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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e31822a00bb
Original Articles: Gastroenterology

Coeliac Disease Diagnosis: ESPGHAN 1990 Criteria or Need For a Change? Results of a Questionnaire

Ribes-Koninckx, C.*; Mearin, ML.; Korponay-Szabó, IR.; Shamir, R.§; Husby, S.||; Ventura, A.; Branski, D.#; Catassi, C.**; Koletzko, S.††; Mäki, M.‡‡; Troncone, R.§§; Zimmer, KP.||||; on Behalf of the ESPGHAN Working Group on Coeliac Disease Diagnosis

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*Pediatric Gastroenterology Unit, La Fe University Hospital, Valencia, Spain

Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands

Department of Paediatrics, Medical and Health Science Centre, University of Debrecen, Nagyerdei, Debrecen, and Heim Pal Children's Hospital, Budapest, Hungary

§Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Tel-Aviv University, Tel-Aviv, Israel

||Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense C, Denmark

Department of Paediatrics, Institute for Child Health IRCCS Burlo Garofolo, University of Trieste, Trieste, Italy

#Department of Paediatrics, Hadassah University Hospitals, Jerusalem, Israel

**Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy

††Dr von Haunersches Kinderspital, Ludwig Maximilians Universität München Lindwurmstr, München, Germany

‡‡Pediatric Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland

§§Department of Pediatrics and European Laboratory for the Investigation of Food Induced Diseases, University Federico II, Naples, Italy

||||Zentrum für Kinderheilkunde und Jugendmedizin, Allgemeine Pädiatrie und Neonatologie, Justus-Liebig-Universität, Feulgenstr, Gießen, Germany.

Address correspondence and reprint requests to C. Ribes Koninckx, Pediatric Gastroenterology, La Fe University Hospital, Valencia, Spain (e-mail: ribes_car@gva.es).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jpgn.org).

Received 4 May, 2011

Accepted 17 June, 2011

The authors report no conflicts of interest.

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Abstract

Background and Objectives: A revision of criteria for diagnosing coeliac disease (CD) is being conducted by The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). In parallel, we have performed a survey aimed to evaluate present practices for CD among paediatric gastroenterologists and to learn their views on the need for modification of present criteria for CD diagnosis.

Patients and Methods: Questionnaires were distributed to experienced paediatric gastroenterologists (ESPGHAN members) via the Internet.

Results: Overall, 95 valid questionnaires were available for analysis, pertaining to 28 different countries, with the majority of responders treating patients with CD for >15 years. Only about 12% of the responders comply with present criteria, noncompliance being related mainly to the challenge policy. Approximately 90% request a revision and modification of the present criteria. Forty-four percent want to omit the small bowel biopsy in symptomatic children with positive anti-tissue transglutaminase immunoglobulin (Ig) A or endomysial IgA antibodies, especially if they are DQ2/DQ8 positive. For silent cases detected by screening with convincingly positive anti-tissue transglutaminase IgA or EMA IgA, about 30% consider that no small bowel biopsy should be required in selected cases. Adding human leukocyte antigen typing in the diagnostic workup was asked for by 42% of the responders. As for gluten challenge, a new policy is advocated restricting its obligation to cases whenever the diagnosis is doubtful or unclear.

Conclusions: Based on these opinions, revision of the ESPGHAN criteria for diagnosing CD is urgently needed.

In 1969 at the Interlaken meeting of the European Society of Pediatric Gastroenterology and Nutrition (ESPGAN), the diagnostic criteria for coeliac disease (CD) were established for the first time (1). Accordingly, CD diagnosis required performing a sequence of 3 small bowel biopsies (SBB), the first one at clinical suspicion and while the child was consuming gluten; then, after characteristic histological lesions were observed, a gluten-free diet (GFD) was advised, followed by a new SBB to ascertain mucosal recovery. To verify permanent gluten sensitivity, a gluten challenge (GC) was performed, and only after confirmation of histological relapse in a third biopsy was the CD diagnosis considered to be definite (1). At that time, all of the diagnosed patients were symptomatic, but it had been shown that symptoms alone were not reliable, and thus they did not form part of the diagnostic criteria.

