Gluten Sensitivity: Celiac Lite versus Celiac Like

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he potential spectrum of so-called gluten-related disorin baker’s asthma).9 Furthermore, these symptoms were not ders has expanded beyond the well-recognized and related to IgE-mediated allergy such as wheat allergy, which is well-validated disorders of celiac disease and dermatitis a distinctly different entity,10 and were without circulating or 1,2 herpetiformis, now encompassing other disorders whose local IgE antibodies to wheat components. So, after the first of these publications, it became fashionable to expand the etiologies have been connected to gluten. Chief among these notion of what was gluten sensitivity. is nonceliac gluten sensitivity, sometimes See related article, p  Further studies from Italy redefined this as referred to as nonceliac wheat sensitivity. nonceliac wheat sensitivity, demonstrating that individuals This entity is considered to be separate from wheat allergies tested with a double-blind food challenge could indeed and wheat-dependent exercise-induced anaphylaxis. The respond to wheat.11 By the early part of 2013, it was largely condition of nonceliac gluten sensitivity has been defined largely symptomatically in individuals who do not have celiac becoming accepted that nonceliac gluten sensitivity or wheat disease but whose clinical symptoms are dependent on sensitivity now extended to patients who did not have any of gluten.3 Although gluten-sensitive gastrointestinal (GI) the features or genetic predictors of celiac disease. However, this expanding acceptance of gluten-related symptoms, particularly diarrhea, have been described now symptoms has run into headwinds. First, a study of commuin several reports over 3 decades; these have largely carried nity-based adults cohort with chronic diarrhea and diarrheasome symptom similarity to or indeed some features of celiac predominant irritable bowel syndrome, unselected because disease, although these features are not sufficient to make of any prior history of gluten symptoms, had relatively that diagnosis. Some patients have positive serology, such modest changes in gut function in a carefully done study. as endomysial and tissue transglutaminase (TTG) antibodies The gluten-related symptoms were largely related to the carwithout any histologic change,4,5 called potential celiac disriage of HLA types associated with celiac disease risk, ease. This could be increased intraepithelial lymphocytosis, although these patients did not have celiac disease.12 most often not a part of the spectrum.6 And, finally, patients who, even though they do not have circulating antiHowever, the current study in this issue of the Journal by bodies against TTG, have secreted antibodies present in the Francavilla et al13 reports on a cohort of children with a clinintestinal lumen and/or IgA antibodies in the mucosa that ical diagnosis of gluten sensitivity without markers for celiac colocalize with the TTG, referred to as intestinal TTG disease in whom symptoms seem to be reproducible by deposits.5 These latter patients have typically carried the single-blind, parent-aware gluten challenge. This group of children, obviously highly selected and relatively rare same HLA at risk alleles as celiac disease, suggesting that compared with the large number of celiac patients seen in they have an incompletely evolved form of celiac disease, “cethese 2 centers, appears to have gluten-inducible symptoms. liac lite,” wherein gluten induces symptoms in the absence of A substantial proportion of patients carry gliadin IgG antifrank malabsorption. bodies, although this was not measured in ideal controls. This field of nonceliac gluten sensitivity was significantly The controls used were disease controls with functional disrupted by the first of 2 reports from Australia by Biesierbowel disease, although it might have helped if those patients kierski et al,7 which demonstrated for the first time that indiwere subjected to a gluten-free diet. Certainly, self-reported viduals who had a history of gluten-sensitive symptoms did responses to a gluten-free diet occur in patients with indeed respond to a double-blind gluten challenge in terms increased intraepithelial lymphocytosis and lack of the HLA of symptoms. These symptoms did not just include GI symptype associated with select celiac disease.6 toms but extended beyond the gut to include fatigue and 8 headache. The same group has expanded their data and In the present report, 15 patients were collected based on showed that the hypersensitivity was not related to gluten symptoms leading to suspicion of celiac disease but without and disappeared after the installment of the patients on a any positivity of serum TTG2 antibodies and with a normal diet low in fermentable, oligo-, di-, mono-saccharides and duodenal histology in all patients except 1, who did not undergo polyols (FODMAPs). Although these patients had claimed biopsy. One-third of the patients were HLA-DQ2/8 positive, as benefit from a gluten-free diet, it may actually be due to fructo be expected from the HLA distribution in the normal poputans (a FODMAP) in wheat or perhaps other immunogens, lation. A major drawback of many studies is the lack of a doublesuch as amylase trypsin inhibitors (the cause of wheat allergy blind, placebo-controlled food challenge (DBPCFC). Although we can be reasonably certain that the patients do not have celiac DBPCFC FODMAP GI TTG

Double-blind, placebo-controlled food challenge Fermentable, oligo-, di-, mono-saccharides and polyols Gastrointestinal Tissue transglutaminase

The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.11.024

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disease, the culpability of gluten remains unproved in the great majority of studies. Blinded challenges and blinded dechallenges would be ideal to substantiate the role of gluten. It is possible that, like in the previously cited work,8 most would not pass the test of double-blind food challenge. So far, no reliable positive biomarkers have been identified for this nonceliac disease gluten sensitivity, neither in the form of antibodies or proteins or peptides in serum nor of histological changes in the small intestine or elsewhere. Antigliadin antibodies long used for celiac disease have been essentially discarded from our clinical use for diagnosis of celiac disease. However, a resurgence of interest in this antibody has occurred in patients with nonceliac gluten sensitivity, but we need to be cautious before interpreting a positive gliadin antibody as a specific marker for nonceliac gluten sensitivity. Any patient with disrupted barrier function may develop IgG antibodies against food antigens; it does not necessarily imply the food antigen is actually harmful. There are other issues— for example, how the reference ranges for antigliadin antibody tests are generated. Are these done by comparing groups of patients with celiac disease vs controls? Are they undertaken in a group of so-called healthy individuals and then 95% CI cutoffs are applied to each end, which by definition would imply that, even if the distribution of these antibody results in normal or in healthy controls was normally distributed, 5% would land outside of the normal range as a matter of design? The lack of reliable biomarkers in nonceliac disease gluten hypersensitivity brings the diagnosis to the level of food allergy in general. IgE antibodies have diagnostic accuracy in food-allergic infants and children below 50%, even though IgE antibodies may perform better in selected populations and for selected allergies (ie, peanut allergy). A lesson from food allergy is that children referred for food allergy only are positive by DBPCFC in one-third of the cases, so actually DBPCFC for purely statistical reasons should be repeated twice.14-16 Another lesson is that the non–IgE-mediated allergies tend to disappear with age (eg, cow’s milk allergy diminishes with 50% per year in the first 5 years of age17). Those who are IgE antibody positive are more prone to persistence of symptoms18 (eg, in subjects allergic to peanut, typically IgE mediated, the symptoms may even worsen19). Where do other food intolerances, such as the FODMAPs, fit into this picture? Although it is possible and was concluded by the Australian group that FODMAPs were responsible for the symptoms, it is possible that perhaps the interaction is more complex and that FODMAPs could induce symptoms because of an intolerance induced by a specific, possibly immunological response to gluten, similar to secondary lactose intolerance that can occur in the context of celiac disease. The differential diagnosis for these symptoms is quite a bit more common than those who have self-identified themselves as being gluten free. One population-based study from the US suggests that

Gluten sensitivity: celiac lite versus celiac like.

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