Coeliac disease 63526 225638690 2008-07-14T18:00:08Z Jfdwolff 46555 rm poorly phrased addition containing numerous errors (e.g. that gluten enters the circulation) - spreading awareness is not Wikipedia's role, nor promoting your group {{Infobox_Disease | 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. | DiseasesDB = 2922 | ICD10 = {{ICD10|K|90|0|k|90}} | ICD9 = {{ICD9|579.0}} | ICDO = | OMIM = 212750 | MedlinePlus = 000233 | eMedicineSubj = med | eMedicineTopic = 308 | eMedicine_mult = {{eMedicine2|ped|2146}} {{eMedicine2|radio|652}} | MeshID = D002446 | }} <!--This article employs British spelling; please do not try to "correct" coeliac to celiac, diarrhoea to diarrhea etc without discussion on the talk page. See [[WP:ENGVAR]] for explanation--> '''Coeliac disease''' ({{pronEng|ˈsiːliːˌæk}}), also spelled '''celiac disease''', is an [[Autoimmunity|autoimmune]] disorder of the [[small intestine]] that occurs in [[Genetic predisposition|genetically predisposed]] people of all ages from middle infancy. Symptoms include chronic [[diarrhea|diarrhoea]], [[failure to thrive]] (in children), and [[fatigue (physical)|fatigue]], but these may be absent and symptoms in all other organ systems have been described. It is estimated to affect about 1% of all [[Indo-European people|Indo-European]] populations, but is thought to be significantly underdiagnosed. A growing portion of diagnoses are being made in [[asymptomatic]] persons as a result of increased [[Screening_%28medicine%29|screening]].<ref name=VanHeelWest>{{cite journal | author = van Heel D, West J | title = Recent advances in coeliac disease | url = http://gut.bmjjournals.com/cgi/content/full/55/7/1037 | journal = Gut | volume = 55 | issue = 7 | pages = 1037–46 | year = 2006 | pmid=16766754 | doi = 10.1136/gut.2005.075119}} <!--PMC 1856316 from Jan 09--></ref> Coeliac disease is caused by a reaction to [[gliadin]], a [[gluten]] protein found in [[wheat]] (and similar proteins of the [[tribe (biology)|tribe]] [[Triticeae]] which includes other [[cultivar|cultivars]] such as [[barley]] and [[rye]]). Upon exposure to gliadin, the enzyme [[tissue transglutaminase]] modifies the protein, and the [[immune system]] cross-reacts with the bowel tissue, causing an [[inflammation|inflammatory reaction]]. That leads to flattening of the lining of the small intestine (called villous atrophy). This [[malabsorption|interferes with the absorption]] of nutrients because the intestinal villi are responsible for absorption. The only effective treatment is a lifelong [[gluten-free diet]]. While the disease is caused by a reaction to wheat proteins, it is not the same as [[wheat allergy]]. This condition has several other names, including: '''cœliac disease''' (with [[Œ|"œ" ligature]]), '''c(o)eliac sprue''', '''non-tropical sprue''', '''endemic sprue''', '''gluten enteropathy''' or '''gluten-sensitive enteropathy''', and '''gluten intolerance'''. The term ''coeliac'' derives from the [[Greek language|Greek]] κοιλιακός (''koiliakόs'', 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 |last=Adams F, translator |title=The extant works of Aretaeus, The Cappadocian |url=http://web.archive.org/web/20070311164628/http://www.chlt.org/sandbox/dh/aretaeusEnglish/index.html |chapter= On The Cœliac Affection |chapterurl=http://web.archive.org/web/20070311164628/http://www.chlt.org/sandbox/dh/aretaeusEnglish/page.102.a.php |accessdate=2006-09-04 |year=1856 |publisher=Sydenham Society |location=London}} See also [http://books.google.com/books?id=v4gIAAAAIAAJ&pg=PP1&ct=title#PRA1-PA350,M1 Google Books entry]</ref> ==Signs and symptoms== {{Gluten sensitivity}} Classic symptoms of coeliac disease include [[diarrhea|diarrhea]], [[weight loss]] (or stunted growth in children), and [[fatigue (physical)|fatigue]], but while coeliac disease is primarily a bowel disease, bowel symptoms may also be limited or even absent. Some patients are diagnosed with symptoms related to the decreased absorption of nutrients or with various symptoms which, although statistically linked, have no clear relationship with the malfunctioning bowel. Given this wide range of possible symptoms, the classic triad is no longer a requirement for diagnosis. Children between 9 and 24 months tend to present with bowel symptoms and growth problems shortly after first exposure to gluten-containing products. Older children may have more malabsorption-related problems and psychosocial problems, while adults generally have malabsorptive problems.<ref name=Ciclitira>{{cite web | first = P | last = Ciclitira | year= 2002 | url = http://www.bsg.org.uk/bsgdisp1.php?id=c9c5177d2b91e3228066 | title = Interim Guidelines for the Management of Patients with Coeliac Disease | publisher = British Society of Gastroenterology | accessdate = 2007-03-07}}</ref> Many adults with subtle disease only have fatigue or [[anaemia]].<ref name=VanHeelWest/> ===Gastrointestinal=== The diarrhoea characteristic of coeliac disease is [[steatorrhoea|pale]], voluminous and malodorous. [[Abdominal pain]] and cramping, bloatedness with abdominal distention (thought to be due to fermentative production of bowel gas) and [[mouth ulcer]]s<ref>{{cite journal | author = Ferguson R, Basu M, Asquith P, Cooke W | title = Jejunal mucosal abnormalities in patients with recurrent aphthous ulceration | journal = Br Med J | volume = 1 | issue = 6000 | pages = 11–13 | year = 1976 | pmid=1247715}} {{PMC|1638254}}</ref> may be present. As the bowel becomes more damaged, a degree of [[lactose intolerance]] may develop. However, the variety of gastrointestinal symptoms that may be present in patients with coeliac disease is great, and some may have a normal bowel habit or even tend towards [[constipation]]. Frequently the symptoms are ascribed to [[irritable bowel syndrome]] (IBS), only later to be recognised as coeliac disease; a small proportion of patients with symptoms of IBS have underlying coeliac disease, and screening may be justified.<ref name=Spiegel>{{cite journal | author = Spiegel BM, DeRosa VP, Gralnek IM, Wang V, Dulai GS | year = 2004 | month = Jun | title = Testing for celiac sprue in irritable bowel syndrome with predominant diarrhea: a cost-effectiveness analysis | journal = Gastroenterology | volume = 126 | issue = 7 | pages = 1721–32 | pmid=15188167 | doi = 10.1053/j.gastro.2004.03.012}}</ref> Coeliac disease leads to an increased risk of both [[adenocarcinoma]] and [[lymphoma]] of the small bowel, which returns to baseline with diet. Longstanding disease may lead to other complications, such as ''ulcerative jejunitis'' (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring).<ref name=AGA>{{cite journal | author = | title = American Gastroenterological Association medical position statement: Celiac Sprue | journal = Gastroenterology | volume = 120 | issue = 6 | pages = 1522–5 | year = 2001 | pmid=11313323 | url = http://www.gastrojournal.org/article/PIIS0016508501701618/fulltext}}</ref> ===Malabsorption-related=== The changes in the bowel make it less able to absorb nutrients, minerals and the fat-soluble vitamins A, D, E, and K.