Coeliac disease
Encyclopedia
Coeliac disease is an autoimmune
disorder of the small intestine
that occurs in genetically predisposed
people of all ages from middle infancy onward. Symptoms include chronic diarrhoea
, failure to thrive
(in children), and fatigue
, but these may be absent, and symptoms in other organ systems
have been described.
A growing portion of diagnoses are being made in asymptomatic
persons as a result of increased screening
; the condition is thought to affect between 1 in 1,750 and 1 in 105 people in the United States.
Coeliac disease is caused by a reaction to gliadin
, a prolamin
(gluten
protein) found in wheat
, and similar proteins found in the crops of the tribe
Triticeae
(which includes other common grains such as barley
and rye). Upon exposure to gliadin, and specifically to three peptides found in prolamins, the enzyme tissue transglutaminase
modifies the protein, and the immune system
cross-reacts with the small-bowel tissue, causing an inflammatory reaction
. That leads to a truncating of the villi lining the small intestine (called villous atrophy). This interferes with the absorption
of nutrients, because the intestinal villi are responsible for absorption. The only known 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
.
and cramping, bloatedness with abdominal distension
(thought to be due to fermentative production of bowel gas) and mouth ulcer
s may be present. As the bowel becomes more damaged, a degree of lactose intolerance
may develop. Frequently, the symptoms are ascribed to irritable bowel syndrome
(IBS), only later to be recognised as coeliac disease; a small proportion of patients with symptoms of IBS have underlying coeliac disease, and screening for coeliac disease is recommended for those with IBS symptoms.
Coeliac disease leads to an increased risk of both adenocarcinoma
(small intestine cancer
) and lymphoma
of the small bowel (enteropathy-associated T-cell lymphoma
or EATL). This risk returns to baseline with diet. Longstanding 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).
Coeliac disease is associated with a number of other medical conditions, many of which are autoimmune disorders: diabetes mellitus type 1
, autoimmune thyroiditis
, primary biliary cirrhosis
, and microscopic colitis
.
A more controversial area is a group of diseases in which anti-gliadin antibodies (an older and non-specific test for coeliac disease) are sometimes detected, but no small bowel disease can be demonstrated. Sometimes, these conditions improve by removing gluten from the diet. This includes cerebellar ataxia
, peripheral neuropathy
, schizophrenia
and autism
.
, semolina
and durum
) and related species such as barley
, rye
, triticale
and Kamut also induce symptoms of coeliac disease. A small minority of coeliac patients also react to oats
. It is most probable that oats produce symptoms due to cross contamination with other grains in the fields or in the distribution channels. Generally, oats are therefore not recommended. Other cereal
s such as maize
(corn), millet
, sorghum
, teff
, rice
, and wild rice
are safe for patients to consume, as well as non cereals such as amaranth
, quinoa
or buckwheat
. Non-cereal carbohydrate-rich foods such as potatoes and banana
s do not contain gluten and do not trigger symptoms.
Almost all coeliac patients have the variant HLA-DQ
2 allele
. However, about 20–30% of people without coeliac disease have inherited an HLA-DQ
2 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-DQ
2 allele
shows incomplete penetrance
, as the gene allele
s associated with the disease appear in most patients but are neither present in all cases nor sufficient by themselves to cause the disease.
The vast majority of coeliac patients have one of two types of HLA-DQ
. This gene
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
. The gene is located on the short arm of the sixth chromosome
and has been labelled CELIAC1.
There are seven HLA-DQ
variants (DQ2 and DQ4–DQ9). Over 95% of coeliac patients 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.
Most coeliac patients bear a two-gene HLA-DQ2 haplotype
referred to as DQ2.5 haplotype. This haplotype is composed of two adjacent gene allele
s, 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 (encoded by the haplotype
DQA1*03:DQB1*0302), 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
and Ireland with highest frequencies) and portions of Africa and is associated with disease in India, but 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
.
Other genetic factors have been repeatedly reported in CD, however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population. 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.
The prevalence of CD 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 practiced the longest (compare with a 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). By now, however, it is apparent that is not the case; on the contrary, there is evidence of positive selection in CD genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections.
s. These are storage proteins rich in proline
(prol-) and glutamine
(-amin) that dissolve in alcohols and are resistant to protease
s and peptidases of the gut. Prolamins are found in cereal grains with different grains having different but related prolamins: wheat
(gliadin
), barley
(hordein
), rye (secalin
), corn
(zein
) and as a minor protein, avenin in oats. One region of α-gliadin stimulates membrane cells, enterocyte
s, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than three amino acid
s to enter circulation.
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. The response to the 33mer occurs in most coeliacs who have a DQ2 isoform. 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. 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. However, not all prolamins 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.
Anti-transglutaminase antibodies
to the enzyme tissue transglutaminase
(tTG) are found in an overwhelming majority of cases. Tissue transglutaminase modifies gluten peptide
s into a form that may stimulate the immune system more effectively. These peptides are modified by tTG in two ways, deamidation or transamidation. 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 which 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. This results in the formation of new epitopes which are believed to trigger the primary immune response by which the autoantibodies against tTg develop.
Stored biopsies from suspected coeliac patients have 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, anaemia or malabsorption phenomena at a much-increased rate over the normal population. 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 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 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. 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.
s, 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 nutrient
s, minerals and fat-soluble vitamin
s 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 enterocyte
s 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.
or human intestinal adenovirus. Some research has suggested that smoking is protective against adult-onset coeliac disease.
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 (within the first three months after birth) had five times the risk of developing coeliac disease relative to those exposed at four to six months after birth. Those exposed even later than six months after birth were found to have only a slightly increased risk relative to those exposed at four to six months after birth. A study conducted in 2006 showed that early introduction of grains was protective against grain allergies; however, this study explicitly excluded any participants found to have coeliac disease and therefore offers no help in this regard. 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.
. The level of symptom
s 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 started on a gluten-free diet, it may be necessary to perform a re-challenge with some gluten-containing food in one meal a day over 2–6 weeks before repeating the investigations.
Combining findings into a prediction rule to guide use of endoscopic biopsy reported a sensitivity of 100% (it would identify all the cases) in a population of subjects with a high index of suspicion for coeliac disease, with a concomitant specificity of 61% (a false positive rate of 39%). The prediction rule recommends that patients with high-risk symptoms or positive serology should undergo endoscopic biopsy of the second part of the duodenum. The study defined high-risk symptoms as weight loss
, anaemia (haemoglobin less than 120 g/l in females or less than 130 g/l in males), or diarrhoea (more than three loose stools per day).
blood
tests are the first-line investigation required to make a diagnosis of coeliac disease. IgA antiendomysial antibodies can detect coeliac disease with a sensitivity
and specificity
of 90% and 99% according to a systematic review
. The systematic review estimates that the prevalence of coeliac disease in primary care patients with gastrointestinal symptoms to be about 3%. Serology
for anti-tTG
antibodies
was initially reported to have a high sensitivity (99%) and specificity (>90%) for identifying coeliac disease; however, the systematic review found the two tests were similar. Modern anti-tTG assays rely on a human recombinant protein as an antigen
. tTG testing should be done first as it is an easier test to perform. An equivocal result on tTG testing should be followed by antibodies to endomysium.
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 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
, tTG).
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.
Antibody testing and HLA
testing have similar accuracies. However, widespread use of HLA typing to rule out coeliac disease is not currently recommended.
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 submucosa
blood vessel
s, 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. 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.
Marsh's classification, introduced in 1992, was subsequently modified in 1999 to six stages, where the previous stage 3 was split in three substages. 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—A, B1 and B2—with A representing lymphocytic infiltration with normal villous appearance and B1 and B2 describing partial and 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. 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.
(by full blood count and iron studies), folic acid
and vitamin B12
deficiency and hypocalcaemia
(low calcium levels, often due to decreased vitamin D
levels). Thyroid function tests may be requested during blood tests to identify hypothyroidism
, which is more common in people with coeliac disease.
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.
