ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation.

OBJECTIVES: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. DESIGN: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected. RESULTS: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion. CONCLUSION: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.

BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia.

OBJECTIVES: Barrett's esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD). METHODS: We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations. RESULTS: In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients. CONCLUSIONS: In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.

Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease.

Biologic agents have now been used in the management of inflammatory bowel disease (IBD) for many years where experience, expertise and confidence in their use has developed over time. In the United Kingdom, there are well established guidelines and recommendations for both single agent biologic treatments, and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy. In recent times, there has been increasing interest and experience using dual biologic therapy (DBT) in IBD, primarily in difficult to treat and refractory cases with high disease burden. However, published data on use, experience and safety profiles is limited and large-scale studies remain low in number in this developing area. We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.

Gastrointestinal and liver adverse effects of anti-tumoral immune therapy: from recognition to treatment.

Anti-tumoral immune therapy consists of monoclonal antibodies that target intra-cellular immune checkpoints-which under normal circumstances, act as regulators of T-cell immunity. By serving as inhibitors of cellular checkpoints, monoclonal antibodies stimulate the immune system thus augmenting the body's response against cancer. These immune-enhancers or stimulators have revolutionized the treatment of malignancy as they continue to show improvement in the overall survival of cancer patients. Currently, in the United States, six immune checkpoint inhibitors are approved for the treatment of a variety of solid tumors (1). As these checkpoint inhibitors are relatively new, only a scant amount of literature is available regarding both their adverse effects and management thereof. In addition, as newer antibodies are being developed, and expected to be enlisted among the armamentarium of cancer chemotherapeutic agents-the need to understand their toxicity and adverse effects is of paramount importance. Herein, we review some of the gastrointestinal and liver sequelea secondary to the usage of immunotherapeutic checkpoint inhibitor agents in cancer chemotherapy, as well as present the diagnosis and recommended treatment strategies for their adverse effects.

Effect of inflammatory bowel disease treatments on patients with diabetes mellitus.

As medical care progresses and the number of patients with chronic conditions increases there is the inevitable challenge of managing patients with multiple co-morbidities. Inflammatory bowel disease (IBD) is an umbrella term for are inflammatory conditions affecting the gastrointestinal tract, the two most common forms being Ulcerative Colitis and Crohn's disease. These diseases, usually diagnosed in young adults, exhibit a relapsing and remitting course and usually require long-term treatment. IBD can be treated with a number of topical and systemic treatments. We conducted a review of the current published evidence for the effects these medications can have on diabetes mellitus (DM) and glycaemic control. Searches were conducted on medline and embase with a timeframe from 1947 (the date from which studies on embase are recorded) to November 2020. Suitable publications were selected and reviewed. Current evidence of the impact of aminosalicylates, corticosteroids, thiopurines, and biologic agents was reviewed. Though there was limited evidence for certain agents, IBD medications have been shown to have an effect of DM and these effects should be considered in managing patients with dual pathologies. The effects of steroids on blood sugar control is well documented, but consideration of other agents is also important. In patients requiring steroids for Ulcerative Colitis, locally acting steroid agents delivered rectally may be preferred to minimise side effects in those with distal bowel Ulcerative Colitis. A switch to other agents should be considered as soon as possible in people with diabetes to limit the impact on glycaemic control. 5-aminosalicylates appear to play a role in the reduction of hemoglobin A1c (HbA1c), although the literature suggests these may be falsely low readings. Consequently, monitoring of people with diabetes on these agents may require daily monitoring of capillary blood sugars rather than relying simply on HbA1c; for example fructosamine performed 3-6 monthly, although this risks missing the rise in readings. There is only limited evidence of the effects of thiopurines on diabetes and further investigation is needed into the possible relationship between them. However, given the current available evidence it may be preferable to commence patients with diabetes on thiopurines as soon as possible, whilst also monitoring for side effects such as pancreatitis. There appears to be more evidence supporting a link between tumor necrosis factor-α inhibitors and DM. Both infliximab and adalimumab have evidence suggesting that both can cause reduced blood sugar levels. Further studies on the effects of the various biological agents mentioned are required alongside any novel biologic therapy and the impact of dual biologic therapy in the future.