<ref name=Ciclitira/> * The inability to absorb carbohydrates and fats may cause [[weight loss]] (or [[failure to thrive]]/stunted growth in children) and [[fatigue (physical)|fatigue]] or lack of energy. * [[Anaemia]] may develop in several ways: iron malabsorption may cause [[iron deficiency anemia|iron deficiency anaemia]], and [[folic acid]] and [[vitamin B12]] 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). * A small proportion (10%) have abnormal [[coagulation]] due to deficiency of [[vitamin K]], and are slightly at risk for abnormal bleeding. * Coeliac disease is also associated with [[small bowel bacterial overgrowth syndrome|bacterial overgrowth]] of the [[small intestine]], which can worsen malabsorption, or cause malabsorption after treatment.<ref name=Tursi>{{cite journal | author = Tursi A, Brandimarte G, Giorgetti G | title = High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal | journal = Am J Gastroenterol | volume = 98 | issue = 4 | pages = 839–43 | year = 2003 | pmid=12738465 | doi = 10.1111/j.1572-0241.2003.07379.x}}</ref> ===Miscellaneous=== Coeliac disease has been linked with a number of 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% of patients with coeliac disease, and in turn this condition features a tenfold increased risk of coeliac disease.<ref>{{cite journal | author = Crabbé P, Heremans J | title = Selective IgA deficiency with steatorrhea. A new syndrome | journal = Am J Med | volume = 42 | issue = 2 | pages = 319–26 | year = 1967 | pmid = 4959869 | doi = 10.1016/0002-9343(67)90031-9}}</ref><ref>{{cite journal | author = Collin P, Mäki M, Keyriläinen O, Hällström O, Reunala T, Pasternack A | title = Selective IgA deficiency and coeliac disease | journal = Scand J Gastroenterol | volume = 27 | issue = 5 | pages = 367–71 | year = 1992| pmid=1529270 | doi = 10.3109/00365529209000089}}</ref> Other features of this condition are an increased risk of [[infection]]s and [[autoimmune disease]]. * [[Dermatitis herpetiformis]]; this itchy cutaneous condition has been linked to a transglutaminase enzyme in the skin, features small bowel changes identical to those in coeliac disease<ref name=Marks>{{cite journal | author = Marks J, Shuster S, Watson A | 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> and occurs more often (in 2%) in patients with coeliac disease.<ref name=Ciclitira/> * Neurological associations: [[epilepsy]], [[ataxia]] (coordination problems), [[myelopathy]], [[peripheral neuropathy]], and [[schizophrenia]] <ref>{{cite journal | author = Eaton W, Mortensen P, Esben A, Byrne M, Mors O, Ewald H | title = Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers | journal = British Medical Journal | volume = 328 | pages = 438–9 | year = 2002 | doi=10.1136/bmj.328.7437.438 | pmid=14976100 | url = http://www.bmj.com/cgi/content/short/328/7437/438}} {{PMC|344262}}</ref> have all been linked with coeliac disease, but the strength of these associations and the causality are still subject to debate.<ref>{{cite journal | author = Pengiran Tengah D, Wills A, Holmes G | title = Neurological complications of coeliac disease | journal = Postgrad Med J | volume = 78 | issue = 921 | pages = 393–8 | year = 2002 | url = http://pmj.bmjjournals.com/cgi/content/full/78/921/393 | pmid=12151653 | doi = 10.1136/pmj.78.921.393}}</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. * [[Miscarriage]] and [[infertility]]. * [[Hyposplenism]] (a small and underactive [[spleen]]) - it is unclear whether this actually increases infection risk in the same way as in other people without a functioning spleen.<ref name=Ferguson>{{cite journal | author = Ferguson A, Hutton M, Maxwell J, 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> * Other auto-immune disorders: [[diabetes mellitus type 1]],<ref name=Holmes>{{cite journal |author=Holmes G |title=Coeliac disease and Type 1 diabetes mellitus - the case for screening |journal=Diabet Med |volume=18 |issue=3 |pages=169–77 |year=2001 |pmid=11318836 |doi=10.1046/j.1464-5491.2001.00498.x}}</ref> [[thyroiditis|autoimmune thyroiditis]],<ref>{{cite journal | author = Collin P, Kaukinen K, Välimäki M, Salmi J | title = Endocrinological disorders and celiac disease | journal = Endocr Rev | volume = 23 | issue = 4 | pages = 464–83 | year = 2002 | url = http://edrv.endojournals.org/cgi/content/full/23/4/464 |pmid=12202461 | doi = 10.1210/er.2001-0035}}</ref> [[primary biliary cirrhosis]],<ref>{{cite journal | author = Kingham J, Parker D | title = The association between primary biliary cirrhosis and coeliac disease: a study of relative prevalences | journal = Gut | volume = 42 | issue = 1 | pages = 120–2 | year = 1998 | pmid=9518232|url=http://gut.bmj.com/cgi/content/full/42/1/120}} {{PMC|1726939}}</ref> and [[microscopic colitis]].<ref>{{cite journal | author = Matteoni C, Goldblum J, Wang N, Brzezinski A, Achkar E, Soffer E | title = Celiac disease is highly prevalent in lymphocytic colitis | journal = J Clin Gastroenterol | volume = 32 | issue = 3 | pages = 225–7 | year = 2001 | pmid=11246349 | doi = 10.1097/00004836-200103000-00009}}</ref> ===Other grains=== Wheat varieties or subspecies containing gluten and related species such as barley and rye also induce symptoms of coeliac disease.<ref name=Kupper>{{cite journal | author = Kupper C | title = Dietary guidelines and implementation for celiac disease | journal = Gastroenterology | volume = 128 | issue = 4 Suppl 1 | pages = S121–7 | year = 2005 | pmid=15825119 | doi = 10.1053/j.gastro.2005.02.024}}</ref> A small minority of coeliac patients also react to [[oats]].<ref>{{cite journal | author = Lundin K, Nilsen E, Scott H, Løberg E, Gjøen A, Bratlie J, Skar V, Mendez E, Løvik A, Kett K | title = Oats induced villous atrophy in coeliac disease | journal = Gut | volume = 52 | issue = 11 | pages = 1649–52 | year = 2003 | url = http://gut.bmjjournals.com/cgi/content/full/52/11/1649 | pmid=14570737 | doi = 10.1136/gut.52.11.1649}} {{PMC|1773854}}</ref><ref>{{cite journal | author = Størsrud S, Olsson M, Arvidsson Lenner R, Nilsson L, Nilsson O, Kilander A | title = Adult coeliac patients do tolerate large amounts of oats | journal = Eur J Clin Nutr | volume = 57 | issue = 1 | pages = 163–9 | year = 2003 | pmid=12548312 | url= http://www.nature.com/ejcn/journal/v57/n1/abs/1601525a.html | doi = 10.1038/sj.ejcn.1601525}}</ref> It is most probable that oats produce symptoms due to cross contamination with other grains in the fields or in the distribution channels.<ref name=Ciclitira/> Generally, oats are therefore not recommended.<ref name=Kupper/> Other [[cereal]]s, such as [[maize]] (corn), [[quinoa]], [[millet]], [[sorghum]], and [[rice]] are safe for patients to consume. Non-cereal carbohydrate-rich foods such as [[potatoes]] and [[banana]]s do not contain gluten and do not trigger symptoms. ==Diagnosis== There are several tests that can be used to assist in diagnosis. The level of symptoms may determine the order of the tests, but ''all'' tests lose their usefulness if the patient is already taking a gluten-free diet. 