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Journal of Pediatric Gastroenterology & Nutrition:
NASPGHAN Clinical Guideline

Guideline for the Diagnosis and Treatment of Celiac Disease in Children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Hill, Ivor D. M.D.; Dirks, Martha H. M.D.; Liptak, Gregory S. M.D.; Colletti, Richard B. M.D.; Fasano, Alessio M.D.; Guandalini, Stefano M.D.; Hoffenberg, Edward J. M.D.; Horvath, Karoly M.D.; Murray, Joseph A. M.D.; Pivor, Mitchell M.D.; Seidman, Ernest G. M.D.

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Author Information

Winston Salem, NC (Hill)

Montreal, QC (Dirks)

Rochester, NY (Liptak)

Burlington, VT (Colletti)

Baltimore, MD (Fasano)

Chicago, IL (Guandalini)

Denver, CO (Hoffenberg)

Baltimore, MD (Horvath)

Rochester, MN (Murray)

Winston Salem, NC (Pivor)

Montreal, QC (Seidman)

Address requests for reprints to: Executive Director, NASPGHAN, 1501 Bethlehem Pike, PO Box 6, Flourtown PA 19031.

Disclaimer: The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

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Abstract

Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion.

The Committee examined the indications for testing, the value of serological tests, human leukocyte antigen (HLA) typing and histopathology and the treatment and monitoring of children with celiac disease. It is recommended that children and adolescents with symptoms of celiac disease or an increased risk for celiac disease have a blood test for antibody to tissue transglutaminase (TTG), that those with an elevated TTG be referred to a pediatric gastroenterologist for an intestinal biopsy and that those with the characteristics of celiac disease on intestinal histopathology be treated with a strict gluten-free diet. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the diagnosis and treatment of celiac disease in children and adolescents.

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SYNOPSIS

Who to Test?

Celiac disease (CD) is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in symptomatic children and adolescents with gastrointestinal and nongastrointestinal symptoms. It also occurs in some asymptomatic individuals who have conditions that are associated with CD. Based on a number of studies in Europe and the United States, the prevalence of CD in children between 2.5 and 15 years of age in the general population is 3 to 13 per 1000 children, or approximately 1:300 to 1:80 children.

Numerous studies demonstrate that children with CD frequently have gastrointestinal (GI) symptoms such as diarrhea with failure to thrive (FTT), abdominal pain, vomiting, constipation and abdominal distension. However, there is little information currently available about the precise prevalence of CD in children with these specific types of GI symptoms. There is strong evidence for an increased occurrence of CD in children with dermatitis herpetiformis, dental enamel defects, type 1 diabetes, IgA deficiency, Down syndrome, Turner syndrome, Williams syndrome and first-degree relatives of patients with CD. There is moderate evidence for an increased prevalence of CD in children with short stature and some evidence for an increased prevalence of CD in children with autoimmune thyroiditis. There is evidence that anemia is common in children with CD, and an increased prevalence of unexplained anemia as a presenting feature is well described in adults with CD. Other conditions that have been described in association with CD include a variety of neurologic disorders; however, the evidence for these associations in children is poor.

It is recommended that CD be an early consideration in the differential diagnosis of children with FTT and persistent diarrhea. In addition, it is recommended that CD be considered in the differential diagnosis of children with other persisting GI symptoms, including recurrent abdominal pain, constipation and vomiting. Testing is recommended for children with nongastrointestinal symptoms of CD (dermatitis herpetiformis, dental enamel hypoplasia of permanent teeth, osteoporosis, short stature, delayed puberty and iron-deficient anemia resistant to oral iron). Testing is also recommended for asymptomatic children who have conditions associated with CD (type 1 diabetes mellitus, autoimmune thyroiditis, Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency and first-degree relatives of celiac patients). It is recommended that testing of asymptomatic children who belong to groups at risk begin around 3 years of age provided they have had an adequate gluten-containing diet for at least 1 year before testing.

There is good evidence that in certain groups (type 1 diabetes, first-degree relatives of affected individuals and Down syndrome) some individuals who initially have a negative serological test may subsequently develop a positive test on repeat testing over a period of years and have biopsies compatible with CD. Therefore, it is recommended that asymptomatic individuals with negative serological tests who belong to groups at risk be considered for repeat testing at intervals. As there is no good evidence that CD is more common in children with autism, there is no indication to routinely test patients with autism for CD.

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How to Test?

Based on the current evidence and practical considerations, including accuracy, reliability and cost, measurement of IgA antibody to human recombinant tissue transglutaminase (TTG) is recommended for initial testing for CD. Although as accurate as TTG, measurement of IgA antibody to endomysium (EMA) is observer dependent and therefore more subject to interpretation error and added cost. Because of the inferior accuracy of the antigliadin antibody tests (AGA), the use of AGA IgA and AGA IgG tests is no longer recommended for detecting CD.

Individuals with CD who are also IgA deficient will not have abnormally elevated levels of TTG IgA or EMA IgA. The occurrence of both CD and IgA deficiency in the same individual appears to be rare in asymptomatic individuals (approximately 1:8500 of the general population) but is more likely in symptomatic children with CD (approximately 2%). Therefore, when testing for CD in children with symptoms suspicious for CD, measurement of quantitative serum IgA can facilitate interpretation when the TTG IgA is low. In individuals with known selective IgA deficiency and symptoms suggestive of CD, testing with TTG IgG is recommended. Even when serological tests for CD are negative, in children with chronic diarrhea or FTT and in those belonging to a group at risk (e.g., selective IgA deficiency or a positive family history of CD) who have symptoms compatible with CD, an intestinal biopsy can be helpful to identify the unusual case of seronegative CD or to detect other mucosal disorders accounting for the symptoms.

It is recommended that confirmation of the diagnosis of CD require an intestinal biopsy in all cases. Because the histologic changes in CD may be patchy, it is recommended that multiple biopsy specimens be obtained from the second or more distal part of the duodenum. There is good evidence that villous atrophy (Marsh type 3) is a characteristic histopathologic feature of CD. The presence of infiltrative changes with crypt hyperplasia (Marsh type 2) on intestinal biopsy is compatible with CD but with less clear evidence. Diagnosis in these cases is strengthened by the presence of positive serological tests (TTG or EMA) for CD. In the event the serological tests are negative, other conditions for the intestinal changes are to be considered and, if excluded, the diagnosis of CD is reconsidered. The presence of infiltrative changes alone (Marsh type 1) on intestinal biopsy is not specific for CD in children. Concomitant positive serological tests for CD (TTG or EMA) increases the likelihood such an individual has CD. In circumstances where the diagnosis is uncertain additional strategies can be considered, including determination of the HLA type, repeat biopsy or a trial of treatment with a gluten-free diet (GFD) and repeat serology and biopsy.

The diagnosis of CD is considered definitive when there is complete symptom resolution after treatment with a strict GFD in a previously symptomatic individual with characteristic histologic changes on small intestinal biopsy. A positive serological test that reverts to negative after treatment with a strict GFD in such cases is further supportive evidence for the diagnosis of CD.

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Who to Treat?

Treatment with a GFD is recommended for all symptomatic children with intestinal histopathologic abnormalities that are characteristic of CD. Clinical experience has demonstrated that children with persistent diarrhea and poor weight gain resulting from CD have complete resolution of symptoms on treatment with a GFD. There is good evidence that treatment with a GFD reverses the reduced bone mineralization in children with CD, and decreases the rate of spontaneous abortions and frequency of low birth weight infants in adult women with CD. Epidemiological evidence suggests treatment of CD can decrease the risk for some intestinal cancers and lower mortality rates to that of the general population. The evidence that early treatment of CD prevents the onset of other autoimmune diseases is weak.

Treatment with a GFD is also recommended for asymptomatic children who have a condition associated with CD and characteristic histologic findings on small intestinal biopsy. In patients with type 1 diabetes who otherwise have no symptoms associated with CD, there is little evidence to demonstrate that a GFD improves their diabetes in the short term. The intermediate and long-term benefits to diabetes care of treating such patients with a GFD are not known. There are no studies on the benefits of treating asymptomatic CD in individuals with other associated conditions.

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How to Treat?

A GFD for life remains the only scientifically proven treatment available for symptomatic individuals with CD. It is recommended that treatment be started only after the diagnosis has been confirmed by intestinal biopsy according to the diagnostic algorithms presented in this guideline.

The Celiac Disease Guideline Committee endorses the recently published American Dietetic Association guidelines (a document produced by members of the Canadian and United States dietetic societies) for the treatment of CD. However, given the dynamics of this field, these recommendations require periodic review and modification in light of new scientific evidence.

