Gluten-related disorders: Difference between revisions

{{about-distinguish2distinguish-text|disorders related to [[gluten]], a natural ingredient in many cereals|sensitivities related to [[Glutamate flavoring|glutamate]], a flavor-enhancing additive}}

[[Gluten]] is a group of [[protein]]s, such as [[prolamin]]s and [[glutelin]]s,<ref name=FDAlabeling2007>{{cite web |url=https://www.fda.gov/OHRMS/DOCKETS/98fr/05n-0279-npr0001.pdf|title= Food Labeling ; Gluten-Free Labeling of Foods |date= January 2007 |author= Food and Drug Administration |website= [[Food and Drug Administration]] |archive-url= https://web.archive.org/web/20070126011901/https://www.fda.gov/OHRMS/DOCKETS/98fr/05n-0279-npr0001.pdf |archive-date= 2007-01-26 }}</ref> stored with [[starch]] in the [[endosperm]] of various [[cereal|cereal (grass) grains]].

{{As of|2017}}, gluten-related disorders were increasing in frequency in different geographic areas. The increase might be explained by the popularity of the [[Western diet]], the expanded reach of the [[Mediterranean diet]] (which also includes grains with gluten), the growing replacement of rice by wheat in many countries,<ref name=TovoliMasi>{{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 J Clin Cases| volume = 3| issue = 3| pages = 275–84| date = March 16, 2015| pmid = 25789300|pmc= 4360499| doi = 10.12998/wjcc.v3.i3.275| doi-access = free}}</ref> the development in recent years of new types of wheat with a higher amount of [[Cytotoxicity|cytotoxic]] gluten [[peptide]]s,<ref name="VoltaCaioQuestions" /> and the higher content of gluten in bread and bakery products, due to the reduction of dough [[fermentation]] time.<ref name="VoltaCaioQuestions" /> However, a 2020 study by the Leibniz-Institute for Food Systems Biology casts doubt on the idea that modern wheat has higher gluten levels. From a seed bank, they grew and analyzed 60 wheat cultivars from between 1891 and 2010 and found no changes in albumin/globulin and gluten contents over time. "Overall, the harvest year had a more significant effect on protein composition than the cultivar. At the protein level, we found no evidence to support an increased immunostimulatory potential of modern winter wheat."<ref name = Scherf>{{cite journal |last1=Pronin |first1=Darina |last2=Borner |first2=Andreas |last3=Weber |first3=Hans |last4=Scherf |first4=Ann |title=Wheat (Triticum aestivum L.) Breeding from 1891 to 2010 Contributed to Increasing Yield and Glutenin Contents but Decreasing Protein and Gliadin Contents |journal=Journal of Agricultural and Food Chemistry |date=10 July 2020 |volume=68 |issue=46 |pages=13247–13256 |doi=10.1021/acs.jafc.0c02815|pmid=32648759 |s2cid=220469138 }}</ref>

The following classification of gluten-related disorders was announced in 2011 by a panel of experts in London, and published in February 2012:<ref>{{cite journal|last1=Sapone|first1=Anna|display-authors=etal|title=Spectrum of gluten-relate disorders: consensus on new nomenclature and classification|journal=BMC Medicine|date=7 February 2012|volume=2012|issue=10:13|pages=13|doi=10.1186/1741-7015-10-13|pmid=22313950|pmc=3292448 |doi-access=free }}</ref><ref name="Czaja-Bulsa-2014-section9-figure2">{{cite journal |author=Czaja-Bulsa G |title=Non coeliac gluten sensitivity - A new disease with gluten intolerance |journal=Clinical Nutrition (Edinburgh, Scotland) |volume= 34|issue= 2|pages= 189–194| date=August 2014 |pmid=25245857 |doi=10.1016/j.clnu.2014.08.012 |type=Review|doi-access=free }} See section 9 and Figure 2: Classification of gluten-dependent disorders.</ref>

[[Coeliac disease]] ([[American and British English spelling differences|American English]]: celiac) (CD) is one of the most common chronic, immune-mediated disorders, triggered by the eating of [[gluten]], a mixture of proteins found in [[wheat]], [[barley]], [[rye]], and [[oats]] and derivatives.<ref name=Biesiekierski2017>{{cite journal| author=Biesiekierski JR| s2cid=6493455 | title=What is gluten? | journal=J Gastroenterol Hepatol | year= 2017 | volume= 32 | issue=Suppl 1 | pages= 78–81 | pmid=28244676 | doi=10.1111/jgh.13703 | type=Review | quote= Similar proteins to the gliadin found in wheat exist as secalin in rye, hordein in barley, and avenins in oats and are collectively referred to as “gluten.” The gluten found in all of these grains has been identified as the component capable of triggering the immune-mediated disorder, coeliac disease.| doi-access=free }}{{open access}}</ref><ref name=LebwoholLudvigsson /> Evidence has shown that this condition not only has an environmental component but a genetic one as well, due to strong associations of CD with the presence of HLA ([[Human leukocyte antigen]]) type II, specifically DQ2 and DQ8 alleles.<ref name=Denham>{{cite journal|last1=Denham|first1=JM|last2=Hill|first2=ID|title=Celiac disease and autoimmunity: review and controversies.|journal=Current Allergy and Asthma Reports|date=August 2013|volume=13|issue=4|pages=347–53|pmid=23681421|doi=10.1007/s11882-013-0352-1|pmc=3725235}}</ref> These alleles can stimulate a [[T&nbsp;cell]], mediated immune response against tissue [[transglutaminase]] (TTG), an enzyme in the extracellular matrix, leading to inflammation of the intestinal mucosa and eventually villous atrophy of the small intestine.<ref name=Pasha>{{cite journal|last1=Pasha|first1=I|last2=Saeed|first2=F|last3=Sultan|first3=MT|last4=Batool|first4=R|last5=Aziz|first5=M|last6=Ahmed|first6=W|s2cid=25585961|title=Wheat Allergy and Intolerence; Recent Updates and Perspectives.|journal=Critical Reviews in Food Science and Nutrition|date=2 January 2016|volume=56|issue=1|pages=13–24|pmid=24915366|doi=10.1080/10408398.2012.659818}}</ref> This is where the innate and adaptive immune response systems collide.