Anxiety Symptoms in Adult Celiac Patients and the Effect of a Gluten-Free Diet: An Iranian Nationwide Study.

INTRODUCTION: Psychiatric disorders, especially anxiety, are considered extraintestinal manifestations of celiac disease (CD). OBJECTIVE: This study aims to evaluate the level of anxiety in treated patients with CD in Iran. METHODS: A total of 283 CD patients (190 female, 93 male) were enrolled in a study during 2016-2018 from 9 centers in Iran. The Zung Self-Rating Anxiety Scale questionnaire was completed. The anxiety index was calculated. Also, demographic data and the duration of treatment with a gluten-free diet (GFD) were recorded. Data were analyzed by SPSS version 20. RESULTS: Anxiety symptoms were reported in 67.8% of patients. Female patients had a higher anxiety index than male patients. Duration of treatment with a GFD did not influence the anxiety index (17.3% were on a GFD for <1 year, 33.6% for 1-2 years, and 49.1% had GFD for >2 years; p = 0.86). CONCLUSIONS: These results suggest that anxiety symptoms are common among patients, especially females, with CD in Iran and GFD duration has no effect on their improvement.

Lack of health care professional's awareness for management of celiac disease may contribute to the under diagnosis of celiac disease.

AIM: We assessed the knowledge of physicians regarding diagnosis and treatment of celiac disease (CD). BACKGROUND: Specialists as the main therapist group of CD patients may play crucial role in the diagnosis and treatment of CD. Therefore, training and ensuring their capabilities is important. METHODS: The population was specialists including Gastroenterologist, GI fellow, consultants, residents and general practitioners graduated in Medical Sciences Universities in Iran. The examination was the experts made and aimed to assess the educational needs of physicians and explore their failures in the diagnosis and treatment of CD with the key feature approach. Data was collected using a questionnaire that its validity and reliability was confirmed by experts (r = 91.6%). The total score was 150 with the classification of participants to the following categories: good (112- 150), intermediate (39-112) and weak ( ≤38). RESULTS: Out of 300 participants, 197 questionnaires were returned (Response rate = 66%). The mean age of the participants was 42.67 years (SD = 7.9 years) with majority were male (63.6%). Average score of participates who had less than three year's experience was significantly higher than others (P≤0.05). Only 12.1% and 9.8% of specialists have got the excellent score for diagnosis and treatment, respectively. CONCLUSION: It may conclude that specialists have had performance gap and around 90% needed training based on the principles of instructional design in order to improve their knowledge and skills to do and practice their assigned tasks. Therefore, development of training packages according to the principles of instructional design is suggested.

The effect of education on the knowledge of patients with celiac disease.

AIM: The aim of this study was to investigate the effects of education on patients' knowledge of celiac disease, in an Iranian population. BACKGROUND: Education can increase patients' knowledge regarding their disease, leading to improvements in their health. METHODS: This cross-sectional study was conducted on patients who had been diagnosed with celiac disease. The patients attended an educational meeting in September, 2016. During the educational meeting information regarding the epidemiology, diagnosis and treatment of celiac disease was provided to the study subjects. Each patient completed a questionnaire regarding celiac disease before and after the educational meeting. The questionnaires were scored. Study data was analyzed using SPSS version 20. RESULTS: 90 patients were recruited (69 [77%] were women). Analysis of questionnaire responses showed that except for awareness of cross contamination with gluten, the education meeting significantly increased the knowledge of patients with celiac disease regarding epidemiology, diagnosis and treatment (p=0.001). CONCLUSION: The result of this study shows that an educational meeting can increase the knowledge of CD patients in treatment. Increasing patients' knowledge may lead to improvements in patients' health.

Barrett's surveillance is worthwhile and detects curable cancers. A prospective cohort study addressing cancer incidence, treatment outcome and survival.