There is evidence to demonstrate that even small amounts of gluten ingested on a regular basis by individuals with CD can lead to mucosal changes on intestinal biopsy. Previously, products containing less than 200 ppm were regarded as gluten free. Currently, a limit of 20 ppm is being considered in the proposed Codex Alimentarius as defining gluten free. Controversy surrounding what constitutes a GFD is the result of inaccurate techniques for detecting gluten and the lack of solid scientific evidence for a threshold of gluten consumption below which no harm occurs. Management of a GFD is facilitated by ongoing collaboration between patients, health care professionals and dieticians.

Most newly diagnosed children will tolerate ingestion of lactose, particularly in moderate amounts; therefore dietary lactose restriction is not usually necessary. Young children with more severe disease may benefit from a lactose-free diet initially.

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How to Monitor?

It is recommended that children with CD be monitored with periodic visits for assessment of symptoms, growth, physical examination and adherence to a GFD. There is little evidence on the most effective means of monitoring patients with CD. The Celiac Disease Guideline Committee recommends measurement of TTG after 6 months of treatment with a GFD to demonstrate a decrease in antibody titer as an indirect indicator of dietary adherence and recovery. Measurement of TTG is also recommended in individuals with persistent or recurrent symptoms at any time after starting a GFD, as a rise in antibody levels suggests dietary non-adherence. In the asymptomatic patient measurement of TTG at intervals of 1 year or longer may serve as a monitor of adherence to the GFD.

Studies in children have shown that adherence to a GFD is reported by 45% to 81% of patients. These may be overestimates, as some patients reporting strict adherence have abnormal small intestinal histology. A complete lack of adherence is reported by 6% to 37% of patients. These may be underestimates, as patients are reluctant to admit that they are not following medical advice. Based on limited data, the rate of adherence in asymptomatic patients who were detected as part of a population screening is similar to the rate of adherence in patients who had symptoms that led to the detection of CD.

Evidence demonstrates that about 95% of children with symptoms of CD, a biopsy characteristic (Marsh type 3) of CD and resolution of symptoms on a GFD do in fact have CD. Therefore, additional biopsies for confirmation of the diagnosis are not recommended in such cases.

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INTRODUCTION

Celiac disease (CD) is defined as a permanent sensitivity to gluten in wheat and related proteins found in barley and rye. It occurs in genetically susceptible individuals and is manifest as an immune-mediated enteropathy as defined by characteristic changes seen on intestinal histology. Although epidemiologic studies in Europe and the United States indicate that CD is common and may occur in 0.5% to 1% of the general population (1-5), long delays between onset of symptoms and diagnosis often occur (6) and the condition remains underdiagnosed. One reason for this is failure by health care professionals to recognize the variable clinical manifestations of CD and to perform the appropriate tests to make the diagnosis. Currently the only available treatment is lifelong adherence to a gluten-free diet (GFD).

The European Society for Paediatric Gastroenterology, Hepatology and Nutrition has published criteria for the diagnosis of CD, but there are no current evidence-based guidelines for the evaluation and treatment of CD in children. Therefore, the CD Guideline Committee was formed by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) to develop a clinical practice guideline for the diagnosis and treatment of CD in children. The Committee consists of a primary care pediatrician, a clinical epidemiologist who is also a primary care pediatrician, eight pediatric gastroenterologists and an internist gastroenterologist. This clinical practice guideline is designed to help all health care professionals who take care of children in both inpatient and outpatient settings, including pediatricians, family practice physicians, pediatric gastroenterologists, pediatric endocrinologists, medical geneticists, physician assistants and nurse practitioners. The desirable outcome of the guideline was defined as the complete resolution of symptoms and the prevention of complications of CD through implementation of a lifelong GFD at an early stage of the disease utilizing the most effective strategy available.

This document represents the official recommendations of NASPGHAN on the diagnosis and treatment of celiac disease in children.

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METHODS

To develop evidence-based guidelines the following search strategy was used. Articles published from 1966 to February 2003 were identified using the medical subject heading (MESH) "Celiac Disease" through searches in PubMed (http://www.ncbi.nih.gov/entrez/query.fcgi), the Database of Abstracts of Reviews of Effects (DARE) (http://nhscrd.york.ac.uk/darehp.htm) and the Cochrane Database of Systematic Reviews (through OVID, Ovid Technologies, Inc. www.ovid.com). Letters to the editors, editorials, case reports and nonsystematic reviews were not included.

No articles were identified in the Cochrane database, and four were identified through DARE. The first subcategory used in PubMed was diagnosis. A total of 317 articles were found, 285 in English and 167 of those limited to children. In the subcategory of prognosis, 117 articles were found, with 86 limited to English and 38 of those limited to children. In the subcategory of therapy, a total of 1503 articles were found, with 1143 in English and 486 limited to children. Thirty articles were duplicated in more than one category. A second search was performed in September 2003, and an additional 73 articles were identified.

Articles were evaluated by two committee members using written criteria developed by Sackett et al. (7-9) (http://www.cebm.net/levels_of_evidence.asp; accessed on 2/3/2004). Twenty-nine randomly chosen articles were independently reviewed by two members of the committee with expertise in clinical epidemiology (GL, MD). Concordance using the criteria was 82%. The Committee based its recommendations on integration of the literature review combined with expert opinion when evidence was insufficient. Consensus was achieved through the Nominal Group Technique, a structured, quantitative method (10). Using the methods of the Canadian Preventive Services Task Force (11), the quality of evidence of each of the recommendations made by the Celiac Disease Guideline Committee was determined and is summarized.

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DIAGNOSIS

Based on a number of studies in Europe and the United States, the prevalence of CD in children between 2.5 and 15 years of age in the general population is 3 to 13 per 1000 children, or approximately 1:300 to 1:80 children (1-3,5,12,13) Therefore, in a pediatric practice of 1500 children there are probably between 5 and 20 children with CD either diagnosed or undiagnosed.

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Who To Test?

Because CD is characterized by intestinal damage, clinical manifestations of the disease are often related to the gastrointestinal tract. However, many patients first present with a variety of signs and symptoms not related to the gastrointestinal tract. Furthermore, some individuals with characteristic changes on small intestinal biopsy may remain asymptomatic or oligosymptomatic for many years and possibly even for life. Failure to appreciate the variable clinical manifestations of CD can lead to delays in diagnosis.

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Gastrointestinal Manifestations

There are numerous studies demonstrating that children with CD have gastrointestinal (GI) symptoms such as diarrhea with failure to thrive (FTT), abdominal pain, vomiting, constipation and abdominal distension, but there is little information currently available about the prevalence of CD in children with these specific types of GI symptoms. Limited data suggest the prevalence of CD may be increased 2-10 times in children with some of these GI symptoms or occur in up to 5% of cases (12).

The classic form of CD in children consists of gastrointestinal symptoms starting between 6 and 24 months of age, after the introduction of gluten in the diet. Infants and young children typically present with chronic diarrhea, anorexia, abdominal distension, abdominal pain, poor weight gain or weight loss and vomiting. Severe malnutrition, and even cachexia, can occur if the diagnosis is delayed. Behavioral changes such as irritability are common. Rarely, severely affected infants present with a celiac crisis characterized by explosive watery diarrhea, marked abdominal distension, dehydration, hypotension and lethargy, often with profound electrolyte abnormalities including severe hypokalemia. Older children with CD presenting with gastrointestinal manifestations may have onset of symptoms at any age. The variability in the age of onset of symptoms may be dependent on the amount of gluten in the diet and other environmental factors such as duration of breast-feeding. Gastrointestinal symptoms in older children include diarrhea, nausea and vomiting, abdominal pain, bloating, weight loss and constipation.

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Nongastrointestinal Manifestations

Many symptomatic patients with newly diagnosed CD initially present with nongastrointestinal manifestations. Table 1 lists the main nongastrointestinal manifestations of CD.

Table 1
Table 1
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There is strong evidence that dermatitis herpetiformis is a skin manifestation of CD (14). Most patients with dermatitis herpetiformis have concomitant intestinal mucosal changes of CD on biopsy, even in the absence of gastrointestinal symptoms. Both the rash and the intestinal mucosal morphology improve on a GFD (15). There is strong evidence for an increased prevalence of CD in children with dental enamel defects involving the secondary dentition (16). These changes may be the only initial presenting manifestation of CD. There is strong evidence that patients with untreated CD are at risk for developing low bone mineral density and osteoporosis (17,18). This has also been found in asymptomatic individuals with CD detected during screening studies (19). Reduced bone mineral density in adults improves on a GFD, but CD patients may be at increased risk for bone fractures (20). Studies in children with CD have shown complete reversal of low bone mineral density after introduction of a GFD (21,22).

There is moderate evidence for an increased prevalence of CD in children with short stature. Serological testing of children with idiopathic short stature identified between 8% to 10% with CD (23). There is moderate evidence that adolescent females with untreated CD may have delayed onset of menarche (24). Iron deficiency anemia, resistant to oral iron supplementation, is the most common nongastrointestinal manifestation of CD reported in some studies and is often the primary clinical manifestation in adults (25,26). Between 5% and 8.5% of adults with unexplained iron deficiency anemia have CD (27). This figure increases to 11% when those with either iron deficient or folate deficient anemia are included (28). Although anemia is a common finding in children with newly diagnosed CD, there is little evidence to demonstrate that CD is common in children presenting with anemia.

