S. Gatti

The New Epidemiology of Celiac Disease

ABSTRACT The prevalence of celiac disease (CD) varies greatly, but several reports have shown that CD is increasing in frequency in different geographic areas. The increase in prevalence can be partially attributed to the improvement in diagnostic techniques and disease awareness; however the equally well documented rise in incidence in the last 30–40 years cannot be so easily explained. The new epidemiology of CD is now characterized by an increase of new cases in the historical CD areas (northern Europe and the United States) and more interestingly in a spread of the disease in new regions (Asian countries). A significant change in diet habits, particularly in gluten consumption as well as in infant feeding patterns are probably the main factors that can account for these new trends in CD epidemiology.

Oats in the Diet of Children with Celiac Disease: Preliminary Results of a Double-Blind, Randomized, Placebo-Controlled Multicenter Italian Study

A gluten-free diet (GFD) is currently the only available treatment for patients with celiac disease (CD). Several clinical trials have demonstrated that most celiac patients can tolerate a medium-high quantity of oats without any negative clinical effects; however, the inclusion of oats in GFD is still a matter of debate. In this study, Italian children with CD were enrolled in a 15-month, randomized, double-blind, placebo-controlled multicenter trial. Participants were randomized in two groups following either A-B treatment (6 months of diet “A”, 3 months of standard GFD, 6 months of diet “B”), or B-A treatment (6 months of diet “B”, 3 months of standard GFD, 6 months of diet “A”). A and B diets included gluten-free (GF) products (flour, pasta, biscuits, cakes and crisp toasts) with either purified oats or placebo. Clinical data (Gastrointestinal Symptoms Rate Scale [GSRS] score) and intestinal permeability tests (IPT), were measured through the study period. Although the study is still blinded, no significant differences were found in GSRS score or the urinary lactulose/mannitol (L/M) ratio between the two groups after 6 months of treatment. These preliminary results suggest that the addition of non-contaminated oats from selected varieties in the treatment of children with CD does not determine changes in intestinal permeability and gastrointestinal symptoms.

The Low FODMAP Diet: Many Question Marks for a Catchy Acronym

FODMAP, “Fermentable Oligo-, Di- and Mono-saccharides And Polyols”, is a heterogeneous group of highly fermentable but poorly absorbed short-chain carbohydrates and polyols. Dietary FODMAPs might exacerbate intestinal symptoms by increasing small intestinal water volume, colonic gas production, and intestinal motility. In recent years the low-FODMAP diet for treatment of irritable bowel syndrome (IBS) has gained increasing popularity. In the present review we aim to summarize the physiological, clinical, and nutritional issues, suggesting caution in the prolonged use of this dietary treatment on the basis of the existing literature. The criteria for inclusion in the FODMAPs list are not fully defined. Although the low-FODMAP diet can have a positive impact on the symptoms of IBS, particularly bloating and diarrhea, the quality of the evidence is lower than optimal, due to frequent methodological flaws, particularly lack of a proper control group and/or lack of blinding. In particular, it remains to be proven whether this regimen is superior to conventional IBS diets. The drastic reduction of FODMAP intake has physiological consequences, e.g., on the intestinal microbiome and colonocyte metabolism, which are still poorly understood. A low-FODMAP diet imposes an important restriction of dietary choices due to the elimination of some staple foods, such as wheat derivatives, lactose-containing dairy products, many vegetables and pulses, and several types of fruits. For this reason, patients may be at risk of reduced intake of fiber, calcium, iron, zinc, folate, B and D vitamins, and natural antioxidants. The nutritional risk of the low-FODMAP diet may be higher in persons with limited access to the expensive, alternative dietary items included in the low-FODMAP diet.

A case of syndromic neutropenia and mutation in G6PC3.

Background A previously unrecognized syndrome with congenital neutropenia and various organ abnormalities has been described recently, caused by mutations in the gene encoding glucose-6-phosphatase, catalytic subunit 3 (G6PC3). Observation A 10-year-old boy from Ecuador suffering from severe neutropenia and multiple nonhematopoietic abnormalities was admitted to our department. We identified a novel mutation in the G6PC3 gene (c. 765_delAG; p.S255fs). Conclusions This is the first case of G6PC3 deficiency in a patient from South America, caused by a novel mutation in the G6PC3 gene. Our results give insights into the molecular and clinical variability of this disease.

