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Vajsova A, Cahova M, Bajer L, Sticova E, Juskova I, Hlavaty M, Fabian O. Unique clinical, morphological, and molecular characteristics of tumors associated with PSC-IBD. Virchows Arch 2025; 486:651-661. [PMID: 40102272 PMCID: PMC12018527 DOI: 10.1007/s00428-025-04072-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 03/20/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree, leading to significant liver function impairment over time. There is a strong association with inflammatory bowel diseases (IBD), together representing a distinct and complex medical condition. Patients with PSC-IBD face a heightened risk of various cancers, particularly colorectal carcinoma (CRC) and cholangiocarcinoma (CCA) as the most common types. In this review, we aim to characterize the distinctive features of PSC-IBD-associated carcinomas. Cancer pathogenesis in PSC-IBD is shaped by various factors including dysregulated bile acid metabolism, gut dysbiosis, and unique immune responses. PSC-IBD-associated CRC is often right-sided and warrants vigilant monitoring due to its higher incidence and unique morphological features compared to CRC arising in the terrain of IBD alone. CCA shares substantial genetic similarities with extrahepatic CCA and poses diagnostic challenges since it is frequently detected at advanced stages due to symptom overlap with PSC. Besides, reliable predictive biomarkers for targeted therapy remain largely unexplored. The distinct molecular, genetic, and histopathological profiles of CRC and CCA in PSC-IBD underscore the complexity of these malignancies and highlight the need for continued research to develop precise therapeutic strategies.
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Affiliation(s)
- Andrea Vajsova
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic.
- Institute of Pathology of the First Faculty of Medicine and General Teaching Hospital, Prague, 12800, Czech Republic.
| | - Monika Cahova
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic
| | - Lukas Bajer
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, 14021 , Czech Republic
- Department of Internal Medicine, Second Faculty of Medicine, Charles University, Prague, 15000, Czech Republic
| | - Eva Sticova
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic
- Department of Pathology, Royal Vinohrady Teaching Hospital, Srobarova 1150/50, Prague, 10000, Czech Republic
| | - Ivana Juskova
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic
| | - Mojmir Hlavaty
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, 14021 , Czech Republic
| | - Ondrej Fabian
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic
- Department of Pathology and Molecular Medicine, 3rd Faculty of Medicine, Charles University and Thomayer Hospital, Prague, 14059, Czech Republic
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Liu XY, Sun XJ. Evaluation of Mayo endoscopic subscore in ulcerative colitis with concomitant primary sclerosing cholangitis. World J Gastrointest Endosc 2025; 17:103448. [PMID: 39989857 PMCID: PMC11843038 DOI: 10.4253/wjge.v17.i2.103448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 02/13/2025] Open
Abstract
This article relates to the discussion of a recent study published by Wohl et al. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease that affects the intra- and extrahepatic bile ducts and is strongly associated with ulcerative colitis (UC). Endoscopic evaluation of UC is feasible and reliable in routine clinical practice, and the Mayo endoscopic subscore (MES) is one of the most commonly used endoscopic evaluation measures for UC. Patients with PSC-UC are at higher risk of developing cancer and biliary tract cancer. Endoscopic scoring alone appears unreliable, and histopathological evaluation is essential to accurately assess and make effective therapeutic decisions for PSC-UC. Therefore, we aimed to discuss the accuracy of MES in patients with UC and PSC-UC and to explore the consistency between MES and the Nancy histological index.
