Perspectives in clinical gastroenterology and hepatology
Suspected Nonceliac Gluten Sensitivity Confirmed in Few Patients After Gluten Challenge in Double-Blind, Placebo-Controlled Trials

https://doi.org/10.1016/j.cgh.2016.08.007Get rights and content

A double-blind, placebo-controlled, gluten challenge has been proposed to confirm a diagnosis of nonceliac gluten sensitivity (NCGS) in patients without celiac disease who respond to a gluten-free diet. To determine the accuracy of this approach, we analyzed data from 10 double-blind, placebo-controlled, gluten-challenge trials, comprising 1312 adults. The studies varied in the duration of the challenge (range, 1 d to 6 wk), daily doses for the gluten challenge (range, 2–52 g; 3 studies administered <8 g/d), and composition of the placebo (gluten-free products, xylose, whey protein, rice, or corn starch containing fermentable carbohydrates). Most of the studies found gluten challenge to significantly increase symptom scores compared with placebo. However, only 38 of 231 NCGS patients (16%) showed gluten-specific symptoms. Furthermore, 40% of these subjects had a nocebo response (similar or increased symptoms in response to placebo). These findings reveal heterogeneity and potential methodology flaws among studies of gluten challenge, cast doubt on gluten as the culprit food component in most patients with presumptive NCGS, and highlight the importance of the nocebo effect in these types of studies.

Section snippets

Methods

A literature search was conducted through PubMed, up to March 31, 2016, examining all published articles linked to the MeSH search terms “non celiac OR nonceliac OR non-celiac OR noncoeliac AND gluten sensitivity” from English language journals. Only randomized DBPC trials evaluating gluten challenge in either NCGS or IBS patients were included. Patients suffering from celiac disease or other gluten-related disorders (gluten ataxia, autism, neurologic symptoms), mostly referenced as “gluten

Results

The review and selection process is detailed in Figure 1. From a total of 325 eligible articles in our initial search, we finally retrieved 10 DBPC trials with gluten/wheat challenge including a total of 1312 patients with suspected NCGS.3, 15, 16, 17, 18, 19, 20, 21, 22, 23 All of these studies were conducted in adult populations. Nine in 10 (90%) studies were published over the past 5 years.

Discussion

The present review shows that more than 80% of nonceliac patients, labeled as suffering from NCGS after a favorable response to a gluten-free diet, cannot reach a formal diagnosis of NCGS after a double-blind, placebo-controlled gluten challenge. Double-blind, placebo-controlled, cross-over trials currently represent the gold standard for confirming dietary factors involved in functional gastrointestinal symptom generation. Accordingly, several conclusions can be drawn from our results. To

Conclusions

In conclusion, more than 80% of patients with suspected NCGS cannot be diagnosed formally after a double-blind, placebo-controlled, cross-over gluten challenge. Many doubts arise from these findings, including the appropriateness of including gluten in the name of the disease, the methodologic flaws of the currently recommended double-blind, placebo-controlled, cross-over trials as the gold standard diagnostic tool for NCGS, along with the possibility of NCGS being a melting pot made up of

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      Citation Excerpt :

      A meta-analysis of 10 food challenge studies including 1312 patients labeled with NCGS found that only 16% of patients with NCGS showed a gluten-specific response and 40% reported increased symptoms with placebo. These findings, consistent with previous studies, cast doubt on the role of gluten in NCGS.69 A double-blinded, placebo-controlled crossover study by Skodje et al70 found that GI symptoms in patients with self-reported NCGS were higher with fructan (wheat starch) in gluten-containing foods than with gluten itself (P = .049).

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    Conflicts of interest The authors disclose no conflicts.

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