Coeliac disease is caused by a reaction to gliadin, a gluten protein found in wheat (and similar proteins of the tribe Triticeae which includes other cultivars such as barley and rye). Upon exposure to gliadin, the enzyme tissue transglutaminase modifies the protein, and the immune system cross-reacts with the bowel tissue, causing an inflammatory reaction. That leads to flattening of the lining of the small intestine (called villous atrophy). This interferes with the absorption of nutrients because the intestinal villi are responsible for absorption. The only effective treatment is a lifelong gluten-free diet. While the disease is caused by a reaction to wheat proteins, it is not the same as wheat allergy.
This condition has several other names, including: cœliac disease (with "œ" ligature), c(o)eliac sprue, non-tropical sprue, endemic sprue, gluten enteropathy or gluten-sensitive enteropathy, and gluten intolerance. The term coeliac derives from the Greek κοιλιακός (koiliakόs, abdominal), and was introduced in the 19th century in a translation of what is generally regarded as an ancient Greek description of the disease by Aretaeus of Cappadocia.
Children between 9 and 24 months tend to present with bowel symptoms and growth problems shortly after first exposure to gluten-containing products. Older children may have more malabsorption-related problems and psychosocial problems, while adults generally have malabsorptive problems. Many adults with subtle disease only have fatigue or anaemia.
Coeliac disease leads to an increased risk of both adenocarcinoma and lymphoma of the small bowel, which returns to baseline with diet. Longstanding disease may lead to other complications, such as ulcerative jejunitis (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring).
Combining findings into a prediction rule to guide use of endoscopy reported a sensitivity of 100% (it would identify all the cases) and specificity of 61% (it would be incorrectly positive in 39%). The prediction rule recommends that patients with high risk symptoms or positive serology should undergo endoscopy. The study defined high risk symptoms as weight loss, anaemia (haemoglobin less than 120 g/l in females and less than 130 g/l in males), or diarrhoea (more than three loose stools per day).
Serological blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Serology for anti-tTG antibodies has superseded older serological tests and has a high sensitivity (99%) and specificity (>90%) for identifying coeliac disease. Modern anti-tTG assays rely on a human recombinant protein as an antigen.
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 and biopsy. A negative serology test may still be followed by a recommendation for endoscopy and duaodenal biopsy if clinical suspicion remains high due to the 1 in 100 "false-negative" result. As such tissue biopsy is still considered the gold standard in the diagnosis of coeliac disease.
Historically three other antibodies were measured: anti-reticulin (ARA), anti-gliadin (AGA) and anti-endomysium (EMA) antibodies. Serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five. Serology tests are based on indirect immunofluorescence (reticulin, gliadin and endomysium) or ELISA (gliadin or tissue transglutaminase).
Guidelines recommend that a total serum IgA level is checked in parallel, as coeliac patients with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those patients, IgG antibodies against transglutaminase (IgG-TTG) may be diagnostic.
An upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum is performed. It is important for the physician to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative.
Most patients with coeliac disease have a small bowel that appears normal on endoscopy; however, five concurrent endoscopic findings have been associated with a high specificity for coeliac disease: scalloping of the small bowel folds (pictured), paucity in the folds, a mosaic pattern to the mucosa (described as a cracked-mud appearance), prominence of the submucosal blood vessels, and a nodular pattern to the mucosa.
Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After X-ray verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. One often-utilised capsule system is the Watson capsule. This method has now been largely replaced by fibre-optic endoscopy, which carries a higher sensitivity and a lower frequency of errors.
In some cases a deliberate gluten challenge, followed by biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicates the diagnosis may have been incorrect. Patients are warned that one does not "outgrow" coeliac disease in the same way as childhood food intolerances.
Almost all coeliac patients have the variant HLA DQ2 allele. However, about 20–30% of people without coeliac disease have inherited an HLA-DQ2 allele. This suggests additional factors are needed for coeliac disease to develop. Furthermore, about 5% of those people who do develop coeliac disease do not have the DQ2 gene.
The HLA-DQ2 allele shows incomplete penetrance, as the gene alleles associated with the disease appear in most patients, but are neither present in all cases nor sufficient by themselves to cause the disease.