There is some evidence for elevated serum transaminases (alanine aminotransferase, aspartate aminotransferase) in untreated adults with CD. Up to 9% of adults with elevated transaminase levels of unclear etiology may have silent celiac disease (29). Liver biopsies in these adults showed nonspecific reactive hepatitis and liver enzymes appeared to normalize on a GFD (30). There is little information on this association in children. Arthritis is fairly common in adults with CD, including those on a GFD (31). Up to 3% of children with juvenile chronic arthritis have been reported to have celiac disease (32). A number of neurologic problems, including the syndrome of epilepsy with intracranial calcifications (33,34), have been reported in patients with CD but the evidence for this association in children with CD is weak.

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Associated Conditions

CD is associated with a number of autoimmune and non-autoimmune conditions (Table 2). There is strong evidence for the association between Type 1 diabetes and CD (35-46). Up to 8% of patients with Type 1 diabetes have the characteristic features of CD on small intestinal biopsy. This figure may be an underestimate, as serial screening of individuals with Type 1 diabetes over a period of years has identified additional cases who initially had negative serological tests (41,42,47). Type 1 diabetes usually manifests years before symptoms related to CD become evident (48). There is moderate evidence for an association between autoimmune thyroiditis and CD in adults. The evidence for this association in children is weak (49,50).

Table 2
Table 2
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There is strong evidence for an association between Down syndrome and CD. The prevalence of CD in individuals with Down syndrome is between 5% and 12% (1,51-55). Those with Down syndrome and symptomatic CD usually have gastrointestinal manifestations such as abdominal bloating, intermittent diarrhea, anorexia or failure to thrive. However, about one third of all Down syndrome patients with CD have no gastrointestinal symptoms (53). Compared with those without CD, individuals with Down syndrome who have CD more often have anemia, low serum iron and calcium and lower weight and height percentiles (53). The youngest child diagnosed with both Down syndrome and CD through screening was 3.2 years. Older cohorts of Down syndrome patients screened for CD have a higher prevalence of CD than childhood cohorts, suggesting an increase with time. An increased prevalence of CD has also been reported in individuals with Turner syndrome and Williams syndrome (56-59). The point prevalence of CD in children with Turner syndrome ranges from 4.1% to 8.1%. The prevalence of CD in children with Williams syndrome (microdeletion 7q11.23) was 8.2% in an Italian study (60).

Strong evidence exists for an association between selective immunoglobulin (Ig)A deficiency and CD. Based on studies involving more than 3,200 adults and children in Italy and Ireland, the frequency of selective IgA deficiency in CD is approximately 2% (61-63). Based on retrospective studies, 1.7% to 7.7% of individuals of European origin with selective IgA deficiency also have CD (61,62,64). The prevalence of selective IgA deficiency in celiac patients who are asymptomatic or oligosymptomatic is unknown. There is also strong evidence demonstrating that first-degree relatives of a confirmed case of CD are at increased risk for CD, with a prevalence of 4% to 5% (1).

In summary, it is recommended that CD be an early consideration in the differential diagnosis of children with a combination of persistent diarrhea and poor weight gain, weight loss or FTT. In children with other persisting GI symptoms, including recurrent abdominal pain, anorexia, constipation and vomiting and those with nongastrointestinal symptoms associated with CD (Table 1, Figure 1), it is recommended that CD be included in the differential diagnosis.

Fig. 1
Fig. 1
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It is also recommended to test asymptomatic children who belong to specific groups at risk, and advise treatment for those proven to have intestinal changes of CD. The groups at risk recommended for screening are type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, individuals with selective IgA deficiency, first-degree relatives of a confirmed case of CD and patients with autoimmune thyroiditis (Table 2, Figure 2).

Fig. 2
Fig. 2
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It is recommended that routine testing of asymptomatic children belonging to these groups at risk begin after 3 years of age provided they have been receiving an adequate gluten-containing diet for at least 1 year. There is good evidence that some children with Type 1 diabetes, Down syndrome and first-degree relatives who initially have negative serological tests may subsequently over a period of some years become positive on repeat testing and have biopsies compatible with CD (41,42,47,65). Therefore, it is recommended that individuals who fall into these categories undergo later testing (Fig. 2). There is no good evidence that CD is more common in children with autism, and for this reason there is no indication to routinely test patients with autism for CD.

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How To Test?
Serological Tests

Although an intestinal biopsy is still considered necessary to confirm the diagnosis of CD, serological tests are frequently used to identify individuals for whom the procedure is indicated. Commercially available tests include anti-gliadin IgA and IgG (AGA IgA and AGA IgG), anti-reticulin IgA (ARA), anti-endomysium IgA (EMA) and anti-tissue transglutaminase IgA (TTG) antibodies. These tests are particularly helpful in individuals without gastrointestinal symptoms and those with conditions associated with CD and for screening asymptomatic first-degree relatives of known cases. They have also been widely used in epidemiologic studies to determine the prevalence of CD.

Numerous studies have evaluated the accuracy of these tests in diverse populations from many countries. Study designs have included population screening studies (e.g., general population or groups at risk), studies of groups preselected to go undergo endoscopy and biopsy, retrospective studies comparing the performance of new tests on stored serum samples from clinically characterized subjects and prospective studies of consecutive patients with symptoms.

Interpretation of the results from these studies in the clinical setting may be problematic for a number of reasons. The technical aspects and performance of the tests have improved over time (e.g., use of more purified antigen). The population selected for study may differ from that in the clinical setting, thus giving unrepresentative results. The definition of a true positive may vary. The number, size and site of biopsies obtained, the processing (e.g., orientation) of the sample and the interpretation of the histology in a research setting (blinded interpretation, use of celiac experts and different scoring systems) are seldom applicable to the clinical setting. In addition, there are limited data on serologic testing of children younger than 5 years of age. For all these reasons, the accuracy of the serologic tests in the clinical setting may not be as good as that reported in the research setting.

In the clinical setting, where children have been identified on the basis of symptoms, the serological tests have been evaluated as a single test, a combination of tests or sequential use of two or more tests. The sensitivity of AGA IgA among reported studies ranges between 0.52 and 1.00 in children (66-72) and between 0.65 and 1.00 in adults (73-75). The specificity of AGA IgA in children ranges between 0.92 and 0.97 (66,70-72) and in adults between 0.71 and 0.97 (73,74). The AGA IgG is similar in sensitivity to the AGA IgA, but the specificity is much lower, approximately 0.5. This indicates that many individuals without CD express AGA IgG antibody (70). False positive tests have been recorded in individuals with a variety of other gastrointestinal disorders, including esophagitis, gastritis, gastroenteritis, inflammatory bowel disease, cystic fibrosis and cow's milk protein intolerance.

The EMA test is based on an immunofluorescent technique using either monkey esophagus or human umbilical cord as substrate; the accuracy of the test is similar for either substrate. The nature of this test renders it more time consuming to perform, generally more expensive and, because the interpretation is operator-dependent, potentially more prone to errors. The sensitivity of the EMA in children ranges from 0.88 to 1.00 (66,68,70-72,76-79) and in adults is reported to be 0.87 to 0.89 (74,75,77). The specificity of the EMA in children ranges from 0.91 to 1.00 (66,70-72,78,79) and in adults is reported to be 0.99 (74). The EMA test may be less accurate in children under 2 years of age (68).

When first introduced, the TTG assays used guinea pig protein. Subsequent cloning of the human TTG gene led to the development of assays based on the human TTG protein. The sensitivity of TTG in both children and adults ranges from 0.92 to 1.00 (66,76-80). The specificity of TTG in both children and adults ranges from 0.91 to 1.00 (66,76-80). There is evidence that TTG assays using human recombinant protein and human derived red cell tissue transglutaminase have a higher sensitivity (0.96 to 1.00 versus 0.89 to 0.94) and specificity (0.84 to 1.00 versus 0.74 to 0.98) when compared with assays using guinea pig protein (81-83).

Most individuals with CD identified as part of routine screening are asymptomatic or have only mild symptoms. In such studies the positive predictive value for biopsy evidence of CD is lower than that reported for clinically identified subjects. In young asymptomatic children with a genetic risk for CD, a positive TTG by RIA had a positive predictive value of 0.70-0.83 for biopsy evidence of CD (5). In studies of adults in the United States (1) and children in Hungary (3) a positive EMA had a positive predictive value of 1.00. A number of other studies have combined AGA plus EMA testing with positive predictive values ranging from 0.62 to 0.90 (3,13,84).

