The symptoms of coeliac disease can be divided into two subtypes, classic and non-classic. The classic form of the disease can affect any age group, but is usually diagnosed in early childhood and causes symptoms ofmalabsorption such asweight loss,diarrhoea, andstunted growth. Non-classic coeliac disease is more commonly seen in adults and is characterized by vague abdominal symptoms and complications in organs outside of the gastrointestinal tract, such asbone disease,anemia, and other consequences ofnutritional deficiencies.
Coeliac disease is caused by an abnormalimmune system response to gluten, found inwheat and other grains such asbarley andrye. When an individual with agenetic predisposition to coeliac disease consumes gluten, it triggers aninflammatory response in the small intestine, damaging theintestinal lining, leading to malabsorption. The development of coeliac disease is believed to be influenced by other environmental factors, such as infections.
Diagnosis is typically made by a combination of blood antibody tests and intestinalbiopsies, helped by specificgenetic testing.[1] Diagnosis is not always straightforward.[2] About 10% of the time, the autoantibodies in the blood are negative,[3][4] and many people have only minor intestinal changes with normalvilli.[5] People may have severe symptoms and they may be investigated for years before a diagnosis is achieved.[6][7] As a result ofscreening, the diagnosis is increasingly being made in people who haveno symptoms.[8] Evidence regarding the effects of screening, however, is as of 2017, insufficient to determine its usefulness.[9] While the disease is caused by apermanent intolerance to gluten proteins,[1] it is distinct fromwheat allergy, which is much rarer.[10][11]
The only known effective treatment is a strict lifelonggluten-free diet, which leads to recovery of the intestinal lining (mucous membrane), improves symptoms, and reduces the risk of developing complications in most people.[12] If untreated, it may result incancers such as intestinallymphoma, and a slightly increased risk of early death.[13] Rates vary between different regions of the world, from as few as 1 in 300 to as many as 1 in 40, with an average of between 1 in 100 and 1 in 170 people.[14] It is estimated that 80% of cases remain undiagnosed, usually because of minimal or absent gastrointestinal complaints and lack of knowledge of symptoms and diagnostic criteria.[15][6][16] Coeliac disease is slightly more common in women than in men.[17]
Coeliac disease causes a wide range of symptoms and complications that can involve several different organs.[18] The presentation of coeliac disease can be classified as classic, non-classic, and subclinical.[19] Classic coeliac disease is commonly seen in young children, but can affect any age group, and is characterized bymalabsorption manifesting asdiarrhoea,weight loss, andfailure to thrive.[18][20] Non-classic coeliac disease is seen more often in adults and symptoms primarily manifest outside of theintestine (extraintestinal).[20] Many undiagnosed individuals who consider themselves asymptomatic are, in fact, not, but rather have become accustomed to living in a state of chronically compromised health. After starting a gluten-free diet and subsequent improvement becomes evident, such individuals are often able to retrospectively recall and recognise prior symptoms of their untreated disease that they had mistakenly ignored.[21][22][16]
Coeliac disease is a systemic disorder, meaning it affects the entire body. Although many common symptoms of the disease are related to the gastrointestinal tract, those with coeliac disease may also experience symptoms and complications in other organs, known as extraintestinal manifestations.[26] These manifestations may be related to malabsorption or systemic inflammation.[27] Common extraintestinal manifestations of coeliac disease include headaches, fatigue, brain fog, muscle pain, and joint pain.[27][28]
The changes in the bowel reduce its ability toabsorb nutrients, minerals, andvitamins:[29]
Malabsorption may cause weight loss (or failure to thrive orstunted growth in children) andfatigue or lack of energy.[24]
Coeliac disease has been linked with many conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.[27][28]
IgA deficiency is present in 2-2.5% of people with coeliac disease, and is itself associated with an increased risk of coeliac disease.[31]
Dermatitis herpetiformis, an itchy cutaneous condition that has been linked to a transglutaminase enzyme in the skin.Enteropathy is commonly seen in dermatitis herpetiformis; however, gastrointestinal symptoms are rare.[28]
