Alimentary tract
Diagnostic methods beyond conventional histology in coeliac disease diagnosis

https://doi.org/10.1016/j.dld.2009.04.004Get rights and content

Abstract

Background

Coeliac disease diagnostic criteria currently require the detection of small bowel mucosal villous atrophy and crypt hyperplasia.

Aims

To compare conventional histological examination to the determination of small bowel mucosal intraepithelial lymphocytes (IELs) and to serum and intestinal coeliac autoantibodies in untreated coeliac disease with villous atrophy and in mild enteropathy coeliac disease.

Patients and methods

Study comprised consecutive adult patients with coeliac disease suspicion; villous height–crypt depth ratio (Vh/CrD), the densities of CD3+, γδ+ and villous tip IELs and serum and intestinal transglutaminase 2 (TG2)-targeted autoantibodies were studied. Coeliac disease was diagnosed in 223 and excluded in 608 patients. Further, 66 patients were considered to suffer from mild enteropathy coeliac disease. Control group consisted of 138 patients.

Results

Vh/CrD determination detected 77% of untreated coeliac disease patients. Serum coeliac autoantibodies had 84% sensitivity for untreated coeliac disease with villous atrophy and 70% sensitivity for mild enteropathy coeliac disease; the specificity was 100%. Intestinal TG2-targeted autoantibodies had sensitivities of 100% and 93%, and 100% specificity, respectively. γδ+ and villous tip IELs proved more reliable than CD3+ IELs.

Conclusions

Conventional histological examination as the golden standard in coeliac disease diagnosis is questionable. Serum and especially intestinal TG2-targeted autoantibodies seem promising in future coeliac disease diagnostics.

Introduction

Small bowel biopsy has remained the confirmatory cornerstone test for coeliac disease for the last 30 years; the diagnosis should only be made when during a normal gluten-containing diet villous atrophy and crypt hyperplasia can be detected in the small bowel mucosal specimens [1]. However, patchy villous atrophy [2] or poor quality of the biopsy specimens [3] can complicate or even hinder the correct diagnosis. Further, small bowel mucosal villous atrophy can also be associated with other diseases [4], [5], and it is nowadays widely recognized that symptoms and even complications of coeliac disease may occur even before the development of villous atrophy [6], [7], [8]. Therefore, coeliac disease diagnostic criteria need revision. Besides conventional histology, serology and investigation of small bowel mucosal inflammation, especially determination of γδ+ intraepithelial lymphocytes (IELs), are considered helpful in borderline cases [9], [10]. Furthermore, recently discovered intestinal transglutaminase 2 (TG2)-targeted coeliac disease autoantibodies seem particularly promising in coeliac disease diagnostics [11], [12]. Coeliac disease autoantibodies are produced in the small bowel mucosa, and it has been recognized for decades that untreated coeliac disease patients have deposited IgA along basement membrane in their small bowel mucosa [13], [14]. It was shown a few years ago that this deposited IgA is directed against TG2 and thus represents local autoantibody production [11]. However, the role of the intestinal autoantibodies in coeliac disease diagnostics compared to conventional histology still requires further elucidation, as do in fact, all of the methods above.

This study aimed at investigating the diagnostic significance of the determination of CD3+, γδ+ and villous tip IELs and serum and intestinal TG2-targeted coeliac autoantibodies compared to conventional histology in untreated coeliac disease with villous atrophy, and in mild enteropathy coeliac disease where the villous atrophy has not yet developed. In order to achieve reliable and statistically relevant results large patient material was required, and hence we pooled the data collected for our previous clinical studies and performed a meta-analysis. By these means we succeeded in increasing the number of mild enteropathy coeliac disease to 66 cases, and in addition to include a large untreated coeliac (n = 223) and non-coeliac (n = 138) group.

Section snippets

Patients and study design

This study was carried out at the Department of Gastroenterology and Alimentary Tract Surgery in Tampere University Hospital. In our gastroenterology department we have collected comprehensive clinical, serological and histological data of all adult patients undergoing endoscopy for coeliac disease suspicion since 1995. These subjects have participated in our previous studies [9], [15], [16], [17], and we now aimed at summarizing all the data from these large patient series. All adult patients

Results

In untreated coeliac disease patients with villous atrophy 85% had increased densities of CD3+, 92% of γδ+ and 95% of villous tip IELs; the percentages in mild enteropathy coeliac disease group were 61%, 82% and 85%, respectively (Table 2). The mean densities of all IELs were statistically significantly higher in untreated coeliac disease group with villous atrophy as well as in mild enteropathy coeliac disease group compared to non-coeliac controls.

IgA-class AGA was positive in 67–68% of

Discussion

This study strengthened the view that the current coeliac disease diagnostic approach based on conventional histological examination of small bowel mucosal villous structures is no longer valid, since patients with mild enteropathy coeliac disease remain undetected and untreated. In this study altogether 289 patients were shown to suffer from untreated coeliac disease. In 66 (23%) of these patients the diagnosis was based not on villous atrophy, but on subsequent development of villous atrophy,

Conflict of interest statement

There is no conflict of interest.

Acknowledgements

The Coeliac Disease Study Group has been financially supported by the Research Council for Health, the Academy of Finland, the Pediatric Research Foundation, the Competitive Research Funding of the Pirkanmaa Hospital District, and the European Commission (contract number MRTN-CT-2006-036032).

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