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. 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 study
in Cambridge
suggested that people with undetected coeliac disease had a beneficial risk profile for cardiovascular disease
(less overweight
, lower cholesterol
levels). There is limited evidence that screen-detected cases benefit from a diagnosis in terms of morbidity and mortality; hence, population-level screening is not presently thought to be beneficial.
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
, as well as in type 1 diabetics, especially those with insufficient weight gain or unexplained weight loss. It is also recommended in autoimmune thyroid disease
, dermatitis herpetiformis
, and in the first-degree relatives of those with confirmed coeliac disease.
There is a large number of scenarios where testing for coeliac disease may be offered given previously described associations, such as the conditions mentioned above in "miscellaneous".
. 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 and in some cases sterility. Dietitian
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.
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. In the United States, the FDA
issued regulations in 2007 limiting the use of "gluten-free" in food products to those with less than 20 ppm of gluten. The current international Codex Alimentarius
standard allows for 20 ppm of gluten in so-called "gluten-free" foods. 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.
or immunosuppressants
(such as azathioprine
) may be considered in this scenario.
) to 1 in 105 (CD defined by presence of IgA TG in blood donors) people in the United States. 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, India, 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 Sahrawi children) and 0.18–1.2% in adults. 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, in part, to many clinicians being unfamiliar with the condition.
Coeliac disease is more prevalent in women than in men.
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. Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with Down
and Turner syndrome
s, type 1 diabetes, and autoimmune thyroid disease, including both hyperthyroidism
(overactive thyroid
) and hypothyroidism
(underactive thyroid).
Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%. Recent increases in the number of reported cases may be due to changes in diagnostic practice, but there is evidence that coeliac disease may be becoming more common in the United States.
in which a wafer or small piece of wheat bread is blessed and then eaten (see Sacramental bread
). A typical wafer weighs about half a gram Wheat flour
contains around 10 to 13% gluten, so a single communion wafer may have more than 50 mg of gluten, an amount which will harm the health of many coeliac patients especially if consumed every day (see Diet above).
Many Christian churches offer their communicants gluten-free alternatives, usually in the form of a rice-based cracker or gluten-free bread. These include United Methodist
, Christian Reformed
, Episcopal
, Lutheran
, and The Church of Jesus Christ of Latter-day Saints.
states that for a valid Eucharist
, the bread to be used at Mass must be made from wheat. In 2002, the Congregation for the Doctrine of the Faith
approved German-made low-gluten hosts, which meets 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 the Eucharist
under either form (bread or wine) is receiving Christ "whole and entire"—his body, blood, soul, and divinity—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 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."
As of January 2004, an extremely low-gluten host became available in the United States. The Benedictine Sisters of Perpetual Adoration
in Clyde, Missouri, produce low-gluten hosts safe for coeliacs and also approved by the Catholic Church for use at Mass. The hosts are made and packaged in a dedicated wheat-free, gluten-free environment. Gluten-content analysis found no detectable amount of gluten, though the reported gluten content is 0.01% as that was the lowest limit of detection possible with the utilised analysis technique. In an article from the Catholic Review (15 February 2004), Dr. Alessio Fasano was quoted as declaring these hosts "perfectly safe for celiac sufferers."
(Passover) may present problems with its obligation to eat matzo
, which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. This rules out many other grains that are normally used as substitutes for people with gluten sensitivity, especially for Ashkenazi Jews
, who also avoid rice
. Many kosher-for-Passover products avoid grains altogether and are therefore gluten-free. Potato starch
is the primary starch used to replace the grains. Consuming matzo
is mandatory on the first night of Pesach only. Jewish law holds that a person should not seriously endanger one's health in order to fulfil a commandment. Thus, a person with severe coeliac disease is not allowed, let alone required, to eat any matzo other than gluten-free matzo. The most commonly used gluten-free matzo is made from oats.
period (beginning about 9500 BCE) in the Fertile Crescent
in Western Asia, and it is likely that 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. 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 mussel
s 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. Sidney V. Haas, an American paediatrician, reported positive effects of a diet of banana
s 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 Karel Dicke. 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. Dicke noticed that the shortage of bread led to a significant drop in the death rate among children affected by CD 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. 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 on samples taken at surgery. This paved the way for biopsy samples taken by endoscopy.
Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965. In 1966, dermatitis herpetiformis
was linked to gluten sensitivity.
May has been designated as "Coeliac Awareness Month".
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
disorder of the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
that occurs in genetically predisposed
Genetic predisposition
A genetic predisposition is a genetic affectation which influences the phenotype of an individual organism within a species or population but by definition that phenotype can also be modified by the environmental conditions. In the rest of the population, conditions cannot have that effect...
people of all ages from middle infancy onward. Symptoms include chronic diarrhoea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, failure to thrive
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
(in children), and fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
, but these may be absent, and symptoms in other organ systems
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
have been described.
A growing portion of diagnoses are being made in asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
persons as a result of increased screening
Screening (medicine)
Screening, in medicine, is a strategy used in a population to detect a disease in individuals without signs or symptoms of that disease. Unlike what generally happens in medicine, screening tests are performed on persons without any clinical sign of disease....
; the condition is thought to affect between 1 in 1,750 and 1 in 105 people in the United States.
Coeliac disease is caused by a reaction to gliadin
Gliadin
Gliadin is a glycoprotein present in wheat and several other cereals within the grass genus Triticum. Gliadins are prolamins and are separated on the basis of electrophoretic mobility and isoelectric focusing.- Types :...
, a prolamin
Prolamin
Prolamins are a group of plant storage proteins having a high proline content and found in the seeds of cereal grains: wheat , barley , rye , corn , sorghum and as a minor protein, avenin in oats. They are characterised by a high glutamine and proline content and are generally soluble only in...
(gluten
Gluten
Gluten is a protein composite found in foods processed from wheat and related grain species, including barley and rye...
protein) found in wheat
Wheat
Wheat is a cereal grain, originally from the Levant region of the Near East, but now cultivated worldwide. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...
, and similar proteins found in the crops of the tribe
Tribe (biology)
In biology, a tribe is a taxonomic rank between family and genus. It is sometimes subdivided into subtribes.Some examples include the tribes: Canini, Acalypheae, Hominini, Bombini, and Antidesmeae.-See also:* Biological classification* Rank...
Triticeae
Triticeae
Triticeae is a tribe within the Pooideae subfamily of grasses that includes genera with many domesticated species. Major crop genera are found in this tribe including wheat , barley, and rye; crops in other genera include some for human consumption and others used for animal feed or rangeland...
(which includes other common grains such as barley
Barley
Barley is a major cereal grain, a member of the grass family. It serves as a major animal fodder, as a base malt for beer and certain distilled beverages, and as a component of various health foods...
and rye). Upon exposure to gliadin, and specifically to three peptides found in prolamins, the enzyme tissue transglutaminase
Tissue transglutaminase
Tissue transglutaminase is an enzyme of the transglutaminase family. Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis...
modifies the protein, and the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
cross-reacts with the small-bowel tissue, causing an inflammatory reaction
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. That leads to a truncating of the villi lining the small intestine (called villous atrophy). This interferes with the absorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
of nutrients, because the intestinal villi are responsible for absorption. The only known effective treatment is a lifelong gluten-free diet
Gluten-free diet
A gluten-free diet is a diet that excludes foods containing gluten. Gluten is a protein found in wheat , barley, rye, malts and triticale. It is used as a food additive in the form of a flavoring, stabilizing or thickening agent, often as "dextrin"...
. While the disease is caused by a reaction to wheat proteins, it is not the same as wheat allergy
Wheat allergy
Wheat allergy is a food allergy, but can also be a contact allergy resulting from occupational exposure. Like all allergies wheat allergy involves IgE and mast cell response. Typically the allergy is limited to the seed storage proteins of wheat, some reactions are restricted to wheat proteins,...
.
This condition has several other names, including: cœliac disease (with œ ligature
Œ
Œ œŒ is a Latin alphabet grapheme, a ligature of o and e. In medieval and early modern Latin, it was used to represent the Greek diphthong οι, a usage which continues in English and French...
), 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
Aretaeus of Cappadocia
Aretaeus , is one of the most celebrated of the ancient Greek physicians, of whose life, however, few particulars are known. There is some uncertainty regarding both his age and country, but it seems probable that he practised in the 1st century CE, during the reign of Nero or Vespasian...
