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Enterochromaffin cells were the first endocrine cells of the gastrointestinal tract to be chemically distinguished, almost 150 years ago. It is now known that the chromaffin reaction of these cells was due to their content of the reactive aromatic amine, 5-hydroxytryptamine (5-HT, also known as serotonin). They have commonly been thought to be a special class of gut endocrine cells (enteroendocrine cells) that are distinct from the enteroendocrine cells that contain peptide hormones. The study by Martin et al. in the current issue of this journal reveals that the patterns of expression of nutrient receptors and transporters differ considerably between chromaffin cells of the mouse duodenum and colon. However, even within regions, chromaffin cells differ; in the duodenum there are chromaffin cells that contain both secretin and 5-HT, cholecystokinin and 5-HT, and all three of secretin, cholecystokinin, and 5-HT. Moreover, the ratios of these different cell types differ substantially between species. And, in terms of function, 5-HT has many roles, including in appetite, motility, fluid secretion, release of digestive enzymes and bone metabolism. The paper thus emphasizes the need to define the many different classes of enterochromaffin cells and relate this to their roles., (© 2017 John Wiley & Sons Ltd.)

Gluten and other related proteins of the wheat, rye and barley, have antigenic properties that may trigger adverse reactions in susceptible individuals. Celiac disease was the first pathology with clear causal association related to the intake of these proteins. Recently, wheat allergy and non celiac gluten sensitivity have been described. Although, clinical presentation and its relation with protein ingestion may be similar and elicit confusion, their pathogenic mechanism, diagnosis and treatment are quite different. Since the prevalence of these diseases is relatively high as a whole, it is essential that these become familiar to primary care doctors and general pediatricians, thus they will know how to differentiate and face them. The aim of this review is to compare the main aspects of epidemiology, pathofisiology, diagnosis and treatment of these 3 conditions.

In epileptic encephalopathies (EE), interictal epileptiform discharges (IEDs) contribute to cognitive impairment. The EE process has been studied in a patient affected by epilepsy with occipital calcification and celiac disease (CEC syndrome) by combining the administration of brain area stimulus specific (visual and auditory) reaction times (RT) during continuous EEG monitoring with the off-line reconstruction of auditory and visual evoked potentials (EP). Visual RT and VEP were abnormal only if recorded concomitantly to the IEDs. Auditory RT and EP were normal. When the EE process is going on, IEDs transiently disrupt aspects of cortical functioning, contributing to the cognitive impairment.

Objective: Transcranial Magnetic Stimulation in de novo patients with Celiac Disease previously revealed an imbalance in the excitability of cortical facilitatory and inhibitory circuits. After a median period of 16 months of gluten-free diet, a global increase of cortical excitability was reported, suggesting a glutamate-mediated compensation for disease progression. We have now evaluated cross-sectionally the changes of cortical excitability to TMS after a much longer gluten-free diet., Methods: Twenty patients on adequate gluten-free diet for a mean period of 8.35 years were enrolled and compared with 20 de novo patients and 20 healthy controls. Transcranial Magnetic Stimulation measures, recorded from the first dorsal interosseous muscle of the dominant hand, consisted of: resting motor threshold, cortical silent period, motor evoked potentials, central motor conduction time, mean short-latency intracortical inhibition and intracortical facilitation., Results: The cortical silent period was shorter in de novo patients, whereas in gluten-free diet participants it was similar to controls. The amplitude of motor responses was significantly smaller in all patients than in controls, regardless of the dietary regimen. Notwithstanding the diet, all patients exhibited a statistically significant decrease of mean short-latency intracortical inhibition and enhancement of intracortical facilitation with respect to controls; more intracortical facilitation in gluten-restricted compared to non-restricted patients was also observed. Neurological examination and celiac disease-related antibodies were negative., Conclusions: In this new investigation, the length of dietary regimen was able to modulate the electrocortical changes in celiac disease. Nevertheless, an intracortical synaptic dysfunction, mostly involving excitatory and inhibitory interneurons within the motor cortex, may persist. The clinical significance of subtle neurophysiological changes in celiac disease needs to be further investigated.

Background/aim: Many autoimmune diseases occur concomitantly with celiac disease (CD). We aimed to determine the frequency of Sjögren's syndrome (SS) in CD patients based on SS-specific serology verified by minor labial salivary biopsy., Materials and Methods: Eight-two patients with CD were included in the study. After examination for objective evidence of sicca complex, all patients were tested for serological presence of rheumatoid factor (RF) and antinuclear antibodies (ANAs) and for ANA profile. Minor labial salivary biopsy was performed for patients with positive serology and/or clinical signs of SS., Results: Of the patients included, 24 (29.3%) had dry eye symptoms while 20 (24.4%) had dry mouth symptoms. Dry eye was detected by Schirmer test in 10 patients (12.2%) and by ocular staining score in only 2 patients (2.4%). All samples were negative for RF while 12 (14.6%) samples were positive for ANAs. Of 82 patients with CD, the diagnosis of SS was established in only one patient (1.2%), while one patient (1.2%) was diagnosed with morphea and 4 patients (4.9%) were classified as having undifferentiated connective tissue disease., Conclusion: The prevalence of SS in CD is low, so there is no need for serologic screening of all patients with CD for SS.

Background: Celiac disease is a chronic inflammatory condition with wide ranging effects on individual's lives caused by a combination of symptoms and the burden of adhering to a gluten-free diet (GFD)., Objectives: To further understand patients' experience of celiac disease, the impact it has on health-related quality of life (HRQOL), and to develop a conceptual model describing this impact., Methods: Adults with celiac disease on a GFD reporting symptoms within the previous 3 months were included; patients with refractory celiac disease and confounding medical conditions were excluded. A semistructured discussion guide was developed exploring celiac disease symptoms and impact on patients' HRQOL. An experienced interviewer conducted in-depth interviews. The data set was coded and analyzed using thematic analysis to identify concepts, themes, and the inter-relationships between them. Data saturation was monitored and concepts identified formed the basis of the conceptual model., Results: Twenty-one participants were recruited, and 32 distinct gluten-related symptoms were reported and data saturation was reached. Analysis identified several themes impacting patients' HRQOL: fears and anxiety, day-to-day management of celiac disease, physical functioning, sleep, daily activities, social activities, emotional functioning, and relationships. The conceptual model highlights the main areas of impact and the relationships between concepts., Conclusions: Both symptoms and maintaining a GFD have a substantial impact on patient functioning and HRQOL in adults with celiac disease. The conceptual model derived from these data may help to design future patient-reported outcomes as well as interventions to improve the quality of life in an individual with celiac disease., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

The study was carried out to trace clinical laboratory parallels between levels of vitamin D under diseases of small intestine in children. The examined sampling included 160 children aged from 6 months to 18 years with diseases of small intestine. The patients were separated to three groups: 60 children with celiac disease aged from 3-16 years; 60 children with chronic post-infectious enterocolitis aged from 2 to 12 years; 40 children with allergic enterocolitis aged from 6 months to 4 years. The control group consisted of 31 children, including 15 children aged from 6 months to 4 years and 16 children aged from 5 to 18 years. The standard clinical, para-clinical and instrumental techniques of investigation were applied to every nosology. To analyze status of vitamin В the levels of calcidiol and parathormone were determined. In the process of tracing clinical laboratory parallels between levels of vitamin D under diseases of small intestine in children high percentage of decreasing of vitamin D (96.9%) was detected, and at that in 100% under celiac disease and chronic post-infectious enterocolitis. The feedback was established between levels of vitamin D and levels of calcidiol and parathormone and also activity of alkaline phosphatase in all groups of patients though more evident in patients with celiac disease and chronic post-infectious enterocolitis. The low values of level of vitamin D were detected in all children with celiac disease and chronic post-infectious enterocolitis whereas only in 87% under allergic enterocolitis. The decreasing of level of vitamin D was accompanied by increasing of content of calcidiol and parathormone and activity of alkaline phosphatase at that the most high numbers are observed in patients with celiac disease and then chronic post-infectious enterocolitis and allergic enterocolitis.

