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.[9][17][18] Moderate quantities of oats, free of contamination with other gluten-containing grains, are usually tolerated.[17][19] The occurrence of problems may depend on the variety of oat.[17][20] It occurs more often in people who are genetically predisposed.[10] 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.[4][21] In the small bowel, this causes an inflammatory reaction and may produce shortening of the villi lining the small intestine (villous atrophy).[10][11] This affects the absorption of nutrients, frequently leading to anaemia.[10][18]
Diagnosis is typically made by a combination of blood antibody tests and intestinal biopsies, helped by specific genetic testing.[10] 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 not sufficient to determine its usefulness.[29] While the disease is caused by a permanent intolerance to gluten proteins,[10] 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.[13] If untreated, it may result in cancers such as intestinal lymphoma, and a slightly increased risk of early death.[3] 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.[5][26][32] Coeliac disease is slightly more common in women than in men.[33]
Signs and symptoms
The classic symptoms of untreated coeliac disease include diarrhea, steatorrhoea, iron-deficiency anemia, and weight loss or failure to gain weight. Other common symptoms may be subtle or primarily occur in organs other than the bowel itself.[34] It is also possible to have coeliac disease without any of the classic symptoms at all.[18] This has been shown to comprise at least 43% of presentations in children.[35] Further, many adults with subtle disease may only present with fatigue, anaemia or low bone mass.[28] 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.[5][27][32]
Coeliac disease leads to an increased risk of both adenocarcinoma and lymphoma of the small bowel (enteropathy-associated T-cell lymphoma (EATL) or other non-Hodgkin lymphomas).[39] This risk is also higher in first-degree relatives such as siblings, parents and children. Whether a gluten-free diet brings this risk back to baseline is not clear.[40] Long-standing and untreated disease may lead to other complications, such as ulcerative jejunitis (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring with obstruction of the bowel).[41]
A small proportion of people have abnormal coagulation because of vitamin K deficiency and are at a slight risk of abnormal bleeding.
Miscellaneous
Coeliac disease has been linked with many conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.
IgA deficiency is present in 2.3% of people with coeliac disease, and is itself associated with a tenfold increased risk of coeliac disease. Other features of this condition are an increased risk of infections and autoimmune disease.[44]
Dermatitis herpetiformis, an itchy cutaneous condition that has been linked to a transglutaminase enzyme in the skin, features small-bowel changes identical to those in coeliac disease and may respond to gluten withdrawal even if no gastrointestinal symptoms are present.[45][46]
Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition. Evaluation of growth failure often includes coeliac screening.[18]
Hyposplenism (a small and underactive spleen)[48] occurs in about a third of cases and may predispose to infection given the role of the spleen in protecting against harmful bacteria.[18]
Coeliac disease is caused by an inflammatory reaction to gliadins and glutenins (gluten proteins)[50] found in wheat and to similar proteins found in the crops of the tribeTriticeae (which includes other common grains such as barley and rye)[18] and to the tribe Aveneae (oats).[51] Wheat subspecies (such as spelt, durum, and Kamut) and wheat hybrids (such as triticale) also cause symptoms of coeliac disease.[51][52]
A small number of people with coeliac disease react to oats.[18] Oat toxicity in coeliac people depends on the oat cultivar consumed because the prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins are different in different oat varieties.[20][53] Also, oats are frequently cross-contaminated with other grains containing gluten.[20][53][54] The term "pure oats" refers to oats uncontaminated with other gluten-containing cereals.[20] The long-term effects of pure oat consumption are still unclear,[55] and further studies identifying the cultivars used are needed before making final recommendations on their inclusion in a gluten-free diet.[54] Coeliac people who choose to consume oats need a more rigorous lifelong follow-up, possibly including periodic intestinal biopsies.[55]
Other grains
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.[52][56] Noncereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.[52]
Risk modifiers
There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include surgery, pregnancy, infection and emotional stress.[57]
The eating of gluten early in a baby's life does not appear to increase the risk of coeliac disease but later introduction after six months may increase it.[58][59] There is uncertainty whether being breastfed reduces risk. Prolonging breastfeeding until the introduction of gluten-containing grains into the diet appears to be associated with a 50% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear.[60] These factors may just influence the timing of onset.[61]
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.[62]
