Non-Celiac Gluten Sensitivity: A Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Gluten Related Disorders (GRDs)
2.2. Epidemiology of Gluten Related Disorders (GRDs)
2.3. Gluten
2.4. Amylase-Tripsin Inhibitors (ATIs)
2.5. Fermentable Oligo-, Di- and Mono-Saccharides and Polyols (FODMAPs)
2.6. The Salerno Experts’ Criteria of NCGS
3. Results
4. Discussion
5. Conclusions
- Symptoms of non-celiac gluten sensitivity are similar to gluten-related disease, irritable bowel syndrome and Crohn’s disease.
- With Salerno Experts’ Criteria of non-celiac gluten sensitivity it is possible to diagnose patients properly and give them advice about nutritional treatment.
Author Contributions
Funding
Conflicts of Interest
References
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Celiac Disease | NCGS | Wheat Allergy | |
---|---|---|---|
Prevalence | 0.5–1.7% | no population studies | 0.5–9% in children |
Pathogenesis | autoimmune | non-specific immune response | IgE mediated response |
DQ2-DQ8 HLA haplotypes | positive in 95% cases | positive in 50% cases | negative |
Serological markers | IgA anti-EMA, IgA anti-tTG, IgG anti-DGP, IgA anti-gliadin | IgA/IgG anti-gliadin in 50% cases | specific IgE antibodies against wheat and gliadin |
Duodenal biopsy * | Marsh I to IV with domination of Marsh III and IV | Marsh 0-II, but according to some experts Marsh III might also be in NCGS | Marsh 0-II |
Duodenal villi atrophy | present | absent | might be present or absent |
References | Study Group | Exclusion Criteria | Methods | Findings | Comments |
---|---|---|---|---|---|
Biesiekierski et al. 2013 | IBS patients fulfilling Rome III criteria in NCGS criteria, on GFD for 6 weeks | CD, IBD, age < 16, serious GI disease (cirrhosis), psychiatric disorders, alcohol abuse, NSAIDs and immunosuppressive treatment | GFD for 6 weeks, next 2-weeks diet low in FODMAPs, then 3 days one of the groups—high gluten 16 g, low gluten 2 g gluten or 14 g whey protein, control for 2 weeks washout period and crossover to another group for 3 days. The primary outcome: GI symptoms measured by using 100-mm VAS scoring. The secondary outcome: Fatigue measured by Daily-Fatigue Impact Scale (D-FIS), gliadin-specific T-cell response, biomarkers. | The primary outcome: Gluten-specific responses only in 8% of patients, 16% had worsening of overall GI symptoms in high gluten diet | Limitations: The nocebo effect was present independent of substances which was delivered |
The secondary outcome: Fatigue measured by D-FIS was lower in the low FOTMAPs diet, no significant difference in biomarkers, physical activity or sleep was observed, only one patient had gliadin-specific T-cell response. | |||||
Capannolo et al. 2014 | Individuals with gluten related symptoms | CD and WA | NCGS finding: on the basis of the disappearance of the symptoms within GFD 6 month, followed by 1month GD. | CD patients: 26 (6.63%); WA patients: 2 (0.51%); NCGS patients: 27 (6.88%). Patients with no change of symptoms after GFD 337 (85.9%) | Limitations: Lack of blindness in GFD challenge |
Missing evaluation of possible influence by other food components | |||||
Symptoms in 74% NCGS patients: | |||||
Intestinal: abdominal pain, diarrhea, constipation, alternating bowel function, epigastric pain | |||||
Extra intestinal: malaise, chronic fatigue, headache, anxiety, confused mind, depression, joint/muscle pain, resembling fibromyalgia, weight loss, anemia, dermatitis, rash | |||||
Related disorders in NCGS patients: lactose intolerance, autoimmune thyroiditis, type 1 diabetes, psoriasis, sarcoidosis | |||||
Zanini et al. 2015 | Individuals on gluten-free diet (GFD) on their own initiative | CD, non-strict adherence to a GFD, symptomatic on GFD | The primary outcome: the ability of the participants to correctly identify flour containing gluten. GSRS questionnaire was performed | Only 34% (12 participants) correctly identified gluten- containing flour fulfilling the clinical diagnostic criteria for NCGS. | The gluten-free flour used in this test contained FODMAP |
