Diagnosis, management and long-term outcomes of seronegative enteropathies in adults: a practical review

Seronegative enteropathies (SNEs) are a group of heterogeneous clinical conditions characterised by villous atrophy (VA) and negative coeliac serology that can be broadly distinguished into two groups including (1) Forms of coeliac disease with negative serology and (2) Chronic enteropathies unrelated to gluten ingestion, that is, non-coeliac enteropathies (NCEs). The differential diagnosis and management of SNEs is challenging due to the rarity of these conditions, their aetiological heterogeneity with overlapping clinical and histopathological features, and the lack of diagnostic markers for some of them. Since seronegative coeliac disease (SNCD) is reported as the most frequent cause of SNEs, patients with NCEs are commonly misdiagnosed as having SNCD and started on a gluten-free diet (GFD). The clinical and histological responses to a GFD after the exclusion of other causes of VA are key to a correct diagnosis of SNCD. Appropriate diagnosis and management of SNEs is crucial to avoid unnecessary treatment with a GFD and avoid poor long-term outcomes, including high risk of complications and mortality. This paper provides a practical and updated guide to the differential diagnosis, clinical management and follow-up of SNEs in adult patients.