Effect of the timing of gluten introduction on the development of celiac disease

Celiac disease(CD) is a permanent auto-immune enteropathy,triggered in genetically predisposed individuals by the ingestion of dietary gluten.Gluten is the alcohol-soluble protein component of the cereals wheat,rye and barley.CD is a multifactorial condition,originating from the interplay of genetic and environmental factors.The necessary environmental trigger is gluten,while the genetic predisposition has been identified in the major histocompatibility complex region on chromosome 6p21,with over 90% of CD ...     

In vivo gluten challenge in celiac disease.

In vivo gluten challenge has been used since the early 1950s to study the role of cereal fractions in celiac disease. While early studies relied on crude indicators of celiac toxicity, the advent of jejunal biopsy and sophisticated immunohistochemical techniques has allowed accurate studies to be performed. Studies to determine the nature of the cereal component that is toxic to patients with celiac disease have concentrated on wheat because of its nutritional importance. A number of in vitro studies indicated the presence of one or more celiac-activating epitopes with the N-terminus of the A-gliadin molecule. In vivo challenge with three synthetic peptides subsequently indicated the toxicity of a peptide corresponding to amino acids 31 to 49 of A-gliadin. In vivo gluten challenge is the gold standard for the assessment of celiac toxicity; however, jejunal biopsy is a relatively invasive procedure, thus, other methods have been investigated. Direct infusion of the rectum with gluten has been shown to result in an increase in mucosal intraepithelial lymphocytes, occurring only in celiac patients. This method has been used to study the celiac toxicity of gliadin subfractions. The in vitro technique of small intestinal biopsy organ culture is also a useful tool and appears to give the same results as in vivo challenge. The importance of tiny amounts of gliadin in the diet, such as that which occurs in wheat starch, has been studied by in vivo challenge; this technique has clarified the position of oats in the gluten-free diet. Several studies suggest that this cereal may be included in the diet of most adult celiac patients. Studies of the transport of gliadin across the enterocyte following ingestion or challenge suggest that gliadin may be metabolized by a different pathway in celiac disease. This could result in an abnormal presentation to the immune system, triggering a pathogenic rather than a tolerogenic response.     

Non-responsive celiac disease in children on a gluten free diet

BACKGROUNDNon-responsive celiac disease (NRCD) is defined as the persistence of symptoms in individuals with celiac disease (CeD) despite being on a gluten-free diet (GFD). There is scant literature about NRCD in the pediatric population.AIMTo determine the incidence, clinical characteristics and underlying causes of NRCD in children.METHODSRetrospective cohort study performed at Boston Children’s Hospital (BCH). Children < 18 years diagnosed with CeD by positive serology and duodenal biopsies compatible with Marsh III histology between 2008 and 2012 were identified in the BCH’s Celiac Disease Program database. Medical records were longitudinally reviewed from the time of diagnosis through September 2015. NRCD was defined as persistent symptoms at 6 mo after the initiation of a GFD and causes of NRCD as well as symptom evolution were detailed. The children without symptoms at 6 mo (responders) were compared with the NRCD group. Additionally, presenting signs and symptoms at the time of diagnosis of CeD among the responders and NRCD patients were collected and compared to identify any potential predictors for NRCD at 6 mo of GFD therapy.RESULTSSix hundred and sixteen children were included. Ninety-one (15%) met criteria for NRCD. Most were female (77%). Abdominal pain [odds ratio (OR) 1.8 95% confidence interval (CI) 1.1-2.9], constipation (OR 3.1 95%CI 1.9-4.9) and absence of abdominal distension (OR for abdominal distension 0.4 95%CI 0.1-0.98) at diagnosis were associated with NRCD. NRCD was attributed to a wide variety of diagnoses with gluten exposure (30%) and constipation (20%) being the most common causes. Other causes for NRCD included lactose intolerance (9%), gastroesophageal reflux (8%), functional abdominal pain (7%), irritable bowel syndrome (3%), depression/anxiety (3%), eosinophilic esophagitis (2%), food allergy (1%), eating disorder (1%), gastric ulcer with Helicobacter pylori (1%), lymphocytic colitis (1%), aerophagia (1%) and undetermined (13%). 64% of children with NRCD improved on follow-up.CONCLUSIONNRCD after ≥ 6 mo GFD is frequent among children, especially females, and is associated with initial presenting symptoms of constipation and/or abdominal pain. Gluten exposure is the most frequent cause.     