CD is not only a gastrointestinal disease. It may involve several organs and cause an extensive variety of non-gastrointestinal symptoms. Most importantly, it may often be completely asymptomatic. Added difficulties for diagnosis are the fact that [[serological]] markers ([[Anti-transglutaminase antibodies#Anti-tissue transglutaminase|anti-tissue transglutaminase]] [TG2]) are not always present<ref name=NEJM2012>{{cite journal|last1=Fasano|first1=A|last2=Catassi|first2=C|title=Clinical practice. Celiac disease.|journal=The New England Journal of Medicine|date=December 20, 2012|volume=367|issue=25|pages=2419–26|pmid=23252527|doi=10.1056/NEJMcp1113994}}</ref> and many people may have minor mucosal lesions, without atrophy of the [[intestinal villi]].<ref name=BoldRostami>{{cite journal | vauthors = Bold J, Rostami K| title = Gluten tolerance; potential challenges in treatment strategies | journal = Gastroenterol Hepatol Bed Bench | volume = 4| issue = 2| pages = 53–7| date = 2011 | pmid = 24834157|pmc= 4017406}}</ref> Diagnosis of CD should be based on a combination of person’sperson's familial history, genetics (i.e. presence of HLA DQ2/DQ8) serology and intestinal histology.<ref name=ElliBranchi />

CD affects approximately 1–2% of general population all over the world,<ref name=LundinWijmenga2015>{{cite journal|vauthors=Lundin KE, Wijmenga C|s2cid=24533103|title=Coeliac disease and autoimmune disease-genetic overlap and screening|journal=Nat Rev Gastroenterol Hepatol|volume=12|issue=9|pages=507–15|date =September 2015|pmid=26303674|doi=10.1038/nrgastro.2015.136}}</ref> but most cases remain unrecognized, undiagnosed and untreated, and exposed to the risk of long-term complications.<ref name="ElliBranchi" /><ref name="Fasano2005Pediatric">{{cite journal | author =Schuppan Fasano& Gisbert-Schuppan A|date=2019 |title =Wheat ClinicalSyndromes: presentationHow ofWheat, celiacGluten diseaseand inATI theCause pediatricInflammation, populationIBS |and journalAutoimmune Diseases |journal= GastroenterologyBook | volume = 128| issue = 4 Suppl 1| pages = S68–73| date doi= April 2005| pmid= |via=Springer 15825129Nature |Switzerland doiAG, = 10.1053/j.gastro.2005.02Switzerland.015}}</ref> People may sufferexperience severe disease symptoms and be subjected to extensive investigations for many years, before a proper diagnosis is achieved.<ref name=LudvigssonCard>{{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 Gastroenterol J | volume = 3 | issue = 2 | pages = 146–59 | date = April 2015 | pmid = 25922674 | pmc = 4406900 |doi = 10.1177/2050640614562599}}</ref> Untreated CD may result in the lack of absorption of nutrients, reduced quality of life, [[iron deficiency]], [[osteoporosis]], an increased risk of intestinal [[lymphoma]]s and greater mortality.<ref name=LebwoholLudvigsson /> CD is associated with some autoimmune diseases, such as [[diabetes mellitus type 1]],<ref name="Denham" /> [[thyroiditis]],<ref name=LundinWijmenga>{{cite journal | vauthors = Lundin KE, Wijmenga C| s2cid = 24533103| title = Coeliac disease and autoimmune disease-genetic overlap and screening| journal = Nat Rev Gastroenterol Hepatol| volume = 12| issue = 9| pages = 507–15| date = September 2015 | pmid = 26303674 | doi = 10.1038/nrgastro.2015.136}}</ref> [[ataxia|gluten ataxia]], [[psoriasis]], [[vitiligo]], [[autoimmune hepatitis]], [[dermatitis herpetiformis]], [[primary sclerosing cholangitis]], and more.<ref name=LundinWijmenga />

To date, the only available medically accepted treatment for people with coeliac disease is to follow a lifelong gluten-free diet.<ref name="ElliBranchi" /><ref name="LamacchiaCamarca2014">{{cite journal |vauthors=Lamacchia C, Camarca A, Picascia S, Di Luccia A, Gianfrani C |title=Cereal-based gluten-free food: how to reconcile nutritional and technological properties of wheat proteins with safety for celiac disease patients |journal=Nutrients |volume=6 |issue=2 |pages=575–90 |year=2014 |pmid=24481131 |pmc=3942718 |doi=10.3390/nu6020575 |type=Review|doi-access=free }}</ref><ref name="De Palma">{{cite journal |last1=Palma |first1=Giada De |last2=Nadal |first2=Inmaculada |last3=Collado |first3=Maria Carmen |last4=Sanz |first4=Yolanda |title=Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects |journal=British Journal of Nutrition |date=2009 |volume=102 |issue=8 |pages=1154–1160 |doi=10.1017/S0007114509371767 |pmid=19445821 |s2cid=4537912 |hdl=10261/15885 |hdl-access=free }}</ref>