Twenty years later, experience in a remarkably large series of children pointed out that the GC could probably be avoided in 95% of cases (2,3). Thus, criteria were revisited, and as a result, new European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) criteria were established in 1990 (4). Consequently, and irrespective of the clinical picture, a definite CD diagnosis could be established in symptomatic subjects older than 2 years with characteristic lesions of the small bowel mucosa and improvement or disappearance of symptoms after a GFD. The presence of CD serological markers, vanishing after gluten withdrawal, was considered to add support to the diagnosis. A mandatory GC for CD confirmation was limited to the following special circumstances (4):

1. Infants younger than 2 years at the first biopsy to exclude other causes of enteropathy

2. Gluten exclusion before or without a biopsy

3. A biopsy at diagnosis not showing characteristic histological lesions for CD

4. Whenever the initial diagnosis is uncertain

Serological markers widely available at that time were the anti-gliadin antibodies (5–7), whereas anti-endomysium antibodies (EMA), which display a higher diagnostic performance, did not spread untill the late 1980s (7–10). Only in the 1990s was it demonstrated that initial EMA positivity in patients with small intestinal villous atrophy was as predictive of CD diagnosis as traditional GC and full Interlaken criteria (10). In 1997, the identification of tissue transglutaminase (tTG) as the autoantigen in CD led to IgA and IgG antibodies detection specific for tTG (anti-tTG), the production of which is related to dietary exposure to gluten (11).

Both IgA EMA and IgA anti-tTG recognise the same autoantigen and show a sensitivity and specificity superior to 95% in the majority of published studies (12–14). Moreover, the strong association of CD with the genetic markers human leukocyte antigen (HLA) DQ2 and/or HLA-DQ8, which when combined reach a sensitivity of >96% in most populations, implies that a negative result of HLA-DQ2 and/or -DQ8 renders CD diagnosis highly unlikely (15–17). More recently, antideamidated gliadin peptide antibodies (18), with higher sensitivity and specificity than conventional anti-gliadin antibodies and point of care tests (19–21), have joined anti-tTG and EMA as tests with high diagnostic performance.

Notwithstanding this new scenario, ESPGHAN CD diagnostic criteria were unchanged since 1990. Even recently, published guidelines maintain the requirement of a characteristic histological lesion of the small bowel mucosa to establish the diagnosis of CD (22,23). Lately, critical voices have been demanding that in view of their high diagnostic accuracy, specific antibody testing replace the SBB in the diagnostic procedure for CD, at least for some selected patients, especially those with high anti-tTG antibody levels (24–27). This position is concordant with accumulated experience showing that conventional histological examination is a questionable criterion standard for the diagnosis of CD (28–32). Additionally, a high relapse rate after GC in children younger than 2 years with positive EMA and villous atrophy at diagnosis has been demonstrated, supporting the view that routine GC should not be obligatory in these cases (33,34).

Consequently, this new scenario prompted us to conduct a survey to gain insight into the present practices followed by ESPGHAN members in the diagnosis of CD. Additionally, we aimed at learning their opinion concerning the need for modification of the present criteria and at identifying what changes, if any, were demanded by the majority of ESPGHAN members.

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PATIENTS AND METHODS

A questionnaire focusing on the most important issues concerning the 1990 ESPGHAN criteria for CD diagnosis was elaborated by the members of the working group. The questionnaire consisted of 3 parts (online-only Appendix 1, http://links.lww.com/MPG/A60). The first part requests general data on the experience of the respondents with CD, considering both the years of clinical practice in CD and the number of patients with CD diagnosed yearly. The second part deals with the present diagnostic practices of the respondents, and the third one with the wishes and suggestions of ESPGHAN members concerning possible changes in the diagnostic criteria for CD in childhood. The questionnaire was successfully validated by comparing the results in 10 colleagues who responded twice within 3 to 6 months.

Between December 2007 and March 2008, the questionnaire was e-mailed by the ESPGHAN secretariat to all of the ESPGHAN members working in gastroenterology. Colleagues who declared working exclusively in hepatology and/or nutrition were not addressed. Completed questionnaires returned via mail or e-mail to the working group before October 2008 were included in the evaluation. Completed questionnaires were excluded from further analysis, if question numbers 4, 5, and 8, considered to be crucial, were not answered (see online-only Appendix 1). For each question, responses were numbered and SPSS 15.0 (SPSS Inc, Chicago, IL) was used for statistical data analysis.

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RESULTS

A total of 111 questionnaires were returned, comprising >40% of all of the members involved with gastroenterology at that time. Of those, 95 were considered for evaluation; they had been returned by ESPGHAN members from 28 different countries (online-only Appendix 2, http://links.lww.com/MPG/A61).

Although the possibility was given to stay anonymous except for the country of origin, 90% of the questionnaires included a complete identification of the respondent.

In Figure 1, we show the distribution of the respondents according to the number of years of experience with the care of patients with CD. More than 70% of the questionnaires (71) were returned by paediatric gastroenterologists (PGs) with >15 years of experience in the field of CD, 25 (35%) of them diagnosing >25 new CD cases per year and 19 (27%) between 15 and 25 annually.

