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Nonceliac Gluten Sensitivity

      Abstract

      Nonceliac gluten sensitivity (NCGS) is the clinical term used to describe gastrointestinal (GI) and/or extraintestinal symptoms associated with gluten ingestion. The prevalence of NCGS is unknown. The condition has clinical features that overlap with those of celiac disease (CD) and wheat allergy (WA). The pathophysiologic process in NCGS is thought to be through an innate immune mechanism, whereas CD and WA are autoimmune- and allergen-mediated, respectively. However, dietary triggers other than gluten, such as the fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, have been implicated. Currently, no clinical biomarker is available to diagnose NCGS. Exclusion of CD and WA is necessary in the evaluation of a patient suspected to have NCGS. The onset of symptoms in patients with NCGS can occur within hours or days of gluten ingestion. Patients with NCGS have GI and extraintestinal symptoms that typically disappear when gluten-containing grains are eliminated from their diets. However, most patients suspected to have NCGS have already initiated a gluten-free diet at the time of an evaluation. A gluten elimination diet followed by a monitored open challenge of gluten intake to document recurrence of GI and/or extraintestinal symptoms can sometimes be helpful. If NCGS is strongly suggested, then a skilled dietitian with experience in counseling on gluten-free diets can provide proper patient education. Additional research studies are warranted to further our understanding of NCGS, including its pathogenesis and epidemiology, and to identify a biomarker to facilitate diagnosis and patient selection for proper management.

      Abbreviations and Acronyms:

      CD (celiac disease), FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), GFD (gluten-free diet), GI (gastrointestinal), IBS (irritable bowel symdrome), NCGS (nonceliac gluten sensitivity), NHANES (National Health and Nutrition Examination Survey), WA (wheat allergy)
      CME Activity
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      Learning Objectives: On completion of this article, you should be able To (1) define nonceliac gluten sensitivity (NCGS); (2) differentiate NCGS from celiac disease and wheat allergy; and (3) properly evaluate a patient with suspected NCGS and establish the diagnosis.
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation.
      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Vazquez-Roque receives research support from Takeda Pharmaceuticals U.S.A. Dr Oxentenko reports no competing interests.
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      Questions? Contact [email protected] .
      Gluten, a protein found in wheat, is considered a major food component that can trigger gastrointestinal (GI) symptoms. The gluten-related disorders are classified by their immunologic pathogenesis: autoimmune, allergic, and those that are neither autoimmune nor allergic.
      • Sapone A.
      • Bai J.C.
      • Ciacci C.
      • et al.
      Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
      Celiac disease (CD) and wheat allergy (WA) are the best examples of autoimmune and allergic gluten-related disorders, respectively. When gluten causes GI symptoms in the absence of CD or a WA, it is considered to be nonceliac gluten sensitivity (NCGS), a condition that is neither allergic nor autoimmune in nature. Nonceliac gluten sensitivity is the clinical term used to describe GI and/or extraintestinal symptoms associated with gluten ingestion that resolve with gluten exclusion when CD and WA have been properly ruled out.
      • Sapone A.
      • Bai J.C.
      • Ciacci C.
      • et al.
      Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
      • Catassi C.
      • Bai J.C.
      • Bonaz B.
      • et al.
      Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders.
      • Ludvigsson J.F.
      • Leffler D.A.
      • Bai J.C.
      • et al.
      The Oslo definitions for coeliac disease and related terms.
      Currently, there is no biomarker to diagnose NCGS, and the diagnosis is made on clinical grounds alone. Nonceliac gluten sensitivity is a food sensitivity thought to trigger an immune-mediated reaction to gluten-derived antigens, contrary to CD, which is also an autoimmune reaction. Nonceliac gluten sensitivity should be distinguished from a food intolerance because they are mechanistically different entities. Food intolerance, with or without malabsorption, is a nonimmunologic adverse reaction that occurs when nutrients are not digested properly or completely because of a lack of necessary digestive enzymes or an excess of a particular nutrient.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report.
      • Fasano A.
      • Sapone A.
      • Zevallos V.
      • Schuppan D.
      Nonceliac gluten sensitivity.
      Lactose and fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) intolerances are the most common food intolerances.