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 re-challenge with 10&nbsp;g of gluten (four slices of bread) per day over 2–6 weeks before repeating the investigations. Those who experience severe symptoms (e.g. diarrhoea) earlier can be regarded as sufficiently challenged and can be tested earlier.<ref name=Ciclitira/> Combining findings into a prediction rule to guide use of endoscopy reported a [[sensitivity (tests)|sensitivity]] of 100% (it would identify all the cases) and [[specificity (tests)|specificity]] of 61% (it would be incorrectly positive in 39%). The prediction rule recommends that patients with high risk symptoms ''or'' positive serology should undergo endoscopy. The study defined high risk symptoms as weight loss, anaemia (haemoglobin less than 120 g/l in females and less than 130 g/l in males), or diarrhoea (more than three loose stools per day).<ref name="pmmid17383983">{{cite journal |author=Hopper A, Cross S, Hurlstone D, McAlindon M, Lobo A, Hadjivassiliou M, Sloan M, Dixon S, Sanders D |title=Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool |journal=BMJ |volume=334 |issue= |pages=729 |year=2007 | url=http://www.bmj.com/cgi/content/full/334/7596/729 | pmid=17383983 |doi=10.1136/bmj.39133.668681.BE}} {{PMC|1847864}}</ref> ===Blood tests=== ====Antibody testing==== [[Serology]] by [[blood test]] is useful both in diagnosing coeliac disease (high sensitivity of about 98%, i.e. it misses 2 in 100 cases) and in excluding it (high [[Specificity (tests)|specificity]] of over 95%, i.e. a positive test is most likely confirmative of coeliac disease rather than another condition). 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. A negative test may still prompt a biopsy if the suspicion remains very high; this would pick up the remaining 2% undiagnosed cases, as well as offering alternative explanations for the symptoms. As such, endoscopy with biopsy is still considered the [[gold standard (test)|gold standard]] in the diagnosis of coeliac disease.<ref name=Ciclitira/><ref name=AGA/> Four serological blood tests exist for coeliac disease. The most widely used ones detect an [[antibody]] of the [[IgA]] type against particular [[antigen]]s in the small bowel. Older tests detected antibodies against [[reticulin]] (ARA) or [[gliadin]] ([[Anti-gliadin antibodies|AGA]]), but recent evidence supports the use of the more modern tests, namely those detecting IgA antibodies against [[endomysium]] (EMA) or [[tissue transglutaminase]] (TTG). Generally, serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five.<ref name=HillNIH>Hill ID. "What are the sensitivity and specificity of serological tests for celiac disease? Do sensitivity and specificity vary in different populations?" In: ''NIH Consensus Development Conference on Celiac Disease''. Bethesda, Md.: U.S. National Institutes of Health, 2004;27–31. [http://consensus.nih.gov/2004/2004CeliacDisease118Program.pdf PDF].</ref> Serology tests are based on [[immunofluorescence|indirect immunofluorescence]] (reticulin, gliadin and endomysium) or [[ELISA]] (gliadin or tissue transglutaminase).<ref>{{cite journal |author=Wong R, Steele R, Reeves G, Wilson R, 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}}</ref> Guidelines recommend that a total serum IgA level is checked in parallel, as coeliac patients with IgA deficiency may be unable to produce the antibodies on which these tests depend ("[[Type I and type II errors|false negative]]"). In those patients, IgG antibodies against transglutaminase (IgG-TTG) may be diagnostic.<ref>{{cite journal | author = Korponay-Szabó I, Dahlbom I, Laurila K, Koskinen S, Woolley N, Partanen J, Kovács J, 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 | url = http://gut.bmjjournals.com/cgi/content/full/52/11/1567 | pmid=14570724 | doi = 10.1136/gut.52.11.1567}} {{PMC|1773847}}</ref> {| class="wikitable" align="right" |+ Blood HLA tests for coeliac disease<ref name="pmid17785484"/> ! width="70px" | Test !! width="90px" | [[sensitivity (tests)|sensitivity]] || width="90px" | [[specificity (tests)|specificity]] |- | [[HLA-DQ2]] || align="center" | 94% || align="center" | 73% |- | [[HLA-DQ8]] || align="center" | 12% || align="center" | 81% |} ====HLA genetic typing==== Antibody testing and [[Human leukocyte antigen|HLA]] testing have similar accuracies.<ref name="pmid17785484"/> ===Endoscopy=== [[Image:celiac 3.jpg|right|thumb|200px|[[Endoscopy|Endoscopic]] still of [[duodenum]] of patient with coeliac disease showing scalloping of folds.]] [[Image:CoeliacDisease.png|right|thumb|300px|Schematic of the Marsh classification of upper [[jejunum|jejunal]] pathology in coeliac disease]] An [[upper endoscopy]] with [[biopsy]] of the [[duodenum]] (beyond the [[duodenal bulb]]) or [[jejunum]] is performed. It is important for the physician 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/> Most patients with coeliac disease have a small bowel that appears normal on endoscopy; however, five concurrent endoscopic findings have been associated with a high specificity for coeliac disease: scalloping of the small bowel folds (''pictured''), paucity in the folds, a [[mosaic]] pattern to the [[mucosa]] (described as a ''cracked-mud'' appearance), prominence of the submucosal blood vessels, and a nodular pattern to the mucosa.<ref>{{cite journal | author = Niveloni S, Fiorini A, Dezi R, Pedreira S, Smecuol E, Vazquez H, Cabanne A, Boerr LA, Valero J, Kogan Z, Maurino 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 = 223–229 | year = 1998 | pmid=9580349 | doi = 10.1016/S0016-5107(98)70317-7}}</ref> 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. One often-utilized capsule system is the [[Watson capsule]]. This method has now been largely replaced by fibre-optic endoscopy, which carries a higher sensitivity and a lower frequency of errors.<ref>{{cite journal |author=Mee A, Burke M, Vallon A, Newman J, Cotton P |title=Small bowel biopsy for malabsorption: comparison of the diagnostic adequacy of endoscopic forceps and capsule biopsy specimens |journal=Br Med J (Clin Res Ed) |volume=291 |issue=6498 |pages=769–72 |year=1985 |pmid=3929934}} {{PMC|1417146}}</ref> ===Pathology=== The classic pathology changes of coeliac disease in the small bowel are categorized by the "Marsh classification":<ref>{{cite journal | author = Marsh M | 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}}</ref> *Marsh stage 0: normal mucosa *Marsh stage 1: increased number of intra-epithelial [[lymphocytes]], usually exceeding 20 per 100 [[enterocyte]]s *Marsh stage 2: proliferation of the [[crypts of Lieberkuhn]] *Marsh stage 3: partial or complete [[intestinal villus|villous]] [[atrophy]] *Marsh stage 4: [[hypoplasia]] of the [[small bowel]] architecture The changes classically improve or reverse after [[gluten]] is removed from the diet, so many official guidelines recommend a repeat [[biopsy]] several (4–6) months after commencement of gluten exclusion.