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Affiliation(s)
- Xin-Yuan Liu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Key Laboratory of Digestive Health, National Clinical Research Center for Digestive System Diseases, Beijing 100050, China
| | - Xiu-Jing Sun
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Key Laboratory of Digestive Health, National Clinical Research Center for Digestive System Diseases, Beijing 100050, China
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Uździcki AW, Wawrzynowicz-Syczewska M. Impact of liver transplantation on intestinal and systemic inflammation markers in patients with colitis ulcerosa concomitant with primary sclerosing cholangitis. PRZEGLAD GASTROENTEROLOGICZNY 2024; 16:439-445. [PMID: 39810863 PMCID: PMC11726230 DOI: 10.5114/pg.2024.145575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 11/27/2023] [Indexed: 01/04/2025]
Abstract
Introduction Primary sclerosing cholangitis (PSC) is an uncommon, chronic liver disease characterised by fibrosis and strictures of a bile ducts, causing cholestasis. In the long term it can lead to complete stenosis leading in turn to liver cirrhosis. In patients with severe form of the disease, the recommended treatment is liver transplantation. Because PSC frequently coexists with ulcerative colitis (UC), it is crucial to determine the effect of liver transplantation on the course of UC. Aim The aim was to determine the impact of liver transplantation on intestinal and systemic inflammation markers with UC concomitant with PSC (PSC-UC). Material and methods Sixty-three patients with PSC-UC were enrolled, 25 of whom underwent liver transplantation (OLTx) due to PSC progression. Clinical symptoms, faecal calprotectin levels, C-reactive protein (CRP) serum concentration, erythrocyte sedimentation rate, and white blood cell count (WBC) were obtained. Results Faecal calprotectin was significantly higher in the post-OLTx group. Mean calprotectin values were 163% higher - 474 ng/ml and 180 ng/ml (p = 0.024) in the post-OLTx group and in the PSC-UC group without the transplantation, respectively. Calprotectin levels exceeded the upper limit of normal (defined as 200 ng/l) in 66% of liver recipients and in 18% of non-transplanted patients (OR = 9.33, p = 0.011). In the post-OLTx group, also CRP concentration (11.01 mg/l vs. 6.54 mg/l, p = 0.30) and WBC (7.58 K/ml vs. 5.72 K/ml, p = 0.006) were higher than in the PSC-UC group without transplantation. Conclusions We found significantly higher inflammation markers in PSC-UC patients who underwent liver transplantation due to PSC. The effect was strongest in faecal calprotectin levels. In PSC-UC patients after liver transplantation, intensification of UC treatment may be needed, despite the lack of worsening of clinical symptoms.
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Affiliation(s)
- Artur W. Uździcki
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Marta Wawrzynowicz-Syczewska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
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Bahceci D, Alpert L, Storozuk T, Liao X, Yozu M, Westerhoff M, Kővári BP, Lauwers GY, Choi WT. Dysplasia Detected in Patients With Serrated Epithelial Change Is Frequently Associated With an Invisible or Flat Endoscopic Appearance, Nonconventional Dysplastic Features, and Advanced Neoplasia. Am J Surg Pathol 2024; 48:1326-1334. [PMID: 38907614 DOI: 10.1097/pas.0000000000002271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/24/2024]
Abstract
The significance of serrated epithelial change (SEC), defined as endoscopically invisible hyperplastic polyp (HP)-like mucosal change identified in patients with inflammatory bowel disease (IBD), remains unclear. Although some studies reported an increased risk of synchronous and/or metachronous colorectal neoplasia in patients with SEC, including advanced neoplasia (high-grade dysplasia or colorectal cancer), the development of SEC is not significantly associated with increased colonic inflammation. This contrasts with the reported positive correlation between increased colonic inflammation and the risk of colorectal neoplasia in ulcerative colitis, arguing against the notion that SEC may represent a form of dysplasia. As such, this study aimed to characterize the features of synchronous and metachronous dysplasia detected in patients with SEC to identify factors contributing to the increased risk of colorectal neoplasia, including advanced neoplasia, observed in a subset of these patients. Clinicopathologic features of 46 IBD patients with SEC (n=109) and synchronous and/or metachronous dysplasia (n=153) were analyzed. All dysplastic lesions were subtyped as either conventional or nonconventional dysplasia. As controls, 45 IBD patients with endoscopically visible or polypoid HP (n=75) and synchronous and/or metachronous dysplasia (n=87) were analyzed. The SEC group included 28 (61%) men and 18 (39%) women with a mean age of 58 years and a long history of IBD (mean duration: 23 years). The majority of patients (n=34; 74%) had ulcerative colitis, and 12 (26%) had Crohn's disease. Thirty-nine (85%) patients had a history of pancolitis, and 2 (4%) had concomitant primary sclerosing cholangitis. Twenty-seven (59%) patients had multifocal SEC. SEC was predominantly found in the left colon (n=52; 48%) and rectum (n=34; 31%). Dysplasia in the SEC group was often endoscopically invisible or flat (n=42; 27%) and demonstrated nonconventional dysplastic features (n=49; 32%). Six nonconventional subtypes were identified in the SEC group, including 17 (11%) dysplasia with increased Paneth cell differentiation, 12 (8%) hypermucinous dysplasia, 8 (5%) crypt cell dysplasia, 7 (5%) goblet cell deficient dysplasia, 3 (2%) sessile serrated lesion-like dysplasia, and 2 (1%) traditional serrated adenoma-like dysplasia. Advanced neoplasia was detected in 11 (24%) patients. The SEC group was more likely to have nonconventional dysplasia (32%, P <0.001), invisible/flat dysplasia (27%, P <0.001), and advanced neoplasia (24%, P <0.001) than the control group (7%, 2%, and 0%, respectively). High-risk nonconventional subtypes (ie, hypermucinous, crypt cell, and goblet cell deficient dysplasias) accounted for 18% of all dysplastic lesions in the SEC group, which were not seen in the control group ( P <0.001). The SEC group (n=35; 76%) also had a higher rate of concordance between the location of SEC and the area of synchronous/metachronous dysplasia than the control group (n=22; 49%) ( P =0.007). In conclusion, dysplasia detected in patients with SEC is often endoscopically invisible/flat (27%), nonconventional (32%, including the high-risk subtypes), and found in the same colonic segment as SEC (76%), which may in part explain why some patients with SEC are associated with an increased risk of colorectal neoplasia, including advanced neoplasia. The finding of SEC may warrant a careful follow-up colonoscopy with increased random biopsy sampling, especially in the segment of colon with SEC.