The age of onset is variable starting in children and adolescence but can also affect individuals of both sexes indistinctly at any age of their lives.<ref name=MendesHissaElian /><ref name=AntigaCaproni>{{cite journal | vauthors = Antiga E, Caproni M | title = The diagnosis and treatment of dermatitis herpetiformis| journal = Clin Cosmet Investig Dermatol| volume = 8 | pages = 257–65 | date = May 13, 2015 | pmid = 25999753 |pmc= 4435051| doi = 10.2147/CCID.S69127| doi-access = free}}</ref>

Early diagnosis and treatment with a [[gluten-free diet]] can improve ataxia and prevent its progression. The effectiveness of the treatment depends on the elapsed time from the onset of the ataxia until diagnosis, because the death of [[Purkinje cells|neurons in the cerebellum]] as a result of gluten exposure is irreversible.<ref name="HadjivassiliouSanders2015" /><ref name="MitomaAdhikari2016">{{cite journal| vauthors=Mitoma H, Adhikari K, Aeschlimann D, Chattopadhyay P, Hadjivassiliou M, Hampe CS et al.| title=Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias | journal=Cerebellum | year= 2016 | volume= 15 | issue= 2 | pages= 213–32 | pmid=25823827 | doi=10.1007/s12311-015-0664-x | pmc=4591117 | type=Review }} </ref>

Gluten ataxia accounts for 40% of ataxias of unknown origin and 15% of all ataxias.<ref name="HadjivassiliouSanders2015">{{cite journal| vauthors=Hadjivassiliou M, Sanders DD, Aeschlimann DP| s2cid=207673823 | title=Gluten-related disorders: gluten ataxia | journal=Dig Dis | year= 2015 | volume= 33 | issue= 2 | pages= 264–8 | pmid=25925933 | doi=10.1159/000369509 | type=Review }} </ref><ref name="pmid12566288">{{cite journal | vauthors = Hadjivassiliou M, Grünewald R, Sharrack B, Sanders D, Lobo A, Williamson C, Woodroofe N, Wood N, Davies-Jones A | title = Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics | journal = Brain | volume = 126 | issue = Pt 3 | pages = 685–91 | date = March 2003 | pmid = 12566288 | doi = 10.1093/brain/awg050 | doi-access = free }}</ref> Less than 10% of people with gluten ataxia present any gastrointestinal symptom, yet about 40% have intestinal damage.<ref name="HadjivassiliouSanders2015" />

Non-celiac gluten sensitivity (NCGS), or gluten sensitivity (GS)intolerance,<ref name="pmid22345659" /> is a possible syndrome in which people develop a variety of intestinal and/or extraintestinal symptoms that improve when [[gluten]] is removed from the diet,<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 excluded.<ref name="FasanoSapone2015" /> NCGS, which is possibly immune-mediated, now appears to be more common than coeliac disease,<ref name="Hogg-Collars-2014">{{cite journal |vauthors=Hogg-Kollars S, Al Dulaimi D, Tait K, Rostami K |title=Type 1 diabetes mellitus and gluten induced disorders |journal=Gastroenterology and Hepatology from Bed to Bench |volume=7 |issue=4 |pages=189–97 |year=2014 |pmid=25289132 |pmc=4185872 |type=Review}}</ref> with a prevalence estimated to be 6–10 times higher.<ref name=MolinaInfanteSantolaria>{{cite journal | vauthors = Molina-Infante J, Santolaria S, Montoro M, Esteve M, Fernández-Bañares F| title = [Non-celiac gluten sensitivity: a critical review of current evidence] [Article in Spanish] | journal = Gastroenterol Hepatol | volume = 37| issue = 6 | pages = 362–71 | date = 2014 | pmid = 24667093 | doi = 10.1016/j.gastrohep.2014.01.005}}</ref>

Gastrointestinal symptoms, which resemble those of [[irritable bowel syndrome]] (IBS),<ref name=ElliRoncorni /><ref name="CatassiBai2013">{{cite journal|vauthors=Catassi C, Bai J, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, Vécsei A, Volta U, Zevallos V, Sapone A, Fasano A|title=Non-celiac gluten sensitivity: the new frontier of gluten related disorders|journal=Nutrients|volume=5|issue=10|year=2013|pages=3839–3853|issn=2072-6643|doi=10.3390/nu5103839|pmid=24077239|type=Review|pmc=3820047|doi-access=free}}</ref> may include any of the following: [[abdominal pain]], [[bloating]], bowel habit abnormalities (either [[diarrhea]] or [[constipation]]),<ref name="CatassiBai2013" /><ref name=VoltaCaio2015>{{cite journal | vauthors = Volta U, Caio G, De Giorgio R, Henriksen C, Skodje G, Lundin KE| title = Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat-related disorders | journal = Best Pract Res Clin Gastroenterol | volume = 29| issue = 3| pages = 477–91| date = June 2015| pmid = 26060112 | doi = 10.1016/j.bpg.2015.04.006}}</ref> [[nausea]], [[aerophagia]], [[gastroesophageal reflux disease]], and [[aphthous stomatitis]].<ref name=FasanoSapone2015 /><ref name="CatassiBai2013" />