Figure 1
Figure 1
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Figure 2 shows the distribution of all 95 respondents, according to the number of new CD cases per year, with 60% diagnosing >15 new patients annually.

Figure 2
Figure 2
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In Table 1, we show the distribution by number of cases diagnosed before age 2 years, with 35 of 95 (37%) respondents diagnosing >10 patients younger than 2 years annually.

Table 1
Table 1
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When specifically asked about compliance with the present 1990 ESPGHAN criteria, 12.5% of the respondents (12/94) stated that they followed them and did not want any modification, as opposed to 77% (72/94) who declared that they followed the 1990 criteria but wanted them modified. Additionally, 10 PGs (10.5%) stated that they do not follow the present criteria, with 6 of them declaring >20 years of clinical experience with CD. Ninety-one of 95 (96%) affirmed that they always perform an initial SBB before starting a GFD in symptomatic patients. The 4 practitioners who stated they not do so have >20 years’ experience and omit the SBB only in DQ2- and/or DQ8-positive patients with positive anti-tTG IgA antibodies, pertaining to high-risk groups, such as first-degree relatives of patients with CD (1 PG) or associated autoimmune disease (3 PGs).

In asymptomatic patients, 97% of the respondents always perform an SBB before advising a GFD.

A majority of respondents (73/95 [76%]) always perform an SBB in IgA-deficient patients, independent of the results of the IgG-specific CD antibodies. The remainder follow the same policy as in non-IgA deficients, but use IgG-class antibodies.

Only 15% of the respondents (14/94) stated that they perform HLA-DQ genotyping in all patients with clinical suspicion of CD. Thirty-seven PGs (39%) carry out HLA typing only in selected cases to support the diagnosis and 11 exclusively to select patients in at-risk groups. Additionally, 7 perform HLA typing for any of both purposes. No facilities for HLA genotyping were reported by 11 respondents (12%).

As for GC practices, only 12% of the respondents (11/94) declared that they comply with the present indications for GC. As shown in Table 2, 4% (4/94) said that they will always perform a GC before establishing a definitive diagnosis of CD, 4% never will, and 41 PGs (43.5%) only perform a GC in selected cases (Table 2). Specifically, only 30% of PGs perform a confirmatory GC in all patients younger than 2 years at the time of the first SBB.

Table 2
Table 2
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Before starting a GC, 33 of 95 (35%) always perform a biopsy, 24 (25%) never perform a biopsy before challenge, and 30 (32%) perform one only in selected circumstances.

After GC, 52 respondents (52%) stated that they always perform a SBB to ascertain recurrence and 8 perform a SBB only in selected cases. Additionally, 32 PGs (32%) consider SBB sufficient for confirmation, if serological and/or clinical response occurs.

When asked about how the 1990 ESPGHAN criteria should be modified regarding the initial diagnostic workup, the working group obtained 93 valid responses. For symptomatic cases, 46% of respondents (43/93) want the first SBB to be maintained in all cases. Nineteen respondents suggest the addition of HLA typing to the diagnostic workup as the only modification to the present criteria. Conversely, 44% (41/93) want to omit the SBB in specific circumstances: 28 (30%) want no first biopsy required for cases with positive tTG IgA or EMA IgA and DQ2/DQ8, and 13 want to omit the first biopsy, independent of HLA, as shown in Table 3.

Table 3
Table 3
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In silent cases detected by screening with convincingly positive tTG IgA or EMA IgA, only 2 PGs believed that an SBB is not required to test the diagnosis of CD. Sixty-nine percent (64/93) consider a first SBB mandatory in all cases, and the remaining 27 believe that no first biopsy should be required in selected cases (Table 3).

Concerning the challenge policy, 13 of 95 (13.7%) believe that criteria for GC should not be modified, as opposed to 82 who propose 1 or several modifications. Thus, 47% (46/95) are of the opinion that GC should not be obligatory for all of the infants diagnosed (first biopsy) before age 2 years, and 8 of them suggest no further modification to the present challenge criteria.

Overall, 50 of 95 (52.6%) consider a GC mandatory, if before the start of a GFD no valid biopsy was performed, and 24 are of the opinion that a GC should be carried out if the first biopsy does not show at least a Marsh 3a lesion, that is, increased intraepithelial lymphocyte count plus crypt hyperplasia plus villous atrophy.

Twenty-one respondents suggest an SBB to assess relapse, if a GC is performed, 14 of them together with serology and clinical response. Twelve rely on serology only and 12 more rely solely on clinical symptoms.