.
Signs and symptoms
Severe coeliac disease leads to the characteristic symptoms of pale, loose and greasy stool (steatorrhoea), and weight loss or failure to gain weight (in young children). People with milder coeliac disease may have symptoms that are much more subtle and occur in other organs rather than the bowel itself. It is also possible to have coeliac disease without any symptoms whatsoever. Many adults with subtle disease only have fatigue or anaemia.Gastrointestinal
The diarrhoea that is characteristic of coeliac disease is (chronic) pale, voluminous and malodorous. Abdominal painAbdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
and cramping, bloatedness with abdominal distension
Abdominal distension
Abdominal distension is a sensation of elevated abdominal pressure and volume. It is estimated that close to 25% of the US population has some degree of abdominal distension on a regular basis. Some describe it as belching, others claim they feel nausea and yet others say they pass excessive gas...
(thought to be due to fermentative production of bowel gas) and mouth ulcer
Mouth ulcer
A mouth or oral ulcer is an open sore in the mouth, or rarely a break in the mucous membrane or the epithelium on the lips or surrounding the mouth. The types of mouth ulcers are diverse, with a multitude of associated causes including: physical abrasion, acidic fruit, infection, other medical...
s may be present. As the bowel becomes more damaged, a degree of lactose intolerance
Lactose intolerance
Lactose intolerance, also called lactase deficiency or hypolactasia, is the inability to digest and metabolize lactose, a sugar found in milk...
may develop. Frequently, the symptoms are ascribed to irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
(IBS), only later to be recognised as coeliac disease; a small proportion of patients with symptoms of IBS have underlying coeliac disease, and screening for coeliac disease is recommended for those with IBS symptoms.
Coeliac disease leads to an increased risk of both adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
(small intestine cancer
Small intestine cancer
In oncology, small intestine cancer, also small bowel cancer and cancer of the small bowel, is a cancer of the small intestine. It is relatively rare compared to other gastrointestinal malignancies such as gastric cancer and colorectal cancer.Small intestine cancer can be subdivided into duodenal...
) and lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
of the small bowel (enteropathy-associated T-cell lymphoma
Enteropathy-Associated T-cell Lymphoma
Enteropathy-Associated T-cell Lymphoma , also enteropathy-type T-cell lymphoma , is a type of T-cell lymphoma that affects the small intestine. It is the most common primary gastrointestinal T-cell lymphoma, arising from the T cells that are found between the cells that line the small intestinal...
or EATL). This risk returns to baseline with diet. Longstanding 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).
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.- The inability to absorb carbohydrates and fats may cause weight lossWeight lossWeight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
(or failure to thriveFailure to thriveFailure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
/stunted growth in children) and fatigueFatigue (physical)Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
or lack of energy. - Anaemia may develop in several ways: iron malabsorption may cause iron deficiency anaemiaIron deficiency anemiaIron-deficiency anemia is a common anemia that occurs when iron loss occurs, and/or the dietary intake or absorption of iron is insufficient...
, and folic acidFolic acidFolic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
and vitamin B12Vitamin B12Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
malabsorption may give rise to megaloblastic anaemiaMegaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
. - CalciumCalcium in biologyCalcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
and vitamin DVitamin DVitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
malabsorption (and compensatory secondary hyperparathyroidismHyperparathyroidismHyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone . The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels...
) may cause osteopeniaOsteopeniaOsteopenia is a condition where bone mineral density is lower than normal. It is considered by many doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis...
(decreased mineral content of the bone) or osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
(bone weakening and risk of fragility fractures). - A small proportion have abnormal coagulationCoagulationCoagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
due to vitamin K deficiencyVitamin K deficiencyVitamin K deficiency is a form of avitaminosis resulting from insufficient vitamin K.-Causes:Vitamin K-deficiency may occur by disturbed intestinal uptake , by therapeutic or accidental intake of vitamin K-antagonists or, very rarely, by nutritional vitamin K deficiency...
and are slightly at risk for abnormal bleeding. - Coeliac disease is also associated with bacterial overgrowthSmall bowel bacterial overgrowth syndromeSmall bowel bacterial overgrowth syndrome , or small intestinal bacterial overgrowth , also termed bacterial overgrowth; is a disorder of excessive bacterial growth in the small intestine. Unlike the colon , which is rich with bacteria, the small bowel usually has less than 104 organisms per...
of the small intestineSmall intestineThe small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
, which can worsen malabsorption or cause malabsorption despite adherence to treatment.
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.- IgA deficiency is present in 2.3% of patients with coeliac disease, and in turn, this condition features a tenfold increased risk of coeliac disease. Other features of this condition are an increased risk of infectionInfectionAn infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s and autoimmune diseaseAutoimmune diseaseAutoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
. - Dermatitis herpetiformisDermatitis herpetiformisDermatitis herpetiformis , or Duhring's disease,Freedberg, et al. . Fitzpatrick's Dermatology in General Medicine. . McGraw-Hill. ISBN 0-07-138076-0. is a chronic blistering skin condition, characterised by blisters filled with a watery fluid...
; this itchy cutaneous condition 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 there are no gastrointestinal symptoms. - Growth failure and/or pubertal delayDelayed pubertyPuberty is described as delayed puberty with exceptions when an organism has passed the usual age of onset of puberty with no physical or hormonal signs that it is beginning. Puberty may be delayed for several years and still occur normally, in which case it is considered constitutional delay, a...
in later childhood can occur even without obvious bowel symptoms or severe malnutritionMalnutritionMalnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
. Evaluation of growth failure often includes coeliac screening. - Recurrent miscarriageHabitual abortionHabitual abortion, recurrent miscarriage or recurrent pregnancy loss is the occurrence of three or more pregnancies that end in miscarriage of the fetus, usually before 20 weeks of gestation...
and unexplained infertilityUnexplained infertilityUnexplained infertility is infertility that is idiopathic in the sense that its cause remains unknown even after an infertility work-up, usually including semen analysis in the man and assessment of ovulation and fallopian tubes in the woman.-Possible causes:...
. - Hyposplenism (a small and underactive spleenSpleenThe spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
); this occurs in about a third of cases and may predispose to infection given the role of the spleen in protecting against bacteria. - Abnormal liver function tests (randomly detected on blood tests).
Coeliac disease is associated with a number of other medical conditions, many of which are autoimmune disorders: diabetes mellitus type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
, autoimmune thyroiditis
Thyroiditis
Thyroiditis is the inflammation of the thyroid gland. The thyroid gland is located on the front of the neck below the laryngeal prominence, and makes hormones that control metabolism.-Classification:...
, primary biliary cirrhosis
Primary biliary cirrhosis
Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts within the liver. When these ducts are damaged, bile builds up in the liver and over time damages the tissue. This can lead to scarring,...
, and microscopic colitis
Microscopic colitis
Microscopic colitis refers to two medical conditions which cause diarrhea: collagenous colitis and lymphocytic colitis. Both conditions are characterised by the following triad of clinicopathological features:# Chronic watery diarrhoea;# Normal colonoscopy;...
.
A more controversial area is a group of diseases in which anti-gliadin antibodies (an older and non-specific test for coeliac disease) are sometimes detected, but no small bowel disease can be demonstrated. Sometimes, these conditions improve by removing gluten from the diet. This includes cerebellar ataxia
Cerebellar ataxia
Cerebellar ataxia is a form of ataxia originating in the cerebellum.-References:...
, peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and autism
Autism spectrum
The term "autism spectrum" is often used to describe disorders that are currently classified as pervasive developmental disorders. Pervasive developmental disorders include autism, Asperger syndrome, Childhood disintegrative disorder, Rett syndrome and Pervasive Developmental Disorder Not Otherwise...
.
Other grains
Wheat subspecies (such as speltSpelt
Spelt is a hexaploid species of wheat. Spelt was an important staple in parts of Europe from the Bronze Age to medieval times; it now survives as a relict crop in Central Europe and northern Spain and has found a new market as a health food. Spelt is sometimes considered a subspecies of the...