A small number of people with coeliac disease react to oats. Sensitivity to oats in coeliac disease may be due tocross-contamination of oats and other foods with gluten, differences between gluten content,immunoreactivity, andgenetic variability seen between oatcultivars or dietary intolerance to oats.[37][38] Most people with coeliac disease do not have adverse reactions to uncontaminated or 'pure' oats, howeverclinical guidelines differ on whether those with coeliac disease should consume oats.[39][40]
Other cereals such asmaize,millet,sorghum,teff,rice, andwild rice are safe for people with coeliac disease to consume, as well as non-cereals such asamaranth,quinoa, andbuckwheat. Noncereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.[41][42]
Environmental factors such as infections, geographiclatitude, birth weight,antibiotic use, intestinalmicrobiota,socioeconomic status, hygiene,breastfeeding, and the timing of introduction of gluten into an infant's diet are theorized to contribute to the development of coeliac disease in genetically predisposed individuals.[43][34][20] The consumption of gluten and timing of introduction in a baby's life does not appear to increase the risk of coeliac disease, however in those who are genetically predisposed to coeliac disease, large amounts of gluten early in life, may increase the risk of developing coeliac disease.[44][45]
Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person.[46]
Almost all people (90%) with coeliac disease have either the variantHLA-DQ2allele or (less commonly) theHLA-DQ8 allele.[19] However, about 40% of people without coeliac disease have also inherited either of these alleles.[47] This suggests that additional factors are needed for coeliac disease to develop; that is, the predisposing HLA risk allele is necessary but not sufficient to develop coeliac disease. Furthermore, around 5% of those people who do develop coeliac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles.[19][48]
There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of people with coeliac disease have theisoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activateT lymphocytes and initiate the autoimmune process.[53]
HLA region of chromosome 6
Most people with coeliac bear a two-gene HLA-DQ2haplotype calledDQ2.5. This haplotype is composed of two adjacent gene alleles, DQA1*0501 andDQB1*0201, which encode the two subunits, DQ α5 and DQ β2.[54][55] In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents (DQ2.5cis). Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it fromboth parents; the latter are especially at risk of coeliac disease as well as being more susceptible to severe complications.[56] The frequency of coeliac disease haplotypes can vary by geography.[46][57]
Some individuals inherit DQ2.5 from one parent and an additional portion of the haplotype (either DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent (DQ2.5trans), and these individuals are at similar risk of coeliac disease as those with a single DQ2.5-bearing chromosome 6.[56][53] Among those with coeliac disease who do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 2-5% have theDQ2.2 isoform, and the remaining 2% lack DQ2 or DQ8.[56]
Other genetic factors have been repeatedly reported in coeliac disease; however, involvement in the disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population. Many of the loci detected have been found in association with other autoimmune diseases.[48]
The prevalence of the HLA-DQ2 genotype and gluten consumption has increased over time. Since untreated coeliac disease can cause serious health problems and affect fertility, it would be expected that HLA-DQ2 and HLA-DQ8 would becomeless common. The opposite is true—they are most common in areas where gluten-rich foods have been eaten for thousands of years.[58] The HLA-DQ2 gene may have beengenetically favoured in the past because it helps protect againsttooth decay.[57][59]
Most of the proteins in food responsible for the immune reaction in coeliac disease areprolamins. These are storage proteins rich inproline (prol-) andglutamine (-amin) that dissolve inalcohols and are resistant toproteases andpeptidases of the gut.[60] Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley (hordein), rye (secalin) and oats (avenin).[35][19]
Illustration of deamidated α-2 gliadin's 33mer, amino acids 56–88, showing the overlapping of three varieties of T-cell epitope[61]
Membrane leaking permits[clarification needed] peptides of gliadin that stimulate two levels of the immune response: the innate response and the adaptive (T-helper cell-mediated) response. One protease-resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release ofinterleukin-15. Thisinnate response to gliadin results in immune-system signalling that attracts inflammatory cells and increases the release of inflammatory chemicals.[8][needs update?]