OBJECTIVES: To establish whether Barrett's surveillance is worthwhile in terms of incident cancers and whether outcomes are favourable. METHODS: A prospective non-randomized single centre Barrett's surveillance programme commencing 1 January 1992 through 1 April 2001 (112 months). Oesophagectomy recommended for high-grade dysplasia or carcinoma. RESULTS: Of 23 725 patients, 506 were diagnosed as Barrett's oesophagus and 24 (5%) had carcinoma at diagnosis (prevalence cancers). One hundred and twenty-six patients had at least one surveillance endoscopy; 248 surveillance endoscopies were performed spanning 338 patient years. Thirteen surveillance (incidence) cancers were detected. In the prevalence cancer group 12 of the 24 patients underwent oesophagectomy. Lymph nodes showed evidence of metastases in 10 of the 12 resections. In the surveillance group 10 patients underwent oesophagectomy. Lymph nodes showed evidence of metastases in one of the 10 resections. One patient in the prevalence cancer group (4% of group; 8% of those operated) and seven patients in the surveillance cancer group (54% of group; 70% of those operated) remain disease-free more than 2 years post-oesophagectomy. The cost per cancer cured is 7546 pounds. One curable cancer was detected per 48 patient years of surveillance. CONCLUSIONS: Few Barrett's surveillance studies have addressed treatment outcomes and survival. In our study 5% of Barrett's patients undergoing endoscopy have prevalent cancers. If surveillance is performed, 4% per year develop cancer and 2% per year are cured of their cancers. Most surveillance cancers are operable and of those undergoing surgery 70% are cured. Barrett's surveillance is cost-effective compared with other cancer screening or surveillance initiatives.

H.pylori associated with iron deficiency anemia even in celiac disease patients; strongly evidence based but weakly reflected in practice.

Inflammation can lead to malabsorption of important micronutrients such as iron. Malabsorption and nutritional deficiency can be caused by a variety of pathological and environmental factors causing a range of other symptoms commonly caused by both H. pylori infection and coeliac disease (CD). National guidelines suggest the routine taking of duodenal biopsies to exclude CD when investigating patients for iron deficiency anemia (IDA). Studies suggest that in absence of positive antibodies, IDA is rarely caused by CD. Recent British Society of Gastroenterology guidelines discourage the routine duodenal biopsies in low risk cases but despite this guidance, taking duodenal biopsies for IDA is a common practice. Many studies have reported that H. pylori infection is associated with IDA even in patients with CD. In countries with low H. pylori prevalence we still detect more H. pylori than CD standing behind IDA. Despite the strong association between IDA and H. pylori, taking biopsies to diagnose H. pylori infection is not usually a routine part of the diagnostic workup to identify the etiology of IDA. In this review we will discuss the impact of H. pylori in IDA and highlight the possible gaps in identifying the IDA etiology.

Microscopic enteritis: Bucharest consensus.

Microscopic enteritis (ME) is an inflammatory condition of the small bowel that leads to gastrointestinal symptoms, nutrient and micronutrient deficiency. It is characterised by microscopic or sub-microscopic abnormalities such as microvillus changes and enterocytic alterations in the absence of definite macroscopic changes using standard modern endoscopy. This work recognises a need to characterize disorders with microscopic and submicroscopic features, currently regarded as functional or non-specific entities, to obtain further understanding of their clinical relevance. The consensus working party reviewed statements about the aetiology, diagnosis and symptoms associated with ME and proposes an algorithm for its investigation and treatment. Following the 5(th) International Course in Digestive Pathology in Bucharest in November 2012, an international group of 21 interested pathologists and gastroenterologists formed a working party with a view to formulating a consensus statement on ME. A five-step agreement scale (from strong agreement to strong disagreement) was used to score 21 statements, independently. There was strong agreement on all statements about ME histology (95%-100%). Statements concerning diagnosis achieved 85% to 100% agreement. A statement on the management of ME elicited agreement from the lowest rate (60%) up to 100%. The remaining two categories showed general agreement between experts on clinical presentation (75%-95%) and pathogenesis (80%-90%) of ME. There was strong agreement on the histological definition of ME. Weaker agreement on management indicates a need for further investigations, better definitions and clinical trials to produce quality guidelines for management. This ME consensus is a step toward greater recognition of a significant entity affecting symptomatic patients previously labelled as non-specific or functional enteropathy.

