Mark Lazarev

The treatment of defective glycosylation in clinical practice has been limited to patients with rare and severe phenotypes associated with congenital disorders of glycosylation (CDG). Carried by approximately 5% of the human population, the discovery of the highly pleiotropic, missense mutation in a manganese transporter ZIP8 has exposed under-appreciated roles for Mn homeostasis and aberrant Mn-dependent glycosyltransferases activity leading to defective N-glycosylation in complex human diseases. Here, we test the hypothesis that aberrant N-glycosylation contributes to disease pathogenesis of ZIP8 A391T-associated Crohn’s disease. Analysis of N-glycan branching in intestinal biopsies demonstrates perturbation in active Crohn’s disease and a genotype-dependent effect characterized by increased truncated N-glycans. A mouse model of ZIP8 391-Thr recapitulates the intestinal glycophenotype of patients carrying mutations in ZIP8. Borrowing from therapeutic strategies employed in the treatment of patients with CDGs, oral monosaccharide therapy with N-acetylglucosamine ameliorates the epithelial N-glycan defect, bile acid dyshomeostasis, intestinal permeability, and susceptibility to chemical-induced colitis in a mouse model of ZIP8 391-Thr. Together, these data support ZIP8 391-Thr alters N-glycosylation to contribute to disease pathogenesis, challenging the clinical paradigm that CDGs are limited to patients with rare diseases. Critically, the defect in glycosylation can be targeted with monosaccharide supplementation, providing an opportunity for genotype-driven, personalized medicine.

Aims We aimed to develop an artificial intelligence (AI) system to assess endoscopic remission (ER) and histologic remission (HR) of ulcerative colitis (UC) in both white light (WL, using Ulcerative Colitis Endoscopic Index of Severity [UCEIS]) and virtual chromoendoscopy (VCE, using Paddington International Virtual ChromoendoScopy ScOre [PICaSSO]). Methods A convolutional neural network (CNN) was developed based on 559 endoscopy videos, from 302 UC patients prospectively included in the PICaSSO multicentre study. The videos were divided in training (254), validation (62), and testing (243), and comprised 67280 frames in total. The CNN was trained to predict both ER (defined as UCEIS≤1 in WL and as PICaSSO≤3 in VCE) and HR (defined as Robarts Histological Index ≤ 3 with no neutrophils in lamina propria or epithelium) in video clips. Results In the validation cohort, our system predicted ER in WL videos with 82% sensitivity, 94% specificity and an area under the ROC curve (AUROC) of 0.92. In VCE, sensitivity was 74%, specificity 95%, and AUROC 0.95. In the testing cohort, the diagnostic performance remained similar. The diagnostic performance for the prediction of HR in the validation set had sensitivity, specificity, and accuracy of 92%, 83%, and 85%, respectively, using VCE; and 83%, 87%, and 86% respectively, with WL. In the testing set, these metrics declined modestly while remaining good. Of note, the algorithm’s prediction of histology was similar with VCE and WL videos. Conclusions Our AI system accurately recognizes ER in videos and predicts HR equally well. Publication Date: 14 April 2022 (online) © 2022. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

A group of Inflammatory Bowel Disease (IBD) specialists have been utilizing a weekly live video conference “IBD Live” to discuss multidisciplinary management of challenging cases. Since 2009 the conference has featured robust interactive case discussions among 150-200 gastroenterologists and colorectal surgeons from multiple academic institutions. Although the majority of cases presented are IBD, there have been a number of cases where IBD was not the ultimate diagnosis. Hence, we sought to characterize these “IBD mimics” to provide a structure for differential diagnosis. All 106 hours of case conferences recorded and archived between May 2018 and June 2021 were reviewed. A total of 183 of the 215 cases discussed had an IBD diagnosis including 124 Crohn’s disease (CD), 54 ulcerative colitis (UC) and 5 IBD unclassified. Many of the remaining 32 (14.9%) cases (Table 1) were referred to a specialist with a prior diagnosis of IBD. There were 10 cases of colonic inflammation initially diagnosed as UC. Etiologies included drug-induced colitis secondary to checkpoint inhibitors for cancers, ocrelizumab for multiple sclerosis, and nintedanib for pulmonary fibrosis. There were cases of ischemic colitis, idiopathic myointimal hyperplasia of mesenteric veins, segmental colitis associated with diverticulosis, and diversion colitis. There were 8 cases of systemic diseases, diagnosed as Common Variable Immunodeficiency, sarcoidosis and vasculitis, including cases of Henoch–Schönlein purpura and CTLA4 haploinsufficiency with autoimmune infiltrates. There were 5 cases of ileal disorders, ultimately diagnosed as lymphoma, tuberculosis, Meckel’s diverticulum, and appendiceal carcinoid all previously thought to be CD. There were small bowel mucosal disorders including collagenous sprue and autoimmune enteropathy, and 2 polyposis cases secondary to Cronkhite-Canada and juvenile polyposis syndromes. There were also cases thought to be penetrating complications of CD, including a case of abdominal actinomyces infection. Finally, there were 3 cases where no consensus diagnosis was made, with broad differential diagnoses including cryptogenic multifocal ulcerous stenosis enteritis. IBD mimics were found in 15% of cases presented at a global IBD webinar in a 3-year period. Clinicians should have a high level of suspicion and actively pursue alternative etiologies when patients do not respond as anticipated to IBD therapy and/or when the disease characteristics are not completely consistent with IBD. These non-IBD diagnoses will lead to a significant change in medical, surgical and pharmacological treatment approaches, which will impact total cost, unplanned care and quality. Our IBD Live conference has positively impacted the care of our patients, and magnified the importance of considering a broad differential for IBD "mimics."