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Coeliac disease
Other names	Celiac sprue, nontropical sprue, endemic sprue, gluten enteropathy
Biopsy of small bowel showing coeliac disease manifested by blunting of villi, crypt hypertrophy, and lymphocyte infiltration of crypts
Pronunciation
Specialty	Gastroenterology, internal medicine
Symptoms	None or non-specific, abdominal distention, diarrhoea, constipation, malabsorption, weight loss, dermatitis herpetiformis[1][2]
Complications	Iron-deficiency anemia, osteoporosis, infertility, cancers, neurological problems, other autoimmune diseases[3][4][5][6][7]
Usual onset	Any age[1][8]
Duration	Lifelong[6]
Causes	Reaction to gluten[9]
Risk factors	Genetic predisposition, type 1 diabetes, autoimmunethyroid disease, Down and Turner syndromes,
Diagnostic method	Family history, blood antibody tests, intestinal biopsies, genetic testing, response to gluten withdrawal[10][11]
Differential diagnosis	Inflammatory bowel disease, intestinal parasites, irritable bowel syndrome, cystic fibrosis[12]
Treatment	Gluten-free diet[13]
Frequency	~1 in [14]

Coeliac disease or celiac disease is a long-term immune disorder that primarily affects the small intestine.^[10] Classic symptoms include gastrointestinal problems such as chronic diarrhoea, abdominal distention, malabsorption, loss of appetite, and among children failure to grow normally.^[1] This often begins between six months and two years of age.^[1] Non-classic symptoms are more common, especially in people older than two years.^[8][15][16] There may be mild or absent gastrointestinal symptoms, a wide number of symptoms involving any part of the body or no obvious symptoms.^[1] Coeliac disease was first described in childhood;^[6][8] however, it may develop at any age.^[1][8] It is associated with other autoimmune diseases, such as Type 1 diabetes mellitus and Hashimoto's thyroiditis, among others.^[6]

Coeliac disease is caused by a reaction to gluten, a group of various proteins found in wheat and in other grains such as barley and rye.^[9][17][18] Moderate quantities of oats, free of contamination with other gluten-containing grains, are usually tolerated.^[17][19] The occurrence of problems may depend on the variety of oat.^[17][20] It occurs in people who are genetically predisposed.^[10] Upon exposure to gluten, an abnormal immune response may lead to the production of several different autoantibodies that can affect a number of different organs.^[4][21] In the small bowel, this causes an inflammatory reaction and may produce shortening of the villi lining the small intestine (villous atrophy).^[10][11] This affects the absorption of nutrients, frequently leading to anaemia.^[10][18]

Diagnosis is typically made by a combination of blood antibody tests and intestinal biopsies, helped by specific genetic testing.^[10] Making the diagnosis is not always straightforward.^[22] Frequently, the autoantibodies in the blood are negative,^[23][24] and many people have only minor intestinal changes with normal villi.^[25] People may have severe symptoms and they may be investigated for years before a diagnosis is achieved.^[26][27] Increasingly, the diagnosis is being made in people without symptoms, as a result of screening.^[28] Evidence regarding the effects of screening, however, is not sufficient to determine its usefulness.^[29] While the disease is caused by a permanent intolerance to gluten proteins,^[10] it is distinct from wheat allergy, which is much more rare.^[30]

The only known effective treatment is a strict lifelong gluten-free diet, which leads to recovery of the intestinal mucosa, improves symptoms and reduces the risk of developing complications in most people.^[13] If untreated, it may result in cancers such as intestinal lymphoma and a slightly increased risk of early death.^[3] Rates vary between different regions of the world, from as few as 1 in to as many as 1 in 40, with an average of between 1 in and 1 in people.^[14] It is estimated that 80% of cases remain undiagnosed, usually because of minimal or absent gastrointestinal complaints and lack of knowledge of symptoms and diagnostic criteria.^[5][26][31] Coeliac disease is slightly more common in women than in men.^[32]

Signs and symptoms[edit]

The classic symptoms of untreated coeliac disease include pale, loose, or greasy stools (steatorrhoea), and weight loss or failure to gain weight. Other common symptoms may be subtle or primarily occur in organs other than the bowel itself.^[33] It is also possible to have coeliac disease without any of the classic symptoms at all.^[18] This has been shown to comprise at least 43% of presentations in children.^[34] Further, many adults with subtle disease may only present with fatigue or anaemia.^[28] Many undiagnosed individuals who consider themselves asymptomatic are in fact not, but rather have become accustomed to living in a state of chronically compromised health. Indeed, after starting a gluten-free diet and subsequent improvement becomes evident, such individuals are often able to retrospectively recall and recognise prior symptoms of their untreated disease which they had mistakenly ignored.^[5][27][31]

