Non-celiac gluten sensitivity : time for sifting the grain

In the last few years, a new nomenclature has been proposed for the disease induced by the ingestion of gluten, a protein present in wheat, rice, barley and oats. Besides celiac disease and wheat allergy, the most studied forms of gluten-related disorders characterized by an evident immune mechanism (autoimmune in celiac disease and IgE-mediated in wheat allergy), a new entity has been included, apparently not driven by an aberrant immune response: the non-celiac gluten sensitivity (NCGS). NCGS is characterized by a heterogeneous clinical picture with intestinal and extraintestinal symptoms arising after gluten ingestion and rapidly improving after its withdrawal from the diet. The pathogenesis of NCGS is largely unknown, but a mixture of factors such as the stimulation of the innate immune system, the direct cytotoxic effects of gluten, and probably the synergy with other wheat molecules, are clues for the complicated puzzle. In addition, the diagnostic procedures still remain problematic due to the absence of efficient diagnostic markers; thus, diagnosis is based upon the symptomatic response to a gluten-free diet and the recurrence of symptoms after gluten reintroduction with the possibility of an important involvement of a placebo effect. The temporary withdrawal of gluten seems a reasonable therapy, but the timing of gluten reintroduction and the correct patient management approach are have not yet been determined

Management of Nonceliac Gluten Sensitivity by Gastroenterology Specialists : Data from an Italian Survey

Background and Aim. Nonceliac gluten sensitivity is syndrome characterized by symptoms disappearing after a gluten-free diet. Its existence is still argument of discussion among specialists. Our aim was to evaluate the knowledge about nonceliac gluten sensitivity among gastroenterology specialists. Methods. During October 2013 a questionnaire was sent through a medical newsletter to Italian gastroenterologists. Twelve questions investigated their knowledge on nonceliac gluten sensitivity, including their diagnostic and therapeutic approach. Results. A total of 212 gastroenterologists filled in the questionnaire. The 98.6% were aware of the existence of a syndrome called "nonceliac gluten sensitivity" and 77% believe in its existence. However, only 56% gave a correct definition of the term. The majority of specialists diagnosed gluten sensitive patients and the number of diagnoses was not statistically different from that of celiac disease. Moreover, a gluten-free diet was prescribed by 64% of the specialists and among them the 73% noted an increase of gluten sensitive patients attending their outpatient services. Conclusions. Our study indicated that most of the specialists recognize nonceliac gluten sensitivity and prescribe gluten-free diet, although 44% of the specialists are not able to give its correct definition; underlining the necessity of medical education on this topic is needed

Hepatic hemangioma in celiac patients : data from a large consecutive series

Background and Aims. Hepatic hemangioma (HH) has a widely ranging prevalence. The etiology is unclear; however, associations with autoimmune disorders have been described. We aimed at evaluating the prevalence of HH in celiac disease. Methods. Ninety-seven consecutive patients with celiac disease (18 M, 79 F, median age 41, and range 17-84 years) underwent liver ultrasound between January 2011 and 2012. The findings were compared with those of 1352 nonceliac patients (581 M, 771 F, median age 50, and range 16-94 years), without liver disease or previously detected HH, who underwent US in the same period. Results. Ultrasonographic findings consistent with HH were observed in 14 celiac patients (14.4%), a prevalence significantly higher than in controls (69 cases, 5.1%) (P=0.0006). Subgroup analysis showed that, among women, the prevalence of HH was 16.4% in the celiac disease group (13/79) compared with 5.9% in controls (46/771) (P=0.002). In celiac setting, HH had a median diameter of 1.3 cm and presented as a single lesion in 12 cases (86%). Conclusions. Our findings are consistent with a significantly higher prevalence of HH in celiac patients. Although mechanisms underlying this association remain unclear, autoimmune and metabolic processes, as well as alterations of gut-liver axis equilibrium, could play a role

Increased mercury levels in patients with celiac disease following a gluten-free regimen

