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Diagnosis of celiac disease in children

Diagnosis of celiac disease in children
Literature review current through: Jan 2024.
This topic last updated: Feb 13, 2023.

INTRODUCTION — Celiac disease, also known as gluten-sensitive enteropathy or celiac sprue, is a common immune-mediated inflammatory disease of the small intestine caused by an autoimmune response to dietary gluten and related proteins in genetically predisposed individuals. It differs from food allergies, which are mediated by immunoglobulin (Ig) E or non-IgE (T cell) mechanisms. For patients with a confirmed diagnosis of celiac disease, the cornerstone of treatment is a lifelong gluten-free diet [1-5].

The diagnosis of celiac disease in children is discussed here. Other aspects of celiac disease in children are discussed in the following topic reviews:

(See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)

(See "Management of celiac disease in children".)

INDICATIONS FOR TESTING — Testing for celiac disease is recommended for patients with suggestive symptoms and also for children in groups at increased risk for having the disease, regardless of symptoms (table 1), provided that they are on a gluten-containing diet [1,5-7]:

Patients with symptoms suggesting celiac disease — We suggest testing patients with any symptoms and signs suggestive of celiac disease. These may include classical gastrointestinal symptoms, nonspecific behavioral symptoms, and/or extraintestinal manifestations. Decisions about diagnostic testing should be based on symptoms, signs, and risk factors, without regard to the individual's country of origin, ancestry or race/ethnicity.

Gastrointestinal symptoms (see "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on '"Classical" gastrointestinal symptoms'):

Persistent diarrhea

Abdominal bloating/distension

Poor weight gain/weight loss

Abdominal pain

Constipation

Vomiting

Extraintestinal manifestations (table 2A-B) (see "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Non-gastrointestinal manifestations'):

Neurologic and behavioral symptoms such as headaches, difficulty concentrating, or irritability

Arthritis or arthralgias (even if there is a presumed underlying rheumatic disease)

Abnormal liver biochemical tests

Chronic fatigue

Short stature or low height velocity

Pubertal delay

Iron deficiency anemia often poorly responsive to supplementation

Dermatitis herpetiformis-like rash (picture 1A-B)

Dental enamel hypoplasia of permanent teeth (symmetric distribution)

Recurrent aphthous stomatitis

Osteopenia, or fracture not explained by the level of trauma

By contrast, screening is not recommended for asymptomatic patients who are not members of a high-risk group, according to the United States Preventive Services Task Force [8]. Although broad screening might permit recognition and correction of subclinical nutritional deficiency states, resolution of mild symptoms, and, potentially, decreased risk for other complications [9], it is also proposed that asymptomatic individuals may have difficulty adhering to dietary treatment.

Members of high-risk groups

Whom to screen – We suggest screening all members of the following high-risk groups (table 1), regardless of symptoms (see "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'High-risk groups'):

First-degree relatives of patients with celiac disease

Autoimmune thyroiditis

Type 1 diabetes

Autoimmune liver disease

Down syndrome

Selective IgA deficiency

Turner syndrome

Williams syndrome

Juvenile chronic arthritis

This suggestion to screen asymptomatic individuals in these high-risk groups is consistent with several pediatric guidelines [1,2,6] but differs from guidelines used for adults in the United States, in which the recommendation is equivocal [5,7]. This difference in recommendations reflects a debate about the utility of screening for celiac disease among truly asymptomatic individuals belonging to a high-risk group because the benefit of treating such individuals has not been proven. Guidelines from the United Kingdom encourage testing for the first three of these high-risk groups and suggest consideration of testing for the other groups on this list, as well as for individuals with a variety of nonspecific symptoms [10]. (See "Diagnosis of celiac disease in adults", section on 'Who should be tested'.)

Method of screening – If screening is undertaken for asymptomatic individuals in these high-risk groups, testing should first be performed at three years of age or older and on a gluten-containing diet for at least one year. If initial results are negative, screening tests should be repeated at intervals or at any time that symptoms develop. The optimal time interval for subsequent testing has not been studied, but, in our practice, we screen asymptomatic members of these groups approximately every three years during childhood or up to annually if other bloodwork is being obtained.