Over 95% of coeliac patients have an isoform of DQ2 (encoded by DQA1*05 and DQB1*02 genes) and DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), which is inherited in families. The reason these genes produce an increase in risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.
Most coeliac patients bear a two-gene HLA-DQ haplotype referred to as DQ2.5 haplotype. This haplotype is composed of 2 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. 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. Some individuals inherit DQ2.5 from one parent and portions of the haplotype (DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent, called a trans-haplotype association, and these individuals are at similar risk for coeliac disease as those with a single DQ2.5 bearing chromosome 6, but in this instance disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5(cis or trans) or DQ8, 4% have the DQ2.2 isoform and the remaining 2% lack DQ2 or DQ8.
The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country, Ireland, with highest frequencies), portions of Africa, and is associated with disease in India, but is not found along portions of the West Pacific rim. DQ8, spread more globally than DQ2.5, is more prevalent from South and Central America (up to 90% phenotype frequency).
Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in an overwhelming majority of cases. Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.
Stored biopsies from suspected coeliac patients has revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anemia or malabsorption phenomena at a much increased rate over the normal population. Endomysial component of antibodies (EMA) to tTG are believed to be directed toward cell surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative coeliac patients tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms including autoimmune disease. In this study the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with recent work showing that gliadin has an innate response component, suggests that gliadin may be more responsible for the primary manifestations of coeliac disease whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of coeliac patients the anti-tTG antibodies also recognize a rotavirus protein called VP7. These antibodies stimulate monocytes proliferation and rotavirus infection might explain some early steps in the cascade of immune cell proliferation. Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy. 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.
Alternative causes of this tissue damage have been proposed and involve release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of enterocytes by lymphocytes in the epithelium. The villous atrophy seen on biopsy may also be due to unrelated causes, such as tropical sprue, giardiasis and radiation enteritis. While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to diet may require these alternative diagnoses to be considered.
A 2005 prospective and observational study found that timing of the exposure to gluten in childhood was an important risk modifier. People exposed to wheat, barley, or rye before the gut barrier has fully developed (three months after birth) had five times the risk of developing coeliac disease over those exposed at 4 to 6 months. Those exposed later had a slightly increased risk relative to those exposed at 4 to 6 months. However a 2006 study with similar numbers found just the reverse, that early introduction of grains was protective. Breastfeeding may also reduce risk. A meta-analysis indicates that prolonging breastfeeding until the introduction of gluten-containing grains into the diet was associated with a 52% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear.
Presently, the only effective treatment is a life-long gluten-free diet. No medication exists that will prevent damage, or prevent the body from attacking the gut when gluten is present. Strict adherence to the diet allows the intestines to heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer. Dietician input is generally requested to ensure the patient is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries gluten-free products are available on prescription and may be reimbursed by health insurance plans. More manufacturers are producing gluten-free products, some of which are almost indistinguishable from their gluten-containing counterparts.
The diet can be cumbersome; failure to comply with the diet may cause relapse. The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence. The exact level at which gluten is harmless is uncertain and controversial. A recent systematic review tentatively concluded that consumption of less than 10 mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done. Regulation of the label "gluten-free" varies widely by country. For example, in the United States the term "gluten-free" is not yet regulated. The current international Codex Alimentarius standard, established in 1981, allows for , although a proposal for a revised standard of 20 ppm in naturally gluten-free products and 200 ppm in products rendered gluten-free has been accepted. Gluten-free products are usually more expensive and harder to find than common gluten-containing foods. Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.
Even while on a diet, health-related quality of life (HRQOL) may be lower in people with coeliac disease. Studies in the United States have found that quality of life becomes comparable to the general population after staying on the diet while studies in Europe have found that quality of life remains lower, although the surveys are not quite the same. Men tend to report more improvement than women. Some have persisting digestive symptoms or dermatitis herpetiformis, mouth ulcers, osteoporosis and resultant fractures. Symptoms suggestive of irritable bowel syndrome may be present, and there is an increased rate of anxiety, fatigue, dyspepsia and musculoskeletal pain.
