Non-classic symptoms are more common, especially in people older than two years.[2][9][10] There may be mild or absent gastrointestinal symptoms, a wide number of symptoms involving any part of the body, or no obvious symptoms.[1] Due to the frequency of these symptoms, coeliac disease is often considered a systemic disease, rather than a gastrointestinal condition.[11][12] Coeliac disease was first described as a disease which initially presents during childhood;[3][2] however, it may develop at any age.[1][2] It is associated with other autoimmune diseases, such as Type 1 diabetes mellitus and Hashimoto's thyroiditis, among others.[12][3]
Coeliac disease is caused by a reaction to gluten, a group of various proteins found in wheat and in other grains such as barley and rye.[13][14][15] Moderate quantities of oats, free of contamination with other gluten-containing grains, are usually tolerated.[14][16] The occurrence of problems may depend on the variety of oat.[14][17] It occurs more often in people who are genetically predisposed.[18] Upon exposure to gluten, an abnormal immune response may lead to the production of several different autoantibodies that can affect a number of different organs.[19][20] In the small bowel, this causes an inflammatory reaction and may produce shortening of the villi lining the small intestine (villous atrophy).[18][21] This affects the absorption of nutrients, frequently leading to anaemia.[18][15]
Diagnosis is typically made by a combination of blood antibody tests and intestinal biopsies, helped by specific genetic testing.[18] Making the diagnosis is not always straightforward.[22] About 10% of the time, the autoantibodies in the blood are negative,[23][24] and many people have only minor intestinal changes with normal villi.[25] People may have severe symptoms and they may be investigated for years before a diagnosis is achieved.[26][27] As a result of screening, the diagnosis is increasingly being made in people who have no symptoms.[28] Evidence regarding the effects of screening, however, is currently insufficient to determine its usefulness.[29] While the disease is caused by a permanent intolerance to gluten proteins,[18] it is distinct from wheat allergy, which is much more rare.[30][31]
The only known effective treatment is a strict lifelong gluten-free diet, which leads to recovery of the intestinal lining (mucous membrane), improves symptoms, and reduces the risk of developing complications in most people.[5] If untreated, it may result in cancers such as intestinal lymphoma, and a slightly increased risk of early death.[32] 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.[6] 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.[33][26][34] Coeliac disease is slightly more common in women than in men.[35]
Signs and symptoms
Coeliac disease can cause a wide range of symptoms and complications that can involve several different organs.[8] The presentation of coeliac disease can be classified as classic, non-classic, and subclinical.[36] Classic coeliac disease is commonly seen in young children, but can affect any age group, and is characterized by malabsorption manifesting as diarrhea, weight loss, and failure to thrive.[8][37] Non-classic celiac disease is seen more often in adults and symptoms primarily manifest outside of the intestine (extraintestinal).[37] Many undiagnosed individuals who consider themselves asymptomatic are, in fact, not, but rather have become accustomed to living in a state of chronically compromised health. Indeed, after starting a gluten-free diet and subsequent improvement becomes evident, such individuals are often able to retrospectively recall and recognise prior symptoms of their untreated disease that they had mistakenly ignored.[38][39][34]
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.[48][50]
IgA deficiency is present in 2-2.5% of people with coeliac disease, and is itself associated with an increased risk of coeliac disease.[51]
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[50]
Coeliac disease is caused by an inflammatory reaction to gliadins and glutenins (gluten proteins)[52] found in wheat and to similar proteins found in the crops of the tribeTriticeae (which includes other common grains such as barley and rye) and to the tribe Aveneae (oats).[53] Wheat subspecies (such as spelt, durum, and Kamut) and wheat hybrids (such as triticale) also cause symptoms of coeliac disease.[54]
