Chronic Inflammation Permanently Reshapes Tissue-Resident Immunity in Celiac Disease.

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD. VIDEO ABSTRACT.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Celiac Disease, Gluten Sensitivity, and Diet Management.

PURPOSE OF REVIEW: Celiac disease is a common chronic inflammatory condition of the small bowel triggered by gluten in wheat, rye and barley in the diet. Non-celiac gluten sensitivity presents with symptoms similar to celiac disease with the ingestion of gluten or other components of wheat. In this article, we review challenges presented by a gluten free diet for the treatment of both disorders. RECENT FINDINGS: Wheat is ubiquitous in the diet and medications/products. A registered dietitian is mandatory for patient education on the gluten free diet. Naturally gluten free foods provide a healthy diet for those with celiac disease. Whole grains labelled gluten free, including oats, are encouraged in the diet as refined grains may be deficient in fiber, protein, and micronutrients, particularly folate. Gluten contamination is the most common cause of persistent symptoms in celiac disease though shared equipment of food preparation may not be as large a problem as suspected. Most with celiac disease on a gluten free diet will fully recover and gain weight that poses a problem for those overweight to start. The gluten free diet may have a negative impact on quality of life for both celiac patients and their families. Those with hypervigilance of the gluten free diet and avoidance of dining out have the lowest quality of life. The gluten free diet is currently the only effective treatment for celiac disease. A registered dietitian is needed to educate patients on the complexity of the gluten free diet with a goal of healthy eating, maintaining a healthy weight, and avoiding disordered eating or diet hypervigilance; key to a good quality of life.

Quality Indicators for Capsule Endoscopy and Deep Enteroscopy.

INTRODUCTION: Capsule endoscopy (CE) and deep enteroscopy (DE) can be useful for diagnosing and treating suspected small-bowel disease. Guidelines and detailed recommendations exist for the use of CE/DE, but comprehensive quality indicators are lacking. The goal of this task force was to develop quality indicators for appropriate use of CE/DE by using a modified RAND/UCLA Appropriateness Method. METHODS: An expert panel of 7 gastroenterologists with diverse practice experience was assembled to identify quality indicators. A literature review was conducted to develop a list of proposed quality indicators applicable to preprocedure, intraprocedure, and postprocedure periods. The panelists reviewed the literature; identified and modified proposed quality indicators; rated them on the basis of scientific evidence, validity, and necessity; and determined proposed performance targets. Agreement and consensus with the proposed indicators were verified using the RAND/UCLA Appropriateness Method. RESULTS: The voting procedure to prioritize metrics emphasized selecting measures to improve quality and overall patient care. Panelists rated indicators on the perceived appropriateness and necessity for clinical practice. After voting and discussion, 2 quality indicators ranked as inappropriate or uncertain were excluded. Each quality indicator was categorized by measure type, performance target, and summary of evidence. The task force identified 13 quality indicators for CE and DE. DISCUSSION: Comprehensive quality indicators have not existed for CE or DE. The task force identified quality indicators that can be incorporated into clinical practice. The panel also addressed existing knowledge gaps and posed research questions to better inform future research and quality guidelines for these procedures.

Quality indicators for capsule endoscopy and deep enteroscopy.

BACKGROUND AND AIMS: Capsule endoscopy (CE) and deep enteroscopy (DE) can be useful for diagnosing and treating suspected small-bowel disease. Guidelines and detailed recommendations exist for the use of CE/DE, but comprehensive quality indicators are lacking. The goal of this task force was to develop quality indicators for appropriate use of CE/DE by using a modified RAND/UCLA Appropriateness Method. METHODS: An expert panel of 7 gastroenterologists with diverse practice experience was assembled to identify quality indicators. A literature review was conducted to develop a list of proposed quality indicators applicable to preprocedure, intraprocedure, and postprocedure periods. The panelists reviewed the literature; identified and modified proposed quality indicators; rated them on the basis of scientific evidence, validity, and necessity; and determined proposed performance targets. Agreement and consensus with the proposed indicators were verified using the RAND/UCLA Appropriateness Method. RESULTS: The voting procedure to prioritize metrics emphasized selecting measures to improve quality and overall patient care. Panelists rated indicators on the perceived appropriateness and necessity for clinical practice. After voting and discussion, 2 quality indicators ranked as inappropriate or uncertain were excluded. Each quality indicator was categorized by measure type, performance target, and summary of evidence. The task force identified 13 quality indicators for CE and DE. CONCLUSIONS: Comprehensive quality indicators have not existed for CE or DE. The task force identified quality indicators that can be incorporated into clinical practice. The panel also addressed existing knowledge gaps and posed research questions to better inform future research and quality guidelines for these procedures.

Superior outcomes with double-balloon enteroscopy for small bowel lesion marking followed by intracorporeal as opposed to extracorporeal resection and reconstruction.