Initial studies associated the HLA class I A*01 and B*08 alleles with celiac disease (CD) susceptibility. Subsequent analyses showed a primary association with HLA class II alleles encoding for the HLA DQ2.5 molecule. Because of the strong linkage disequilibrium of A*01 and B*08 alleles with the DR3-DQ2.5 haplotype and a recent genome-wide association study indicating that B*08 and B*39 are predisposing genes, the etiologic role of HLA class I in CD pathogenesis needs to be addressed. We screened gliadin proteins (2α-, 2ω-, and 2γ-gliadin) using bioinformatic algorithms for the presence of peptides predicted to bind A*0101 and B*0801 molecules. The top 1% scoring 9- and 10-mer peptides ( N = 97, total) were synthesized and tested in binding assays using purified A*0101 and B*0801 molecules. Twenty of ninety-seven peptides bound B*0801 and only 3 of 97 bound A*0101 with high affinity (IC 50 < 500 nM). These 23 gliadin peptides were next assayed by IFN-γ ELISPOT for recognition in peripheral blood cells of CD patients and healthy controls carrying the A*0101 and/or B*0801 genes and in A*0101/B*0801 - CD patients. Ten of the twenty-three peptides assayed recalled IFN-γ responses mediated by CD8 + T cells in A*0101/B*0801 + patients with CD. Two peptides were restricted by A*0101, and eight were restricted by B*0801. Of note, 50% (5/10) of CD8 + T cell epitopes mapped within the γ-gliadins. Our results highlight the value of predicted binding to HLA molecules for identifying gliadin epitopes and demonstrate that HLA class I molecules restrict the anti-gluten T cell response in CD patients., (Copyright © 2017 by The American Association of Immunologists, Inc.)

The epidemiology of coeliac disease (CD) is changing. Presentation of CD with malabsorptive symptoms or malnutrition is now the exception rather than the rule and, it now affects those underweight and overweight equally. In concert with these epidemiological shifts, the incidence of CD is increasing. These changing patterns of disease presentation are challenging traditional management paradigms, and clinicians now need to adapt to these changes and respond to the demands of an increasingly well-informed consumer population. This article aims to provide historical context to the epidemiological changes in CD, which provides context to direct future research. Changing definitions and diagnostic paradigms are complicating the management of CD. The gold standard of diagnosis, treatment goals, guidelines for follow-up, and the role of population screening in CD remain controversial and unresolved. Although the patient population is interested in new treatments for CD and alternatives to a gluten-free diet, most therapies are not yet widely available or sufficiently researched, and our understanding of the natural history of CD is limited despite a number of retrospective and population-based studies. The management of asymptomatic CD has only recently been examined despite up to half of patients now presenting with no or minimal symptoms. There is surprisingly little evidence to resolve many of these issues, and only with robust prospective studies will our understanding of the true natural history of coeliac disease be clarified., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose: A gluten-free diet (GFD) has been reported to negatively impact the quality of life (QoL) of coeliac disease (CD) patients. The gut-brain axis hormones ghrelin and leptin, with the brain-derived neurotrophic factor (BDNF), may affect QoL of CD patients undergoing GFD. Our aims were to evaluate whether: (a) the circulating concentrations of leptin, ghrelin and BDNF in CD patients were different from those in healthy subjects; (b) GFD might induce changes in their levels; (c) BDNF Val66Met polymorphism variability might affect BDNF levels; and (d) serum BDNF levels were related to dietary docosahexaenoic acid (DHA) as a neurotrophin modulator., Methods: Nineteen adult coeliac patients and 21 healthy controls were included. A QoL questionnaire was administered, and serum concentrations of ghrelin, leptin, BDNF and red blood cell membrane DHA levels were determined at the enrolment and after 1 year of GFD. BDNF Val66Met polymorphism was analysed., Results: Results from the questionnaire indicated a decline in QoL after GFD. Ghrelin and leptin levels were not significantly different between groups. BDNF levels were significantly (p = 0.0213) lower in patients after GFD (22.0 ± 2.4 ng/ml) compared to controls (31.2 ± 2.2 ng/ml) and patients at diagnosis (25.0 ± 2.5 ng/ml). BDNF levels correlated with DHA levels (p = 0.008, r = 0.341) and the questionnaire total score (p = 0.041, r = 0.334)., Conclusions: Ghrelin and leptin seem to not be associated with changes in QoL of patients undergoing dietetic treatment. In contrast, a link between BDNF reduction and the vulnerability of CD patients to psychological distress could be proposed, with DHA representing a possible intermediate.

Impairment of bone mineral density (BMD) is frequent in celiac disease (CD) patients on a gluten-free diet (GFD). The normalization of intestinal mucosa is still difficult to predict. We aim to investigate the relationship between BMD and duodenal mucosa healing (DMH) in CD patients on a GFD. Sixty-four consecutive CD patients on a GFD were recruited. After a median period of a 6-year GFD (range 2-33 years), patients underwent repeat duodenal biopsy and dual-energy X-ray absorptiometry (DXA) scan. Twenty-four patients (38%) displayed normal and 40 (62%) low BMD, 47 (73%) DMH, and 17 (27%) duodenal mucosa lesions. All patients but one with normal BMD (23 of 24, 96%) showed DMH, while, among those with low BMD, 24 (60%) did and 16 (40%) did not. At multivariate analysis, being older (odds ratio (OR) 1.1, 95% confidence interval (CI) 1.03-1.18) and having diagnosis at an older age (OR 1.09, 95% CI 1.03-1.16) were associated with low BMD; in turn, having normal BMD was the only variable independently associated with DMH (OR 17.5, 95% CI 1.6-192). In older CD patients and with late onset disease, BMD recovery is not guaranteed, despite a GFD. A normal DXA scan identified CD patients with DMH; thus, it is a potential tool in planning endoscopic resampling.

Background: Previous studies suggest that the prevalence of wheat/gluten sensitivity and adherence to a gluten-free diet (GFD) are high in Latin population despite a poor diagnosis of celiac disease. However, these prevalence rates still remain unknown in most Latin American countries., Methods: A cross-sectional survey study was conducted in Santa Fe, Argentina., Results: The estimated self-reported prevalence rates were (95% Confidence Interval [CI]): self-reported gluten sensitivity (SR-GS) 7.61% (6.2-9.2), SR-GS currently following a GFD 1.82% (1.2-2.7), celiac disease 0.58% (0.3-1.2), wheat allergy 0.33% (0.12-0.84), self-reported non-celiac gluten sensitivity (SR-NCGS) 6.28% (5.1-7.8), SR-NCGS currently following a GFD 0.91% (0.5-1.6), and adherence to a GFD 6.37% (5.1-7.9). SR-GS was more common in women (6.0%; p < 0.001) and associated with irritable bowel syndrome ( p < 0.001). Among the GFD followers, 71.4% were doing it for reasons other than health-related benefits and 50.6% without medical/dietitian advice. In the non-SR-GS group, the main motivations for following a GFD were weight control and the perception that a GFD is healthier., Conclusion: In Argentina, gluten sensitivity is commonly reported and it seems that physicians/gastroenterologists are aware of celiac disease diagnosis. Trustable information about the benefits and potential consequences of following a GFD should be given to the general population., Competing Interests: All authors declare no conflict of interest.