<ref name=Ciclitira/> In some cases a deliberate gluten challenge, followed by 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=Ciclitira/> Patients are warned that one does not "outgrow" coeliac disease in the same way as childhood food intolerances. ===Other diagnostic tests=== Other tests that may assist in the diagnosis are [[blood test]]s for a [[full blood count]], [[electrolyte]]s, [[calcium]], [[renal function]], [[liver enzyme]]s, [[vitamin B12]] and [[folic acid]] levels. [[Coagulation]] testing ([[prothrombin time]] and [[partial thromboplastin time]]) may be useful to identify deficiency of [[vitamin K]], which predisposes patients to [[hemorrhage]]. These tests should be repeated on follow-up, as well as [[anti-transglutaminase antibodies|anti-tTG]] titres.<ref name=Ciclitira/> Some professional guidelines<ref name=Ciclitira/> recommend screening of all patients for [[osteoporosis]] by [[dual energy X-ray absorptiometry|DXA/DEXA]] scanning. ==Pathophysiology== Coeliac disease appears to be polyfactorial, both in that more than one genetic factor can cause the disease and also more than one factor is necessary for the disease to manifest in a patient. Almost all coeliac patients have the variant [[HLA DQ]]2 [[allele]].<ref name=VanHeelWest/> However, about 20–30% of people without coeliac disease have inherited an [[HLA-DQ]]2 [[allele]].<ref name="pmid17785484"/> This suggests additional factors are needed for coeliac disease to develop. Furthermore, about 5% of those people who do develop coeliac disease do not have the DQ2 gene.<ref name=VanHeelWest/> The [[HLA-DQ]]2 [[allele]] shows incomplete [[penetrance]], as the gene [[allele]]s associated with the disease appear in most patients, but are neither present in all cases nor sufficient by themselves to cause the disease. ===Genetics=== The vast majority of coeliac patients have one of two types of [[HLA DQ]].<ref name="pmid17785484">{{cite journal |author=Hadithi M, von Blomberg BM, Crusius JB, ''et al'' |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=|url=http://www.annals.org/cgi/content/full/147/5/294}}</ref> This [[gene]] 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]]. There are 7 HLA DQ variants (DQ2 and DQ4 through 9). Two of these variants—[[HLA-DQ2|DQ2]] and [[HLA-DQ8|DQ8]]—are associated with coeliac disease. The gene is located on the short arm of the [[Chromosome 6 (human)|sixth chromosome]], and as a result of the [[genetic linkage|linkage]] this [[locus (genetics)|locus]] has been labeled ''[[CELIAC1]]''. Over 95% of coeliac patients have an isoform of DQ2 (encoded by DQA1*05 and DQB1*02 genes) and [[HLA-DQ8|DQ8]] (encoded by the [[haplotype]] DQA1*03:DQB1*0302), which is inherited in families. The reason these genes produce an increase in 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/> [[Image:DQa2b5 da gliadin.JPG|frame|left|DQ α<sup>5</sup>-β<sup>2</sup> -binding cleft with a deamidated gliadin peptide (yellow), modified from {{PDB|1S9V}}<ref>{{cite journal | author = 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 U S A | volume = 101 | issue = 12 | pages = 4175–9 | year = 2004 | pmid=15020763 | url=http://www.pnas.org/cgi/content/full/101/12/4175 | doi = 10.1073/pnas.0306885101}} {{PMC|384714}}</ref>]] Most coeliac patients bear a two-gene [[HLA-DQ]] [[haplotype]] referred to as [[HLA-DQ2#DQ2.5|DQ2.5 haplotype]]. This haplotype is composed of 2 adjacent gene [[allele]]s, DQA1*0501 and [[HLA-DQ2#DQB1.2A0201|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 [[Chromosome 6 (human)|chromosomes 6]] inherited from parents. 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 | author = Jores RD, Frau F, Cucca F, ''et al'' | 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 portions of the haplotype ([[HLA-DQ|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, 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 disease tends not to be familial. Among the 6% of European celiacs that do not have DQ2.5(cis or trans) or DQ8, 4% are [[HLA-DQ2#DQB1.2A0202|DQB1*0202]] and 2% DQA1*05, 0.4% cannot be linked to DQ8, DQA1*05, or DQB1*02.<ref name="pmid12651074">{{cite journal |author=Karell K, Louka AS, Moodie SJ, ''et al'' |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 (historical territory)|Basque Country]], [[Ireland]],<ref>{{cite journal | author = Michalski J, McCombs C, Arai T, Elston R, Cao T, McCarthy C, Stevens F | 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}}</ref> with highest frequencies), portions of Africa, and is associated disease in India,<ref>{{cite journal |author=Kaur G, Sarkar N, Bhatnagar S, ''et al'' |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=}}</ref> but is not found along portions of the West Pacific rim. DQ8, spread more globally than DQ2.5, is more prevalent from South and Central America (up to 90% [[phenotype]] frequency).<ref>{{cite journal | author = 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> In addition to the ''CELIAC1'' locus, ''CELIAC2'' ([[Chromosome 5 (human)|5]]q31-q33 - ''IBD5'' locus), ''CELIAC3'' ([[Chromosome 2 (human)|2]]q33 - ''CTLA4'' locus), ''CELIAC4'' ([[Chromosome 19 (human)|19]]q13.1 - ''MYOIXB'' locus), have been linked to coeliac disease. The [[CTLA4]] and [[myosin IXB]] genes have been found to be linked to coeliac disease and other autoimmune diseases.<ref name="pmid16025348">{{cite journal | author = Zhernakova A, Eerligh P, Barrera P, ''et al'' | title = CTLA4 is differentially associated with autoimmune diseases in the Dutch population | journal = Hum. Genet. | volume = 118 | issue = 1 | pages = 58–66 | year = 2005 | pmid = 16025348 | doi = 10.1007/s00439-005-0006-z}}</ref><ref name="pmid17584584">{{cite journal | author = Sánchez E, Alizadeh BZ, Valdigem G, ''et al'' | title = MYO9B gene polymorphisms are associated with autoimmune diseases in Spanish population | journal = Hum. Immunol. | volume = 68 | issue = 7 | pages = 610–5 | year = 2007 | pmid = 17584584 | doi = 10.1016/j.humimm.2007.03.006}}</ref> Two additional loci on [[Chromosome 4 (human)|chromosome 4]], 4q27 (''IL2'' or ''IL21'' locus) and 4q14, have been found to be linked to coeliac disease.<ref name="pmid17558408">{{cite journal | author = van Heel DA, Franke L, Hunt KA, ''et al'' | title = A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21 | journal = Nat Genet | volume = 39 | issue = 7 | pages = 827–9 | year = 2007 | pmid = 17558408 | doi = 10.1038/ng2058}}</ref><ref>{{cite journal | author = Popat S, Bevan S, Braegger C, Busch A, O'Donoghue D, Falth-Magnusson K, Godkin A, Hogberg L, Holmes G, Hosie K, Howdle P, Jenkins H, Jewell D, Johnston S, Kennedy N, Kumar P, Logan R, Love A, Marsh M, Mulder C, Sjoberg K, Stenhammar L, Walker-Smith J, Houlston R | title = Genome screening of coeliac disease | journal = J Med Genet | volume = 39 | issue = 5 | pages = 328–31 | year = 2002 | url = http://jmg.bmjjournals.com/cgi/content/full/39/5/328 | pmid=12011149 | doi = 10.1136/jmg.39.5.328}}</ref> ===Prolamins=== 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 [[pepsin]] and [[chymotrypsin]], the two main digestive [[protease]]s in the gut. Gliadin in wheat is the best-understood member of this family, but other prolamins exist and [[hordein]] (from barley), and [[secalin]] (from rye) may contribute to coeliac disease.