The response to the 33mer occurs in most coeliacs who havea DQ2isoform. This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cellepitopes. This increases the likelihood that the DQ2 isoform will bind, and stay bound to, peptide when recognised by T-cells.[61]
Tissue transglutaminase modifies glutenpeptides into a form that may stimulate the immune system more effectively.[60] These peptides are modified by tTG in two ways,deamidation ortransamidation.[62]
Deamidation is the reaction by which a glutamate residue is formed by cleavage of the epsilon-amino group of a glutamine side chain.[63] Transamidation is thecross-linking of a glutamine residue from the gliadin peptide to alysine residue of tTg in a reaction that is catalysed by the transglutaminase.[62] Crosslinking may occur either within or outside the active site of the enzyme. The latter case yields a permanentlycovalently linked complex between the gliadin and the tTg. This results in the formation of new epitopes believed to trigger the primary immune response by which the autoantibodies against tTg develop.[64]
Stored biopsies from people with suspected coeliac disease have revealed thatautoantibody deposits in thesubclinical coeliacs are detected prior to clinical disease.[60]
The inflammatory process, mediated byT cells, 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 absorbnutrients from food.[48][47]
Alternative causes of this tissue damage have been proposed and involve the release ofinterleukin 15 and activation of theinnate immune system by a shorter gluten peptide (p31–43/49).[60]
Thediagnosis of coeliac disease is often complicated by the variety in symptoms, overlap with other disorders, and lack of awareness in medical professionals, leading to adelay in the diagnosis being made.[65][21] A diagnosis may take more than a decade after symptoms develop, and most people with coeliac disease remain undiagnosed.[22][66] Delays in diagnosis can reducequality of life, use more medical resources and increase risk of complications associated with the disease.[65][67][68]
Coeliac disease is diagnosed based on symptoms,blood tests, andbiopsies of the small intestine.[65] To make an accurate diagnosis, an individual must be consuming gluten, as the reliability of biopsies and blood tests reduces if a person is on agluten-free diet. In those who have already reduced their gluten intake, reintroducing gluten (gluten challenge) may be required to reach an accurate diagnosis.[69] Within months of eliminating gluten from one's diet,antibodies associated with coeliac disease decrease, meaning that gluten has to be reintroduced several weeks before diagnostic testing.[69][70]
Immunofluorescence staining pattern of endomysial antibodies on a monkey oesophagus tissue sample
Currentmedical guidelines recommend testing tissue transglutaminase 2immunoglobulin A (TTG IgA) in those with suspected coeliac disease.[71][72] BecauseIgA deficiency is more common in those with coeliac disease,[73] guidelines recommend testing for IgA deficiency as a part of the diagnostic workup for coeliac disease. If an individual with IgA deficiency is getting tested for coeliac disease,immunoglobulin G (IgG) based tests such as deamidated gliadin peptide IgG (DGP IgG) orendomysial antibody (EMA) can be used instead of IgA-based tests.[71][72]Antigliadin antibodies (AGA) and antireticulin antibodies (ARA) were historically used to test for coeliac disease, however due to the development of more accurate tests, they are no longer recommended.[43][73] Due to the risk offalse positive or negative serological tests and the consequences of leaving coeliac disease untreated or introducing unnecessary dietary restrictions in the case of a false positive, biopsies are used to confirm the diagnosis regardless of blood tests.[43][72]
TG2 IgA has a highsensitivity (92.8%) and specificity (97.9%), is cost-efficient and widely available, making it the first choice for serological tests in the diagnosis of coeliac disease.[74][69] Despite this, performance of the TG2 IgA test differs between labs and no formal standardisation between assays exists.[21] The severity of small intestine damage generally correlates with the levels of TG2 IgA found in the blood, meaning that the sensitivity is lower in people who have less damage to their intestines.[74][73]
EMA has a lower sensitivity, but its specificity is near 100%.[74] Because of the high specificity, EMA can be used to confirm coeliac disease in those who have borderline TG2 IgA levels.[69] EMA testing is costly, hard to interpret and vulnerable tointerobserver and inter-site variability.[21][75]
DGP IgG is used to evaluate coeliac disease in those with IgA-deficiency. Coeliac disease is more common in those with IgA-deficiency, so medical guidelines recommend that people being tested for coeliac disease are also tested for IgA-deficiency. Because IgA-based tests are unreliable in those with IgA deficiency, IgG-based tests are used instead. These include EMA IgG, DGP IgG, and TTG IgA, which are less accurate than IgA testing.[73][76]
A 2020 guideline by the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) suggests biopsy can be avoided in children who have symptoms of coeliac disease, TTG IgA levels ten times higher than normal, and a positive EMA antibody. However there is not enough evidence to suggest that a nonbiopsy approach can be used in adults.[72]
Genetic testing is not needed to diagnose coeliac disease, but is sometimes used to clarify discrepancies between blood tests and histology. In those who have already started a gluten-free diet, HLA testing can help to determine whether a gluten challenge should be performed.[72]
