Clinical classification and long‐term outcomes of seronegative coeliac disease: a 20‐year multicentre follow‐up study

Abstract

Background: Seronegative coeliac disease is poorly defined. Aims:To study clinical phenotypes and long-term outcomes of seronegative coeliac disease in a multicentre cohort over 20 years.Methods: Seronegative coeliac disease was diagnosed in HLA-DQ2/DQ8-positive patients with villous atrophy (VA), negative IgA endomysial (EmA), tissue transglutaminase (tTG) and deamidated-gliadin antibodies (DGP), clinical and histological response to a gluten-free diet (GFD), and no alternative causes for VA. In patients with IgA deficiency, coeliac disease was diagnosed through VA, positive IgG EmA/tTG/ DGP and clinical/histological response to a GFD (coeliac disease+IgAd). Patients with seropositive coeliac disease served as controls.Results: Of 227 patients previously diagnosed with seronegative coeliac disease, true seronegative coeliac disease was confirmed in 84, coeliac disease+IgAd in 48, and excluded in 55. Lack of follow-up duodenal biopsy precluded diagnosing seronegative coeliac disease in 40 patients. 2084 patients with seropositive coeliac disease served as controls. True seronegative coeliac disease had more severe symptoms at diagnosis and a higher risk of complications (HR 10.87,, P < 0.001) and mortality (HR 2.18, 95% CI 1.12-4.26, P < 0.01) than seropositive coeliac disease.There were no differences between true seronegative coeliac disease and coeliac disease+IgAd. On multivariate analysis, age at diagnosis, lack of clinical response to a GFD, true seronegative coeliac disease, coeliac disease+IgAd, and classical presentation predicted complications. Age at diagnosis, complications and absence of clinical response to a GFD predicted mortality. Conclusions:Seronegative coeliac disease has a more aggressive disease phenotype than seropositive coeliac disease. These data argue against over-reliance on serology for the diagnosis of coeliac disease and support a strict clinical and histologic followup in seronegative coeliac disease.

Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus

“…Approaching the differential diagnosis of enteropathies characterised by VA and negative coeliac serology is complex, as the underlying causes described in the literature are extremely heterogeneous. Apart from CD presenting with negative serology, VA can be found also in chronic enteropathies unrelated to gluten ingestion, which are often misdiagnosed as seronegative forms of CD 1–3 7–15. Interestingly, VA is the diagnostic hallmark for some of these NCEs, whereas for others, it is only one of the elements contributing to the entire clinical and histopathological picture.…”

“…Although the diagnosis of CD is straightforward in the vast majority of cases, diagnostic challenges can occur when VA is found in patients reporting GI symptoms and testing negative to coeliac specific antibodies 1–3 7. The first step is to ensure that there have been no errors of inadequate sampling, collection or processing of either serum samples or duodenal biopsies, the latter potentially resulting in incorrect orientation and evaluation of duodenal specimens; another key requirement is that the diet has not been gluten restricted prior to endoscopy 1–3 7–9. Thereafter, the clinical scenarios characterised by VA and negative coeliac serology can be broadly attributed to two main clinical entities: CD presenting with negative antibodies and chronic enteropathies unrelated to CD and gluten ingestion, which we have defined as non-coeliac enteropathies (NCEs) 1–3…”

“…The differential diagnosis between forms of CD with negative serology and NCEs remains challenging, and patients with NCEs are frequently misdiagnosed as seronegative CD 1–3 7 9 10. Reasons for this include the rarity of these enteropathies, the overlapping clinical and histopathological features and the lack of biomarkers for some of these conditions.…”

“…Although in adults seronegative CD is the most common aetiology of VA with negative coeliac serology,1–3 11–15 discriminating between seronegative CD and NCEs is key to reduce diagnostic delay and avoid unnecessary lifelong gluten-free diet (GFD). Furthermore, accurate characterisation of NCEs ensures both appropriate management and a clinical perspective for our patients with regards to long-term morbidity and mortality 9 11–14 16 17…”

The Role of the Gluten-Free Diet in the Management of Seronegative Enteropathy

“…In the largest study to date involving 227 adult patients previously diagnosed with SNVA, Schiepatti et al found that SNCD had more severe symptoms at diagnosis, nearly 11 times higher risk of complications, and 2 times higher risk of mortality than seropositive CD [15].…”