Objective: Type 1 diabetes mellitus (T1DM) and celiac disease (CD) are autoimmune diseases and have similar genetic patterns. T1DM treatment is based on diet, physical activity and insulin therapy, whereas CD depends on dietary changes with restriction of wheat, rye and barley. The aim of the study was to evaluate the quality of life (QoL) of individuals with the association of T1DM and CD, to characterize their nutritional status and to compare it with those with only one disease and healthier controls., Subjects/methods: Sixty patients controlled by sex, age and body mass index (BMI) were stratified by previous diagnosis in: T1DM and CD (DMCD group); T1DM (DM group); CD (CD group); or healthy participants (HC). The SF-36 questionnaire was applied to assess psychological well being and results were compared with glycemic control and presence of complications related to diabetes, adhesion to gluten-free diet (GFD). Nutritional status and body mass composition were determined by BMI, waist circumference, bioimpedance, general laboratory tests and whole-body densitometry., Results: The time of diagnosis of T1DM was similar between DMCD and DM groups; however, the duration of CD was significantly higher in the CD group compared with DMCD. The SF-36 analysis revealed statistically significant differences between DM and HC groups in two domains: general health (P=0.042) and energy/vitality (P=0.012). QoL was also correlated with compliance to a GFD, and scores were similar in both groups: DMCD and CD. Forty percent of individuals in the CD group had visceral fat area above 100 cm 2 , as opposed to 20% in the other groups., Conclusions: Individuals of DMCD group had similar scores to DM, CD and HC on QoL, as well as on their nutritional status and bone metabolism. Thereby, we should conclude that the association of T1DM and CD did not deteriorate their health status.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of coeliac disease. The burden of illness in untreated coeliac disease is known to be considerable, but corresponding evidence for DH is lacking. In this study the burden of DH was evaluated prospectively in 52 patients newly diagnosed with DH using a study questionnaire and a validated Psychological General Well-Being (PGWB) questionnaire. The PGWB scores were compared with those of 110 healthy controls. Quality of life was significantly (p < 0.001) lower among patients with DH at the time of diagnosis, but after 1 year on a gluten-free diet their quality of life was at same level as that of the controls. The presence of gastrointestinal symptoms was shown to significantly increase the burden of untreated DH. We conclude that there is a significant burden related to untreated, but not to treated, DH, and the burden is even greater among DH patients with gastrointestinal symptoms.

Disaccharidases (DS) are brush border enzymes embedded in the microvillous membrane of small intestinal enterocytes. In untreated coeliac disease (CD), a general decrease of DS activities is seen. This manuscript reviews different aspects of DS activities in CD: their utility in the diagnosis and their application to in vitro toxicity testing. The latter has never been established in CD research. However, with the recent advances in small intestinal organoid techniques, DS might be employed as a biomarker for in vitro studies. This includes establishment of self-renewing epithelial cells raised from tissue, which express differentiation markers, including the brush border enzymes. Determining duodenal DS activities may provide additional information during the diagnostic workup of CD: (i) quantify the severity of the observed histological lesions, (ii) provide predictive values for the grade of mucosal villous atrophy, and (iii) aid diagnosing CD where minor histological changes are seen. DS can also provide additional information to assess the response to a gluten-free diet as marked increase of their activities occurs four weeks after commencing it. Various endogenous and exogenous factors affecting DS might also be relevant when considering investigating the role of DS in other conditions including noncoeliac gluten sensitivity and DS deficiencies.

Background & Objectives: Type 1 diabetes mellitus (T1DM) and celiac disease (CD) tend to co-exist due to similar underlying genetic predisposition. Failure to recognize CD in patients with T1DM predisposes them to complications. The present study was aimed to assess children with T1DM for the presence of CD., Methods: This was a retrospective analysis of the records of children with T1DM attending paediatric endocrinology clinic at a tertiary care hospital in north India from January 2006 to May 2014. All children were screened for CD at the time of diagnosis of T1DM using IgA anti-tissue transglutaminase (anti-tTG) levels in serum. Seropositive children were subjected to upper gastrointestinal endoscopy and duodenal biopsy for histopathological confirmation. The children also underwent thyroid function testing (TFT); those with deranged TFT were evaluated for thyroid-specific antibodies., Results: Positive serology for CD was present in 43 of 126 children with T1DM whose records were reviewed [34.1%; 95% confidence interval (CI): 25.9-43.1]. Confirmed CD was diagnosed in 17 (13.5%; CI: 8.1-20.7) of the children screened and 17 of 40 (42.5%; CI: 27.1-59.1) seropositive participants. Four out of 17 children with coexisting CD and T1DM also had autoimmune thyroiditis with overt hypothyroidism. The children with confirmed CD were more likely to have short stature [odds ratios (OR)-3.16; 95% CI: 1.09-9.20, P<0.05] and hypothyroidism (OR-6.4; 95% CI: 1.52-26.90, P<0.05)., Interpretation & Conclusions: Our study showed a higher proportion of CD in children with T1DM as compared to that reported in general population. Regular screening of children with T1DM for CD is needed to improve metabolic control and prevent long-term complications.

A fundamental function of the intestinal epithelium is to act as a barrier that limits interactions between luminal contents such as the intestinal microbiota, the underlying immune system and the remainder of the body, while supporting vectorial transport of nutrients, water and waste products. Epithelial barrier function requires a contiguous layer of cells as well as the junctions that seal the paracellular space between epithelial cells. Compromised intestinal barrier function has been associated with a number of disease states, both intestinal and systemic. Unfortunately, most current clinical data are correlative, making it difficult to separate cause from effect in interpreting the importance of barrier loss. Some data from experimental animal models suggest that compromised epithelial integrity might have a pathogenic role in specific gastrointestinal diseases, but no FDA-approved agents that target the epithelial barrier are presently available. To develop such therapies, a deeper understanding of both disease pathogenesis and mechanisms of barrier regulation must be reached. Here, we review and discuss mechanisms of intestinal barrier loss and the role of intestinal epithelial barrier function in pathogenesis of both intestinal and systemic diseases. We conclude with a discussion of potential strategies to restore the epithelial barrier.

