The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000-2015).
Seronegative villous atrophy (SNVA) is commonly attributed to coeliac disease (CD). However, there are other causes of SNVA. More recently angiotensin-2-receptor-blockers (A2RBs) have been reported as an association but data on SNVA have been limited to centres evaluating complex case referrals and not SNVA in general.



To provide clinical outcomes and associations in a large prospective study overseeing all newcomers with SNVA.



Over a 15-year period (2000-2015) we evaluated 200 adult patients with SNVA at a UK centre. A diagnosis of either seronegative CD (SNCD) or seronegative non-CD (SN-non-CD) was reached. Baseline comparisons were made between the groups, with 343 seropositive CD subjects serving as controls.



Of the 200 SNVA cases, SNCD represented 31% (n=62) and SN-non-CD 69% (n=138). The human leucocyte antigen (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 A2RBs). However, no cause was found in 18% (n=36) and of these 72% (n=26/36) spontaneously normalised duodenal histology while consuming a gluten-enriched diet. Following multivariable logistic regression analysis an independent factor associated with SN-non-CD was non-white ethnicity (OR 10.8, 95% CI 2.2 to 52.8); in fact, 66% of non-whites had GI 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.



Most patients with SNVA do not have CD, in particular those who are not white. Furthermore, a subgroup with no obvious aetiology will show spontaneous histological resolution while consuming gluten. These findings suggest caution in empirically prescribing a gluten-free diet without investigation.
Academic Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK.|University of Sheffield, Sheffield, UK.
Imran
I
Aziz
Academic Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK.
Mohammad F
MF
Peerally
Academic Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK.|University of Sheffield, Sheffield, UK.
Jodie-Hannah
JH
Barnes
Academic Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK.|University of Sheffield, Sheffield, UK.
Vigneswaran
V
Kandasamy
Academic Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK.|University of Sheffield, Sheffield, UK.
Jack C
JC
Whiteley
Department of Microbiology, Royal Hallamshire Hospital, Sheffield, UK.
David
D
Partridge
Department of Histopathology, Royal Hallamshire Hospital, Sheffield, UK.
Patricia
P
Vergani
University of Sheffield, Sheffield, UK.|Department of Histopathology, Royal Hallamshire Hospital, Sheffield, UK.
Simon S
SS
Cross
Department of Medicine, Columbia University College of Physicians and Surgeons, Celiac Disease Center, New York, New York, USA.
Peter H
PH
Green
Academic Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK.|University of Sheffield, Sheffield, UK.
David S
DS
Sanders
D000328:Adult; D000368:Aged; D001284:Atrophy; D001323:Autoantibodies / Q000097:blood; D001706:Biopsy / Q000379:methods; D002446:Celiac Disease / Q000178:diet therapy / Q000453:epidemiology / Q000276:immunology / Q000473:pathology; D055050:Diet, Gluten-Free / Q000379:methods*; D005260:Female; D006683:HLA-DQ Antigens / Q000276:immunology*; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D008297:Male; D008871:Microvilli / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D011446:Prospective Studies; D012698:Serologic Tests / Q000379:methods; D013223:Statistics as Topic; D011503:Transglutaminases / Q000276:immunology*; D006113:United Kingdom / Q000453:epidemiology
D001323:Autoantibodies; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D011503:Transglutaminases
CELIAC DISEASE; SMALL BOWEL DISEASE; SMALL INTESTINAL BIOPSY