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Affiliation(s)
- Dorukhan Bahceci
- Department of Pathology, University of California at San Francisco, San Francisco, CA
| | - Lindsay Alpert
- Department of Pathology, University of Chicago, Chicago, IL
| | | | - Xiaoyan Liao
- Department of Pathology, University of Rochester, Rochester, NY
| | - Masato Yozu
- Histopathology Department, Middlemore Hospital, Auckland, New Zealand
| | | | - Bence P Kővári
- Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL
| | | | - Won-Tak Choi
- Department of Pathology, University of California at San Francisco, San Francisco, CA
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Zhang R, Wang D, Lauwers GY, Choi WT. Increased Active Inflammation in the Colon is Not a Reliable Predictor of an Elevated Risk of Dysplasia in Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis. Am J Surg Pathol 2024; 48:1154-1163. [PMID: 38809303 DOI: 10.1097/pas.0000000000002255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2024]
Abstract
Although the increased risk of colorectal neoplasia in patients with both primary sclerosing cholangitis (PSC) and ulcerative colitis (UC; termed PSC-UC) is well documented, the mechanism through which concomitant PSC increases the risk of colorectal neoplasia remains unclear. Given that the risk of colorectal neoplasia in UC is positively correlated with increased histologic inflammation, this study sought to investigate whether increased histologic inflammation could be used to stratify the risk of dysplasia development in patients with PSC-UC. Twenty patients with PSC-UC and dysplasia were compared with 30 control patients with PSC-UC who had no history of neoplasia. For each patient, all surveillance biopsies were scored using a 4-point scoring system: (1) no epithelial neutrophils = 0, (2) cryptitis only = 1, (3) cryptitis plus crypt abscess in <50% of crypts = 2, and (4) crypt abscess in ≥50% of crypts, erosion, neutrophilic exudate, and/or ulceration = 3. A score was designated for each biopsy, and both mean and maximum inflammation scores were calculated from all biopsies taken during each colonoscopy. The inflammation burden score was calculated for each surveillance interval by multiplying the average maximum score between each pair of surveillance episodes by the length of the surveillance interval in years. The average scores derived from all colonoscopies for each patient were used to determine the patient's overall mean, maximum, and inflammation burden scores. In both the dysplasia and control groups, the 3 summative inflammation scores were calculated independently for the entire colon, right colon, and left colon. The dysplasia group consisted of 14 (70%) men and 6 (30%) women, with a mean age of 27 years at UC diagnosis and a long history of pancolitis (mean duration: 17 y). A total of 49 dysplastic lesions were detected in the dysplasia group, and 8 (40%) of the 20 patients had multifocal dysplasia. The majority of dysplastic lesions belonged to nonconventional subtypes (n = 28; 57%) and were located in the right colon (n = 37; 76%). Irrespective of the colon segment, there was no significant difference in the 3 summative inflammation scores between the dysplasia and control groups ( P > 0.05). However, in each group, the 3 summative inflammation scores were significantly higher in the right colon than in the left colon ( P < 0.05). In conclusion, patients with PSC-UC exhibit increased histologic inflammation in the right colon compared with the left colon, regardless of the presence of dysplasia. Although this may provide an explanation for the predominance of right-sided colorectal neoplasia in patients with PSC-UC, increased histologic inflammation does not reliably predict an elevated risk of dysplasia in patients with PSC-UC. These findings reinforce the current recommendation for annual endoscopic surveillance for all patients with PSC-UC, irrespective of the extent and severity of inflammation.