Hollon et al. 2015 | Individuals with Active CD, CD in Remission, Gluten Sensitivity (GS) | Positive CD serology, abnormal duodenal histopathology, unresponsive to gluten open challenge | GS finding: on the basis of the disappearance of the symptoms within GFD; non-blinded gluten challenge (10 g) for a minimum of 2 months before endoscopy | Increase of gut permeability after PT-gliadin ex-vivo administration in all three study groups, and in control group | Limitations: Lack of blindness in GFD challenge—possible placebo-response; Lack of GFD challenge in the control group—possible individuals with undiagnosed GS/CD |
Shahbazkhani et al. 2015 | Individuals with newly diagnosed IBS based on the Rome III criteria | Patients with CD, GFD introduced ever in medical history, self-exclusion of wheat from the diet, IBD, diabetes, concurrent drugs for depression/anxiety, NSAI drugs intake, abnormal levels of: glucose, urea, creatinine, sodium, potassium, hemoglobin, erythrocyte sedimentation rate, thyroid function tests | GS finding: IBS diagnosed patients responding to gluten challenge by means of statistically significant worsening of symptoms after gluten meal packet. Patients previously following strict GFD, continued gluten challenge for 6 weeks | Significant increase for following symptoms after gluten-containing meal challenge: bloating, abdominal pain, stool consistence, tiredness, nausea | Limitations: Packets containing gluten meal in the form of powder—not recommended according to Salerno criteria |
Pros: double-blind randomized placebo-controlled trial | |||||
Di Sabatino et al. 2015 | Suspected NCGS individuals | CD, WA | Individuals were randomly assigned to groups given gluten or placebo for 1 week, each via gastro-soluble capsules. After a 1 week of gluten-free diet, participants crossed over to the other group. | Gluten group: significantly increased overall symptoms (intestinal symptoms: abdominal bloating and pain, extra-intestinal symptoms: foggy mind, depression, aphthous stomatitis) vs. placebo group. | Limitation: small study group |
Elli et al. 2016 | Individuals with functional gastroenterological symptoms with enrolled on 3-week-long GFD | CD, WA, IBS psychiatric disorders, major abdominal surgery, diabetes mellitus, systemic autoimmune diseases, previous anaphylactic episodes, any systemic disorders, pregnant, breast feeding women, GFD in previous 6 months, patients on pharmacological therapy | Phase 1. GFD response individuals: questionnaire and next 3-week GFD. Patients with significantly improvement carried on to next phase. Phase 2. 98 subjects. GFD response patients—maintain strict GFD and underwent placebo-controlled double-blind gluten challenge with crossover. Patients were randomized to take gluten in capsules or placebo (rice starch) for 7 days. Total duration: 21 days: 7 days on gluten or placebo, 7 days wash-out, 7 days on gluten or placebo. | 28 individuals from phase 2 reported a symptomatic relapse and deterioration of quality of life. 14 patients responded to the placebo ingestion. About 14 patients responding to gluten withdrawal showed a symptomatic relapse during the gluten challenge—they are suspected to have NCGS. | Strengths: The blinding of patients and doctors, and the crossover design. |
Weaknesses: arbitrary choice of timing and gluten dosage, the protocol did not make use of a scheduled diet besides GFD, other diet variables cannot be excluded (ATIs). Symptomatic deterioration was also observed in placebo group. | |||||
Rosinach et al. 2016 | Individuals with clinical GI symptoms and clinical and histological remission after GFD | Age < 18, CD, NSAIDs and Olmesartan immunosuppressive treatment in last month, immunosuppressive therapy, parasitic or H. pylori infection, AD, pregnant or breastfeeding women, participation in other randomized controlled trials in the last 4 weeks, serious GI diseases and GI surgery, severe comorbidities, failure to comply with the protocol requirements | Patients were randomly assigned to gluten group (20 g/day, n = 11) and placebo (n = 7). Clinical symptoms were measured by VAS, quality of life using GIQLI. Scientists examined the presence of gamma/delta+ cells and transglutaminase deposits. | 91% of patients with clinical relapse during gluten challenge compared to 28.5% after placebo. Worsening results in clinical scores and GIQLI was observed in patients on gluten diet, but not in the placebo | Limitations: a small study group |
