AGA Clinical Practice Update on the Evaluation and Management of Seronegative Enteropathies: Expert Review

Clinical classification and long‐term outcomes of seronegative coeliac disease: a 20‐year multicentre follow‐up study

“…Initial histology was reevaluated by an expert gastrointestinal histopathologist. 5,6 Patients without evidence of VA after revision of their initial histology, those in whom investigations leading to initial diagnosis were performed while already on a GFD and/or on immunosuppressive therapy, those with negative HLA-DQ2 and DQ8, and those in whom VA was due to other non-coeliac enteropathies were defined "mimics", excluded from the main study cohort and considered separately.…”

“…We specify that before diagnosing true seronegative coeliac disease all the causes of SNVA unrelated to gluten ingestion were thoroughly investigated, and excluded by means of an algorithmic approach. [4][5][6][7]9,10 These included autoimmune enteropathy with positive enterocyte antibodies, common variable immunodeficiency, giardiasis and other parasitic infections, Whipple's disease, HIV enteropathy, tuberculosis, small intestinal bacterial overgrowth, tropical sprue, lymphoproliferative disorders affecting the small bowel, graft versus host disease, drug-related enteropathies (ARB2s particularly olmesartan, chronic use of NSAIDs, radio/chemotherapy, methotrexate, azathioprine), peptic duodenitis (± Helicobacter pylori)). [5][6][7]9,10 For patients affected by total IgA deficiency (serum IgA < 0.08 g/ dL) and VA, positive class IgG tTG/EmA/DGP supported the diagnosis of coeliac disease associated with IgA deficiency, together with a clinical/histological response to a GFD.…”

“…[1][2][3] A minority of coeliac patients present with negative specific serology and are considered as affected by seronegative coeliac disease. [4][5][6] Although in Western Countries seronegative coeliac disease is the most common aetiology among patients with VA and negative coeliac serology (seronegative villous atrophy-SNVA), [4][5][6][7][8][9][10][11][12] there are still uncertainties concerning the serological and histological criteria for the definition and diagnosis of seronegative coeliac disease. This is due to the different study designs and diagnostic criteria adopted, endpoints and limited sample sizes of the populations under investigation in previous studies.…”

“…Indeed, debate exists on whether to consider positive coeliac IgG based serology in the context of IgA deficiency as seronegative coeliac disease, 9,10 or instead as a conventional form of coeliac disease associated with IgA deficiency. [4][5][6]11 Finally, negative coeliac serology was reported to occur in patients already on immunosuppressive therapies or a GFD prior to serological testing, 4,5,15,20 early stage disease, 14,19 late stage disease (with possible refractory coeliac disease or lymphoma), 21 dermatitis herpetiformis 26 and seldom in first-degree relatives of coeliac patients. 27 Therefore, the epidemiology, clinical features and natural history of seronegative coeliac disease are still poorly defined.…”

Letter: increased incidence of tissue transglutaminase antibody in Israel—is it always related to coeliac disease? Authors' reply

“…In our opinion, in the era of the no biopsy approach that is gaining acceptance both outside Europe and in the adult population, 5 it would be harder to estimate coeliac disease diagnosis based only on histopathology results. Therefore, our study design was focused on coeliac disease autoimmunity rather than coeliac disease.…”