Endoscopic still ofduodenum of a person with coeliac disease showing scalloping of folds and "cracked-mud" appearance to mucosa
Anupper endoscopy withbiopsy of theduodenum (beyond theduodenal bulb) orjejunum is performed to obtain multiple samples from the duodenum.[72] Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative. Even in the same bioptic fragment, different degrees ofdamage may be present.[69]
Most people with coeliac disease have asmall intestine that appears to be normal on endoscopy before the biopsies are examined.[77] Endoscopic features of coeliac disease include scalloping of the small bowel folds (pictured), fissures, amosaic pattern to themucosa, prominence of thesubmucosablood vessels, and a nodular pattern to the mucosa.[35]
Capsule endoscopy (CE) allows identification of typical mucosal changes observed in coeliac disease and may be used as an alternative to endoscopy in those who cannot or do not want one.[43]
The Marsh-Oberhuber classification is commonly used to assess thepathological changes seen in coeliac disease.[20]Marsh originally described three different stages of coeliac disease lesions in 1992. These three stages were updated in 1999 by Oberhuber to further classify stage three.[78][79] The Marsh classification is based on threehistological features:intraepithelial lymphocytes count above 25/100 enterocytes (intraepithelial lymphocytosis), elongatedcrypts of Lieberkuhn (crypt hyperplasia), and shortening or absence of villi (villous atrophy). As these features can be seen in other disorders, they are not diagnostic for coeliac disease without serological or clinical indications.[78] Current guidelines do not recommend a repeat biopsy unless there is no improvement in the symptoms on a gluten free diet.[70]
Currently,gluten challenge is no longer required to confirm the diagnosis in patients with intestinal lesions compatible with coeliac disease and a positive response to a gluten-free diet. A gluten challenge involves consuming over 10 grams of gluten a day for three months or until an individual tests positive for TG2 IgA.[74] Nevertheless, in some cases, a gluten challenge with a subsequent biopsy may be useful to support the diagnosis, for example, in people with positive HLA genetic testing who have negative blood antibodies and are already on a gluten-free diet.[43] Gluten challenge is discouraged before the age of 6 years and duringpubertal growth.[74]
Positive blood tests for coeliac disease with a lack of changes in the bowels can be caused by errors in collecting blood for the test, recent infections,congestive heart failure,chronic liver disease, andhypergammaglobulinemia. Potential coeliac disease, formerly known as "latent coeliac disease" is diagnosed when there is positive coeliac blood tests, positive HLA genetic testing, and a lack of villous atrophy.[75][43]
Non-celiac gluten sensitivity (NCGS) is a functional disorder that causes intestinal and extraintestinal symptoms in response to gluten. The symptoms of NCGS are often similiar to those seen in coeliac disease, however they tend to have a more rapid onset and offset when compared to coeliac disease. The diagnosis of NCGS is made based on the exclusion of coeliac disease and wheat allergy, and a resolution of symptoms after adhering to a gluten free diet.[79][35]
Up to 30% of people redevelop or still have frequent symptoms after starting a gluten-free diet.[12] A careful interpretation of the symptomatic response is needed, as a lack of response in a person with coeliac disease may be due to continued ingestion of small amounts of gluten, either voluntary or inadvertent,[80] or be due to other commonly associated conditions such assmall intestinal bacterial overgrowth (SIBO),lactose intolerance,fructose,[81]sucrose,[82] andsorbitol[83] malabsorption,exocrine pancreatic insufficiency,[84][85] andmicroscopic colitis,[85] among others. In untreated coeliac disease, these are often transient conditions derived from the intestinal damage.[82][83][86][87][88] They normally revert or improve several months after starting a gluten-free diet, but may need temporary interventions such as supplementation withpancreatic enzymes,[87][88] dietary restrictions of lactose, fructose, sucrose or sorbitol containing foods,[82][86] or treatment with oral antibiotics in the case of associated bacterial overgrowth.[88] In addition to gluten withdrawal, some people need to follow a low-FODMAPs diet or avoid consumption of commercial gluten-free products, which are usually rich inpreservatives andadditives (such assulfites,glutamates,nitrates andbenzoates) and might have a role in triggering functional gastrointestinal symptoms.[89]
There is debate as to the benefits of widespreadscreening measures for coeliac disease.[68] In 2017, theUnited States Preventive Services Task Force published a report found insufficient evidence to make a recommendation regarding screening for coeliac disease in those without symptoms.[9] Due to the lack of evidence that screening for coeliac disease in those without symptoms, clinical guidelines advise testing people based on symptoms and selective screening for certain populations at a higher risk of developing coeliac disease.[69][43]