Gastrointestinal[edit]

Diarrhoea that is characteristic of coeliac disease is chronic, sometimes pale, of large volume, and abnormally bad smelling. Abdominal pain, cramping, bloating with abdominal distension (thought to be due to fermentative production of bowel gas), and mouth ulcers^[35] may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop.^[18] Frequently, the symptoms are ascribed to irritable bowel syndrome (IBS), only later to be recognised as coeliac disease. In populations of people with symptoms of IBS, a diagnosis of coeliac disease can be made in about % of cases, or 4x more likely than in general.^[36] Screening them for coeliac disease is recommended by the National Institute for Health and Clinical Excellence (NICE), the British Society of Gastroenterology and the American College of Gastroenterology, but is of unclear benefit in North America.^[36][37]

Coeliac disease leads to an increased risk of both adenocarcinoma and lymphoma of the small bowel (enteropathy-associated T-cell lymphoma (EATL) or other non-Hodgkin lymphomas).^[38] This risk is also higher in first-degree relatives such as siblings, parents and children. Whether or not a gluten-free diet brings this risk back to baseline is not clear.^[39] Long-standing 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).^[40]

Malabsorption-related[edit]

The changes in the bowel make it less able to absorb nutrients, minerals, and the fat-soluble vitamins A, D, E, and K.^[18][41]

Miscellaneous[edit]

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.

Coeliac disease is associated with several other medical conditions, many of which are autoimmune disorders: diabetes mellitus type 1, hypothyroidism, primary biliary cholangitis, microscopic colitis, gluten ataxia, psoriasis, vitiligo, autoimmune hepatitis, dermatitis herpetiformis, primary sclerosing cholangitis, and more.^[4]

Cause[edit]

Coeliac disease is caused by a reaction to gliadins and glutenins (gluten proteins)^[48] found in wheat, and similar proteins found in the crops of the tribeTriticeae (which includes other common grains such as barley and rye)^[18] and the tribe Aveneae (oats).^[49] Wheat subspecies (such as spelt, durum and Kamut) and wheat hybrids (such as triticale) also induce symptoms of coeliac disease.^[49][50]

A small number of people with coeliac react to oats.^[18] Oats toxicity in coeliac people depends on the oat cultivar consumed because of prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins, which are different among oat varieties.^[20][51] Also, oats are frequently cross-contaminated with other grains containing gluten.^[20][51][52] "Pure oat" refers to oats uncontaminated with other gluten-containing cereals.^[20] The long-term effects of pure oats consumption are still unclear^[53] and further studies identifying the cultivars used are needed before making final recommendations on their inclusion in the gluten-free diet.^[52] Coeliac people who choose to consume oats need a more rigorous lifelong follow-up, possibly including periodic performance of intestinal biopsies.^[53]

Other grains[edit]

Other cereals such as corn, millet, sorghum, teff, rice, and wild rice are safe for people with coeliac to consume, as well as noncereals such as amaranth, quinoa, and buckwheat.^[50][54] Noncereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.^[50]

Risk modifiers[edit]

There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include surgery, pregnancy, infection and emotional stress.^[55]

The eating of gluten early in a baby's life does not appear to increase the risk of coeliac disease but later introduction after 6 months may increase it.^[56][57] There is uncertainty whether being breastfed reduces risk. Prolonging breastfeeding until the introduction of gluten-containing grains into the diet appears to be associated with a 50% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear.^[58] These factors may just influence the timing of onset.^[59]

Pathophysiology[edit]

Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person.

Almost all people (95%) with coeliac disease have either the variant HLA-DQ2allele or (less commonly) the HLA-DQ8allele.^[28][60] However, about 20–30% of people without coeliac disease have also inherited either of these alleles.^[61] This suggests additional factors are needed for coeliac disease to develop; that is, the predisposing HLA risk allele is necessary but not sufficient to develop coeliac disease. Furthermore, around 5% of those people who do develop coeliac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles (see below).^[28]

Genetics[edit]

DQ α⁵-β² -binding cleft with a deamidated gliadin peptide (yellow), modified from PDB: 1S9V&#;^[62]

The vast majority of people with coeliac have one of two types of the HLA-DQ protein.^[61] HLA-DQ 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 two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of chromosome 6.