primary end-point: disease relapse after 6 months | |||||
Carroccio et al. 2017 | Induviduals with NCWS | Data collecting from a previous study of NCWS. | 88% subjects improved after a diagnosis of NCWS; 145 of 148 patients on strict GFD (98%) had reduced symptoms, compared to 30 of 52 patients who was not on GFD, 20 (from 22) subjects who repeated DBPC challenge reacted to wheat. NCWS is a persistent condition. | Limitations: not thoroughly discussed exclusion criteria | |
Skodje et al. 2018 | Individuals self-reported NCGS on gluten-free diet (GFD) on their own initiative for at least 6 months | Exclusion criteria: CD, WA, IBD, gastrointestinal comorbidity, allergy to nuts and sesame, alcohol abuse, pregnancy, breast feeding, women in fertile age without using contraception, long travel distance, considerable infection, patients on immunosuppressive agents’ therapy | GFD for 6 months, next 7 days on one of three diets challenge (gluten 5,7g, fructans 2,1g and placebo), 7 days washout, then crossover to next diet. The primary outcome: gastrointestinal symptoms measured by GSRS-IBS. The secondary outcome: daily GI symptoms measured by VAS, life quality depends on symptoms by SF-36, depression and anxiety symptoms measured by Hospital Anxiety and Depression Scale, Fatigue measured by Giessen Subjective Complaint List and VAS | The primary outcome: overall GSRS-IBS higher in the fructans group (38,6) than in the gluten group (33,1) and placebo (34,3). The secondary outcome: overall GI symptoms measured by VAS higher in FODMAPs diet, decreased vitality and greater weakness in the group of patients receiving fructans | Limitations: high nocebo response |
Roncoroni et al. 2019 | Individuals with NCGS criteria, complaining about functional GI symptoms | CD, WA, IBD, adult age (<18 years old), positive anti-tissue transglutaminase IgA, psychiatric disorders, major abdominal surgery, diabetes, GFD for previous six months, autoimmune diseases and systemic disorders, pregnancy, breast feeding, experience of anaphylaxis and patients during pharmacotherapy | GFD for 3 weeks, then exposure to diets with gradually increasing the amount of gluten: low-gluten diet (3.5–4 g gluten/day, week 1, n = 22 + 2 dropped out patients), mid-gluten diet (6.7–8 g gluten/day, week 2, n = 14), and a high-gluten diet (10–13 g gluten/day, week 3, n = 8). Patients without GI symptoms on a previous diet were classified into more gluten- containing diet. Patients with GI symptoms were shifted back to a well-tolerated diet. Daily GI symptoms measured by VAS, life quality depends on symptoms by SF-36 | Different reactions of patients after the introduction of gluten. | Limitation: a small study group |
References | Study Group | Exclusion Criteria | Methods | Findings | Comments |
---|---|---|---|---|---|
Carroccio et al. 2011 | Individuals who fulfilled Rome II criteria for IBS | Individuals with organic diseases | Symptom severity questionnaire was analyzed, fecal samples were assayed, and levels of specific immunoglobulin E were measured. Patients were observed for 4 weeks, placed on an elimination diet (without cow’s milk and derivatives, wheat, egg, tomato, and chocolate) for 4 weeks, and kept a diet diary. Those who reported improvements after the elimination diet period were then diagnosed with food hypersensitivity (FH), based on the results of a double-blind, placebo-controlled, oral food challenge (with cow’s milk proteins and then with wheat proteins). | 40 of patients with IBS (25%) were found to have FH. Levels of fecal ECP and tryptase were significantly higher among patients with IBS and FH than those without FH. The ECP assay was the most accurate assay for diagnosis of FH, showing 65% sensitivity and 91% specificity. | Limitations: recruitment of patients not in line with Salerno criteria. |
