916215312/http://www.eden.co.uk/shop/peoples-alter-breads-single-cross-sealed-edge-white-125972.html |date=16 September 2011 | work = Eden.co.uk | archive-date = 16 September 2011 | access-date = 3 September 2013 }}</ref> [[Wheat flour]] contains around 10–13% gluten, so a single communion wafer may have more than 50&nbsp;mg of gluten, an amount that harms many people with coeliac, especially if consumed every day (see ''Diet'' above).{{citation needed|date=December 2022}}

Many Christian churches offer their communicants gluten-free alternatives, usually in the form of a rice-based cracker or gluten-free bread. These include the [[United Methodist Church|United Methodist]], [[Christian Reformed Church in North America|Christian Reformed]], [[Episcopal Church (United States)|Episcopal]], the Anglican Church (Church of England, UK) and [[Lutheranism|Lutheran]]. [[Catholic Church|Catholics]] may receive from the Chalice alone, or ask for gluten-reduced hosts; gluten-free ones however are not considered to still be wheat bread and hence invalid matter.<ref>{{cite web | url = http://www.catholicceliacs.org/Bishops.html | title = Statement by the National Conference of Catholic bishops on the use of low gluten hosts at Mass | archive-url = https://web.archive.org/web/20130716100106/http://www.catholicceliacs.org/Bishops.html |archive-date=16 July 2013 | work = BCL Newsletter | date = November 2003 }}</ref>

====Roman Catholic position====
Roman Catholic [[doctrine]] states that for a valid [[Eucharist]], the bread to be used at [[Mass (liturgy)|Mass]] must be made from wheat. Low-gluten [[Host (Holy Communion)|hosts]] meet all of the Catholic Church's requirements, but they are not entirely gluten free. Requests to use rice wafers have been denied.<ref>{{Cite news |agency=Associated Press |url=http://www.nbcnews.com/id/5762478 |archive-url=https://web.archive.org/web/20131113165203/http://www.nbcnews.com/id/5762478/ |url-status=dead |archive-date=13 November 2013 |title=Girl with digestive disease denied Communion |work=NBC News |publisher=Microsoft |date=8 December 2004 |access-date=30 May 2006 |df=dmy-all}}</ref>

The issue is more complex for priests. As a celebrant, a priest is, for the fullness of the sacrifice of the Mass, absolutely required to receive under both species. On 24 July 2003, the Congregation for the Doctrine of the Faith stated, "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm."<ref>[[Pope Benedict XVI|Ratzinger, Joseph]] (24 July 2003). ''Prot. 89/78-174 98''. [[Congregation for the Doctrine of the Faith]]. Full text at: {{cite web |url=http://www.usccb.org/liturgy/innews/1103.shtml |title=The Use of Mustum and Low-Gluten Hosts at Mass |access-date=7 March 2007 |work=BCL Newsletter |date=November 2003 |publisher=[[United States Conference of Catholic Bishops]] |url-status=live |archive-url=https://web.archive.org/web/20070102174658/http://usccb.org/liturgy/innews/1103.shtml |archive-date=2 January 2007}}</ref>

By January 2004, extremely low-gluten Church-approved hosts had become available in the United States, Italy and Australia.<ref>{{cite web |url=http://www.catholic.org/featured/headline.php?ID=1340 |title=Liturgy: Gluten-free Hosts |access-date=17 June 2007 | vauthors = McNamara E |date=15 September 2004 |work=Catholic Online |url-status=live |archive-url=https://web.archive.org/web/20070929130110/http://www.catholic.org/featured/headline.php?ID=1340 |archive-date=29 September 2007}}</ref> As of July 2017, the Vatican still outlawed the use of gluten-free bread for Holy Communion.<ref>{{Cite news |url=https://www.telegraph.co.uk/news/2017/07/08/vatican-outlaws-use-gluten-free-bread-holy-communion/ |title=Vatican outlaws use of gluten free bread for Holy Communion |access-date=3 August 2017 |url-status=live |archive-url=https://web.archive.org/web/20170804012531/http://www.telegraph.co.uk/news/2017/07/08/vatican-outlaws-use-gluten-free-bread-holy-communion/ |archive-date=4 August 2017 |newspaper=The Telegraph |date=2017-07-08 | vauthors = Millward D }}</ref>

===Passover===
{{citation needed|date=December 2022}} The Jewish festival of [[Passover|Pesach]] (Passover) may present problems with its obligation to eat [[Matzah]], which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye.
In addition, many other grains that are normally used as substitutes for people with gluten sensitivity, including rice, are avoided altogether on Passover by [[Ashkenazi Jews]]. Many kosher-for-Passover products avoid grains altogether and are therefore gluten-free. [[Potato starch]] is the primary starch used to replace the grains.