BACKGROUND: Double-balloon enteroscopy (DBE) is used for the diagnosis and therapy of small bowel disease. Endoscopic sampling and marking small bowel lesions destined for surgery permit intracorporeal resection and reconstruction (IRR), thereby facilitating a complete minimally invasive technique. There are limited data that compare outcomes of IRR to conventional extracorporeal resection and reconstruction (ERR). The purpose of this study was to evaluate the surgical outcomes of patients undergoing pre-operative DBE for lesion marking followed by laparoscopic IRR compared to those undergoing ERR. METHODS: A retrospective chart review was performed on patients who underwent DBE followed by small bowel resection from 2006 to 2017 at a single tertiary care medical center. IRR was defined as laparoscopic inspection to identify the lesion (previously marked by DBE or by laparoscopic-assisted DBE) followed by intra-abdominal bowel resection and anastomosis with specimen extraction via minimal extension of a laparoscopic port site. ERR was defined as extracorporeal resection and/or reconstruction performed via a conventional or mini-laparotomy abdominal incision. RESULTS: A total of 82 patients met inclusion criteria and were reviewed. Thirty-two patients (39%) had ERR and 50 patients (61%) had IRR. The most common indications for DBE were small bowel bleeding (76%) and small bowel mass or thickening on prior imaging studies (16%). Successful DBE was higher in the IRR group when compared to the ERR group, but not significantly different (90% vs 75%, p-value 0.07). Patients who underwent IRR had faster bowel function recovery (2 vs 4 days, p < 0.01), shorter time to discharge (3 vs 7 days, p < 0.01), and fewer post-operative complications (10 vs 18; p < 0.01), when compared to the ERR group. CONCLUSION: DBE successfully facilitated laparoscopic small bowel IRR and this approach was associated with faster return of bowel function, shorter recovery time, and decreased morbidity when compared to ERR.

Celiac Disease and Its Role in the Development of Metabolic Bone Disease.

Celiac disease (CD) is an immune-mediated enteropathy that occurs in genetically susceptible hosts with the ingestion of gluten-containing products. Ongoing gluten consumption leads to intestinal damage, characterized by villous blunting and increased intraepithelial lymphocytes, resulting in malabsorption. Pertinent to the development of bone disease, malabsorption of calcium and vitamin D leads to secondary hyperparathyroidism and metabolic bone disease among individuals with CD. In this article, we review the pathogenesis of CD and the effects of malabsorption on bone health. Imbalances in bone resorption and formation particularly in individuals with CD and persistent disease activity ultimately lead to a state of bone loss and impaired mineralization. Initiation of a gluten-free diet is critical in the management of CD-related metabolic bone disease, demonstrating improvements in bone mineral density within the first year of dietary adherence.

Obesity and Cardiovascular Risk in Adults With Celiac Disease.

BACKGROUND: Patients with celiac disease (CD) may be at an increased risk of cardiovascular disease (CVD), yet CVD risk factors are not well defined in CD. The validated Framingham Heart Study 10-year general CVD risk score (FRS) that incorporates traditional CVD risk factors including body mass index (BMI) has not been previously studied in CD patients. AIMS: To compare BMI and FRS in CD patients with population-based controls. METHODS: Biopsy-proven CD patients were ascertained retrospectively and data on BMI, systolic blood pressure, hypertension, smoking status, and diabetes were obtained at initial and follow-up visits. FRS was calculated and compared with 4 matched general population non-CD controls from the 2009 to 2010 National Health and Nutrition Examination Survey (NHANES). RESULTS: Of 258 total CD patients, 38.3% were overweight or obese compared with 69.8% of controls (P<0.001). In total, 174 CD patients met the inclusion criteria for FRS calculation. Of these, the median FRS was lower in CD patients compared with controls (3.9 vs. 4.2; P=0.011). In CD patients, tobacco use was significantly lower (P<0.001), whereas systolic blood pressure was significantly higher (P<0.01) than controls. CONCLUSIONS: Global CVD risk is lower among patients with CD compared with population controls. Lower BMI and tobacco use among CD patients could account for this difference. These results suggest that factors other than those measured by FRS could contribute to the increased risk of CVD in CD observed in some studies.

Gastro 2013 APDW/WCOG Shanghai working party report: chronic diarrhea: definition, classification, diagnosis.