Almost all people (95%) with coeliac disease have either the variant HLA-DQ2allele or (less commonly) the HLA-DQ8allele.[28][63] However, about 20–30% of people without coeliac disease have also inherited either of these alleles.[64] This suggests that additional factors are needed for coeliac disease to develop; that is, the predisposing HLA risk allele is necessary but not sufficient to develop coeliac disease. Furthermore, around 5% of those people who do develop coeliac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles (see below).[28]
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 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.[28]
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. 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.[66]
Some individuals inherit DQ2.5 from one parent and an additional portion of the haplotype (either DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent (DQ2.5trans) (called a trans-haplotype association), and these individuals are at similar risk for coeliac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, the disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 4% have the DQ2.2 isoform, and the remaining 2% lack DQ2 or DQ8.[67]
The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country and Ireland[68] with highest frequencies) and portions of Africa and is associated with disease in India,[69] 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.[70]
Other genetic factors have been repeatedly reported in coeliac disease; however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population.[71] Many of the loci detected have been found in association with other autoimmune diseases. One locus, the LPP or lipoma-preferred partner gene, is involved in the adhesion of extracellular matrix to the cell surface, and a minor variant (SNP=rs1464510) increases the risk of disease by approximately 30%. This gene strongly associates with coeliac disease (p < 10−39) in samples taken from a broad area of Europe and the US.[71]
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).[72] 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.[73][74]
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.[28][75] Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley (hordein), rye (secalin) and oats (avenin).[51] One region of α-gliadin stimulates membrane cells, enterocytes, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than three amino acids to enter the intestinal lining.[76]
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] The strongest and most common adaptive response to gliadin is directed toward an α2-gliadin fragment of 33amino acids in length.[28]
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.[77] Gliadin in wheat is the best-understood member of this family, but other prolamins exist, and hordein (from barley), secalin (from rye), and avenin (from oats) may contribute to coeliac disease.[28][51][78] Avenin's toxicity in people with coeliac disease depends on the oat cultivar consumed, as prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins vary among oat varieties.[20]
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] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.[28] These peptides are modified by tTG in two ways, deamidation or transamidation.[79]
Deamidation is the reaction by which a glutamate residue is formed by cleavage of the epsilon-amino group of a glutamine side chain. Transamidation, which occurs three times more often than deamidation, is the cross-linking of a glutamine residue from the gliadin peptide to a lysine residue of tTg in a reaction that is catalysed by the transglutaminase. Crosslinking may occur either within or outside the active site of the enzyme. The latter case yields a permanently covalently linked complex between the gliadin and the tTg.[80] This results in the formation of new epitopes believed to trigger the primary immune response by which the autoantibodies against tTg develop.[81][82][83]
Stored biopsies from people with suspected coeliac disease have revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in people who present with other autoimmune diseases, anaemia, or malabsorption phenomena at a much increased rate over the normal population.[84] Endomysial components of antibodies (EMA) to tTG are believed to be directed toward cell-surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative people with coeliac tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms, including autoimmune disease.[85] In this study, the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with work showing that gliadin has an innate response component,[86] suggest that gliadin may be more responsible for the primary manifestations of coeliac disease, whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of people with coeliac, the anti-tTG antibodies also recognise a rotavirus protein called VP7. These antibodies stimulate monocyte proliferation, and rotavirus infection might explain some early steps in the cascade of immune cell proliferation.[87]
Indeed, earlier studies of rotavirus damage in the gut showed this causes villous atrophy.[88]This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a second source of crossreactive antibodies.[citation needed]
Other intestinal disorders may have biopsy that look like coeliac disease including lesions caused by Candida.[89]