There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of people with coeliac have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.^[28]

HLA region of chromosome 6

Most people with coeliac bear a two-gene HLA-DQ2 haplotype referred to as DQ haplotype. This haplotype is composed of two adjacent gene alleles, DQA1* and DQB1*, which encode the two subunits, DQ α⁵ and DQ β². In most individuals, this DQ isoform is encoded by one of two chromosomes 6 inherited from parents (DQcis). Most coeliacs inherit only one copy of this DQ 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.^[63]

Some individuals inherit DQ from one parent and an additional portion of the haplotype (either DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent (DQtrans) (called a trans-haplotype association), and these individuals are at similar risk for coeliac disease as those with a single DQbearing chromosome 6, but in this instance disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ (cis or trans) or DQ8 (encoded by the haplotype DQA1*DQB1*), 4% have the DQ isoform, and the remaining 2% lack DQ2 or DQ8.^[64]

The frequency of these genes varies geographically. DQ has high frequency in peoples of North and Western Europe (Basque Country and Ireland^[65] with highest frequencies) and portions of Africa and is associated with disease in India,^[66] but it is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ 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.^[67]

Other genetic factors have been repeatedly reported in coeliac disease; however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population.^[68] 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 = rs) 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.^[68]

The prevalence of coeliac disease 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 practised the longest (compare with a similar condition, Lactose intolerance, which has been negatively selected so strongly that its prevalence went from ~% in ancestral populations to less than 5% in some European countries). This expectation was first proposed by Simoons ().^[69] By now, however, it is apparent that this is not the case; on the contrary, there is evidence of positive selection in coeliac disease genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections.^[70][71]

Prolamins[edit]

The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine (-amin) that dissolve in alcohols and are resistant to proteases and peptidases of the gut.^[28][72] Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley (hordein), rye (secalin) and oats (avenin).^[49] One region of α-gliadin stimulates membrane cells, enterocytes, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than three amino acids to enter the intestinal lining.^[73]

Illustration of deamidated α-2 gliadin's 33mer, amino acids 56–88, showing the overlapping of three varieties of T-cell epitope^[74]

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 This innate response to gliadin results in immune-system signalling that attracts inflammatory cells and increases the release of inflammatory chemicals.^[28] The strongest and most common adaptive response to gliadin is directed toward an α2-gliadin fragment of 33&#;amino acids in length.^[28]

The response to the 33mer occurs in most coeliacs who have a DQ2isoform. 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.^[74] Gliadin in wheat is the best-understood member of this family, but other prolamins exist, and hordein (from barley), secalin (from rye), and avenin (from oats) may contribute to coeliac disease.^[28][49][75] Avenins toxicity in people with coeliac disease depends on the oat cultivar consumed because of prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins, which vary among oat varieties.^[20]

Tissue transglutaminase[edit]

Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in the blood of the majority of people with classic symptoms and complete villous atrophy, but only in 70% of the cases with partial villous atrophy and 30% of the cases with minor mucosal lesions.^[23] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.^[28] These peptides are modified by tTG in two ways, deamidation or transamidation.^[76]

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 that 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.^[77] This results in the formation of new epitopes believed to trigger the primary immune response by which the autoantibodies against tTg develop.^[78][79][80]

Stored biopsies from people with suspected coeliac disease have revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in people who present with other autoimmune diseases, anaemia, or malabsorption phenomena at a much increased rate over the normal population.^[81] 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 study showed that EMA-negative people with coeliac tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms, including autoimmune disease.^[82] 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,^[83] suggest 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 people with coeliac, 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.^[84]

Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy.^[85] 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.

Other intestinal disorders may have biopsy that look like coeliac disease including lesions caused by Candida.^[86]

Villous atrophy and malabsorption[edit]

The inflammatory process, mediated by T cells, 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 nutrients, minerals, and fat-soluble vitamins A, D, E, and K from food. Lactose intolerance may be present due to the decreased bowel surface and reduced production of lactase but typically resolves once the condition is treated.