Uncertainties – The debate continues about the utility of screening asymptomatic individuals in these high-risk groups and in the general population, and recommendations may change as new information arises about the potential risks and benefits of screening. As an example, evidence is conflicting regarding the balance of benefits and burdens of mass screening for celiac disease among children with type 1 diabetes. In a study of children with type 1 diabetes mellitus, those with asymptomatic celiac disease were slightly thinner (as indicated by a lower body mass index Z-score), but height, bone mineral density, and glycemic control were similar compared with matched controls [11]. Similarly, in a randomized trial of individuals with type 1 diabetes and celiac disease, a gluten-free diet resulted in no differences in outcomes after one year [12].

Arguments against mass screening are that the burden of a gluten-free diet may negatively affect quality of life and may have few benefits for individuals with truly asymptomatic celiac disease. Moreover, there is a concern that mass screening programs may prompt self-diagnosis and self-treatment without medical oversight.

Arguments in favor of mass screening are that identifying apparently asymptomatic individuals may provide some benefits by improving subclinical signs and symptoms and preventing long-term complications [13]. Several studies suggest that having both celiac disease and type 1 diabetes is associated with a higher prevalence of microvascular complications and metabolic bone disease, suggesting that these two conditions may have additive complications [14-16]. (See "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus".)

The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines recommend screening for celiac disease in these high-risk groups [2]. However, until the balance of benefits and burdens of mass screening for this population are better understood, it is reasonable to make screening and treatment decisions on a case-by-case basis, based on a collaborative discussion of estimated risks, symptoms, and treatment burden.

INITIAL SEROLOGIC TESTING — The first step is to perform serologic testing. The serology results and level of clinical suspicion determine whether to move on to endoscopic biopsy (algorithm 1).

Pretesting diet — Testing should ideally be performed while on a gluten-containing diet because a gluten-free diet increases the risk of false-negative results. The pretesting diet should ideally include at least 3 g gluten per day (equivalent to approximately one slice of bread daily) for at least six weeks prior to testing.

If the child is already on a gluten-free diet prior to testing, it is reasonable to proceed with serologic testing. In this case, a positive result is valid and suggests celiac disease. However, if the results are negative, we suggest an attempt at a formal gluten rechallenge with at least 10 g gluten daily for 8 to 12 weeks before retesting (algorithm 2). The duration and amount of gluten required for diagnostic accuracy has not been fully established [17]. Serologies may become negative within weeks of beginning a gluten-free diet but may take up to two years or even longer in some cases [18]. A diagnostic approach for patients who are unwilling or unable to resume a gluten-containing diet before testing is outlined below. (See 'Patients already on a gluten-free diet' below.)

We do not recommend empiric initiation of a gluten-free diet, because the symptoms of celiac disease are nonspecific. Furthermore, a gluten-free diet is complex, expensive, and has far-reaching implications for the child's quality of life.

Tissue transglutaminase antibodies — For most patients, the most valuable test is for IgA antibodies against tissue transglutaminase (tTG-IgA) [5,19]. Total IgA should also be measured (if not previously tested) to exclude IgA deficiency.

Interpretation – Next steps depend on the degree of tTG-IgA elevation and level of symptoms:

Clearly elevated – If the results are ≥3 times the upper limit of normal (ULN), we proceed to endoscopy. If the results are strongly positive (≥10 times the ULN), we discuss the option of pursuing a serologic diagnosis, as outlined in European guidelines [20] and discussed below. (See 'Subsequent evaluation' below.)

Mildly elevated – If tTG-IgA antibodies are only mildly elevated (levels that are between 1 and 3 times the ULN), we proceed to endoscopy if the patient has clinically significant symptoms (eg, loose stools, frequent abdominal pain, and/or poor weight gain).

If the patient has few or no symptoms or if the family is reluctant to proceed to endoscopy, we offer additional serologic testing with anti-endomysial antibodies (EMA):

-If EMA is positive, the diagnosis of celiac disease is more likely and we suggest proceeding to endoscopy to confirm it. If the family is still reluctant to proceed to endoscopy, we advise continuing a gluten-containing diet and recheck tTG-IgA in six months. (See 'Subsequent evaluation' below.)