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, minerals, and fat-soluble vitamins A, D, E, and K from food. Lactose intolerance may be present due to the decreased bowel surface and reduced production of lactase but typically resolves once the condition is treated.[citation needed]
Alternative causes of this tissue damage have been proposed and involve the release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of enterocytes by lymphocytes in the epithelium.[28] The villous atrophy seen on biopsy may also be due to unrelated causes, such as tropical sprue, giardiasis and radiation enteritis. While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to the diet may require these alternative diagnoses to be considered.[41]
Diagnosis
Diagnosis is often difficult and as of 2019, there continues to be a lack of awareness among physicians about the variability of presentations of coeliac disease and the diagnostic criteria, such that most cases are diagnosed with great delay.[26][22] It can take up to 12 years to receive a diagnosis from the onset of symptoms and the majority of those affected in most countries never receive it.[26]
Several tests can be used. The level of symptoms may determine the order of the tests, but all tests lose their usefulness if the person is already eating a gluten-free diet. Intestinal damage begins to heal within weeks of gluten being removed from the diet, and antibody levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a rechallenge with some gluten-containing food in one meal a day over six weeks before repeating the investigations.[21]
Blood tests
Immunofluorescence staining pattern of endomysial antibodies on a monkey oesophagus tissue sample
Serological blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Its sensitivity correlates with the degree of histological lesions. People who present with minor damage to the small intestine may have seronegative findings so many patients with coeliac disease often are missed. In patients with villous atrophy, anti-endomysial (EMA) antibodies of the immunoglobulin A (IgA) type can detect coeliac disease with a sensitivity and specificity of 90% and 99%, respectively.[90]Serology for anti-transglutaminase antibodies (anti-tTG) was initially reported to have a higher sensitivity (99%) and specificity (>90%). However, it is now thought to have similar characteristics to anti-endomysial antibodies.[90] Both anti-transglutaminase and anti-endomysial antibodies have high sensitivity to diagnose people with classic symptoms and complete villous atrophy, but they are only found in 30–89% of the cases with partial villous atrophy and in less than 50% of the people who have minor mucosal lesions (duodenal lymphocytosis) with normal villi.[23][24]
Tissue transglutaminase (abbreviated as tTG or TG2) modifies gluten peptides into a form that may stimulate the immune system more effectively.[28] These peptides are modified by tTG in two ways, deamidation or transamidation.[79] Modern anti-tTG assays rely on a human recombinant protein as an antigen.[91] tTG testing should be done first as it is an easier test to perform. An equivocal result on tTG testing should be followed by anti-endomysial antibodies.[21]
Guidelines recommend that a total serum IgA level is checked in parallel, as people with coeliac with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those people, IgG antibodies against transglutaminase (IgG-tTG) may be diagnostic.[21][92]
If all these antibodies are negative, then anti-DGP antibodies (antibodies against deamidated gliadin peptides) should be determined. IgG class anti-DGP antibodies may be useful in people with IgA deficiency. In children younger than two years, anti-DGP antibodies perform better than anti-endomysial and anti-transglutaminase antibodies tests.[8]
Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive blood test is still followed by an endoscopy/gastroscopy and biopsy. A negative serology test may still be followed by a recommendation for endoscopy and duodenal biopsy if clinical suspicion remains high.[21][41][93]
Historically three other antibodies were measured: anti-reticulin (ARA), anti-gliadin (AGA) and anti-endomysial (EMA) antibodies.[94] ARA testing, however, is not accurate enough for routine diagnostic use.[95] Serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five.[94] Serology tests are based on indirect immunofluorescence (reticulin, gliadin and endomysium) or ELISA (gliadin or tissue transglutaminase, tTG).[96]
Other antibodies such as anti–Saccharomyces cerevisiae antibodies occur in some people with coeliac disease but also occur in other autoimmune disorders and about 5% of those who donate blood.[97]
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 maximises sensitivity and negative predictive values.[64] 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.[21]
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.[41] Even in the same bioptic fragment, different degrees of damage may be present.[16]
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.[98]
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).[8]
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.[99]
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.[100]
Pathology
The classic pathology changes of coeliac disease in the small bowel are categorised by the "Marsh classification":[101]
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.[103] 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:[18][104]
