Abstract
BackgroundAssessment of the gluten-induced small-intestinal mucosal injury remains the cornerstone of celiac disease diagnosis. Usually the injury is evaluated using grouped classifications (e.g. Marsh groups), but this is often too imprecise and ignores minor but significant changes in the mucosa. Consequently, there is a need for validated continuous variables in everyday practice and in academic and pharmacological research.MethodsWe studied the performance of our standard operating procedure (SOP) on 93 selected biopsy specimens from adult celiac disease patients and non-celiac disease controls. The specimens, which comprised different grades of gluten-induced mucosal injury, were evaluated by morphometric measurements. Specimens with tangential cutting resulting from poorly oriented biopsies were included. Two accredited evaluators performed the measurements in blinded fashion. The intraobserver and interobserver variations for villus height and crypt depth ratio (VH:CrD) and densities of intraepithelial lymphocytes (IELs) were analyzed by the Bland-Altman method and intraclass correlation.ResultsUnevaluable biopsies according to our SOP were correctly identified. The intraobserver analysis of VH:CrD showed a mean difference of 0.087 with limits of agreement from −0.398 to 0.224; the standard deviation (SD) was 0.159. The mean difference in interobserver analysis was 0.070, limits of agreement −0.516 to 0.375, and SD 0.227. The intraclass correlation coefficient in intraobserver variation was 0.983 and that in interobserver variation 0.978. CD3+ IEL density countings in the paraffin-embedded and frozen biopsies showed SDs of 17.1% and 16.5%; the intraclass correlation coefficients were 0.961 and 0.956, respectively.ConclusionsUsing our SOP, quantitative, reliable and reproducible morphometric results can be obtained on duodenal biopsy specimens with different grades of gluten-induced injury. Clinically significant changes were defined according to the error margins (2SD) of the analyses in VH:CrD as 0.4 and in CD3+-stained IELs as 30%.
Highlights
In celiac disease the characteristic gluten-induced smallintestinal mucosal injury develops gradually [1,2]
In the Bland-Altman method, the differences between two quantitative measurements are plotted against the averages of the two measurements, and the results reported as the mean difference between the two measurements and limits of agreement, which are defined as the mean difference plus and minus twice the standard deviation of the differences
All 12 preselected biopsy specimens with tangential cuttings rendering them unacceptable for values as measured morphometrically (VH):CrD analyses were correctly identified by both study evaluators
Summary
In celiac disease the characteristic gluten-induced smallintestinal mucosal injury develops gradually [1,2]. Well-known grouped classifications in histological assessment are one described by Marsh and modified by Oberhuber and another produced by Corazza and Villanacci [1,3,4].These classifications are practical in clinical work, but allocation to specific groups may be challenging and minor histologic changes are missed [4]. Such small but significant changes can be caused even by relatively small amounts of gluten and are important when the clinical effectiveness of pharmacological therapies is evaluated. There is a need for validated continuous variables in everyday practice and in academic and pharmacological research
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