*Department of Gastroenterology and Alimentary Tract Surgery
†Pediatric Research Center, Tampere University Hospital and Medical School, University of Tampere, Finland
Coeliac Disease Study Group has been financially supported by the Research Council for Health, the Academy of Finland, the Juselius Foundation, the Paediatric Research Foundation, the Mary and Georg C. Ehrnrooth Foundation, the Competitive Research Funding of the Pirkanmaa Hospital District, the Research Fund of the Finnish Coeliac Society, and the European Commission (contract number MRTN-CT-2006-036032).
Financial disclosure: None.
Reprints: Pekka Collin, MD, PhD, Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and Medical School, University of Tampere, Finland (e-mail: firstname.lastname@example.org).
Conflicts of interests: None.
Celiac disease is a gluten-sensitive disorder affecting approximately 2% of the Western population. However, the clinical detection rate is much lower; in the United States a clinical prevalence of 57/100,000 (0.06%) was recently reported.1 The widespread application of serologic screening tests in primary care makes it possible to increase the detection rate considerably, the latest prevalence figure for instance in Finland being 0.55%.2 Serologic screening is indispensable for celiac disease case finding, as symptoms are often vague, atypical, or even absent.
In interpreting serologic screening studies, ascertainment bias is the major flaw. Patients may have been selected for biopsy because of positive serology, which may probably yield falsely high sensitivity. The selection of control group is also important; some use healthy volunteers and others use patients with a suspicion of celiac disease. Until now, the most frequently used screening assays use antibodies against IgA-class endomysium (EmA) and tissue transglutaminase (tTGA). Both tests are highly sensitive and specific with values for both parameters exceeding 95% in most studies.3 EmA seems to offer a higher specificity and tTGA a somewhat better sensitivity. The tTGA is based on enzyme-linked immunosorbent assay, easier to perform, less observer-dependent, and hence also more widely used than EmA, which requires indirect immunofluorescence evaluation.
Do we need additional screening tests? Probably yes. First, some celiac disease patients remain negative for the current antibodies. Secondly, positive serology tests without villous atrophy may be confusing: are the tests falsely positive, or indicative of the subsequent development of villous atrophy and crypt hyperplasia?4 Thirdly, in the follow-up of dietary transgressions the current tests seem to be far from complete, becoming negative even in the absence of villous recovery.5,6
Some studies have reported unsatisfactory sensitivity particularly among patients with mild intestinal damage.7 In contrast, one may ask whether seronegative patients with borderline mucosal damage really suffer from celiac disease. It is indeed curious that although in some reports the sensitivity of current serologic tests is poor in cases with mild intestinal damage, others show that the antibodies precede the development of intestinal damage. Different mechanisms may thus be involved in this apparent discrepancy. In contrast, we would emphasize that the seronegative mild atrophy (Marsh I, II, and even IIIa) may indicate condition other than celiac disease. Mild enteropathy does not thus indicate false-negative serology, but false-positive histology.4 Our opinion is further reinforced by the reports where the quality of biopsy samples has been far from perfect even in specialized centers.8 Determination of human leukocyte antigen DQ2 and DQ8 helps in the exclusion of celiac disease, but not in the diagnosis. Additional histologic markers, an increased density of villous tip intraepithelial lymphocytes, γ δ receptor-bearing T-cells, and the presence of mucosal tissue transglutaminase targeted IgA deposits may be helpful, but are not in use everywhere.4
Traditional gliadin antibodies (AGA) have been disappointing in terms of both sensitivity and specificity, and we have therefore long since discouraged their use for diagnostic purposes. Does the new antibody test against deamidated gliadin (DPG-AGA) resolve the problems involved in earlier tests?
In this issue, Volta and coworkers9 searched for the best serologic approach for screening of celiac disease. They compared 2 DPG-AGA kits in both IgA and IgG-class to IgA-class tTGA and EmA in 144 patients with a suspicion of celiac disease. The authors concluded that a combination of IgG-class DPG-AGA and IgA-class tTGA provides the best diagnostic accuracy, identifying all except 1 patient with celiac disease. These results do not completely do justice for IgA-class tTGA and EmA, as 2 patients had selective IgA deficiency. In fact, DPG-AGA detected only one IgA-competent tTGA-negative celiac disease patient.
As many as 50% of the subjects were seropositive for at least one of the serologic tests and 33% had biopsy-proven celiac disease. These percentages were higher than in any groups at risk of celiac disease: in autoimmune conditions such as type I diabetes and autoimmune thyroid disease approximately 5% to 10% are seropositive, and 15% in first-degree relatives of celiac disease patients.10 Even in this highly selected population the sensitivity of IgA DPG-AGA was disappointingly low, less than 90%, being inferior to EmA and tTGA. These results are in line with a recent meta-analysis, where the sensitivity of IgA DPG-AGA (87.8%) was lower than that of IgA tTGA (93.0%); the specificities showed no significant differences, 94.1% and 96.5%, respectively.11 In this meta-analysis, comparison of DPG-AGA in IgA and IgG-class yielded conflicting results, but the IgG test was less sensitive and more specific in the majority of the studies discussed, as also shown in the study of Volta and coworkers.9
Interestingly, in this study,9 7 patients showed signs of potential celiac disease, with increased numbers of intraepithelial lymphocytes (again reflecting the selected series in this study). It was not stated whether the biopsy specimens were evaluated without prior knowledge of serologic test results. In any case, all 7 patients were positive for EmA (and had celiac type human leukocyte antigen), which is strongly suggestive of potential or early celiac disease. These 7 were also positive for tTGA, whereas 5 remained negative in IgG and 4 in IgA DPG-AGA. This suggests that DPG-AGA does not give additional benefit in the diagnosis of potential or early celiac disease.
As stated above, the normalization of EMA or tTGA does not necessarily guarantee good dietary compliance or mucosal recovery. In our earlier study,12 the DPG-AGA test detected 6 of the 9 cases with small-bowel mucosal damage persisting on a gluten-free diet, whereas tTGA was positive in 2 and EmA in 1. In another study by Volta and coworkers,13 the diagnostic accuracy in predicting the status of duodenal mucosa after gluten-free diet was the same for DPG-AGA and tTGA.
In conclusion, the combination of DPG-AGA and tTGA seems to work well in series with a high probability of celiac disease.9 It may not replace the tTGA test, but offers an alternative especially in patients seronegative for tTGA. More studies are needed to prove that DPG-AGA works in early developing celiac disease, or whether it can replace the biopsy in estimating dietary response. At the moment, the new DPG-AGA test is ready for use in celiac clinics, provided that it is not confused with the traditional AGA test.
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