Coeliac disease

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Coeliac disease
Classification & external resources
Biopsy of small bowel showing coeliac disease manifested by blunting of villi, crypt hyperplasia, and lymphocyte infiltration of crypts.
ICD-10 K90.0
ICD-9 579.0
OMIM 212750
DiseasesDB 2922
MedlinePlus 000233
eMedicine med/308  ped/2146 radio/652
MeSH D002446

Coeliac disease or celiac disease is an autoimmune disorder of the small intestine[1] that occurs in genetically predisposed individuals in all age groups. Symptoms may begin to appear after early infancy when cereals are first introduced into the diet[2] or later in life. Symptoms may include diarrhoea, failure to thrive (in children) and fatigue, but these may be absent and associated symptoms in all other organ systems have been described. It affects approximately 1% of Caucasian populations, though it is significantly underdiagnosed. A growing portion of diagnoses are being made in asymptomatic persons as a result of increasing screening.[3]

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, which interferes with the absorption of nutrients. The only effective treatment is a lifelong gluten-free diet.

This condition has several other names, including: cœliac disease (with 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 κοιλιά (koilia, abdomen), 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.[4]

Contents

[edit] Signs and symptoms

Classic symptoms of coeliac disease include diarrhoea, weight loss (or stunted growth in children) and fatigue, but while coeliac disease is primarily a bowel disease, bowel symptoms may also be limited or even absent. Some patients are diagnosed with symptoms related to the decreased absorption of nutrients or with various symptoms which, although statistically linked, have no clear relationship with the malfunctioning bowel. Given this wide range of possible symptoms, the classic triad is no longer a requirement for diagnosis.

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.[5] Many adults with subtle disease only have fatigue or anaemia.[3]

[edit] Gastrointestinal

The diarrhoea characteristic of coeliac disease is pale, voluminous and malodorous. Abdominal pain and cramping, bloatedness with abdominal distention (thought to be due to fermentative production of bowel gas) and mouth ulcers[6] may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop. However, the variety of gastrointestinal symptoms that may be present in patients with coeliac disease is great, and some may have a normal bowel habit or even tend towards constipation. Frequently the symptoms are ascribed to irritable bowel syndrome (IBS), only later to be recognized as coeliac disease; a small proportion of patients with symptoms of IBS have underlying coeliac disease, and screening may be justified.[7]

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).[8]

[edit] Malabsorption-related

The changes in the bowel make it less able to absorb nutrients, minerals and the fat-soluble vitamins A, D, E and K.[5]

[edit] 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.

[edit] Role of other grains

Wheat varieties or subspecies containing gluten such as spelt and Kamut®, and the rye/wheat hybrid triticale, also trigger symptoms.[19]

Barley and rye also induce symptoms of coeliac disease.[19] A small minority of coeliac patients also react to oats.[20][21] Most probably oats produced symptoms due to cross contamination with other grains in the fields or in the distribution channels.[5] There is at least one oat vendor (McCann's) which, while not claiming to be gluten-free, points out that the risk of contamination is low due to the processes they use.[22] Other cereals, such as maize (corn), sorghum, rice are safe for a patient to consume. Other carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.

[edit] Diagnosis

There are several tests that can be used to assist in diagnosis. The level of symptoms may determine the order of the tests, but all tests lose their usefulness if the patient is already taking 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 commenced themselves on a gluten-free diet, it may be necessary to perform a re-challenge with 10 g of gluten (four slices of bread) per day over 2-6 weeks before repeating the investigations. Those who experience severe symptoms (e.g. diarrhoea) earlier can be regarded as sufficiently challenged and can be tested earlier.[5]

[edit] Blood tests

Serology by blood test is useful both in diagnosing coeliac disease (high sensitivity of about 98%, i.e. it misses 2 in 100 cases) and in excluding it (high specificity of over 95%, i.e. a positive test is most likely confirmative of coeliac disease rather than another condition). 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. A negative test may still prompt a biopsy if the suspicion remains very high; this would pick up the remaining 2% undiagnosed cases, as well as offering alternative explanations for the symptoms. As such, endoscopy with biopsy is still considered the gold standard in the diagnosis of coeliac disease.[5][8]