-If EMA is negative, it is reasonable to defer doing a biopsy if the patient is asymptomatic because the chance of finding the characteristic histologic changes of celiac disease is relatively low. In this case, we observe the patient on a gluten-containing diet and repeat serologies in six months, or sooner if symptoms occur [21]. However, if serologies remain positive after one to two years, we usually proceed to endoscopy because celiac disease is occasionally found in individuals with mild elevations of tTG-IgA and negative EMA.

Normal – If tTG-IgA antibodies are within the normal range, active celiac disease is unlikely. In this case, it is reasonable to observe the patient and repeat the test if symptoms develop or worsen. For patients who are members of a high-risk group (eg, children with type 1 diabetes or autoimmune thyroiditis), we repeat the test in approximately three years, or earlier if symptoms develop.

Test characteristics – tTG-IgA is highly sensitive, specific, and more cost-effective than other antibody tests (table 3). However, false-positive and false-negative results may still occur in populations with a low risk for celiac disease. The sensitivity and specificity of tTG-IgA antibodies for biopsy-proven celiac disease are generally above 96 percent, using second-generation enzyme-linked immunosorbent assays (ELISA) technology [2,22,23]. Sensitivities are reported to be lower in children younger than two years, although this is controversial [24-26] (see 'Children younger than two years' below). Rapid office-based test kits have somewhat lower sensitivity and specificity, so a laboratory-based assay is recommended in patients with positive results of the rapid test or those with negative results of the rapid test but strong clinical suspicion of celiac disease [27,28]. Limited evidence suggests that tTG-IgA antibodies may be falsely elevated during a febrile illness [29] or in patients with other autoimmune diseases and conditions [30].

Other tests — Other serologic tests that are sometimes used to support the diagnosis of celiac disease include:

EMA – EMA is typically used as a second-line test to clarify the diagnosis in patients with equivocal results of tTG-IgA, including asymptomatic members of a high-risk group. EMA is also included as one of the required criteria for a serologic diagnosis, according to European guidelines and described below [1,19,31]. (See 'Nonbiopsy diagnosis (option for selected patients)' below.)

EMA is an immunofluorescence test for IgA antibodies to endomysium, a structure of the smooth muscle connective tissue [32]. It is more specific than tTG-IgA but is more expensive and somewhat dependent on operator interpretation.

Deamidated gliadin peptide (DGP) – DGP also has good diagnostic accuracy and may be particularly useful for young children. It is a second-generation antigliadin antibody test [33-36]. (See 'Children younger than two years' below.)

Antireticulin antibodies – Tests of antireticulin antibodies have reasonably high specificity, but lower sensitivity, and are no longer used [37].

Antigliadin antibodies – Standard (first-generation) IgA or IgG antigliadin antibodies are considerably less reliable and are not recommended [5,38,39].

Human leukocyte antigen (HLA) testing – HLA testing has limited value in evaluating for celiac disease. Although virtually all individuals with celiac disease have either HLA-DQ2 or DQ8 haplotypes, this is also the case for approximately 40 percent of the general population [2,27,40,41]. Moreover, these HLA types are particularly common among members of groups at high risk for celiac disease (eg, first-degree relatives of patients with celiac disease or patients with autoimmune diseases). Thus, the presence of HLA-DQ2 or DQ8 is not informative, while the absence of these haplotypes essentially excludes celiac disease. HLA testing is no longer required for a nonbiopsy diagnosis [1]. (See 'Nonbiopsy diagnosis (option for selected patients)' below.)

Efforts are being made to define potential nonserologic biomarkers for celiac disease activity, which might be used as an index of the immune response to the gluten challenge [42].

