The traditional concept of coeliac disease is a chronic inflammatory disorder of the small intestine characterized by the clinical features of malabsorption. The characteristic histological lesion, small intestinal villous atrophy, occurs in genetically susceptible individuals and responds to exclusion of gluten from the diet . However, it is now clear that coeliac disease can present in adults of all ages, and that the clinical features are often subtle, with problems such as mild anaemia or tiredness [2,3]. In addition to the wide range of clinical manifestations of coeliac disease, there is also a spectrum of histological abnormalities [4,5].
The current diagnostic criteria for coeliac disease are based on the revised European Society of Paediatric Gastroenterology and Nutrition criteria published in 1990, with the characteristic small-intestinal histology showing villous atrophy . In contrast to the original criteria , a follow-up biopsy showing histological improvement after a period of dietary gluten exclusion is no longer required, except in children under 2 years of age, in whom coeliac disease must be distinguished from transient gluten intolerance. The British Society of Gastroenterology guidelines continue to recommend a follow-up biopsy at 4-6 months . It may be difficult to quantify mucosal recovery after 3-6 months and this may often be incomplete, raising questions as to how significant is the need for a complete histological response. However, documentation of a clinical or serological response to gluten withdrawal is essential to the diagnosis of coeliac disease, since a similar mucosal lesion may be found in several other diseases.
The variable clinical presentation of coeliac disease, increased awareness of subclinical disease in primary care and the invasive nature of small intestinal biopsy have motivated the search for simple, less invasive and more acceptable screening tests for coeliac disease. Over the past decade several tests have become available that may be supportive to the diagnosis, and a change in diagnostic criteria may be required to take account of these.
IgA antigliadin antibodies (IgA-AGA) were initially widely used in both the diagnosis of coeliac disease and in the monitoring of dietary compliance, their main advantage being that they were inexpensive. In view of their low sensitivity and specificity, IgA-AGA have largely been superseded in many diagnostic laboratories by IgA antiendomysial antibodies (IgA-EMA) and IgA antibodies to tissue transglutaminase (IgA-TTG). IgA-EMA is detected by indirect immunofluorescence, uses human umbilical cord or monkey oesophagus as substrate and is relatively laborious and observer dependent. The test is relatively costly and this has limited its use in screening for coeliac disease. Since IgA-EMA has a high sensitivity and specificity, it has been proposed that, if positive, it would make confirmation by duodenal biopsy unnecessary [9,10], although this has not been confirmed in all studies.
IgA-TTG is a specific endomysial autoantigen released during cellular stress and, by deamidation of gliadin peptides as well as by binding with them, facilitates their interaction with HLA-DQ2 and HLA-DQ8 cells . The detection of IgA-TTG by ELISA has been proposed as an ideal first-line diagnostic test for coeliac disease since it is less costly than IgA-EMA and, being an ELISA test, is more readily standardized. Many commercial ELISA kits are now available, although unfortunately the individual absolute values are not interchangeable. As was previously identified with IgA-AGA, the need for standardization of these assays is now required. The use of ELISA techniques makes IgA-TTG more suitable for case finding and population screening than IgA-EMA. Several studies have used IgA-TTG as a first-line test, followed by confirmation with IgA-EMA and then proceeding to duodenal biopsy in those with positive IgA-EMA. Divergent results on the value of these serological tests have been reported from various studies. The reasons for these discrepancies are identified in the paper by Collin et al.  in this issue. This may relate to the different commercial kits used, variation in inclusion criteria for patients or controls, biopsy confirmation may not be obtained in all control patients and histopathologists are not always blinded as to the results of the serological tests. In Northern Ireland we have found that the sensitivity and specificity of IgA-TTG were intermediate between that of IgA-AGA and the superior IgA-EMA .
Whereas the typical histological changes of villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis and an infiltrate of lymphocytes into the lamina propria are characteristic of coeliac disease, it is widely recognized that these changes are at one end of a spectrum of histological changes . This may range from minor changes such as an infiltrate of intraepithelial lymphocytes in villi which have otherwise normal morphology, at one end, to total villous atrophy at the other [14,15]. The extent of the mucosal lesion may depend on the degree of gluten exposure, the extent of genetic predisposition and probably other unknown environmental factors.
Potential problems associated with using duodenal histology as the main diagnostic criteria for coeliac disease have been identified in the paper by Collin et al. . In their study, 29 patients (10%) were excluded on account of inadequate histological specimens. Duodenal biopsies are often poorly orientated, although this may be reduced by taking several biopsies with jumbo forceps, by orientation of duodenal biopsies on cellulose acetate paper before fixation to limit artefacts and by performing a regular quality-control exercise. The variability in expression of the histological lesion may also make diagnostic interpretation more difficult. Histopathologists should be aware of the coeliac spectrum of histological change and standardized reference to the Marsh criteria in histological reports would be helpful.
The value of IgA-based assays in screening for coeliac disease is obviously limited in patients with IgA deficiency, in whom coeliac disease is more common . Since none of the assays for coeliac-related IgA antibodies consistently has a sensitivity and specificity of 100% and the fact that coeliac disease may rarely occur in patients with negative serology on routine testing, a duodenal biopsy should still be performed if the clinical suspicion for coeliac disease is high.
The problem of equivocal biopsies has also been highlighted in this study and a practical diagnostic approach is proposed which may include HLA typing. The genetic predisposition for coeliac disease is associated with HLA-DR3-DQ2 inherited as an extended haplotype. Patients who are negative for DQ2 are often positive for DQ8, and together these account for 90-95% of individuals with coeliac disease. However, DQ2 is also present in 25% of the normal population in western Europe. HLA-DQ typing is expensive and clearly not suitable for routine diagnostic use, although it may be of value in patients with equivocal duodenal biopsies. In patients with mild partial villous atrophy and negative serology with normal IgA levels, who are unlikely to have coeliac disease, HLA-DQ analysis may be useful to exclude the diagnosis. However, HLA-DQ testing is of no value in confirming the diagnosis of coeliac disease in equivocal cases.
Particular difficulty in interpretation of small intestinal biopsies occurs in patients with the minimum histological lesion, which may only be recognized if quantitative morphometric analysis, including evaluation of intraepithelial lymphocytes, is performed . In addition, immunohistochemistry has enabled the identification of a specific subset of intraepithelial lymphocytes which express the γ/δ receptor and seem to be a constant finding in coeliac disease [17,18]. In equivocal cases, estimation of γ/δ T cells may be used to identify latent coeliac disease, although these cells are not specific for coeliac disease [19,20].
Diagnosis of coeliac disease requires a high index of suspicion in view of the wide range of clinical presentation and many cases go unrecognized. It is apparent that the criteria on which coeliac disease has been diagnosed have evolved over the years and may need to change, since the problems with relying on duodenal histology as the gold standard are well known. The term, gluten sensitivity, has been proposed as a more reliable reflection of the full spectrum of patients, from those who are symptomatic with the minimum or no histological lesion at one end, to those who are asymptomatic with a clearly defined histological lesion at the other . Despite advances in the use of serological assays with high sensitivity and specificity, these have not been consistently high to replace duodenal biopsy as the gold standard. Since all tests have their limitations, a combination of these diagnostic tests may be valuable in equivocal cases.
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