An updated overview of spectrum of gluten-related disorders: clinical and diagnostic aspects.

The incidence of gluten-related disorders (GRDs) continues to increase and its global prevalence is estimated at approximately 5% of the population. Celiac disease (CD), dermatitis herpetiformis (DH), gluten ataxia (GA), wheat allergy (WA), and non-celiac gluten sensitivity (NCGS) are the five major GRDs that present with a wide range of clinical manifestations. The diagnosis of GRDs can be challenging because the typical and atypical clinical manifestations of the GRDs overlap. In this review, the current definitions of gluten-related disorders, focusing on their clinical features, diagnostic and therapeutic approaches are presented. We concluded that GRDs are usually diagnosed using a combination of clinical features, serological tests, and histopathological findings. Treatment usually involves dietary modification.

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett's esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS: We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS: Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS: We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Elemental diets role in treatment of high ileostomy output and other gastrointestinal disorders.

Elemental diet (ED) has been used widely in the treatment of gastrointestinal disorders, especially with the management of Crohn's disease. This modality of diets provides all essential nutrients, and contains protein in the form of free amino acids that are theoretically easily absorbed. High output ileostomies are a rare but important complications of stoma formation following bowel surgery. Treatments could be challenging and include anti-diarrhoeals, octreotide and proton pump inhibitors. There is very little research regarding the use of elemental diets in the treatment of patients with post-operative high ileostomy outputs. Adequate management of high output ileostomies might prevent significant morbidity. In this case report, we describe a patient who underwent a subtotal colectomy for ulcerative colitis complicated by refractory high ileostomy output despite maximal standard medical therapy for years. The ileostomy output was dramatically reduced following the introduction of an elemental diet. This case suggests a possible role for the introduction of an elemental diet in the management of high output ileostomies. Besides presenting this case with high output ileostomy, we reviewed the role of ED in other gastrointestinal disorders.

The role of infectious mediators and gut microbiome in the pathogenesis of celiac disease.

Celiac disease (CD) is an immune disorder that is associated with gluten sensitivity in people who are genetically predisposed. In celiac disease, food containing gluten mounts inflammatory response that results in villous atrophy in small bowel and increased permeability. This disorder is not only related to complications in the small bowel, but also has association with manifestations outside the GI tract. Small bowel mucosal immunity, exposed to infectious agents, is affected by CD; therefore, it is likely that patients with untreated celiac disease are more susceptible to infectious diseases. It is possible that sensitivity to gluten increases in patients infected with infectious diseases, and consequently infection may trigger CD in susceptible individuals. It is likely that, due to reduced immunity following the loss of intestinal villi, viral, bacterial, and parasitic infections develop faster in celiac disease patients and systemic complication occur more frequently. In addition, increased permeability, changing the microbiota following the chronic inflammation of the small intestine and abnormal immunological reactions are associated with celiac disease. PubMed, Medline, Google scholar, SID, and Magiran were searched for full text articles published between 1999 and 2014 in Persian and English. The associated keywords were used, and papers, which described particularly the impact of infectious agents on celiac disease, were selected. In this review, we have focused on the role of infectious agents and gut microbiota in the pathogenesis of celiac disease.

Recent advances in oesophageal diseases.

