NICE guidelines recommend that people with a negative serological test should be referred to a gastrointestinal specialist for further assessment if coeliac disease is still clinically suspected. 

Villous atrophy is seen in untreated coeliac disease but is not specific to coeliac disease and is seen in other conditions including giardiasis, inflammatory conditions or due to certain medications. 

What is seronegative coeliac disease? 

The exact definition of seronegative coeliac disease can vary, but it is often defined as patients with the following features: 

• With or without symptoms of coeliac disease.
• Presence of villous atrophy.
• Genetics compatible with coeliac disease.
• Negative immunoglobulin A (IgA) tissue transglutaminase (tTG), IgA endomysial antibodies (EMA) and IgA deamidated gluten peptides (DGP).  
• Normal total IgA.
• Other causes of villous atrophy have been excluded.
• Clinical and histological response to the gluten free diet.

IgA deficiency and seronegative coeliac disease 

IgA deficiency is more common in people with coeliac disease than in the general population. Therefore, NICE guidelines recommend that total IgA and IgA tTG should be used as the first– choice test. If IgA deficient, IgG EMA, IgG DGP or IgG tTG can be used. Patients with IgA deficiency but with positive IgG based serology tests and villous atrophy are not considered to have seronegative coeliac disease. 

How common is seronegative coeliac disease? 

Experience from a tertiary referral centre in Italy identified 810 patients with coeliac disease over a 16 year period and 14 of these patients (1.7%) met the criteria for seronegative coeliac disease. 

In a UK centre, a prospective evaluation of 200 adult patients with a negative antibody test for coeliac disease, but who had villous atrophy, over a 15 year period found that 62 (31%) had seronegative coeliac disease. 

A multicentre combined retrospective-prospective longitudinal study enrolled 227 patients with an initial diagnosis of seronegative coeliac disease over a 20 year period. The study found only 84 patients (37%) met the criteria and had true seronegative coeliac disease and coeliac disease with IgA deficiency in 48 (21%). In 55 patients (24%) seronegative coeliac disease was excluded and the remaining 40 (18%) did not have a follow up biopsy to show the response to a gluten free diet.  

Importance of including gluten in the diet during testing 

It is essential that patients are eating gluten during testing for coeliac disease to obtain a reliable result. NICE recommends that gluten should be included in more than one meal a day, every day for six weeks before testing is carried out. 

Follow up for patients with seronegative coeliac disease 

As with all patients with coeliac disease, patients with seronegative coeliac disease should be referred to a dietitian for gluten free diet education. 

Secondary care follow up is also essential to assess the clinical and histological response to the gluten free diet in these patients. A follow up biopsy should be carried out approx. 12 months after diagnosis, or sooner in those with severe illness, to assess the response to the gluten free diet. 

The Rare Disease Collaborative Network for non-responsive and refractory coeliac disease, is based at two clinics with specialist teams led by Prof David Sanders in Sheffield and Dr Jeremy Woodward in Cambridge, both are available to provide support with the diagnosis and care of difficult cases.