A small number of people with coeliac disease react to oats. Sensitivity to oats in coeliac disease may be due to cross-contamination of oats and other foods with gluten, differences between gluten content, immunoreactivity, and genetic variability seen between oat cultivars or dietary intolerance to oats.[55][56] Most people with coeliac disease do not have adverse reactions to uncontaminated or 'pure' oats, however clinical guidelines differ on whether those with coeliac disease should consume oats.[57][58]
Other cereals such as corn, millet, sorghum, teff, rice, and wild rice are safe for people with coeliac disease to consume, as well as non-cereals such as amaranth, quinoa, and buckwheat. Noncereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.[59][60]
Risk modifiers
Environmental factors such as infections, geographic latitude, birth weight, antibiotic use, intestinal microbiota, 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.[61][52][37] 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 gentically predisposed to coeliac disease, large amounts of gluten early in life, may increase the risk of developing coeliac disease.[62][63]
Mechanism
Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person.[64]
Almost all people (90%) with coeliac disease have either the variant HLA-DQ2allele or (less commonly) the HLA-DQ8allele.[36] However, about 40% of people without coeliac disease have also inherited either of these alleles.[65] 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.[36][66]
Genetics
DQ α -β -binding cleft with a deamidated gliadin peptide (yellow), modified from PDB: 1S9V
There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of people with coeliac disease have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.[69]
HLA region of chromosome 6
Most people with coeliac bear a two-gene HLA-DQ2 haplotype referred to as DQ2.5 haplotype. This haplotype is composed of two adjacent gene alleles, DQA1*0501 and DQB1*0201, which encode the two subunits, DQ α5 and DQ β2.[70][71] In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents (DQ2.5cis). Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk for coeliac disease as well as being more susceptible to severe complications.[72]
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 for coeliac disease as those with a single DQ2.5-bearing chromosome 6.[72][69] Among those with coeliac disease that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 2-5% have the DQ2.2 isoform, and the remaining 2% lack DQ2 or DQ8.[72]
The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country and Ireland[73] with highest frequencies) and portions of Africa and is associated with disease in India,[74] but it is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ2.5 and is particularly common in South and Central America; up to 90% of individuals in certain Amerindian populations carry DQ8 and thus may display the coeliac phenotype.[75][needs update]
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.[66]
The prevalence of coeliac disease genotypes in the modern population is not completely understood. Given the characteristics of the disease and its apparent strong heritability, it would normally be expected that the genotypes would undergo negative selection and to be absent in societies where agriculture has been practised the longest (compare with a similar condition, lactose intolerance, which has been negatively selected so strongly that its prevalence went from ~100% in ancestral populations to less than 5% in some European countries). This expectation was first proposed by Simoons (1981).[76] By now, however, it is apparent that this is not the case; on the contrary, there is evidence of positive selection in coeliac disease genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections.[77][78][needs update?]
Prolamins
The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine (-amin) that dissolve in alcohols and are resistant to proteases and peptidases of the gut.[79] Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley (hordein), rye (secalin) and oats (avenin).[53][36]
Illustration of deamidated α-2 gliadin's 33mer, amino acids 56–88, showing the overlapping of three varieties of T-cell epitope
Membrane leaking permits peptides of gliadin that stimulate two levels of the immune response: the innate response and the adaptive (T-helper cell-mediated) response. One protease-resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. This innate response to gliadin results in immune-system signalling that attracts inflammatory cells and increases the release of inflammatory chemicals.[28][needs update?]