At present, the only effective treatment is a lifelonggluten-free diet.[90] Strict adherence to the diet helps the intestines heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer and in some cases sterility.[91] Compliance to a strict gluten-free diet is difficult for the patient, but evidence has accumulated that a strict gluten-free diet can result in resolution of diarrhoea, weight gain, and normalization of nutrient malabsorption, with normalization of biopsies in 6 months to 2 years on a gluten-free diet.[92]
Dietitians advise which foods contain gluten, which foods are safe, and how to eat a balanced diet despite the limitations. In many countries, gluten-free products are available onprescription and may be reimbursed byhealth insurance plans. Gluten-free products are usually more expensive and harder to find than common gluten-containing foods.[93] Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.[94]
The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence.[95] The exact level at which gluten is harmless is uncertain and controversial. A recentsystematic review tentatively concluded that consumption of less than 10 mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done.[95] Regulation of the label "gluten-free" varies. In the European Union, theEuropean Commission issued regulations in 2009 limiting the use of "gluten-free" labels for food products to those with less than 20 mg/kg of gluten, and "very low gluten" labels for those with less than 100 mg/kg.[96] In the United States, theFDA issued regulations in 2013 limiting the use of "gluten-free" labels for food products to those with less than 20 ppm[clarification needed]of gluten.[97][98][99] The internationalCodex Alimentarius standard allows for 20 ppm of gluten in so-called "gluten-free" foods.[100]
A gluten-free diet improveshealthcare-related quality of life, and strict adherence to the diet gives more benefit than incomplete adherence. Nevertheless, a gluten-free diet does not completely normalise the quality of life.[101]
Even though it is unclear if coeliac patients have a generally increased risk of infectious diseases, they should generally be encouraged to receive all common vaccines againstvaccine preventable diseases (VPDs) as the general population. Moreover, some pathogens could be harmful to coeliac patients. According to the European Society for the Study of Coeliac Disease (ESsCD), coeliac disease can be associated with hyposplenism or functional asplenia, which could result in impaired immunity to encapsulated bacteria, with an increased risk of such infections. So patients who are known to be hyposplenic should be offered at least the pneumococcal vaccine.[102] However, the ESsCD states that it is not clear whether vaccination with the conjugated vaccine is preferable in this setting and whether additional vaccination againstHaemophilus,meningococcus, andinfluenza should be considered if not previously given.[102]
Less than 1% of affected people haverefractory disease, which means that they have persistent villous atrophy on a gluten-free diet despite the lack of gluten exposure for more than 12 months.[72] Nevertheless, inadvertent exposure to gluten is the main cause of persistent villous atrophy, and must be ruled out before a diagnosis of refractory disease is made.[75] People with poor basic education and understanding of gluten-free diet often believe that they are strictly following the diet, but are making regular errors.[12][85][103][obsolete source] Also, a lack of symptoms is not a reliable indicator of intestinal recuperation.[85] If alternative causes of villous atrophy have been eliminated,steroids orimmunosuppressants (such asazathioprine) may be considered.[104]
Refractory coeliac disease can be divided into types I and II. A 2023 study compared patients with type I and type II. Refractory coeliac disease type I more frequently exhibits diarrhoea, anaemia, hypoalbuminemia, parenteral nutrition need, ulcerative jejuno-ileitis, and extended small intestinal atrophy. Among patients with refractory coeliac disease type II, it is more common for lymphoma to develop. Among these patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality.[non-primary source needed][105]
In most countries, between 1 in 50 and 1 in 200 people have coeliac disease.[106]Rates vary in different regions of the world; coeliac disease is less common in places where gluten-containing crops are rarely eaten, and in parts of east Asia and sub-Saharan Africa where populations rarely carry theHLA-DQ genes that predispose to the disease.[106] The risk of developing coeliac disease is higher in those who have a first degree relative with the disease, a less dramatic increase in risk is also seen second degree relatives.[107]
Diagnoses of coeliac disease have increased dramatically in recent decades due to increased awareness of the disease and availability of blood testing. However, the disease is still thought to be underdiagnosed, with an estimated 70% of people with coeliac undiagnosed and untreated. Undiagnosed cases are more common in poorer areas, and in countries which do not regularly test at-risk people.[106]
While coeliac disease can arise at any age, most people develop the disease before age 10.[108] Roughly 20 percent of individuals with coeliac disease are diagnosed after 60 years of age.[109] Coeliac disease is slightly more common in women than in men; though some of that may be due to differences in diagnostic practice – men with gastrointestinal symptoms are less likely to receive a biopsy than women.[108] Other populations at increased risk for coeliac disease, include individuals withDown andTurner syndromes,type 1 diabetes, and autoimmune thyroid disease, including bothhyperthyroidism (overactivethyroid) andhypothyroidism (underactive thyroid).[79]
