Coeliac disease

CD is a chronic inflammatory enteropathy caused by dietary exposure to gluten⁽ Reference Mooney, Hadjivassiliou and Sanders ^{12 )}. Although the manifestations of CD may have been described more than 100 years ago, it is only from the 1940s that the relationship between gluten and CD has been established⁽ Reference van Berge-Henegouwen and Mulder ^{13 )}. However, more than 70 years later, the pathogenesis of CD has yet to be fully elucidated, but it is agreed that the ingestion of gluten in genetically predisposed individuals carrying the human leucocyte antigen DQ2 and/or DQ8 alleles can arise in a T-cell mediated immune reaction, leading to small bowel villous atrophy and subsequent clinical manifestations⁽ Reference Marsh ^{14 ,} Reference Sollid, Markussen and Ek ^{15 )}.

Historically, CD was rare with an incidence of one in 8000 being reported in the 1950s⁽ Reference Davidson and Fountain ^{16 )}. However, contemporary epidemiological studies estimate a worldwide prevalence of approximately one in 100 or 1 %⁽ Reference Fasano, Berti and Gerarduzzi ^{17 ,} Reference Volta, Bellentani and Bianchi ^{18 )}. Nevertheless, a considerable proportion of patients still remain undiagnosed with estimates that for every patient diagnosed with CD approximately eight cases are yet to be detected. Furthermore, our understanding of the coeliac patient has drastically changed. In fact previously most of the cases that were diagnosed were children, whereas now it has been shown that adult cases (characteristically presenting between the fourth and sixth decades) are more frequently occurring at a ratio of 9:1 compared with the paediatric cohort.

The clinical manifestations of CD are heterogeneous. The classical presentation of malabsorption characterised by chronic diarrhoea, weight loss and failure to thrive is relatively rare. Far more commonly, patients present with non-classical symptoms which include irritable bowel type syndrome (IBS)⁽ Reference Sanders, Carter and Hurlstone ^{19 )}, iron deficiency anaemia⁽ Reference Corazza, Valentini and Andreani ^{20 )}, osteoporosis⁽ Reference Kemppainen, Kröger and Janatuinen ^{21 )}, ataxia or peripheral neuropathy⁽ Reference Hadjivassiliou, Gibson and Davies-Jones ^{22 )}. Indeed, given that IBS is extremely common affecting about 11 % of the population national guidelines now propose that all patients presenting with such symptoms should have CD excluded⁽ Reference Kemppainen, Kröger and Janatuinen ^{21 )}. In fact, a recent meta-analysis has shown that CD accounts for 4 % of those cases presenting with IBS⁽ Reference Richey, Howdle and Shaw ^{23 ,} Reference Ford, Chey and Talley ^{24 )}.

To date, the only therapy for CD is a lifelong gluten-free diet (GFD)⁽ Reference Rubio-Tapia, Hill and Kelly ^{25 )}. Adherence to a restrictive GFD leads to gradual healing of the mucosa of the small bowel and to the resolution of malabsorptive symptoms⁽ Reference Lee, Lo and Memeo ^{26 )}, although there is a consistent proportion of patients who continue to show a low grade of mucosal inflammation even on a GFD⁽ Reference Lanzini, Lanzarotto and Villanacci ^{27 )}. The Codex standard (which is used in the UK and Europe), and similarly the Food and Drug Administration in the United States, suggest that foods containing ≤20 mg/kg or 20 parts per million (ppm) gluten can be labelled as ‘gluten-free’ and that foods containing between 21 and 100 ppm gluten can be labelled as ‘very low gluten’.

Gluten-free diet in the absence of coeliac disease

Historically, gluten-free products have been of limited availability with knowledge of CD among the general population shown to be lacking⁽ Reference Karajeh, Hurlstone and Patel ^{28 )}. This inevitably contributed to the social phobia that individuals with CD experienced when dining out⁽ Reference Sverker, Hensing and Hallert ^{29 )}. However, over the last decade there has been a paradigm shift with a drastic rise in the availability of gluten-free products paralleled by an increase in awareness among the public⁽ Reference Aziz, Karajeh and Zilkha ^{30 )}. Such findings are not only as a consequence of a rise in the incidence and recognition of CD. In fact, surveys conducted among the general population confirm that a greater number of consumers worldwide are following a GFD irrespective of the presence of CD⁽ Reference Aziz, Lewis and Hadjivassiliou ^{31 ,} Reference Tanpowpong, Ingham and Lampshire ^{32 )}. Observational studies have reported that up to 13 % of the population may self-report sensitivity to gluten-based products and that up to 5 % of the population may be taking a GFD of their own volition⁽ Reference Aziz, Lewis and Hadjivassiliou ^{31 ,} Reference Tanpowpong, Ingham and Lampshire ^{32 )}. In some, the avoidance of gluten-containing food is viewed as a healthier lifestyle change rather than an actual treatment, whereas in others it is a consequence of reporting ill-effects to ingestion of gluten-based products. In fact, the relationship between the ingestion of gluten-containing products and the development of clinical symptoms even in the absence of CD has been described since the late 1970s⁽ Reference Cooper, Holmes and Ferguson ^{33 ,} Reference Ellis and Linaker ^{34 )}. However, it is only in the last few years that the scientific community has focused its attention on this field, prompted by patient demands and by the sudden media pressure regarding the ‘gluten-free lifestyle’.