The response to the 33mer occurs in most coeliacs who have a DQ2isoform. This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 isoform will bind, and stay bound to, peptide when recognised by T-cells.[80]
Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in the blood of the majority of people with classic symptoms and complete villous atrophy, but only in 70% of the cases with partial villous atrophy and 30% of the cases with minor mucosal lesions.[23][needs update] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.[79] These peptides are modified by tTG in two ways, deamidation or transamidation.[81]
Deamidation is the reaction by which a glutamate residue is formed by cleavage of the epsilon-amino group of a glutamine side chain.[82] Transamidation, which occurs three times more often than deamidation,[verification needed] is the cross-linking of a glutamine residue from the gliadin peptide to a lysine residue of tTg in a reaction that is catalysed by the transglutaminase.[81] Crosslinking may occur either within or outside the active site of the enzyme. The latter case yields a permanently covalently linked complex between the gliadin and the tTg. This results in the formation of new epitopes believed to trigger the primary immune response by which the autoantibodies against tTg develop.[83]
Stored biopsies from people with suspected coeliac disease have revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease.[79]
Villous atrophy and malabsorption
The inflammatory process, mediated by T 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 absorb nutrients from food.[66][65]Lactose intolerance may be present due to the decreased bowel surface and reduced production of lactase, but typically resolves once the coeliac disease is under control. Rarely, lactose intolerance may be the only noticeable symptom of underlying coeliac disease.[84][undue weight?–discuss]
Alternative causes of this tissue damage have been proposed and involve the release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49).[79]
Diagnosis
The diagnosis of coeliac disease is often complicated by the variety in symptoms, overlap with other disorders, and lack of awareness in medical professionals, leading to a delay in the diagnosis being made.[85][38] The time between the development of symptoms and a diagnosis can reach up to 13 years in some cases, and the majority of those with coeliac disease remain undiagnosed.[39][86] Delays in diagnosis can cause reduced quality of life, higher utilization of medical resources and an increased risk of complications associated with the disease.[85][87][88]
Coeliac disease is diagnosed based on symptoms, blood tests, and biopsies of the small intestine.[85] 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 a gluten-free diet. In those who have already reduced their gluten intake, reintroducing gluten (gluten challenge) may be required to reach an accurate diagnosis.[89] 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.[89][90]
Blood tests
Immunofluorescence staining pattern of endomysial antibodies on a monkey oesophagus tissue sample
Current medical guidelines recommend testing tissue transglutaminase 2immunoglobulin A (TTG IgA) in those with suspected coeliac disease.[91][92] Because IgA deficiency is more common in those with coeliac disease,[93] 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) or endomysial antibody (EMA) can be used instead of IgA-based tests.[91][92]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 by guidelines.[61][93] Due to the risk of false 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.[61][92]
TG2 IgA has a high sensitivity (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.[94][89] Despite this, preformance of the TG2 IgA test differes between different labs and no formal standardation between assays exists.[38] The severity of small intestine damage generally correlated to the levels of TG2 IgA found in the blood, meaning that the sensitivity is lower in people who have less damage to their intestines.[94][93]
EMA has a lower sensitivity, but its specificity is near 100%.[94] Because of the high specificity, EMA can be used to confirm coeliac disease in those who have borderline TG2 IgA levels.[89] EMA testing is costly, hard to interpret and vulnerable to interobserver and inter-site variability.[38][95]
DGP IgG is used to evaluate coeliac disease in those with IgA-deficiency. Coeliac disease is more common in those with IgA-deficiency, leading to medical guidelines recommending that those who are undergoing testing for coeliac disease also be 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.[93][96]
Antibody testing may be combined with HLA testing if the diagnosis is unclear. TGA and EMA testing are the most sensitive serum antibody tests, but as a negative HLA-DQ type excludes the diagnosis of coeliac disease, testing also for HLA-DQ2 or DQ8 maximizes sensitivity and negative predictive values.[97] In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) does not (as of 2015) recommend the use of HLA typing to rule out coeliac disease outside of a specialist setting, for example, in children who are not having a biopsy, or in patients who already have limited gluten ingestion and opt not to have a gluten challenge.[20]
Endoscopy
Endoscopic still of duodenum of a person with coeliac disease showing scalloping of folds and "cracked-mud" appearance to mucosaSchematic of the Marsh classification of upper jejunal pathology in coeliac disease
An upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum is performed to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative.[98] Even in the same bioptic fragment, different degrees of damage may be present.[10]
Most people with coeliac disease have a small intestine that appears to be normal on endoscopy before the biopsies are examined. However, five findings have been associated with high specificity for coeliac disease: scalloping of the small bowel folds (pictured), paucity in the folds, a mosaic pattern to the mucosa (described as a "cracked-mud" appearance), prominence of the submucosablood vessels, and a nodular pattern to the mucosa.[99]
European guidelines suggest that in children and adolescents with symptoms compatible with coeliac disease, the diagnosis can be made without the need for intestinal biopsy if anti-tTG antibodies titres are very high (10 times the upper limit of normal).[2]
Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After x-ray verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. Often-utilised capsule systems were the Watson capsule and the Crosby–Kugler capsule. This method has now been largely replaced by fibre-optic endoscopy, which carries a higher sensitivity and a lower frequency of errors.[100]
Capsule endoscopy (CE) allows identification of typical mucosal changes observed in coeliac disease, but has a lower sensitivity compared to regular endoscopy and histology. CE is therefore not the primary diagnostic tool for coeliac disease. However, CE can be used for diagnosing T-cell lymphoma, ulcerative jejunoileitis, and adenocarcinoma in refractory or complicated coeliac disease.[101]
Pathology
The classic pathology changes of coeliac disease in the small bowel are categorised by the "Marsh classification":[102]
Marsh stage 0: normal mucosa
Marsh stage 1: increased number of intra-epithelial lymphocytes (IELs), usually exceeding 20 per 100 enterocytes
Marsh's classification, introduced in 1992, was subsequently modified in 1999 to six stages, where the previous stage 3 was split in three substages.[104] Further studies demonstrated that this system was not always reliable and that the changes observed in coeliac disease could be described in one of three stages:[15][105]
A representing lymphocytic infiltration with normal villous appearance;
B1 describing partial villous atrophy; and
B2 describing complete villous atrophy.