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.[5][8]

Four serological blood tests exist for coeliac disease. The most widely used ones detect an antibody of the IgA type against particular antigens in the small bowel. Older tests detected antibodies against reticulin (ARA) or gliadin (AGA), but recent evidence supports the use of the more modern tests, namely those detecting IgA antibodies against endomysium (EMA) or tissue transglutaminase (TTG). Generally, serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five.[23] Serology tests are based on indirect immunofluorescence (reticulin, gliadin and endomysium) or ELISA (gliadin or tissue transglutaminase).[24]

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.[25]

[edit] Endoscopy

Endoscopic still of duodenum of patient with coeliac disease showing scalloping of folds.
Endoscopic still of duodenum of patient with coeliac disease showing scalloping of folds.
Schematic of the Marsh classification of upper jejunal pathology in coeliac disease
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. 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, it would result in false negative results.[8]

Most patients with coeliac disease have a small bowel that appears normal on endoscopy; however, five endoscopic findings have been associated with a high specificity for coeliac disease when all are found: 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.[26]

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 much utilized capsule system is the Watson capsule. This method has now been largely replaced by fiberoptic endoscopy, which carries a higher sensitivity rate and a lower error frequency.[27]

[edit] Pathology

The classic pathology changes of coeliac disease in the small bowel are categorized by the "Marsh classification":[28]

The changes classically improve or reverse after gluten is removed from the diet, so many official guidelines recommend a repeat biopsy several (4–6) months after commencement of gluten exclusion.[5]

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.[5] Patients are warned that one does not "outgrow" coeliac disease in the same way as childhood food intolerances.

[edit] Other diagnostic tests

Other tests that may assist in the diagnosis are blood tests for a full blood count, electrolytes, calcium, renal function, liver enzymes, vitamin B12 and folic acid levels. Coagulation testing (prothrombin time and partial thromboplastin time) may be useful to identify deficiency of vitamin K, which predisposes patients to hemorrhage. These tests should be repeated on follow-up, as well as anti-tTG titres.[5]

Some professional guidelines[5] recommend screening of all patients for osteoporosis by DXA/DEXA scanning.

[edit] Screening and case finding

There is significant debate as to the benefits of screening. Some studies suggest that early detection would decrease the risk of osteoporosis and anaemia. In contrast, a cohort studied in Cambridge suggested that people with undetected coeliac disease had a beneficial risk profile for cardiovascular disease (less overweight, lower cholesterol levels).[3]

Clinical scenarios in which screening may be justified include type 1 diabetes,[15] unexplained iron-deficiency anemia,[29][30] Down's syndrome, Turner's syndrome, irritable bowel syndrome,[7] lupus, and autoimmune thyroid disease.[31]

[edit] Pathophysiology

[edit] Genetics

The vast majority of coeliac patients have one of two types of HLA DQ, a gene that is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. There are 7 HLA DQ variants (DQ2 and D4 through 9). Two of these variants—DQ2 and DQ8—are associated with coeliac disease. Every person inherits two copies, one from each parent. The gene is located on the short arm of the sixth chromosome, and as a result of the linkage this locus has been labeled CELIAC1.

Coeliac disease 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 cause the disease. Over 95% of coeliac patients have an isoform of DQ2 (DQA1*0501:DQB1*0201 haplotype or more simply DQ2.5) and DQ8 (DQA1*0301:DQB1*0302), which is inherited in families. The reason these genes produce an increase in risk of celiac 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 is more likely to activate T lymphocytes and initiate the autoimmune process.[3]

Every person carries two HLA-DQ genes, one inherited from their mother and one from their father. About 20–30% of people carry HLA-DQ2 but most of them do not have coeliac disease, suggesting 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.[3] The frequency of these genes vary greatly; DQ2.5 is highly frequent in people originating from Sardinia,[32] Basque Country, Ireland,[33]and Scandinavia. DQ8 is more prevalent in those originating from South and Central America (up to 90% phenotype frequency),[34] and also those from Sweden.