      Background

      The idea of gluten intake leading to GI symptoms is not new.
      • Ellis A.
      • Linaker B.D.
      Non-coeliac gluten sensitivity?.
      The concept of gluten sensitivity was first described in a case series that was published in 1980.
      • Cooper B.T.
      • Holmes G.K.
      • Ferguson R.
      • Thompson R.A.
      • Allan R.N.
      • Cooke W.T.
      Gluten-sensitive diarrhea without evidence of celiac disease.
      Cooper et al
      • Cooper B.T.
      • Holmes G.K.
      • Ferguson R.
      • Thompson R.A.
      • Allan R.N.
      • Cooke W.T.
      Gluten-sensitive diarrhea without evidence of celiac disease.
      described 8 patients who did not appear to have CD on the basis of biochemical and histologic results. These patients had chronic diarrhea and abdominal pain, resolution of symptoms on a gluten-free diet (GFD), and subsequent recurrence of symptoms with a gluten challenge. However, there had been a subsequent paucity of data until 2007, when Wahnschaffe et al
      • Wahnschaffe U.
      • Schulzke J.D.
      • Zeitz M.
      • Ullrich R.
      Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome.
      described a group of patients with diarrhea-predominant irritable bowel syndrome (IBS) who had clinical improvement on a GFD in the absence of CD. However, this response was only significant in patients who were HLA-DQ2 positive and had IgG antibodies against tissue transglutaminase and gliadin. Although not a randomized clinical trial, this study did explore the relationship between IBS-like symptoms and gluten, suggested potential mechanisms for symptom generation, revived the concept of gluten sensitivity diarrhea, and enticed further investigations in the field.
      Biesiekierski et al
      • Biesiekierski J.R.
      • Newnham E.D.
      • Irving P.M.
      • et al.
      Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial.
      performed the first randomized, double-blind, placebo-controlled clinical trial in patients with IBS who had a history of GI symptoms controlled with a GFD. Patients were randomized to either a gluten-containing diet or a placebo diet (continuation of previous GFD) for 6 weeks, with assessment of GI and overall symptoms as well as markers of inflammation and intestinal injury. Of the patients in the gluten-containing diet group, 68% reported worsening symptoms of pain, bloating, stool consistency, and tiredness within a week compared with the placebo group. However, no difference in inflammatory markers or intestinal injury was observed between the groups. There was no difference in HLA-DQ2 and HLA-DQ8 status in any of the study end points. Although this study was not able to elucidate a mechanism for symptom development, it suggested gluten as a dietary trigger for GI symptoms.
      A subsequent trial by Vazquez-Roque et al
      • Vazquez-Roque M.I.
      • Camilleri M.
      • Smyrk T.
      • et al.
      A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
      randomized patients with IBS to a GFD or a gluten-containing diet for 30 days, assessing stool frequency, colonic transit by scintigraphy, and intestinal permeability. Patients consuming a gluten-containing diet had increased stool frequency and increased small-intestine permeability, an effect that was more notable in those who were HLA-DQ2 positive. No difference in colonic transit was observed between patients on a GFD vs a gluten-containing diet. A recent randomized, double-blind, placebo-controlled, crossover trial evaluated the effects of low doses of gluten in patients with suspected NCGS.

      Di Sabatino A, Volta U, Salvatore C, et al. Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial [published online ahead of print February 19, 2015]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2015.01.029.

      Patients with NCGS had a significant increase in severity of overall symptoms such as abdominal bloating and pain 1 week after intake of small amounts of gluten compared with patients who received placebo.

      Di Sabatino A, Volta U, Salvatore C, et al. Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial [published online ahead of print February 19, 2015]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2015.01.029.

      The results of these clinical trials suggest that NCGS does exist as a clinical entity, but there is still much to learn regarding its pathogenesis and epidemiology. Nonetheless, considerable controversy still exists about whether gluten is the actual dietary trigger causing the GI symptoms. Other dietary elements have been suggested as the source of GI distress, such as other components in wheat products (leading to the concept of nonceliac wheat sensitivity), FODMAP, or the amylase-trypsin inhibitors that are naturally occurring pesticides in wheat.
      • Biesiekierski J.R.
      • Peters S.L.
      • Newnham E.D.
      • Rosella O.
      • Muir J.G.
      • Gibson P.R.
      No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly-absorbed, short-chain carbohydrates.
      • Junker Y.
      • Zeissig S.
      • Kim S.J.
      • et al.
      Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.
      In a follow-up study, Biesiekierski et al
      • Biesiekierski J.R.
      • Peters S.L.
      • Newnham E.D.
      • Rosella O.
      • Muir J.G.
      • Gibson P.R.
      No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly-absorbed, short-chain carbohydrates.
      performed a double-blind crossover trial in 37 patients with NCGS and IBS (based on Rome III criteria). Patients were given a 2-week diet of reduced FODMAP and were then randomized to a high-gluten (16 g/d), low-gluten (2 g/d of gluten and 14 g/d of whey protein), or control (16 g/d of whey protein only) diet for 1 week. Gastrointestinal symptoms improved in all participants with a FODMAP-reduced diet. However, no GI symptoms were reproduced on gluten exposure, supporting the theory that FODMAP and not gluten may be the trigger for GI symptoms. In addition to FODMAP, recent data suggest that amylase-trypsin inhibitors, which are naturally occurring pesticides, may trigger GI symptoms because they serve as potent innate immune system stimulants in vitro.
      • Junker Y.
      • Zeissig S.
      • Kim S.J.
      • et al.
      Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.
      Controversy regarding NCGS continues, and further investigations are warranted.