The changes classically improve or reverse after gluten is removed from the diet. However, most guidelines do not recommend a repeat biopsy unless there is no improvement in the symptoms on diet.[98][106] In some cases, a deliberate gluten challenge, followed by a biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicate the diagnosis may have been incorrect.[98]
In untreated coeliac disease, villous atrophy is more common in children younger than three years, but in older children and adults, it is common to find minor intestinal lesions (duodenal lymphocytosis) with normal intestinal villi.[21][25]
Osteopenia and osteoporosis, mildly and severely reduced bone mineral density, are often present in people with coeliac disease, and investigations to measure bone density may be performed at diagnosis, such as dual-energy X-ray absorptiometry (DXA) scanning, to identify the risk of fracture and need for bone protection medication.[98][107]
Gluten withdrawal
Although blood antibody tests, biopsies, and genetic tests usually provide a clear diagnosis,[24][108] occasionally, the response to gluten withdrawal on a gluten-free diet is needed to support the diagnosis. 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.[24] Nevertheless, in some cases, a gluten challenge with a subsequent biopsy may be useful to support the diagnosis, for example, in people with a high suspicion for coeliac disease, without a biopsy confirmation, who have negative blood antibodies and are already on a gluten-free diet.[24] Gluten challenge is discouraged before the age of 5 years and during pubertal growth.[109] The alternative diagnosis of non-coeliac gluten sensitivity may be made where there is only symptomatic evidence of gluten sensitivity.[110] Gastrointestinal and extraintestinal symptoms of people with non-coeliac gluten sensitivity can be similar to those of coeliac disease,[10] and improve when gluten is removed from the diet,[111][112] after coeliac disease and wheat allergy are reasonably excluded.[113][114]
Up to 30% of people often continue having or redeveloping symptoms after starting a gluten-free diet.[5] 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,[21] or be due to other commonly associated conditions such as small intestinal bacterial overgrowth (SIBO), lactose intolerance, fructose,[115]sucrose,[116] and sorbitol[117] malabsorption, exocrine pancreatic insufficiency,[118][119] and microscopic colitis,[119] among others. In untreated coeliac disease, these are often transient conditions derived from the intestinal damage.[116][117][120][121][122] They normally revert or improve several months after starting a gluten-free diet, but may need temporary interventions such as supplementation with pancreatic enzymes,[121][122] dietary restrictions of lactose, fructose, sucrose or sorbitol containing foods,[116][120] or treatment with oral antibiotics in the case of associated bacterial overgrowth.[122] 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 in preservatives and additives (such as sulfites, glutamates, nitrates and benzoates) and might have a role in triggering functional gastrointestinal symptoms.[123]
Some evidence has found that early detection may decrease the risk of developing health complications, such as osteoporosis, anaemia, and certain types of cancer, neurological disorders, cardiovascular diseases, and reproductive problems.[126][28][127][128][129] They thus recommend screening in people with certain health problems.[129]
Serology has been proposed as a screening measure, because the presence of antibodies would detect some previously undiagnosed cases of coeliac disease and prevent its complications in those people. However, serologic tests have high sensitivity only in people with total villous atrophy and have a very low ability to detect cases with partial villous atrophy or minor intestinal lesions.[24] Testing for coeliac disease may be offered to those with commonly associated conditions.[15][20]
At present, the only effective treatment is a lifelong gluten-free diet.[130] No medication exists that prevents damage or prevents the body from attacking the gut when gluten is present. Strict adherence to the diet helps the intestines heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer and in some cases sterility.[131] Compliance to a strict gluten-free diet is difficult for the patient, but evidence has accumulated that a strict gluten-free diet can result in resolution of diarrhea, weight gain, and normalization of nutrient malabsorption, with normalization of biopsies in 6 months to 2 years on a gluten-free diet.[132]
