Alimentary Tract
Gluten sensitivity and ‘normal’ histology: is the intestinal mucosa really normal?

https://doi.org/10.1016/S1590-8658(03)00457-2Get rights and content

Abstract

Background. Early pathogenetic events of gluten intolerance may be overlooked in patients with serologic markers of celiac disease and normal intestinal mucosa by both conventional histology and immunohistochemistry.

Aims. To investigate if a submicroscopical damage of the absorptive cell surface was associated with developing gluten sensitivity.

Patients and methods. Duodenal biopsies of seven subjects with positive anti-endomysial antibodies and normal histology underwent ultrastructural evaluation of the epithelial surface by means of both scanning and transmission electron microscopy. Specimens of intestinal mucosa of 14 children with non-celiac conditions were used as controls.

Results. In four patients, electron microscopy revealed alterations of the enterocyte brush border with a significant reduction of the height of microvilli. After several months, three of them had a second biopsy that eventually showed histological modifications suggestive of celiac disease. In the other three patients, no significant alteration of enterocyte ultrastructure was observed. One of them, rebiopsied after 12 months, still showed a normal duodenal histology.

Conclusions. Gluten sensitivity can be associated with ‘minimal’ mucosal changes not detectable with conventional light microscopy. Such lesions, which primarily involve microvillous structure, may imply a reduction of intestinal absorptive surface already in the latent stage of the disease.

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-DQA10501/DQB10201 and of HLA-DQA10301/DQB10302 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.

References (27)

  • F. Biagi et al.

    Clinical features of coeliac disease

    Dig. Liver Dis.

    (2002)
  • K. Kaukinen et al.

    Celiac disease without villous atrophy. Revision of criteria called for

    Dig. Dis. Sci.

    (2001)
  • A. Arató et al.

    Immunoistochemical findings in the jejunal mucosa of patients with coeliac disease

    Scand. J. Gastroenterol.

    (1998)
  • Cited by (42)

    • Coeliac disease novel histological quantification

      2019, Computers in Biology and Medicine
    • Microscopic enteritis: Novel prospect in coeliac disease clinical and immuno-histogenesis. Evolution in diagnostic and treatment strategies

      2009, Digestive and Liver Disease
      Citation Excerpt :

      The prevalence of GS in architecturally normal small bowel is increasing [53,54]. The spectrum of histological changes in CD includes features beyond the conventional mucosal abnormality consisting of ME [3,55]. Recent progresses in immuno-histochemistry and electronic microscopy have altered the diagnostic criteria for CD.

    • IgA anti-actin antibodies ELISA in coeliac disease: A multicentre study

      2007, Digestive and Liver Disease
      Citation Excerpt :

      The enormous increase in CD diagnoses in recent decades is in large part due to the availability of serum tests with excellent diagnostic accuracy, such the anti-endomysium and anti-transglutaminase assays [4–6]. However, these assays do not reflect the severity of the intestinal mucosa damage [7,8]. In this respect, the immunofluorescence (IF) assay of IgA anti-actin antibodies (AAA) has been suggested as a useful method [9,10] and we recently described an ELISA which demonstrated to be an accurate assay for their determination [11].

    View all citing articles on Scopus
    View full text