Background and Aim. Although mercury is involved in several immunological diseases, nothing is known about its implication in celiac disease. Our aim was to evaluate blood and urinary levels of mercury in celiac patients. Methods. We prospectively enrolled 30 celiac patients (20 treated with normal duodenal mucosa and 10 untreated with duodenal atrophy) and 20 healthy controls from the same geographic area. Blood and urinary mercury concentrations were measured by means of flow injection inductively coupled plasma mass spectrometry. Enrolled patients underwent dental chart for amalgam fillings and completed a food-frequency questionnaire to evaluate diet and fish intake. Results. Mercury blood/urinary levels were 2.4 \ub1 2.3 / 1.0 \ub1 1.4, 10.2 \ub1 6.7 / 2.2 \ub1 3.0 and 3.7 \ub1 2.7 / 1.3 \ub1 1.2 in untreated CD, treated CD, and healthy controls, respectively. Resulting mercury levels were significantly higher in celiac patients following a gluten-free diet. No differences were found regarding fish intake and number of amalgam fillings. No demographic or clinical data were significantly associated with mercury levels in biologic samples. Conclusion. Data demonstrate a fourfold increase of mercury blood levels in celiac patients following a gluten-free diet. Further studies are needed to clarify its role in celiac mechanism

Histological evaluation of duodenal biopsies from coeliac patients : the need for different grading criteria during follow-up

Background: Coeliac disease is characterised by villous atrophy, which usually normalises after gluten withdrawal. Sometimes the revaluation of duodenal histology is required during follow-up, even if the methodology for comparing duodenal histology before and after introducing a gluten-free diet is not yet established. Our aim was to evaluate a novel criterion to compare duodenal histology in coeliac disease before and after gluten withdrawal. Methods: Duodenal biopsies from coeliac patients were retrospectively reviewed to compare duodenal histology at diagnosis and after at least one year on a gluten-free diet. Two different methods were used: the first was represented by the classical Marsh-Oberhuber score, the second compared the areas covered by each Marsh-Oberhuber grade and expressed as percentages, the final grade being calculated from the analysis of ten power fields per duodenal biopsy. Results: Sixty-nine patients (17 males 52 females, age at diagnosis 36\ub115 years) who underwent duodenal biopsies, were considered. According to the classical Marsh-Oberhuber scale, 32 patients did not present atrophy during follow-up while 37 showed duodenal atrophy, among whom 26 improved the grade of severity and 11 retained the same one. Of these latter, according to the second method, eight patients were considered improved, two showed a worsened duodenal damage and only one remained unchanged; the evaluation changed in 91 % of cases. Conclusions: The proposed semi-quantitative approach (i.e. the second method) for the evaluation of histology at follow-up provides additional information about the progression/regression of the mucosal damage

Safety of occasional ingestion of gluten in patients with celiac disease: a real-life study

Background Gluten-free diet (GFD) decreases the quality of life of celiac disease (CD) patients, who frequently ask to occasionally ingest gluten-containing food. We evaluated CD patients reporting voluntary and occasional transgressions to their GFD. Methods From October 2017 to September 2018, the patients reporting occasional and voluntary gluten ingestion (GFD-noncompliant) were prospectively enrolled. These patients underwent clinical examination, blood tests, duodenal biopsy, capsule enteroscopy (CE), and a validated food-frequency questionnaire (FFQ) assessing the frequency and quantity of gluten intake. Mortality was calculated and compared to the general population. A group of patients on strict GFD (GFD-adherent) acted as controls. Results One thousand three hundred seventy-eight CD patients were evaluated during the study period. One hundred nine (8%) reported occasional (weekly or monthly) voluntary ingestion of gluten. The mean gluten intake was 185.2 +/- 336.9 g/year, and the duration of their incorrect GFD was 8.6 +/- 6.9 years. Among the noncompliant patients, 57% did not present any histological alteration; furthermore, the Marsh score profile was not different between compliant and noncompliant patients. Seventy percent did not present any alteration at CE. Seventy-five percent of patients reported no gastrointestinal symptoms after gluten ingestion. Twenty-three percent of patients in the GFD-noncompliant group presented positive tTG-IgA. No association was found between gluten intake, clinical symptoms, and biomarkers. Mortality was not different between the groups and the general population. Conclusions Our results are that in a real-life scenario, a group of CD patients on long-term gluten intake showed no significant clinical symptoms or small bowel damage, thus suggesting that a degree of tolerance towards gluten consumption can be reached

Exposure to different amounts of dietary gluten in patients with non-celiac gluten sensitivity (Ncgs): An exploratory study