<ref name=VanHeelWest/> However, not all prolamins will cause this immune reaction and there is [[Gluten sensitivity#The oat controversy|ongoing controversy]] on the ability of [[avenin]] (the prolamin found in [[oats]]) to induce this response in coeliac disease. ===Tissue transglutaminase=== [[Image:Tissue transglutaminase.png|thumb|150px|[[Tissue transglutaminase]], drawn from {{PDB|1FAU}}.]] [[Anti-transglutaminase antibodies]] to the enzyme [[tissue transglutaminase]] (tTG) are found in an overwhelming majority of cases.<ref name=Dieterich>{{cite journal | author = Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken E, Schuppan D | title = Identification of tissue transglutaminase as the autoantigen of celiac disease | journal = Nat Med | volume = 3 | issue = 7 | pages = 797–801 | year = 1997 | pmid=9212111 | doi = 10.1038/nm0797-797}}</ref> Tissue transglutaminase modifies gluten [[peptide]]s into a form that may stimulate the immune system more effectively.<ref name=VanHeelWest/> Stored biopsies from suspected coeliac patients has revealed that [[autoantibody]] deposits in the [[Wiktionary:subclinical|subclinical]] coeliacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anemia or malabsorption phenomena at a much increased rate over the normal population.<ref name=Kaukinen>{{cite journal | author = Kaukinen K, Peraaho M, Collin P, Partanen J, Woolley N, Kaartinen T, Nuuntinen T, Halttunen T, Maki M, Korponay-Szabo I | title = Small-bowel mucosal tranglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: A Prospective and radmonized clinical study | journal = Scand J Gastroenterology | volume = 40 | pages = 564–572 | year = 2005 | pmid=16036509 | doi = 10.1080/00365520510023422}}</ref> Endomysial component 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 coeliac patients 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 |author=Salmi T, Collin P, Korponay-Szabó I, 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 | url=http://gut.bmj.com/cgi/content/full/55/12/1746 |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 recent work showing that gliadin has an innate response component,<ref name=InnateReview>{{cite journal | author = Londei M, Ciacci C, Ricciardelli I, Vacca L, Quaratino S, and 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> suggests 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 coeliac patients the anti-tTG antibodies also recognize a [[rotavirus]] protein called VP7. These antibodies stimulate [[monocytes]] proliferation and rotavirus infection might explain some early steps in the cascade of immune cell proliferation.<ref name = "toll-like">{{cite journal |author=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 | url=http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030358 |doi=10.1371/journal.pmed.0030358}} {{PMC|1569884}}</ref> Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy.<ref>{{cite journal | author = Salim A, Phillips A, Farthing M | title = Pathogenesis of gut virus infection | journal = Baillieres Clin Gastroenterol | volume = 4 | issue = 3 | pages = 593–607 | year = 1990 | pmid=1962725 | doi = 10.1016/0950-3528(90)90051-H}}</ref> 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. ===Villous atrophy and malabsorption=== 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. Alternative causes of this tissue damage have been proposed and involve 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 diet may require these alternative diagnoses to be considered.<ref name=AGA/> ===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 infection by [[rotavirus]]<ref>{{cite journal |author=Stene L, Honeyman M, Hoffenberg E, Haas J, Sokol R, Emery L, Taki I, Norris J, Erlich H, Eisenbarth G, Rewers M |title=Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study |journal=Am J Gastroenterol |volume=101 |issue=10 |pages=2333–40 |year=2006 |pmid=17032199| doi=10.1111/j.1572-0241.2006.00741.x}}</ref> or human intestinal [[adenovirus]].<ref>{{cite journal | author = Kagnoff M, Paterson Y, Kumar P, Kasarda D, Carbone F, Unsworth D, Austin R | title = Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease | journal = Gut | volume = 28 | issue = 8 | pages = 995–1001 | year = 1987 | pmid=2822550|url=http://gut.bmj.com/cgi/reprint/28/8/995|format=PDF | doi = 10.1136/gut.28.8.995}} {{PMC|1433141}}</ref> Some research has suggested that smoking is protective against adult onset coeliac disease.<ref>{{cite journal | author = Suman S, Williams E, Thomas P, Surgenor S, Snook J | title = Is the risk of adult coeliac disease causally related to cigarette exposure? | journal = Eur J Gastroenterol Hepatol | volume = 15 | issue = 9 | pages = 995–1000 | year = 2003 | pmid=12923372 | doi = 10.1097/00042737-200309000-00009}}</ref> A 2005 prospective and observational study found that timing of the exposure to gluten in childhood was an important risk modifier. People exposed to wheat, barley, or rye before the [[Gut flora|gut barrier]] has fully developed (three months after birth) had five times the risk of developing coeliac disease over those exposed at 4 to 6 months. Those exposed later had a slightly increased risk relative to those exposed at 4 to 6 months.<ref name="Norris">{{cite journal|author= Norris JM, Barriga K, Hoffenberg EJ, Taki I, Miao D, Haas JE, Emery LM, Sokol RJ, Erlich HA, Eisenbarth GS, Rewers M.|title=Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease | journal=JAMA | year=2005| volume=293 | issue=19| pages=2343–2351 | pmid=15900004 | url=http://jama.ama-assn.org/cgi/content/full/293/19/2343|doi=10.1001/jama.293.19.2343}}</ref> However a 2006 study with similar numbers found just the reverse, that early introduction of grains was protective.<ref>{{cite journal |author=Poole J, Barriga K, Leung D, Hoffman M, Eisenbarth G, Rewers M, Norris J |title=Timing of initial exposure to cereal grains and the risk of wheat allergy |journal=Pediatrics |volume=117 |issue=6 |pages=2175–82 |year=2006 |pmid=16740862 | url=http://pediatrics.aappublications.org/cgi/content/full/117/6/2175 |doi=10.1542/peds.2005-1803}}</ref> Breastfeeding may also reduce risk. A [[meta-analysis]] indicates that prolonging [[breastfeeding]] until the introduction of gluten-containing grains into the diet was associated with a 52% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear.<ref>{{cite journal |author=Akobeng A, Ramanan A, Buchan I, Heller R |title=Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies |journal=Arch Dis Child |volume=91 |issue=1 |pages=39–43 |year=2006 |pmid=16287899| url=http://adc.bmj.com/cgi/content/full/91/1/39 |doi=10.1136/adc.2005.082016}}</ref> ==Treatment== ===Diet=== {{main|Gluten-free diet}} Presently, the only effective treatment is a life-long [[gluten-free diet]].<ref name=Kupper/> No medication exists that will prevent damage, or prevent the body from attacking the gut when gluten is present. Strict adherence to the diet allows the intestines to 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.