Timing of introduction of solid food and risk of allergic disease development: Understanding the evidence

Strategies to prevent or reduce the risk of allergic diseases are needed. The time of exclusive breastfeeding and introduction of solid foods is a key factor that may influence the development of allergy. For this reason, the aim of this review was to examine the association between exposure to solid foods in the infant's diet and the development of allergic diseases in children. Classical prophylactic feeding guidelines recommended a delayed introduction of solids for the prevention of atopic diseases. Is it really true that a delayed introduction of solids (after the 4th or 6th month) is protective against the development of eczema, asthma, allergic rhinitis and food or inhalant sensitisation?In recent years, many authors have found that there is no statistically significant association between delayed introduction of solids and protection for the development of allergic diseases. Furthermore, late introduction of solid foods could be associated with increased risk of allergic sensitisation to foods, inhalant allergens and celiac disease in children. Tolerance may be driven by the contact of the mucosal immune system with the allergen at the right time of life; the protective effects seem to be enhanced by the practice of the breastfeeding at the same time when weaning is started.Therefore, recent guidelines propose a “window” approach for weaning practice starting at the 17th week and introducing almost all foods within the 27th week of life to reduce the risk of chronic diseases such as allergic ones and the celiac disease. Guidelines emphasize the role of breastfeeding during the weaning practice.     

Effect of gluten supplementation in healthy siblings of children with celiac disease

The clinical, functional, and histopathological effects of 18 g additional gluten intake daily for 4 wk was studied in 13 healthy siblings of Spanish children with celiac disease, including two pairs of discordant monozygotic twins. Five of the 13 children were HLA-DR identical to the celiac sibling, 5 shared only one HLA-DR antigen with the celiac sibling, and 3 had completely different HLA-DR antigens than their respective celiac brothers or sisters. Clinical evaluation and functional tests (routine blood, xylose absorption, and fecal fat excretion studies) were performed before, during, and after gluten challenge. A jejunal biopsy specimen was taken at the end of the 4-wk period of gluten supplementation. No clinical abnormalities were found during the period of the study and there was no significant decrease of xylose absorption. Fecal fat excretion studies gave normal results, both before and after gluten challenge. The high gluten diet did not lead to histopathologic abnormalities in any of the jejunal biopsy specimens, which showed a normal range of crypt to villus ratio and surface-cell height. The present results do not support the view that excessive gluten intake is toxic for individuals who are genetically predisposed but do not have overt celiac disease. The findings also suggest that other factors besides HLA-DR antigens and gluten intake are important for expression of the disease.     

The perspective of celiac disease patients on emerging treatment options and non-celiac gluten sensitivity

BackgroundNon-celiac gluten sensitivity (NCGS) and emerging treatment options are hot topics in the celiac disease (CeD) scientific literature. However, very little is known about the perspective on these issues of CeD patients.MethodsWe performed a large patient survey among unselected CeD patients in Switzerland.ResultsA total of 1689 patients were analyzed. 57.5% have previously heard of NCGS. 64.5% believe in the existence of this entity. Regarding a potential influence of NCGS on CeD awareness, 31.7% show a positive and 27.5% a negative perception. Patients with prior use of alternative medicine and women more often have heard of and believe in the existence of NCGS vs. those never having used alternative methods and men, respectively (66.9 vs. 56.9%, p = 0.001 and 78.5 vs. 69.0%, p = 0.001; 60.7 vs. 44.2%, p < 0.001 and 71.0 vs. 60.8%, p = 0.002). Women and patients ≥30 years more often show a negative attitude towards NCGS (32.2% vs. 24.8%, p = 0.024 and 32.2% vs. 24.2%, p = 0.018). With regard to emerging treatment options for CeD, 43.3% have previously heard of novel agents, more women than men (46.0 vs. 38.0%, p = 0.019).ConclusionsPerception of and attitude towards NCGS differ depending on sex, age and prior use of alternative medicine. Knowledge of the progress towards emerging treatment options is currently limited.     

Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease

Celiac disease, also known as celiac sprue, is a gluten-induced autoimmune-like disorder of the small intestine, which is strongly associated with HLA-DQ2. The structure of DQ2 complexed with an immunogenic epitope from gluten, QLQPFPQPELPY, has been determined to 2.2-A resolution by x-ray crystallography. The glutamate at P6, which is formed by tissue transglutaminase-catalyzed deamidation, is an important anchor residue as it participates in an extensive hydrogen-bonding network involving Lys-beta71 of DQ2. The gluten peptide-DQ2 complex retains critical hydrogen bonds between the MHC and the peptide backbone despite the presence of many proline residues in the peptide that are unable to participate in amide-mediated hydrogen bonds. Positioning of proline residues such that they do not interfere with backbone hydrogen bonding results in a reduction in the number of registers available for gluten peptides to bind to MHC class II molecules and presumably impairs the likelihood of establishing favorable side-chain interactions. The HLA association in celiac disease can be explained by a superior ability of DQ2 to bind the biased repertoire of proline-rich gluten peptides that have survived gastrointestinal digestion and that have been deamidated by tissue transglutaminase. Finally, surface-exposed proline residues in the proteolytically resistant ligand were replaced with functionalized analogs, thereby providing a starting point for the design of orally active agents for blocking gluten-induced toxicity.     

Delayed gastric emptying does not normalize after gluten withdrawal in adult celiac disease

Objective Delayed gastric emptying has been frequently detected in patients with untreated celiac disease. According to several studies, gluten withdrawal showed to be effective in normalizing the gastric emptying rate. The aim of this study was to evaluate the gastric emptying rate of solids in patients with celiac disease before and after a gluten-free diet. Methods Twelve adult patients with celiac disease (age range 20–57 years) and 30 healthy controls (age range 30–54 years) underwent a ¹³C-octanoic acid breath test to measure gastric emptying. Half emptying time (t_1/2) and lag phase (tlag) were calculated. After at least 12 months of a gluten-free diet, celiac patients underwent a new ¹³C-octanoic acid breath test. A symptom score was utilized to detect dyspeptic and malabsorption symptoms in all the patients. Results The gastric motility parameters, t_1/2 and t_lag, were significantly longer in patients than in controls. On a gluten-free diet, surprisingly, the gastric emptying did not normalize despite an improvement of symptom score. No significant correlation between abnormal gastric emptying and specific symptom patterns, anthropometric parameters or severity of histological damage was found. Conclusions This finding supports the hypothesis that gluten-driven mucosal inflammation might determine motor abnormalities by affecting smooth muscle contractility or impairing gut hormone function. The persistence of these abnormalities on a gluten free diet suggests the presence of a persistent low-grade mucosal inflammation with a permanent perturbation of the neuro-immunomodulatory regulation.     

Screening for celiac disease in high risk groups

Several epidemiological studies show that celiac disease with extraintestinal manifestations is 15 times more frequent than celiac disease with intestinal symptoms. Fifteen years ago the iceberg model was proposed to explain the epidemiology of this disease. On the one hand, there are a quantifiable number of patients who are correctly diagnosed since they have symptoms suggestive of this disease and who form the visible part of the iceberg. However, several studies using screening serology demonstrate that for each patient diagnosed, there is a mean of 5-10 patients without a diagnosis. These patients form the submerged part of the iceberg (monosymptomatic or silent celiac disease). The most widely accepted strategy to investigate the submerged part of the "celiac iceberg" is screening of known risk groups through a systematic search for celiac disease in these groups.     

Maternal non-diagnosed celiac disease and risk of low birth weight

AIMS: In order to know the prevalence of celiac disease in mothers with newborns weighing less or more than 2,500 g at birth we carried out a case-control study. PATIENTS: mothers of newborns in Cabue?es Hospital. Case group: Mothers with babies weighing less than 2,500 g at birth. Controls: Mothers with babies weighing more than 2,500 g at birth. One control for each case. METHODS: epidemiological and clinical interviews, and celiac disease serology. RESULTS: We studied 1103 women: 577 cases and 526 controls. We diagnosed 4 celiac disease cases, 2 in the case group and 2 in the control group. These 4 mothers had 3 term newborns (1 case in each 235 mothers; prevalence 0.42%) and 1 preterm newborn (1 case in each 389 mothers; prevalence 0.26%). Two cases had babies with adequate birth weight for their gestational age (1 case in each 419 mothers; prevalence 0.24%) and two cases had babies with low birth weight for their gestational age (1 in each 132 mothers; prevalence 0.75%). The odds ratio for low birth weight was 0.91 (95% CI: 0.12-6.49), the odds ratio for preterm birth was 0.61 (95% CI: 0.06-5.89), ad the odds ratio for low birth weight for gestational age was 3.19 (95% CI: 0.44-22.79).CONCLUSIONS: The prevalence of celiac disease in fertile women in our geographic area was 0.36% (1 case in each 275 mothers), and no differences were found between study groups.     

