NICE and BSG 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?  

A diagnosis of seronegative can be made in patients with the following:  

• With or without symptoms of coeliac disease.  

• Presence of villous atrophy. 

• Genetics compatible with coeliac disease.  

• Negative immunoglobulin A (IgA) tissue transglutaminase (tTG), or IgG tTG.  

• 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, guidelines recommend that total IgA and IgA tTG should be used as the first- choice test. If IgA deficient, IgG tTG, IgG EMA, or IgG DGP 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?  

Research suggests seronegative accounts for 2-3% of coeliac disease and around a third of patients with seronegative villous atrophy.  

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.  

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. Guidelines recommend 3-6g of gluten should be consumed, 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 specialist 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 may be considered after 1-2 years of starting the gluten free diet 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.