Special populations — Variations in the diagnostic approach outlined above are appropriate for the following populations:

Children younger than two years — For children younger than two years, tTG-IgA is the best initial test for IgA-sufficient children, as it is for older individuals, with >97 percent sensitivity for detecting celiac disease [43,44]. Total IgA should be measured concurrently to exclude IgA deficiency. If the tTG-IgA is negative and there is a high clinical suspicion for celiac disease (or if the patient is IgA deficient), we suggest sequential testing with DGP-IgG to detect the few patients with positive DGP-IgG but normal tTG-IgA [1]. Although early studies raised the possibility that DGP-IgG may be more sensitive than tTG-IgA in this age group [45,46], subsequent studies indicate that tTG-IgA is at least as sensitive as DGP-IgG (except for patients with IgA deficiency) [5,26,43,44]. No serologic test is 100 percent sensitive, and, if there is strong clinical suspicion for celiac disease, biopsy should still be pursued even in the absence of positive serologies.

Immunoglobulin A deficiency — Approximately 2 percent of children with celiac disease will have previously unrecognized IgA deficiency. Conversely, approximately 8 percent of individuals with selective IgA deficiency have celiac disease (see "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis"). Because of this association, we measure total IgA as part of the initial testing for celiac disease (if not already done).

If total IgA is below the normal range (indicating IgA deficiency), the tTG-IgA test is invalid [5]. Instead, testing should be performed with IgG antibodies to tTG (tTG-IgG). Because tTG-IgG has limited specificity, we suggest concurrent measurement of DGP-IgG [1]. If one or both of these IgG-based tests is elevated, the patient should be further evaluated with an intestinal biopsy; a nonbiopsy diagnosis is not appropriate for this group of patients. (See 'Subsequent evaluation' below.)

Patients already on a gluten-free diet — For patients who are already on a gluten-free diet, our first-line approach is to reintroduce moderate amounts of wheat into the diet before performing serologic testing, as described above (algorithm 2) [20,47]. (See 'Pretesting diet' above.)

For those who are unwilling to reintroduce gluten, we suggest serologic testing for tTG-IgA, with or without EMA. If these antibodies are elevated, an intestinal biopsy should be obtained to confirm the diagnosis of celiac disease. If these antibodies are not elevated, celiac disease is not excluded. In this case, we suggest HLA-DQ2/DQ8 testing to determine whether the patient is genetically susceptible to celiac disease [5,19].

If the patient tests negative for HLA-DQ2/DQ8, celiac disease is essentially excluded. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Genetic factors'.)

If the patient tests positive for HLA-DQ2/DQ8, a gluten challenge is needed to make a definitive diagnosis of celiac disease. In this case, we reintroduce gluten into the diet (10 g gluten per day), then retest for tTG-IgA after 8 to 12 weeks, or sooner if symptoms occur [20,47].

For children younger than five years who have negative antibody testing, we generally avoid a gluten challenge because they may not be able to verbalize symptoms. For these patients, we generally advise continuing the gluten-free diet until the child is at least five years of age, then proceeding to a gluten challenge if the family is willing to do so.

Dermatitis herpetiformis — Patients with dermatitis herpetiformis established by skin biopsy are presumed to have celiac disease and can be treated with a gluten-free diet without other diagnostic studies. However, a baseline measurement of tTG-IgA is valuable to monitor improvement after institution of a gluten-free diet. Dermatitis herpetiformis likely occurs more commonly than clinically recognized, with one study finding one case of dermatitis herpetiformis for every eight celiac disease patients [48]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Non-gastrointestinal manifestations' and "Dermatitis herpetiformis".)

SUBSEQUENT EVALUATION

Intestinal biopsy (most patients)

Indications – Individuals with positive IgA antibodies against tissue transglutaminase (tTG-IgA) or anti-endomysial antibodies (EMA) should undergo an intestinal biopsy to establish the diagnosis of celiac disease [5]. A possible exception is selected patients with very high tTG-IgA results and classic symptoms of celiac disease. (See 'Nonbiopsy diagnosis (option for selected patients)' below.)

Technique – The biopsy should be performed with the patient on a gluten-containing diet. Multiple biopsies should be taken (four from the distal duodenum and at least one from the duodenal bulb) because the disease may have a patchy distribution or initially be confined to the duodenal bulb [5,49-53]. Endoscopy and biopsy are also appropriate for patients with negative serologic testing if there is a strong clinical suspicion of celiac disease [5]. Capsule endoscopy should not be used as a substitute for endoscopy, because it is much less sensitive for detecting celiac disease.

