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Non-celiac gluten sensitivity: A work-in-progress entity in the spectrum of wheat-related disorders

https://doi.org/10.1016/j.bpg.2015.04.006Get rights and content

Abstract

Non-celiac gluten sensitivity is an undefined syndrome with gastrointestinal and extra-intestinal manifestations triggered by gluten in patients without celiac disease and wheat allergy. The pathogenesis involves immune-mediated mechanisms requiring further research. Symptoms disappear in a few hours or days after gluten withdrawal and recur rapidly after gluten ingestion. Besides gluten, other wheat proteins as well as fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) may contribute to this syndrome. This syndrome occurs mainly in young women, being rare in children. Its prevalence ranges from 0.6% to 6%, based on primary or tertiary care center estimates. No biomarker is available, but half of patients tests positive for IgG anti-gliadin antibodies, which disappear quickly after gluten-free diet together with symptoms. Also, genetic markers are still undefined. Although currently limited to a research setting, double-blind, placebo-controlled, cross-over trial strategy is recommended to confirm the diagnosis. Treatment is based on dietary restriction with special care to nutrient intake.

Introduction

Until a few years ago gluten and wheat proteins were considered responsible for the occurrence of two well-defined clinical entities, i.e. celiac disease (CD) and wheat allergy (WA) [1], [2]. The evidence of gluten sensitive patients, i.e. symptoms evoked by gluten/wheat in patients without CD or WA, was brought up for the first time at the beginning of the '80s by Geoffrey Holmes' group in the UK [3]. That remarkable report highlighting the existence of gluten sensitivity fell into shadow as most clinicians were dissatisfied by the lack of established diagnostic criteria to identify those patients. Likewise functional bowel disorders, most subjects with a suspicion of gluten sensitivity were thought to be imaginary (i.e. 'psychiatric') patients belonging to a sort of 'no man's land' of gluten related disorders [4]. Nonetheless, with the increasing number of patients complaining of symptoms following gluten ingestion, the awareness of a new gluten-related syndrome (currently referred to as non-celiac gluten sensitivity, NCGS) has grown with a progressive pace over the years ∗[5], [6], ∗[7], [8], ∗[9].

Why NCGS has markedly increased over time? The answer(s) to this question is / are still unclear, although a number of factors should be considered. First, the novel variants of wheat that are known to contain high amount of toxic gluten peptides potentially harmful to the integrity of the enteric mucosa; secondly, the mechanization of farming and the growing industrial use of pesticides; thirdly, the overall reduced time of dough fermentation resulting in a higher content of toxic gluten fractions in bakery products [10]. Finally, the media hype and the growing awareness of clinicians towards this condition contributed to the increasing rate of NCGS diagnosis, not always supported by evidence [11].

Currently, NCGS should be regarded as a new entity although with a possible overlap with other conditions, i.e. mainly functional bowel disorders (irritable bowel syndrome, IBS) and a variety of food hypersensitivities [12]. In this respect, dietary components other than gluten, such as wheat proteins (i.e. amylase- and trypsin-inhibitors – ATIs) and fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) could have a role in symptom generation of NCGS ∗[13], ∗[14]. However, the relative contribution exerted by single dietary factors in NCGS-related symptoms is still unclear as cereals contain both ATIs and FODMAPs admixed with gluten. NCGS should be suspected in patients displaying intestinal symptoms (often dismissed as 'IBS patients') and extraintestinal manifestations, which occur soon after gluten ingestion [15], ∗[16]. A diagnostic pre-requisite for establishing NCGS in a symptomatic patient is that both CD and WA have been ruled out. Due to the lack of biomarkers, the diagnosis of NCGS remains strictly related to clinical criteria [17], [18]. The improvement of symptoms after gluten exclusion is regarded as one of the major diagnostic criteria for NCGS, although the possibility of a 'placebo effect' (associated to a dietary exclusion of certain foods) should not be discarded [19]. Thus, a cautionary approach in recommending a gluten free diet (GFD) should be adopted in symptomatic patients lacking a clear diagnosis of NCGS [20].

