Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease

Abstract

Objective Coeliac disease is defined by gluten responsiveness, yet there are few data on gluten challenge (GC) in adults on a gluten free diet. Lack of data regarding the kinetics of responses to gluten is a limitation in clinical practice and research when GC is performed. Design 20 adults with biopsy-proven coeliac disease participated. The study included two run-in visits followed by a 14 day GC at a randomly assigned dose of 3 or 7.5 grams of gluten/day. Study visits occurred 3, 7, 14 and 28 days after starting GC. Duodenal biopsy was performed during the run-in and at days 3 and 14 of GC. Villous height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocyte (IEL) count/100 enterocytes were measured by two pathologists. Antibodies to tTG and DGP, lactulose to mannitol ratio (LAMA), and symptoms were assessed at each visit. Results Significant reduction in Vh:Cd (2.2 to 1.1, p < 0.001) and increase in IELs (32.6 to 51.8, p < 0.001) were seen from baseline to day 14. Antibody titers increased slightly from baseline to day 14 of GC but markedly by day 28. LAMA did not change significantly. Gastrointestinal symptoms increased significantly by day 3 and returned to baseline by day 28. No differences were seen between the two gluten doses. Conclusions 14 day GC at ≥3 grams of gluten/day induces histological and serological changes in the majority of adults with coeliac disease. These data permit accurate design of clinical trials and indicate that many individuals will meet coeliac diagnostic criteria after a two week GC.

Dietary gluten triggers concomitant activation of CD4 + and CD8 + αβ T cells and γδ T cells in celiac disease

“…However, we find that αEβ7 + CD38 + T cells express markers of differentiated effector cells before gut recruitment, and their appearance parallels the appearance of gluten-reactive CD4 + T cells in blood, rather than occurring later. Also, although increased numbers of IELs and mildly increased levels of IL-15 are present in celiac patients on a glutenfree diet (38), the recruitment we describe precedes significant intestinal inflammation and tissue damage, which only reliably occur histologically after 2-4 wk of continuous gluten exposure (39). These findings suggest that IELs in CD are not simply activated as bystanders as a consequence of gut inflammation.…”

“…Available tests, including antibody levels and intestinal biopsy results, can be completely normal in CD patients on a gluten-free diet. Consequently, such individuals are often asked to continually eat gluten-containing foods for 2-4 wk before testing (39). This is often intolerable and precludes an accurate diagnosis.…”

Diagnostic challenges in celiac disease

“…16 Recent study shows that intake of ≥ 3 g of gluten a day (amount equal to 1.5 slices of bread) will induce histopathological findings consistent with celiac disease in approximately 90% of patients after 14 day trial. 23 Extending the challenge for another 6 weeks in patients who tolerate the challenge well may further improve diagnostic sensitivity. If repeated biopsy and serology after gluten challenge are negative, CD is unlikely.…”

“…Final follow-up serologic test is performed after 6-12 months of gluten containing diet. 23 Another approach, where initial response to a GFD is assessed seems less accurate, as 38% of patients with LD who improve on a GFD are HLA DQ2/DQ8 negative. 16 …”

Management of Celiac Disease: Beyond the Gluten-Free Diet

“…It is somewhat surprising that serologic titers did not increase in the placebo group given that a 3 g gluten challenge for 2 weeks was shown to be sufficient to induce histologic changes in intestinal biopsies as well as increased titers of tissue transglutaminase immunoglobulin A. 17 Another pharmacologic approach to reduce the uptake of gluten from the intestinal lumen beyond a gluten-free diet is larazotide acetate, a described. In a study to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease, 12 the readout of permeability was sufficiently variable such that an accurate assessment of the effect of larazotide acetate on intestinal permeability was not possible.…”