Miscellaneous Coeliac disease has been linked with a number of 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. Pathophysiology 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. 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  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. 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  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. 250px|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  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. The strongest and most common adaptive response to gliadin is directed toward an α2-gliadin fragment of 33 amino acids in length. 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. There are several tests that 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 6 weeks before repeating the investigations. 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 minor damage of 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. 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 antibody . 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. Endoscopy Endoscopic still of duodenum of  person with coeliac disease showing scalloping of folds and "cracked-mud" appearance to mucosa Schematic 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. Even in the same bioptic fragment, different degrees of damage may be present. 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 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 submucosa blood vessels, and a nodular pattern to the mucosa. 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. Pathology The classic pathology changes of coeliac disease in the small bowel are categorised by the "Marsh classification": Marsh stage 0: normal mucosa Marsh stage 1: increased number of intra-epithelial lymphocytes (IELs), usually exceeding 20 per 100 enterocytes Marsh stage 2:  proliferation of the crypts of Lieberkühn Marsh stage 3: partial or complete villous atrophy and crypt hypertrophy Marsh stage 4: hypoplasia of the small intestine architecture 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. 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. 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  risk of fracture and need for bone protection medication. 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  very low ability to detect cases with partial villous atrophy or minor intestinal lesions. Testing for coeliac disease may be offered to those with commonly associated conditions. Humans first started to cultivate grains in the Neolithic period (beginning about 9500 BCE) in the Fertile Crescent in Western Asia, and it is likelythat 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. His "Cœliac Affection" (coeliac from Greek κοιλιακός koiliakos, "abdominal") 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 the 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." The paediatrician Samuel 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. 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.Statement by the National Conference of Catholic bishops on the use of low gluten hosts at Mass . BCL Newsletter. November 2003. Attempts to modulate the immune response with regard to coeliac disease are mostly still in phase I of clinical testing; one agent (CCX282-B) has been evaluated in a phase II clinical trial on the basis of small-intestinal biopsies taken from people with coeliac disease before and after gluten exposure.
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. Pathophysiology 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. 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. 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. 250px|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. The strongest and most common adaptive response to gliadin is directed toward an α2-gliadin fragment of 33 amino acids in length. Indeed, earlier studies of rotavirus damage in the gut showed this causes 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 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. 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. 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 6 weeks before repeating the investigations. 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. 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 . 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. Endoscopy Endoscopic still of duodenum of a person with coeliac disease showing scalloping of folds and "cracked-mud" appearance to mucosa Schematic 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. Even in the same bioptic fragment, different degrees of damage may be present. 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 submucosa blood vessels, and a nodular pattern to the mucosa. 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. Pathology The classic pathology changes of coeliac disease in the small bowel are categorised by the "Marsh classification": Marsh stage 0: normal mucosa Marsh stage 1: increased number of intra-epithelial lymphocytes (IELs), usually exceeding 20 per 100 enterocytes Marsh stage 2: a proliferation of the crypts of Lieberkühn Marsh stage 3: partial or complete villous atrophy and crypt hypertrophy Marsh stage 4: hypoplasia of the small intestine architecture 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. 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. 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. 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. Testing for coeliac disease may be offered to those with commonly associated conditions. Humans first started to cultivate grains in the Neolithic period (beginning about 9500 BCE) 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. His "Cœliac Affection" (coeliac from Greek κοιλιακός koiliakos, "abdominal") 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." The paediatrician Samuel 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. 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.Statement by the National Conference of Catholic bishops on the use of low gluten hosts at Mass . BCL Newsletter. November 2003. 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.
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