===Spelling===
Coeliac disease is the preferred spelling in [[American and British English spelling differences#ae and oe|Commonwealth English]], while celiac disease is typically used in [[North American English]].<ref>{{Cite web |url=https://dictionary.cambridge.org/dictionary/english/coeliac-disease |title=COELIAC DISEASE {{!}} meaning in the Cambridge English Dictionary|website=dictionary.cambridge.org|language=en |access-date=2018-12-15}}</ref><ref>{{Cite web |url=http://www.glutenfreedublin.com/coeliac-vs-celiac |title=Coeliac vs. Celiac |website=www.glutenfreedublin.com |language=en-us |access-date=2018-12-15 |archive-date=17 December 2018 |archive-url=https://web.archive.org/web/20181217110644/http://www.glutenfreedublin.com/coeliac-vs-celiac |url-status=dead}}</ref>

==Research directions==
The search for environmental factors that could be responsible for genetically susceptible people becoming intolerant to gluten has resulted in increasing research activity looking at gastrointestinal infections.<ref name="pmid27840181">{{cite journal |vauthors=Kemppainen KM, Lynch KF, Liu E, Lönnrot M, Simell V, Briese T, Koletzko S, Hagopian W, Rewers M, She JX, Simell O, Toppari J, Ziegler AG, Akolkar B, Krischer JP, Lernmark Å, Hyöty H, Triplett EW, Agardh D |title=Factors That Increase Risk of Celiac Disease Autoimmunity After a Gastrointestinal Infection in Early Life |journal=Clinical Gastroenterology and Hepatology |volume=15 |issue=5 |pages=694–702.e5 |date=May 2017 |pmid=27840181 |pmc=5576726 |doi=10.1016/j.cgh.2016.10.033 }}</ref> Research published in April 2017 suggests that an often-symptomless infection by a common strain of [[reovirus]] can increase sensitivity to foods such as gluten.<ref name="Verdu_2017">{{cite journal |vauthors=Verdu EF, Caminero A |s2cid=206659081 |title=How infection can incite sensitivity to food |journal=Science |volume=356 |issue=6333 |pages=29–30 |date=April 2017 |pmid=28385972 |doi=10.1126/science.aan1500 |bibcode=2017Sci...356...29V}}</ref>

Various treatment approaches are being studied, including some that would reduce the need for dieting. All are still under development, and are not expected to be available to the general public for a while.<ref name=VanHeelWest/><ref name="pmid24199026">{{cite journal |vauthors=Freeman HJ |title=Non-dietary forms of treatment for adult celiac disease |journal=World Journal of Gastrointestinal Pharmacology and Therapeutics |volume=4 |issue=4 |pages=108–12 |date=November 2013 |pmid=24199026 |pmc=3817285 |doi=10.4292/wjgpt.v4.i4.108 |type=Review |doi-access=free }}</ref><ref name="pmid24882720">{{cite journal |vauthors=Vanga RR, Kelly CP |title=Novel therapeutic approaches for celiac disease |journal=Discovery Medicine |volume=17 |issue=95 |pages=285–93 |date=May 2014 |pmid=24882720}}</ref>

Three main approaches have been proposed as new therapeutic modalities for coeliac disease: gluten detoxification, modulation of the [[intestinal permeability]], and modulation of the immune response.<ref name="Castillo-etal-2015">{{cite journal |vauthors=Castillo NE, Theethira TG, Leffler DA |title=The present and the future in the diagnosis and management of celiac disease |journal=Gastroenterology Report |volume=3 |issue=1 |pages=3–11 |year=2015 |pmid=25326000 |pmc=4324867 |doi=10.1093/gastro/gou065 |type=Review}}</ref>

Using [[Genetic engineering|genetically engineered]] wheat species, or wheat species that have been [[plant breeding|selectively bred]] to be minimally immunogenic, may allow the consumption of wheat. This, however, could interfere with the effects that gliadin has on the quality of dough.