Due to its high sensitivity, serology has been proposed as a screening measure, because the presence of antibodies would detect previously undiagnosed cases of coeliac disease and prevent its complications in those patients. Serology may also be used to monitor adherence to diet: in those who still ingest gluten, antibody levels remain elevated.
In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommends screening for coeliac disease in patients with newly diagnosed chronic fatigue syndrome and irritable bowel syndrome.
A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic patients, 2.6% in second-degree relatives of a patient with coeliac disease and 4.5% in first-degree relatives. This profile is similar to the prevalence in Europe.
Most mainline Christian churches offer their communicants gluten-free alternatives to the sacramental bread, usually in the form of a rice-based cracker or gluten-free bread. These include United Methodist, Christian Reformed, Episcopal, Lutheran, The Church of Jesus Christ of Latter-day Saints, and many others.
Roman Catholic doctrine states that for a valid Eucharist the bread must be made from wheat. In 2002, the Congregation for the Doctrine of the Faith approved German-made low-gluten hosts, which meet all of the Catholic Church's requirements, for use in Italy; although not entirely gluten-free, they were also approved by the Italian Celiac Association. Some Catholic coeliac sufferers have requested permission to use rice wafers; such petitions have always been denied. The issue is more complex for priests. Though a Catholic (lay or ordained) receiving under either form is considered to have received Christ "whole and entire", the priest, who is acting in persona Christi, is required to receive under both species when offering Mass — not for the validity of his Communion, but for the fullness of the sacrifice of the Mass. On 22 August 1994, the Congregation for the Doctrine of the Faith apparently barred coeliacs from ordination, stating, "Given the centrality of the celebration of the Eucharist in the life of the priest, candidates for the priesthood who are affected by coeliac disease or suffer from alcoholism or similar conditions may not be admitted to holy orders." After considerable debate, the congregation softened the ruling on 24 July 2003 to "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm.
As of January 2004, an extremely low-gluten host became available in the United States. The Benedictine Sisters of Perpetual Adoration in Clyde, MO, after ten years of perseverance, trial, and error, have produced a low-gluten host safe for celiacs and also approved by the Catholic Church for use at Mass. Each host is made and packaged in a dedicated wheat-free / gluten-free environment. The hosts are made separately by hand, unlike the common host which is stamped out of a long thin sheet of bread by a cutter. Therefore, each host is a slightly different size and shape. Most importantly, the finished hosts have been analyzed for gluten content. The gluten content of these hosts is reported as 0.01 %. In actuality, the gluten content is probably less than 0.01%. Sister Lynn, OSB, said that the result of the analysis of the finished host revealed "no gluten detected". The hosts are labeled as 0.01 % since the lowest limit of detection of this analysis was 0.01 %. In an article from the Catholic Review (15 February 2004) Dr. Alessio Fasano was quoted as declaring these hosts "perfectly safe for celiac sufferers."
The paediatrician Samuel Gee gave the first modern-day description of the condition 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). Unlike Aretaeus, he included children in the scope of the affliction, particularly those between one and five years old. Gee found the cause to be obscure and failed to spot anything abnormal during post-mortem examination (the lining of the small bowel quickly deteriorates on death). 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.
Christian Archibald Herter, an American physician, wrote a book in 1908 on children with coeliac disease, which he called "intestinal infantilism". He noted their growth was retarded and that fat was better tolerated than carbohydrate. The eponym Gee-Herter disease was sometimes used to acknowledge both contributions. Sydney V. Haas, an American paediatrician, reported positive effects of a diet of bananas in 1924. This diet remained in vogue until the actual cause of coeliac disease was determined.
While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Dr Willem Dicke. It is likely that clinical improvement of his patients during the Dutch famine of 1944 (during which flour was sparse) may have contributed to his discovery. The link with the gluten component of wheat was made in 1952 by a team from Birmingham, England. Villous atrophy was described by British physician John W. Paulley in 1954. Paulley was able to examine biopsies taken from patients during abdominal operations. Dr Margo Shiner, working on Prof Sheila Sherlock's team at the Postgraduate Medical School in London, described the principles of small bowel biopsy in 1956.
Throughout the 1960s other features of coeliac disease were elucidated. Its hereditary character was recognized in 1965. In 1966 dermatitis herpetiformis was linked to gluten sensitivity.