Alternative causes of this tissue damage have been proposed and involve release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of enterocytes by lymphocytes in the epithelium.^[28] 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.^[40]

Diagnosis[edit]

Diagnosis is often difficult and as of , there continues to be a lack of awareness among physicians about the variability of presentations of coeliac disease and the diagnostic criteria, such that most cases are diagnosed with great delay.^[26][22] It can take up to 12 years to receive a diagnosis from the onset of symptoms and the majority of those affected in most countries never receive it.^[26]

There are several tests that can be used. The level of symptoms may determine the order of the tests, but all tests lose their usefulness if the person is already eating a gluten-free diet. Intestinal damage begins to heal within weeks of gluten being removed from the diet, and antibody levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a rechallenge with some gluten-containing food in one meal a day over 6 weeks before repeating the investigations.^[21]

Blood tests[edit]

Immunofluorescence staining pattern of endomysial antibodies on a monkey oesophagus tissue sample.

Serological blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Its sensitivity correlates with the degree of histological lesions. People who present minor damage of the small intestine may have seronegative findings so many patients with coeliac disease often are missed. In patients with villous atrophy, anti-endomysial (EMA) antibodies of the immunoglobulin A (IgA) type can detect coeliac disease with a sensitivity and specificity of 90% and 99%, respectively.^[87]Serology for anti-transglutaminase antibodies (anti-tTG) was initially reported to have a higher sensitivity (99%) and specificity (>90%). However, it is now thought to have similar characteristics to anti-endomysial antibody.^[87] Both anti-transglutaminase and anti-endomysial antibodies have high sensitivity to diagnose people with classic symptoms and complete villous atrophy, but they are only found in 30–89% of the cases with partial villous atrophy and in less than 50% of the people who have minor mucosal lesions (duodenal lymphocytosis) with normal villi.^[23][24]

Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.^[28] These peptides are modified by tTG in two ways, deamidation or transamidation.^[76] Modern anti-tTG assays rely on a human recombinant protein as an antigen.^[88] tTG testing should be done first as it is an easier test to perform. An equivocal result on tTG testing should be followed by anti-endomysial antibodies.^[21]

Guidelines recommend that a total serum IgA level is checked in parallel, as people with coeliac with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those people, IgG antibodies against transglutaminase (IgG-tTG) may be diagnostic.^[21][89]

If all these antibodies are negative, then anti-DGP antibodies (antibodies against deamidated gliadin peptides) should be determined. IgG class anti-DGP antibodies may be useful in people with IgA deficiency. In children younger than two years, anti-DGP antibodies perform better than anti-endomysial and anti-transglutaminase antibodies tests.^[8]

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.^[21][40][90]

Historically three other antibodies were measured: anti-reticulin (ARA), anti-gliadin (AGA) and anti-endomysial (EMA) antibodies.^[91] ARA testing, however, is not accurate enough for routine diagnostic use.^[92] Serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five.^[91] Serology tests are based on indirect immunofluorescence (reticulin, gliadin and endomysium) or ELISA (gliadin or tissue transglutaminase, tTG).^[93]

Other antibodies such as anti–Saccharomyces cerevisiae antibodies occur in some people with coeliac disease but also occur in other autoimmune disorders and about 5% of those who donate blood.^[94]

Antibody testing may be combined with HLA testing if the diagnosis is unclear. TGA and EMA testing are the most sensitive serum antibody tests, but as a negative HLA-DQ type excludes the diagnosis of coeliac disease, testing also for HLA-DQ2 or DQ8 maximises sensitivity and negative predictive values.^[61] However, widespread use of HLA typing to rule out coeliac disease is not currently recommended.^[21]

Endoscopy[edit]

Endoscopic still of duodenum of person with coeliac disease showing scalloping of folds and "cracked-mud" appearance to mucosa

Schematic of the Marsh classification of upper jejunal pathology in coeliac disease.

An upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum is performed to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative.^[40] Even in the same bioptic fragment, different degrees of damage may be present.^[16]

Most people with coeliac disease have a small intestine that appears to be normal on endoscopy before the biopsies are examined. However, five findings have been associated with a high specificity for coeliac disease: scalloping of the small bowel folds (pictured), paucity in the folds, a mosaic pattern to the mucosa (described as a "cracked-mud" appearance), prominence of the submucosablood vessels, and a nodular pattern to the mucosa.^[95]

European guidelines suggest that in children and adolescents with symptoms compatible with coeliac disease, the diagnosis can be made without the need for intestinal biopsy if anti-tTG antibodies titres are very high (10 times the upper limit of normal).^[8]

Until the s, 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.^[96]