Gluten is likely responsible for the appearance of symptoms, but it has been suggested than in a subgroup of people with NCGS and symptoms like IBS, other components of wheat and related grains (oligosaccharides like fructans), or other plant proteins contained in gluten-containing cereals (agglutinins, lectins, and [[amylase trypsin inhibitor]]s (ATIs)) may play a role in the development of gastrointestinal symptoms.<ref name=ElliBranchi>{{cite journal | vauthors = Elli L, Branchi F, Tomba C, Villalta D, Norsa L, Ferretti F, Roncoroni L, Bardella MT| title = Diagnosis of gluten related disorders: Celiac disease, wheat allergy and non-celiac gluten sensitivity | journal = World J Gastroenterol | volume = 21 | issue = 23 | pages = 7110–9 | date = June 2015 | pmid = 26109797 |pmc= 4476872 | doi = 10.3748/wjg.v21.i23.7110 | doi-access = free }}</ref> ATIs are about 2–4% of the total protein in modern wheat and 80–90% in gluten.<ref name="FasanoSapone2015" /> In a review of May 2015 published in [[Gastroenterology (journal)|''Gastroenterology'']], [[Alessio Fasano|Fasano]] ''et al.'' conclude that ATIs may be the inducers of innate immunity in people with coeliac disease or NCGS.<ref name=FasanoSapone2015 /> As of 2019, reviews conclude that although [[FODMAP]]s present in wheat and related grains may play a role in non-celiac gluten sensitivity, they only explain certain gastrointestinal symptoms, such as [[bloating]], but not the [[non-celiac gluten sensitivity#Extraintestinal|extra-digestive symptoms]] that people with non-celiac gluten sensitivity may develop, such as [[neurological disorder]]s, [[fibromyalgia]], psychological disturbances, and [[dermatitis]].<ref name=Verbeke2018>{{cite journal |last1=Verbeke |first1=K |title=Nonceliac Gluten Sensitivity: What Is the Culprit? |journal=Gastroenterology |date=February 2018 |volume=154 |issue=3 |pages=471–473 |doi=10.1053/j.gastro.2018.01.013 |pmid=29337156| quote=Although intolerance to fructans and other FODMAPs may contribute to NCGS, they may only explain gastrointestinal symptoms and not the extraintestinal symptoms observed in NCGS patients, such as neurologic dysfunction, psychological disturbances, fibromyalgia, and skin rash.15 Therefore, it is unlikely that they are the sole cause of NCGS.|doi-access=free }}</ref><ref name=VoltaDeGiorgio2019>{{cite journal| vauthors=Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A| title=Nonceliac Wheat Sensitivity: An Immune-Mediated Condition with Systemic Manifestations | journal=Gastroenterol Clin North Am | date= March 2019 | volume= 48 | issue= 1 | pages= 165–182 | pmid=30711208 | doi=10.1016/j.gtc.2018.09.012 | pmc=6364564 | type=Review |quote=Furthermore, a role for the FODMAP (eg, fructans) component of wheat as the sole trigger for symptoms is somewhat doubtful, because many patients with NCWS report resolution of symptoms after the withdrawal of wheat and related cereals, while continuing to ingest vegetables and fruits with high FODMAP content in their diets.59 On the whole, it is conceivable that more than one culprit may be involved in symptoms of NCWS (as they are currently defined), including gluten, other wheat proteins, and FODMAPs.60–62 }} </ref><ref name="FasanoSapone2015" /> As occurs in people with coeliac disease, the treatment is a [[gluten-free diet]] (GFD) strict and maintained, without making any dietary transgression.<ref name=VoltaCaio2015 /> Whereas coeliac disease requires adherence to a strict lifelong gluten-free diet, it is not yet known whether NCGS is a permanent, or a transient condition.<ref name=VriezingaSchweizer /><ref name=VoltaCaio2015 /> The results of a 2017 study suggest that NCGS may be a chronic disorder, as is the case with celiac disease.<ref name=VoltaDeGiorgio2019 /> Theoretically, a trial of gluten reintroduction to observe reaction after 1–2 years of strict gluten-free diet might be advisable.<ref name=VoltaCaio2015 />

Approximately one-third of persons with NCGS continue having symptoms despite gluten withdrawal. This may be due to diagnostic error, poor dietary compliance, or other reasons. Those afflicted with NCGS may be under the impression that they do not need to follow a strictly [[gluten free diet]]. However, the ingestion of even a small amount of gluten may cause more immediate symptoms in people suffering fromwith NCGS as compared with those afflicted with coeliac disease. People with NCGS should carefully read ingredient labels on food and be aware of potential [[cross contamination]] as a source of gluten in otherwise gluten-free foods. To find out if there are unintended ingestions of gluten, an exhaustive evaluation with the advice of a coeliac disease specialized dietitian could be necessary.<ref name=VoltaCaio2015 />

In some cases, people can significantly improve with a low FODMAPs diet in addition to gluten withdrawal<ref name="VoltaCaioQuestions" /> and/or a GFD with a low content of preservatives and additives.<ref name="VoltaCaioQuestionsQuotation">{{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 and Molecular Immunology|volume=10|issue=5|year=2013|pages=383–392|issn=1672-7681|doi=10.1038/cmi.2013.28|pmid=23934026|type=Review|pmc=4003198}}</ref> Furthermore, associated to gluten sensitivity, NCGS people may often present IgE-mediated [[allergy|allergies]] to one or more foods<ref name=VoltaCaio2015 /> and it is estimated that around 35% of people sufferwith some [[food intolerance]]s, mainly [[lactose intolerance]].<ref name=AzizHadjivassiliou2015>{{cite journal | vauthors = Aziz I, Hadjivassiliou M, Sanders DS | s2cid = 2867448 | title = The spectrum of noncoeliac gluten sensitivity | journal = Nat Rev Gastroenterol Hepatol | volume = 12| issue = 9| pages = 516–26| date = September 2015| pmid = 26122473 | doi = 10.1038/nrgastro.2015.107 | type= Review }}</ref>