Gluten Contamination in Naturally or Labeled Gluten-Free Products Marketed in Italy

Background: A strict and lifelong gluten-free diet is the only treatment of celiac disease. Gluten contamination has been frequently reported in nominally gluten-free products. The aim of this study was to test the level of gluten contamination in gluten-free products currently available in the Italian market. Method: A total of 200 commercially available gluten-free products (including both naturally and certified gluten-free products) were randomly collected from different Italian supermarkets. The gluten content was determined by the R5 ELISA Kit approved by EU regulations. Results: Gluten level was lower than 10 part per million (ppm) in 173 products (86.5%), between 10 and 20 ppm in 9 (4.5%), and higher than 20 ppm in 18 (9%), respectively. In contaminated foodstuff (gluten > 20 ppm) the amount of gluten was almost exclusively in the range of a very low gluten content. Contaminated products most commonly belonged to oats-, buckwheat-, and lentils-based items. Certified and higher cost gluten-free products were less commonly contaminated by gluten. Conclusion: Gluten contamination in either naturally or labeled gluten-free products marketed in Italy is nowadays uncommon and usually mild on a quantitative basis. A program of systematic sampling of gluten-free food is needed to promptly disclose at-risk products.

Re-challenge Studies in Non-celiac Gluten Sensitivity: A Systematic Review and Meta-Analysis

Background: Non-celiac gluten sensitivity (NCGS) is a clinical entity characterized by intestinal and/or extra-intestinal symptoms related to the ingestion of gluten in individuals that are not affected by either celiac disease (CD) or wheat allergy (WA). Since we do not have specific biomarkers for NCGS, the diagnosis is based on the evidence of a clear relationship between the ingestion of gluten (re-challenge) and clinical symptoms, after a remission during the gluten-free diet (GFD). Several re-challenge studies have been published so far to evaluate the real prevalence of NCGS, reporting conflicting results. In the present article, we provide a systematic review with meta-analysis of the existing literature on re-challenge studies to evaluate prevalence figures of NCGS after re-challenge procedures. Methods: All clinical trials performing a gluten re-challenge with or without a placebo control in patients with a suspected diagnosis of NCGS were included. Search results were limited to studies published in English language. No publication date or publication status restrictions were imposed. Results: Eleven studies were included in the meta-analysis. There was a considerable heterogeneity related to different sample size, type, and amount of gluten administered, duration of challenge and different type of placebo. The overall pooled percentage of patients with a diagnosis of NCGS relapsing after a gluten challenge was 30%, ranging between 7 and 77%. The meta-analysis showed a not significant relative risk (RR) of relapse after gluten challenge as compared to placebo (RR = 0.4; 95% CI = −0.15–0.9; p = 0.16). The overall pooled percentage of patients with a diagnosis of NCGS relapsing after a gluten challenge performed according to the recent Salerno criteria was significantly higher as compared to the percentage of patients relapsing after placebo (40 vs. 24%; p = 0.003), with a significant RR of relapse after gluten challenge as compared to placebo (RR = 2.8; 95% CI = 1.5–5.5; p = 0.002). Conclusions: The prevalence of NCGS after gluten re-challenge is low, and the percentage of relapse after a gluten or a placebo challenge is similar. However, a higher number of patients will be correctly classified with NCGS if applying the recent Salerno criteria.

Effect of Early Versus Late Azathioprine Therapy in Pediatric Ulcerative Colitis

Background:We aimed at describing the efficacy of azathioprine (AZA) in pediatric ulcerative colitis, comparing the outcomes of early (0–6 months) versus late (6–24 months) initiation of therapy. Methods:Children with ulcerative colitis treated with AZA within 24 months of diagnosis were included. Corticosteroid (CS)-free remission and mucosal healing (MH), assessed by endoscopy or fecal calprotectin, at 12 months were the primary outcomes. Patients were also compared for CS-free remission and MH, need for treatment escalation or surgery, number of hospitalizations, and adverse events during a 24-month follow-up. Results:A total of 121 children entered the study (median age 10.5 ± 4.0 years, 59% girls). Seventy-six (63%) started AZA between 0 and 6 months (early group) and 45 (37%) started between 6 and 24 months (late group). Seventy-five percent and 53% of patients in the early and late group, respectively, received CS at the diagnosis (P = 0.01). CS-free remission at 1 year was achieved by 30 (50%) of the early and 23 (57%) of the late patients (P = 0.54). MH occurred in 37 (37%) patients at 1 year, with no difference between the 2 groups (33% early, 42% late; P = 0.56). No difference was found for the other outcomes. Conclusions:Introduction of AZA within 6 months of diagnosis seems not more effective than later treatment to achieve CS-free remission in pediatric ulcerative colitis. MH does not depend on the timing of AZA initiation; however, because of the incomplete comparability of the 2 groups at the diagnosis and the use of fecal calprotectin as a surrogate marker of MH, our results should be further confirmed by prospective studies.

Beyond the Intestinal Celiac Mucosa: Diagnostic Role of Anti-TG2 Deposits, a Systematic Review.