, semolina
Semolina
Semolina is the coarse, purified wheat middlings of durum wheat used in making pasta, and also used for breakfast cereals and puddings. Semolina is also used to designate coarse middlings from other varieties of wheat, and from other grains such as rice and corn.-Name:The term semolina derives from...
and durum
Durum
Durum wheat or macaroni wheat is the only tetraploid species of wheat of commercial importance that is widely cultivated today...
) and related species such as barley
Barley
Barley is a major cereal grain, a member of the grass family. It serves as a major animal fodder, as a base malt for beer and certain distilled beverages, and as a component of various health foods...
, rye
Rye
Rye is a grass grown extensively as a grain and as a forage crop. It is a member of the wheat tribe and is closely related to barley and wheat. Rye grain is used for flour, rye bread, rye beer, some whiskeys, some vodkas, and animal fodder...
, triticale
Triticale
Triticale is a hybrid of wheat and rye first bred in laboratories during the late 19th century. The grain was originally bred in Scotland and Sweden. Commercially available triticale is almost always a second generation hybrid, i.e., a cross between two kinds of primary triticales...
and Kamut also induce symptoms of coeliac disease. A small minority of coeliac patients also react to oats
OATS
OATS - Open Source Assistive Technology Software - is a source code repository or "forge" for assistive technology software. It was launched in 2006 with the goal to provide a one-stop “shop” for end users, clinicians and open-source developers to promote and develop open source assistive...
. It is most probable that oats produce symptoms due to cross contamination with other grains in the fields or in the distribution channels. Generally, oats are therefore not recommended. Other cereal
Cereal
Cereals are grasses cultivated for the edible components of their grain , composed of the endosperm, germ, and bran...
s such as maize
Maize
Maize known in many English-speaking countries as corn or mielie/mealie, is a grain domesticated by indigenous peoples in Mesoamerica in prehistoric times. The leafy stalk produces ears which contain seeds called kernels. Though technically a grain, maize kernels are used in cooking as a vegetable...
(corn), millet
Millet
The millets are a group of small-seeded species of cereal crops or grains, widely grown around the world for food and fodder. They do not form a taxonomic group, but rather a functional or agronomic one. Their essential similarities are that they are small-seeded grasses grown in difficult...
, sorghum
Sorghum
Sorghum is a genus of numerous species of grasses, one of which is raised for grain and many of which are used as fodder plants either cultivated or as part of pasture. The plants are cultivated in warmer climates worldwide. Species are native to tropical and subtropical regions of all continents...
, teff
Teff
Eragrostis tef, known as teff, taf , or khak shir , is an annual grass, a species of lovegrass native to the northern Ethiopian Highlands of Northeast Africa....
, rice
Rice
Rice is the seed of the monocot plants Oryza sativa or Oryza glaberrima . As a cereal grain, it is the most important staple food for a large part of the world's human population, especially in East Asia, Southeast Asia, South Asia, the Middle East, and the West Indies...
, and wild rice
Wild rice
Wild rice is four species of grasses forming the genus Zizania, and the grain which can be harvested from them. The grain was historically gathered and eaten in both North America and China...
are safe for patients to consume, as well as non cereals such as amaranth
Amaranth
Amaranthus, collectively known as amaranth, is a cosmopolitan genus of herbs. Approximately 60 species are recognized, with inflorescences and foliage ranging from purple and red to gold...
, quinoa
Quinoa
Quinoa , a species of goosefoot , is a grain-like crop grown primarily for its edible seeds. It is a pseudocereal rather than a true cereal, or grain, as it is not a member of the grass family...
or buckwheat
Buckwheat
Buckwheat refers to a variety of plants in the dicot family Polygonaceae: the Eurasian genus Fagopyrum, the North American genus Eriogonum, and the Northern Hemisphere genus Fallopia. Either of the latter two may be referred to as "wild buckwheat"...
. Non-cereal carbohydrate-rich foods such as potatoes and banana
Banana
Banana is the common name for herbaceous plants of the genus Musa and for the fruit they produce. Bananas come in a variety of sizes and colors when ripe, including yellow, purple, and red....
s do not contain gluten and do not trigger symptoms.
Pathophysiology
Coeliac disease appears to be polyfactorial, both in that more than one genetic factor can cause the disease and that more than one factor is necessary for the disease to manifest in a patient.Almost all coeliac patients have the variant HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
2 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
. However, about 20–30% of people without coeliac disease have inherited an HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
2 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
. 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-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
2 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
shows incomplete penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
, as the gene allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s associated with the disease appear in most patients but are neither present in all cases nor sufficient by themselves to cause the disease.
Genetics
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
. This gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is part of the MHC class II antigen-presenting receptor
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(also called the human leukocyte antigen
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
) system and distinguishes cells between self and non-self for the purposes of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. The gene is located on the short arm of the sixth chromosome
Chromosome 6 (human)
Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs and represents between 5.5 and 6% of the total DNA in cells...
and has been labelled CELIAC1.
There are seven HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
variants (DQ2 and DQ4–DQ9). Over 95% of coeliac patients 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
Gliadin
Gliadin is a glycoprotein present in wheat and several other cereals within the grass genus Triticum. Gliadins are prolamins and are separated on the basis of electrophoretic mobility and isoelectric focusing.- Types :...
peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
and initiate the autoimmune process.
Most coeliac patients bear a two-gene HLA-DQ2 haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
referred to as DQ2.5 haplotype. This haplotype is composed of two adjacent gene allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s, 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
Chromosome 6 (human)
Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs and represents between 5.5 and 6% of the total DNA in cells...
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 (encoded by the haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
DQA1*03:DQB1*0302), 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
Western Europe
Western Europe is a loose term for the collection of countries in the western most region of the European continents, though this definition is context-dependent and carries cultural and political connotations. One definition describes Western Europe as a geographic entity—the region lying in the...
(Basque Country
Basque Country (historical territory)
The Basque Country is the name given to the home of the Basque people in the western Pyrenees that spans the border between France and Spain on the Atlantic coast....
and Ireland with highest frequencies) and portions of Africa and is associated with disease in India, but 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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
.
Other genetic factors have been repeatedly reported in CD, however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population. Many of the loci detected have been found in association with other autoimmune diseases. One locus, the LPP
LPP (gene)
Lipoma-preferred partner is a protein that in humans is encoded by the LPP gene.- Function :Lipoma-preferred partner is a subfamily of LIM domain proteins that are characterized by an N-terminal proline rich region and three C-terminal LIM domains. The encoded protein localizes to the cell...
or lipoma-preferred partner gene is involved in the adhesion of extracellular matrix to the cell surface and a minor variant (SNP
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
= 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.
The prevalence of CD 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 practiced the longest (compare with a a similar condition, Lactose intolerance
Lactose intolerance
Lactose intolerance, also called lactase deficiency or hypolactasia, is the inability to digest and metabolize lactose, a sugar found in milk...
, 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). By now, however, it is apparent that is not the case; on the contrary, there is evidence of positive selection in CD genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections.
Prolamins
The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolaminProlamin
Prolamins are a group of plant storage proteins having a high proline content and found in the seeds of cereal grains: wheat , barley , rye , corn , sorghum and as a minor protein, avenin in oats. They are characterised by a high glutamine and proline content and are generally soluble only in...
s. These are storage proteins rich in proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
(prol-) and glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
(-amin) that dissolve in alcohols and are resistant to protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s and peptidases of the gut. Prolamins are found in cereal grains with different grains having different but related prolamins: wheat
Wheat
Wheat is a cereal grain, originally from the Levant region of the Near East, but now cultivated worldwide. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...
(gliadin
Gliadin
Gliadin is a glycoprotein present in wheat and several other cereals within the grass genus Triticum. Gliadins are prolamins and are separated on the basis of electrophoretic mobility and isoelectric focusing.- Types :...
), barley
Barley
Barley is a major cereal grain, a member of the grass family. It serves as a major animal fodder, as a base malt for beer and certain distilled beverages, and as a component of various health foods...