A comparison between several commercially available serological tests using standardized serum demonstrated that EMA and TTG are superior to AGA, with EMA being more reproducible than TTG (85). However, human derived TTG was not used in this study. Tests on selected adult stored sera using commercially available human TTG ELISA kits demonstrated the human TTG based kits performed better (improved specificity) than guinea pig TTG based kits (82,86). There are insufficient data on the accuracy of currently available commercial panels of tests compared with individual tests.

In summary, there is good evidence that EMA and TTG are highly sensitive and specific tests for identifying individuals with CD. In symptomatic individuals, the positive predictive value of EMA and TTG assays for finding biopsy evidence of CD approaches 1.00. In screening-identified individuals, AGA+EMA, EMA alone and TTG alone have positive predictive values for biopsy evidence of CD ranging from 0.6 to 1.00. A positive serological test in an individual with normal small intestinal histology may represent a false positive serological test, milder disease or a more sensitive test that identifies latent CD before mucosal injury. Based on the available evidence and practical considerations, including relatively low cost, ease of test performance and reliability, the TTG assay is recommended for the initial testing for CD. Even if serological tests for CD are negative in symptomatic children with chronic diarrhea or FTT and those with IgA deficiency or a positive family history of CD, an intestinal biopsy may be useful to identify the unusual case of seronegative CD or to detect other intestinal mucosal disorders to account for the symptoms. Because of the variable and generally inferior accuracy of the antigliadin antibody tests (AGA), the use of AGA IgA and AGA IgG tests is no longer recommended for identifying individuals with CD.

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HLA DQ2 and DQ8

Susceptibility to CD is determined in part by a common HLA association: specifically, the major histocompatibility complex class II antigens HLA-DQA1*0501-DQB1*02(DQ2) and HLA-DQA1*0301-DQB1*0302(DQ8). These genes (located on chromosome 6p21.3) code for glycoproteins that bind to peptides, forming an HLA-antigen complex that can be recognized by CD4+ T cell receptors in the intestinal mucosa. DQ2, present in 86%-100% of patients, is in strong linkage disequilibrium with DR3 and DR5/7 (87-96). Homozygosity for DQ2 alleles may be associated with the early onset classic form of disease (97) and confer the highest concordance in twins (98). Almost all CD patients without HLA DQ2 (∼5%) have a DQ8 molecule, encoded by DQB1*0302 and DQA1*0301, in linkage disequilibrium with DR4. Although DQ2 genes form a basis for the genetic susceptibility to CD, approximately 30% of the general population in North America is DQ2-positive (5). Other genetic loci possibly associated with CD have been reported, including loci on chromosome 15q11-13 (99) and chromosomes 5 and 11 (100). The development of CD is clearly multigenic, with the presence of DQ2 or DQ8 being an essential component. Thus, probes for DQ2 and DQ8 have high sensitivity but poor specificity, indicating a low positive predictive value but a very high negative predictive value for CD.

In Type 1 diabetics, a positive EMA or TTG is found predominantly in those with the HLA DQ2 or DQ8 genotype (101,102). Up to one third of diabetics with HLA DQ2 have positive TTG, compared with less than 2% of diabetics without HLA DQ2 or DQ8 (101). Some diabetics who were TTG-positive were EMA negative and had normal histology on intestinal biopsy (101); therefore some investigators recommend a positive TTG be followed by a positive EMA before biopsy in patients with Type 1 diabetes, but the evidence supporting this approach is limited and the management of those with a positive TTG but a negative EMA remains unclear. Others have found HLA DQ2 is present in approximately 80% of Type I diabetics with CD, compared with 49% of diabetics without CD (103). In first-degree relatives of Type I diabetics, CD mainly occurs in those who are HLA DQ2 positive (80%). HLA DQ2 is also found in 28% of siblings who do not have CD (104). Those with CD in the absence of DQ2 had the DQ8 genotype (104). Thus, type 1 diabetics who are DQ2 or DQ8 positive are at risk for CD.

CD in individuals with Down syndrome is mainly linked to the presence of the DQ2 heterodimer, with the carriage rate of DQ2 among Down syndrome persons who also have CD approaching 100% (54,65,105). An additional allele (DQB1*0301) is also implicated in 20% of Down syndrome individuals in some series (54,105), and the DQA*0101 allele in one (106). A few Down syndrome individuals with DQ8 and CD have been identified (105,107). All children with Turner syndrome and CD were positive for HLA DQ2, whereas the frequency of this heterodimer was not elevated in Turner syndrome without CD compared with the general population (59,108). HLA DQ2 or DQ8 heterodimer identification has not been specifically studied in Williams syndrome. HLA DQ2 correlates strongly with EMA and TTG positivity in first-degree relatives of individuals with CD (97%). In a study of healthy members of multiple case celiac disease families the positive predictive value of the EMA was 67% (109). Whether some of these family members developed small intestinal histopathologic abnormalities of CD at a later stage remains to be determined, as follow-up was short. For relatives without DQ2 the risk of having CD was minimal.

No studies have been designed to evaluate whether determining HLA DQ2/DQ8 status is of value in screening children. However, given the strong association between HLADQ2/DQ8 and CD, it may have a role as part of the screening strategy for asymptomatic individuals who belong to groups at risk for CD. These include first-degree relatives of a confirmed case, Type 1 diabetics, and those with Down syndrome, Turner syndrome and, possibly, Williams syndrome (Fig. 2). A negative result for HLA DQ2/DQ8 renders CD highly unlikely, and hence there is no need for subsequent serological testing of such individuals.

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IgA Deficiency

The definition of selective IgA deficiency for purposes of CD evaluation has been inconsistent. Assays used for quantitating IgA are not always adjusted to accurately measure lower levels. Furthermore, cut-off values used by various laboratories vary and have included <5 mg/dL (64,110) in children and <5-7 mg/dL in adults (111,112), age-adjusted values (113), <15% of mean population values and age-specific values (114). When defined by a serum IgA <5 mg/dL, selective IgA deficiency occurs in 1:163-1:965 healthy blood donors in Europe, the United States and Brazil (115-117).

Although CD occurs with increased frequency in those with selective IgA deficiency, screening studies of the general population suggest that very few cases will be missed by not routinely measuring IgA levels as part of the screening regimen (110). In one such study involving more than 17,000 children, the prevalence of CD occurring together with IgA deficiency was only 1 in 8500 (2). Nor is the frequency of selective IgA deficiency increased in those with type 1 diabetes (118). In addition, very few asymptomatic cases of CD with selective IgA deficiency have been identified on the basis of a positive test for AGA IgG (84,119). Thus the strategy of routinely determining serum IgA levels or adding IgG-based serology as part of a panel to screen asymptomatic individuals in the general population is not warranted. However, in symptomatic patients with a clinical suspicion for CD, a test for IgA deficiency during the screening process is a consideration so as to more accurately evaluate the significance of a negative serological test. This strategy is also a consideration when screening asymptomatic individuals who belong to a group at risk for CD, although based on the available evidence only a few cases of CD in IgA deficient individuals will be identified in this manner.

IgG antibody tests have been used in individuals with known selective IgA deficiency to identify those requiring an intestinal biopsy for the diagnosis of CD. AGA IgG tests are more frequently used for this purpose than are EMA IgG or TTG IgG tests (120). However, in individuals with selective IgA deficiency and symptoms suggestive of CD, the positive predictive value of a high titer AGA IgG for biopsy confirmation of CD is poor; in one study it was only 0.31 (110,114). Based on these findings, the use of AGA IgG tests is considered a poor option for identifying individuals with CD who have selective IgA deficiency.

There is some evidence that EMA IgG and TTG IgG tests are more accurate than AGA IgG for identifying individuals with CD. Testing with TTG IgG in a small number of subjects has shown promise (120-122). TTG IgG or EMA IgG1 had almost 100% sensitivity in selected series of symptomatic individuals with known selective IgA deficiency (123,124), and there was near-perfect concordance between TTG IgG and EMA IgG1 in adults with symptoms of malabsorption (122). The sensitivity and specificity of TTG IgG ranges from 0.84 to0.97 and 0.91to 0.93, respectively, in thesymptomatic population, with a positive predictive value of 0.63 (121-123,125) for small intestinal histologic features of CD. However, if those with total villous atrophy are excluded, accuracy decreases significantly, suggesting that TTG IgG may fail to identify individuals with less severe histologic changes. EMA IgG in selective IgA-deficient individuals has a sensitivity of 0.83, a specificity of 0.80 and a positive predictive value of 0.925 (120). Based on these studies, EMA IgG and TTG IgG are considered better tests than AGA IgG for identifying individuals with selective IgA deficiency that require a biopsy to confirm the diagnosis of CD. However, these tests have not been prospectively evaluated in a large cohort of selective IgA-deficient subjects, and there are no good data on their accuracy for identifying CD in asymptomatic individuals with selective IgA deficiency.

