Seronegative Villous Atrophy in Children: Clinical and Immunohistochemical Features

Objectives: Villous atrophy (VA) is not pathognomonic of celiac disease (CD). We aimed at reporting distribution, clinical and immunohistochemical features of seronegative VA (SNVA) in a pediatric population. Methods: We retrospectively collected data from patients who underwent intestinal biopsies between 2010 and 2017 and showed VA without serum CD-associated autoantibodies. Marsh-Oberhuber grading was used. Density of intraepithelial lymphocytes (IELs) expressing CD3 or TCRγδ+ receptor and of lamina propria CD25+ cells was assessed by immunohistochemistry. Intestinal deposits of anti-tissue tranglutaminase2 (anti-TG2) were also investigated by double immunofluorescence. Results: Over a 7 year period, 64 out of 1282 patients with VA had negative serum CD serology. Diagnoses were: inflammatory bowel diseases (IBD) (21/64), Gastro-Esophageal Reflux Disease (GERD) (12/64), food allergy (8/64), infections (7/64, of which 3 HIV infections), immune deficiency (3/64), short bowel syndrome (3/64), congenital diarrhea (2/64), other/inconclusive diagnosis (8/64). 44, 15 and 5 showed Marsh 3a, 3b and 3c lesion, respectively. The latter category included 2 patients with Crohn's disease, 2 with immunodeficiencies, 1 with lymphohistiocytosis. In 41/46 (89%) patients mononuclear CD25+ cells were above the cut-off, indicating mucosal inflammation, but only 18/46 (39%) had IELs and TCRγδ+ IELs above limits of normality. In 10/46 (22%) patients a positive immunofluorescence indicated the presence of anti-TG2 mucosal antibodies. Conclusions: SNVA is not rare representing up to 5% of the cases of VA. Most patients have a Marsh 3a lesion. Immunohistochemical analysis may be helpful in excluding CD, while the finding of mucosal anti-TG2, particularly with a weak staining, shows no absolute specificity for CD.