DQ α5-β2 peptide-binding cleft with deamidated gliadin peptide, modified from PDB 1S9V
DQ α5-β2 peptide-binding cleft with deamidated gliadin peptide, modified from PDB 1S9V[35]

As the MHC class II antigen-presenting receptor functions as a dimer containing two protein subunits, these receptors can be made from the products of two different DQ alleles. Consequently, any one person with alleles A and B can produce 4 different receptor dimers, 2 in the cis-haplotype homodimer pairing (AA and BB) and 2 in the heterodimer pairing (AB and BA). DQ2.5 (haplotype product is DQ α5-β2) and DQ8 (DQ α3-β302) produce susceptibility in their cis-haplotype pair. However, trans-pairing of some receptor subunits can also produce disease. This is seen with a third pairing of haplotypes, DQA1*0201:DQB1*0202(DQ2.2) / DQA1*0505:DQB1*0301 (DQ7.55) that, when both are found in a single patient, can produce susceptibility to coeliac disease through trans-pairing of the DQA1*0505-DQB1*0202 subunits (producing the DQ α5-β2 heterodimer).[36] Other MHC class II genes may alter the risk produced by the main disease genes. For example, the genotype DQ2.2/DQ2.5 shows increased susceptibility.[37] However, without the presence of DQ7.55 and DQ2.5, DQ2.2 is not usually associated with coeliac disease.[38]

In addition to the HLA locus on chromosome 6q21.3, several other regions have been linked (especially 19p13.3 and 4p14).[39] Mendelian Inheritance in Man designates five regions as CELIAC1-5 (6q21.3, 5q31-q33, 2q33, 19p13.1, 15q11-q13). For CELIAC3, the CTLA4 gene was found to be linked, and CELIAC4 the gene coding for myosin IXB. CELIAC2 and CELIAC5 have no suspected gene association.

[edit] Prolamins

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 pepsin and chymotrypsin, the two main digestive proteases in the gut. Gliadin in wheat is the best-understood member of this family, but other prolamins exist and hordein (from barley), and secalin (from rye) may contribute to coeliac disease.[3] However, not all prolaminins will cause this immune reaction and there is ongoing controversy on the ability of avenin (the prolamin found in oats) to induce this response in coeliac disease.

[edit] Tissue transglutaminase

Tissue transglutaminase, drawn from PDB 1FAU.
Tissue transglutaminase, drawn from PDB 1FAU.

Antibodies to the enzyme tissue transglutaminase (tTG) are found in an overwhelming majority of cases, and cross-react to gluten.[40] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.[3]

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.[41] 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.[42] 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,[43] suggests that gliadin may be more responsible for the primary manifestations of coeliac disease whereas as tTG is a bigger factor in secondary effects such as allegic 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.[44] Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy.[45] 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.

[edit] Villous atrophy and malabsorption

The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel's mucous 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.

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.[3] 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.[8]

[edit] 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 infection by rotavirus[46] or human intestinal adenovirus[47] Some research has suggested that smoking is protective against adult onset coeliac disease.[48]

A 2005 prospective and observational study found that timing of the exposure to gluten in childhood was important risk modifier. Early exposure to wheat, barley, or rye before the gut barrier has developed fully over the first three months after birth. People exposed during this period 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 4-6 months.[49] However a 2006 study with similar numbers, found just the reverse, that early introduction of grains was protective.[50] 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.[51]

[edit] Treatment

[edit] Diet

Main article: Gluten-free diet

Presently, the only effective treatment is a life-long gluten-free diet.[52] No medication exists that will prevent damage, nor 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 the vast majority of cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer.[53] 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; while young children can be kept compliant by their parents, teenagers may wish to hide their problem or rebel against the dietary restrictions, risking relapse. Many food products contain traces of gluten even if apparently wheat-free. Gluten-free products are usually more expensive and harder to find than common wheat-containing foods.