Capsule endoscopy (CE) allows identification of typical mucosal changes observed in coeliac disease but has a lower sensitivity compared to regular endoscopy and histology. CE is therefore not the primary diagnostic tool for coeliac disease. However, CE can be used for diagnosing T-cell lymphoma, ulcerative jejunoileitis and adenocarcinoma in refractory or complicated coeliac disease.^[97]

Pathology[edit]

The classic pathology changes of coeliac disease in the small bowel are categorised by the "Marsh classification":^[98]

Marsh's classification, introduced in , was subsequently modified in 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:^[18][]

• A representing lymphocytic infiltration with normal villous appearance;
• B1 describing partial villous atrophy; and
• B2 describing 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.^[40][90] 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.^[40]

In untreated coeliac disease, villous atrophy is more common in children younger than three years, but in older children and adults, it is common to find minor intestinal lesions (duodenal lymphocytosis) with normal intestinal villi.^[11][25]

Other diagnostic tests[edit]

At the time of diagnosis, further investigations may be performed to identify complications, such as iron deficiency (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.^[41]

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.^[40][41]

Gluten withdrawal[edit]

Although blood antibody tests, biopsies, and genetic tests usually provide a clear diagnosis,^[24][87] occasionally the response to gluten withdrawal on a gluten-free diet is needed to support the diagnosis. Currently, gluten challenge is no longer required to confirm the diagnosis in patients with intestinal lesions compatible with coeliac disease and a positive response to a gluten-free diet.^[24] Nevertheless, in some cases, a gluten challenge with a subsequent biopsy may be useful to support the diagnosis, for example in people with a high suspicion for coeliac disease, without a biopsy confirmation, who have negative blood antibodies and are already on a gluten-free diet.^[24] Gluten challenge is discouraged before the age of 5 years and during pubertal growth.^[] The alternative diagnosis of non-coeliac gluten sensitivity may be made where there is only symptomatic evidence of gluten sensitivity.^[] Gastrointestinal and extraintestinal symptoms of people with non-coeliac gluten sensitivity can be similar to those of coeliac disease,^[16] and improve when gluten is removed from the diet,^[][] after coeliac disease and wheat allergy are reasonably excluded.^[]

Up to 30% of people often continue having or redeveloping symptoms after starting a gluten-free diet.^[13] A careful interpretation of the symptomatic response is needed, as a lack of response in a person with coeliac disease may be due to continued ingestion of small amounts of gluten, either voluntary or inadvertent,^[11] or be due to other commonly associated conditions such as small intestinal bacterial overgrowth (SIBO), lactose intolerance, fructose,^[]sucrose,^[] and sorbitol^[] malabsorption, exocrine pancreatic insufficiency,^[][] and microscopic colitis,^[] among others. In untreated coeliac disease, these are often transient conditions derived from the intestinal damage.^[][][][][] They normally revert or improve several months after starting a gluten-free diet, but may need temporary interventions such as supplementation with pancreatic enzymes,^[][] dietary restrictions of lactose, fructose, sucrose or sorbitol containing foods,^[][] or treatment with oral antibiotics in the case of associated bacterial overgrowth.^[] In addition to gluten withdrawal, some people need to follow a low-FODMAPs diet or avoid consumption of commercial gluten-free products, which are usually rich in preservatives and additives (such as sulfites, glutamates, nitrates and benzoates) and might have a role in triggering functional gastrointestinal symptoms.^[]

Screening[edit]

There is debate as to the benefits of screening. As of , the United States Preventive Services Task Force found insufficient evidence to make a recommendation among those without symptoms.^[29] In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommend testing for coeliac disease in first-degree relatives of those with the disease already confirmed, in people with persistent fatigue, abdominal or gastrointestinal symptoms, faltering growth, unexplained weight loss or iron, vitamin B12 or folate deficiency, severe mouth ulcers, and with diagnoses of type 1 diabetes, autoimmune thyroid disease,^[21] and with newly diagnosed chronic fatigue syndrome^[] and irritable bowel syndrome.^[37]Dermatitis herpetiformis is included in other recommendations.^[] The NICE also recommend offering serological testing for coeliac disease in people with metabolic bone disease (reduced bone mineral density or osteomalacia), unexplained neurological disorders (such as peripheral neuropathy and ataxia), fertility problems or recurrent miscarriage, persistently raised liver enzymes with unknown cause, dental enamel defects and with diagnose of Down syndrome or Turner syndrome