Background: Caregiver burden is documented in several chronic diseases, but it has not been investigated in celiac disease (CD)., Aims: We aim to quantify the burden to partners of CD patients and identify factors that affect the perceived burden., Methods: We surveyed patients with biopsy-proven CD and their partners. Patients completed CD-specific questions, including the validated Celiac Symptom Index (CSI) survey. Partners completed the validated Zarit Burden Interview (ZBI) and questions regarding sexual and relationship satisfaction. Univariable and multivariable analyses were used to assess the association between demographics, CD characteristics, and partner burden., Results: In total, 94 patient/partner pairs were studied. Fifteen patients (16 %) reported a CSI score associated with a poor quality of life, and 34 partners (37 %) reported a ZBI score corresponding to mild-to-moderate burden. Twenty-two partners (23 %) reported moderate-to-low overall relationship satisfaction, and 12 (14 %) reported moderate-to-low sexual satisfaction. The degree of partner burden was directly correlated with patient CSI score (r = 0.27; p = 0.008), and there were moderate-to-strong inverse relationships between partners' burden and relationship quality (r = -0.70; p < 0.001) and sexual satisfaction (r = -0.42; p < 0.001). On multivariable logistic regression, predictors of mild-to-moderate partner burden were low partner relationship satisfaction (OR 17.06, 95 % CI 2.88-101.09, p = 0.002) and relationship duration ≥10 years (OR 14.42, 95 % CI 1.69-123.84, p = 0.02)., Conclusions: Partner burden is common in CD, with more than one-third of partners experiencing mild-to-moderate burden. Partner burden is directly correlated with patient symptom severity, and it increases with poorer sexual and relationship satisfaction. Healthcare providers should address relationship factors in their care of patients with CD.

The main purposes of this undertaking were to determine how often patients with Down syndrome (DS) are screened for celiac disease (CD) across five DS specialty clinics, which symptoms of CD are most often reported to DS specialty providers at these clinics, and, how many individuals were diagnosed with CD by these clinics. This was accomplished by following 663 individuals with DS for 1 year, across five clinics in different states specializing in the comprehensive care of people with DS. Of the 663 participants, 114 individuals were screened for CD at their visit to a DS specialty clinic. Protracted constipation (43.2%) and refractory behavioral problems (23.7%) were symptoms most often reported to DS specialty providers. During the 1 year study period, 13 patients screened positive for CD by serology. Of those, eight underwent duodenal biopsy, and three were diagnosed with CD. We conclude that CD is an important consideration in the comprehensive care of individuals with DS. However, while symptoms are common, diagnoses are infrequent in DS specialty clinics. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Celiac disease (CD) is the most common autoimmune enteropathy, triggered by a deregulated immune response to gliadin. It has been hypothesized that human intestinal microbiota may interfere with the pathogenesis of the disease and in the clinical course of CD. In the present review, we analyzed the microbiota alterations observed in the course of CD, how they may influence the pathogenesis of CD, and the possible applications for a microbiota modulation in CD. In detail, most of the current literature underlined that the dysbiosis in CD is hallmarked by an increase in gram-negative and Bacteroidetes species, and by a decrease in Bifidobacteria and Lactobacilli. As the intestinal microbiota is able to modulate the cytokine environment, an unfavorable microbiota could amplify the immune response to gliadin in individuals with CD, whereas the administration of probiotic species could lead to a decrease in proinflammatory cytokine production. Therefore, dysbiosis could represent an important trigger in CD pathogenesis, along with genetic (HLA-haplotypes) and environmental factors (antibiotic administration, mode of delivery, and breastfeeding). Although data on the modulation of microbiota by GFD are conflicting, current evidence has demonstrated that probiotic administration could be useful to improve symptoms and to reduce molecular mucosal inflammation, by downregulating the cytokines involved in CD pathogenesis. However, studies analyzing this aspect are few in number, thus stimulating the exploration of this field, with the aim of achieving a solid pathophysiological basis for probiotic administration in CD.

Introduction: Celiac disease is an autoimmune disease of the small intestine which occurs in genetically predisposed people of all ages. A large clinical spectrum of manifestations accompanies the onset of the disease with diarrhoea, flatulence and weight loss being the most common. However, findings like osteoporosis, iron deficiency, anaemia and hypocalcaemia could also insinuate the existence of the disease., Case Presentation: We report the case of a 55-year-old man with numbness and tingling of the upper extremities due to hypocalcaemia that proved to be an uncommon case of celiac disease., Conclusion: A non-negligible number of adult patients with celiac disease can present with only minor and subclinical manifestations of the disease. As such, hypocalcaemia may be the sole manifestation of celiac disease. A high index of suspicion is needed for prompt diagnosis., (© The Author(s) 2016.)

Background/aims: Celiac disease (CD)-associated cardiologic disorders is a growing concern. However, data regarding cardiac affection in children with CD are few. This study aimed at assessing the subclinical impact of CD on the global myocardial performance in Saudi children with CD using Doppler tissue imaging (DTI)., Patients and Methods: Conventional two-dimensional echocardiography was performed among 20 Saudi children with CDas well as 20 age and sex-matched healthy controls. DTI were used to determine right ventricular (RV) and left ventricular (LV) Tei indexes. These findings were correlated with the Modified Marsh Classification of the histologic findings in CD., Results: LV and RV Tei indexes were significantly higher in children with CD than the control group (mean ± standard deviation: 0.47 ± 0.05 vs. 0.31 ± 0.18; P< 0.0005 and 0.51 ± 0.04 vs. 0.32 ± 0.05; P< 0.0001, respectively). RV Tei index was found to be positively correlated with the Modified Marsh Classification of CD (r = 0.7753, P< 0.0001). LV Tei index tended to be more affected in patients with more severe histologic findings, however, such relation did not reach statistical significance (r = 0.2479, P = 0.292). Fractional shortening did not correlate with the Modified Marsh Classification of histologic findings in CD patients (r= -0.11, P = 0.641)., Conclusions: Subclinical myocardial dysfunction of both ventricles occurs in children with CD. The DTI method appears to be more sensitive than conventional two-dimensional echocardiography in the early detection of myocardial dysfunction in children with CD., Competing Interests: There are no conflicts of interest.

Adherence and non-adherence to a gluten-free diet (GFD) may impact negatively on health-related quality of life (HRQoL). Understanding the factors that influence compliance could help inform management and also guide support. With a particular focus on adolescence, this narrative review critiques current literature on the burdens associated with following a GFD and the factors associated with adherence. Studies highlight a variety of burdens faced by individuals with coeliac disease, including the cost, access and availability of gluten-free (GF) foods, as well as the dilemmas experienced when eating out, travelling and socialising with friends. A number of studies report that adolescents face stigmatisation and feel isolated in social situations and at school. Additional burdens that are highlighted are a lack of knowledge regarding CD and GFD difficulties in interpreting food labels, as well as dissatisfaction with the organoleptic properties of GF foods. Factors associated with poor adherence in adolescence include older age, an absence of immediate symptoms, difficulties eating out and poor palatability of GF foods. Conversely, better emotional support and stronger organisation skills have been associated with superior adherence. Significant associations have been reported between HRQoL measures and adherence, although the findings are inconsistent. Limitations in research methodologies exist and data are restricted to just a few countries. Further research specific to adolescence is required to identify independent predictors of adherence., (© 2016 The British Dietetic Association Ltd.)

Coeliac disease is a common digestive disorder that affects 1% of adults. It is characterised by mucosal damage of the small intestine caused by dietary gluten. The main treatment for coeliac disease is a lifelong gluten-free diet, which can reduce morbidity and mortality and also improve quality of life. Despite the benefits, adhering to this diet is often challenging, with patients often struggling to sustain dietary restriction. Structured follow-up for coeliac disease is recommended in international guidelines for improving adherence and for detecting complications;however, uncertainty exists concerning exactly who should be administering this follow-up care. Here, we undertake a review of the current approaches described in the literature to follow-up patients with coeliac disease, and assess the efficacy of these differing models. We also explore future directions for the care of these patients in the context of the UK National Health Service (a publicly funded healthcare system). Although the focus of this review pertains to follow-up within the UK healthcare system, these problems are recognised to be international, and so the findings of our review are likely to be of interest to all healthcare professionals seeing and managing patients with coeliac disease., (© 2016 The British Dietetic Association Ltd.)

