The Clinical Challenge of Seronegative Villous Atrophy: A Preview

Chiara Maruggi, MD

Credit: Cleveland Clinic

Affecting approximately 1% of the population in the United States, celiac disease, an immune response due to the ingestion of gluten in genetically susceptible individuals, is the most common enteropathy.^1,2 Studies have estimated approximately 93% of patients with duodenal villous atrophy have seropositive celiac disease, defined as the serologic presence of IgA tissue transglutaminase and/or endomysial antibodies.³

When villous atrophy is found in the context of negative celiac serology testing, it presents a clinical challenge. The aim of this single-center retrospective study was to characterize the differential diagnosis of seronegative villous atrophy by reviewing clinical and histological criteria.

Conducted at a large academic medical center, this study included patients with seronegative villous atrophy seen between 2000 and 2023. Inclusion criteria were adult patients with seronegative villous atrophy, defined as histologic evidence of duodenal villous atrophy and a negative tissue transglutaminase antibody with normal total IgA. Of note, patients with positive gliadin peptide antibody and/or endomysial antibody were excluded.

Medical records were reviewed for clinical and pathological data. Patients were classified according to nomenclature proposed by the Paris consensus using predefined criteria and physician consensus.⁴

Among 2924 patients with confirmed duodenal villous atrophy, 720 with normal total IgA and negative tissue transglutaminase antibody were included. Among this cohort, the median age was 52 years, 67% of patients were female, and 81% were White.

This abstract, presented at Digestive Disease Week in Washington, DC, in May 2024, was based on the analysis of approximately the first half of those patients with seronegative villous atrophy. Among these 376 patients, the median age was 53 years, 69% were female, and 84% were White.

After chart review, 27 (7%) patients were excluded for a prior diagnosis of seropositive celiac disease. Additionally, classification according to Paris consensus was not possible for 259 (69%) patients, primarily due to a lack of systematic evaluation and/or clinical follow-up.

Among the remaining 90 (24%) patients with enough information for classification by Paris consensus, the most common diagnoses were seronegative celiac disease (SNCD) (n = 29; 32%), Crohn’s disease (n = 17; 19%), and medication-induced, commonly immunosuppressants and olmesartan (n = 13, 14%). Other diagnoses included CVID (n = 3), HIV (n = 4), H. pylori enteritis (n = 7), eosinophilic enteritis (n = 4), idiopathic (n = 4), SIBO (n = 3), and radiation enteritis (n = 2) (Figure 1).

This study demonstrates the heterogeneous makeup of seronegative enteropathies previously described in the Paris consensus. Of the patients reviewed, only 26% could be classified using current definitions. This highlights the need for systematic evaluation and clinical follow-up for patients with villous atrophy and negative celiac serologic testing to ensure adequate diagnosis. Further studies in this field are needed to help guide clinicians on this systematic evaluation and understand the clinical implications of the various enteropathies.

Figure 1. Etiologies of seronegative enteropathies according to Paris consensus (n = 90)

References

1. ^{Lebwohl B, Rubio-Tapia A. Epidemiology, Presentation, and Diagnosis of Celiac Disease. Gastroenterology. 2021;160(1):63-75. doi:10.1053/j.gastro.2020.06.098}
2. ^{Makharia GK, Singh P, Catassi C, et al. The global burden of coeliac disease: opportunities and challenges. Nat Rev Gastroenterol Hepatol. 2022;19(5):313-327. doi:10.1038/s41575-021-00552-z}
3. ^{Aziz I, Peerally MF, Barnes JH, et al. The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000-2015). Gut. 2017;66(9):1563-1572. doi:10.1136/gutjnl-2016-312271}
4. ^{Schiepatti A, Sanders DS, Baiardi P, et al. Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus. Gut. 2022;71(11):2218-2225. doi:10.1136/gutjnl-2021-326645}