      Epidemiology of NCGS

      The prevalence of NCGS and the demographic characteristics of affected patients are currently unknown. Establishing the prevalence of NCGS is challenging given that many patients initiate a GFD before seeking medical evaluation and there is no biomarker for diagnosis. Although we do not have accurate estimates of the prevalence of NCGS, we have data from the National Health and Nutrition Examination Survey (NHANES) and from cross-sectional studies on the prevalence of people avoiding gluten.
      • DiGiacomo D.V.
      • Tennyson C.A.
      • Green P.H.
      • Demmer R.T.
      Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: results from the Continuous National Health and Nutrition Examination Survey 2009-2010.
      • Tavakkoli A.
      • Lewis S.K.
      • Tennyson C.A.
      • Lebwohl B.
      • Green P.H.
      Characteristics of patients who avoid wheat and/or gluten in the absence of celiac disease.
      • Ludvigsson J.F.
      • Rubio-Tapia A.
      • van Dyke C.T.
      • et al.
      Increasing incidence of celiac disease in a North American population.
      • Choung R.S.
      • Ditah I.C.
      • Nadeau A.M.
      • et al.
      Trends and racial/ethnic disparities in gluten-sensitive problems in the United States: findings from the National Health and Nutrition Examination Surveys from 1988 to 2012.
      A study of 7762 NHANES participants from 2009 and 2010 found that 0.55% of them were consuming a GFD.
      • DiGiacomo D.V.
      • Tennyson C.A.
      • Green P.H.
      • Demmer R.T.
      Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: results from the Continuous National Health and Nutrition Examination Survey 2009-2010.
      At the time of this particular survey, NCGS was not clearly defined as a clinical entity, and the reasons for gluten avoidance were not addressed. However, a recent evaluation of the NHANES participants from 2009-2012 distinguished patients with and without CD who were consuming a GFD. The study found an overall prevalence of 0.8% of patients without a CD diagnosis who were consuming a GFD, irrespective of ethnic background.
      • Choung R.S.
      • Ditah I.C.
      • Nadeau A.M.
      • et al.
      Trends and racial/ethnic disparities in gluten-sensitive problems in the United States: findings from the National Health and Nutrition Examination Surveys from 1988 to 2012.
      Furthermore, a cross-sectional tertiary referral center study of patients who had been avoiding gluten found that 82% of patients started a GFD before receiving any medical advice, supporting the fact that the prevalence of NCGS will be difficult to assess and will be progressively more challenging given the popularity of the GFD in the general population.
      • Tavakkoli A.
      • Lewis S.K.
      • Tennyson C.A.
      • Lebwohl B.
      • Green P.H.
      Characteristics of patients who avoid wheat and/or gluten in the absence of celiac disease.
      • Ludvigsson J.F.
      • Rubio-Tapia A.
      • van Dyke C.T.
      • et al.
      Increasing incidence of celiac disease in a North American population.
      Double-blind, placebo-controlled challenge studies in patients with IBS have suggested that the frequency of NCGS is approximately 30% in that patient population.
      • Carroccio A.
      • Mansueto P.
      • Iacono G.
      • et al.
      Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity.
      Despite the availability of some data on the prevalence of people with or without CD consuming a GFD, prevalence data on NCGS is still lacking. Further studies are warranted to have a better estimate of the prevalence of NCGS in general.