The termcoeliac comes from Greek κοιλιακός (koiliakós) 'abdominal' and was introduced in the 19th century in a translation of what is generally regarded as anAncient Greek description of the disease byAretaeus of Cappadocia.[110][111]
Humans first started to cultivate grains in theNeolithic period (beginning about 9500 BCE) in theFertile Crescent in Western Asia, and, likely, coeliac disease did not occur before this time.[112]Aretaeus of Cappadocia, living in the second century in the same area, recorded a malabsorptive syndrome with chronic diarrhoea, causing a debilitation of the whole body.[110]
A 15th-century medical prescription fromMamluk Cairo, attributed to Shams al-Din ibn al-'Afif, the personal physician to SultanBarsbay and director of theQalawun complex hospital, describes a treatment for symptoms consistent with coeliac disease. Found inFustat and now held in theMuseum of Islamic Art in Cairo, the remedy combines herbs and plant waters for patients intolerant to wheat.[113]
Aretaeus of Cappadocia's "Cœliac Affection" gained the attention of Western medicine whenFrancis Adams presented a translation of Aretaeus's work at theSydenham Society in 1856. The patient described in Aretaeus' work had stomach pain and was atrophied, pale, feeble, and incapable of work. The diarrhoea manifested as loose stools that were white, malodorous, and flatulent, and the disease was intractable and liable to periodic return. The problem, Aretaeus believed, was a lack of heat in the stomach necessary to digest the food and a reduced ability to distribute the digestive products throughout the body, this incomplete digestion resulting in diarrhoea. He regarded this as an affliction of the old and more commonly affecting women, explicitly excluding children. The cause, according to Aretaeus, was sometimes either another chronic disease or even consuming "a copious draught of cold water."[110][111]
ThepaediatricianSamuel Gee gave the first modern-day description of the condition in children in a lecture at theHospital for Sick Children, Great Ormond Street, London, in 1887. Gee acknowledged earlier descriptions and terms for the disease and adopted the same term as Aretaeus (coeliac disease). He perceptively stated: "If the patient can be cured at all, it must be by means of diet." Gee recognised that milk intolerance is a problem with coeliac children and that highly starched foods should be avoided. However, he forbade rice, sago, fruit, and vegetables, which all would have been safe to eat, and he recommended raw meat as well as thin slices of toasted bread. Gee highlighted particular success with a child "who was fed upon a quart of the best Dutchmussels daily." However, the child could not bear this diet for more than one season.[111][114]
Christian Archibald Herter, an American physician, wrote a book in 1908 on children with coeliac disease, which he called "intestinalinfantilism". He noted their growth was retarded and that fat was better tolerated than carbohydrate. TheeponymGee-Herter disease was sometimes used to acknowledge both contributions.[115][116]Sidney V. Haas, an American paediatrician, reported positive effects ofa diet of bananas in 1924.[117] This diet remained in vogue until the actual cause of coeliac disease was determined.[111]
While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatricianWillem Karel Dicke.[118] It is likely that clinical improvement of his patients during theDutch famine of 1944–1945 (during which flour was scarce) may have contributed to his discovery.[119] Dicke noticed that the shortage of bread led to a significant drop in the death rate among children affected by coeliac disease from greater than 35% to essentially zero. He also reported that once wheat was again available after the conflict, the mortality rate soared to previous levels.[120] The link with the gluten component of wheat was made in 1952 by a team fromBirmingham, England.[121] Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery.[122] This paved the way for biopsy samples taken by endoscopy.[111]
Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965.[123] In 1966, dermatitis herpetiformis was linked togluten sensitivity.[111][124]
Speaking generally, the various denominations of Christians celebrate aEucharist in which a wafer or small piece ofsacramental bread from wheat bread is blessed and then eaten. A typical wafer weighs about half a gram.[127] Small communion wafers typically contain 2-5 mg of gliadin if they are not a gluten-free variety,[128] and many people with coeliac disease report altering their religious practices because of coeliac symptoms caused by these wafers.[129]
Many Christian churches offer their communicants gluten-free alternatives, usually in the form of a rice-based cracker or gluten-free bread. These include theUnited Methodist,Christian Reformed,Episcopal,Anglican andLutheran Churches.Catholics may receive from thechalice alone, or ask for gluten-reduced hosts; gluten-free ones however are not considered still to be wheat bread, and hence are invalid matter.[130]
Roman Catholicdoctrine states that for a validEucharist, the bread to be used atMass must be made from wheat. Low-glutenhosts meet all of the Catholic Church's requirements, but they are not entirely gluten-free. Requests to use rice wafers have been denied.[131] In 2003, the Congregation for the Doctrine of the Faith stated, "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm."[132]