Interpretation – The intestinal histopathology should be interpreted by an expert pathologist. The histologic features of celiac disease are usually described using the Marsh classification (table 4 and figure 1); they range from a mild alteration characterized only by increased intraepithelial lymphocytes (Marsh type 1 lesion) to a flat mucosa with total villous atrophy, intraepithelial lymphocytosis, enhanced epithelial apoptosis, and crypt hyperplasia (Marsh type 3 lesion) (picture 2) [54-59]. The Marsh type 4 lesion has the same histologic features seen in the type 3 lesion, except that the crypts are hypoplastic. A gradient of decreasing severity from the proximal to the distal small intestine is often observed, correlating with the higher proximal concentration of dietary gluten. The degree of the villous atrophy does not necessarily correlate with the severity of clinical symptoms, and sampling errors can occur due to some inhomogeneity of mucosal inflammation.

Abnormal findings – Patients with histologic findings consistent with celiac disease (Marsh type 2 or higher) are diagnosed with celiac disease and should be prescribed a gluten-free diet. Rarely, other disorders can cause similar histologic findings (table 5). For patients with equivocal findings (eg, Marsh type 1 lesions), management decisions depend on the level of suspicion for celiac disease, including type and severity of symptoms and results of celiac-specific antibody tests.

Normal findings – Patients with positive tests for tTG-IgA or EMA but normal small bowel histopathology are considered to have potential celiac disease (table 6) [60]. It is important that the evaluation of such patients include expert review of multiple intestinal biopsies since the histologic abnormalities can be patchy. In some cases in which the diagnosis of celiac disease is unclear, testing for human leukocyte antigen (HLA)-DQ2/DQ8 may be helpful because, if the result is negative, this essentially excludes the possibility of celiac disease [5].

In general, we suggest not treating patients with potential celiac disease with a gluten-free diet if they are asymptomatic. However, these patients should be carefully monitored for growth failure and other symptoms that might suggest active celiac disease and should be rebiopsied if symptoms develop or if antibody levels remain positive after several years on a gluten-containing diet. Decisions about whether to begin a gluten-free diet for patients with positive serologic tests but normal biopsy results should be made on a case-by-case basis with the family, after consideration of the patient's level of symptoms, appropriate exclusion of other causes of the symptoms, the burden of maintaining a gluten-free diet, and the adequacy of the biopsied tissue samples.

The natural history of potential celiac disease was described in a long-term study from Italy that found that 43 percent of children with positive tTG and EMA antibodies but normal histopathology progressed to villous atrophy and subsequent diagnosis of celiac disease over 12 years [61]. These observations suggest that a substantial number of children with seropositivity (tTG and EMA) and normal histopathology can progress to celiac disease over time, while others have transient seropositivity.

Nonbiopsy diagnosis (option for selected patients) — For selected patients who meet serologic criteria, we offer the option of forgoing the endoscopy, after a full discussion with the patient and family including the considerations outlined below. This approach is based on guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) [1,62,63].

Criteria for nonbiopsy diagnosis – Diagnosis without an intestinal biopsy is an option for patients with the following characteristics:

tTG-IgA >10 times the upper limit of normal (ULN), and

Positive EMA-IgA (must be from a separate blood draw)

Evidence – Support for a nonbiopsy diagnosis in selected patients comes from three large case series that reported that more than 98 percent of symptomatic patients with very high tTG-IgA and positive EMA had intestinal biopsy results consistent with celiac disease [21,64,65]. In one of these studies, the combination of very high tTG-IgA and positive EMA had a sensitivity, specificity, and positive predictive value of 69.3, 96.8, and 99.6 percent, respectively [64]. If malabsorption symptoms (diarrhea, weight loss, poor weight gain, or iron deficiency anemia) were included, the specificity and positive predictive value rose to 100 percent. The need to include the second antibody test in this diagnostic approach has been questioned since adding EMA testing does not improve the positive predictive value [66]. HLA typing has also been suggested to add strength to the diagnosis (because celiac disease would be effectively excluded in any patient that does not have HLA types DQ2 or DQ8) but is no longer required, because the additional diagnostic value of HLA typing in this setting appears to be small [1,64]. Symptoms are also no longer required according to ESPGHAN criteria [1].

