Diagnosis of seronegative and ultrashort celiac disease

Nowadays celiac disease (CD) in its conventional form, characterized by both positive serology and flat villi in the duodenum, is well known by gastroenterologists and general practitioners. The aim of the present review is to shed light on two neglected and not yet well defined celiac phenotypes, i.e. seronegative and ultrashort celiac disease. Seronegative celiac disease can be suspected in the presence of flat villi, positive HLA-DQ2 and/or -DQ8 and absence of CD antibodies. After having ruled out other seronegative enteropathies, the diagnosis can be confirmed by both clinical and histological improvement after 1-year of gluten-free diet. Ultrashort celiac disease is characterized by the finding of flat villi in the duodenal bulb in the absence of mucosal damage in the distal duodenum and with serological positivity. Data on the prevalence, clinical manifestations, histological lesions, genetic features and outcome of seronegative and ultrashort celiac disease are inconclusive due the few studies available and the small number of diagnosed patients. Some additional diagnostic tools have been developed recently, such as assessing of intestinal transglutaminase 2 (TG2) deposits, the flow-cytometry technique, micro-RNA detection or proteomic analysis and they seem to be useful in the identification of complex patients. Further co-operative studies are highly desirable to improve the knowledge of these two still obscure variants of celiac disease.