Alternatively, gluten exposure can be minimised by the ingestion of a combination of [[enzyme]]s ([[prolyl endopeptidase]] and a barley glutamine-specific [[cysteine endopeptidase]] ([[EP-B2]])) that degrade the putative 33-mer peptide in the [[duodenum]].<ref name="VanHeelWest" /> Latiglutenase (IMGX003) is a [[Biopharmaceutical|biotheraputic]] digestive enzyme therapy currently being trialled that aims to degrade gluten proteins and aid gluten digestion. It was shown to mitigate intestinal mucosal damage and reduce the severity and frequency of symptoms in phase 2 clinical trials<ref>{{cite journal | vauthors = Murray JA, Syage JA, Wu TT, Dickason MA, Ramos AG, Van Dyke C, Horwath I, Lavin PT, Mäki M, Hujoel I, Papadakis KA, Bledsoe AC, Khosla C, Sealey-Voyksner JA | title = Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge | journal = Gastroenterology | volume = 163 | issue = 6 | pages = 1510–1521.e6 | date = December 2022 | pmid = 35931103 | pmc = 9707643 | doi = 10.1053/j.gastro.2022.07.071 }}</ref> and is scheduled for phase 3 clinical trials.<ref>{{Cite web |title=Entero Therapeutics |url=https://enterothera.com/ |access-date=2024-05-21 |website=enterothera.com |language=en-GB}}</ref>

Alternative treatments under investigation include the inhibition of [[zonulin]], an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system. One inhibitor of this pathway is [[larazotide acetate]], which is currently scheduled for phase 3 clinical trials.<ref>{{Cite web |url=http://www.innovatebiopharma.com/inn-202.html |title=Innovate Biopharmaceuticals |website=www.innovatebiopharma.com |access-date=17 April 2016 |url-status=live |archive-url=https://web.archive.org/web/20160418041125/http://www.innovatebiopharma.com/inn-202.html |archive-date=18 April 2016}}</ref>{{Update inline|date=May 2024}} Other modifiers of other well-understood steps in the pathogenesis of coeliac disease, such as the action of HLA-DQ2 or tissue transglutaminase and the MICA/NKG2D interaction that may be involved in the killing of enterocytes.<ref name="VanHeelWest" />

Attempts to modulate the immune response concerning coeliac disease are mostly still in phase I of clinical testing; one agent (CCX282-B) has been evaluated in a phase II clinical trial based on small-intestinal biopsies taken from people with coeliac disease before and after gluten exposure.<ref name="Castillo-etal-2015"/>

Although popularly used as an [[complementary and alternative medicine|alternative treatment]] for people with autism, there is no good evidence that a [[gluten-free diet]] is of benefit in the treatment of autism.<ref name=Buie>{{cite journal |vauthors=Buie T |title=The relationship of autism and gluten |journal=Clin Ther |volume=35 |issue=5 |pages=578–83 |year=2013 |pmid=23688532 |doi=10.1016/j.clinthera.2013.04.011 |type=Review |quote=At this time, the studies attempting to treat symptoms of autism with diet have not been sufficient to support the general institution of a gluten-free or other diet for all children with autism.|doi-access=free }}</ref><ref name="MariBausetZazpe">{{cite journal |vauthors=Marí-Bauset S, Zazpe I, Mari-Sanchis A, Llopis-González A, Morales-Suárez-Varela M |s2cid=19874518 |title=Evidence of the gluten-free and casein-free diet in autism spectrum disorders: a systematic review |journal=J Child Neurol |volume=29 |issue=12 |pages=1718–27 |date=December 2014 |pmid=24789114 |doi=10.1177/0883073814531330 |hdl=10171/37087 |hdl-access=free}}</ref><ref name="Millward2008">{{cite journal |vauthors=Millward C, Ferriter M, Calver S, Connell-Jones G |title=Gluten- and casein-free diets for autistic spectrum disorder |journal=Cochrane Database Syst Rev |year=2008 |issue=2 |pages=CD003498 |pmid=18425890 |doi=10.1002/14651858.CD003498.pub3 | veditors = Ferriter M |pmc=4164915}}</ref> In the subset of autistic people who have [[non-celiac gluten sensitivity|gluten sensitivity]], there is limited evidence that suggests that a gluten free diet may improve hyperactivity and mental confusion in those with autism.<ref name=Buie /><ref name=VoltaCaio>{{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 |quote=autism spectrum disorders (ASD) have been hypothesized to be associated with NCGS [47,48]. Notably, a gluten- and casein-free diet might have a positive effect in improving hyperactivity and mental confusion in some patients with ASD. This very exciting association between NCGS and ASD deserves further study before conclusions can be firmly drawn}}</ref><ref name=SanMauroGaricano>{{cite journal |vauthors=San Mauro I, Garicano E, Collado L, Ciudad MJ |title=¿Es el gluten el gran agente etiopatogenico de enfermedad en el siglo XXI? |trans-title=Is gluten the great etiopathogenic agent of disease in the XXI century? |language=es |journal=Nutr Hosp |volume=30 |issue=6 |pages=1203–10 |date=December 2014 |pmid=25433099 |doi=10.3305/nh.2014.30.6.7866}}</ref>

==References==
{{Reflist}}

==External links==
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{{Medical condition classification and resources
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[[Category:Autoimmune diseases]]
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