Why is non-coeliac gluten sensitivity different?

The definition of NCGS encompasses a spectrum of gastrointestinal and extra-intestinal symptoms which are triggered by the ingestion of gluten-containing food, even in the absence of the serologic and histological hallmarks of CD or wheat allergy⁽ Reference Sapone, Bai and Ciacci ^{11 ,} Reference Catassi, Bai and Bonaz ^{35 )}. This terminology was defined following double-blind placebo-controlled studies showing gluten per se to induce symptoms in the absence of CD⁽ Reference Biesiekierski, Newnham and Irving ^{36 )}. The symptoms reported include abdominal pain, diarrhoea, constipation and bloating, as well as chronic fatigue, behavioural changes, bone or joint pain and muscle cramps⁽ Reference Sapone, Bai and Ciacci ^{11 ,} Reference Catassi, Bai and Bonaz ^{35 ,} Reference Biesiekierski, Newnham and Irving ^{36 )}. Symptoms typically occur shortly after the ingestion of gluten, resolve on a GFD and relapse after gluten challenge.

NCGS is often self-reported or suspected by the patients themselves and then confirmed by physicians after other forms of gluten-related disorders have been excluded⁽ Reference Catassi, Bai and Bonaz ^{35 )}. In fact, whilst the diagnosis of CD can be made in most patients on the basis of positive serology (presence of endomysial and/or tissue transglutaminase antibodies) and villous atrophy at duodenal biopsy⁽ Reference Rubio-Tapia, Hill and Kelly ^{25 ,} Reference Ludvigsson, Bai and Biagi ^{37 )}; patients with NCGS present with negative serology and absence of villous atrophy⁽ Reference Sapone, Bai and Ciacci ^{11 )}. However, the presence of antigliadin antibodies has been described in up to 50 % patients with NCGS⁽ Reference Carroccio, Mansueto and Iacono ^{38 –} Reference Volta, Bardella and Calabrò ^{40 )}, and an increase in duodenal intraepithelial lymphocytes, corresponding to the grade 1 of the Marsh–Oberhuber histologic classification, has been observed in a subset of patients with NCGS in the absence of other criteria for CD⁽ Reference Carroccio, Mansueto and Iacono ^{38 )}. Moreover, the prevalence of NCGS seem to be higher in first-degree relatives of subjects with CD, and carriers of human leucocyte antigen DQ2 and/or DQ8 seem to be at greater risk of experiencing symptoms related to NCGS than the general population although these data have not been confirmed in different epidemiological studies⁽ Reference Carroccio, Mansueto and Iacono ^{38 ,} Reference Volta, Bardella and Calabrò ^{40 )}.

The growing interest in this clinical entity has led to the advancing of several hypotheses about NCGS pathogenesis, yet all of them still remain to be fully elucidated. Altered intestinal permeability similar to that involved in the pathogenesis of CD and activation of the innate immune system following gluten exposure have been considered and are under investigation⁽ Reference Sapone, Bai and Ciacci ^{11 ,} Reference Sapone, Lammers and Mazzarella ^{41 –} Reference Brottveit, Beitnes and Tollefsen ^{43 )}.

