Seronegative Celiac Disease: Prevalence and Clinical Features in a Tertiary Referral Center

Background: Although serological tests are extremely useful for identifying celiac disease, it is well-established that a minority of celiacs are seronegative. Aims: To define the prevalence and the features of seronegative compared to seropositive celiac disease, and to establish whether celiac disease is a common cause of seronegative villous atrophy. Methods: We retrospectively characterized seronegative celiac disease among 810 celiac patients consecutively diagnosed from 1998 to 2014. Diagnostic criteria included duodenal biopsy, serology and HLA typing (when necessary). Results: Of the 810 celiac patients, 796 were seropositive (780 with IgA tissue transglutaminase and/or endomysial antibodies, 16 with IgA deficiency with IgG tissue transglutaminase and/or deamidated gliadin peptide antibodies). Fourteen celiacs were classified as seronegative based on antibody negativity, villous atrophy, HLA-DQ2/-DQ8 positivity and clinical/histological improvement after gluten free diet. Compared to seropositive, seronegative CD showed a significantly higher median age at diagnosis (49 vs. 36 years), a significantly higher prevalence of classical phenotype (malabsorpion), a more frequent occurrence of autoimmune disorders and a higher frequency of total villous atrophy. The most frequent diagnosis in the 31 cases with seronegative flat mucosa was celiac disease (45%), whereas other frequent diagnoses were Giardiasis (20%), common variable immnodeficiency (16%) and autoimmune enteropathy (10%). Conclusions: Seronegative celiac disease is a very rare clinical setting, characterized by a high median age at diagnosis, a close association with malabsorption and flat mucosa and a high prevalence of autoimmune disorders. Although rare, seronegative celiac disease can be regarded as the most frequent cause of seronegative villous atrophy.