<ref>{{cite journal | author = Treem W | 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> [[Dietician]] input is generally requested to ensure the patient 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. More manufacturers are producing gluten-free products, some of which are almost indistinguishable from their gluten-containing counterparts. The diet can be cumbersome; failure to comply with the diet may cause relapse. 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 |author=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 |year=2008 |month=June |pmid=18315587 |doi=10.1111/j.1365-2036.2008.03669.x |doi_brokendate=2008-06-25}}</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 widely by country. For example, in the United States the term "gluten-free" is not yet regulated.<ref name=FDAregulation>{{cite web | publisher = US FDA | title = Questions and Answers on the Gluten-Free Labeling Proposed Rule | date = 2007-01-23 | url = http://www.cfsan.fda.gov/~dms/glutqa.html | accessdate=2008-06-26}}</ref> The current international [[Codex Alimentarius]] standard, established in 1981, allows for {{nowrap|50 mg N/100 g on [[dry matter]]}},<ref name=CodexOfficial>{{cite web | publisher = FAO/WHO | title = Current Official Standards | url = http://www.codexalimentarius.net/web/standard_list.jsp | accessdate=2008-06-26}}</ref> although a proposal for a revised standard of 20&nbsp;[[parts-per notation|ppm]] in naturally gluten-free products and 200&nbsp;ppm in products rendered gluten-free has been accepted.<ref name=Troncone2008>{{cite journal |author=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 |month=June |pmid=18315588 |doi=10.1111/j.1365-2036.2008.03668.x |url=http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2036.2008.03669.x}}</ref> Gluten-free products are usually more expensive and harder to find than common gluten-containing foods.<ref name=economicburden>{{cite journal |author=Lee AR, Ng DL, Zivin J, Green PH |title=Economic burden of a gluten-free diet |journal=J Hum Nutr Diet |volume=20 |issue=5 |pages=423–30 |year=2007 |month=October |pmid=17845376 |doi=10.1111/j.1365-277X.2007.00763.x |url=}}</ref> Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.<ref name=Troncone2008/> Even while on a diet, health-related quality of life (HRQOL) may be lower in people with coeliac disease. Studies in the United States have found that quality of life becomes comparable to the general population after staying on the diet while studies in Europe have found that quality of life remains lower, although the surveys are not quite the same.<ref name=Hauser2007>{{cite journal |author=Häuser W, Stallmach A, Caspary WF, Stein J |title=Predictors of reduced health-related quality of life in adults with coeliac disease |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=5 |pages=569–78 |year=2007 |month=March |pmid=17305757 |doi=10.1111/j.1365-2036.2006.03227.x |doi_brokendate=2008-06-25}}</ref> Men tend to report more improvement than women.<ref name=Goddard2006>{{cite journal |author=Goddard CJ, Gillett HR |title=Complications of coeliac disease: are all patients at risk? |journal=Postgrad Med J |volume=82 |issue=973 |pages=705–12 |year=2006 |month=November |pmid=17099088 |doi=10.1136/pgmj.2006.048876 |url=http://pmj.bmj.com/cgi/content/full/82/973/705}}</ref> Some have persisting digestive symptoms or [[dermatitis herpetiformis]], mouth ulcers, osteoporosis and resultant fractures. Symptoms suggestive of [[irritable bowel syndrome]] may be present, and there is an increased rate of anxiety, fatigue, [[dyspepsia]] and musculoskeletal pain.<ref name=Hauser2006>{{cite journal |author=Häuser W, Gold J, Stein J, Caspary WF, Stallmach A |title=Health-related quality of life in adult coeliac disease in Germany: results of a national survey |journal=Eur J Gastroenterol Hepatol |volume=18 |issue=7 |pages=747–54 |year=2006 |month=July |pmid=16772832 |doi=10.1097/01.meg.0000221855.19201.e8}}</ref> ===Refractory disease=== A tiny minority of patients suffer from refractory disease, which means they do not improve on a gluten-free diet. This may be because the disease has been present for so long that the intestines are no longer able to heal on diet alone, or because the patient is not adhering to the diet, or because the patient is consuming foods that are inadvertently contaminated with gluten. If alternative causes have been eliminated, [[glucocorticoid|steroids]] or [[Immunosuppressive drug|immunosuppressants]] (such as [[azathioprine]]) may be considered in this scenario.<ref name=AGA/> ===Experimental treatments=== Various other approaches are being studied that would reduce the need of dieting. All are still under development, and are not expected to be available to the general public for a while:<ref name=VanHeelWest/> * [[Genetic engineering|Genetically engineered]] wheat species, or wheat species that have been [[plant breeding|selectively bred]] to be minimally immunogenic. This, however, could interfere with the effects that gliadin has on the quality of dough. * 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]]. This combination would enable coeliac disease patients to consume gluten-containing products.<ref>{{cite journal | author = Siegel M, Bethune M, Gass J, Ehren J, Xia J, Johannsen A, Stuge T, Gray G, Lee P, Khosla C | title = Rational design of combination enzyme therapy for celiac sprue | journal = Chem Biol | volume = 13 | issue = 6 | pages = 649–58 | year = 2006 | pmid=16793522 | url=http://www.chembiol.com/content/article/fulltext?uid=PIIS1074552106001499 | doi = 10.1016/j.chembiol.2006.04.009}}</ref> * Inhibition of [[zonulin]], an endogenous signaling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system.<ref>{{cite journal | author = Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, Goldblum S | title = Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease | journal = Lancet | volume = 355 | issue = 9214 | pages = 1518–9 | year = 2000 | pmid=10801176 | doi = 10.1016/S0140-6736(00)02169-3}}</ref> * Other treatments aimed at 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 [[enterocyte]]s (bowel lining cells). ==Screening and case finding== There is significant debate as to the benefits of [[Screening (medicine)|screening]]. Some studies suggest that early detection would decrease the risk of osteoporosis and anaemia. In contrast, a [[cohort study|cohort studied]] in [[Cambridge]] suggested that people with undetected coeliac disease had a beneficial risk profile for [[cardiovascular disease]] (less [[overweight]], lower [[cholesterol]] levels).<ref name=VanHeelWest/> Due to its high sensitivity, [[serology]] has been proposed as a screening measure, because the presence of antibodies would detect previously undiagnosed cases of coeliac disease and prevent its complications in those patients. Serology may also be used to monitor adherence to diet: in those who still ingest gluten, antibody levels remain elevated.<ref name=Ciclitira/><ref name=AGA/> In the [[United Kingdom]], the [[National Institute for Health and Clinical Excellence]] (NICE) recommends screening for coeliac disease in patients with newly diagnosed [[chronic fatigue syndrome]]<ref>{{NICE|53|Chronic fatigue syndrome/myalgic encephalomyelitis|2007}}</ref> and [[irritable bowel syndrome]].