Background: Refractory coeliac disease is a severe complication of coeliac disease with heterogeneous outcome., Aim: To create a prognostic model to estimate survival of patients with refractory coeliac disease., Methods: We evaluated predictors of 5-year mortality using Cox proportional hazards regression on subjects from a multinational registry. Bootstrap resampling was used to internally validate the individual factors and overall model performance. The mean of the estimated regression coefficients from 400 bootstrap models was used to derive a risk score for 5-year mortality., Results: The multinational cohort was composed of 232 patients diagnosed with refractory coeliac disease across seven centres (range of 11-63 cases per centre). The median age was 53 years and 150 (64%) were women. A total of 51 subjects died during a 5-year follow-up (cumulative 5-year all-cause mortality = 30%). From a multiple variable Cox proportional hazards model, the following variables were significantly associated with 5-year mortality: age at refractory coeliac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38-3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22-6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61-0.85). A simple weighted three-factor risk score was created to estimate 5-year survival., Conclusions: Using data from a multinational registry and previously reported risk factors, we create a prognostic model to predict 5-year mortality among patients with refractory coeliac disease. This new model may help clinicians to guide treatment and follow-up., Competing Interests: DECLARATION OF INTEREST Author’s declaration of personal interest: The authors declare no conflict of interest related to this manuscript, (© 2016 John Wiley & Sons Ltd.)

Background: Coeliac disease (CD) is managed by life-long adherence to a gluten-free diet and dietitians have the potential to facilitate this. Patient involvement through shared decision-making is central to behaviour-change skills used by dietitians, although there is little evidence supporting its inclusion in evaluating dietetic interventions. The present study aimed to explore patients' preferences for diet and nutrition-related outcomes in CD., Methods: Adults with CD or adult carers of children with CD were invited through support networks. Participants took part in a telephone, face-to-face interview or focus group which was audio-recorded and transcribed. Themes were developed using a framework method. Ethical approval was obtained., Results: Twenty-nine adult patients and five parents of CD children participated 0-34 years after diagnosis. Four main outcome-related themes emerged: (i) Participants wanted information specific to their lifestyle and time since diagnosis, focussing on food containing gluten, practical issues, prescribable items and general nutrition. (ii) The degree of satisfaction with the consultation process impacted on participants' experience, including the dietitian's CD expertise, consistency of the dietitian seen, and the frequency and length of appointments. (iii) Health concerns were important to participants and focussed on risk of osteoporosis, unwanted weight gain, and the fat and sugar content of manufactured gluten-free products. (iv) Clinical monitoring, including bone scans and antibody measurements, was mentioned but was not described as being of importance for most participants., Conclusions: The outcomes preferred by CD patients and carers focussed primarily on information and resources received and satisfaction with their dietetic consultation., (© 2016 The British Dietetic Association Ltd.)

Migraine is a recurrent and commonly disabling primary headache disorder that affects over 17% of women and 5%-8% of men. Migraine susceptibility is multifactorial with genetic, hormonal and environmental factors all playing an important role. The physiopathology of migraine is complex and still not fully understood. Many different neuropeptides, neurotransmitters and brain pathways have been implicated. In connection with the myriad mechanisms and pathways implicated in migraine, a variety of multisystemic comorbidities (e.g., cardiovascular, psychiatric and other neurological conditions) have been found to be closely associated with migraine. Recent reports demonstrate an increased frequency of gastrointestinal (GI) disorders in patients with migraine compared with the general population. Helicobacter pylori infection, irritable bowel syndrome, gastroparesis, hepatobiliary disorders, celiac disease and alterations in the microbiota have been linked to the occurrence of migraine. Several mechanisms involving the gut-brain axis, such as a chronic inflammatory response with inflammatory and vasoactive mediators passing to the circulatory system, intestinal microbiota modulation of the enteric immunological milieu and dysfunction of the autonomic and enteric nervous system, have been postulated to explain these associations. However, the precise mechanisms and pathways related to the gut-brain axis in migraine need to be fully elucidated. In this review, we survey the available literature linking migraine with GI disorders. We discuss the possible physiopathological mechanisms, and clinical implications as well as several future areas of interest for research., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest.

Background: The prevalence and factors associated with transaminasemia in celiac disease are poorly known., Aims: To investigate these issues in paediatric celiac patients and controls., Methods: Alanine aminotransferase (ALT) was studied in 150 children with untreated celiac disease, 161 disease controls and 500 population-based controls. The association between ALT and clinical and histological variables and the effect of a gluten-free diet were investigated in celiac patients., Results: ALT was >30U/l: celiac disease 14.7%, ulcerative colitis 37.2%, Crohn's disease 16.7%, reflux disease 16.2%, functional gastrointestinal symptoms 8.9%, and controls 3.6%. Factors associated with increased ALT were poor growth (45.5% vs 24.2%, P=0.039) and severe villous atrophy (median 23.0U/l vs partial atrophy 19.0U/l, P=0.008), but not age, sex, body-mass index, type or severity of symptoms and co-morbidities. ALT had a moderate correlation with endomysial (r=0.334, P<0.001) and transglutaminase antibodies (r=0.264, P=0.002) and ferritin (r=-0.225, P=0.03), but not with other laboratory values. On gluten-free diet median ALT decreased from 22.0U/l to 18.0U/l (P=0.002) and 80% of the high values normalized., Conclusion: Increased ALT is associated with more advanced serological and histological celiac disease. Adherence to a gluten-free diet appears to result in normalization or reduction of ALT levels., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: A gluten free diet (GFD) is the only available treatment for celiac disease (CD). However many patients fail to respond fully clinically or histologically. Several surveys highlight the psychosocial implications of adherence to a GFD. Hence, efforts are ongoing to develop therapeutic strategies beyond a GFD., Areas Covered: We conducted a search of PubMed and clinicaltrials.gov to extract articles on CD using keywords including 'celiac disease' and 'refractory celiac disease' (RCD) and focused on articles conducting pathophysiologic and therapeutic research in/ex-vivo models and human trials. We highlight novel therapeutics that manipulate these mechanisms including tight junction regulators, glutenases, gluten sequestrants and immunotherapy using vaccines, nanoparticles that may serve as adjuncts to a GFD or more ambitiously to allow for gluten consumption. We also highlight the role of anti-inflammatories, immunosuppressants and monoclonal antibodies in RCD. Expert commentary: Therapeutics including tight junction regulators, glutenases have the potential to be approved for non-responsive CD or as gluten adjuncts. We expect results of various phase 1/2 trials using AMG 714, BL 7010, IgY antibodies to be published. In the interim, off-label use of 5 amino-salicylates, budesonide, nucleoside analogues and newer biologics developed for other inflammatory diseases will be used in RCD.