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.[41][93] In some cases, a deliberate gluten challenge, followed by a biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicates the diagnosis may have been incorrect.[41]
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.[11][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.[41][42]
Gluten withdrawal
Although blood antibody tests, biopsies, and genetic tests usually provide a clear diagnosis,[24][90] 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.[105] The alternative diagnosis of non-coeliac gluten sensitivity may be made where there is only symptomatic evidence of gluten sensitivity.[106] Gastrointestinal and extraintestinal symptoms of people with non-coeliac gluten sensitivity can be similar to those of coeliac disease,[16] and improve when gluten is removed from the diet,[107][108] after coeliac disease and wheat allergy are reasonably excluded.[109]
Up to 30% of people often continue having or redeveloping symptoms after starting a gluten-free diet.[13] 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,[11] or be due to other commonly associated conditions such as small intestinal bacterial overgrowth (SIBO), lactose intolerance, fructose,[110]sucrose,[111] and sorbitol[112] malabsorption, exocrine pancreatic insufficiency,[113][114] and microscopic colitis,[114] among others. In untreated coeliac disease, these are often transient conditions derived from the intestinal damage.[111][112][115][116][117] They normally revert or improve several months after starting a gluten-free diet, but may need temporary interventions such as supplementation with pancreatic enzymes,[116][117] dietary restrictions of lactose, fructose, sucrose or sorbitol containing foods,[111][115] or treatment with oral antibiotics in the case of associated bacterial overgrowth.[117] 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.[118]
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.[7][28][47][121][122] They thus recommend screening in people with certain health problems.[122]
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.[18][21]
At present, the only effective treatment is a lifelong gluten-free diet.[52] 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.[123] 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.[124]
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.[125] Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.[126]
The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence.[127] 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.[127] 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.[128] 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.[129][130][131] The current international Codex Alimentarius standard allows for 20ppm of gluten in so-called "gluten-free" foods.[132]
Gluten-free diet improves healthcare-related quality of life, and strict adherence to the diet gives more benefit than incomplete adherence. Nevertheless, gluten-free diet does not completely normalise the quality of life.[133]
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 Celiac Disease (ESsCD), coeliac disease can be associated with hyposplenism or functional asplenia, which could result in impaired immunity to encapsulated bacteria, with an increased risk of such infections. For this reason, patients who are known to be hyposplenic should be offered at least the pneumococcal vaccine.[134] 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.[134] However, Mårild et al. suggested considering additional vaccination against influenza because of an observed increased risk of hospital admission for this infection in celiac patients.[135]
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.[114] 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.[114] 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.[13][114][136] Also, a lack of symptoms is not a reliable indicator of intestinal recuperation.[114]
Refractory celiac disease can be divided in type I and II. A recent studied compared patients with type I and II. Refractory celiac disease type I more frequently exhibits diarrhea, anemia, hypoalbuminemia, parenteral nutrition need, ulcerative jejuno-ileitis, and extended small intestinal atrophy. Among patients with refractory celiac disease type II is more common to develope lymphoma. Among these patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality. [137]
Epidemiology
Globally coeliac disease affects between 1 in 100 and 1 in 170 people.[14][138] Rates, however, vary between different regions of the world from as few as 1 in 300 to as many as 1 in 40.[14] In the United States it is thought to affect between 1 in 1750 (defined as clinical disease including dermatitis herpetiformis with limited digestive tract symptoms) to 1 in 105 (defined by presence of IgA TG in blood donors).[139] Due to variable signs and symptoms it is believed that about 85% of people affected are undiagnosed.[140] 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[141]) 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%.[90] In Australia, approximately 1 in 70 people have the disease.[142] The rate amongst adult blood donors in Iran, Israel, Syria and Turkey is 0.60%, 0.64%, 1.61% and 1.15%, respectively.[40]