On the balance of evidence, for those individuals with known selective IgA deficiency and symptoms or signs strongly suggestive of CD (e.g., chronic diarrhea with failure to thrive) serological testing offers little advantage over directly proceeding to intestinal biopsy to establish the diagnosis. For individuals known to have IgA deficiency but with a lower clinical index of suspicion for CD, TTG IgG, which is commercially available, may be of value to identify those who need an intestinal biopsy. For those individuals with known selective IgA deficiency who are truly asymptomatic but at high risk for CD (e.g., first-degree relatives, Type 1 diabetics), TTG IgG is a consideration. Determination of the HLA DQ2/DQ8 heterodimer status is an additional consideration in some of these cases. However, IgA-deficient individuals have a higher prevalence of the HLA DQ2 genotype than the general population (126), and thus the proportion of individuals who will be reassured by having neither DQ2 nor DQ8 may be smaller than for some other high risk groups.

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Intestinal Biopsy and Histopathology

It is currently recommended that confirmation of the diagnosis of CD requires an intestinal biopsy in all cases. A clinical diagnosis in children on the basis of gastrointestinal symptoms alone was incorrect in more than 50% of cases (127,128). Radiological and other nonserological laboratory tests are also unable to separate those with or without villous atrophy (129). Serological tests for CD have enhanced the ability to identify individuals who may have CD but are still not sufficiently reliable to confidently diagnose a condition requiring lifelong adherence to a strict GFD (130-132).

The initial biopsy based criteria for the diagnosis of CD were published by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition in 1970 (133). These criteria required three biopsies over a period exceeding 1 year. Retrospective analysis of more than 3,000 patients who had multiple biopsies demonstrated the diagnosis of CD was correct in more than 95% of those who had symptoms suggestive of CD, the characteristic findings on small intestinal mucosal histology while on a gluten-containing diet and complete symptom resolution on a GFD (134). Most of the remaining 5% who did not have CD were younger than 18 months of age and had a final diagnosis of cow's milk protein enteropathy. Based on these findings, revised criteria for the diagnosis of CD were published in 1990 (135). These state that for children older than 2 years of age having symptoms suggestive of CD, the characteristic histologic findings on small intestinal biopsy and unequivocal clinical resolution after institution of a GFD, the diagnosis can be considered definitive for lifelong CD without need for additional biopsies. The addition of positive serological tests for CD that revert to negative after a period on a GFD is considered supportive evidence for the diagnosis in these cases.

Small intestinal biopsies are now generally obtained by grasp biopsy forceps during an endoscopic procedure. Endoscopic biopsies appear comparable to suction capsule biopsies for the purposes of making a definitive diagnosis in children and adults (136-140). With either technique the biopsy specimen was considered satisfactory in approximately 90% of cases. Both suction and endoscopic biopsies are considered relatively safe (141-147). Potential advantages to use of the endoscopic procedure include the ability to inspect the mucosa and obtain multiple samples, a shorter procedure time and absence of radiation. The main disadvantage is the higher cost involved. Suction biopsies are generally obtained from the region of the ligament of Treitz. The number of biopsies taken has varied from two to four specimens at the same level (135,137,140,145,148) to three specimens at different levels (149). Comparison of biopsies from the second, third and fourth parts of the duodenum, the ligament of Treitz and the proximal jejunum has demonstrated each site is suitable for diagnosing CD (150). However, the presence of Brunner glands in the duodenal bulb and the second part of the duodenum can adversely affect interpretation of the histology, rendering assessment of the villous:crypt ratio difficult (150-152). For this reason it may be preferable to obtain biopsies from the more distal segments of the duodenum.

Endoscopic features of duodenal villous atrophy described in CD include the absence of folds, scalloped folds, visible submucosal blood vessels and a mosaic pattern of the mucosa between the folds. These features may only be reliable in cases with subtotal and total villous atrophy (Marsh 3b and 3c) (153). Interobserver agreement in the interpretation of these endoscopic findings was good for the mosaic pattern and the scalloped folds but judged to be only fair for reduction in number or loss of duodenal folds (149,154,155). Furthermore, with partial villous atrophy the endoscopic appearance can be normal.

There is good evidence that the mucosal changes in CD may be patchy in nature and vary in severity (156). In some cases a biopsy from one site had total villous atrophy whereas that from an adjacent site was normal or showed only mild lymphocyte and plasma cell infiltration of the lamina propria (157). The coexistence of villous atrophy with relatively normal adjacent mucosa on histology has been reported in children with newly diagnosed CD (158) and is also frequently found in cow's milk protein intolerance and in postinfectious enteritis (159,160). Patchy lesions have been described in 35% of children with CD after 1 to 4 months of a gluten challenge (160). Milder changes and patchy lesions may be more likely when CD is diagnosed in patients with minimal or no symptoms.

It is recommended that multiple endoscopic biopsies be obtained from the more distal segments of the duodenum. Areas with a mucosal mosaic pattern or scalloping of the duodenal folds, when present, are preferred sites for obtaining a biopsy (161). Correct orientation of the biopsy specimens will greatly facilitate identification of the histologic features of CD (136,139,140,149,162). Evaluation of the biopsy specimens includes an assessment of the characteristic histologic changes seen with CD and a grading of severity. There is a recognized spectrum of histologic features varying from mild to severe as described by Marsh et al. (153,163,164). None of the individual features is pathognomonic for CD, as each may be seen in other disease states. However, the combination of histopathologic features in a compatible clinical setting is sufficient evidence for a diagnosis of CD.

The characteristic changes described in CD include an increased number of intraepithelial lymphocytes (>30 lymphocytes per 100 enterocytes), an intraepithelial lymphocyte mitotic index greater than 0.2%, a decreased height of the epithelial cells (changes from columnar to cuboid to flat epithelium), a loss of nuclear polarity with pseudostratification of the epithelial cells, a decrease in the number of goblet cells and brush border abnormalities. Structural changes include elongation of the crypts (increased crypt length), partial to total villous atrophy and a decreased villous:crypt ratio. Lamina propria changes include an increased crypt mitotic index and infiltration of plasma cells, lymphocytes, mast cells and eosinophils. An increase in the intraepithelial lymphocytes maybe a more sensitive index of gluten sensitivity than the changes in villous structure, as they are found early in the course of the disease and disappear before other features of structural recovery can be detected (165,166). Marsh and Miller proposed that a mitotic index >0.2% of intraepithelial lymphocytes is useful to differentiate CD from other childhood enteropathies (167). A decrease in the height of the villi and enterocytes is the most readily recognized change in CD; this occurs in the more advanced stages of the disease (153). Less well recognized and reported by pathologists are an increase in the mitotic cells in the epithelial crypts, a reduction in the number of goblet cells and an altered ratio of gamma/delta cells. Most pathologists subjectively grade the degree of cell infiltrate and the increase in the ratio of intraepithelial lymphocytes to enterocytes. Morphometric techniques have been used in an attempt to generate more objective data but are not widely used in clinical practice (159,168,169).

Histological grading systems used include the conventional system and that introduced by Marsh (153). The conventional system grades the mucosal findings as normal, slight partial villous atrophy, marked partial villous atrophy, subtotal and total villous atrophy. Marsh classified the histologic changes of CD as Type 0 or preinfiltrative stage (normal), Type 1 or infiltrative lesion (increased intraepithelial lymphocytes), Type 2 or hyperplastic lesion (Type 1+ hyperplastic crypts), Type 3 or destructive lesion (Type 2 + variable degree of villous atrophy) and Type 4 or hypoplastic lesion (total villous atrophy with crypt hypoplasia). Type 3 has been modified to include Type 3a (partial villous atrophy), Type 3b (subtotal villous atrophy) and Type 3c (total villous atrophy) (170). There is good evidence that villous atrophy (Marsh Type 3) is clearly a feature of CD. The evidence that hyperplastic changes (Marsh Type 2) are distinctive features of CD is not as clear. The presence of Marsh Type 2 changes on intestinal biopsy is suggestive of CD. In these cases the diagnosis is strengthened by the presence of positive serological tests for CD. In the event the serological tests are negative, other conditions for the intestinal changes are to be considered and, if excluded, reconsideration of the diagnosis of CD is warranted. The presence of only infiltrative changes (Marsh Type 1) on intestinal biopsy is nonspecific in children. The presence of positive serological tests for CD (TTG or EMA) in children with Marsh Type I changes increases the likelihood the individual has CD. Under such circumstances additional strategies to confirm the diagnosis can be considered. These include determination of the HLA type, repeat biopsies or a trial of treatment with a GFD and repeat serology and biopsy.