Dietitian input is generally requested to ensure the person is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries, gluten-free products are available on prescription and may be reimbursed by health insurance plans. Gluten-free products are usually more expensive and harder to find than common gluten-containing foods.[133] Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.[134]
The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence.[135] The exact level at which gluten is harmless is uncertain and controversial. A recent systematic review tentatively concluded that consumption of less than 10mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done.[135] Regulation of the label "gluten-free" varies. In the European Union, the European Commission issued regulations in 2009 limiting the use of "gluten-free" labels for food products to those with less than 20mg/kg of gluten, and "very low gluten" labels for those with less than 100mg/kg.[136] In the United States, the FDA issued regulations in 2013 limiting the use of "gluten-free" labels for food products to those with less than 20ppm of gluten.[137][138][139] The international Codex Alimentarius standard allows for 20ppm of gluten in so-called "gluten-free" foods.[140]
A gluten-free diet improves healthcare-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.[141]
Vaccination
Even though it is unclear if coeliac patients have a generally increased risk of infectious diseases, they should generally be encouraged to receive all common vaccines against vaccine preventable diseases (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. For this reason, patients who are known to be hyposplenic should be offered at least the pneumococcal vaccine.[142] However, the ESsCD states that it is not clear whether vaccination with the conjugated vaccine is preferable in this setting and whether additional vaccination against Haemophilus, meningococcus, and influenza should be considered if not previously given.[142] However, Mårild et al. suggested considering additional vaccination against influenza because of an observed increased risk of hospital admission for this infection in coeliac patients.[143]
Refractory disease
Between 0.3% and 10% of affected people have refractory disease, which means that they have persistent villous atrophy on a gluten-free diet despite the lack of gluten exposure for more than 12 months.[119] 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.[119] 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.[5][119][144] Also, a lack of symptoms is not a reliable indicator of intestinal recuperation.[119]
Refractory coeliac disease can be divided into types I and II. A recent study compared patients with type I and type II. Refractory coeliac disease type I more frequently exhibits diarrhea, anemia, 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][145]
Epidemiology
In most countries, between 1 in 50 and 1 in 200 people have coeliac disease.[146]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 the HLA-DQ genes that predispose to the disease.[146] In the United States, it is thought to affect between 1 in 1,750 (defined as clinical disease including dermatitis herpetiformis with limited digestive tract symptoms) to 1 in 105 (defined by the presence of IgA TG in blood donors).[147] The percentage of people with clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the percentage of people with the disease may be between 0.33 and 1.06% in children (but 5.66% in one study of children of the predisposed Sahrawi people[148]) and 0.18–1.2% in adults.[28] Among those in primary care populations who report gastrointestinal symptoms, the rate of coeliac disease is about 3%.[108] A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic people, 2.6% in second-degree relatives (like grandparents, aunt or uncle, grandchildren, etc.) of a person with coeliac disease and 4.5% in first-degree relatives (siblings, parents or children).[149] This profile is similar to the prevalence in Europe.[149]
Diagnoses of coeliac disease have increased dramatically in recent decades due to increased awareness of the disease and availability of blood testing.[146] However, the disease is still thought to be underdiagnosed, with an estimated 70% of people with coeliac undiagnosed and untreated.[146] Undiagnosed cases are more common in lower wealth areas, and in countries where regular testing of at-risk people is not performed.[146]
While coeliac disease can arise at any age, most people develop the disease before age 10.[150] Roughly 20 percent of individuals with coeliac disease are diagnosed after 60 years of age.[151] 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.[150] Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with Down and Turner syndromes, type 1 diabetes, and autoimmune thyroid disease, including both hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid).[152]
History