People of African, Japanese and Chinese descent are rarely diagnosed;[143] this reflects a much lower prevalence of the genetic risk factors, such as HLA-B8.[144] People of Indian ancestry seem to have a similar risk to those of Western Caucasian ancestry.[40] Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due, in part, to many clinicians being unfamiliar with the condition and also due to the fact it can be asymptomatic.[145] Coeliac disease is slightly more common in women than in men.[33] 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).[40] This profile is similar to the prevalence in Europe.[40] 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).[146]
Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%.[146] The reason for the recent increases in the number of reported cases is unclear.[138] It may be at least in part due to changes in diagnostic practice.[147] There also appears to be an approximately 4.5 fold true increase that may be due to less exposure to bacteria and other pathogens in Western environments.[138] In the United States, the median age at diagnosis is 38 years.[148] Roughly 20 percent of individuals with coeliac disease are diagnosed after 60 years of age.[148]
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.[149][150]
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.[149] His "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."[149][150]
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.[150][151]
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.[152][153]Sidney V. Haas, an American paediatrician, reported positive effects of a diet of bananas in 1924.[154] This diet remained in vogue until the actual cause of coeliac disease was determined.[150]
While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Dr Willem Karel Dicke.[155] It is likely that clinical improvement of his patients during the Dutch famine of 1944 (during which flour was scarce) may have contributed to his discovery.[156] 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.[157] The link with the gluten component of wheat was made in 1952 by a team from Birmingham, England.[158] Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery.[159] This paved the way for biopsy samples taken by endoscopy.[150]
Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965.[160] In 1966, dermatitis herpetiformis was linked to gluten sensitivity.[150][45]
May has been designated as "Coeliac Awareness Month" by several coeliac organisations.[161][162]
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.[163]Wheat flour contains around 10–13% gluten, so a single communion wafer may have more than 50mg of gluten, an amount that harms many people with coeliac, especially if consumed every day (see Diet above).[citation needed]
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 to still be wheat bread and hence invalid matter.[164]
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.[165]
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."[166]
By January 2004, extremely low-gluten Church-approved hosts had become available in the United States, Italy and Australia.[167] As of July 2017, the Vatican still outlawed the use of gluten-free bread for Holy Communion.[168]
Passover
[citation needed] 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.
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.[171] 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.[172]
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][173][174]
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.[175]
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.
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 biotheraputic digestive enzyme therapy currently being trialled that aims to degrade gluten proteins and aid gluten digestion. It was shown to mitigate intestinal mucosal damage and reduce the severity and frequency of symptoms in phase 2 clinical trials[176] and is scheduled for phase 3 clinical trials.[177]
Alternative treatments under investigation include the inhibition of zonulin, an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system. One inhibitor of this pathway is larazotide acetate, which is currently scheduled for phase 3 clinical trials.[178][needs update] 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.[175]
Although popularly used as an alternative treatment for people with autism, there is no good evidence that a gluten-free diet is of benefit in the treatment of autism.[179][180][181] In the subset of autistic people who have gluten sensitivity, there is limited evidence that suggests that a gluten free diet may improve hyperactivity and mental confusion in those with autism.[179][182][183]
Related Research Articles
Gluten is a structural protein naturally found in certain cereal grains. The term gluten usually refers to the elastic network of a wheat grain's proteins, gliadin and glutenin primarily, that forms readily with the addition of water and often kneading in the case of bread dough. The types of grains that contain gluten include all species of wheat, and barley, rye, and some cultivars of oat; moreover, cross hybrids of any of these cereal grains also contain gluten, e.g. triticale. Gluten makes up 75–85% of the total protein in bread wheat.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating and changes in the consistency of bowel movements. These symptoms may occur over a long time, sometimes for years. IBS can negatively affect quality of life and may result in missed school or work or reduced productivity at work. Disorders such as anxiety, major depression, and chronic fatigue syndrome are common among people with IBS.