(hordein
Hordein
Hordein is a glycoprotein, present in barley and some other cereals, together with gliadin and other glycoproteins as gluten.Some people are sensitive to hordein due to disorders such as celiac disease or gluten intolerance....
), rye (secalin
Secalin
Secalin is a protein found in the grain rye.Secalin is one of the forms of gluten that people with coeliac disease cannot tolerate, and thus rye should be avoided by people with this disease. It is generally recommended that such people follow a gluten free diet.In bread making with rye flour, this...
), corn
Maize
Maize known in many English-speaking countries as corn or mielie/mealie, is a grain domesticated by indigenous peoples in Mesoamerica in prehistoric times. The leafy stalk produces ears which contain seeds called kernels. Though technically a grain, maize kernels are used in cooking as a vegetable...
(zein
Zein
Zein is a class of prolamine protein found in maize. It is usually manufactured as a powder from corn gluten meal.-Commercial uses:Zein is one of the best understood plant proteins and has a variety of industrial and food uses...
) and as a minor protein, avenin in oats. One region of α-gliadin stimulates membrane cells, enterocyte
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
s, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than three amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s to enter circulation.
Hordein
Hordein is a glycoprotein, present in barley and some other cereals, together with gliadin and other glycoproteins as gluten.Some people are sensitive to hordein due to disorders such as celiac disease or gluten intolerance....
(from barley) and secalin
Secalin
Secalin is a protein found in the grain rye.Secalin is one of the forms of gluten that people with coeliac disease cannot tolerate, and thus rye should be avoided by people with this disease. It is generally recommended that such people follow a gluten free diet.In bread making with rye flour, this...
(from rye) may contribute to coeliac disease. However, not all prolamins 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.
Tissue transglutaminase
Anti-transglutaminase antibodies
Anti-transglutaminase antibodies are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign and also can be producd...
to the enzyme tissue transglutaminase
Tissue transglutaminase
Tissue transglutaminase is an enzyme of the transglutaminase family. Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis...
(tTG) are found in an overwhelming majority of cases. Tissue transglutaminase modifies gluten peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s into a form that may stimulate the immune system more effectively. These peptides are modified by tTG in two ways, deamidation or transamidation. 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 which 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. This results in the formation of new epitopes which are believed to trigger the primary immune response by which the autoantibodies against tTg develop.
Stored biopsies from suspected coeliac patients have revealed that autoantibody
Autoantibody
An autoantibody is an antibody manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body"...
deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anaemia or malabsorption phenomena at a much-increased rate over the normal population. 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 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 recognise a rotavirus
Rotavirus
Rotavirus is the most common cause of severe diarrhoea among infants and young children, and is one of several viruses that cause infections often called stomach flu, despite having no relation to influenza. It is a genus of double-stranded RNA virus in the family Reoviridae. By the age of five,...
protein called VP7. These antibodies stimulate monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
proliferation, and rotavirus infection might explain some early steps in the cascade of immune cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
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.
Villous atrophy and malabsorption
The inflammatory process, mediated by T cellT cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s, leads to disruption of the structure and function of the small bowel's mucosal lining and causes malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
as it impairs the body's ability to absorb nutrient
Nutrient
A nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...
s, minerals and fat-soluble vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
s A, D, E and K from food
Food
Food is any substance consumed to provide nutritional support for the body. It is usually of plant or animal origin, and contains essential nutrients, such as carbohydrates, fats, proteins, vitamins, or minerals...
. Lactose intolerance
Lactose intolerance
Lactose intolerance, also called lactase deficiency or hypolactasia, is the inability to digest and metabolize lactose, a sugar found in milk...
may be present due to the decreased bowel surface and reduced production of lactase
Lactase
Lactase , a part of the β-galactosidase family of enzymes, is a glycoside hydrolase involved in the hydrolysis of the disaccharide lactose into constituent galactose and glucose monomers...
but typically resolves once the condition is treated.
Alternative causes of this tissue damage have been proposed and involve release of interleukin 15
Interleukin 15
Interleukin 15 is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through the IL-2/IL-15 beta chain and the common gamma chain . IL-15 is secreted by mononuclear phagocytes following infection by virus...
and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of enterocyte
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
s by lymphocytes in the epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
. The villous atrophy seen on biopsy may also be due to unrelated causes, such as tropical sprue
Tropical sprue
Tropical sprue is a malabsorption disease commonly found in the tropical regions, marked with abnormal flattening of the villi and inflammation of the lining of the small intestine.It differs significantly from coeliac sprue.-Symptoms and signs:...
, giardiasis
Giardiasis
Giardiasis or beaver fever in humans is a diarrheal infection of the small intestine by a single-celled organism Giardia lamblia. Giardiasis occurs worldwide with a prevalence of 20–30% in developing countries. In the U.S., 20,000 cases are reported to the CDC annually, but the true annual...
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.
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 rotavirusRotavirus
Rotavirus is the most common cause of severe diarrhoea among infants and young children, and is one of several viruses that cause infections often called stomach flu, despite having no relation to influenza. It is a genus of double-stranded RNA virus in the family Reoviridae. By the age of five,...
or human intestinal adenovirus. Some research has suggested that smoking is protective against adult-onset coeliac disease.
A 2005 prospective and observational study
Observational study
In epidemiology and statistics, an observational study draws inferences about the possible effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator...
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
Gut flora
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora....
has fully developed (within the first three months after birth) had five times the risk of developing coeliac disease relative to those exposed at four to six months after birth. Those exposed even later than six months after birth were found to have only a slightly increased risk relative to those exposed at four to six months after birth. A study conducted in 2006 showed that early introduction of grains was protective against grain allergies; however, this study explicitly excluded any participants found to have coeliac disease and therefore offers no help in this regard. Breastfeeding may also reduce risk. A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
indicates that prolonging breastfeeding
Breastfeeding
Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk. It is recommended that mothers breastfeed for six months or...
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.
Diagnosis
There are several tests that can be used to assist in diagnosisMedical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
. The level of symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s may determine the order of the tests, but all tests lose their usefulness if the patient is already taking a gluten-free diet
Gluten-free diet
A gluten-free diet is a diet that excludes foods containing gluten. Gluten is a protein found in wheat , barley, rye, malts and triticale. It is used as a food additive in the form of a flavoring, stabilizing or thickening agent, often as "dextrin"...
. Intestinal
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
damage begins to heal within weeks of gluten being removed from the diet, and antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a re-challenge with some gluten-containing food in one meal a day over 2–6 weeks before repeating the investigations.
Combining findings into a prediction rule to guide use of endoscopic biopsy reported a sensitivity of 100% (it would identify all the cases) in a population of subjects with a high index of suspicion for coeliac disease, with a concomitant specificity of 61% (a false positive rate of 39%). The prediction rule recommends that patients with high-risk symptoms or positive serology should undergo endoscopic biopsy of the second part of the duodenum. The study defined high-risk symptoms as weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, anaemia (haemoglobin less than 120 g/l in females or less than 130 g/l in males), or diarrhoea (more than three loose stools per day).
Blood tests
SerologicalSerology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
tests are the first-line investigation required to make a diagnosis of coeliac disease. IgA antiendomysial antibodies can detect coeliac disease with a sensitivity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
and specificity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of 90% and 99% according to a systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
. The systematic review estimates that the prevalence of coeliac disease in primary care patients with gastrointestinal symptoms to be about 3%. Serology
Serology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
for anti-tTG
Anti-transglutaminase antibodies
Anti-transglutaminase antibodies are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign and also can be producd...
antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
was initially reported to have a high sensitivity (99%) and specificity (>90%) for identifying coeliac disease; however, the systematic review found the two tests were similar. Modern anti-tTG assays rely on a human recombinant protein as an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
. tTG testing should be done first as it is an easier test to perform. An equivocal result on tTG testing should be followed by antibodies to endomysium.
Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
is still followed by an endoscopy
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
/gastroscopy and biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
. A negative serology test may still be followed by a recommendation for endoscopy and duodenal 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
Gold standard (test)
In medicine and statistics, gold standard test refers to a diagnostic test or benchmark that is the best available under reasonable conditions. It does not have to be necessarily the best possible test for the condition in absolute terms...
in the diagnosis of coeliac disease.
