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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e31823255c9
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Are Immunoglobulin A Anti-gliadin Antibodies Helpful in Diagnosing Coeliac Disease in Children Younger Than 2 Years?

Foucher, Barbara*; Johanet, Catherine; Jégo-Desplat, Sophie; Sanmarco, Marielle; Dubucquoi, Sylvain; Fily-Nalewajk, Sandrine; Olsson, Nils-Olivier; Lakomy, Daniela; Escande, Andrée; Chrétien, Pascale; Fortenfant, Françoise; Chevailler, Alain; André, Chantal; Goetz, Joëlle; Humbel, René-Louis; Monier, Jean-Claude; Sibilia, Jean; Taillefer, Marie-France; Abreu, Isabelle; Fabien, Nicole*

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*Department of Immunology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Inserm U851, Pierre-Benite

Groupe d’Etude de l’Auto-Immunité (GEAI), Angers

Department of Immunology, CHRU Lille, Lille, France.

Address correspondence and reprint requests to Nicole Fabien, Department of Immunology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Inserm U851, 69495 Pierre-Benite Cedex, France (e-mail: nicole.fabien@chu-lyon.fr).

Received 31 March, 2011

Accepted 10 August, 2011

The authors report no conflicts of interest.

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Abstract

ABSTRACT: The usefulness of immumoglobulin (Ig) A antibodies to gliadin (AGA-IgA) in addition to IgA anti-endomysium and tissue transglutaminase antibodies was evaluated in 4122 children younger than 2 years with a suspicion of coeliac disease (CD). Eight percent (312/4122) displayed IgA anti-endomysium and/or IgA anti-tissue transglutaminase, whereas 2.1% (85/4122) displayed only AGA-IgA. Clinical data were obtained for 62 of 85 children with isolated AGA-IgA, and 33 children underwent a duodenal biopsy. Histologically proven CD was established for 5 patients, whereas 57 children were diagnosed to experience other diseases. The systematic detection of AGA-IgA using native gliadin conferred no additional diagnostic benefit for the diagnosis of CD in children younger than 2 years of age, except for rare cases.

Coeliac disease (CD) is defined as a small bowel enteropathy triggered by the ingestion of wheat gliadin in genetically susceptible individuals. The diagnosis of CD can be made at any age of life but especially during the early childhood, between 9 and 24 months, or in the third or fourth decade of life (1). The prevalence of CD between 2.5 and 15 years in the general population ranges from 3 to 13/1000 children, or approximately 1:300 to 1:80 children in Europe and the United States (2).

CD encompasses a large spectrum of clinical manifestations ranging from serious symptomatic forms to completely asymptomatic ones (2–6). Early childhood CD frequently has gastrointestinal symptoms such as diarrhoea with failure to thrive, abdominal pain, vomiting, constipation and abdominal distension starting between 6 and 24 months of age, and nongastrointestinal manifestations (1,4). Children may have a milder constellation of symptoms such as abdominal discomfort, indigestion, or only nongastrointestinal symptoms. In parallel, histological changes in the small intestinal mucosa can also range from typical severe lesions (villous atrophy, hyperplasia of the crypts) to mild forms characterized by minor degrees of enteropathy with a lymphocytic infiltrate and increased epithelial cell proliferation (7).

Along with the duodenal biopsy, serological and genetic tests have acquired greater importance in CD diagnosis in both symptomatic and nonsymptomatic forms. The finding of immunoglobulin (Ig) A antibodies to gliadin (AGA-IgA), endomysium (EMA-IgA), and tissue transglutaminase (tTG-IgA) and their disappearance on a gluten-free diet are considered as supporting evidence for the diagnosis of CD.

The utility to perform these 3 serological tests simultaneously was reconsidered when it was demonstrated that EMA-IgA and tTG-IgA had a higher diagnostic performance than AGA-IgA (2,8,9). EMA-IgA and tTG-IgA are greatly sensitive (88%–100%) and specific (95%–99%) tests to identify individuals experiencing CD (8,10,11). For this reason, the use of AGA-IgA was no longer recommended (2,12). However, there is still doubt about the interest of detection of AGA-IgA especially in children younger than 2 years with neither EMA-IgA nor tTG-IgA, as it has been shown that AGA-IgA are more accurate in these cases (13–16).