A gluten-free diet (GFD) is a nutritional plan that strictly excludes gluten, which is a mixture of prolamin proteins found in wheat, as well as barley, rye, and oats. The inclusion of oats in a gluten-free diet remains controversial, and may depend on the oat cultivar and the frequent cross-contamination with other gluten-containing cereals.
Gliadin is a class of proteins present in wheat and several other cereals within the grass genus Triticum. Gliadins, which are a component of gluten, are essential for giving bread the ability to rise properly during baking. Gliadins and glutenins are the two main components of the gluten fraction of the wheat seed. This gluten is found in products such as wheat flour. Gluten is split about evenly between the gliadins and glutenins, although there are variations found in different sources.
Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows nutrients to pass through the gut, while also maintaining a barrier function to keep potentially harmful substances from leaving the intestine and migrating to the body more widely. In a healthy human intestine, small particles can migrate through tight junction claudin pore pathways, and particles up to 10–15 Å can transit through the paracellular space uptake route. There is some evidence abnormally increased intestinal permeability may play a role in some chronic diseases and inflammatory conditions. The most well understood condition with observed increased intestinal permeability is celiac disease.
Gluten is the seed storage protein in mature wheat seeds. It is the sticky substance in bread wheat which allows dough to rise and retain its shape during baking. The same, or very similar, proteins are also found in related grasses within the tribe Triticeae. Seed glutens of some non-Triticeae plants have similar properties, but none can perform on a par with those of the Triticeae taxa, particularly the Triticum species. What distinguishes bread wheat from these other grass seeds is the quantity of these proteins and the level of subcomponents, with bread wheat having the highest protein content and a complex mixture of proteins derived from three grass species.
Gluten-related disorders is the term for the diseases triggered by gluten, including celiac disease (CD), non-celiac gluten sensitivity (NCGS), gluten ataxia, dermatitis herpetiformis (DH) and wheat allergy. The umbrella category has also been referred to as gluten intolerance, though a multi-disciplinary physician-led study, based in part on the 2011 International Coeliac Disease Symposium, concluded that the use of this term should be avoided due to a lack of specificity.
Gluten-sensitive enteropathy–associated conditions are comorbidities or complications of gluten-related gastrointestinal distress. GSE has key symptoms typically restricted to the bowel and associated tissues; however, there are a wide variety of associated conditions. These include bowel disorders, eosinophilic gastroenteritis and increase with coeliac disease (CD) severity. With some early onset and a large percentage of late onset disease, other disorders appear prior to the coeliac diagnosis or allergic-like responses markedly increased in GSE. Many of these disorders persist on a strict gluten-free diet, and are thus independent of coeliac disease after triggering. For example, autoimmune thyroiditis is a common finding with GSE.
Anti-gliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies. Some of these antibodies can detect proteins in specific grass taxa such as Triticeae, while others react sporadically with certain species in those taxa, or over many taxonomically defined grass tribes.
Anti-transglutaminase antibodies (ATA) are autoantibodies against the transglutaminase protein. Detection is considered abnormal, and may indicate one of several conditions.
HLA-DQ2 (DQ2) is a serotype group within HLA-DQ (DQ) serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles, DQB1*0201 and DQB1*0202. HLA-DQ2 and HLA-DQB1*02 are almost synonymous in meaning. DQ2 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1 alleles, to form the cis-haplotype isoforms. These isoforms, nicknamed DQ2.2 and DQ2.5, are also encoded by the DQA1*0201 and DQA1*0501 genes, respectively.