Even while on a diet, health-related quality of life (HRQOL) may be decreased in people with coeliac disease. Some have persisting digestive symptoms or dermatitis herpetiformis, mouth ulcers, osteoporosis and fractures. Symptoms suggestive of irritable bowel syndrome may be present, and there is an increased rate of anxiety, fatigue, dyspeptic and musculoskeletal pain.[54]

[edit] Refractory disease

A tiny minority of patients suffer from refractory disease, which means they do not improve on a gluten-free diet. This may be because the disease has been present for so long that the intestines are no longer able to heal on diet alone, or because the patient is not adhering to the diet, or because the patient is consuming foods that are inadvertently contaminated with gluten. If alternative causes have been eliminated, steroids or immunosuppressants (such as azathioprine) may be considered in this scenario.[8]

[edit] Experimental treatments

Various other approaches are being studied that would reduce the need of dieting. All are still under development, and are not expected to be available to the general public for a while:[3]

  • Genetically engineered wheat species, or wheat species that have been selectively bred to be minimally immunogenic. This, however, could interfere with the effects that gliadin has on the quality of dough.
  • 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. This combination would enable coeliac disease patients to consume gluten-containing products.[55]
  • Inhibition of zonulin, a substance linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system.[56]
  • Other treatments aimed at 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 (bowel lining cells).

[edit] Epidemiology

The prevalence of clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, South America, Australasia and the USA (using serology and biopsy) indicate that the prevalence may be between 0.33 and 1.06% in children (5.66% in one study of Saharawi children[57]) and 0.18–1.2% in adults.[3] People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors. Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due to many clinicians being unfamiliar with the condition.[58]

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.[59]

[edit] Social and religious issues

[edit] Roman Catholic position

Roman Catholic doctrine states that for a valid Eucharist the bread must be made from wheat. The Catholic Church has approved the use of low-gluten hosts, but even these are not gluten-free. Some Catholic coeliac sufferers have requested permission to use rice wafers; such petitions have always been denied.[60]

The issue is more complex for priests. Although 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 August 22, 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."[61]

[edit] Coeliacs and Passover

The Jewish festival of Pesach (Passover) may present problems with its obligation to eat matzo. Matzo is normally made from wheat or other gluten-containing grains, so oat matzo is used. Many products prepared for Passover are free of wheat, barley, spelt, oats, and rye, as many Orthodox (especially Hasidic) Jews avoid non-matzo wheat products (gebroks) altogether. Potato starch is the primary starch used to replace the grains.[62]

[edit] History

Aretaeus of Cappadocia, living in the second century, recorded a malabsorptive syndrome with chronic diarrhoea. His "Cœliac Affection" is a translation of the Greek κοιλιά (koilia, abdomen). It gained the attention of Western medicine when Francis Adams presented a translation of Aretaeus' work at the Sydenham Society in 1856. 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 resulted in loose stools that were white, malodorous and flatulent. The patient had stomach pain and was atrophied, pale, feeble and incapable of work. The disease was intractable and liable to periodic return. 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".[4]

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 acknowledges earlier descriptions and terms for the disease and adopts the same term as Aretaeus. Unlike Aretaeus, he includes children in the scope of the affection, particularly those between one and five years old. Gee finds the cause to be obscure and fails to spot anything abnormal during post-mortem examination (the lining of the small bowel quickly deteriorates on death).[63] He perceptively states "if the patient can be cured at all, it must be by means of diet." Gee recognises that milk intolerance is a problem with coeliac children and that highly starched foods should be avoided. He forbids rice, sago, fruit and vegetables, which all would have been safe to eat. Raw meat is recommended as are thin slices of toasted bread. Gee highlights particular success with a child "who was fed upon a quart of the best Dutch mussels daily". However, the child cannot bear this diet for more than one season.[64]

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.[65][66] Sydney V. Haas, an American paediatrician, reported positive effects of a diet of bananas in 1924.[67] 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 1950 by the Dutch paediatrician Dr Willem Dicke.[68] 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.[69] The link with the gluten component of wheat was made in 1952 by a team from Birmingham, England.[70] Villous atrophy was described by British physician John W. Paulley in 1954.[71] Paulley was able to examine biopsies taken from patients during abdominal operations.[63] 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.[72]

Throughout the 1960s other features of coeliac disease were elucidated. Its hereditary character was recognized in 1965.[73] In 1966 dermatitis herpetiformis was linked to gluten sensitivity,[12] and in 1970 features of hyposplenism (decreased activity of the spleen) were linked to coeliac disease.[14] The link with tissue transglutaminase was not made until 1997.[40]

[edit] References

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Health science - Medicine - Gastroenterology (primarily K)
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