Dong Y, Qi B, Feng XY, Jiang CM. Meta-analysis of Barrett's esophagus in China. World J Gastroenterol 2013;19(46):8770-8779 The disease pattern of Barrett's esophagus (BE) in China is poorly characterised particularly in comparison with other developed countries. This meta-analysis of 3873 cases of BE collated from 69 clinical studies conducted in 25 provinces between 2000 and 2011 investigated the epidemiology and characteristics of BE in China compared to Western countries. The total endoscopic detection rate of BE was 1.0% (95%CI: 0.1%-1.8%) with an average patient age of 49.07 ± 5.09 years, lower than many Western countries.The authors postulate this may be attributed to environmental risk factor variation, distinct genetics and different medical practice including diagnostic criteria for BE and expertise in endoscopy. This study identified a 1.781 male predominancefor BE in China, consistent with Western reports. Short-segment BE accounted for 80.3% of cases with island type and cardiac type the most common endoscopic (44.8%) and histological (40.0%) manifestations respectively. Of the 1283 BE cases followed up for three to 36 months the incidence of esophageal cancer was 1.418 per 1000 person-years, lower than the incidence reported in Western countries. Lee HS, Jeon SW. Barrett esophagus in Asia: same disease with different pattern. ClinEndosc 2014;47(1):15-22 Barrett's esophagus (BE) is a common, pre-cancerous condition characterised by intestinal metaplasia of squamous esophageal epithelium usually attributed to chronic gastric acid exposure. This review article explores important differences in the disease pattern of BE between Asian and the Western countries. Overall the prevalence of BE is lower in Asia compared to the West with a greater proportion of short-segment type. The authors identify great variability in the endoscopic and pathologic diagnostic criteria for BE. Many of the studies in Asian countries did not use a standardised four-quadrant biopsy protocol which may have led to an underestimation of BE prevalence. The review highlights an increasing incidence of esophageal adenocarcinoma in the West but unclear disease trend in Asia with inter-country variability. Similarly in Asian and Western countries BE is associated with the presence of hiatus hernia, advancing age, male gender, alcohol consumption, smoking, abdominal obesity and longer duration of gastro-esophageal reflux disease. The authors postulate that Helicobacter pylori infection, more prevalent in Asia than the West, may have a protective effect on BE. There is a need for larger, prospective studies to further clarify the disease pattern of BE in Asian countries. Clearly standardisation of the diagnostic process for BE is important to validate the differences in disease trends between Asian and Western countries. Kiadaliri AA. Gender and social disparities in esophagus cancer incidence in Iran, 2003-2009: a time trend province-level study.Asian Pac J Cancer Prev 2014;15(2):623-7 Esophageal cancer (EC) is a major cause of morbidity and mortality particuarly in Iran where the incidence rate exceeds the global average. An understanding of the factors influencing the province-specific incidence of EC in Iran is important to inform disease-prevention strategies and address health inequalities. This ecological study used cancer registry data to investigate the relationship between gender and social class and the incidence of EC in Iran at province-level between 2003 and 2009. The age standardised incidence rates (ASIR) of EC were greatest in the Northern provinces of Iran, specifically Razavi Khorasan in males and Kordestan in females. Overall the EC incidence did not significantly differ according to gender. Interestingly, during the study period the ASIR increased by 4.6% per year in females (p=0.08) and 6.5% per year in males (p=0.02). This may reflect increasing rates of establised risk factors for EC including obsesity and gastro-esophageal reflux disease alongside more vigilant recording of new cases. Social class was inversely associated with the ASIR of EC regardless of gender which may be attributed to class differences in risk factor distribution particularly smoking, diet and obesity. An appreciation for the limitations of an epidemiological study is important when interpreting results which should be further evaluated in future studies. Islami F et al.Determinants of gastroesophageal reflux disease, including hookah smoking and opium use- A cross-sectional analysis of 50,000 individuals. PLoS One 2014;9(2):e89256 Gastroesophageal reflux disease (GERD) is a highly prevalent cause of gastrointestinal symptoms worldwide incurring great cost to the primary and secondary healthcare sectors. An improved understanding of the factors which influence GERD symptoms in low- to medium- income countries may inform public health initiatives. This study analysed prospective data from the Golestan cohort study, primarily established to investigate determinants of upper gastrointestinal cancers, toexplore the risk factors influencing GERD symptoms (regurgitation and/or heartburn) in 50,045 individuals aged 40-75 years in Golestan Province, Iran enrolled between 01/2004 and 06/2008.Of note, 39.12% of individuals denied ever experiencing GERD symptoms. A further 19.89% reported at least once weekly GERD symptoms with 11.83% experiencing daily symptoms. Severe symptoms, defined as disturbing daily work or sleep, were recorded by 11.33% of individuals. Separately the occurrence of daily GERD symptoms and severe symptoms were inversely associated with male gender (OR 0.36, 95% CI 0.33-0.39 both), level of formal education (p=0.01 and p=0.001 respectively), wealth score (p<0.001 both) and regular nass chewing (OR 0.86, 95% CI 0.75-0.98 and OR 0.87, 95% CI 0.76-0.99 respectively)and were positively associated with body mass index (p<0.001 both), intensity of physical activity (p=0.04 both), cigarette pack years (p<0.001 both), alcohol consumption (OR 1.36, 95% CI 1.13-1.64 and OR 1.53, 95% CI 1.28-1.83 respectively) and opium use (OR 1.82, 95% CI 1.67-1.99 and OR 1.70, 95% CI 1.55-1.87 respectively).In addition hookah smoking had a borderline significant correlation with mild and moderate severity GERD symptoms in individuals who had never smoked cigarettes (OR 1.41, 95% CI 1.00-1.99 and OR 1.25, 95% CI 0.99-1.57 respectively). Overall this large study contributes useful data to inform the prevention and management of GERD symptoms particularly regarding the use of hookah, opium and nass which was previously unclear. Barbera M et al. The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation. Gut 2014;0:1-9. doi:10.1136/gutjnl-2013-306171 Current knowledge on human esophageal tissue homeostasis and injury repair is derived predominantly from murine models and hence may be inaccurate due to cellular and architectural differences. This study used 3D imaging in conjunction withstaining for cell lineage markers to investigate the cellular mechanisms involved in homeostasis of the normal human squamous esophagus in 10 participants undergoing esophagectomy for esophageal cancer. The self-renewal potential of cell subpopulations was also assessed using in vitro and in vivo assays. A decreasing gradient of cell proliferation was observed from the inter-papillary basal layer to the tip of the papilla where there was no evidence of mitosis. The expression ofß1-integrin, a putative stem cell marker, was consistent throughout the basal layer and therefore the entire basal layer can be considered undifferentiated. Quiescent ß1-integrin/CD34-positive cells which failed to stain for CD45, S-100 or F4-80were identified at the tip of the papilla suggesting this is an extension of the basal layer. Contrary to previous data, this study found progenitor cells widely distributed in human esophageal tissue and included already differentiated epithelial cells. This insight into esophageal homeostasis may inform future studies exploring the pathological mechanisms underpinning homeostatic disruption in disease states such as Barrett's esophagus. Papers were prepared by: Drs Ishfaq Ahmad and Luke Materacki, Department of Medicine, Alexandra Hospital, Redditch, UK.