Historically three other antibodies were measured: anti-reticulin (ARA), anti-gliadin
Gliadin
Gliadin is a glycoprotein present in wheat and several other cereals within the grass genus Triticum. Gliadins are prolamins and are separated on the basis of electrophoretic mobility and isoelectric focusing.- Types :...
(AGA
Anti-gliadin antibodies
Antigliadin 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...
) and anti-endomysium
Endomysium
The endomysium, meaning within the muscle, is a layer of connective tissue that ensheaths a muscle fiber and is composed mostly from reticular fibers. It also contains capillaries, nerves, and lymphatics...
(EMA) antibodies. Serology may be unreliable in young children, with anti-gliadin
Gliadin
Gliadin is a glycoprotein present in wheat and several other cereals within the grass genus Triticum. Gliadins are prolamins and are separated on the basis of electrophoretic mobility and isoelectric focusing.- Types :...
performing somewhat better than other tests in children under five. Serology tests are based on indirect immunofluorescence
Immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows...
(reticulin, gliadin and endomysium) or ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
(gliadin or tissue transglutaminase
Transglutaminase
Transglutaminases are a family of enzymes that catalyze the formation of a covalent bond between a free amine group and the gamma-carboxamid group of protein- or peptide-bound glutamine. Bonds formed by transglutaminase exhibit high resistance to proteolytic degradation.Transglutaminases were...
, tTG).
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.
Antibody testing and HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
testing have similar accuracies. However, widespread use of HLA typing to rule out coeliac disease is not currently recommended.
| Test | | sensitivity | specificity |
|---|---|---|
| HLA-DQ2 HLA-DQ2 HLA-DQ2 is a serotype group within HLA-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,... |
94% | 73% |
| HLA-DQ8 HLA-DQ8 HLA-DQ8 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302.... |
12% | 81% |
Endoscopy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
of the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
(beyond the duodenal bulb
Duodenal bulb
The duodenal bulb is the portion of the duodenum which is closest to the stomach. It normally has a length of about 5 centimeters. The duodenal bulb begins at the pylorus and ends at the neck of the gallbladder. It is located anterior to the liver and the gallbladder, and superior to the pancreatic...
) or jejunum
Jejunum
The jejunum is the middle section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms middle intestine or mid-gut may be used instead of jejunum.The jejunum lies between the duodenum...
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
Mosaic
Mosaic is the art of creating images with an assemblage of small pieces of colored glass, stone, or other materials. It may be a technique of decorative art, an aspect of interior decoration, or of cultural and spiritual significance as in a cathedral...
pattern to the mucosa (described as a "cracked-mud" appearance), prominence of the submucosa
Submucosa
In the gastrointestinal tract, the submucosa is the layer of dense irregular connective tissue or loose connective tissue that supports the mucosa, as well as joins the mucosa to the bulk of underlying smooth muscle .-Contents:Blood vessels, lymphatic vessels, and nerves will run through...
blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s, 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
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
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
Watson capsule
The Watson peroral small intestinal biopsy capsule was a system used through from the 1960s to obtain small intestinal wall biopsies in patients with suspected coeliac disease and other diseases affecting the proximal small bowel....
and the Crosby-Kugler capsule
Crosby-Kugler capsule
The Crosby-Kugler capsule, also called the Crosby capsule, is a device used for obtaining biopsies of small bowel mucosa, necessary for the diagnosis of various small bowel diseases. This capsule was originally invented by Dr. William H Crosby to assist in diagnosing sprue.The capsule, attached to...
. This method has now been largely replaced by fibre-optic endoscopy, which carries a higher sensitivity and a lower frequency of errors.
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, usually exceeding 20 per 100 enterocyteEnterocyteEnterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
s - Marsh stage 2: proliferation of the crypts of LieberkuhnCrypts of LieberkühnIn histology, an intestinal crypt is a gland found in the epithelial lining of the small intestine and colon...
- Marsh stage 3: partial or complete villous atrophyAtrophyAtrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
- Marsh stage 4: hypoplasiaHypoplasiaHypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
of the small bowel architecture
Marsh's classification, introduced in 1992, was subsequently modified in 1999 to six stages, where the previous stage 3 was split in three substages. 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—A, B1 and B2—with A representing lymphocytic infiltration with normal villous appearance and B1 and B2 describing partial and complete villous atrophy.
The changes classically improve or reverse after gluten
Gluten
Gluten is a protein composite found in foods processed from wheat and related grain species, including barley and rye...
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.
Other diagnostic tests
At the time of diagnosis, further investigations may be performed to identify complications, such as iron deficiencyIron deficiency (medicine)
Iron deficiency is one of the most common of the nutritional deficiencies. Iron is present in all cells in the human body, and has several vital functions...
(by full blood count and iron studies), folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
and vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
deficiency and hypocalcaemia
Hypocalcaemia
In medicine, hypocalcaemia is the presence of low serum calcium levels in the blood, usually taken as less than 2.1 mmol/L or 9 mg/dl or an ionized calcium level of less than 1.1 mmol/L or 4.5 mg/dL. It is a type of electrolyte disturbance...
(low calcium levels, often due to decreased vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
levels). Thyroid function tests may be requested during blood tests to identify hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
, which is more common in people with coeliac disease.
Osteopenia
Osteopenia
Osteopenia is a condition where bone mineral density is lower than normal. It is considered by many doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis...
and osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, 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
Dual energy X-ray absorptiometry
Dual-emission X-ray absorptiometry is a means of measuring bone mineral density . Two X-ray beams with differing energy levels are aimed at the patient's bones. When soft tissue absorption is subtracted out, the BMD can be determined from the absorption of each beam by bone...
(DXA) scanning, to identify risk of fracture and need for bone protection medication.
Screening
Due to its high sensitivity, serologySerology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
has been proposed as a screening
Screening (medicine)
Screening, in medicine, is a strategy used in a population to detect a disease in individuals without signs or symptoms of that disease. Unlike what generally happens in medicine, screening tests are performed on persons without any clinical sign of disease....
measure, because the presence of antibodies would detect previously undiagnosed cases of coeliac disease and prevent its complications in those patients. 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 study
Cohort study
A cohort study or panel study is a form of longitudinal study used in medicine, social science, actuarial science, and ecology. It is an analysis of risk factors and follows a group of people who do not have the disease, and uses correlations to determine the absolute risk of subject contraction...
in Cambridge
Cambridge
The city of Cambridge is a university town and the administrative centre of the county of Cambridgeshire, England. It lies in East Anglia about north of London. Cambridge is at the heart of the high-technology centre known as Silicon Fen – a play on Silicon Valley and the fens surrounding the...
suggested that people with undetected coeliac disease had a beneficial risk profile for cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
(less overweight
Overweight
Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...
, lower cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
levels). There is limited evidence that screen-detected cases benefit from a diagnosis in terms of morbidity and mortality; hence, population-level screening is not presently thought to be beneficial.
In the United Kingdom, the National Institute for Health and Clinical Excellence
National Institute for Health and Clinical Excellence
The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...
(NICE) recommends screening for coeliac disease in patients with newly diagnosed chronic fatigue syndrome
Chronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
and irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
, as well as in type 1 diabetics, especially those with insufficient weight gain or unexplained weight loss. It is also recommended in autoimmune thyroid disease
Autoimmune thyroiditis
Autoimmune thyroiditis is a form of thyroiditis associated with an autoimmune disease where the body treats the thyroid gland and sometimes the hormones it produces as foreign bodies, therefore rejecting and attacking both.-Treatment:...
, dermatitis herpetiformis
Dermatitis herpetiformis
Dermatitis herpetiformis , or Duhring's disease,Freedberg, et al. . Fitzpatrick's Dermatology in General Medicine. . McGraw-Hill. ISBN 0-07-138076-0. is a chronic blistering skin condition, characterised by blisters filled with a watery fluid...
, and in the first-degree relatives of those with confirmed coeliac disease.
There is a large number of scenarios where testing for coeliac disease may be offered given previously described associations, such as the conditions mentioned above in "miscellaneous".