Diarrhea is best defined as passage of loose stools often with more frequent bowel movements. For clinical purposes, the Bristol Stool Form Scale works well to distinguish stool form and to identify loose stools. Laboratory testing of stool consistency has lagged behind. Acute diarrhea is likely to be due to infection and to be self-limited. As diarrhea becomes chronic, it is less likely to be due to infection; duration of 1 month seems to work well as a cut-off for chronic diarrhea, but detailed scientific knowledge is missing about the utility of this definition. In addition to duration of diarrhea, classifications by presenting scenario, by pathophysiology, and by stool characteristics (e.g. watery, fatty, or inflammatory) may help the canny clinician refine the differential diagnosis of chronic diarrhea. In this regard, a careful history remains the essential part of the evaluation of a patient with diarrhea. Imaging the intestine with endoscopy and radiographic techniques is useful, and biopsy of the small intestine and colon for histological assessment provides key diagnostic information. Endomicroscopy and molecular pathology are only now being explored for the diagnosis of chronic diarrhea. Interest in the microbiome of the gut is increasing; aside from a handful of well-described infections because of pathogens, little is known about alterations in the microbiome in chronic diarrhea. Serological tests have well-defined roles in the diagnosis of celiac disease but have less clearly defined application in autoimmune enteropathies and inflammatory bowel disease. Measurement of peptide hormones is of value in the diagnosis and management of endocrine tumors causing diarrhea, but these are so rare that these tests are of little value in screening because there will be many more false-positives than true-positive results. Chemical analysis of stools is of use in classifying chronic diarrhea and may limit the differential diagnosis that must be considered, but interpretation of the results is still evolving. Breath tests for assessment of carbohydrate malabsorption, small bowel bacterial overgrowth, and intestinal transit are fraught with technical limitations that decrease sensitivity and specificity. Likewise, tests of bile acid malabsorption have had limited utility beyond empirical trials of bile acid sequestrants.

A rapid and accurate method to detect active small bowel gastrointestinal bleeding on video capsule endoscopy.

BACKGROUND: Video capsule endoscopy (VCE) is indicated to evaluate for suspected small bowel bleeding, but "standard view" (SV) evaluation is time-consuming. Rapid Reader 6.0 software (Given Imaging, Duluth GA) contains two computer algorithmic systems: (1) "Quickview" (QV) which automatically skips similar images and (2) a pixel analysis program that identifies suspected blood (SBI). Combining the two modalities (QV + SBI) may provide a faster modality to assess for active small bowel bleeding. AIMS: This study was designed to assess the accuracy of QV + SBI for small bowel bleeding compared to SV findings. METHODS: This is a retrospective, case-control study at a single tertiary care referral hospital including all patients with VCE performed for suspected small bowel bleeding from 4/2007 to 3/2011. All studies were previously read using SV by one of two experienced faculty (CS, DR). The primary outcome was diagnostic accuracy of QV + SBI in assessing for active small bowel bleeding compared to SV. RESULTS: A total of 116 VCE were included, 28 with active small bowel bleeding identified by original SV. Using QV + SBI, all 28 VCEs with active small bowel bleeding were identified. The sensitivity of QV + SBI to detect active bleeding was 100%, while the specificity was 93-94%. The mean time to identify landmarks and read the entire study was 3 min 20 s. CONCLUSIONS: The QV + SBI reading format of VCE is an efficient, highly sensitive modality to assess for potential small bowel bleeding.

Gall Bladder Disease and the Risk of Small Bowel Cancer-Results from a Nationwide Swedish Cohort Study.

BACKGROUND AND AIMS: Small bowel cancer is a rare but rising malignancy. The etiology is poorly understood and there is a need for large-scale studies. Gallbladder disease (GBD), inducing localized inflammation, has been suggested to increase small bowel cancer risk. METHODS: We retrieved nationwide data from Sweden's 28 pathology departments on all adults (age 20-79) with pathology-confirmed GBD diagnosed in 1965-2017. In total 156,390 GBD patients were matched with up to 5 matched comparators from the general population and follow-up started one year after GBD diagnosis. We used stratified Cox regression to calculate hazard ratios (HRs) for small bowel adenocarcinoma, adenomas, and carcinoids. RESULTS: During a median follow-up of 12 years, we identified 92 small bowel adenocarcinomas, 132 adenomas, and 81 carcinoid tumors in the GBD cohort. Corresponding incidence rates were 4.8, 6.9, and 4.2 per 100,000 person-years (PY), compared to 3.2, 3.2, and 1.8 in matched comparators. The adjusted HR was 1.42 (95% CI = 1.08-1.87) for small bowel adenocarcinoma, 1.79 (95% CI = 1.41-2.27) for adenoma, and 2.07 (95% CI = 1.52-2.81) for carcinoid. The excess cancer risk was most pronounced during the first year of follow-up for adenocarcinomas and during the first six years for adenomas while for carcinoids the HR peaked 10-15 years after start of follow-up. CONCLUSIONS: In this nationwide cohort study, GBD was associated with an increased risk of small bowel cancer. The excess risk of small bowel adenocarcinoma was mainly seen during the first years of follow-up while small bowel carcinoid risk peaked 11-16 years after GBD diagnosis.

Advances in small bowel imaging.