Type 1 diabetes mellitus and gluten induced disorders.

Over the last five decades the association between coeliac disease and other autoimmune disorders such as autoimmune thyroid disease or diabetes mellitus type 1 has been well established through many studies and to this day is subject to on-going clinical and scientific investigation worldwide. While no link has been established between celiac disease and type-2 diabetes mellitus, coeliac disease is common in patients with type 1 diabetes. The improvement of symptoms in patients with both conditions through dietary intervention, in the form of a gluten free diet, has been widely described within the literature. Our objectives were to review and synthesise the current knowledge on the nutritional treatment for patients with both conditions.

The role of Helicobacter pylori and CagA in response to treatment in Iranian Gastroesophageal Reflux Diseases patients.

AIM: This study was conducted to evaluate the influence H. pylori infection and anti-CagA status on the efficacy of Omeperazole 20 m.g. b.d. for patients with endoscopic oesophagitis. BACKGROUND: The influence of Helicobacter pylori (H. pylori) infection and its virulent strain (cytotoxin-associated gene A: CagA) has not been evaluated on efficacy of treatment for patients with erosive oesophagitis in Iran. PATIENTS AND METHODS: One hundred and ten patients (55 H. Pylori positive and 55 H. Pylori negative) with endoscopic evidence of oeosphagitis were enrolled in this interventional study and treated with Omeprazole 20 m.g. b.d. Healing was assessed at repeat endoscopy after 8 weeks of treatment. H. Pylori infection and anti-CagA-IgG (immunoglobulin G) antibodies were determined for each subject by the rapid urease test, pathological assessment and ELISA. RESULTS: At repeat endoscopy, following 8 weeks of Omeprazole 20 m.g. b.d. therapy, endoscopic healing of oesophagitis had occurred in 32 % of the HP +ve patients and 23 % of the HP -ve patients (chi square p < 0.01). Among the HP +ve endoscopic healing occurred resolved in 11 (32.4 %) of the CagA +ve patients and 19 (90.5 %) of the CagA -ve patients. This difference was significant (chi-square p <0.001). CONCLUSION: H. pylori infection and the CagA virulence factor are associated with an increased rate of healing amongst patients with endoscopic oesophagitis treated with Omperazole 20 m.g. b.d. compared to patients without H. pylori infection.