Additional considerations

Advantages of a biopsy-based diagnosis – It is important to recognize the potential value of including intestinal biopsy as part of the diagnostic process for all patients, including those with very high tTG antibodies. Histologic confirmation provides for maximal diagnostic certainty, which is important because of the lifelong burden of a gluten-free diet. In particular, the endoscopy permits evaluation for concurrent mucosal inflammation other than celiac disease, including eosinophilic esophagitis, Helicobacter pylori, and Crohn disease of the proximal small intestine [67-69]. Moreover, despite the high sensitivity estimates reported above, occasional false-positive results occur [21,64,65]. Finally, there are concerns about the quantitative variability and lack of standardization between commercially available serologic tests for celiac disease. These considerations should be discussed with the patient and family before deciding whether to proceed with intestinal biopsy to confirm the diagnosis before embarking on a gluten-free diet.

Not valid in IgA deficiency – Patients with IgA deficiency should always have a biopsy-based diagnosis, even if their tTG-IgG antibody test is very high, because IgG-based antibody tests have not been sufficiently validated as biomarkers of disease [70]. Moreover, tTG-IgG is not a reliable marker of response to a gluten-free diet.

Uncertain validity outside of Europe – These criteria for a nonbiopsy diagnosis are based on studies of European children and with specific tTG-IgA assays. These criteria have not been formally approved by the North American Society, in part because they have not been validated for the tTG-IgA assays that are commonly used in North America. However, a Canadian study suggests that this will also apply in North America, while accepting a slight degree of uncertainty [21]. These regional recommendations may also reflect different values and preferences regarding the tolerance for uncertainty versus the patient burden and cost of endoscopy [71].

DIAGNOSIS

Biopsy-based diagnosis – A diagnosis of celiac disease is made if the results of celiac-specific antibody testing and the intestinal biopsy are both abnormal. The diagnosis is reinforced when symptoms resolve subsequently on a gluten-free diet (algorithm 1). Serologic tests that revert from positive to negative on a gluten-free diet may be used as supportive evidence of the diagnosis and are particularly valuable in individuals with minimal symptoms [72]. Patients who do not demonstrate a robust serologic response to a gluten-free diet, or whose initial endoscopic biopsies are not typical for celiac disease based on the Marsh criteria, may require a second endoscopy with biopsy while on a gluten-free diet to clarify the diagnosis.

Nonbiopsy diagnosis – European society guidelines offer the option of an alternate approach to diagnosis for selected patients with very high results of serologic tests (IgA antibodies against tissue transglutaminase [tTG-IgA] >10 times the upper limit of normal [ULN]) and a positive anti-endomysial antibody (EMA) obtained on a separate serum sample [1]. The diagnosis is reinforced if the serologic tests revert to normal and symptoms resolve on a gluten-free diet. Considerations relevant to the diagnostic approach for this group of patients are discussed above. (See 'Nonbiopsy diagnosis (option for selected patients)' above.)

Treatment of individuals with confirmed celiac disease consists of a lifelong gluten-free diet, which improves gastrointestinal symptoms as well as most of the non-gastrointestinal symptoms of celiac disease and may reduce the risk of long-term adverse health consequences. Patients with dermatitis herpetiformis confirmed by skin biopsy also should be treated with a gluten-free diet. Details of the gluten-free diet and monitoring are discussed separately. (See "Management of celiac disease in children".)