INTRODUCTION Celiac disease (CD) is an immune-mediated enteropathy related to permanent gluten intolerance, characterized by gastrointestinal symptoms as well as nongastrointestinal symptoms, including neurologic ones. The presence of neuron-specific enolase (NSE), interleukin 10 (IL-10), and antiganglioside M1 (anti-GM1) antibodies has been demonstrated for neurologic conditions as well as immune disorders with neurologic manifestations. OBJECTIVES The aim of the study was to determine the concentrations of IL-10, NSE, and anti-GM1 antibodies in the course of CD and their correlation with changes in electrogastrography (EGG) and with heart rate variability (HRV). PATIENTS AND METHODS The study included 68 participants: 34 patients with CD and 34 healthy individuals. We assessed the concentrations of IL-10 and NSE as well as the presence of anti-GM1 antibodies in serum. We investigated correlations between the concentrations of IL-10, NSE, and anti-GM1 antibodies and the results of EGG and HRV. RESULTS Patients with CD had a higher level of anti-GM1 antibodies than controls (1.38 ng/ml [0.98-2.03 ng/ml] vs 0.81 ng/ml [0.35-1.15 ng/ml]). Median IL-10 concentrations in patients with CD differed significantly from those in controls (7 pg/ml [4.33-11.48 pg/ml] vs 4.27 pg/ml [2.44-7 pg/ml]; P = 0.010). In HRV analysis, a positive correlation between IL-10 concentrations and very low frequency spectrum was observed (r = 0.63; P = 0.003). There was no correlation between the concentrations of IL-10, NSE, or anti-GM1 antibodies and EGG parameters. CONCLUSIONS Chronic inflammation in the course of CD may lead to autonomic nervous system impairment and development of neurologic disorders. Therefore, anti-GM1 antibodies and IL-10 may be considered as markers of nervous system impairment in the course of CD.

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 (13)C-octanoic acid breath test to measure gastric emptying. Half emptying time (t1/2) and lag phase (tlag) were calculated. After at least 12 months of a gluten-free diet, celiac patients underwent a new (13)C-octanoic acid breath test. A symptom score was utilized to detect dyspeptic and malabsorption symptoms in all the patients. Results The gastric motility parameters, t1/2 and tlag, 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.

Objectives: Celiac disease (CD) is a systemic immune disorder. We assessed serum levels of adhesion molecules as a marker of endothelial dysfunction in patients with CD at first diagnosis and in those on a gluten-free diet., Methods: Sixty-five patients with CD (mean age 6.74 ± 4.6 years) and 51 age- and sex-matched control patients participated in the present case-controlled, prospective clinical study. Serum levels of vascular adhesion molecule-1, intercellular adhesion molecule-1, endothelial selectin, vascular endothelial cadherin, high-sensitivity C-reactive protein, and homocysteine levels were measured., Results: Average soluble vascular adhesion molecule-1 (CD vs control group: 1320 ± 308 vs 1120 ± 406 ng/mL, P = 0.006), soluble intercellular adhesion molecule-1 (336 ± 99 vs 263 ± 67 ng/mL, P = 0.025), and soluble endothelial selectin (113.9 ± 70 vs 76.9 ± 32 ng/mL, P = 0.007) levels were significantly higher in cases of newly diagnosed CD than in the control group. Soluble vascular adhesion molecule-1 (1050 ± 190 ng/mL) and soluble endothelial selectin (68.7 ± 45 ng/mL) levels in patients with CD, who were fully compliant with a gluten-free diet, were significantly lower than that in those newly diagnosed as having CD (P = 0.003 and P = 0.0012, respectively)., Conclusions: These results show that serum adhesion molecule levels are higher in patients with CD. Some of the risks associated with endothelial dysfunction may be related to CD and these risks can be reduced with an appropriate and fully controlled diet.

Objectives: Response to gluten challenge (GC) is a key feature in diagnostic algorithms and research trials in celiac disease (CD). Currently, autoantibody titers, late responders to GC, and invasive duodenal biopsies are used to evaluate gluten responsiveness. This study investigated the accuracy of serum intestinal-fatty acid binding protein (I-FABP), a marker for intestinal epithelial damage, to predict intestinal damage during GC in patients with CD., Methods: Twenty adult CD patients in remission underwent a two-week GC with 3 or 7.5 g of gluten daily. Study visits occurred at day -14, 0, 3, 7, 14, and 28. Serum I-FABP, antibodies to tissue transglutaminase (tTG-IgA), deamidated gliadin peptides (IgA-DGP), and anti-actin (AAA-IgA) were assessed at each visit. Villous-height to crypt-depth ratio (Vh:Cd) and intraepithelial lymphocyte (IEL) count were evaluated at day -14, 3, and 14. Forty-three CD-serology negative individuals were included to compare serum I-FABP levels in CD patients on a gluten-free diet (GFD) with those in healthy subjects., Results: Serum I-FABP levels increased significantly during a two-week GC. In contrast, the most pronounced autoantibody increase was found at day 28, when patients had already returned to a GFD for two weeks. IgA-AAA titers were only significantly elevated at day 28. I-FABP levels and IEL count correlated at baseline (r=0.458, P=0.042) and at day 14 (r=0.654, P=0.002) of GC. Neither gluten dose nor time on a GFD influenced I-FABP change during GC., Conclusions: Serum I-FABP levels increased significantly during a two-week GC in adult CD patients and correlated with IEL count. The data suggest that serum I-FABP is an early marker of gluten-induced enteropathy in celiac patients and may be of use in both clinical and research settings.

Aim: To evaluate the effectiveness of Native-complex functional food to correct nutritional disorders and to normalize gastrointestinal motor activity in celiac disease (CD)., Methods: 20 CD patients with constipation and metabolic disorders were included in the study (age 31.8?9.5 years, male to female ratio 1:5.3). The diagnosis of CD was confirmed by clinical and anamnestic data, endoscopy, histopathology of duodenal biopsy specimens, HLA-DQ2 and HLA-DQS typing. All patients received Native-complex Fucus jelly (Kelp jelly) within 2 months., Results: At the beginning of the study45% of patients had stools corresponding to the Bristol Stool Form ScaleType 1,40% of patients had Type 2 stools and 15% of patient had Type 3 stools. 15 patients (75%) showed a decrease in fat mass and 13 patients (65%) showed a decrease in fat-free mass indicated by bloimpedance measurement. All patients had low values of total bacterial counts and increased abundance of pathobionts including fungi and viruses in fecal microbiota. Supple- mentary nutrition significantly improved symptoms, intestinal circadian rhythms and stool consistency in CD patients. At the end of the study 70% of patients had daily bowel movements, 30% of patients had stools every other day. The average stool frequency was 5,95 ? 1,80 per week. 80% of patients had Type 4 or Type 5 stools,20% of patients had Type 3 stools according to the Bristol Scale. Supplementary nutrition significantly improved gut microbiota profile., Conclusion: Long-term gluten-free diet in celiac disease leads to a decrease in dietary fiber and polysaccharides consumption and promotes intestinal dysbiosis. Functional foods improve symptoms; stool consistency and gut microbiota profile in adult celiac patients on gluten-free diet.

Based on the results of a comprehensive study of 35 people aged from 19 to 52 years, among them 20 women and 15 men with celiac disease features of their physiological status were studied, reflecting the severity of the disease and quality of life. The diagnosis was based on the clinical and anamnestic data, endoscopy, histomorphological, immunological and genetic exams. Psychophysiological analysis showed that in celiac disease is characterized by the formation reactions with anxiety, anxiety-phobic, neurotic, affective, and hypochondriacal symptoms. The results of the study emphasized the importance of adaptive physiological capacity of the body to build tolerance to the development of psycho-vegetative, hypochondriacaldepressive and other disorders.