Microscopic Enteritis; clinical features and correlations with symptoms.

AIM: To assess the clinical characteristic of CD as well as correlation of symptoms and the degrees of intestinal mucosal lesions in Iranian children. BACKGROUND: Microscopic Enteritis (Marsh 0-II) is associated with malabsorption. PATIENTS AND METHODS: From August 2005 to September 2009, 111 cases with malabsorption and classical gastrointestinal symptoms were evaluated. RESULTS: The mean (±SD) age of children with CD was 4.9±3.5 years (range, 6 month - 16 years) and the mean duration of symptoms was 8 ± 20.5 months. 50 cases (45%) were female and 61 cases (55%) were male. The most common clinical presentation was failure to thrive in 72%, chronic diarrhea in 65.8% and Iron deficiency anemia in 59.5%. Sensitivity of EMA was 100% in patients with Marsh IIIb and Marsh IIIc. EMA was also positive in 77% of cases with Marsh 0, 18% in Marsh I, 44% in Marsh II and 81.8% in patients with Marsh IIIa. CONCLUSION: Histopathology did not reflect the severity of gluten sensitivity. This would suggest that the degree of intestinal mucosal damage might not be a reliable prognostic factor. Significant symptoms can be present with minor histological change on biopsy.

Clinical and histological presentation of Helicobacter pylori and gluten related gastroenteropathy.

BACKGROUND: Celiac disease has been reported to be associated with gastric abnormalities. The aim of this study was to assess the relationship between the prevalence of celiac disease and Helicobacter pylori infection in an Iranian population of 250 patients. METHODS: Biopsies were taken from the gastric antrum and duodenum. Morphology and histology were evaluated using the updated Sydney system and modified Marsh criteria, respectively. To simplify the interpretation of gastric lesions we classified gastritis in macroscopic and microscopic stages. Serology for anti-tissue transglutaminase antibody was performed to determine the presence of celiac disease. RESULTS: Among 250 patients, 232 (93%) had histological evidence of Helicobacter pylori infection. Histological abnormalities (Marsh I to IIIc) were present in 24 (10%). Of 24 patients, 20 (83%) with histological abnormalities were infected with Helicobacter pylori. Of 250 patients, 25 (10%) had a positive anti-tissue transglutaminase antibody. Of 25 anti-tissue transglutaminase antibody positive patients, 9 (3.6%) had microscopic and macroscopic enteritis (Marsh I to IIIc). CONCLUSIONS: Clinical presentation of celiac disease was not distinguishable from cases infected with Helicobacter pylori. Histology, even in patients with positive serology, was non-specific and unhelpful. We found a high prevalence of Helicobacter pylori infection and chronic gastritis, but neither was associated with celiac disease, in agreement with studies in Western populations.

Microscopic enteritis and pathomechanism of malabsorption.

Microscopic enteritis (ME) is the stage of microscopic and sub-microscopic changes (microenteropathy) associated with the symptoms of gluten sensitive enteropathy leading to micronutrient deficiencies. It is characterized by subtle mucosal abnormalities without prominent inflammation, villous effacement, erosions or ulcerations on conventional light microscopy. The intraepithelial lymphocytes are usually in normal range <25/100 enterocytes (microenteropathy) or increased (lymphocytic enteritis). ME is the entity behind atypical forms of CD previously known as potential and latent CD. Systemic inflammation predominantly is found to be engaged in pathophysiology of micro-nutrient deficiency even in absence of macroscopic mucosal changes.