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Affiliation(s)
- Ruth Zhang
- Department of Pathology, University of California, San Francisco, CA
| | - Dongliang Wang
- Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY
| | - Gregory Y Lauwers
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Won-Tak Choi
- Department of Pathology, University of California, San Francisco, CA
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Bahceci D, Wang D, Lauwers GY, Choi WT. The Development of Serrated Epithelial Change in Ulcerative Colitis is not Significantly Associated With Increased Histologic Inflammation. Am J Surg Pathol 2024; 48:719-725. [PMID: 38584461 DOI: 10.1097/pas.0000000000002216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Serrated epithelial change (SEC) in inflammatory bowel disease is most often defined as hyperplastic polyp-like mucosal change detected on random biopsies. Although SEC has been reported to be associated with an increased risk of synchronous and/or metachronous colorectal neoplasia, it remains unknown if SEC represents a form of dysplastic lesion despite the lack of morphologic evidence of dysplasia. Since the risk of colorectal neoplasia in ulcerative colitis (UC) is positively correlated with increased histologic inflammation, this study investigated if increased colonic inflammation is an independent risk factor for SEC. A cohort of 28 UC patients with SEC was analyzed and compared with 51 control UC patients without SEC. None of these patients had a history of colorectal neoplasia. For each patient with SEC, all biopsies conducted before and at the time of SEC diagnosis (versus all biopsies for each control patient) were scored by using a 4-point scoring system: no activity (no epithelial infiltration by neutrophils=0); mild activity (cryptitis only=1); moderate activity (cryptitis plus crypt abscess formation in <50% of crypts=2); and severe activity (crypt abscess formation in ≥50% of crypts, erosion, neutrophilic exudate, and/or ulceration=3). Each biopsy was designated a score, and both mean and maximum inflammation scores were calculated from all biopsies taken during each colonoscopy. The inflammation burden score was calculated for each surveillance interval by multiplying the average maximum score between each pair of surveillance episodes by the length of the surveillance interval in years. The average scores of all colonoscopies for each patient were used to assign the patient's overall mean, maximum, and inflammation burden scores. The SEC cohort included 12 (43%) men and 16 (57%) women with a mean age of 47 years at the time of the first SEC diagnosis and a long history of UC (mean: 13 y). The majority of patients (n=21; 75%) had pancolitis, and only 1 (4%) patient had primary sclerosing cholangitis. A total of 37 SEC were identified in the 28 patients, 4 (14%) of whom had multifocal SEC. SEC was predominantly found in the left colon (n=32; 86%). In the multivariate analysis, none of the 3 summative inflammation scores, including overall mean (odds ratio [OR] 1.9, P =0.489), maximum (OR 0.4, P =0.259), and inflammation burden scores (OR 1.2, P =0.223), were significantly associated with the development of SEC. Similarly, no other potential risk factors, including age, gender, ethnicity, and duration and extent of UC, were significantly correlated with the detection of SEC ( P >0.05). In conclusion, the development of SEC in UC is not significantly associated with increased histologic inflammation. Given the reported association of SEC with an increased risk of synchronous and/or metachronous colorectal neoplasia, along with the presence of molecular alterations in some cases (such as TP53 mutations and aneuploidy), SEC may represent an early morphologic indicator of segmental or pan-colonic molecular abnormalities that have not advanced enough to result in colorectal neoplasia, as opposed to being a form of dysplasia.
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Affiliation(s)
- Dorukhan Bahceci
- Department of Pathology, University of California at San Francisco, San Francisco, CA
| | - Dongliang Wang
- Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY
| | - Gregory Y Lauwers
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Won-Tak Choi
- Department of Pathology, University of California at San Francisco, San Francisco, CA
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Kellermayer R, Carbone M, Horvath TD, Szigeti RG, Buness C, Hirschfield GM, Lewindon PJ. Identifying a therapeutic window of opportunity for people living with primary sclerosing cholangitis: Embryology and the overlap of inflammatory bowel disease with immune-mediated liver injury. Hepatology 2024:01515467-990000000-00881. [PMID: 38743006 DOI: 10.1097/hep.0000000000000926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
Primary sclerosing cholangitis (PSC) is a variably progressive, fibrosis-causing autoimmune disorder of the intrahepatic and extrahepatic bile ducts of unclear etiology. PSC is commonly (in 60%-90% of cases) associated with an inflammatory bowel disease (IBD) like PSC-IBD and less commonly with an autoimmune hepatitis (AIH) like PSC-AIH or AIH-overlap disorder. Hepatologists and Gastroenterologists often consider these combined conditions as distinctly different from the classical forms in isolation. Here, we review recent epidemiologic observations and highlight that PSC-IBD and PSC-AIH overlap appear to represent aspects of a common PSC clinico-pathological pathway and manifest in an age-of-presentation-dependent manner. Particularly from the pediatric experience, we hypothesize that all cases of PSC likely originate from a complex "Early PSC"-"IBD"-"AIH" overlap in which PSC defines the uniquely and variably associated "AIH" and "IBD" components along an individualized lifetime continuum. We speculate that a distinctly unique, "diverticular autoimmunity" against the embryonic cecal- and hepatic diverticulum-derived tissues may be the origin of this combined syndrome, where "AIH" and "IBD" variably commence then variably fade while PSC progresses with age. Our hypothesis provides an explanation for the age-dependent variation in the presentation and progression of PSC. This is critical for the optimal targeting of studies into PSC etiopathogenesis and emphasizes the concept of a "developmental window of opportunity for therapeutic mitigation" in what is currently recognized as an irreversible disease process. The discovery of such a window would be critically important for the targeting of interventions, both the administration of current therapies and therapeutic trial planning.