Diet
At present, the only effective treatment is a life-long gluten-free dietGluten-free diet
A gluten-free diet is a diet that excludes foods containing gluten. Gluten is a protein found in wheat , barley, rye, malts and triticale. It is used as a food additive in the form of a flavoring, stabilizing or thickening agent, often as "dextrin"...
. 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 and in some cases sterility. Dietitian
Dietitian
Dietitians supervise the preparation and service of food, develop modified diets, participate in research, and educate individuals and groups on good nutritional habits. The goals of dietitians are to provide medical nutritional intervention, and to obtain, safely prepare, serve and advise on...
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
Medical prescription
A prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
and may be reimbursed by health insurance
Health insurance
Health insurance is insurance against the risk of incurring medical expenses among individuals. By estimating the overall risk of health care expenses among a targeted group, an insurer can develop a routine finance structure, such as a monthly premium or payroll tax, to ensure that money is...
plans.
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
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
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. In the United States, the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
issued regulations in 2007 limiting the use of "gluten-free" in food products to those with less than 20 ppm of gluten. The current international Codex Alimentarius
Codex Alimentarius
The Codex Alimentarius is a collection of internationally recognized standards, codes of practice, guidelines and other recommendations relating to foods, food production and food safety. Its name derives from the Codex Alimentarius Austriacus...
standard allows for 20 ppm of gluten in so-called "gluten-free" foods. 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
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
(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
Dermatitis herpetiformis
Dermatitis herpetiformis , or Duhring's disease,Freedberg, et al. . Fitzpatrick's Dermatology in General Medicine. . McGraw-Hill. ISBN 0-07-138076-0. is a chronic blistering skin condition, characterised by blisters filled with a watery fluid...
, mouth ulcers, osteoporosis and resultant fractures. Symptoms suggestive of irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
may be present, and there is an increased rate of anxiety, fatigue, dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
and musculoskeletal pain.
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, steroidsGlucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
or immunosuppressants
Immunosuppressive drug
Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...
(such as azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
) may be considered in this scenario.
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:- Genetically engineeredGenetic engineeringGenetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
wheat species, or wheat species that have been selectively bredPlant breedingPlant breeding is the art and science of changing the genetics of plants in order to produce desired characteristics. Plant breeding can be accomplished through many different techniques ranging from simply selecting plants with desirable characteristics for propagation, to more complex molecular...
to be minimally immunogenic. This, however, could interfere with the effects that gliadin has on the quality of dough. - A combination of enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s (prolyl endopeptidaseProlyl endopeptidaseProlyl endopeptidase or prolyl oligopeptidase, sometimes post-proline cleaving enzyme) is a large cytosolic enzyme that belongs to a distinct class of serine peptidases. It was first described in the cytosol of rabbit brain as an oligopeptidase, which degrades the nonapeptide bradykinin at the...
and a barley glutamine-specific cysteine endopeptidase (EP-B2EP-B2Endoprotease B, isoform 2 is a cysteine protease found in barley. In studies, it has shown promise as a possible therapeutic for coeliac disease. Aspergillopepsin from Aspergillus niger has been shown to enhance the effects of EP-B2....
)) that degrade the putative 33-mer peptide in the duodenumDuodenumThe duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
. This combination would enable coeliac disease patients to consume gluten-containing products. - Inhibition of zonulinZonulinZonulin is a protein that participates in tight junctions between cells of the wall of the digestive tract. Initially discovered in 2000 as the target of zonula occludens toxin, secreted by cholera pathogen Vibrio cholerae, it has been implicated in the pathogenesis of coeliac disease and diabetes...
, an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system. - Scavenging of gliadin in the gastrointestinal tract by a polymeric binder to prevent its digestion into the immunogenic peptide.
- 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 enterocyteEnterocyteEnterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
s (bowel lining cells).
Epidemiology
The disease is thought to affect between 1 in 1750 (with CD defined as clinical cases including dermatitis herpetiformisDermatitis herpetiformis
Dermatitis herpetiformis , or Duhring's disease,Freedberg, et al. . Fitzpatrick's Dermatology in General Medicine. . McGraw-Hill. ISBN 0-07-138076-0. is a chronic blistering skin condition, characterised by blisters filled with a watery fluid...
) to 1 in 105 (CD defined by presence of IgA TG in blood donors) people in the United States. 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, India, 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 Sahrawi children) and 0.18–1.2% in adults. People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors
Risk factors
A risk factor is a concept in finance theory such as the CAPM, APT and other theories that use pricing kernels. In these models, the rate of return of an asset is a random variable whose realization in any time period is a linear combination of other random variables plus a disturbance term or...
. 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.
Coeliac disease is more prevalent in women than in men.
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. Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with Down
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
and Turner syndrome
Turner syndrome
Turner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
s, type 1 diabetes, and autoimmune thyroid disease, including both hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
(overactive thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
) and hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
(underactive thyroid).
Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%. Recent increases in the number of reported cases may be due to changes in diagnostic practice, but there is evidence that coeliac disease may be becoming more common in the United States.
Christian churches & the Eucharist
Speaking generally, the various denominations of Christians celebrate a EucharistEucharist
The Eucharist , also called Holy Communion, the Sacrament of the Altar, the Blessed Sacrament, the Lord's Supper, and other names, is a Christian sacrament or ordinance...
in which a wafer or small piece of wheat bread is blessed and then eaten (see Sacramental bread
Sacramental bread
Sacramental bread, sometimes called the lamb, altar bread, host or simply Communion bread, is the bread which is used in the Christian ritual of the Eucharist.-Eastern Catholic and Orthodox:...
). A typical wafer weighs about half a gram Wheat flour
Wheat flour
Wheat flour is a powder made from the grinding of wheat used for human consumption. More wheat flour is produced than any other flour. Wheat varieties are called "clean," "white," or "brown" if they have high gluten content, and they are called "soft" or "weak" flour if gluten content is low...
contains around 10 to 13% gluten, so a single communion wafer may have more than 50 mg of gluten, an amount which will harm the health of many coeliac patients especially if consumed every day (see Diet above).
Many Christian churches offer their communicants gluten-free alternatives, usually in the form of a rice-based cracker or gluten-free bread. These include United Methodist
United Methodist Church
The United Methodist Church is a Methodist Christian denomination which is both mainline Protestant and evangelical. Founded in 1968 by the union of The Methodist Church and the Evangelical United Brethren Church, the UMC traces its roots back to the revival movement of John and Charles Wesley...
, Christian Reformed
Christian Reformed Church in North America
The Christian Reformed Church in North America is a Protestant Christian denomination in the United States and Canada. Having roots in the Dutch Reformed churches of the Netherlands, the Christian Reformed Church was founded by Gijsbert Haan and Dutch immigrants who left the Reformed Church in...
, Episcopal
Episcopal Church (United States)
The Episcopal Church is a mainline Anglican Christian church found mainly in the United States , but also in Honduras, Taiwan, Colombia, Ecuador, Haiti, the Dominican Republic, Venezuela, the British Virgin Islands and parts of Europe...
, Lutheran
Lutheranism
Lutheranism is a major branch of Western Christianity that identifies with the theology of Martin Luther, a German reformer. Luther's efforts to reform the theology and practice of the church launched the Protestant Reformation...
, and The Church of Jesus Christ of Latter-day Saints.
Roman Catholic position
Roman Catholic doctrineDoctrine
Doctrine is a codification of beliefs or a body of teachings or instructions, taught principles or positions, as the body of teachings in a branch of knowledge or belief system...
states that for a valid Eucharist
Eucharist
The Eucharist , also called Holy Communion, the Sacrament of the Altar, the Blessed Sacrament, the Lord's Supper, and other names, is a Christian sacrament or ordinance...