It is unclear whether patients with non-celiac gluten sensitivity (NCGS) can tolerate gluten. We have evaluated the changes of both gastrointestinal symptoms and quality of life for NCGS patients after the re-introduction of dietary gluten. Twenty-two NCGS patients reporting functional gastroenterological symptoms and on gluten-free diet (GFD) for the previous three weeks were exposed to incremental gluten-containing diets. Three groups were compared at baseline (immediately after 3-weeks on GFD) and immediately after the return of symptomatology: (i) a group tolerating a low-gluten diet (3.5 g gluten/day, week 1, n = 8), (ii) a group tolerating a mid-gluten diet (8 g gluten/day, week 2, n = 6), and (iii) a group tolerating a high-gluten diet (13 g gluten/day, week 3, n = 8). Their gastrointestinal symptoms and quality of life were assessed at baseline and post-intervention. The most common symptoms were: constipation (46%), abdominal pain (50%) and dyspepsia (38%). A decrease in several short form health survey (SF-36) sub-scores (all p < 0.03) after gluten re-introduction was only observed in the group tolerating the low-gluten diet; the same group showed a lower post-intervention role-emotional SF-36 score (p = 0.01). Most gastrointestinal symptoms remained similar after gluten re-introduction. However, a decrease in the general perception of well-being was only found after gluten re-introduction in the group tolerating a low-gluten diet (p = 0.01); the same was true when comparing the post-intervention general well-being perception among the three groups (p = 0.050). In conclusion, dissimilar responses from patients with NCGS were observed after the re-introduction of gluten, with gluten at a low dosage affecting the quality of life and general well-being of a group of patients, whereas others tolerate even higher doses of dietary gluten

Anti-sulfatide reactivity in patients with celiac disease

Objective: To explore a possible significance of the presence of anti-ganglioside and anti-sulfatide antibodies in sera of adult patients with celiac disease (CD) in different clinical scenario. Methods: We selected 22 adult patients with newly diagnosed CD and 20 age\u2013sex matched non-CD controls. Patients\u2019 serum was tested\u2013before and after at least 6 months on a gluten-free diet (GFD)\u2013for anti-GM1, GM2, GM3, GD1a, GD1b, GD3, GT1a, GT1b, GQ1b and sulfatide IgM, IgG and IgA auto-antibodies, by means of a dot blot technique and enzyme-linked immunosorbent assay (ELISA). Results: We found the presence of auto-antibodies in untreated patients. In particular, anti-sulfatide IgG antibodies were present in 8 (36%) patients independently of the presence of neurological symptoms. Anti-sulfatide IgA antibodies were present in 3 (19%) patients. During GFD, anti-sulfatide IgG disappeared in all the patients, whereas IgA were observed in 2 patients. Anti-sulfatide, anti-GM1 and anti-GM2 IgM antibodies were also observed in 2 patients on a GFD. All the other auto-antibodies were absent and no demographic or clinical parameters were associated. Non-CD controls did not present any auto-antibody. Conclusions: We found anti-sulfatide IgG antibodies in CD patients on a gluten-containing diet. Anti-sulfatide IgA antibodies persisted during GFD together with the occurrence of other IgM auto-antibodies. These data suggest a possible link between gluten and IgG auto-antibodies

A low FODMAP gluten-free diet improves functional gastrointestinal disorders and overall mental health of celiac disease patients: A randomized controlled trial

A subset of patients with celiac disease (CD) on a gluten-free diet (GFD) reported the persistence of functional gastrointestinal disorders. Foods containing fermentable, oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) can trigger a broad range of gastrointestinal symptoms in sensitive individuals. We evaluated the effects of a low FODMAP diet (LFD) on gastrointestinal and psychological symptomatology in CD patients. A total of 50 celiac patients on GFDs and with persistence of gastrointestinal symptoms were included. The patients were randomly allocated to one of two dietary groups\u2014one on a low FODMAP GFD (LF-GFD, n = 25) and the other on a regular GFD (R-GFD, n = 25)\u2014for 21 days. Psychological symptomatology and quality of life were evaluated by the Symptom Checklist-90-R (SCL-90) and the Short Form (36) Health Survey (SF-36) questionnaires, respectively. Gastrointestinal symptomatology and general well-being were evaluated by visual analogue scale (VAS) scores. After 21 days, 21 and 23 patients completed the dietary treatment on LF-GFD and R-GFD, respectively. A reduced global SCL-90 index (p < 0.0003) was found in the LF-GFD group but not in the R-GFD one. However, the SF-36 scores did not differ between groups after treatment. The VAS for abdominal pain was much lower, and the VAS for fecal consistency enhanced after treatment in the LF-GFD group. General well-being increased in both groups but with a much higher improvement in the LF-GFD (p = 0.03). A short-term LFD regimen helps to improve the psychological health and gastrointestinal symptomatology with enhanced well-being of CD patients with persisting functional gastrointestinal symptomatology. The long-term clinical effects of LFD in particular subgroups of CD patients need further evaluation

Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p Results: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p= 1.3x10(-08), and rs842647 p= 5.26x10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappa B) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain similar to 40% of the heritability of coeliac disease