Carroccio et al. 2012 | Individuals with non-celiac wheat sensitivity (NCWS), | IgA deficiency, self-exclusion of wheat from the diet, lack of DBPC-challenge method in the diagnosis | A review of the clinical charts of patients with IBS-like presentation, diagnosed with WS challenge in the years 2001-2011. | 1/3 IBS patients who underwent DBPC wheat challenge were really suffering from WS. WS group: higher frequency of anemia, weight loss, self-reported wheat intolerance, coexistent atopy, and food allergy in infancy than the IBS controls, higher frequency of positive serum assays for IgG/IgA anti-gliadin and cytometric basophil activation in “in vitro” assay, eosinophil infiltration of the duodenal and colon mucosa. Two groups with distinct clinical characteristics were identified: WS alone (with similar to CD clinical features) and WS with multiple food hypersensitivity (clinical features similar to those found in allergic patients) | Limitations: recruitment of patients not in line with Salerno criteria. |
Volta et al. 2012 | Individuals with GS (NCGS) | CD, WA | Retrospective evaluation of collected samples from GS (study group) and CD (control group) individuals. Assessment of IgG/IgA AGA, IgA EmA, IgA tTGA, IgG DGP-AGA. HLA DQ2/DQ8 presence was assessed | GS is characterized by IgG AGA positivity (50%), although is less common comparing to CD. IgA AGA are rare. GS patients were lacking EmA, tTGA, and DGP-AGA. | Limitations: not thoroughly described exclusion criteria for study group |
Caio et al. 2014 | Individuals with NCGS with simultaneous AGA IgG positivity | CD, WA | AGA of both IgG and IgA classes were assayed by ELISA in 44 NCGS and 40 CD patients after 6 months of gluten-free diet. | AGA IgG in NCGS patients disappear after introduction of GFD. | |
Carroccio et al. 2015 | NCWS patients of the retrospective cohort study | Incomplete clinical charts were excluded from retrospective study; for both studies: EmA in the culture medium of the duodenal biopsies, self-exclusion of wheat from the diet and refusal to reintroduce it before entering the study, other organic gastrointestinal diseases. | NCWS patients—tTG IgG, EmA IgA and IgG negative, absence of intestinal villous atrophy and WA. Patient medical records were reviewed to identify those with autoimmune disease (AD). CD or IBS served as controls. Serum samples were collected from all subjects and ANA levels were measured by immunofluorescence analysis. Participants completed a questionnaire and their medical records were reviewed to identify those with ADs. Individuals were randomly assigned to groups given gluten or placebo for 1 week, each via gastro-soluble capsules. After a 1 week of gluten-free diet, participants crossed over to the other group. | Patients with NCWS were more likely to be ANA positive than both patients with CD and IBS, in both the retrospective and prospective studies. Patients with NCWS showed a frequency of AD similar to CD, but significantly higher than IBS controls, in both the retrospective and prospective studies. NCWS or CD are more likely to be ANA-positive, have DQ2/DQ8 haplotypes and AD compared with patients with IBS. | Limitations: selection bias of the tertiary centers conducting research; evaluation of the duodenal histology; not in line with Salerno criteria |
NCWS patients of the prospective study | |||||
Infantino et al. 2015 | Induviduals with suspected NCGS | CD, WA | Evaluation of collected samples from GS (study group), CD and healthy (control group) individuals. Assessment of IgG/IgA AGA, IgA EmA, IgA tTGA, IgG/IgA DGP-AGA. HLA DQ2/DQ8 presence was assessed | Statistically significant correlation between AGA IgG and NCGS were found. However, AGA IgG still remains to be weak NCGS marker. | Limitations: recruitment of patients not in line with Salerno criteria; small study group |
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Roszkowska, A.; Pawlicka, M.; Mroczek, A.; Bałabuszek, K.; Nieradko-Iwanicka, B. Non-Celiac Gluten Sensitivity: A Review. Medicina 2019, 55, 222. https://doi.org/10.3390/medicina55060222
Roszkowska A, Pawlicka M, Mroczek A, Bałabuszek K, Nieradko-Iwanicka B. Non-Celiac Gluten Sensitivity: A Review. Medicina. 2019; 55(6):222. https://doi.org/10.3390/medicina55060222
Chicago/Turabian StyleRoszkowska, Anna, Marta Pawlicka, Anna Mroczek, Kamil Bałabuszek, and Barbara Nieradko-Iwanicka. 2019. "Non-Celiac Gluten Sensitivity: A Review" Medicina 55, no. 6: 222. https://doi.org/10.3390/medicina55060222