This chapter has been designed to provide a practical guidance in the various aspects related to NCGS, i.e. basic immunological mechanisms and pathogenesis, epidemiology and clinical picture, diagnostic criteria, treatment (including a possible approach by enzyme therapy) and future tasks, in order to provide specialists and general practitioners with a most updated review on this emerging topic.

Section snippets

Basic immunological mechanisms and pathogenesis

Gluten is an essential triggering factor in CD. However, the term “gluten” is complicated, because there are at least three different meanings of the word. A GFD is a diet without wheat, rye and barley (and all related cross-bred cereals). Gluten is also the glue-like mass obtained after washing flour with water, and denotes a mix of gliadin and glutenin proteins from wheat and related proteins derived from other gluten-containing cereals. In plants, these proteins serve as storage for amino

Epidemiological and clinical picture

Epidemiological data on NCGS are still scant and approximate. In the US this syndrome seems to be observed much more frequently in tertiary referral centers compared to primary care. Data from the National Health and Nutrition Examination Survey (NHANES), a primary care program, based on interviews, physical examination and blood samples, showed that NCGS prevalence was 0.6% over 7,762 subjects in the 2009–2010 period [42]. The low prevalence of NCGS detected in the NHANES study might be

Diagnostic criteria

The identification of NCGS starts when patients seek medical advice as a result of symptoms / manifestations which are clearly associated with gluten ingestion still present in the diet. According to the diagnostic criteria established by two Consensus Conferences (London 2011 and Munich 2012), the current view to NCGS diagnosis is based on symptom / manifestation evaluation along with the exclusion of CD and WA ∗[5], ∗[7]. The latter should be established by: normal levels of IgA tissue

Dietary treatment

Patients should avoid self-diagnosis and should not withdraw gluten by themselves before CD or NCGS condition has been verified in a referral center [16]. The auto-diagnosis of a presumed gluten intolerance is a problem since once GFD is started many subjects find it difficult to reintroduce gluten to rule out CD [62]. Once CD is adequately excluded, the patient can start GFD. Most patients referred to the dietitian with suspicion of NCGS are already self-instituted on a GFD. The dietitian will

Management of patients with persistent gastrointestinal symptoms

About one third of patients with self-reported NCGS complain of persistent symptoms while on a GFD, a figure comparable to that found in treated CD [17], [76]. This observation might have several explanations. In addition to wrong diagnosis of NCGS, a poor compliance to diet is the first option that should be considered. In the Biesiekierski et al study only 58% of self-diagnosed NCGS patients reported adherence to GFD [17]. As these patients do not suffer from CD, they may feel they do not

Future tasks

A wide spectrum of clinical and research tasks represents future objectives in the field of gluten-related disorders, in particular for NCGS. The increasing number of patients who experience symptoms after gluten ingestion without evidence of CD and WA has contributed to the recognition of NCGS as a new gluten-related disorder ∗[5], ∗[7], ∗[16]. Although the existence of NCGS has been accepted worldwide, the knowledge regarding this syndrome is still limited, with many aspects awaiting further

Conclusions and summary

NCGS has been recognized as a new gluten-related syndrome by the scientific community, but the knowledge on this syndrome is still incomplete with few certainties and many unsettled issues. The epidemiology of NCGS is to be clarified, but there is growing evidence that it is likely more frequent than CD and mainly affecting young women. NCGS is regarded as an immune-mediated disorder characterized by an activation of innate immunity, but further studies are needed to confirm this and to

Conflict of interest statement

Umberto Volta, Giacomo Caio, Roberto De Giorgio, Christine Henriksen, Gry Irene Skodje and Knut E. A. Lundin do not have conflict of interest.

Practice points

  • NCGS is still a poorly defined syndrome, characterized by gastrointestinal and extra-intestinal symptoms elicited by gluten ingestion in patients without celiac disease and wheat allergy;

  • Symptoms disappear quickly in a few hours or days after gluten removal from the diet and recur rapidly when gluten is reintroduced;

  • In addition to gluten,

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