The Clinical and Phenotypic Assessment of Seronegative Villous Atrophy; A Prospective UK Centre Experience Evaluating 200 Cases over a 15 Year Period (2000–2015)

Background: Seronegative villous atrophy (SNVA) is commonly attributed to coeliac disease. However, there are other causes of SNVA. More recently angiotensin-2-receptor-blockers have been reported as an association but data on SNVA has been limited to centres evaluating complex case referrals and not SNVA in general. Objectives: To provide clinical outcomes and associations in a large prospective study overseeing all newcomers with SNVA. Design: Over a 15-year period (2000-2015) we evaluated 200 adult patients with SNVA at a UK centre. A diagnosis of either seronegative coeliac disease (SNCD) or SN-non-CD was reached. Baseline comparisons were made between the groups, with 343 seropositive CD subjects serving as controls. Results: Of the 200 SNVA cases, SNCD represented 31% (n=62) and SN-non-CD 69% (n=138). The HLA-DQ2 and/or DQ8 genotype was present in 61%, with a 51% positive predictive value for SNCD. The breakdown of identifiable causes in the SN-non-CD group comprised infections (27%, n=54), inflammatory/immune-mediated disorders (17.5%, n=35) and drugs (6.5%, n=13; two cases related to angiotensin-2-receptor-blockers). However, no cause was found in 18% (n=36) and of these 72% (n=26/36) spontaneously normalised duodenal histology whilst consuming a gluten-enriched diet. Following multivariable logistic regression analysis an independent factor associated with SN-non-CD was non-white ethnicity (odds ratio 10.8, 95% confidence interval 2.2-52.8); in fact, 66% of nonwhites had gastrointestinal infections. On immunohistochemistry all groups stained positive for CD8- T-cytotoxic intraepithelial lymphocytes. However, additional CD4-T-helper intraepithelial lymphocytes were occasionally seen in SN-non-CD mimicking the changes associated with refractory CD. Conclusions: Most patients with SNVA do not have coeliac disease, in particular those who are not white. Furthermore, a subgroup with no obvious aetiology will show spontaneous histological resolution whilst consuming gluten. These findings suggest caution in empirically prescribing a gluten-free diet without investigation. 4 Significance of this study What is already known on this subject? Seronegative villous atrophy (SNVA) is a diagnostic and therapeutic dilemma. The causes of SNVA are vast but can be broadly grouped into seronegative CD (SNCD) and SN-nonCD. To date no study has systematically evaluated all newcomers with SNVA. What are the new findings? SNCD accounts for 31% of SNVA cases, with the remaining 69% due to SN-non-CD. A positive HLA-DQ2 and/or DQ8 status is seen in 61% of SNVA cases; its positive predictive value for SNCD is roughly 51%. An independent risk factor associated with SN-non-CD is non-white ethnicity, suggestive of infective aetiology. Overall, almost one-in-five SNVA patients will have no identifiable cause; reassuringly, the majority of these will spontaneously normalise duodenal histology despite undertaking a gluten challenge. How might it impact on clinical practice in the foreseeable future? Individuals with SNVA should not be prescribed a gluten-free diet prior to further investigations. This is because of the wide differential diagnoses and that a subgroup with no obvious aetiology spontaneously normalise their duodenal histology whilst maintaining gluten intake.