By 2004, extremely low-gluten Church-approved hosts had become available in the United States, Italy and Australia.[133] As of 2017, theVatican still outlawed the use of gluten-free bread for Holy Communion.[134]
The Jewish festival ofPesach (Passover) may present problems with its obligation to eatMatzah, which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. In addition, many other grains that are normally used as substitutes for people with gluten sensitivity, including rice, are avoided altogether on Passover byAshkenazi Jews. Many kosher-for-Passover products avoid grains altogether and are therefore gluten-free.Potato starch is the primary starch used to replace the grains.[135]
The search for environmental factors that could be responsible for genetically susceptible people becoming intolerant to gluten has resulted in increasing research activity looking at gastrointestinal infections.[138] Research published in April 2017 suggests that an often-symptomless infection by a common strain ofreovirus can increase sensitivity to foods such as gluten.[139]
Various treatment approaches are being studied, including some that would reduce the need for dieting. All are still under development and are not expected to be available to the general public for a while.[8][140][141] Three main approaches have been proposed: gluten detoxification, modulation of theintestinal permeability, and modulation of the immune response.[142]
Alternatively, gluten exposure can be minimised by the ingestion of a combination ofenzymes (prolyl endopeptidase and a barley glutamine-specificcysteine endopeptidase (EP-B2)) that degrade the putative 33-mer peptide in theduodenum.[8] Latiglutenase (IMGX003) is abiotherapeutic digestive enzyme therapy currently being trialled that aims to degrade gluten proteins and aid gluten digestion. It was shown to mitigate intestinal mucosal damage and reduce the severity and frequency of symptoms in phase 2 clinical trials[143] and is scheduled for phase 3 clinical trials.[144]
Other potential approaches to pharmacotherapy include the inhibition ofzonulin, an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system.[145] Other modifiers of other well-understood steps in the pathogenesis of coeliac disease, such as the action of HLA-DQ2 or tissue transglutaminase and the MICA/NKG2D interaction that may be involved in the killing of enterocytes.[8][clarification needed]
Attempts to modulate the immune response concerning coeliac disease are mostly still in phase I of clinical testing; one agent (CCX282-B) has been evaluated in a phase II clinical trial based on small-intestinal biopsies taken from people with coeliac disease before and after gluten exposure.[142][needs update]
^Matthias T, Pfeiffer S, Selmi C, Eric Gershwin M (April 2010). "Diagnostic challenges in celiac disease and the role of the tissue transglutaminase-neo-epitope".Clin Rev Allergy Immunol (Review).38 (2–3):298–301.doi:10.1007/s12016-009-8160-z.PMID19629760.
^Molina-Infante J, Santolaria S, Sanders DS, Fernández-Bañares F (May 2015)."Systematic review: noncoeliac gluten sensitivity".Alimentary Pharmacology & Therapeutics (Review).41 (9):807–820.doi:10.1111/apt.13155.PMID25753138.Furthermore, seronegativity is more common in coeliac disease patients without villous atrophy (Marsh 1-2 lesions), but these 'minor' forms of coeliac disease may have similar clinical manifestations to those with villous atrophy and may show similar clinical–histological remission with reversal of haematological or biochemical disturbances on a gluten-free diet (GFD).
^abCichewicz AB, Mearns ES, Taylor A, Boulanger T, Gerber M, Leffler DA, et al. (August 2019). "Diagnosis and Treatment Patterns in Celiac Disease".Digestive Diseases and Sciences (Review).64 (8):2095–2106.doi:10.1007/s10620-019-05528-3.PMID30820708.
^abBibbins-Domingo K, Grossman DC, Curry SJ, Barry MJ, Davidson KW, Doubeni CA, et al. (March 2017). "Screening for Celiac Disease: US Preventive Services Task Force Recommendation Statement".JAMA.317 (12):1252–1257.doi:10.1001/jama.2017.1462.PMID28350936.
^abcSee JA, Kaukinen K, Makharia GK, Gibson PR, Murray JA (October 2015). "Practical insights into gluten-free diets".Nature Reviews. Gastroenterology & Hepatology (Review).12 (10):580–591.doi:10.1038/nrgastro.2015.156.PMID26392070.A lack of symptoms and/or negative serological markers are not reliable indicators of mucosal response to the diet. Furthermore, up to 30% of patients continue to have gastrointestinal symptoms despite a strict GFD.122,124 If adherence is questioned, a structured interview by a qualified dietitian can help to identify both intentional and inadvertent sources of gluten.
^Lebwohl B, Ludvigsson JF, Green PH (October 2015)."Celiac disease and non-celiac gluten sensitivity".BMJ (Review).351 h4347.doi:10.1136/bmj.h4347.PMC4596973.PMID26438584.Celiac disease occurs in about 1% of the population worldwide, although most people with the condition are undiagnosed. It can cause a wide variety of symptoms, both intestinal and extra-intestinal, because it is a systemic autoimmune disease that is triggered by dietary gluten. Patients with coeliac disease are at increased risk of cancer, including a twofold to fourfold increased risk of non-Hodgkin lymphoma and a more than 30-fold increased risk of small intestinal adenocarcinoma, and they have a 1.4-fold increased risk of death.
^Fasano A, Catassi C (December 2012). "Clinical practice. Celiac disease".The New England Journal of Medicine (Review).367 (25):2419–2426.doi:10.1056/NEJMcp1113994.PMID23252527.
