Coeliac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barley.[10] Classic symptoms include gastrointestinal problems such as chronic diarrhoea, abdominal distention, malabsorption, loss of appetite, and among children failure to grow normally.[1] Non-classic symptoms are more common, especially in people older than two years.[8][15][16] There may be mild or absent gastrointestinal symptoms, a wide number of symptoms involving any part of the body, or no obvious symptoms.[1] Coeliac disease was first described in childhood;[6][8] however, it may develop at any age.[1][8] It is associated with other autoimmune diseases, such as Type 1 diabetes mellitus and Hashimoto's thyroiditis, among others.[6]
Coeliac disease
Celiac sprue, nontropical sprue, endemic sprue, gluten enteropathy
None or non-specific, abdominal distention, diarrhoea, constipation, malabsorption, weight loss, dermatitis herpetiformis[1][2]
Lifelong[6]
Family history, blood antibody tests, intestinal biopsies, genetic testing, response to gluten withdrawal[10][11]
~1 in 135[14]
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]
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][31] Coeliac disease is slightly more common in women than in men.[32]
Screening[edit]
There is debate as to the benefits of screening. As of 2017, the United States Preventive Services Task Force found insufficient evidence to make a recommendation among those without symptoms.[29] In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommend testing for coeliac disease in first-degree relatives of those with the disease already confirmed, in people with persistent fatigue, abdominal or gastrointestinal symptoms, faltering growth, unexplained weight loss or iron, vitamin B12 or folate deficiency, severe mouth ulcers, and with diagnoses of type 1 diabetes, autoimmune thyroid disease,[21] and with newly diagnosed chronic fatigue syndrome[118] and irritable bowel syndrome.[37] Dermatitis herpetiformis is included in other recommendations.[119] The NICE also recommend offering serological testing for coeliac disease in people with metabolic bone disease (reduced bone mineral density or osteomalacia), unexplained neurological disorders (such as peripheral neuropathy and ataxia), fertility problems or recurrent miscarriage, persistently raised liver enzymes with unknown cause, dental enamel defects and with diagnose of Down syndrome or Turner syndrome.[21]
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][46][120][121] They thus recommend screening in people with certain health problems.[121]
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]
Epidemiology[edit]
Globally coeliac disease affects between 1 in 100 and 1 in 170 people.[14][137] 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).[138] Due to variable signs and symptoms it is believed that about 85% of people affected are undiagnosed.[139] 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[140]) 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%.[89] In Australia, approximately 1 in 70 people have the disease.[141] The rate amongst adult blood donors in Iran, Israel, Syria and Turkey is 0.60%, 0.64%, 1.61% and 1.15%, respectively.[39]
People of African, Japanese and Chinese descent are rarely diagnosed;[142] this reflects a much lower prevalence of the genetic risk factors, such as HLA-B8.[143] People of Indian ancestry seem to have a similar risk to those of Western Caucasian ancestry.[39] 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.[144] Coeliac disease is slightly more common in women than in men.[32] 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).[39] This profile is similar to the prevalence in Europe.[39] 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).[145]
Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%.[145] The reason for the recent increases in the number of reported cases is unclear.[137] It may be at least in part due to changes in diagnostic practice.[146] 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.[137] In the United States, the median age at diagnosis is 38 years.[147] Roughly 20 percent of individuals with coeliac disease are diagnosed after 60 years of age.[147]
History[edit]
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.[148][149]
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.[148] 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."[148][149]
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.[149][150]
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.[151][152] Sidney V. Haas, an American paediatrician, reported positive effects of a diet of bananas in 1924.[153] This diet remained in vogue until the actual cause of coeliac disease was determined.[149]
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.[154] 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.[155] 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.[156] The link with the gluten component of wheat was made in 1952 by a team from Birmingham, England.[157] Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery.[158] This paved the way for biopsy samples taken by endoscopy.[149]
Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965.[159] In 1966, dermatitis herpetiformis was linked to gluten sensitivity.[149][44]
Research directions[edit]
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.[170] 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.[171]
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][172][173]
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.[174]
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[175] and is scheduled for phase 3 clinical trials.[176]
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.[177] 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.[174]
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.[178][179][180] 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.[178][181][182]