The term coeliac comes from Greek κοιλιακός (koiliakós) 'abdominal' and was introduced in the 19th century in a translation of what is generally regarded as an Ancient Greek description of the disease by Aretaeus of Cappadocia.[153][154]
Humans first started to cultivate grains in the Neolithic period (beginning about 9500BCE) in the Fertile Crescent in Western Asia, and, likely, coeliac disease did not occur before this time. Aretaeus of Cappadocia, living in the second century in the same area, recorded a malabsorptive syndrome with chronic diarrhoea, causing a debilitation of the whole body.[153]
A 15th-century medical prescription from Mamluk Cairo, attributed to Shams al-Din ibn al-'Afif, the personal physician to Sultan Barsbay and director of the Qalawun complex hospital, describes a treatment for symptoms consistent with coeliac disease. Found in Fustat and now held in the Museum of Islamic Art in Cairo, the remedy combines herbs and plant waters for patients intolerant to wheat.[155]
Aretaeus of Cappadocia's "Cœliac Affection" gained the attention of Western medicine when Francis Adams presented a translation of Aretaeus's work at the Sydenham Society in 1856. The patient described in Aretaeus' work had stomach pain and was atrophied, pale, feeble, and incapable of work. The diarrhoea manifested as loose stools that were white, malodorous, and flatulent, and the disease was intractable and liable to periodic return. The problem, Aretaeus believed, was a lack of heat in the stomach necessary to digest the food and a reduced ability to distribute the digestive products throughout the body, this incomplete digestion resulting in diarrhoea. He regarded this as an affliction of the old and more commonly affecting women, explicitly excluding children. The cause, according to Aretaeus, was sometimes either another chronic disease or even consuming "a copious draught of cold water."[153][154]
The paediatricianSamuel Gee gave the first modern-day description of the condition in children in a lecture at Hospital for Sick Children, Great Ormond Street, London, in 1887. Gee acknowledged earlier descriptions and terms for the disease and adopted the same term as Aretaeus (coeliac disease). He perceptively stated: "If the patient can be cured at all, it must be by means of diet." Gee recognised that milk intolerance is a problem with coeliac children and that highly starched foods should be avoided. However, he forbade rice, sago, fruit, and vegetables, which all would have been safe to eat, and he recommended raw meat as well as thin slices of toasted bread. Gee highlighted particular success with a child "who was fed upon a quart of the best Dutch mussels daily." However, the child could not bear this diet for more than one season.[154][156]
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 eponymGee-Herter disease was sometimes used to acknowledge both contributions.[157][158]Sidney V. Haas, an American paediatrician, reported positive effects of a diet of bananas in 1924.[159] This diet remained in vogue until the actual cause of coeliac disease was determined.[154]
While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Willem Karel Dicke.[160] It is likely that clinical improvement of his patients during the Dutch famine of 1944–1945 (during which flour was scarce) may have contributed to his discovery.[161] 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.[162] The link with the gluten component of wheat was made in 1952 by a team from Birmingham, England.[163] Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery.[164] This paved the way for biopsy samples taken by endoscopy.[154]
Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965.[165] In 1966, dermatitis herpetiformis was linked to gluten sensitivity.[154][166]
May has been designated as "Coeliac Awareness Month" by several coeliac organisations.[167][168]
Christian churches and the Eucharist
Speaking generally, the various denominations of Christians celebrate a Eucharist in which a wafer or small piece of sacramental bread from wheat bread is blessed and then eaten. A typical wafer weighs about half a gram.[169] Small communion wafers typically contain 2-5 mg of gliadin if they are not a gluten-free variety,[170] and many people with coeliac disease report altering their religious practices because of coeliac symptoms caused by these wafers.[171]
Many Christian churches offer their communicants gluten-free alternatives, usually in the form of a rice-based cracker or gluten-free bread. These include the United Methodist, Christian Reformed, Episcopal, the Anglican Church (Church of England, UK) and Lutheran. Catholics may receive from the chalice alone, or ask for gluten-reduced hosts; gluten-free ones however are not considered still to be wheat bread, and hence are invalid matter.[172]
Roman Catholic position