Celiac disease (CeD) is one of the most common immune-mediated diseases. Symptoms and disease activity are incompletely controlled by the gluten-free diet, which is currently the only available therapy. Although no therapies are yet approved, there is a growing field of candidates and an improving understanding of the regulatory pathway. In this review, we briefly discuss the epidemiology, pathophysiology, and current treatment paradigm for CeD. We also review the major classes of therapies being considered for CeD and discuss extensively what is known and can be surmised regarding the regulatory pathway for approval of a CeD therapeutic. The coming years will see an increasing number and diversity of potential therapies entering clinical trials and hopefully the first approved agents targeting this significant unmet medical need. Although biomarkers including histology and serology will always be important in therapeutic clinical trials, they currently lack the necessary evidence linking them to improved patient outcomes required for use as primary outcomes for drug approval. For this reason, patient-reported outcomes will likely be primary end points in Phase III CeD trials for the foreseeable future.

There are few reports in the literature where celiac disease presents with tongue manifestations, although atypical presentations of celiac disease are not uncommon. This case report highlights an atypical presentation of celiac disease in an elderly female. Our patient presented to clinic with complaints of a burning tongue for the past two years as well as occasional loose stools and fatigue. Work-up revealed iron deficiency anemia, zinc deficiency and an abnormal celiac panel. Complete symptom improvement was noted by 10 weeks into the initiation of a gluten free diet. Celiac disease can present at any age and should be considered as a differential in findings of malabsorption and gastrointestinal symptoms.

Background & Aims: Refractory celiac disease type II (RCDII) and EATL (Enteropathy Associated T-cell Lymphoma) are (pre)malignant complications of celiac disease (CD). Data on malnutrition and intestinal absorption is lacking in these patients. Therefore, the aim of the study is to comprehensively assess nutritional status and intestinal absorption capacity of patients with RCDII and EATL, compared with data of newly diagnosed CD patients., Methods: Observational study in tertiary care setting in RCDII (n = 24, 63.8 ± 8.2 y), EATL (n = 25, 62.3 ± 5.7 y) and CD patients (n = 43, 45.6 ± 14.8 y). At diagnosis, anthropometry (BMI, unintentional weight loss, fat-free mass index (FFMI), handgrip strength (HGS), nutritional intake, fecal losses and Resting Energy Expenditure (REE)) were assessed., Results: Low BMI (<18.5) was more often observed in RCDII patients than in CD or EATL patients (in 33%, 12% and 12%, respectively, p = 0.029). EATL patients more frequently had unintentional weight loss (>10%) than CD or RCDII patients (in 58%, 19% and 39% of patients, respectively; p = 0.005/0.082). Energy malabsorption (<85%) was detected in 44% and 33% of RCDII and EATL patients, vs 21.6% in CD (NS). Fecal energy losses were higher in RCDII than in CD patients (589 ± 451 vs 277 ± 137 kcal/d, p = 0.017). REE was underestimated by predicted-REE with>10% in 60% of RCDII, 89% of EATL, and 38% of CD patients (p = 0.006). Low FFMI and HGS were detected in one third and two thirds of all patients, respectively., Conclusions: The nutritional status of patients with RCDII and EATL is inferior compared with untreated naïve CD patients at presentation. Both malabsorption as well as hypermetabolism contribute to malnutrition., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Type II refractory celiac disease (RCD), as defined according to the amount of aberrant intraepithelial lymphocytes, is a condition characterized by severe malabsorption syndrome and poor prognosis, with no effective treatment. Based on the regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs), we investigated the feasibility, safety, and efficacy of serial infusions of autologous bone marrow-derived MSCs in a 51-year-old woman with type II RCD. Mesenchymal stem cells were isolated, expanded, and characterized following standard protocols. Monitoring of the patient's malabsorption indexes, mucosal architecture, and percentage of aberrant intraepithelial lymphocytes was scheduled for the time of enrollment, at each infusion, and after 6 months. Determination of mucosal expression of interleukin (IL)-15 and its receptor was also performed. Expansion of MSCs was feasible, and the patient underwent 4 systemic infusions of 2 × 10(6) MSCs/kg body weight 4 months apart, without adverse effects. During the treatment period, she experienced gradual and durable amelioration of her general condition, with normalization of stool frequency, body mass index, laboratory test results, and mucosal architecture. Remarkably, the expression of IL-15 and its receptor almost completely disappeared. Thus, treatment of RCD with serial MSC infusions seems promising, leading to recovery from the life-threatening condition while blocking the IL-15 pathogenic pathway., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: Celiac disease (CD) is a common comorbidity of type 1 diabetes (T1D). Long-term consequences of CD are not completely understood, and adhering to a gluten-free diet is a burden for many patients. We investigated the effect of CD on vascular risk factors in a large cohort of T1D patients aged <20 yr., Research Design and Methods: Within the longitudinal Diabetes Patienten Verlaufsdokumentation (DPV)-diabetes registry, data were analyzed from 59,909 < 20-yr-old T1D patients treated at 392 centers in Germany and Austria. A total of 974 patients with biopsy-proven celiac disease (BPCD) were compared with 28,398 patients without CD with respect to blood pressure (BP), lipids, glycohemoglobin (HbA1c ), body mass index (BMI), and reported smoking behavior., Results: Patients with T1D and BPCD showed significantly lower high-density lipoprotein (HDL) cholesterol levels [median (interquartile range): 53.0 (43.0-62.6) mg/dL] than patients without CD [55.0 (45.0-66.0) mg/dL; p < 0.01; p < 0.001 after adjustment for confounding variables]. Systolic BP was lower in patients with CD [105.5 (100.0-112.5) mmHg] than in patients without CD [110.0 (102.0-117.0) mmHg; p < 0.0001; p < 0.001 after adjustment]. There were no significant differences regarding smoking behavior, BMI, or HbA1c . In a subgroup of 335 patients with BPCD, HDL cholesterol was measured 1 yr after diagnosis of CD:HDL increased by 8% (p < 0.01)., Conclusion: Young people with T1D and CD have lower HDL cholesterol values than patients without CD. As low HDL cholesterol is associated with vascular risk, our findings support screening for CD and monitoring of HDL cholesterol in young people with T1D., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although many people have symptoms of celiac disease, it can take a while to diagnose. Villous atrophy may be present long before any gastrointestinal symptoms. An important point to acknowledge is that celiac disease could be identified earlier in some women with a positive family history. The disease also could be the cause of some women's reproductive problems. Primary care providers, using comprehensive history taking, are in the unique position to identify individuals who may have celiac disease, assist women in gaining knowledge about a gluten-free diet, order diagnostic testing, and refer to a gastroenterologist. The positive change in fertility with a simultaneous improvement of nutrient deficiencies shortly after adopting a gluten-free diet indicates a possible link between such nutrients and sex hormone function. High levels of homocysteine, which can negatively impact fertility, have also been linked to individuals with problems, such as celiac disease, that decrease vitamin B12 absorption. The purpose of this article is to review the literature and the evidence-based care guidelines for comprehensive screening, diagnostics, and pathophysiology of celiac disease, with a specific focus on the female reproductive system, anemia management, and gluten-free diet integration.