The small intestine has been difficult to examine by traditional endoscopic and radiologic techniques. Within the past 10 years, advances have led to an explosion of technologies that facilitate examination of the entire small intestine. Wireless video capsule endoscopy, deep enteroscopy using balloon-assisted or spiral techniques, computer tomography (CT) and magnetic resonance (MR) enterography have facilitated the diagnosis, monitoring, and management of patients with small intestinal diseases. These technologies are complementary, each with its advantages and limitations. Capsule endoscopy provides a detailed view of the mucosal surface and has excellent patient acceptance, but does not allow therapeutics. Deep enteroscopy allows careful inspection of the mucosa and therapeutics, but is time consuming and invasive. Enterography (CT or MR) allows examination of the small bowel wall and surrounding structures. The initial best test for detecting small intestinal disease depends on clinical presentation and an astute differential diagnosis.

Role of Video Capsule Endoscopy as a Prelude to Deep Enteroscopy.

Video capsule endoscopy and device-assisted enteroscopy are complementary technologies. Capsule endoscopy is a highly acceptable technology with high diagnostic yield that can guide a subsequent enteroscopy approach. This article aims to focus on the role of video capsule endoscopy as a prelude to deep enteroscopy with a focus on the strengths and limitations of either approach.

Novel endoscopic triangulation approach to percutaneous transgastric placement of jejunal extension feeding tube.

In patients who have surgically-altered upper gastrointestinal anatomy, postoperative endoscopic enteral nutrition options can be limited by issues such as bowel stenosis and/or acute angulation. This report details the use of an endoscopic triangulation method combining per-oral and percutaneous transgastric approaches to overcome an efferent gastrojejunostomy limb stenosis, to successfully place a jejunal extension feeding tube through a newly placed PEG site. This description provides an alternative endoscopically feasible option for successful enteral nutrition access, thus obviating the need for additional operations to place surgical feeding tubes or to commit patients to long-term total parenteral nutrition.

Long-term outcomes after double-balloon enteroscopy for obscure gastrointestinal bleeding.

BACKGROUND & AIMS: Long-term outcomes after doubleballoon enteroscopy (DBE), performed for the evaluation of obscure gastrointestinal bleeding, have not been determined. METHODS: We invited 274 patients undergoing DBE at Stanford University or the University of Chicago between 2004 and 2006 to participate in the study; 135 (49%) agreed (mean age, 64 +/- 14.8; range, 23-90 years). Telephone interviews were conducted at a mean of 11 and 30 months after DBE. RESULTS: Arteriovenous malformations (AVMs) were detected in 43% of the cohort. One hundred one patients (37%; 56 with overt, 45 with occult bleeding) were interviewed 12 +/- 5 (range, 6-26) months after DBE. At 12 months, 43% reported no further overt bleeding or iron/transfusion needs, 23% reported overt bleeding, and 35% reported ongoing iron and/or transfusions. Eighty-five patients (31%) participated in the second survey, conducted 30 +/- 5.7 (range, 19-51) months after DBE. Fifty (59%) reported no overt bleeding or iron/transfusion needs, 20 (24%) reported overt bleeding, and 15 (18%) reported ongoing iron and/or transfusions. In the 40 patients evaluated after endoscopic treatment for AVMs, 17 (43%) reported no bleeding or iron therapy at 12 months and 16 of 29 (55%) at 30 months. Of the 40 patients with normal DBE examinations to the depth of insertion, 19 of 40 (48%) reported no bleeding or iron/transfusion needs at 12 months and 25 of 43 (58%) at 30 months. CONCLUSIONS: At 30 months after DBE, up to 60% of patients report no further bleeding. Patients with AVMs or normal examinations to the depth of insertion are most likely to report recurrent hemorrhage.

Small bowel enteroscopy: territory conquered, future horizons.

PURPOSE OF REVIEW: To review recent advances in small bowel enteroscopy, focusing on indications, modifications to improve imaging and techniques, pitfalls, and clinical applications. RECENT FINDINGS: The need for endoscopic access to improve diagnosis and treatment of small bowel disease has led to the development of novel technologies, video capsule, and double balloon endoscopy. Newer devices, single balloon and spiral endoscopy, are just entering clinical use. With new technologies come the trials and tribulations of learning new endoscopic skills and determining their role in the diagnosis and treatment of small bowel disease. Identification of small bowel lesions has dramatically improved. However, small bowel angulations, peristalsis, and bilious fluid in the lumen can result in false readings or missed lesions. Studies are underway to determine the best strategy to apply new enteroscopy technologies for the diagnosis and management of small bowel disease, particularly bleeding. SUMMARY: Complete enteroscopy of the small bowel is now possible. However, because of the length of the small bowel, endoscopic examination and therapeutic maneuvers require patience and significant skill. Prospective randomized studies are needed to guide diagnostic testing and therapy with these new endoscopic techniques.