      Pathogenesis of NCGS

      The pathophysiology of NCGS and the development of GI and extraintestinal symptoms in the absence of CD are not clear. A study by Sapone et al
      • Sapone A.
      • Lammers K.M.
      • Casolaro V.
      • et al.
      Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.
      found that the pathogenesis of CD and NCGS were different. They suggested that NCGS triggers an innate immune response as illustrated by increased innate markers such as toll-like receptors, which is different from the adaptive response seen in CD. It is important to note that the innate immune response is a first line of defense that depends on cytokines and does not confer long-lasting immunity, contrary to the adaptive response seen in CD that relies on antibody production and does confer immunologic memory for future antigenic exposure. However, further evidence supporting an innate immune response in NCGS is lacking, and further investigation is warranted.
      Much of the controversy surrounding NCGS relates to whether it is truly a clinical entity separate from CD or IBS or whether it represents CD in its earliest clinical form and whether gluten is the actual trigger for GI symptoms rather than another dietary trigger found in wheat. Some experts suggest that NCGS is a subgroup of IBS because of their overlapping symptoms, given that prior studies have found that a subset of patients with IBS have a symptomatic response to a GFD.
      • Vazquez-Roque M.I.
      • Camilleri M.
      • Smyrk T.
      • et al.
      A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
      • Biesiekierski J.R.
      • Peters S.L.
      • Newnham E.D.
      • Rosella O.
      • Muir J.G.
      • Gibson P.R.
      No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly-absorbed, short-chain carbohydrates.
      Nonceliac gluten sensitivity may be considered a different entity from IBS because the potential underlying mechanism leading to GI symptoms is different. Moreover, certain studies have suggested that FODMAP may be the trigger for GI symptoms rather than gluten.
      • Biesiekierski J.R.
      • Peters S.L.
      • Newnham E.D.
      • Rosella O.
      • Muir J.G.
      • Gibson P.R.
      No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly-absorbed, short-chain carbohydrates.
      • Halmos E.P.
      • Power V.A.
      • Shepherd S.J.
      • Gibson P.R.
      • Muir J.G.
      A diet low in FODMAPs reduces symptoms of irritable bowel syndrome.
      However, the potential pathogenesis for symptom generation with gluten and FODMAP seems to be different. Gluten, as it relates to NCGS, is regarded as a food sensitivity, whereas a reaction to FODMAP-containing foods is considered a food intolerance. Food sensitivities are immune-mediated reactions to nutrients that elicit GI and extraintestinal symptoms that are not shared with food intolerances.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report.
      Studies have found that on gluten ingestion, some patients have increased intestinal permeability with reduced expression of tight junction proteins.
      • Vazquez-Roque M.I.
      • Camilleri M.
      • Smyrk T.
      • et al.
      A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
      A recent study used confocal laser endomicroscopy in 36 patients with IBS-like symptoms and performed food provocation studies in the duodenum through the endoscope, evaluating intervillous space, epithelial breaks, and intraepithelial lymphocyte density compared with subsequent histologic examination findings.
      • Fritscher-Ravens A.
      • Schuppan D.
      • Ellrichmann M.
      • et al.
      Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome.
      Of the 36 patients, 22 had positive confocal laser endomicroscopic findings, with 13 patients reacting to wheat and more than 50% with GI symptom improvement after exclusion of the food antigen over a 4-week period. These studies suggest that there is stimulation of the innate immune system with food triggers, supporting a potential pathogenesis of NCGS and suggesting that it may be a different entity from IBS.
      The pathogenesis of NCGS is not fully understood, and whether gluten itself may be the cause of symptom development or a different trigger such as foods high in FODMAP or the amylase-trypsin inhibitors found in wheat may be the causative factors remains controversial. Further studies are warranted to further elucidate this association and the pathogenesis of gluten-induced GI symptoms.