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TREATMENT

The only treatment currently available for CD is strict adherence to a GFD for life. There is evidence that diagnosed but untreated CD is associated with a significant increase in morbidity and mortality. Prolonged adherence to a GFD may reduce this risk for both morbidity and mortality to the levels found in the general population. For these reasons prompt diagnosis and treatment with a GFD as early as possible is desirable. The GFD has both lifestyle and financial implications for the individual and thus has potential for impacting adversely on their quality of life. Hence, it is strongly recommended that an intestinal biopsy be performed to establish the diagnosis of CD before instituting treatment. A trial of a GFD before biopsy is not recommended, as this has potential to promote mucosal healing and to normalize serological tests for CD, thus rendering it impossible to make a positive diagnosis without first challenging the individual with gluten.

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Who To Treat?

Clinical experience has demonstrated that treatment of children with FTT and persistent diarrhea resulting from CD results in resolution of symptoms. When children with symptomatic CD adhere to a GFD, it generally results in resolution of gastrointestinal symptoms, normalization of nutritional measures, improved growth in height and weight with resultant normal or expected stature and normalization of hematological and biochemical parameters (171-174). There is good evidence demonstrating that treatment with a GFD reverses the decrease in bone mineralization in children with CD (175). In adults with CD and established osteoporosis, treatment appears effective in restoring bone mineralization, but it is uncertain whether it has an effect on reducing the risk for fractures (176). Studies in symptomatic children with CD treated with a GFD demonstrate improvement in their sense of physical and psychological well being. The quality of life of children on a GFD who were symptomatic at the time of diagnosis is similar to that of children without CD (177). Improved physical and psychological well being can occur after starting a GFD in screening-detected celiac disease patients who were apparently asymptomatic at the time of diagnosis (178).

There are data suggesting that treatment can decrease the occurrence of spontaneous abortions in fertile females, lower the incidence of low birth weight infants, decrease the risk of some cancers and avoid other consequences of late or delayed diagnosis (179-183). Compared with those on a GFD, women with untreated CD have an increased relative risk for spontaneous abortion (8.9:1), for delivery of a low birth weight infant (5.8:1) and for a shortened duration of breast feeding (2.5:1) (182). In longitudinal studies, institution of a GFD reverses these effects (183). There is little evidence that treating CD in patients with Type 1 diabetes, who have no symptoms associated with CD, affects the course of the diabetes in the short term. The intermediate and long-term benefits of treating such patients with a GFD are not known. There are no studies on the benefits of treating asymptomatic CD in individuals with other associated conditions. It has been suggested that untreated CD may lead to the onset of other autoimmune disorders in genetically susceptible individuals, but the evidence supporting this hypothesis is conflicting (184-189).

Although CD is associated with an overall increase in mortality in adults, primarily as a result of malignancy, there is good evidence that treatment of symptomatic individuals with CD decreases the mortality rate compared with those who remain untreated (179-181). When CD is diagnosed in childhood or adolescence there appears to be no increased cancer risk, presumably because of early initiation of a GFD (190).

Thus treatment with a GFD is recommended for all symptomatic children with intestinal histopathologic abnormalities that are characteristic of CD. Treatment with a GFD is also recommended for asymptomatic children who have a condition associated with CD and characteristic histologic findings on small intestinal biopsy.

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How To Treat?

The only treatment available for CD is a GFD for life. It is recommended that treatment for CD be started only after the diagnosis has been confirmed by intestinal biopsy according to the diagnostic algorithms presented in this guideline. Wheat, rye and barley are the predominant grains containing the peptides known to cause CD. Triticale (a combination of wheat and rye), kamut and spelt (sometimes called farro) are also known to be harmful. Other forms of wheat are semolina (durum wheat), farina, einkorn, bulgur and couscous. The harmful potential of rendered gluten-reduced wheat starch is controversial. Many celiac societies in southern Europe exclude wheat starch; however, there is some evidence that it does not cause villous damage (191). Additional data regarding this issue are necessary before definitive conclusions can be made. Malt is also harmful because it is a partial hydrolysate of barley prolamins. It may contain 100-200 mg of barley prolamins per 100 g of malt (192). In general, any ingredient with malt in its name (barley malt, malt syrup, malt extract, malt flavorings) is made from barley.

Previously, oats were implicated in the development of the villous damage in CD. More recently this has been questioned as both in vivo and in vitro immunologic studies suggest oats are safe (193-199). Despite the accumulating evidence that oats are safe for individuals with CD, there remains some concern about recommending consumption of this grain to CD patients. Contamination of oats with gluten during the harvesting and milling process is known to occur, so unless the purity of the oats can be guaranteed, their safety remains questionable.

There is evidence to demonstrate that even small amounts of gluten ingested on a regular basis can lead to mucosal changes on intestinal biopsy. However, the strict definition of a GFD remains contentious. Products containing less than 200 ppm (<200 mg/kg) were previously regarded as effectively gluten free. Currently, <20 ppm (<20 mg/kg) is being considered in the proposed Codex Alimentarius Guidelines to define "gluten free." The National Food Authority has recently redefined their term for "gluten free." By their definition "gluten free" now refers to no gluten, and <200 ppm is regarded as low gluten. Controversies surrounding what constitutes a GFD are in part the result of inaccurate gluten detecting techniques and lack of solid scientific evidence for a threshold of gluten consumption below which no harm occurs.

The American Dietetic Association (ADA) recently published guidelines for the dietary treatment of CD (200). This document was produced by members of the Canadian and United States dietetic societies, and the recommendations were based on the best available evidence. The CD Guideline Committee recommends acceptance of the ADA recommendations for treatment of CD. However, given the dynamics of this field, the diet requires ongoing collaboration between patients, health care professionals and dieticians, and the recommendations require periodic review and modification in light of new scientific evidence. At this time, a GFD for life remains the only scientifically proven treatment available for symptomatic individuals with CD.

Most children with newly diagnosed CD will tolerate ingestion of lactose, particularly in moderate amounts; therefore dietary lactose restriction is not usually necessary. Young children with more severe disease may benefit from a lactose-free diet initially (201).

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How To Monitor?

It is recommended that children with CD be monitored with periodic visits for assessment of symptoms, growth, physical examination and adherence to the GFD (Fig. 3). The range of adherence to a strict GFD as reported by patients is 45% to 81%. These may be overestimates, as some patients reporting strict adherence have abnormal intestinal histopathology (171,173,174,202-206). The range of reported complete lack of adherence is 6% to 37%. These may be underestimates, as patients are reluctant to admit they are not following physician advice. The rate of adherence in patients who were detected as part of a population screening may be comparable to that of patients who had symptoms that led to detection of celiac disease (178,206).

Fig. 3
Fig. 3
Image Tools

There is little evidence on the most effective means of monitoring patients with CD. The Celiac Disease Guideline Committee recommends measurement of TTG after 6 months of treatment with a GFD to demonstrate a decrease in antibody titer as an indirect indicator of dietary adherence and recovery. Measurement of TTG is also recommended in individuals with persistent or recurrent symptoms at any time after starting a GFD, as a rise in antibody levels suggests dietary nonadherence. In the asymptomatic patient measurement of TTG at intervals of 1 year or longer may serve as a monitor of adherence to the GFD.

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ALGORITHMS FOR THE EVALUATION AND MANAGEMENT OF INFANTS AND CHILDREN WITH SUSPECTED CELIAC DISEASE

Evaluation of the Symptomatic Child

Identification of children with symptoms who need an intestinal biopsy to diagnose CD requires that health care professionals appreciate the variable clinical manifestations of the disorder. This includes recognition of both gastrointestinal and nongastrointestinal manifestations (Figure 1, Box 1; Table 1). After a detailed history and physical examination (Figure 1, Box 2), if CD is a consideration in the differential diagnosis, serological testing with TTG is recommended (Figure 1, Box 3). If TTG is normal, it is unlikely the child has CD, and other conditions are considered (Figure 1, Boxes 4 and 5). Symptomatic children with a positive TTG are referred to a pediatric gastroenterologist for small intestinal biopsy (Figure 1, Boxes 5 and 6). Those with histologic features of CD on biopsy are treated with a strict GFD (Figure 1, Boxes 8 and 9). If there is complete symptom resolution on a GFD, the diagnosis of CD can be considered definitive for life.

Children with symptoms who are TTG-positive but without characteristic changes of CD on small intestinal histology present a diagnostic challenge (Figure 1, Boxes 7 and 8). Possibilities in these cases include the following: the child does not have CD and the TTG was a false positive, the child has CD but the histologic changes were either not detected by the pathologist or were missed on biopsy because of the patchy nature of the disease or a positive TTG with a truly normal biopsy represents an early stage of the disease that is manifest by seropositivity only. Under such circumstances several strategies are available that may help establish a diagnosis (Figure 1, Box 7). These include a careful review of the original biopsy specimens by an experienced pathologist, measurement of EMA, repeating an endoscopy to obtain multiple small intestinal biopsy samples and determination of the HLA DQ2 and DQ8 genotypes. In the event the child is negative for both HLA DQ2 and DQ8, it is highly unlikely that CD is the cause of the symptoms and other conditions would be considered.

