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.

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.

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.

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.

Capsule Endoscopy and Enteroscopy in Celiac Disease.

Celiac disease predominantly involves the proximal small bowel, but villus atrophy can be patchy, spare the duodenum, and be present more distally. Video capsule endoscopy is more sensitive than standard endoscopy to detect villus atrophy, and can define extent of disease, though it cannot obtain biopsies. Duodenal biopsy is the gold standard for diagnosis. Video capsule endoscopy assists in special circumstances when biopsy is not possible, and in equivocal diagnosis. Video capsule endoscopy and enteroscopy are recommended for evaluating complicated celiac disease, especially refractory celiac disease type II. Future developments include computer-assisted capsule programs and advanced capsule and enteroscope design.

Small Bowel Endoscopy.

OPINION STATEMENT: The small bowel is a challenging area for endoscopic evaluation and therapy due to its length and angulated configuration. A small lumen diameter and segmental peristalsis made it a perfect fit for examination by a novel ingestible wireless camera in a capsule. The development of capsule endoscopy changed the diagnosis and management of bleeding lesions, ulcers, and tumors deep in the small bowel, allowing earlier diagnosis with excellent patient acceptance. Device-assisted enteroscopy revolutionized small bowel therapy, particularly management of bleeding, Peutz-Jeghers polyposis, and tumor marking for minimally invasive surgery. Small bowel stricture dilation in select patients is safe and effective. Tools for a spectrum of small bowel therapies are available but remain suboptimal to tackle lesions on angulated folds deep in the small bowel. Universal terminology to describe the endoscopic appearance of vascular lesions will facilitate studies of endoscopic and medical therapy. The future holds improvements in imaging, easier advancement through the small bowel, and therapeutic capacity. This review focuses on methods of small bowel endoscopy, therapy, and outcomes.

Clinical nutrition in the hepatogastroenterology curriculum.

Gastroenterology (GE) used to be considered a subspecialty of internal medicine. Today, GE is generally recognized as a wide-ranging specialty incorporating capacities, such as hepatology, oncology and interventional endoscopy, necessitating GE-expert differentiation. Although the European Board of Gastroenterology and Hepatology has defined specific expertise areas in Advanced endoscopy, hepatology, digestive oncology and clinical nutrition, training for the latter topic is lacking in the current hepatogastroenterology (HGE) curriculum. Given its relevance for HGE practice, and being at the core of gastrointestinal functioning, there is an obvious need for training in nutrition and related issues including the treatment of disease-related malnutrition and obesity and its associated metabolic derangements. This document aims to be a starting point for the integration of nutritional expertise in the HGE curriculum, allowing a central role in the management of malnutrition and obesity. We suggest minimum endpoints for nutritional knowledge and expertise in the standard curriculum and recommend a focus period of training in nutrition issues in order to produce well-trained HGE specialists. This article provides a road map for the organization of such a training program. We would highly welcome the World Gastroenterology Organisation, the European Board of Gastroenterology and Hepatology, the American Gastroenterology Association and other (inter)national Gastroenterology societies support the necessary certifications for this item in the HGE-curriculum.

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.

Gastric mucosal necrosis with vascular degeneration induced by doxycycline.

We encountered 2 patients who underwent esophagogastroduodenoscopy for epigastric abdominal pain, which showed gastric mucosal erosions covered with adherent exudate. Microscopic examination of biopsies from the lesions obtained from the 2 cases revealed characteristic pathologic abnormalities that shared striking similarities. These included superficial mucosal necrosis and capillary vascular degenerative change in a background of reactive or chemical gastropathy. Further review of records identified ongoing oral doxycycline use in both patients. After cessation of the drug both patients' symptoms resolved. A follow-up esophagogastroduodenoscopy in 1 patient showed normal gastric mucosa. This pattern of injury had not been previously described and seems to be characteristic for doxycycline-induced gastric mucosal toxicity. Recognition of the clinical, endoscopic, and pathologic features described here may facilitate prompt diagnosis and management of this condition.

Small bowel imaging in celiac disease.

Celiac disease is a common inflammatory disease of the small intestine triggered by gluten in genetically susceptible individuals. Diagnosis is made by serologic testing and upper endoscopy with small bowel biopsy in most individuals. Celiac patients may present with abdominal pain or nonspecific gastrointestinal complaints that result in radiologic imaging before diagnosis of celiac disease. Wireless video capsule endoscopy, device-assisted enteroscopy, and enterography allow careful examination of the entire small bowel and targeted sampling of suspicious lesions. This review focuses on the role of device-assisted enteroscopy and radiologic imaging, in particular enterography, in celiac disease.

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.

Small bowel tumors.

Although rare, small bowel tumors may cause significant morbidity and mortality if left undetected. New endoscopic modalities allow full examination of the small bowel with improved diagnosis. However, isolated mass lesions may be missed by capsule endoscopy or incomplete balloon-assisted enteroscopy. Therefore the use of radiologic imaging and intraoperative enteroscopy for diagnosis should not be forgotten. Endoscopic resection of small bowel polyps and certain vascular tumors is possible but requires proper training. Advances in endoscopic tools are likely to broaden the endoscopic management of small bowel tumors. This article describes the general features of small bowel tumors, clinical presentation, and diagnostic tests followed by a description of the more common tumor types and their management.

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.

Screening for celiac disease in short bowel syndrome.

BACKGROUND: Malabsorptive diarrhea due to short bowel syndrome (SBS) results in nutrition compromise, often requiring parenteral nutrition (PN). Activation of latent celiac disease can occur after gastrointestinal surgery. Our objective was to determine whether undiagnosed celiac disease contributes to malabsorption in patients with SBS. METHODS: Adult subjects with SBS were tested for celiac disease using immunoglobulin A (IgA) tissue transglutaminase (TTG) antibody and total IgA level. Subjects with an elevated IgA tissue transglutaminase were offered upper endoscopy with biopsies of the duodenum. RESULTS: Eighteen subjects were enrolled. The subjects were predominantly white, and the most common cause of SBS was Crohn's disease. The mean length of remaining small bowel was 93.1 +/- 54.6 cm. All subjects had undergone surgeries, resulting in loss of the ileocecal valve. Five subjects were found to have an elevated total IgA. A single patient was found to have an elevated IgA tissue transglutaminase antibody, and subsequent endoscopy demonstrated active gastroduodenal Crohn's disease, without features of celiac disease. CONCLUSIONS: No subjects were IgA deficient, but 5 subjects were found to have elevated IgA levels. Undiagnosed celiac disease did not contribute to malabsorption in our small cohort of predominantly white SBS patients. Larger studies are warranted.

Hepatitis B virus reactivation after kidney transplantation and new onset lymphoma.

A case of hepatitis B virus (HBV) reactivation after kidney transplantation is reported. The presence of antibodies against hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) before transplantation indicated previous infection with HBV. Eight years after transplantation, a diffuse, large B-cell lymphoma occurred, and the patient was positive for HBsAg and hepatitis B e antigen, in association with normal activity of serum aminotransferases. Postmortem liver histology did not show any sign of portal tract or lobular inflammation despite the presence at immunostaining of extensive intranuclear and cytoplasmic positivity for HBcAg, indicating active viral replication. Natural immunity to HBV may not protect against reactivation in patients with a suppressed immune system. In this setting, periodic follow-up of HBV serology in patients at highest risk for HBV reactivation to allow for early diagnosis and prompt treatment with lamivudine is highly recommended.