      Clinical Presentation of NCGS

      The onset of symptoms in patients with NCGS can occur within hours or days of gluten ingestion. The symptoms of NCGS include GI symptoms as well as extraintestinal features. Commonly reported GI symptoms include abdominal pain, bloating, diarrhea, and constipation.
      • Volta U.
      • De Giorgio R.
      New understanding of gluten sensitivity.
      • Carroccio A.
      • Mansueto P.
      • D'Alcamo A.
      • Iacono G.
      Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review.
      • Volta U.
      • Tovoli F.
      • Cicola R.
      • et al.
      Serological tests in gluten sensitivity (nonceliac gluten intolerance).
      Extraintestinal features of NCGS include “foggy” mind, fatigue, headache, leg or arm numbness, depression, joint pain, anemia, and rash, among others.
      • Volta U.
      • De Giorgio R.
      New understanding of gluten sensitivity.
      • Carroccio A.
      • Mansueto P.
      • D'Alcamo A.
      • Iacono G.
      Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review.
      Table 1 summarizes the GI and extraintestinal symptoms reported in patients with NCGS. These symptoms disappear when gluten-containing grains are eliminated from the diet. It is difficult to distinguish NCGS and CD on the basis of symptoms alone because there is considerable overlap between the 2 conditions, and further investigations are necessary to make the appropriate diagnosis.
      Table 1Symptoms in Patients With Nonceliac Gluten Sensitivity
      GastrointestinalExtraintestinal
      Bloating“Foggy” mind
      DiarrheaTiredness
      ConstipationFatigue
      Abdominal painJoint pain
      NauseaDepression
      VomitingNumbness
      Anal fissuresLoss of balance
      Eczema
      Anemia
      Weight fluctuations
      Rash
      Headaches
      In the clinical evaluation of a patient suspected to have NCGS, it is important to rule out CD and WA. Table 2 summarizes the key differences between these clinical disorders and NCGS. The initial evaluation should include tissue transglutaminase IgA serology (with or without measurement of the IgA level) while the patient is consuming a gluten-containing diet and measurement of the serum wheat IgE level to exclude CD and WA, respectively.
      • Kabbani T.A.
      • Vanga R.R.
      • Leffler D.A.
      • et al.
      Celiac disease or non-celiac gluten sensitivity? an approach to clinical differential diagnosis.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      ACG clinical guidelines: diagnosis and management of celiac disease.
      If the patient is consuming a GFD at the time of the evaluation, then performing HLA testing to assess for the presence of DQ2 and DQ8 permissive gene types is necessary. If HLA-DQ2 and HLA-DQ8 are both absent, then CD can be excluded. However, if either permissive HLA type is found and the patient is consuming a GFD, then a minimum 2-week gluten challenge can be pursued and repeated CD testing can be performed thereafter.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      ACG clinical guidelines: diagnosis and management of celiac disease.
      Upper endoscopy with small-bowel biopsies may be necessary to differentiate NCGS, CD, and latent CD. If after a 2-week gluten challenge a patient has positive results on CD serologic examination and normal small-bowel biopsy findings, they likely have latent CD and need to be counseled and treated accordingly. In NCGS, there will be no villous atrophy or crypt hyperplasia as seen in CD. The presence of isolated intraepithelial lymphocytosis on duodenal biopsy specimens is not specific for CD, and other conditions need to be considered if that is the only histologic feature noted.
      • Shmidt E.
      • Smyrk T.C.
      • Boswell C.L.
      • Enders F.T.
      • Oxentenko A.S.
      Increasing duodenal intraepithelial lymphocytosis found at upper endoscopy: time trends and associations.
      To facilitate the diagnosis of NCGS, a patient can undergo an elimination diet followed by a monitored open challenge of gluten intake to document if there is recurrence of GI and/or extraintestinal symptoms. However, an open food challenge is not without limitations. When measuring subjective symptoms in an open food challenge, there are false-positive results with a high nocebo effect. Once NCGS is suspected, a skilled dietitian with experience in counseling on GFDs can ensure proper patient education and avoid long-term restrictive diets. The most effective duration of a GFD in a patient with NCGS is not well established. The natural history of NCGS is not clear, and the possible benefits of a rechallenge with gluten within months or years is yet to be determined.
      Table 2Comparison of Gluten-Related Disorders
      Adapted from Gastroenterology,
      • Fasano A.
      • Sapone A.
      • Zevallos V.
      • Schuppan D.
      Nonceliac gluten sensitivity.
      with permission from Elsevier.
      VariableCeliac diseaseNonceliac gluten sensitivityWheat allergy
      Symptom onsetDays to weeksHours to daysMinutes to hours
      PathogenesisAutoimmunity and innate immunityInnate immunity?Allergic immunity
      HLAHLA-DQ2/HLA-DQ8 restrictedNot HLA-DQ2/HLA-DQ8 restrictedNot HLA-DQ2/HLA-DQ8 restricted
      AutoantibodiesAlmost always presentAlways absentAlways absent
      Enteropathy
      Enteropathy is defined histologically by villous atrophy and crypt hyperplasia.
      Almost always presentAlways absentAlways absent
      FeaturesIntestinal and extraintestinalIntestinal and extraintestinalIntestinal and extraintestinal
      ComplicationsComorbidities, long-term complicationsComorbidities, long-term complications?No comorbidities, anaphylaxis
      a Enteropathy is defined histologically by villous atrophy and crypt hyperplasia.

      Conclusion

      Nonceliac gluten sensitivity is a clinical entity with GI and extraintestinal features that requires exclusion of CD and WA for proper diagnosis because of the overlapping features of these disorders. Current pathogenic and diagnostic challenges in NCGS preclude complete understanding of this clinical entity in practice. Future investigations are needed to further our understanding of its pathogenesis and to identify a biomarker to facilitate diagnosis. Better understanding of these features of NCGS will facilitate treatment selection and long-term therapeutic goals.

      Supplemental Online Material

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