The aim of our study was to evaluate the real usefulness of AGA-IgA in a large children population, younger than 2 years of age, with a suspicion of CD to find out whether the determination of AGA-IgA should be abolished as it was suggested by others (2,12,17) or should still be used in daily practice.

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PATIENTS AND METHODS

Patients

The present retrospective study analysed 4122 children (median age at diagnostic 15 months, range 3–24 months, with a sex ratio F:M equal to 1:3) experiencing clinical symptoms that could be associated with CD and had been investigated for AGA-IgA along with tTG-IgA and/or EMA-IgA. The patients came from the paediatric departments of several hospitals (Angers, Annonay, Bourg en Bresse, Dijon, Chalon-sur-saône, Saone, Chambery, Lons-le-Saunier, Lyon, Marseille, Montceau les Mines, Montluçon, Montpellier, Paris, and Strasbourg). Clinical data and histological findings of intestinal biopsies were obtained from 62 and 33 children displaying isolated positive AGA-IgA, respectively. The severity of mucosal atrophy was described according to the histological Marsh classification (18). Definitive diagnosis of CD was confirmed according to the consensus statement on CD of the National Institutes of Health (12).

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Detection of Antibodies

The serological markers most commonly used in clinical routine were performed in 10 different laboratories (Angers, Dijon, Lyon, Marseille, Montpellier, Paris, and Strasbourg). Detection of EMA-IgA was performed by indirect immunofluorescence technique using tissue sections from monkey oesophagus as substrate (Biorad, Marnes la Coquette, France; The Binding site, Saint Egrève, France). tTG-IgA were detected by an enzyme-linked immunosorbent assay and fluorimetry using as antigen human recombinant transglutaminase, according to the manufacturer's instructions (Eurospital, Trieste, Italy; Phadia, Saint Quentin en Yvelines, France; FIDIS Biomedical, BMD, Marne la Vallée, France). AGA-IgA were identified by enzyme-linked immunosorbent assay using a native gliadin antigen (fraction of gliadin from wheat gluten) according to the manufacturer's instructions (BMD; Menarini, Rungis, France; Phadia).

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RESULTS

Three hundred and twelve children of 4122 (8%) displayed at least EMA-IgA and/or tTG-IgA (Table 1). Eighty-five children of 3810 (2,2%) that were both EMA-IgA and tTG-IgA negative were shown to display AGA-IgA.

Table 1
Table 1
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The clinical data were obtained for 62 of 85 children (Fig. 1). Thirty-three of the 62 children underwent a duodenal biopsy; 24 had small intestinal mucosal evaluation without revealing any degree of villous atrophy. Nine duodenal biopsies were classified as total (Marsh IIIc) (n = 1), subtotal (Marsh IIIb) (n = 5), and partial (Marsh IIIa) (n = 3) villous atrophy. Only 5 of those 9 patients were finally diagnosed as having a biopsy-proven CD, whereas the 4 other patients belong to the group of children with a diagnosis of non-CD; these children (57/62) experienced isolated diarrhoea or constipation (n = 38), growth deficiency (n = 10), cow's-milk protein intolerance (n = 2), iron-deficient anaemia (n = 1), Helicobacter pylori–associated gastritis (n = 1), other gastritis associated with recurrent abdominal pain (n = 2), cystic fibrosis (n = 1), schwannoma (n = 1), and myelodysplastic syndrome (n = 1).

Figure 1
Figure 1
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DISCUSSION

Our results suggest that in a population of children younger than 2 years suspected of having CD, there is no need to simultaneously perform the detection of AGA-IgA in addition to EMA-IgA/tTG-IgA. It is well known that a majority of children diagnosed as having CD displayed tTG-IgA and EMA-IgA during their first year of life, but it has been shown that AGA-IgA can precede detectable tTG-IgA levels in serum (13). The presence of AGA-IgA before tTG-IgA is not well understood; AGA-IgA could reach the peripheral circulation, whereas tTG-IgA may stay mainly in the intestine (14,19,20).