People can also experience adverse effects of wheat as result of a [[wheat allergy]].<ref name=ElliBranchi /> Gastrointestinal symptoms of wheat allergy are similar to those of coeliac disease and non-celiac gluten sensitivity, but there is a different interval between exposure to wheat and onset of symptoms. Wheat allergy has a fast onset (from minutes to hours) after the consumption of food containing wheat and could be [[anaphylaxis]].<ref name=NEJM2012 /><ref name=ScherfBrockowQuotation>{{cite journal|vauthors=Scherf KA, Brockow K, Biedermann T, Koehler P, Wieser H|title=Wheat-Dependent Exercise-Induced Anaphylaxis|journal=Clin Exp Allergy [Epub ahead of print]|volume=46|issue=1|pages=10–20|date=September 18, 2015|pmid=26381478|doi =10.1111/cea.12640|s2cid=25066563}}</ref>

The treatment of wheat allergy consists of complete withdrawal of any food containing wheat and other gluten-containing cereals.<ref name=ScherfBrockowQuotation /><ref name=HischenhuberCrevelQuotation>{{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=Aliment Pharmacol Ther |volume=23|issue=5|pages=559–75|date=March 1, 2006|pmid =16480395|doi=10.1111/j.1365-2036.2006.02768.x|doi-access=free}}</ref> Nevertheless, some people can tolerate barley, rye or oats.<ref name=Pietzak>{{cite journal|author=Pietzak M|title=Celiac disease, wheat allergy, and gluten sensitivity: when gluten free is not a fad|journal=JPEN J Parenter EnteralEnter Nutr|volume=36|issue=1 Suppl|pages=68S–75S|date=Jan 2012|pmid=22237879|doi=10.1177/0148607111426276}}</ref>

=== Other conditions or risk factors ===

[[Anti-gliadin antibodies|Antibodies to α-gliadin]] have been significantly increased in non-celiacs individuals with [[oral ulceration]].<ref name="pmid1753350">{{cite journal |vauthors=O'Farrelly C, O'Mahony C, Graeme-Cook F, Feighery C, McCartan BE, Weir DG | author-link1 = Cliona O’Farrelly | title = Gliadin antibodies identify gluten-sensitive oral ulceration in the absence of villous atrophy | journal = Journal of Oral Pathology and Medicine | volume = 20 | issue = 10 | pages = 476–8 | year = 1991 | pmid = 1753350 | doi =10.1111/j.1600-0714.1991.tb00407.x }}</ref> Anti-α-gliadin antibodies are frequently found in celiac disease (CD), to a lesser degree [[wikt:subclinical|subclinical]] CD, but are also found in a subset who do not have the disease. Of people with [[pseudo-exfoliation syndrome]], 25% showed increased levels of anti-gliadin IgA.<ref name="pmid7656149">{{cite journal |vauthors=Ringvold A, Overgaard RG | title = Increased IgA antibodies to gluten and gliadin in serum of persons with ocular pseudo-exfoliation | journal = Acta Ophthalmologica Scandinavica | volume = 73 | issue = 2 | pages = 171–2 | year = 1995 | pmid = 7656149 | doi =10.1111/j.1600-0420.1995.tb00662.x | type=Comparative Study}}</ref> Other people that are also at risk are those taking gluten despite having the disorder, or whose family members have CD. In addition people with autoimmune conditions are also at risk for CD. It has just been found that there is a risk of death in CD. Therefore, gluten intake should be limited before or even after the diagnosis.<ref name="coeliac disease in children">{{Cite journal|date=2015-08-05|title=Coeliac disease in children|journal=Nursing Standard|volume=29|issue=49|pages=36–41|doi=10.7748/ns.29.49.36.e10022|pmid=26243121|issn=0029-6570|last1=Paul|first1=Siba Prosad|last2=Kirkham|first2=Emily Natasha|last3=Pidgeon|first3=Sarah|last4=Sandmann|first4=Sarah}}</ref> One-fourth of people with [[Sjögren's syndrome]] had responses to gluten; of five that had positive response to gluten, only one could be confirmed as CD and another was potentially {{clarify|text=GSE|reason=Is GSE (gluten-sensitive enteropathy) meant to stand for coeliac disease, or for what else? see http://www.aafp.org/afp/2002/1215/p2259.html|date=December 2014}}, the remaining three appeared to be gluten-sensitive. All were HLA-DQ2 and/or DQ8-positive.<ref name="pmid17613926">{{cite journal |vauthors=Lidén M, Kristjánsson G, Valtýsdóttir S, Hällgren R | s2cid = 26333122 | title = Gluten sensitivity in patients with primary Sjögren's syndrome | journal = Scand. J. Gastroenterol. | volume = 42 | issue = 8 | pages = 962–7 | year = 2007 | pmid = 17613926 | doi = 10.1080/00365520701195345|type=Research Support, Non-U.S. Gov't}}</ref>