Enteropathy-associated T-cell lymphoma (EATL), previously termed enteropathy-associated T-cell lymphoma, type I and at one time termed enteropathy-type T-cell lymphoma (ETTL), is a complication of coeliac disease in which a malignant T-cell lymphoma develops in areas of the small intestine affected by the disease's intense inflammation. While a relatively rare disease, it is the most common type of primary gastrointestinal T-cell lymphoma.
Oat sensitivity represents a sensitivity to the proteins found in oats, Avena sativa. Sensitivity to oats can manifest as a result of allergy to oat seed storage proteins either inhaled or ingested. A more complex condition affects individuals who have gluten-sensitive enteropathy in which there is an autoimmune response to avenin, the glutinous protein in oats similar to the gluten within wheat. Sensitivity to oat foods can also result from their frequent contamination by wheat, barley, or rye particles.
The immunochemistry of Triticeae glutens is important in several inflammatory diseases. It can be subdivided into innate responses, class II mediated presentation, 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 gluten sensitive enteropathy, there are four types of recognition, innate immunity, HLA-DQ, and antibody recognition of gliadin and transglutaminase. With idiopathic gluten sensitivity only antibody recognition to gliadin has been resolved. In wheat allergy, the response pathways are mediated through IgE against other wheat proteins and other forms of gliadin.
Dermatitis herpetiformis (DH) is a chronic autoimmune blistering skin condition, characterised by intensely itchy blisters filled with a watery fluid. DH is a cutaneous manifestation of coeliac disease, although the exact causal mechanism is not known. DH is neither related to nor caused by herpes virus; the name means that it is a skin inflammation having an appearance similar to herpes.
FODMAPs or fermentable oligosaccharides, disaccharides, monosaccharides, and polyols are short-chain carbohydrates that are poorly absorbed in the small intestine and ferment in the colon. They include short-chain oligosaccharide polymers of fructose (fructans) and galactooligosaccharides, disaccharides (lactose), monosaccharides (fructose), and sugar alcohols (polyols), such as sorbitol, mannitol, xylitol, and maltitol. Most FODMAPs are naturally present in food and the human diet, but the polyols may be added artificially in commercially prepared foods and beverages.
Non-celiac gluten sensitivity (NCGS) or gluten sensitivity is a controversial disorder which can cause both gastrointestinal and other problems.
The gluten challenge test is a medical test in which gluten-containing foods are consumed and (re-)occurrence of symptoms is observed afterwards to determine whether and how much a person reacts to these foods. The test may be performed in people with suspected gluten-related disorders in very specific occasions and under medical supervision, for example in people who had started a gluten-free diet without performing duodenal biopsy.
Duodenal lymphocytosis, sometimes called lymphocytic duodenitis, lymphocytic duodenosis, or duodenal intraepithelial lymphocytosis, is a condition where an increased number of intra-epithelial lymphocytes is seen in biopsies of the duodenal mucosa when these are examined microscopically. This form of lymphocytosis is often a feature of coeliac disease but may be found in other disorders.
Ludvig M. Sollid is a Norwegian physician-scientist whose laboratory has made discoveries in the pathogenesis of HLA associated human disorders, most notably celiac disease. He is currently a Professor of Medicine (immunology) at the University of Oslo and a Senior Consultant at Oslo University Hospital.
1 2 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's lymphoma and a more than 30-fold increased risk of small intestinal adenocarcinoma, and they have a 1.4-fold increased risk of death.
1 2 3 Lundin KE, Wijmenga C (September 2015). "Coeliac disease and autoimmune disease-genetic overlap and screening". Nature Reviews. Gastroenterology & Hepatology (Review). 12 (9): 507–15. doi:10.1038/nrgastro.2015.136. PMID26303674. S2CID24533103. The abnormal immunological response elicited by gluten-derived proteins can lead to the production of several different autoantibodies, which affect different systems.
