Seronegative Enteropathies: FG | May 2026

Introduction

Seronegative enteropathies (SNEs) represent a challenging group of disorders characterised by villous atrophy with negative coeliac serology. They include both seronegative coeliac disease (SNCD) and a broad spectrum of non-coeliac enteropathies such as infections, immune disorders, and drug-related causes. Their rarity, overlapping features, and lack of specific biomarkers make diagnosis difficult in routine practice.

Problem Statement

The biggest clinical issue is misdiagnosis. Many patients with non-coeliac enteropathies are incorrectly labelled as seronegative coeliac disease and started on a gluten-free diet. This leads to unnecessary lifelong dietary restriction, delayed diagnosis of the true underlying condition, and risk of poor outcomes. Differentiating SNCD from other causes of villous atrophy remains complex due to overlapping clinical and histological findings.

Summary

This review provides a practical framework for evaluating and managing SNEs. The key principle is systematic exclusion of non-coeliac causes before diagnosing SNCD. A definitive diagnosis of SNCD requires clinical and histological response to a gluten-free diet after other etiologies are ruled out.

Non-coeliac enteropathies must be actively considered, including infections, immune-mediated diseases, medications, and malignancies. Accurate diagnosis is essential, as these conditions often require entirely different treatments.

Long-term outcomes vary significantly. While appropriately treated SNCD has a favorable prognosis, misdiagnosed or untreated non-coeliac enteropathies may lead to serious complications and increased mortality.

Overall, this review emphasizes a structured diagnostic approach, cautious use of gluten-free diet, and tailored management strategy to improve patient outcomes and avoid diagnostic pitfalls.