Clinical and pathological significance of seronegative celiac disease

Seronegative celiac disease (SNCD) represents a diagnostic challenge for clinicians, as its diagnosis relies on a high index of suspicion combined with compatible gastrointestinal symptoms. Specifically, negative serology for anti-TG2, anti-endomysial, and anti-deamidated gliadin peptides autoantibodies complicates diagnosis, given that SNCD accounts for a very small percentage of total celiac disease (CD) cases. This review addresses various aspects of the condition to shed light on the disease and improve diagnostic accuracy, as it is likely an underdiagnosed condition. Key aspects covered in this review include: a) epidemiology; b) clinical manifestations; c) diagnostic tests; d) follow-up and morbidity-mortality; and e) the immunopathological causes underlying the negative serology. The review incorporates the most relevant articles on CD, comparing seronegative and seropositive cases. Consequently, differences between the two presentations are identified and discussed, differences that, to date, have not been reported in any previous review of this condition.