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Evaluation of the Asymptomatic Child in an At-Risk Group

It is recommended that asymptomatic children who are first-degree relatives of an individual with confirmed CD and those with autoimmune and nonautoimmune conditions known to be associated with CD undergo testing for CD beginning in childhood (Figure 2, Box 1; Table 2). It is recommended that testing occur after 3 years of age after the child has been on an adequate gluten containing diet for at least 1 year before testing. The initial test of choice for this purpose is the TTG (Figure 2, Box 2). For those individuals who are selective IgA deficient, measurement of TTG IgG is recommended. If the TTG is negative, it is unlikely the child has CD at that time. However, as demonstrated on interval testing in some patients with type 1 diabetes and Down syndrome, an initial negative serological test for CD does not entirely exclude the possibility the individual will develop CD later in life. Strategies for addressing this possibility include repeat TTG testing at intervals over a period of some years and at any time that the child develops symptoms compatible with CD or determining whether the child has the HLA DQ2 or DQ8 genotype (Figure 2, Boxes 3 and 4). Those who have neither of these genotypes may be reassured they are at minimal risk for CD and need no further testing. Conversely, those who are either HLA DQ2 or DQ8 positive are considered potentially at risk and may warrant later testing.

In the event the initial TTG is positive, the child is referred to a pediatric gastroenterologist for an intestinal biopsy (Figure 2, Boxes 4 and 5). If the histology is compatible with CD, the child is treated with a GFD for life (Figure 2, Boxes 7 and 8). Those with a positive TTG but without characteristic changes of CD on histology require additional strategies to clarify the situation (Figure 2, Boxes 6 and 7). These include reviewing the pathology with an experienced pathologist, repeating the endoscopy and obtaining multiple biopsies to exclude a patchy lesion, testing for EMA and determining whether the individual has either the HLA DQ2 or DQ8 genotype (Figure 2, Box 6). In the event the child is neither HLA DQ2 nor DQ8 positive, the likelihood of having CD is extremely small and no further testing is warranted. (For type 1 diabetics, see section 3.2.2.)

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Treatment and Monitoring of Patients with CD

The treatment of CD is a GFD for life. Untreated CD carries a significant increased risk for both morbidity and mortality. After histologic identification of intestinal mucosal features compatible with CD (Figure 3, Box 1), it is recommended that education be provided about CD and the potential adverse health consequences associated with continued ingestion of gluten and related products. It is recommended the patient be referred to a nutritionist for education about a GFD (Figure 3, Box 2). Referral to a CD support group is also considered beneficial by providing the opportunity for emotional and psychologic support and serving as a source of information for gluten-free products available locally.

Periodic assessment by the physician and nutritionist is recommended to monitor for symptom resolution, maintenance of continued growth and development, dietary review and repeat serological testing (Figure 3, Box 3). During these assessments health care professionals can reinforce the benefits of compliance with a strict GFD for life. Failure of the TTG level to decline over a period of 6 months after starting the GFD suggests continued ingestion of gluten or related products. In these cases there is need for careful dietary review looking for sources of gluten, and reinforcement of the need to remain on a strict GFD (Figure 3, Boxes 4 and 5). Normalization of TTG on repeat testing suggests compliance with the GFD. The complete resolution of symptoms in the previously symptomatic child is further supportive evidence that the patient is adhering to treatment (Figure 3, Boxes 5 and 6). These patients then receive annual assessment, providing they remain asymptomatic (Figure 3, Boxes 3 and 6).

Children whose symptoms persist or who develop symptoms again after a period of symptom resolution may be failing to adhere to treatment or may have an additional problem not related to CD (Figure 3, Boxes 6 and 7). Repeat serological testing in these cases is recommended. A positive test suggests nonadherence and requires dietary review and reinforcement of the need for compliance (Figure 3, Box 4). A negative test suggests the symptoms are not related to CD but does not entirely exclude the possibility of CD (Figure 3, Box 7). If, after evaluation for other conditions, no alternative cause for the symptoms is identified, it is reasonable to consider repeating the intestinal biopsy to detemine whether there are still changes compatible with CD.

Celiac Disease Guidelines Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Ivor D. Hill, M.D.

Winston Salem, NC

Martha H. Dirks, M.D.

Montreal, QC

Gregory S. Liptak, M.D.

Rochester, NY

Richard B. Colletti, M.D.

Burlington, VT

Alessio Fasano, M.D.

Baltimore, MD

Stefano Guandalini, M.D.

Chicago, IL

Edward J. Hoffenberg, M.D.

Denver, CO

Karoly Horvath, M.D.

Baltimore, MD

Joseph A. Murray, M.D.

Rochester, MN

Mitchell Pivor, M.D.

Winston Salem, NC

Ernest G. Seidman, M.D.

Montreal, QC

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Sensitive detection of cereal fractions that are toxic to celiac disease patients by using monoclonal antibodies to a main immunogenic wheat peptide
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American Journal of Clinical Nutrition, 87(2): 405-414.

Gastrointestinal Endoscopy
How many duodenal biopsy specimens are required to make a diagnosis of celiac disease?
Pais, WP; Duerksen, DR; Pettigrew, NM; Bernstein, CN
Gastrointestinal Endoscopy, 67(7): 1082-1087.
10.1016/j.gie.2007.10.015
CrossRef
Acta Gastro-Enterologica Belgica
Lymphocytic colitis in a child with non-responsive celiac disease
Ozturk, Y; Soylu, OB; Ozer, E
Acta Gastro-Enterologica Belgica, 71(4): 393-395.

Mayo Clinic Proceedings
Celiac disease in type 1 diabetes mellitus in a North American community: Prevalence, serologic screening, and clinical features
Mahmud, FH; Murray, JA; Kudva, YC; Zinsmeister, AR; Dierkhising, RA; Lahr, BD; Dyck, PJ; Kyle, RA; El-Youssef, M; Burgart, LJ; Van Dyke, CT; Brogan, DL; Melton, LJ
Mayo Clinic Proceedings, 80(): 1429-1434.

Revista Medica De Chile
Improving the management of celiac disease. An urgent challenge
Araya, M
Revista Medica De Chile, 134(3): 361-364.

Journal of the American Dietetic Association
Advances in celiac disease and gluten-free diet
Niewinski, MM
Journal of the American Dietetic Association, 108(4): 661-672.
10.1016/j.jada.2008.01.011
CrossRef
American Journal of Gastroenterology
A Report on the International Transglutaminase Autoantibody Workshop for Celiac Disease
Li, M; Yu, LP; Tiberti, C; Bonamico, M; Taki, I; Miao, DM; Murray, JA; Rewers, MJ; Hoffenberg, EJ; Agardh, D; Mueller, P; Stern, M; Bonifacio, E; Liu, E
American Journal of Gastroenterology, 104(1): 154-163.
10.1038/ajg.2008.8
CrossRef
Pediatric Diabetes
Intraepithelial lymphocytes in duodenum from Brazilian adolescents with type 1 diabetes. Influence of Helicobacter pylori
Cabral, VLR; Patricio, FRD; Gabbay, MAL; Dib, SA; Miszputen, SJ
Pediatric Diabetes, 10(5): 316-320.
10.1111/j.1399-5448.2008.00478.x
CrossRef
International Journal of Food Science and Technology
Effect of water, albumen and fat on the quality of gluten-free bread containing amaranth
Schoenlechner, R; Mandala, I; Kiskini, A; Kostaropoulos, A; Berghofer, E
International Journal of Food Science and Technology, 45(4): 661-669.
10.1111/j.1365-2621.2009.02154.x
CrossRef
Archives of Pathology & Laboratory Medicine
Gluten-Sensitive Enteropathy (Celiac Disease) Controversies in Diagnosis and Classification
Ensari, A
Archives of Pathology & Laboratory Medicine, 134(6): 826-836.

Journal of Gastroenterology and Hepatology
Effect of a gluten-free diet on growth and small-bowel histology in children with celiac disease in India
Yachha, SK; Srivastava, A; Mohindra, S; Krishnani, N; Aggarwal, R; Saxena, A
Journal of Gastroenterology and Hepatology, 22(8): 1300-1305.
10.1111/j.1440-1746.2007.04929.x
CrossRef
Nutrients
Is Dietitian Use Associated with Celiac Disease Outcomes?
Mahadev, S; Simpson, S; Lebwohl, B; Lewis, SK; Tennyson, CA; Green, PHR
Nutrients, 5(5): 1585-1594.
10.3390/nu5051585
CrossRef
Clinical Chemistry and Laboratory Medicine
A multiplex assay to rapidly exclude HLA-DQ2.5 and HLA-DQ8 expression in patients at risk for celiac disease
van Beek, EM; Roelandse-Koop, EA; Vijzelaar, R; Yilmaz, R; van Hoogstraten, IMW; Schreurs, MWJ; Verheul, AAM; van Houte, AJ; Kortlandt, W
Clinical Chemistry and Laboratory Medicine, 51(6): 1191-1198.
10.1515/cclm-2012-0774
CrossRef
Paediatrics & Child Health
Antitissue transglutaminase antibody determination versus upper endoscopic biopsy diagnosis of paediatric celiac disease
Saginur, M; AlRefaee, FAM; Spady, DW; Girgis, SAM; Huynh, HQ; Prosser, CI; Persad, R; Turner, JM
Paediatrics & Child Health, 18(5): 246-250.

