Systematic Review

Noncoeliac Gluten Sensitivity

J. Molina-Infante; S. Santolaria; D. S. Sanders; F. Fernández-Bañares


Aliment Pharmacol Ther. 2015;41(9):807-820. 

In This Article

Abstract and Introduction


Background Noncoeliac gluten sensitivity (NCGS) is a controversial emerging disorder. Despite reported symptoms related to the ingestion of gluten, NCGS remains a diagnosis based on the exclusion of coeliac disease, given the absence of reliable biomarkers.

Aim To evaluate the prevalence, diagnostic exclusion of coeliac disease and the efficacy of a gluten-free diet (GFD) for NCGS patients.

Methods A PubMed search was performed up to December 2014. According to consensus diagnostic criteria, NCGS was defined as self-reported gluten intolerance, negative coeliac serology and absence of villous atrophy. Studies evaluating the impact of a GFD on patients with irritable bowel syndrome (IBS) were also included.

Results Prevalence rates of NCGS (0.5–13%) differed widely. Seventeen studies, including 1561 patients (26 children), met the inclusion criteria for NCGS. HLA haplotypes could not be linked to histology [normal or lymphocytic enteritis (LE)] in 1123 NCGS patients. HLADQ2/DQ8 haplotypes were present in 44% of NCGS patients. After advanced diagnostic techniques in 189 NCGS patients combining LE and HLADQ2/DQ8 haplotypes, 39 (20%) were reclassified as coeliac disease. There was a higher than expected family history of coeliac disease and autoimmune disorders in NCGS patients. A GFD resulted in variable results for variable, but significantly improved stool frequency in HLADQ2 positive diarrhoea-predominant IBS patients.

Conclusions Prevalence rates for NCGS are extremely variable. A subset of NCGS patients might belong in the so-called 'coeliac-lite' disease. The benefit of a GFD for NCGS patients is currently controversial. HLADQ2 positive diarrhoea-type IBS patients might gain symptom improvement from a GFD.


Noncoeliac gluten sensitivity (NCGS) was originally described in 1976 and 1978[1,2] and the first series dates back to 1980,[3] but only since 2010 a rapidly increasing number of studies have called our attention to an apparently novel syndrome or entity, which has challenged physicians and researchers. NCGS is characterised by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either coeliac disease or wheat allergy.[4,5,6] NCGS has been reported to affect up to 5–10% of western population and gluten-free foods among noncoeliac patients have grown in popularity.[7,8,9] Sales of gluten-free food in the US have risen three-fold from 2006 to 2010 and another three-fold increase is expected by 2015.[7] A recent report revealed that about a third of US adults (the highest percentage ever) expressed their willingness to exclude gluten from their diets.[10] This perspective is largely related to the belief that eliminating gluten from the diet increases health and helps with weight loss, or even that gluten can be harmful to every human being. Therefore, NCGS is now recognised as a gluten-related disorder which has clinical, social and economical relevance.

Currently there is an absence of any reliable biomarkers, therefore, NCGS remains a diagnosis of exclusion. It is essential to exclude coeliac disease in clinical practice, based on clinical, laboratory and histological findings.[4,5,6,11] The current clinical consensus is that the diagnostic criteria for NCGS should include self-reported gluten intolerance, negative coeliac disease serology (including IgA endomysial antibodies, IgA tissue transglutaminase antibodies and IgG deamidated gliadin peptide antibodies) and the absence of villous atrophy on duodenal histology (whilst on a gluten containing diet).[5,6,11] As such, it is accepted that NGCS patients might have an increased number of duodenal intraepithelial lymphocytes (IELs) (>25 IEL/100EC), i.e., lymphocytic enteritis (LE), which represents Marsh 1 lesions (Marsh-Oberhuber) or grade A lesions (Corazza) in the histological classification for coeliac disease.[4,5,6,11] LE is a nonspecific histological lesion which may be associated not only with coeliac disease but also to Helicobacter pylori infection, small intestine bacterial overgrowth or the use of anti-inflammatory drugs. However, the most frequent cause of LE in patients with positive HLA-DQ2/DQ8 haplotypes after undertaking an exhaustive diagnostic work-up has been coeliac disease, with reported prevalences ranging from 16% to 43%.[12,13,14,15,16] Furthermore, seronegativity is more common in coeliac disease patients without villous atrophy (Marsh 1-2 lesions), but these 'minor' forms of coeliac disease may have similar clinical manifestations to those with villous atrophy[16,17,18] and may show similar clinical–histological remission with reversal of haematological or biochemical disturbances on a gluten-free diet (GFD).[19,20]

Among gluten-related disorders, it is critical to make a clear distinction between coeliac disease and NCGS, since both entities could have radically different natural history, prognosis and need for strict long-term gluten avoidance.[21] This recognition and differentiation becomes difficult in patients with negative coeliac disease serology and histological findings (Marsh 1 lesions or LE) not diagnostic for coeliac disease. In this regard, consensus guidelines from the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) state that a high count of γδ cells (or γδ/CD3 ratio) in immunohistochemical assessment of biopsies or the presence of IgA anti-TG2 intestinal deposits might be specific for CD in patients with LE.[22] In fact, coeliac patients with grade I Marsh mucosal changes show an increase in γδ IELs and deposition of subepithelial anti-tTG IgA when compared to individuals with NCGS.[23] For these hard to diagnose patients, Catassi and Fasano recently proposed that either LE associated with IgA subepithelial deposits or a histological response to a GFD in seronegative patients could be taken as features supporting a diagnosis of coeliac disease.[24] Therefore, this review aims to critically review the available evidence on NCGS, firstly focusing on prevalence figures and diagnostic efforts to rule out coeliac disease and secondly on the results of different dietary interventions for NCGS patients.