Aim: To review the existing literature on the role and significance of intestinal transglutaminase 2 immunoglobulin A deposits (TG2 deposits) in patients with overt celiac disease (CD), potential celiac disease (PCD), and other autoimmune or gluten-related conditions. Methods: We conducted a systematic review of studies published in English, evaluating presence and characteristics of TG2 deposits in subjects with overt CD, PCD, gluten-related diseases [dermatitis herpetiformis (DH), gluten-ataxia (GA)], autoimmune disorders (type-1 diabetes), and other conditions. Studies were identified through a MEDLINE search (1950–2013). Results: Twenty-three studies were included in the review. Eleven studies were performed in children. Overall TG2 deposits were present in 100% of adults with overt CD, while in children prevalence ranged from 73.2 to 100%. Six studies with an established definition of PCD were considered, prevalence of deposits ranging from 64.7 to 100%. A single study followed-up PCD patients with repeated biopsies and identified presence of intestinal deposits as the best marker to reveal progression toward villous atrophy. Two studies investigated presence of deposits in DH, reporting prevalence between 63 and 79%. A single study documented TG2 deposits in 100% of patients with GA. In children with type-1 diabetes (T1D), positivity of intestinal TG2 deposits ranged from 25 to 78%. Conclusion: Transglutaminase 2 IgA deposits seem to be a constant feature in overt CD patients and are frequently detectable in other gluten-related conditions (DH and GA). The vast majority of PCD patients express TG2 deposits at the intestinal level, but no sufficient data are available to exactly define their prognostic role as a marker of evolution toward overt CD. The frequent finding of TG2 deposits in the intestinal mucosa of patients with T1D is an interesting observation deserving further evaluation.

Pediatric Chronic Intestinal Failure in Italy: Report from the 2016 Survey on Behalf of Italian Society for Gastroenterology, Hepatology and Nutrition (SIGENP)

Background: Intestinal failure (IF) is the reduction in functioning gut mass below the minimal level necessary for adequate digestion and absorption of nutrients and fluids for weight maintenance in adults or for growth in children. There is a paucity of epidemiologic data on pediatric IF. The purpose of this study was to determine the prevalence, incidence, regional distribution and underlying diagnosis of pediatric chronic IF (CIF) requiring home parenteral nutrition (HPN) in Italy. Methods: Local investigators were selected in 19 Italian centers either of reference for pediatric HPN or having pediatric gastroenterologists or surgeons on staff and already collaborating with the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition with regard to IF. Data requested in this survey for children at home on Parenteral Nutrition (PN) on 1 December 2016 included patient initials, year of birth, gender, family’s place of residence and underlying diagnosis determining IF. Results: We recorded 145 CIF patients on HPN aged ≤19 years. The overall prevalence was 14.12/million inhabitants (95% CI: 9.20–18.93); the overall incidence was 1.41/million inhabitant years (95% CI: 0.53–2.20). Conclusion: Our survey provides new epidemiological data on pediatric CIF in Italy; these data may be quantitatively useful in developing IF care strategy plans in all developed countries.

Safety of Oats in Children with Celiac Disease: A Double-Blind, Randomized, Placebo-Controlled Trial

Objective To evaluate the long‐term validity and safety of pure oats in the treatment of children with celiac disease. Study design This noninferiority clinical trial used a double‐blind, placebo‐controlled, crossover design extended over 15 months. Three hundred six children with a biopsy‐proven diagnosis of celiac disease on a gluten‐free diet for ≥2 years were randomly assigned to eat specifically prepared gluten‐free food containing an age‐dependent amount (15‐40 g) of either placebo or purified nonreactive varieties of oats for 2 consecutive 6‐month periods separated by washout standard gluten‐free diet for 3 months. Clinical (body mass index, Gastrointestinal Symptoms Rating Scale score), serologic (IgA antitransglutaminase antibodies, and IgA anti‐avenin antibodies), and intestinal permeability data were measured at baseline, and after 6, 9, and 15 months. Direct treatment effect was evaluated by a nonparametric approach using medians (95% CI) as summary statistic. Results After the exclusion of 129 patients who dropped out, the cohort included 177 children (79 in the oats–placebo and 98 in the placebo–oats group; median, 0.004; 95% CI, −0.0002 to 0.0089). Direct treatment effect was not statistically significant for clinical, serologic, and intestinal permeability variables (body mass index: median, −0.5; 95% CI, −0.12 to 0.00; Gastrointestinal Symptoms Rating Scale score: median, 0; 95% CI, −2.5 to 0.00; IgA antitransglutaminase antibodies: median, −0.02; 95% CI, −0.25 to 0.23; IgA anti‐avenin antibodies: median, −0.0002; 95% CI, −0.0007 to 0.0003; intestinal permeability test: median, 0.004; 95% CI, −0.0002 to 0.0089). Conclusions Pure nonreactive oat products are a safe dietary choice in the treatment of children with celiac disease. Trial registration ClinicalTrials.gov: NCT00808301.