How to diagnose non-coeliac gluten sensitivity

In the absence of clear serologic or histopathologic criteria to orient towards a diagnosis, NCGS has often been perceived as being an IBS-like entity, mainly due to an evident overlap of clinical features between those two syndromes⁽ Reference Verdu, Armstrong and Murray ^{44 )}. Furthermore, it has also been observed that IBS patients, previously naive to the effects of gluten, may benefit from a GFD⁽ Reference Vazquez-Roque, Camilleri and Smyrk ^{45 )}. To date, the reference standard for the diagnosis of ‘true’ NCGS is an elimination diet followed by double-blind placebo-controlled gluten challenge, a method which could hardly be introduced into clinical practice⁽ Reference Sapone, Bai and Ciacci ^{11 )}. Recently, a diagnostic algorithm based on the absence or presence of clinical, serologic and histological criteria has been proposed to diagnose and differentiate NCGS from CD⁽ Reference Kabbani, Vanga and Leffler ^{46 )}. This novel study provides a clinically pragmatic approach as it takes into consideration the difficulties that arise when evaluating patients who present with gluten-based sensitivity and are already taking a GFD, which in cases of CD can lead to negative coeliac serology and normal duodenal biopsies⁽ Reference Kabbani, Vanga and Leffler ^{46 )}. It has been suggested that where available negative human leucocyte antigen DQ2 and DQ8 genotype is useful, in that in can exclude CD with certainty given its 100 % negative predictive value; this will account for almost half of presenting cases⁽ Reference Aziz, Lewis and Hadjivassiliou ^{31 )}. However, if human leucocyte antigen-DQ typing is not readily available, or is positive, then a gluten challenge followed by coeliac investigations is required⁽ Reference Kabbani, Vanga and Leffler ^{46 )}. Traditionally, a gluten challenge has been suggested to be ≥10 g gluten (equivalent to about 4 slices of bread) daily for 6 weeks, prior to formalised testing. More recently this could be as little as ≥3 g gluten (equivalent to 1·5 slices of bread) daily for 2 weeks⁽ Reference Leffler, Schuppan and Pallav ^{47 )}, which may be more suited to patients specifically presenting with gluten sensitivity. By adopting this approach in secondary-care gastrointestinal practice only a minority of adult patients will have a diagnosis of CD (7 %), with the remaining 93 % subsequently diagnosed as NCGS⁽ Reference Aziz, Lewis and Hadjivassiliou ^{31 )}. Furthermore, individuals with NCGS do not appear to suffer the nutritional deficiencies (anaemia and haematinic deficiencies) and low mean BMI commonly associated with CD, which is a reflection of the state of normal villi as seen in NCGS as opposed to the villous atrophy in CD⁽ Reference Aziz, Lewis and Hadjivassiliou ^{31 )}.

The controversies surrounding non-coeliac gluten sensitivity

Given the scattered data regarding the pathogenesis of NCGS, it is unclear when faced with a patient diagnosed with NCGS whether gluten is genuinely responsible for their symptom complaint. Firstly, there are no diagnostic biomarkers for NCGS and as previously mentioned carrying out double-blind placebo-controlled gluten challenges is impractical and cumbersome in routine clinical practice. Secondly, evidence concerning the efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) in controlling IBS symptoms has disclosed the concept that other components of wheat may be responsible for triggering symptoms instead (Table 1)⁽ Reference Shepherd, Parker and Muir ^{48 ,} Reference Gibson and Shepherd ^{49 )}. In fact, FODMAP such as fructans, largely contained in wheat and related grains, can trigger gastrointestinal symptoms by means of a combination of osmotic effect and increased gas production from bacterial fermentation⁽ Reference Gibson and Shepherd ^{50 ,} Reference Murray, Wilkinson-Smith and Hoad ^{51 )}. It has recently been demonstrated that individuals with NCGS on a self-imposed GFD show further improvement when placed on a low FODMAP diet and that subsequent blinded gluten re-introduction shows no specific or dose-dependent effect⁽ Reference Biesiekierski, Peters and Newnham ^{52 )}. This has led to the concept of NCGS being challenged although this study actually demonstrated a nocebo response to low-dose gluten, high-dose gluten, or whey protein which may be as a consequence of an anticipatory effect in view of the crossover design of the study rather than dismiss the effects of gluten⁽ Reference Biesiekierski, Peters and Newnham ^{52 )}. Moreover, it has also been suggested that other proteins contained in wheat, such as lectins, agglutinins and amylase-trypsin inhibitors can trigger the innate immune response and therefore lead to the development of symptoms after ingestion of wheat⁽ Reference Junker, Zeissig and Kim ^{53 –} Reference Dalla Pellegrina, Perbellini and Scupoli ^{55 )}. For these reasons, it has been advised that in clinical practice it may be more appropriate to describe patients with NCGS using the preface ‘self-reported’, or alternatively use the term non-coeliac wheat sensitivity⁽ Reference Carroccio, Rini and Mansueto ^{56 ,} Reference Sanders and Aziz ^{57 )}. Nevertheless, this complex field opens a gateway for future studies to identify means of delineating which gluten-based component is responsible for triggering any particular individual's symptoms.

Table 1. Main characteristics of the gluten-free diet and the low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet

ppm, parts per million.