Although the last guidelines for the diagnosis of CD, based on the current evidence, practical considerations including accuracy, reliability, and cost, indicated that measurement of AGA-IgA was no longer recommended (2), there are reports in which AGA-IgA seemed to be more sensitive than tTG-IgA and EMA-IgA with a prevalence of 97%, 83%, and 83%, respectively, in the population of children younger than 2 years (14). It was also demonstrated that tTG-IgA and EMA-IgA are less sensitive than AGA-IgA, with a positivity of 87%, 88%, and 89% of the cases, respectively (16); however, these studies only focused on children with biopsy-verified CD and not on a large population of children with a suspicion of CD. Therefore, it was important to analyse a large cohort of children who were investigated for CD but with no confirmed diagnosis at the time the serological tests were performed. Moreover, the present multicentric study was done with different serological tests avoiding the bias of a lack of sensitivity of a particular technique to detect AGA-IgA or difference in the clinical screening of patients.

In our study, only 2.1% (85/4122) of patients displayed isolated AGA-IgA with no tTG-IgA and EMA-IgA. Considering AGA-IgA as a second-line test when tTG-IgA and EMA-IgA were negative, the accuracy of the test was also poor, with 85 of 3811 children (2.2%) being positive. Clinical data were obtained for 62 of 85 children because 23 children were no longer studied by the paediatric departments, certainly because of weak symptoms and recovery. The CD diagnosis was probably excluded for those 23 patients. Thirty-three children with isolated AGA-IgA underwent a duodenal biopsy, and histologically proven CD was established for 5 patients. From a clinical point of view, 8.1% and 0.12% of the children, when considering the population of isolated AGA-IgA or the entire population, experienced CD, respectively. The vast majority of children displaying isolated AGA-IgA experienced non-CDs that were previously shown to be associated with these antibodies, except for schwannoma (21).

Our study is in accordance with previous studies showing that AGA-IgA should no longer be performed because of a lack of specificity or a lack of sensitivity when compared with tTG-IgA and EMA-IgA (11,15,22,23). Another study gave the same results, showing that all of the AGA-IgA–positive results in the presence of negative tTG/EMA were false-positives (17).

In addition, in our experience, isolated AGA-IgA does not really help the choice of stepping up to the biopsy level, this decision remaining clinically based, as recommended in the case of unusual seronegative CD by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (2). Although the sensitivity of this test has been described to be higher, we believe it should not be used in daily practice because of its poor specificity. The systematic test of AGA-IgA conferred no additional diagnostic benefit in comparison with tTG-IgA.

Because 5 patients were finally diagnosed as having CD, AGA-IgA could be proposed as a second-line test. We also must take into account that new generation of serological tests using antigen derived from gliadin or synthetic deamidated gliadin peptides are now available. The benefit of these new tests in patients with neither tTG-IgA nor EMA-IgA (5,16,24), as well as other tests such as HLA-DQ2/-DQ8 genotype typing, need to be evaluated in large populations.

In conclusion, although some children with CD younger than 2 years display isolated AGA-IgA, our data confirm in a large cohort of patients that the last guidelines for the diagnosis of CD should be followed with suppression of testing AGA-IgA in daily practice.

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Acknowledgments

The authors thank all of the paediatricians and the anatomopathologists (hospitals: Angers, Dijon, Lyon, Marseille, Montpellier, Paris, and Strasbourg) who contributed to the study.

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Cited By:

This article has been cited 1 time(s).

World Journal of Gastroenterology
Persistent hypertransaminasemia in asymptomatic children: A stepwise approach
Vajro, P; Maddaluno, S; Veropalumbo, C
World Journal of Gastroenterology, 19(): 2740-2751.
10.3748/wjg.v19.i18.2740
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Keywords:

celiac disease; IgA anti-endomysium antibodies; IgA anti-gliadin antibodies; IgA anti-transglutaminase antibodies

Copyright 2012 by ESPGHAN and NASPGHAN

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