International Immunology
Anti-transglutaminase immunoreactivity and histological lesions of the duodenum in coeliac patients
Nenna, R; Tiberti, C; Petrarca, L; Mennini, M; Mastrogiorgio, G; Lucantoni, F; Panimolle, F; Pontone, S; Bavastrelli, M; Magliocca, FM; Bonamico, M
International Immunology, 25(6): 389-394.
10.1093/intimm/dxs159
CrossRef
Nutrition Metabolism and Cardiovascular Diseases
Changes of body mass index in celiac children on a gluten-free diet
Brambilla, P; Picca, M; Dilillo, D; Meneghin, F; Cravidi, C; Tischer, MC; Vivaldo, T; Bedogni, G; Zuccotti, GV
Nutrition Metabolism and Cardiovascular Diseases, 23(3): 177-182.
10.1016/j.numecd.2011.10.002
CrossRef
Clinica Chimica Acta
Chemiluminescence and ELISA-based serum assays for diagnosing and monitoring celiac disease in children: A comparative study
Aita, A; Rossi, E; Basso, D; Guariso, G; Bozzato, D; Pelloso, M; Pescarin, M; Zambon, CF; Navaglia, F; Greco, E; Gasparetto, M; Fogar, P; Padoan, A; Moz, S; Plebani, M
Clinica Chimica Acta, 421(): 202-207.
10.1016/j.cca.2013.03.024
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Endocrine
Celiac disease in subjects with type 1 diabetes mellitus: a prevalence study in western Sicily (Italy)
Greco, D; Pisciotta, M; Gambina, F; Maggio, F
Endocrine, 43(1): 108-111.
10.1007/s12020-012-9718-8
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Gastroenterology Nursing
Pediatric Celiac Disease
Tully, M
Gastroenterology Nursing, 31(2): 132-140.
10.1097/01.SGA.0000316532.69484.44
PDF (360) | CrossRef
Journal of Clinical Gastroenterology
Strongly Positive Tissue Transglutaminase Antibodies are Associated With Marsh 3 Histopathology in Adult and Pediatric Celiac Disease
Neuhausen, SL; Donaldson, MR; Book, LS; Leiferman, KM; Zone, JJ
Journal of Clinical Gastroenterology, 42(3): 256-260.
10.1097/MCG.0b013e31802e70b1
PDF (101) | CrossRef
Journal of Clinical Gastroenterology
Celiac Disease: Prevention and Treatment
Selimoglu, MA; Karabiber, H
Journal of Clinical Gastroenterology, 44(1): 4-8.
10.1097/MCG.0b013e3181b7ead2
PDF (113) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Acute Pancreatitis in a Child With Celiac Disease
Bultron, G; Latif, U; Park, A; Phatak, U; Pashankar, D; Husain, S
Journal of Pediatric Gastroenterology and Nutrition, 49(1): 137-138.
10.1097/MPG.0b013e318172aad1
PDF (99) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition Consensus Report on Celiac Disease
Fasano, A; Araya, M; Bhatnagar, S; Cameron, D; Catassi, C; Dirks, M; Mearin, M; Ortigosa, L; Phillips, A; Celiac Disease Working Group:,
Journal of Pediatric Gastroenterology and Nutrition, 47(2): 214-219.
10.1097/MPG.0b013e318181afed
PDF (196) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Novel Screening Assay Performance in Pediatric Celiac Disease and Adult Dermatitis Herpetiformis
Jaskowski, TD; Donaldson, MR; Hull, CM; Wilson, AR; Hill, HR; Zone, JJ; Book, LS
Journal of Pediatric Gastroenterology and Nutrition, 51(1): 19-23.
10.1097/MPG.0b013e3181c992be
PDF (139) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Changing Phenotype of Celiac Disease After Long-term Gluten Exposure
Kurppa, K; Koskinen, O; Collin, P; Mäki, M; Reunala, T; Kaukinen, K
Journal of Pediatric Gastroenterology and Nutrition, 47(4): 500-503.
10.1097/MPG.0b013e31817d8120
PDF (202) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Deamidated Gliadin Peptides Form Epitopes That Transglutaminase Antibodies Recognize
Korponay-Szabó, IR; Vecsei, Z; Király, R; Dahlbom, I; Chirdo, F; Nemes, É; Fésüs, L; Mäki, M
Journal of Pediatric Gastroenterology and Nutrition, 46(3): 253-261.
10.1097/MPG.0b013e31815ee555
PDF (172) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Prediction of Clinical and Mucosal Severity of Coeliac Disease and Dermatitis Herpetiformis by Quantification of IgA/IgG Serum Antibodies to Tissue Transglutaminase
Dahlbom, I; Korponay-Szabó, IR; Kovács, JB; Szalai, Z; Mäki, M; Hansson, T
Journal of Pediatric Gastroenterology and Nutrition, 50(2): 140-146.
10.1097/MPG.0b013e3181a81384
PDF (552) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
HLA-DQB1*02 Dose Effect on RIA Anti-tissue Transglutaminase Autoantibody Levels and Clinicopathological Expressivity of Celiac Disease
Tiberti, C; Bonamico, M; Nenna, R; Mora, B; Megiorni, F; Mazzilli, MC; Magliocca, FM
Journal of Pediatric Gastroenterology and Nutrition, 47(3): 288-292.
10.1097/MPG.0b013e3181615ca7
PDF (146) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Duodenal Bulb Biopsies in Celiac Disease: A Multicenter Study
Bonamico, M; Thanasi, E; Mariani, P; Nenna, R; Luparia, R; Barbera, C; Morra, I; Lerro, P; Guariso, G; De Giacomo, C; Scotta, S; Pontone, S; Carpino, F; Magliocca, FM; and the Società Italiana di Gastroenterologica, Epatologia, e Nutrizione Pediatrica,
Journal of Pediatric Gastroenterology and Nutrition, 47(5): 618-622.
10.1097/MPG.0b013e3181677d6e
PDF (204) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Serum and Intestinal Dipeptidyl Peptidase IV (DPP IV/CD26) Activity in Children With Celiac Disease
Detel, D; Peršic, M; Varljen, J
Journal of Pediatric Gastroenterology and Nutrition, 45(1): 65-70.
10.1097/MPG.0b013e318054b085
PDF (160) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Growth Hormone Treatment in Prepubertal Children With Celiac Disease and Growth Hormone Deficiency
Giovenale, D; Meazza, C; Cardinale, GM; Farinelli, E; Mastrangelo, C; Messini, B; Citro, G; Del Vecchio, M; Di Maio, S; Possenti, I; Bozzola, M
Journal of Pediatric Gastroenterology and Nutrition, 45(4): 433-437.
10.1097/MPG.0b013e3180de5e0a
PDF (119) | CrossRef
Journal of Pediatric Gastroenterology and Nutrition
Antigliadin Immunoglobulin A Best in Finding Celiac Disease in Children Younger Than 18 Months of Age
Lagerqvist, C; Dahlbom, I; Hansson, T; Jidell, E; Juto, P; Olcén, P; Stenlund, H; Hernell, O; Ivarsson, A
Journal of Pediatric Gastroenterology and Nutrition, 47(4): 428-435.
10.1097/MPG.0b013e31817d80f4
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Journal of Pediatric Gastroenterology and Nutrition
A New Indirect Chemiluminescent Immunoassay to Measure Anti–tissue Transglutaminase Antibodies
Basso, D; Guariso, G; Fasolo, M; Pittoni, M; Schiavon, S; Fogar, P; Greco, E; Navaglia, F; Zambon, C; Plebani, M
Journal of Pediatric Gastroenterology and Nutrition, 43(5): 613-618.
10.1097/01.mpg.0000239739.09983.38
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Journal of Pediatric Hematology/Oncology
A Rare Condition Associated With Celiac Disease: Evans Syndrome
Yarali, N; Demirceken, F; Kondolat, M; Ozkasap, S; Kara, A; Tunc, B
Journal of Pediatric Hematology/Oncology, 29(9): 633-635.
10.1097/MPH.0b013e318142ac48
PDF (144) | CrossRef
Orthopaedic Nursing
Celiac Disease: Its Implications for Orthopaedic Nursing
Hans, ZJ
Orthopaedic Nursing, 27(5): 291-294.
10.1097/01.NOR.0000337279.63293.6d
PDF (250) | CrossRef
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