^abLionetti E, Gatti S, Pulvirenti A, Catassi C (June 2015). "Celiac disease from a global perspective".Best Practice & Research. Clinical Gastroenterology (Review).29 (3):365–379.doi:10.1016/j.bpg.2015.05.004.PMID26060103.
^Biesiekierski JR (March 2017)."What is gluten?".Journal of Gastroenterology and Hepatology.32 (Suppl 1):78–81.doi:10.1111/jgh.13703.PMID28244676.Similar proteins to the gliadin found in wheat exist as secalin in rye, hordein in barley, and avenins in oats and are collectively referred to as "gluten." Derivatives of these grains, such as triticale and malt, and other ancient wheat varieties, such as spelt and kamut, also contain gluten. The gluten found in all of these grains has been identified as the component capable of triggering the immune-mediated disorder, coeliac disease.
^Vivas S, Vaquero L, Rodríguez-Martín L, Caminero A (November 2015)."Age-related differences in celiac disease: Specific characteristics of adult presentation".World Journal of Gastrointestinal Pharmacology and Therapeutics (Review).6 (4):207–212.doi:10.4292/wjgpt.v6.i4.207.PMC4635160.PMID26558154.In addition, the presence of intraepithelial lymphocytosis and/or villous atrophy and crypt hyperplasia of small-bowel mucosa, and clinical remission after withdrawal of gluten from the diet, are also used for diagnosis antitransglutaminase antibody (tTGA) titers and the degree of histological lesions inversely correlate with age. Thus, as the age of diagnosis increases, antibody titers decrease, and histological damage is less marked. It is common to find adults without villous atrophy showing only an inflammatory pattern in duodenal mucosa biopsies: Lymphocytic enteritis (Marsh I) or added crypt hyperplasia (Marsh II)
^abcdeLevy J, Bernstein L, Silber N (December 2014). "Celiac disease: an immune dysregulation syndrome".Current Problems in Pediatric and Adolescent Health Care (Review).44 (11):324–327.doi:10.1016/j.cppeds.2014.10.002.PMID25499458.Initially, reduced levels of lactase and sucrase activities might necessitate further dietary restrictions until the villi have healed and those sugars are better tolerated.
^abLeffler DA, Green PH, Fasano A (October 2015). "Extraintestinal manifestations of coeliac disease".Nature Reviews. Gastroenterology & Hepatology (Review).12 (10):561–571.doi:10.1038/nrgastro.2015.131.PMID26260366.
^abcGarcía-Manzanares A, Lucendo AJ (April 2011). "Nutritional and dietary aspects of celiac disease".Nutrition in Clinical Practice (Review).26 (2):163–173.doi:10.1177/0884533611399773.PMID21447770.
^Troncone R, Ivarsson A, Szajewska H, Mearin ML (2008). "Review article: future research on coeliac disease – a position report from the European multistakeholder platform on coeliac disease (CDEUSSA)".Aliment. Pharmacol. Ther.27 (11):1030–1043.doi:10.1111/j.1365-2036.2008.03668.x.PMID18315588.
^"What is Gluten-Free? FDA Has an Answer".Food and Drug Administration. 2 August 2013. Archived fromthe original on 4 August 2013. Retrieved2 August 2013.As one of the criteria for using the claim 'gluten-free,' FDA is setting a gluten limit of less than 20 ppm (parts per million) in foods that carry this label. This is the lowest level that can be consistently detected in foods using valid scientific analytical tools. Also, most people with celiac disease can tolerate foods with very small amounts of gluten. This level is consistent with those set by other countries and international bodies that set food safety standards.
^Section 206 of the Food Allergen Labeling and Consumer Protection Act of 2004, Title II ofPub. L.108–282 (text)(PDF), 118 Stat.891, enactedAugust 2, 2004
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^Mulder CJ, van Wanrooij RL, Bakker SF, Wierdsma N, Bouma G (2013). "Gluten-free diet in gluten-related disorders".Dig. Dis. (Review).31 (1):57–62.doi:10.1159/000347180.PMID23797124.
^Elli L, et al. (February 2023). "Clinical features of type 1 and 2 refractory celiac disease: Results from a large cohort over a decade".Digestive and Liver Disease.55 (2):235–242.doi:10.1016/j.dld.2022.08.022.PMID36096991.
^abLebwohl B, Rubio-Tapia A (January 2021). "Epidemiology, Presentation, and Diagnosis of Celiac Disease".Gastroenterology.160 (1):63–75.doi:10.1053/j.gastro.2020.06.098.PMID32950520.
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