<ref>{{NICE|61|Irritable bowel syndrome|2008}}</ref> Other clinical scenarios in which screening may be justified include type 1 diabetes,<ref name=Holmes/> unexplained iron-deficiency anemia,<ref>{{cite journal |author=Corazza G, Valentini R, Andreani M, D'Anchino M, Leva M, Ginaldi L, De Feudis L, Quaglino D, Gasbarrini G |title=Subclinical coeliac disease is a frequent cause of iron-deficiency anaemia |journal=Scand J Gastroenterol |volume=30 |issue=2 |pages=153–6 |year=1995 |pmid=7732338 |doi=10.3109/00365529509093254}}</ref><ref>{{cite journal |author=Ransford R, Hayes M, Palmer M, Hall M |title=A controlled, prospective screening study of celiac disease presenting as iron deficiency anemia |journal=J Clin Gastroenterol |volume=35 |issue=3 |pages=228&ndash;33 |year=2002 |pmid=12192198 |doi=10.1097/00004836-200209000-00006}}</ref> [[Down's syndrome]], [[Turner's syndrome]], [[Lupus erythematosus|lupus]], and autoimmune thyroid disease.<ref>{{cite journal |author=Sjöberg K, Carlsson A |title=Screening for celiac disease can be justified in high-risk groups |journal=Lakartidningen |volume=101 |issue=48 |pages=3912, 3915–6, 3918&ndash;9 |year=2004 |pmid=15631226|language=Swedish}}</ref> ==Epidemiology== The prevalence of 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 prevalence may be between 0.33 and 1.06% in children (5.66% in one study of [[Sahara]]wi children<ref name="Catassi1999">{{cite journal | author = Catassi C, Rätsch I, Gandolfi L, Pratesi R, Fabiani E, El Asmar R, Frijia M, Bearzi I, Vizzoni L | title = Why is coeliac disease endemic in the people of the Sahara? | journal = Lancet | volume = 354 | issue = 9179 | pages = 647–8 | year = 1999|pmid = 10466670 | doi = 10.1016/S0140-6736(99)02609-4}}</ref>) and 0.18–1.2% in adults.<ref name=VanHeelWest/> People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors. Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due to many clinicians being unfamiliar with the condition.<ref>{{cite journal |author=Zipser R, 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| doi=10.1111/j.1525-1497.2005.0107.x| url=http://www.blackwell-synergy.com/doi/full/10.1111/j.1525-1497.2005.0107.x |doi_brokendate=2008-06-25}} {{PMC|1490146}}</ref> 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 patients, 2.6% in second-degree relatives of a patient with coeliac disease and 4.5% in first-degree relatives. This profile is similar to the prevalence in Europe.<ref name="Fasano2003">{{cite journal | author = Fasano A, Berti I, Gerarduzzi T, Not T, Colletti R, Drago S, Elitsur Y, Green P, Guandalini S, Hill I, Pietzak M, Ventura A, Thorpe M, Kryszak D, Fornaroli F, Wasserman S, Murray J, Horvath K | title = Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study | journal = Archives of Internal Medicine | volume = 163 | issue = 3 | pages = 286–92 | year = 2003 | url = http://archinte.ama-assn.org/cgi/content/full/163/3/286 | pmid=12578508 | doi = 10.1001/archinte.163.3.286}}</ref> ==Social and religious issues== ===Christian churches & the Eucharist=== With exception of the Roman Catholic Church, most mainline Christian churches offer their communicants gluten-free alternatives to the [[sacramental bread]], usually in the form of a rice-based cracker or gluten-free bread. These include United Methodist, Christian Reformed, Episcopal, Lutheran, The Church of Jesus Christ of Latter-day Saints, and many others.<ref> Jax Peter Lowell, [http://books.google.com/books?id=IRhm1A2_EkkC&printsec=frontcover&source=gbs_summary_r&cad=0 ''The Gluten-Free Bible''], p. 279.</ref> ===Roman Catholic position=== [[Roman Catholic]] [[doctrine]] states that for a valid [[Eucharist]] the bread must be made from wheat. In 2002, the [[Congregation for the Doctrine of the Faith]] approved German-made low-gluten [[Host (Holy Communion)|hosts]], which meet all of the Catholic Church's requirements, for use in Italy; although not entirely gluten-free, they were also approved by the Italian Celiac Association.<ref>{{cite web | author = Scott Adams |url = http://www.celiac.com/st_prod.html?p_prodid=696 | title = Bishops in Italy Approve a German-made Low Gluten Eucharistic Host | date = [[August 2]], [[2002]] | publisher = Celiac.com}}</ref> Some Catholic coeliac sufferers have requested permission to use rice wafers; such petitions have always been denied.<ref>{{cite news | author = Associated Press |url = http://www.msnbc.msn.com/id/5762478/ |title = Girl with digestive disease denied Communion | work = MSNBC |publisher = Microsoft | date = [[December 8]], [[2004]] |accessdate = 2006-05-30}}</ref> The issue is more complex for priests. Though a Catholic (lay or ordained) receiving under either form is considered to have received Christ "whole and entire", the priest, who is acting ''[[in persona Christi]]'', is required to receive under both species when offering Mass &mdash; not for the validity of his Communion, but for the fullness of the sacrifice of the Mass. On [[August 22]], [[1994]], the [[Congregation for the Doctrine of the Faith]] apparently barred coeliacs from ordination, stating, "Given the centrality of the celebration of the Eucharist in the life of the priest, candidates for the priesthood who are affected by coeliac disease or suffer from alcoholism or similar conditions may not be admitted to holy orders." After considerable debate, the congregation softened the ruling on [[24 July]] [[2003]] to "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]] ([[July 24]], [[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 | accessdate = 2007-03-07 | work = BCL Newsletter | month = November | year = 2003 | publisher = [[United States Conference of Catholic Bishops]]}}</ref> As of January 2004, an extremely low-gluten host became available in the United States. The [[Benedictine Sisters of Perpetual Adoration]] in Clyde, MO, after ten years of perseverance, trial, and error, have produced a low-gluten host safe for celiacs and also approved by the Catholic Church for use at Mass. Each host is made and packaged in a dedicated wheat-free / gluten-free environment. The hosts are made separately by hand, unlike the common host which is stamped out of a long thin sheet of bread by a cutter. Therefore, each host is a slightly different size and shape. Most importantly, the finished hosts have been analyzed for gluten content. The gluten content of these hosts is reported as 0.01 %. In actuality, the gluten content is probably less than 0.01%. Sister Lynn, OSB, said that the result of the analysis of the finished host revealed "no gluten detected". The hosts are labeled as 0.01 % since the lowest limit of detection of this analysis was 0.01 %. In an article from the Catholic Review ([[February 15]], [[2004]]) Dr. Alessio Fasano was quoted as declaring these hosts "perfectly safe for celiac sufferers." <ref>{{cite web |url=http://www.catholic.org/featured/headline.php?ID=1340 |title=Liturgy: Gluten-free Hosts |accessdate=2007-06-17 |last=McNamara |first= Father Edward |date=[[2004-09-15]] |year=|month= |format= |work= Catholic Online}}</ref> ===Coeliacs and Passover=== The Jewish festival of [[Passover|Pesach]] (Passover) may present problems with its obligation to eat [[matzo]], which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. This rules out many other grains that are normally used as substitutes for people with gluten sensitivity, especially for [[Ashkenazi Jews]] who also avoid [[rice]]. Many kosher for Passover products avoid grains altogether and are therefore gluten-free. Potato starch is the primary starch used to replace the grains. Consuming matzo is mandatory on the first night of Pesach only. Jewish law holds that a person should not seriously endanger one's health in order to fulfill a commandment. Thus, a person with severe coeliac disease is not required, or even allowed, to eat any matzo other than gluten-free matzo. The most commonly used gluten-free matzo is made from oats.