More than 250 symptoms of gluten sensitivity have been reported, including [[bloating]], abdominal discomfort or pain, constipation and diarrhea.<ref name="Korn">{{cite book|last=Korn|first=Danna|title=Living gluten-free for dummies|url=https://archive.org/details/livingglutenfree00korn|url-access=registration|location=Hoboken, NJ|publisher=Wiley Pub.|year=2006|pages=[https://archive.org/details/livingglutenfree00korn/page/14 14], 27–31|isbn=9780471773832}}</ref> Sensitivity may also present with extraintestinal symptoms, including headache, "[[Brain Fog|brain fog]]", tingling and/or numbness in hands and feet, fatigue, as well as muscular disturbances and bone or joint pain;<ref name="sapone-etal-2010-a">{{cite journal |vauthors=Sapone A, Lammers KM, Mazzarella G, etal |title=Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease |journal=Int. Arch. Allergy Immunol. |volume=152 |issue=1 |pages=75–80 |year=2010 |pmid=19940509 |pmc=2956008 |doi=10.1159/000260087 |type=Research Support, N.I.H., Extramural}}</ref><ref name="ReferenceB">{{cite journal |vauthors=Hadjivassiliou M, Chattopadhyay AK, Grünewald RA, etal |title=Myopathy associated with gluten sensitivity |journal=Muscle Nerve |volume=35 |issue=4 |pages=443–50 | date=April 2007 |pmid=17143894 |doi=10.1002/mus.20709 |s2cid=29048674 |type=Research Support, Non-U.S. Gov't}}</ref><ref name="nijeboer-etal-2013">{{cite journal |vauthors=Nijeboer P, Bontkes HJ, Mulder CJ, Bouma G |title=Non-celiac gluten sensitivity. Is it in the gluten or the grain? |journal=Journal of Gastrointestinal and Liver Diseases |volume=22 |issue=4 |pages=435–40 | date=December 2013 |pmid=24369326 |type=Review}}</ref> also neuropsychiatric manifestations ("[[gluten-sensitive idiopathic neuropathies]]") have been reported on.<ref name="GenuisLobo2014">{{cite journal|vauthors=Genuis S, Lobo RA |title=Gluten Sensitivity Presenting as a Neuropsychiatric Disorder|journal=Gastroenterology Research and Practice|volume=2014|year=2014|pages=1–6|issn=1687-6121|doi=10.1155/2014/293206|pmid=24693281|type=Review|pmc=3944951|doi-access=free}}</ref>

Studies using [[anti-gliadin antibodies]] (AGA) reveal that {{clarify|text=diagnosed or untreated|reason=Diagnosed/untreated for what?|date=December 2014}} individuals with AGA have an increasing risk for lymphoid cancers and decreased risk for other conditions associated with affluence.<ref name="pmid17206762">{{cite journal |vauthors=Anderson LA, McMillan SA, Watson RG, etal | title = Malignancy and mortality in a population-based cohort of patients with coeliac disease or "gluten sensitivity" | journal = World J. Gastroenterol. | volume = 13 | issue = 1 | pages = 146–51 | year = 2007 | pmid = 17206762 | pmc = 4065872 | doi = 10.3748/wjg.v13.i1.146 | type=Retrospective Studies | doi-access = free }}</ref>

The pathogenesis of NCGS is not yet well understood. There is evidence that not only [[gliadin]] (the main cytotoxic antigen of gluten), but also other proteins named ATIs which are present in gluten-containing cereals ([[wheat]], [[rye]], [[barley]], and their derivatives) may have a role in the development of symptoms. ATIs are potent activators of the [[innate immune system]].<ref name="FasanoSapone2015">{{cite journal |vauthors=Fasano A, Sapone A, Zevallos V, Schuppan D|title=Nonceliac gluten sensitivity |journal=Gastroenterology |volume=148|issue=6|pages=1195–204|date=May 2015|pmid=25583468 |doi=10.1053/j.gastro.2014.12.049|type=Review|doi-access=free}}</ref><ref name=Verbeke2018 /> [[FODMAP]]s, especially [[fructans]], are present in small amounts in gluten-containing grains and have been identified as a possible cause of some gastrointestinal symptoms in persons with NCGS.<ref name=FasanoSapone2015 /><ref name="VoltaCaioQuestions" /><ref name=Verbeke2018 /><ref name=OntiverosHardy>{{cite journal |vauthors=Ontiveros N, Hardy MY, Cabrera-Chavez F |title=Assessing of Celiac Disease and Nonceliac Gluten Sensitivity |journal=Gastroenterology Research and Practice |volume=2015 |pages=1–13 |year=2015 |pmid=26064097 |pmc=4429206 |doi=10.1155/2015/723954 |type=Review |doi-access=free }}</ref> As of 2019, reviews have concluded that although FODMAPs may play a role in NCGS, they only explain certain gastrointestinal symptoms, such as [[bloating]], but not the [[#Extraintestinal|extra-digestive symptoms]] that people with NCGS may develop, such as [[neurological disorder]]s, [[fibromyalgia]], psychological disturbances, and [[dermatitis]].<ref name=Verbeke2018 /><ref name=VoltaDeGiorgio2019 /><ref name="FasanoSapone2015" />