Regression of mesenteric lymph node cavitation syndrome complicating celiac disease after a gluten free diet

We report the case of a 39-year old woman with celiac disease in association with a cavitating mesenteric lymph node, hyposplenism and intra-hepatic haematopoiesis. The serious initial clinical picture evoked a diagnosis of non-Hodgkin lymphoma but was not confirmed on multiple biopsies. Despite the usual poor prognostic clinical outcome in such a setting, treatment with a strict gluten-free diet resulted in a remarkable persistent improvement in clinical status and lead to almost complete regression in radiological signs observed for up to 30 months follow-up.     

Mapping of gluten T-cell epitopes in the bread wheat ancestors: implications for celiac disease

BACKGROUND AND AIMS: Celiac disease is a prevalent disorder characterized by a chronic intestinal inflammation driven by HLA-DQ2 or -DQ8-restricted T cells specific for ingested wheat gluten peptides. The dominant T-cell responses are to epitopes that cluster within a stable 33mer fragment formed by physiologic digestion of distinct alpha-gliadins. Celiac disease is treated by excluding all gluten proteins from the diet. Conceivably, a diet based on baking-quality gluten from a wheat species that expresses no or few T-cell stimulatory gluten peptides should be equally well tolerated by the celiac patients and, importantly, also be beneficial for disease prevention. METHODS: To identify baking quality, harmless wheat, we followed the evolution of the wheat back to the species that most likely have contributed the AA, BB, and DD genomes to the bread wheat. Gluten were extracted from a large collection of these ancient wheat species and screened for T-cell stimulatory gluten peptides. RESULTS: Distinct differences in the intestinal T-cell responses to the diploid species were identified. Interestingly, we found that the fragments identical or equivalent to the immunodominant 33mer fragment are encoded by alpha-gliadin genes on the wheat chromosome 6D and thus absent from gluten of diploid einkorn (AA) and even certain cultivars of the tetraploid (AABB) pasta wheat. CONCLUSIONS: These findings have implications for celiac disease because they raise the prospect of identifying or producing by breeding wheat species with low or absent levels of harmful gluten proteins.     

The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides

BACKGROUND & AIMS: Gluten (GLU)-specific T-cell responses in HLA-DQ2 positive adult celiac disease (CD) patients are directed to an immunodominant alpha-gliadin (GLIA) peptide that requires deamidation for T-cell recognition. The aim of the current study was to determine which GLU peptide(s) are involved early in disease. METHODS: We have characterized the GLU-specific T-cell response in HLA-DQ2 positive children with recent onset CD. RESULTS: We found that 50% of these patients do not respond to the alpha-GLIA peptide but to a diverse set of GLIA and glutenin (GLT) peptides, including 6 novel epitopes. Moreover, individual patients respond to distinct (combinations of) GLU peptides. T-cell cross-reactivity toward homologous GLIA and GLT peptides was observed, which might play a role in the initial spreading of the GLU-specific T-cell response. Although all pediatric patients displayed deamidation-dependent responses, deamidation-independent responses were found in the majority of patients as well. Finally, T-cell responses to 3 of these novel GLU peptides were found in adult CD patients. CONCLUSIONS: The diversity of the GLU-specific T-cell response is far greater than was previously appreciated. Both adult and young CD patients can respond to a diverse repertoire of GLU peptides. The observation that T-cell responses to 3 of the novel peptides are independent of deamidation indicates that T-cell responses can be initiated toward native GLU peptides. The possibility that deamidation drives the GLU response toward immunodominant T-cell stimulatory peptides after disease initiation is discussed.