As for government support to cover the costs of gluten-free products, 20 of 90 (22%) respondents declared that patients with CD do not receive any financial support in their country at all, 65 say that patients will receive some reimbursement of costs if a physician statement is procured, and 39 of them state that a biopsy-based diagnosis is required.

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DISCUSSION

The present survey was answered by experienced PGs, the majority treating patients with CD for >15 years and 35% diagnosing >25 new cases per year. Concerning present diagnostic practices, >95% always perform an SBB before starting a GFD in both symptomatic and asymptomatic patients, independent of a high level of suspicion supported by clinical presentation, serology, or HLA typing. HLA typing is generally only used to select patients in at-risk groups and/or in ambiguous cases. Only a minority of PGs reported no facilities for HLA typing.

Concerning GC practices, at present only 30% of PGs always carry out a GC when the first biopsy was performed before the age of 2 years. The majority restrict the indication to special situations, such as an equivocal diagnosis in view of a missing first SBB or no characteristic serology at initial investigation, or in face of dietary transgressions (unintentional challenge). The majority of them will perform a prechallenge as well as a postchallenge biopsy to confirm a histological relapse after the reintroduction of gluten; it is noteworthy that as much as 17.5% will rely solely on serology or symptoms to establish disease recurrence.

Although 90% of PGs claim to follow the present ESPGHAN criteria, this contradicts the challenge practices admitted in the questionnaire, as discussed before. Indeed, only 12.5% of respondents perform a GC according to the specific indications, and thus only this small minority complies with the 1990 criteria for CD diagnosis. This is in keeping with the approximately 90% calling for a revision and modification of the present criteria.

A recent survey carried out to investigate the present implementation of the 1990 ESPGHAN criteria for the diagnosis of CD in Italy concluded that 85% of centres theoretically use the 1990 ESPGHAN criteria, but 80% do not perform a GC in children younger than 2 years (35). These results are comparable to the corresponding findings in the present survey. Although almost all of the Italian centres still perform an SBB for diagnostic purposes, it can be concluded that histology plays a less relevant role; also minor degree lesions, such as Marsh 1 (ie, increased IEL without villous atrophy) or 2 (ie, increased intraepithelial lymphocyte plus crypt hyperplasia), were considered to be consistent with CD diagnosis. This is somewhat different from the present survey results, in which a low-grade lesion generally leads to further workup for diagnostic confirmation, including a GC followed by an SBB.

About half of the ESPGHAN PGs who responded consider a first SBB mandatory even in symptomatic cases, but a similar number believe that this could be avoided in convincingly positive tTG or EMA cases, all the more in DQ2- and/or DQ8-positive individuals, but not restricted to them. There is a need to exactly define the value for high tTG, and although a few studies have addressed this issue, this matter is still controversial caused by, mainly but not exclusively, heterogeneity of assays (24–27). In the same context, the higher specificity of EMA should also be taken into consideration (32).

For silent cases detected by screening, a higher percentage (80%) of respondents believe that SBB should be obligatory to confirm the diagnosis. Adding HLA typing to the diagnostic workup was requested by 42% of the respondents.

The majority of respondents demand a modification of present challenge criteria, and the modification most frequently warranted is the omission of mandatory GC for children younger than 2 years with a suspected diagnosis. This is a matter of concern among our colleagues participating in the survey and led to multiple comments and observations in different parts of the questionnaire. This is related to the still relatively high proportion of patients diagnosed before age 2 years in our milieu.

Respondents repeatedly requested quality controls of serological methods and for identification of cutoff levels with the highest diagnostic accuracy, which in the near future could render an SBB dispensable in the diagnosis of CD.

The general conclusion is that the majority of ESPGHAN members want the present CD diagnostic criteria to be modified in 2 main aspects: first, a challenge not to be obligatory in all cases with a first diagnostic biopsy before age 2 years, and second, avoidance of the biopsy in selected cases, especially in symptomatic children who are DQ2 and/or DQ8 positive with high EMA or tTG levels.

The implications for changes in the present criteria according to ESPGHAN members’ demands are obvious, especially regarding the omission of a biopsy in well-selected cases. This would be in agreement with a new and broader definition of CD as a systemic disorder with different degrees of mucosal lesions not restricted to villous atrophy (29,32). Accordingly, the diagnosis cannot rely on a single parameter but on a combination of clinical symptoms, CD-specific autoantibodies, histology, and genetics. A literature review of evidence is being conducted by the working group to obtain adequate scientific support to review present criteria and modify them accordingly.

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Keywords:

coeliac disease diagnosis; ESPGHAN 1990 criteria; questionnaire

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