[[Triticeae glutens|''Triticeae'' glutens]] are important factors in several inflammatory diseases. The immunochemistry can be subdivided into innate responses (direct stimulation of immune system), [[MHC class II|class II]] mediated presentation ([[HLA-DQ]]), [[MHC class I|class I]] mediated stimulation of [[killer cells]], and [[antibody]] recognition. The responses to [[gluten]] proteins and [[polypeptide]] regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the [[human leukocyte antigen]] genes. In enteropathy, there are at least 3 types of recognition, [[innate immunity]] (a form of cellular immunity priming), HLA-DQ and antibody recognition of gliadin and transglutaminase.<ref name="pmid16766754">{{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> In NCGS, there is high [[Anti-gliadin antibodies#Anti-gliadin IgG|AGA IgG]] in more than half of the cases.<ref>{{cite journal|author=Catassi C, Bai J, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, [[Detlef Schuppan|Schuppan D]], Ullrich R, Vécsei A, Volta U, Zevallos V, Sapone A, [[Alessio Fasano|Fasano A]]|title=Non-celiac gluten sensitivity: the new frontier of gluten related disorders|journal=Nutrients|volume=5|issue=10|year=2013|pages=3839–3853|issn=2072-6643|doi=10.3390/nu5103839|pmid=24077239|type=Review|pmc=3820047|doi-access=free}}</ref> In [[wheat allergy]], there appears to be an innate component and the response pathways are mediated through IgE against gliadin and other wheat proteins.<ref name="pmid18036646">{{cite journal |vauthors=Bittner C, Grassau B, Frenzel K, Baur X |title=Identification of wheat gliadins as an allergen family related to baker's asthma|issue=3 |pages=744–9 |date=March 2008 |pmid=18036646 |doi=10.1016/j.jaci.2007.09.051 |type=Research Support, Non-U.S. Gov't |volume=121 |journal=Journal of Allergy and Clinical Immunology}}</ref><ref name="pmid18186814">{{cite journal |vauthors=Matsuo H, Dahlström J, Tanaka A, etal |title=Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis |journal=Allergy |volume=63 |issue=2 |pages=233–6 |date=February 2008 |pmid=18186814 |doi=10.1111/j.1398-9995.2007.01504.x|s2cid=46107806 |type=Evaluation Studies}}</ref><ref name="pmid17655322">{{cite journal |vauthors=Akagawa M, Handoyo T, Ishii T, Kumazawa S, Morita N, Suyama K |title=Proteomic analysis of wheat flour allergens |journal=Journal of Agricultural and Food Chemistry |volume=55 |issue=17 |pages=6863–70 |date=August 2007 |pmid=17655322 |doi=10.1021/jf070843a |type=Research Support, Non-U.S. Gov't}}</ref>

A literature review of 2014 found that people suffering fromwith NCGS "are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis and clinical history, and, probably, clinical course".<ref name="mansueto-etal-2014">{{cite journal|author1=Mansueto P |author2=Seidita A |author3=D’Alcamo A |author4=Carroccio A |title=Non-Celiac Gluten Sensitivity: Literature Review|journal=Journal of the American College of Nutrition|volume=33|issue=1|year=2014|pages=39–54|issn=0731-5724|doi=10.1080/07315724.2014.869996|pmid=24533607|type=Review|hdl=10447/90208 |s2cid=22521576 |hdl-access=free}}</ref>

Celiac disease (CD) and NCGS are closely linked with [[human leukocyte antigen]] (HLA) class II genes, [[HLA-DQ2]] and [[HLA-DQ8]], located on [[Chromosome 6 (human)#p-arm|chromosome 6p21]].<ref name="sapone-etal-2010-b">{{cite journal |vauthors=Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A |title=Spectrum of gluten-related disorders: consensus on new nomenclature and classification |journal=BMC Medicine |volume=10 |pages=13 |year=2012 |pmid=22313950 |pmc=3292448 |doi=10.1186/1741-7015-10-13 |type=Review |doi-access=free }}</ref> Nearly all CD people are HLA-DQ2/HLA-DQ8 positive, with 95% HLA-DQ2 and the rest usually HLA-DQ8 (which is carried by 30% of Caucasians).<ref name="sapone-etal-2010-b"/> However, the [[Sensitivity and specificity|specificity]] of HLA-DQ2 and/or HLA-DQ8 for CD is low, with estimates ranging from 36% to 53%. In persons with NCGS, the HLA-DQ2 and/or HLA-DQ8 alleles are present in only about 50%, which is still a greater proportion than in the general population.<ref name="sapone-etal-2010-b"/>

A four-of-five rule was proposed 2010 for confirming celiac disease, with the disease confirmed if at least four of the following five criteria are satisfied:<ref name="sapone-etal-2010-b"/><ref name="pmid20670718">{{cite journal |vauthors=Catassi C, Fasano A |title=Celiac disease diagnosis: simple rules are better than complicated algorithms |journal=The American Journal of Medicine |volume=123 |issue=8 |pages=691–3 | date=August 2010 |pmid=20670718 |doi=10.1016/j.amjmed.2010.02.019 |hdl=11566/54123 |type=Research Support, Non-U.S. Gov't}}</ref>

For people with celiac disease, a lifelong strict gluten-free diet is the only effective treatment to date;<ref name="LamacchiaCamarca2014" /><ref name="Czaja-Bulsa-2014-table2">{{cite journal |author=Czaja-Bulsa G |title=Non coeliac gluten sensitivity -– A new disease with gluten intolerance |journal=Clinical Nutrition (Edinburgh, Scotland) |volume= 34|issue= 2|pages= 189–194| date=August 2014 |pmid=25245857 |doi=10.1016/j.clnu.2014.08.012 |type=Review|doi-access=free }} See [http://www.clinicalnutritionjournal.com/article/S0261-5614%2814%2900218-0/fulltext#tbl2 Table 2: Characteristics of gluten-dependent disorders].</ref>