The role of celiac disease in severity of liver disorders and effect of a gluten free diet on diseases improvement.

CONTEXT: Celiac disease (CD) is defined as a permanent intolerance to ingested gluten. The intolerance to gluten results in immune-mediated damage of small intestine mucosa manifested by villous atrophy and crypt hyperplasia. These abnormalities resolve with initiationa gluten-free diet. EVIDENCE ACQUISITION: PubMed, Ovid, and Google were searched for full text articles published between 1963 and 2012. The associated keywords were used, and papers described particularly the impact of celiac disease on severity of liver disorder were identified. RESULTS: Recently evidence has emerged revealingthat celiac disease not only is associated with small intestine abnormalities and malabsorption, but is also a multisystem disorder affecting other systems outside gastrointestinal tract, including musculo-skeletal, cardiovascular and nervous systems. Some correlations have been assumed between celiac and liver diseases. In particular, celiac disease is associated with changes in liver biochemistry and linked to alter the prognosis of other disorders. This review will concentrate on the effect of celiac disease and gluten-free diets on the severity of liver disorders. CONCLUSIONS: Although GFD effect on the progression of CD associated liver diseases is not well defined, it seems that GFD improves liver function tests in patients with a hypertransaminasemia.

Geographic trends and risk of gastrointestinal cancer among patients with celiac disease in Europe and Asian-Pacific region.

Celiac disease is an autoimmune disorder that affects genetically predisposed individuals upon the ingestion of gluten. It is now considered one of the most common genetic disorders in Europe and Asian Pacific region with a prevalence of up to 2.67% of the population. The true prevalence of celiac disease may still be underestimated. Studies remain limited by sample size and selection bias. Celiac disease predisposes to the development of gastrointestinal malignancies, especially lymphomas and small bowel adenocarcinoma. The risk of developing a celiac disease associated malignancies remains uncertain, despite numerous studies. In Middle Eastern countries, the literature regarding celiac disease has expanded significantly in recent years. These studies reported have largely concentrated on the epidemiology of Celiac disease and there is an absolute and relative paucity of published research regarding celiac disease associated malignancy. The aim of this article is to review the current literature and evaluate the risk of gastrointestinal malignancies among patients with celiac disease and then review studies from the Asian Pacific region of the world.

The effects of gluten-free diet on hypertransaminasemia in patients with celiac disease.

BACKGROUND: Celiac disease (CD) is an immune mediated condition that leads to small bowel atrophy and improve with a gluten free diet (GFD). Extra-intestinal manifestations of CD include hypertransaminasemia. In this study, the effects of a GFD on hypertransaminasemia in patients with newly diagnosed CD were studied. METHODS: Ninety eight new diagnosed consecutive patients with CD 40 males and 58 females) with mean age of 32 ± 17.1 were studied. All patients with CD were treated with a GFD. Patients with hypertransaminasemia, at diagnosis, had a cirrhosis screen performed. Patients with a negative cirrhosis screen were reviewed, 6 months after the introduction of a GFD, and serum levels of liver transaminases were measured again. RESULTS: Nine patients had hypertransaminasemia. One patient was Hepatitis B surface antigen positive and was excluded from this study. The 8 remaining patients had no obvious cause for the hypertransaminasemia. Mean (± SD) of baseline aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were 42.6 ± 16.5 IU/L (range: 16-66 IU/L) and 69.3 ± 9.3 IU/L (range: 52-81 IU/L). Six months after treatment with a GFD, mean AST and ALT levels decreased to 24.5 ± 5.1 IU/L (range: 18-31 IU/L) (P: 0.04) and 24.6 ± 6 IU/L (range: 17-32 IU/L) (P: 0.01), respectively. In 7 patients the hypertransaminasemia, at diagnosis had resolved. CONCLUSIONS: This study provides further evidence that some patients with CD have a reversible hypertransaminasemia that resolves with a GFD.