Celiac disease (CeD) is a complex immune-mediated disease. Genetic studies have implicated 43 predisposing loci that collectively explain some 50% of the genetic variance in CeD. More than ∼90% of CeD-associated single nucleotide polymorphisms (SNPs) localize to the non-coding genome, which we need to better understand to translate genetic knowledge into clinical practice. New genomic technologies and resources are permitting a systematic analysis of the functional elements in the non-coding part of the genome. Here we explain how investigating the regulatory and epigenomic landscape will help to pinpoint the cell types involved in CeD, and the driver genes and gene regulatory networks that are affected by CeD-associated SNPs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Endocytosis is a fundamental cell biological process, which carries out essential functions in a polarized epithelial cell such as enterocytes provided with a huge surface area of the brush border membrane. Major tasks of enterocytes, which are regulated by endocytic signals, are digestion and absorption of nutrients and drugs/pharmacological agents, barrier permeability to microorganism, toxins and antigens, and transcytotic crosstalk between intestinal lumen and lamina propria cells with access to the circulation.Investigations on inflammatory bowel diseases such as food allergy, celiac disease, Crohn's disease, and ulcerative colitis focus on immune processes originating within enterocytes as antigen presenting cells. Thus the initiation of oral tolerance, that is, the binding of food antigens to MHC class II proteins, might be localized within late endosomes of enterocytes. Furthermore, the late endosomal compartment of enterocytes seems to be involved in the processing of luminal antigens during the pathogenesis of celiac disease and inflammatory bowel diseases. Investigations of inherited diseases such as microvillus inclusion disease have revealed a pathogenetic defect in the autophagocytotic and/or recycling pathway of enterocytes.Our progress in the cell and molecular biological understanding of the endocytosis and the methodical opportunities of translational research offer now new therapeutic options for patients suffering from endocytosis-related diseases of enterocytes.

Objectives: The aim of the study was to assess health-related quality of life (HRQOL) using the Coeliac Disease Dutch Questionnaire (CDDUX) in Spanish children with coeliac disease., Methods: The CDDUX was cross-culturally adapted according to international consensus guidelines. HRQOL was assessed in coeliac members of the Madrid Coeliac Association ages 8 to 18 years using the adapted CDDUX. Cronbach α coefficient was determined as a measure of intraquestionnaire reliability and intraclass correlation coefficients as a measure of reliability between scores awarded by children and parents. Demographic and clinical variables associated with HRQOL were also assessed., Results: A total of 1602 children of 3122 registered Madrid Coeliac Association members ages 8 to 18 years were invited to participate. The questionnaire was completed by 480 families (30%): 214 only by parents, 214 by parents and their children, and 52 only by children. Cronbach α coefficient for the total score for parents was 0.90, and for children 0.88 (0.75-0.90 by scales). Mean total (standard deviation [SD]) HRQOL scores in children and parents were 55.5 (SD 12.7) and 53.89 (SD 12.19), respectively, with no differences detected in paired comparisons between the 2 groups. Significantly worse HRQOL scores were recorded in children showing a nonclassical clinical presentation, in those not adhering to treatment and in those reporting difficulties in following the diet., Conclusions: The CDDUX questionnaire emerged as reliable for use in Spanish children with celiac disease. Overall, both children and parents felt the disease had no substantial negative impacts on patient HRQOL.

Gluten ataxia (GA) has customarily been considered to be the main neurological manifestation of celiac disease (CD). In recent years, the condition of non-celiac gluten sensitivity (NCGS) has been defined, which includes some patients who are not considered "true celiacs." We performed a comparative clinicopathological study of these three entities. We studied 31 GA, 48 CD and 37 NCGS patients, prospectively in the same center for a period of 7 years. The protocol study included two serological determinations for gluten sensitivity [anti-gliadin IgA and IgG (AGA) and anti-tissue transglutaminase IgA (TG) antibodies], HLA-DQ2 typing, and duodenal histological assessment. Demographics and investigative findings were compared. Females were 55 % in GA, 75 % in CD (p < 0.001), and 47 % in NCGS (N.S.). GA patients were older (59 ± 14 years) than CD (43 ± 13 years) and NCGS (41 ± 8 years) groups (p < 0.001). AGA positivity was higher in GA (100 %) than in CD (48 %) groups (p < 0.001), but similar to NCGS patients (89 %; N.S.); TG positivity was lower in GA (3.2 %) than in CD (33.3 %; p < 0.001), but similar to NCGS (2.7 %; N.S.). DQ2 (+) was lower in GA (32.2 %) than in CD (89.6 %; p < 0.001), but similar to NCGS (29.7 %; N.S.). Lymphocytic enteritis (Marsh type 1) was lower in GA (9.6 %) than in CD (66.7 %; p < 0.001), but similar to NCGS (10.8 %; N.S.). The other gluten sensitivity-related characteristics measured were different to CD patients, but very close to NCGS. We conclude that GA patients are better classified within the NCGS group, than within CD.

Compromised intestinal calcium absorption affecting a deterioration of bone state is a sign of coeliac disease. Experimental calcium-fortified gluten-free bread (GFB) of improved calcium bioavailability could increase calcium content in the diets of coeliac disease patients, allowing them to obtain the amount of calcium they need for therapeutic use. Prebiotics, including inulin-type fructans (IFs) have a beneficial effect on calcium bioavailability. In the present study, the in vitro model composed of the intestinal-like Caco-2 cells and the human intestinal bacteria (Lactobacillus, Enterococcus and Enterobacteriaceae) were used to analyse the effect of inulin and fructooligosaccharide (FOS) of different chain lengths, on calcium uptake and absorption from experimental GFB. Analysed IFs, especially short-chain FOS, significantly (p < 0.05) increased cellular calcium uptake from GFB digest and stimulated the intestinal bacteria applied in the cultures to the intensive synthesis of organic acids. In particular, the concentration of butyric, valeric and lactic acids increased significantly. Similarly, in the calcium absorption experiment, IFs increased the cellular calcium retention but concomitantly reduced its content in basolateral filtrates. The results obtained suggest that the applied IFs affected differentially calcium uptake and absorption from the experimental calcium-enriched GFB, therefore a further study is needed to assess whether these observations made in vitro contribute to IF effects on calcium absorption from experimental GFB in vivo.

Objectives: Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms without enteropathy that symptomatically benefit from gluten-free diet (GFD). Little is known about its pathophysiology, propensity to neurological manifestations, and if these differ from patients with coeliac disease (CD). We investigated the clinical and immunological characteristics of patients presenting with neurological manifestations with CD and those with NCGS., Methods: We compared clinical, neurophysiological, and imaging data of patients with CD and NCGS presenting with neurological dysfunction assessed and followed up regularly over a period of 20 years., Results: Out of 700 patients, 562 were included. Exclusion criteria included no bowel biopsy to confirm CD, no HLA type available, and failure to adhere to GFD. All patients presented with neurological dysfunction and had circulating anti-gliadin antibodies. Out of 562 patients, 228 (41%) had evidence of enteropathy (Group 1, CD) and 334 (59%) did not (Group 2, NCGS). The most common neurological manifestations were cerebellar ataxia, peripheral neuropathy, and encephalopathy. There was a greater proportion of patients with encephalopathy in Group 1 and with a greater proportion of neuropathy in Group 2. The severity of ataxia did not differ between the two groups. Patients in Group 1 had more severe neuropathy. All patients from both groups responded to gluten-free diet. Anti-tissue transglutaminase (TG2) antibodies were found in 91% of patients in Group 1 and in 29% of patients in Group 2. Comparison between those patients in Group 2 with HLA-DQ2/DQ8 and those without as well as those with positive TG2 compared with those with negative TG2 antibodies identified no differences within these subgroups. Serological positivity for TG6 antibodies was similar in the two groups (67 and 60%)., Conclusions: The neurological manifestations of CD and NCGS are similar and equally responsive to a GFD suggestive of common pathophysiological mechanisms.