Preferably, newly diagnosed celiacs seek the help of a dietician to receive support for identifying hidden sources of gluten, planning balanced meals, reading labels, food shopping, dining out, and dining during travel.<ref name="pmid24444577">{{cite journal |vauthors=Pelkowski TD, Viera AJ |title=Celiac disease: diagnosis and management |journal=American Family Physician |volume=89 |issue=2 |pages=99–105 | date=January 2014 |pmid=24444577 }}</ref> Knowledge of hidden sources of gluten is important for people with celiac disease as they need to be very strict regarding eating only gluten-free food.<ref>{{cite journal|vauthors=Cristofori F, Arezzo F, Gentile A, Francavilla R |s2cid=71854723|title=Gluten Sensitivity in Pediatrics: A Clinical Conundrum|journal=Current Pediatrics Reports|date=September 2014|volume=2|issue=3|pages=204–210|doi=10.1007/s40124-014-0053-9|doi-access=free}}</ref> The degree of gluten [[cross contamination]] tolerated by people with non-celiac gluten sensitivity is not clear but there is some evidence that they can present with symptoms even after consumption of small amounts.<ref name=VoltaCaio2015 /> Sporadic accidental contaminations with gluten can reactivate [[movement disorder]]s associated with non-celiac gluten sensitivity.<ref name=VinagreAragonZis>{{cite journal| vauthors=Vinagre-Aragón A, Zis P, Grunewald RA, Hadjivassiliou M| title=Movement Disorders Related to Gluten Sensitivity: A Systematic Review | journal=Nutrients | year= 2018 | volume= 10 | issue= 8 | page=1034 | pmid=30096784 | doi=10.3390/nu10081034 | pmc=6115931 | type=Systematic Review | doi-access=free }} </ref> A part of people with gluten-related neuropathy or [[ataxia#Gluten ataxia|gluten ataxia]] appears not to be able to tolerate even the traces of gluten allowed in most foods labeled as "gluten-free".<ref name=HadjivassiliouGrunewald2002>{{cite journal| vauthors=Hadjivassiliou M, Grünewald RA, Davies-Jones GA| title=Gluten sensitivity as a neurological illness. | journal=J Neurol Neurosurg Psychiatry | year= 2002 | volume= 72 | issue= 5 | pages= 560–3 | pmid=11971034 | doi= 10.1136/jnnp.72.5.560| pmc=1737870 | type=Review }} </ref>

The inclusion of [[oats]] in gluten-free diets remains controversial. [[Oat#Protein|Avenin]] present in oats may also be toxic for celiacindividuals with sufferersceliacs.<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 = November 18, 2013| pmid = 24253052|pmc= 3847748| doi = 10.3390/nu5114553| doi-access = free }}</ref> Its toxicity depends on the [[cultivar]] consumed.<ref name=CominoMoreno>{{cite journal | vauthors = Comino I, Moreno Mde L, Sousa C | title = Role of oats in celiac disease | journal = World J Gastroenterol | volume = 21 | issue = 41 | pages = 11825–31 | date = November 7, 2015 | pmid = 26557006 |pmc= 4631980 | doi = 10.3748/wjg.v21.i41.11825 | doi-access = free }}</ref> Furthermore, oats are frequently cross-contaminated with gluten-containing cereals.<ref name=PenaginiDilillo />

Gluten proteins have low [[Nutrition|nutritionalnutrition]]al value and replacing grains that contain gluten is easy from the nutritional point of view.<ref name=LamacchiaCamarca2014>{{cite journal |vauthors=Lamacchia C, Camarca A, Picascia S, Di Luccia A, Gianfrani C |title=Cereal-based gluten-free food: how to reconcile nutritional and technological properties of wheat proteins with safety for celiac disease patients |journal=Nutrients |volume=6 |issue=2 |pages=575–90 |year=2014 |pmid=24481131 |pmc=3942718 |doi=10.3390/nu6020575 |type=Review}}</ref> However, an unbalanced selection of food and an incorrect choice of gluten-free replacement products may lead to nutritional deficiencies. Replacing flour from wheat or other gluten-containing cereals with gluten-free flours in commercial products may lead to a lower intake of important nutrients, such as [[iron]] and [[B vitamins]]. Some gluten-free commercial replacement products are not enriched or fortified as their gluten-containing counterparts, and often have greater [[lipid]]/[[carbohydrate]] content. Children especially often over-consume these products, such as snacks and biscuits.<ref name=PenaginiDilillo />

Research has attempted to discern, by [[double-blind placebo-controlled trial]]s, between a "fad component" to the recent popularity of the [[gluten-free diet]] and an actual sensitivity to gluten or other components of wheat.<ref name=FasanoSapone2015 /><ref name="CatassiBai2013" /><ref>{{cite journal |vauthors=Di Sabatino A, Volta U, Salvatore C, Biancheri P, Caio G, De Giorgio R, Di Stefano M, Corazza GR |title=Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial |journal=Clinical Gastroenterology and Hepatology |volume=13 |issue=9 |pages=1604–12 |year=2015 |doi=10.1016/j.cgh.2015.01.029 |pmid=25701700|hdl=11392/2375087 |url=https://www.cghjournal.org/article/S1542-3565(15)00153-6/fulltext |doi-access=free |hdl-access=free }}</ref>

A 2016 review of the recent research advancements in understanding diet’sdiet's role in attenuating IBS patient’spatient's symptoms concluded that gluten was a common trigger. However, because on the different compounds responsible for symptoms, many patients that could be inaccurately labelled non-coeliac gluten sensitive; and it may be more appropriate to use nomenclature such as "non-coeliac wheat sensitive" (NCWS), "non-coeliac wheat protein sensitive" (NCWPS), or even FODMAP sensitive when referring to these patients.<ref>{{cite journal |last1=Giorgio |first1=Roberto De |last2=Volta |first2=Umberto |last3=Gibson |first3=Peter R. |title=Sensitivity to wheat, gluten and FODMAPs in IBS: facts or fiction? |journal=Gut |date=1 January 2016 |volume=65 |issue=1 |pages=169–178 |doi=10.1136/gutjnl-2015-309757 |s2cid=6012463 |pmid=26078292 |doi-access=free |hdl=11392/2375077 |hdl-access=free }}</ref>