Alimentary TractGluten sensitivity and ‘normal’ histology: is the intestinal mucosa really normal?
Introduction
Increasing sensitivity of serologic markers of celiac disease (CD) and the widespread use of a screening policy in high-risk groups (e.g. close relatives of CD subjects and patients with autoimmune diseases or other CD-related conditions) have been raising the problem of individuals with positive tests and ‘normal’ intestinal mucosa at histology (about 15% of CD diagnoses among patients with Type 1 diabetes, in our experience). The presence of anti-endomysial (and more recently, of anti-tissue transglutaminase) antibodies is today considered a reliable marker of developing gluten intolerance [1] and their appearance may precede, by months or years, the clinical and histological progression of the disease [2], [3], [4], [5].
CD can produce a wide spectrum of morphological abnormalities within the intestinal mucosa, (sub)total villous atrophy being the hallmark of severe gluten enteropathy. At the end of the spectrum, there are subjects (often asymptomatic) with no enteropathy, but with features of gluten-induced immune activation [6]. Marsh [7] identified an increased intraepithelial lymphocyte (IEL) infiltration as the first recognisable event of gluten sensitivity at the level of small bowel mucosa. Patients with such a picture have been recently defined as having a potential CD [8]. Natural history of gluten intolerance in a number of them (maintained on a gluten-containing diet) showed progression to severe enteropathy that, retrospectively, confirmed a latent CD [2], [3], [4], [5].
Current diagnostic criteria for CD, requiring substantial villous damage of intestinal mucosa, seem too strict and there is a strong need for more sensitive and reliable approaches that allow definite confirmation of CD at an earlier stage of the disease [9], [10]. Indeed, early pathogenetic events may be overlooked both by conventional histology and immunohistochemistry. ‘Minimal changes’ of epithelial tight junctions were observed on freeze-fractured specimens in children treated with a gluten-free diet, suggesting the existence of a submicroscopical lesion in CD [11]. Moreover, scanning electron microscopy (SEM) revealed lesions of variable degree in 70% of cases with normal histology after dietary treatment [12]. However, detailed studies on the absorptive surface, in patients with serologic markers of CD and normal histology, are lacking.
In this study, we evaluated the ultrastructural pattern of epithelial microvilli in intestinal biopsies of individuals with serologic markers of CD and normal histology. The aim was to investigate if a submicroscopical damage at the level of the absorptive cell surface was associated with developing gluten sensitivity.
Section snippets
Patients and methods
The study was performed on seven subjects (Table 1) with positive anti-endomysial antibodies (EMA) test and normal duodenal mucosa histology, who underwent ultrastructural evaluation of the epithelial surface by means of SEM and transmission electron microscopy (TEM). Fourteen children having intestinal mucosa with constitutional short stature (n=11), Type 1 diabetes (DM1) (n=1), recurrent abdominal pain (n=1) or gastritis (n=1) were used as control group for the evaluation of the absorptive
Results
Clinical features of the patients are detailed in Table 1. Four subjects had DM1. Three subjects with DM1 were screened for CD in a symptomless condition, while the other one complained of intestinal symptoms. Three other children had symptoms suggestive of CD and one of them had a Pierre–Robin syndrome. Genetic susceptibility for CD identified by the presence of HLA-DQA1∗0501/DQB1∗0201 and of HLA-DQA1∗0301/DQB1∗0302 haplotypes was found in three of the four patients who had HLA typing. The
Discussion
The present study suggests that, in some subjects with serologic evidence of gluten sensitivity and normal morphology of intestinal mucosa, a submicroscopical lesion of microvilli can be demonstrated. This abnormality may represent an early manifestation of developing gluten intolerance that takes place at the surface of intestinal absorptive cells in susceptible individuals.
Such a severe reduction of the height of microvilli can lead to a significant impairment of intestinal absorptive surface
Conflict of interest statement
None declared.
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