Note that symptom response to a gluten-free diet alone is not sufficient to diagnose celiac disease, because these features do not distinguish between celiac disease and "nonceliac gluten sensitivity," which is defined as dose-dependent intolerance to gluten-containing grains after exclusion of celiac disease or wheat allergy [2,17]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Nonceliac gluten sensitivity'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Celiac disease" and "Society guideline links: Dermatitis herpetiformis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Celiac disease (The Basics)")

Beyond the Basics topic (see "Patient education: Celiac disease in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Indications for testing

Children with suggestive symptoms – Serologic testing for celiac disease should be performed for children who present with findings consistent with classic celiac disease, which include persistent diarrhea, chronic constipation, recurrent abdominal pain, and failure to thrive, as well as for those who present with a dermatitis herpetiformis-type rash (picture 1A-B). Testing is also appropriate for children who present with other associated non-gastrointestinal symptoms (table 2A), in whom no other underlying cause can be identified. (See 'Patients with symptoms suggesting celiac disease' above.)

Children in high-risk groups – We also suggest testing asymptomatic individuals with the following characteristics, which are associated with an increased risk for celiac disease: first-degree relatives of patients with celiac disease and children with autoimmune thyroiditis, type 1 diabetes, autoimmune liver disease, juvenile chronic arthritis, Down syndrome, Turner syndrome, Williams syndrome, or selective IgA deficiency (Grade 2C). (See 'Members of high-risk groups' above.)

Avoid premature initiation of a gluten-free diet – A gluten-free diet should not be started prior to a full evaluation for celiac disease. This is because the symptoms of celiac disease are nonspecific and both antibody testing and intestinal biopsy results are only valid if they are performed while the patient is exposed to gluten. Moreover, a clinical response to a gluten-free diet is not sufficient to establish the diagnosis of celiac disease versus nonceliac gluten sensitivity. (See 'Pretesting diet' above.)

How to test

Serology – Serologic testing is performed by measuring one of several antibodies that are specific for celiac disease, with the patient on a gluten-containing diet (table 3). The most clinically useful test is for IgA antibodies against tissue transglutaminase (tTG-IgA), which is highly sensitive, specific, and more cost-effective than other antibody tests. (See 'Tissue transglutaminase antibodies' above.)

Intestinal biopsy – Most patients with positive results of the serologic testing should undergo endoscopy, with biopsies from several areas of the duodenum including the duodenal bulb (algorithm 1). The histologic features of celiac disease range from a mild alteration characterized only by increased intraepithelial lymphocytes (Marsh type 1 lesion) to a flat mucosa with total mucosal atrophy, complete loss of villi, enhanced epithelial apoptosis, and crypt hyperplasia (Marsh type 3 lesion) (figure 1 and picture 2). (See 'Intestinal biopsy (most patients)' above.)

Intestinal biopsy is valuable for all patients to achieve maximal diagnostic certainty and exclude other gastrointestinal diseases (eg, eosinophilic esophagitis). However, the biopsy is considered optional for selected patients with very high levels of tTG-IgA, positive anti-endomysial antibodies (EMA), and typical symptoms. For patients with these characteristics, the decision whether to perform endoscopy and biopsy should be made collaboratively with the patient and family. (See 'Nonbiopsy diagnosis (option for selected patients)' above.)

Diagnosis

Celiac disease – A diagnosis of celiac disease is made if the results of celiac-specific antibody testing and the intestinal biopsy are both abnormal. The diagnosis is reinforced when symptoms resolve subsequently on a gluten-free diet. Serologic tests that revert from positive to negative on a gluten-free diet may be used as supportive evidence of the diagnosis and are particularly valuable in individuals with minimal symptoms. (See 'Diagnosis' above.)

"Potential" celiac disease – "Potential" celiac disease refers to patients who have positive serologic tests for celiac disease (tTG-IgA or EMA) but have normal small bowel histopathology. A gluten-free diet is not necessary in such patients if they are asymptomatic. However, it is important to ensure that the evaluation included multiple intestinal biopsies since histologic abnormalities can be patchy. These patients should be carefully monitored for growth failure and other symptoms that might suggest active celiac disease, and they should be rebiopsied if symptoms develop. (See 'Intestinal biopsy (most patients)' above and "Management of celiac disease in children", section on 'Potential celiac disease'.)

Management – Implementation of a gluten-free diet and other details of treatment and monitoring of children with established celiac disease are discussed in a separate topic review. (See "Management of celiac disease in children".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ivor D Hill, MD, who contributed to earlier versions of this topic review.

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