, the bread to be used at Mass must be made from wheat. In 2002, the Congregation for the Doctrine of the Faith
Congregation for the Doctrine of the Faith
The Congregation for the Doctrine of the Faith , previously known as the Supreme Sacred Congregation of the Roman and Universal Inquisition , and after 1904 called the Supreme...
approved German-made low-gluten hosts, which meets 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 the Eucharist
Eucharist
The Eucharist , also called Holy Communion, the Sacrament of the Altar, the Blessed Sacrament, the Lord's Supper, and other names, is a Christian sacrament or ordinance...
under either form (bread or wine) is receiving Christ "whole and entire"—his body, blood, soul, and divinity—the priest, who is acting in persona Christi
In persona Christi
In persona Christi is a Latin phrase meaning “in the person of Christ,” an important concept in Roman Catholicism and, in varying degrees, to other Christian traditions...
, 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 24 July 2003, the Congregation for the Doctrine of the Faith
Congregation for the Doctrine of the Faith
The Congregation for the Doctrine of the Faith , previously known as the Supreme Sacred Congregation of the Roman and Universal Inquisition , and after 1904 called the Supreme...
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."
As of January 2004, an extremely low-gluten host became available in the United States. The Benedictine Sisters of Perpetual Adoration
Benedictine Sisters of Perpetual Adoration
The Benedictine Sisters of Perpetual Adoration are a congregation of nuns within the Benedictine Confederation. The original monastery was founded in 1874 by a group of five nuns, led by Sister Mary Anselma Felber, O.S.B., who came from the young monastery of Maria-Rickenbach in Switzerland...
in Clyde, Missouri, produce low-gluten hosts safe for coeliacs and also approved by the Catholic Church for use at Mass. The hosts are made and packaged in a dedicated wheat-free, gluten-free environment. Gluten-content analysis found no detectable amount of gluten, though the reported gluten content is 0.01% as that was the lowest limit of detection possible with the utilised analysis technique. In an article from the Catholic Review (15 February 2004), Dr. Alessio Fasano was quoted as declaring these hosts "perfectly safe for celiac sufferers."
Passover
The Jewish festival of PesachPassover
Passover is a Jewish holiday and festival. It commemorates the story of the Exodus, in which the ancient Israelites were freed from slavery in Egypt...
(Passover) may present problems with its obligation to eat matzo
Matzo
Matzo or matzah is an unleavened bread traditionally eaten by Jews during the week-long Passover holiday, when eating chametz—bread and other food which is made with leavened grain—is forbidden according to Jewish law. Currently, the most ubiquitous type of Matzo is the traditional Ashkenazic...
, which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. This rules out many other grains that are normally used as substitutes for people with gluten sensitivity, especially for Ashkenazi Jews
Ashkenazi Jews
Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim , are the Jews descended from the medieval Jewish communities along the Rhine in Germany from Alsace in the south to the Rhineland in the north. Ashkenaz is the medieval Hebrew name for this region and thus for Germany...
, who also avoid rice
Rice
Rice is the seed of the monocot plants Oryza sativa or Oryza glaberrima . As a cereal grain, it is the most important staple food for a large part of the world's human population, especially in East Asia, Southeast Asia, South Asia, the Middle East, and the West Indies...
. Many kosher-for-Passover products avoid grains altogether and are therefore gluten-free. Potato starch
Potato starch
Potato starch is starch extracted from potatoes. The cells of the root tubers of the potato plant contain starch grains . To extract the starch, the potatoes are crushed; the starch grains are released from the destroyed cells...
is the primary starch used to replace the grains. Consuming matzo
Matzo
Matzo or matzah is an unleavened bread traditionally eaten by Jews during the week-long Passover holiday, when eating chametz—bread and other food which is made with leavened grain—is forbidden according to Jewish law. Currently, the most ubiquitous type of Matzo is the traditional Ashkenazic...
is mandatory on the first night of Pesach only. Jewish law holds that a person should not seriously endanger one's health in order to fulfil a commandment. Thus, a person with severe coeliac disease is not allowed, let alone required, to eat any matzo other than gluten-free matzo. The most commonly used gluten-free matzo is made from oats.
History
Humans first started to cultivate grains in the NeolithicNeolithic
The Neolithic Age, Era, or Period, or New Stone Age, was a period in the development of human technology, beginning about 9500 BC in some parts of the Middle East, and later in other parts of the world. It is traditionally considered as the last part of the Stone Age...
period (beginning about 9500 BCE) in the Fertile Crescent
Fertile Crescent
The Fertile Crescent, nicknamed "The Cradle of Civilization" for the fact the first civilizations started there, is a crescent-shaped region containing the comparatively moist and fertile land of otherwise arid and semi-arid Western Asia. The term was first used by University of Chicago...
in Western Asia, and it is likely that coeliac disease did not occur before this time. Aretaeus of Cappadocia
Aretaeus of Cappadocia
Aretaeus , is one of the most celebrated of the ancient Greek physicians, of whose life, however, few particulars are known. There is some uncertainty regarding both his age and country, but it seems probable that he practised in the 1st century CE, during the reign of Nero or Vespasian...
, living in the second century in the same area, recorded a malabsorptive syndrome with chronic diarrhoea. His "Cœliac Affection" (coeliac from Greek κοιλιακός koiliakos, "abdominal") gained the attention of Western medicine when Francis Adams
Francis Adams (translator)
Francis Adams was a Scottish medical doctor and translator of Greek medical works.Adams had a practice in Banchory, Aberdeenshire, from 1819 to 1861...
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
Pediatrics
Pediatrics or paediatrics is the branch of medicine that deals with the medical care of infants, children, and adolescents. A medical practitioner who specializes in this area is known as a pediatrician or paediatrician...
Samuel Gee
Samuel Gee
Samuel Jones Gee was an English physician and paediatrician. In 1888, Gee published the first complete modern description of the clinical picture of coeliac disease, and theorised on the importance of diet in its control. His contribution led to the eponym Gee's disease...
gave the first modern-day description of the condition in children in a lecture at Hospital for Sick Children, Great Ormond Street
Great Ormond Street Hospital
Great Ormond Street Hospital for Children is a children's hospital located in London, United Kingdom...
, 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 mussel
Mussel
The common name mussel is used for members of several families of clams or bivalvia mollusca, from saltwater and freshwater habitats. These groups have in common a shell whose outline is elongated and asymmetrical compared with other edible clams, which are often more or less rounded or oval.The...
s daily." However, the child could not bear this diet for more than one season.
Christian Archibald Herter
Christian Archibald Herter (physician)
-Further reading:...
, 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
Eponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
Gee-Herter disease was sometimes used to acknowledge both contributions. Sidney V. Haas, an American paediatrician, reported positive effects of a diet of banana
Banana
Banana is the common name for herbaceous plants of the genus Musa and for the fruit they produce. Bananas come in a variety of sizes and colors when ripe, including yellow, purple, and red....
s 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 Karel Dicke. It is likely that clinical improvement of his patients during the Dutch famine of 1944
Dutch famine of 1944
The Dutch famine of 1944, known as the Hongerwinter in Dutch, was a famine that took place in the German-occupied part of the Netherlands, especially in the densely populated western provinces above the great rivers, during the winter of 1944-1945, near the end of World War II. A German blockade...
(during which flour was scarce) may have contributed to his discovery. Dicke noticed that the shortage of bread led to a significant drop in the death rate among children affected by CD 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. The link with the gluten component of wheat was made in 1952 by a team from Birmingham
Birmingham
Birmingham is a city and metropolitan borough in the West Midlands of England. It is the most populous British city outside the capital London, with a population of 1,036,900 , and lies at the heart of the West Midlands conurbation, the second most populous urban area in the United Kingdom with a...
, England. Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery. This paved the way for biopsy samples taken by endoscopy.
Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965. In 1966, dermatitis herpetiformis
Dermatitis herpetiformis
Dermatitis herpetiformis , or Duhring's disease,Freedberg, et al. . Fitzpatrick's Dermatology in General Medicine. . McGraw-Hill. ISBN 0-07-138076-0. is a chronic blistering skin condition, characterised by blisters filled with a watery fluid...
was linked to gluten sensitivity.
May has been designated as "Coeliac Awareness Month".
External links
- Celiac Disease Awareness Campaign from the National Institutes of Health
- Celiac Disease practice guideline from the World Gastroenterology Organisation (WGO)
- Outcomes of 2004 consensus development conference, U.S. National Institutes of HealthNational Institutes of HealthThe National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...