<ref>{{cite web | url = http://oukosher.org/index.php/articles/single/gluten_intolerance_celiac_allergies_and_pesach/ | title = Gluten Intolerance, Celiac, Allergies And Pesach | accessdate = 2006-09-03 | author = Rabbi Avraham Juravel | publisher = Orthodox Union }}</ref> ==History== [[Aretaeus of Cappadocia]], living in the second century, recorded a malabsorptive syndrome with chronic diarrhoea. His "Cœliac Affection" (coeliac from [[Greek language|Greek]] κοιλιακός ''koiliakos'', abdominal) gained the attention of Western medicine when [[Francis Adams (translator)|Francis Adams]] presented a translation of Aretaeus' work at the Sydenham Society in 1856. The patient 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 the 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"/> The [[pediatrics|paediatrician]] [[Samuel Gee]] gave the first modern-day description of the condition 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). Unlike Aretaeus, he included children in the scope of the affliction, particularly those between one and five years old. Gee found the cause to be obscure and failed to spot anything abnormal during post-mortem examination (the lining of the small bowel quickly deteriorates on death).<ref name=Holmes2006>{{cite web | url = http://www.coeliac.co.uk/coeliac_disease/68.asp | title = History of coeliac disease | accessdate = 2007-03-20 | last = Holmes | first = Geoff | year = 2006 | publisher = Coeliac UK}}</ref> 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>{{cite journal | last = Gee | first = 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}}</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". 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 | last = Herter | first = CA | year = 1908 | title = On infantilism from chronic intestinal infection; characterized by the overgrowth and persistence of flora in the nursing period | 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 | accessdate = 2007-03-20 | author = Ole Daniel Enersen | publisher = Who Named It?}}</ref> Sydney V. Haas, an American paediatrician, reported positive effects of a diet of [[banana]]s in 1924.<ref>{{cite journal|author=Haas SV|year=1924|title= The value of the banana in the treatment of coeliac disease|journal=Am J Dis Child|volume=24| pages=421–37}}</ref> This diet remained in vogue until the actual cause of coeliac disease was determined. While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Dr Willem Dicke.<ref>{{cite journal | author = van Berge-Henegouwen G, Mulder C | 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 | url= http://gut.bmj.com/cgi/reprint/34/11/1473 | format=PDF | doi = 10.1136/gut.34.11.1473}} {{PMC|1374403}}</ref> It is likely that clinical improvement of his patients during the [[Dutch famine of 1944]] (during which flour was sparse) may have contributed to his discovery.<ref>Dicke WK. ''Coeliakie: een onderzoek naar de nadelige invloed van sommige graansoorten op de lijder aan coeliakie'' [PhD thesis]. Utrecht, the Netherlands: University of Utrecht, 1950.</ref> The link with the gluten component of wheat was made in 1952 by a team from [[Birmingham]], England.<ref>{{cite journal | author = Anderson C, French J, Sammons H, Frazer A, Gerrard J, Smellie J | 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.<ref>{{cite journal | author = Paulley JW | title = Observation on the aetiology of idiopathic steatorrhoea; jejunal and lymph-node biopsies | journal = Br Med J | volume = 4900 | issue = | pages = 1318–21 | year =1954 |pmid=13209109}} {{PMC|2080246}}</ref> Paulley was able to examine biopsies taken from patients during abdominal operations.<ref name=Holmes2006/> Dr Margo Shiner, working on Prof Sheila Sherlock's team at the [[Royal Postgraduate Medical School|Postgraduate Medical School]] in London, described the principles of small bowel biopsy in 1956.<ref>{{cite journal | author = Shiner M | title = Duodenal biopsy | journal = Lancet | volume = 270 | issue = 6906 | pages = 17–9 | year = 1956 | pmid=13279152 | doi = 10.1016/S0140-6736(56)91854-2}}</ref> Throughout the 1960s other features of coeliac disease were elucidated. Its hereditary character was recognized in 1965.<ref>{{cite journal |author=Macdonald W, Dobbins W, Rubin C |title=Studies of the familial nature of celiac sprue using biopsy of the small intestine |journal=N Engl J Med |volume=272 |issue= |pages=448–56 |year=1965 |pmid=14242522}}</ref> In 1966 [[dermatitis herpetiformis]] was linked to gluten sensitivity.<ref name=Marks/> ==References== {{reflist|2}} ==External links== {{Cookbook|Gluten-Free}} *{{dmoz|Health/Conditions_and_Diseases/Digestive_Disorders/Intestinal/Celiac_Disease/}} * [http://www.celiac.com Celiac.com] - U.S. resource * [http://www.coeliac.co.uk/ Coeliac UK] - leading UK charity * [http://www.celiac.nih.gov Celiac Disease Awareness Campaign from the National Institutes of Health] * [http://www.celiac.org/ Celiac Disease Foundation] - U.S. * [http://www.worldgastroenterology.org/04_celiac_disease.pdf.html Celiac Disease practice guideline] from the World Gastroenterology Organisation (WGO) * [http://www.csaceliacs.org Celiac Sprue Association] - U.S. * Outcomes of 2004 [http://consensus.nih.gov/2004/2004CeliacDisease118html.htm consensus development conference], U.S. [[National Institutes of Health]] * [http://digestive.niddk.nih.gov/ddiseases/pubs/celiac/ National Digestive Diseases Clearinghouse] - page on coeliac disease * [http://www.celiaccentral.org/ National Foundation for Celiac Awareness] - U.S. * [http://www.celiaccenter.org University of Maryland Center for Celiac Research] - U.S. {{Gastroenterology}} {{featured article}} [[Category:Autoimmune diseases]] [[Category:Gastroenterology]] [[Category:Genetic disorders]] [[Category:Malnutrition]] [[Category:Pediatrics]] {{Link FA|de}} [[ca:Celiaquia]] [[cs:Celiakie]] [[da:Cøliaki]] [[de:Zöliakie]] [[es:Celiaquía]] [[eo:Celiakio]] [[fa:بیماری سیلیاک]] [[fr:Maladie cœliaque]] [[it:Celiachia]] [[he:כרסת]] [[lv:Celiakija]] [[hu:Cöliákia]] [[nl:Coeliakie]] [[ja:セリアック病]] [[no:Cøliaki]] [[oc:Celiaquia]] [[pl:Celiakia]] [[pt:Doença celíaca]] [[ro:Celiachie]] [[ru:Целиакия]] [[sk:Celiakia]] [[sr:Целијачна болест]] [[fi:Keliakia]] [[sv:Glutenintolerans]] [[tr:Çölyak hastalığı]] [[ur:مرض سیلیئک]]