1 2 3 4 Ciccocioppo R, Kruzliak P, Cangemi GC, Pohanka M, Betti E, Lauret E, etal. (22 October 2015). "The Spectrum of Differences between Childhood and Adulthood Celiac Disease". Nutrients (Review). 7 (10): 8733–51. doi:10.3390/nu7105426. PMC4632446. PMID26506381. Several additional studies in extensive series of coeliac patients have clearly shown that TG2A sensitivity varies depending on the severity of duodenal damage, and reaches almost 100% in the presence of complete villous atrophy (more common in children under three years), 70% for subtotal atrophy, and up to 30% when only an increase in IELs is present. (IELs: intraepithelial lymphocytes)
1 2 3 4 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): 207–12. 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)
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1 2 3 4 See JA, Kaukinen K, Makharia GK, Gibson PR, Murray JA (October 2015). "Practical insights into gluten-free diets". Nature Reviews. Gastroenterology & Hepatology (Review). 12 (10): 580–91. doi:10.1038/nrgastro.2015.156. PMID26392070. S2CID20270743. 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.
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1 2 3 4 5 Comino I, Moreno M, Sousa C (November 2015). "Role of oats in celiac disease". World Journal of Gastroenterology. 21 (41): 11825–31. 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.
1 2 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. S2CID33661098.
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): 807–20. doi:10.1111/apt.13155. PMID25753138. S2CID207050854. 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 3 4 Biesiekierski JR (March 2017). "What is gluten?". Journal of Gastroenterology and Hepatology. 32 (Suppl 1): 78–81. doi:10.1111/jgh.13703. PMID28244676. S2CID6493455. 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.
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1 2 Skovbjerg H, Norén O, Anthonsen D, Moller J, Sjöström H (2002). "Gliadin is a good substrate of several transglutaminases: possible implication in the pathogenesis of coeliac disease". Scand J Gastroenterol. 37 (7): 812–7. doi:10.1080/713786534. PMID12190095.
↑ Londei M, Ciacci C, Ricciardelli I, Vacca L, Quaratino S, Maiuri L (2005). "Gliadin as a stimulator of innate responses in celiac disease". Mol Immunol. 42 (8): 913–918. doi:10.1016/j.molimm.2004.12.005. PMID15829281.
1 2 3 4 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): 1738–46. 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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↑ McNamara E (15 September 2004). "Liturgy: Gluten-free Hosts". Catholic Online. Archived from the original on 29 September 2007. Retrieved 17 June 2007.
↑ Marí-Bauset S, Zazpe I, Mari-Sanchis A, Llopis-González A, Morales-Suárez-Varela M (December 2014). "Evidence of the gluten-free and casein-free diet in autism spectrum disorders: a systematic review". J Child Neurol. 29 (12): 1718–27. doi:10.1177/0883073814531330. hdl:10171/37087. PMID24789114. S2CID19874518.
↑ Volta U, Caio G, De Giorgio R, Henriksen C, Skodje G, Lundin KE (June 2015). "Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat-related disorders". Best Pract Res Clin Gastroenterol. 29 (3): 477–91. doi:10.1016/j.bpg.2015.04.006. PMID26060112. autism spectrum disorders (ASD) have been hypothesized to be associated with NCGS [47,48]. Notably, a gluten- and casein-free diet might have a positive effect in improving hyperactivity and mental confusion in some patients with ASD. This very exciting association between NCGS and ASD deserves further study before conclusions can be firmly drawn
↑ San Mauro I, Garicano E, Collado L, Ciudad MJ (December 2014). "¿Es el gluten el gran agente etiopatogenico de enfermedad en el siglo XXI?" [Is gluten the great etiopathogenic agent of disease in the XXI century?]. Nutr Hosp (in Spanish). 30 (6): 1203–10. doi:10.3305/nh.2014.30.6.7866. PMID25433099.
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