Roman Catholic doctrine states that for a valid Eucharist, the bread to be used at Mass must be made from wheat. Low-gluten hosts meet all of the Catholic Church's requirements, but they are not entirely gluten-free. Requests to use rice wafers have been denied.[173]
The issue is more complex for priests. As a celebrant, a priest is, for the fullness of the sacrifice of the Mass, absolutely required to receive under both species. On 24 July 2003, the Congregation for the Doctrine of the Faith stated, "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm."[174]
By January 2004, extremely low-gluten Church-approved hosts had become available in the United States, Italy and Australia.[175] As of July 2017, the Vatican still outlawed the use of gluten-free bread for Holy Communion.[176]
Passover
The Jewish festival of Pesach (Passover) may present problems with its obligation to eat Matzah, which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. In addition, many other grains that are normally used as substitutes for people with gluten sensitivity, including rice, are avoided altogether on Passover by Ashkenazi Jews. Many kosher-for-Passover products avoid grains altogether and are therefore gluten-free. Potato starch is the primary starch used to replace the grains.[citation needed]
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.[179] Research published in April 2017 suggests that an often-symptomless infection by a common strain of reovirus can increase sensitivity to foods such as gluten.[180]
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.[28][181][182]
Three main approaches have been proposed as new therapeutic modalities for coeliac disease: gluten detoxification, modulation of the intestinal permeability, and modulation of the immune response.[183]
Using genetically engineered wheat species, or wheat species that have been selectively bred to be minimally immunogenic, may allow the consumption of wheat. This, however, could interfere with the effects that gliadin has on the quality of dough.[citation needed]
Alternatively, gluten exposure can be minimised by the ingestion of a combination of enzymes (prolyl endopeptidase and a barley glutamine-specific cysteine endopeptidase (EP-B2)) that degrade the putative 33-mer peptide in the duodenum.[28] Latiglutenase (IMGX003) is a biotherapeutic 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[184] and is scheduled for phase 3 clinical trials.[185]
Other potential approaches to pharmacotherapy include the inhibition of zonulin, an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system.[186] 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.[28]
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.[183]
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↑ Comino I, Moreno M, Sousa C (November 2015). "Role of oats in celiac disease". World Journal of Gastroenterology. 21 (41): 11825–11831. doi:10.3748/wjg.v21.i41.11825. PMC4631980. PMID26557006. It is necessary to consider that oats include many varieties, containing various amino acid sequences and showing different immunoreactivities associated with toxic prolamins. As a result, several studies have shown that the immunogenicity of oats varies depending on the cultivar consumed. Thus, it is essential to thoroughly study the variety of oats used in a food ingredient before including it in a gluten-free diet.
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1 2 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).
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1 2 van der Windt DA, Jellema P, Mulder CJ, Kneepkens CM, van der Horst HE (2010). "Diagnostic testing for celiac disease among patients with abdominal symptoms: a systematic review". JAMA. 303 (17): 1738–1746. doi:10.1001/jama.2010.549. PMID20442390. Most studies used similar histological criteria for diagnosing celiac disease (Marsh grade ≥III), but the level of damage may vary across populations. Only 4 studies presented the proportion of patients in whom only partial villous atrophy was found (Marsh grade of IIIA), which ranged from 4% to 100%. The presence of positive serum antibodies has been shown to correlate with the degree of villous atrophy, and patients with celiac disease who have less severe histological damage may have seronegative findings. This could be important, especially in primary care, in which levels of mucosal damage may be lower, and consequently, more patients with celiac disease may be missed.
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↑ "What is Gluten-Free? FDA Has an Answer". Food and Drug Administration. 2 August 2013. Archived from the original on 4 August 2013. Retrieved 2 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 of Pub. L.108–282 (text)(PDF), 118Stat.891 , enacted August 2, 2004
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