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Affiliation(s)
- Richard Kellermayer
- Division of Pediatric Gastroenterology, Department of Pediatrics, Texas Children's Hospital; Baylor College of Medicine, Houston, Texas, USA
- USDA/ARS Children's Nutrition Research Center (CNRC), Houston, Texas, USA
| | - Marco Carbone
- Centre for Autoimmune Liver Diseases, School of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
- Liver Unit, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Thomas D Horvath
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
- Department of Pathology, Texas Children's Hospital, Houston, Texas, USA
| | - Reka G Szigeti
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Cynthia Buness
- Global Liver Institute Pediatric and Rare Liver Diseases Research Council, Washington DC, USA
- Autoimmune Liver Disease Network for Kids (A-LiNK), Stanford University, Stanford, CA, USA
- National Patient Advocate Foundation, Washington DC, USA
| | - Gideon M Hirschfield
- Department of Medicine, Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | - Peter J Lewindon
- Queensland Children's Hospital, Brisbane, QLD, Australia University of Queensland, Brisbane, QLD, Australia
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van Munster KN, Bergquist A, Ponsioen CY. Inflammatory bowel disease and primary sclerosing cholangitis: One disease or two? J Hepatol 2024; 80:155-168. [PMID: 37940453 DOI: 10.1016/j.jhep.2023.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 09/01/2023] [Accepted: 09/29/2023] [Indexed: 11/10/2023]
Abstract
Primary sclerosing cholangitis (PSC) was declared one of the biggest unmet needs in hepatology during International Liver Congress 2016 in Berlin. Since then, not much has changed unfortunately, largely due to the still elusive pathophysiology of the disease. One of the most striking features of PSC is its association with inflammatory bowel disease (IBD), with the majority of patients with PSC being diagnosed with extensive colitis. This review describes the epidemiology of IBD in PSC, its specific phenotype, complications and potential pathophysiological mechanisms connecting the two diseases. Whether PSC is merely an extra-intestinal manifestation of IBD or if PSC and IBD are two distinct diseases that happen to share a common susceptibility that leads to a dual phenotype is debated. Implications for the management of the two diseases together are also discussed. Overall, this review summarises the available data in PSC-IBD and discusses whether PSC and IBD are one or two disease(s).
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Affiliation(s)
- Kim N van Munster
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Annika Bergquist
- Department of Medicine Huddinge, Division of Hepatology, Karolinska Institutet, Department of Upper GI Disease, Karolinska University Hospital, Stockholm, Sweden
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands.
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Carbone M, Della Penna A, Mazzarelli C, De Martin E, Villard C, Bergquist A, Line PD, Neuberger JM, Al-Shakhshir S, Trivedi PJ, Baumann U, Cristoferi L, Hov J, Fischler B, Hadzic NH, Debray D, D’Antiga L, Selzner N, Belli LS, Nadalin S. Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement. Transpl Int 2023; 36:11729. [PMID: 37841645 PMCID: PMC10570452 DOI: 10.3389/ti.2023.11729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/14/2023] [Indexed: 10/17/2023]
Abstract
Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.
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Affiliation(s)
- M. Carbone
- Centre for Autoimmune Liver Diseases, Department of Medicina and Surgery, University of Milano-Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS San Gerardo dei Tintori, Monza, Italy
| | - A. Della Penna
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - C. Mazzarelli
- Hepatology and Gastroenterology Unit, ASST GOM Niguarda, Milan, Italy
| | - E. De Martin
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-Immunes, Villejuif, France
| | - C. Villard
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS San Gerardo dei Tintori, Monza, Italy
- Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - A. Bergquist
- Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - P. D. Line
- Norwegian PSC Research Center and Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - J. M. Neuberger
- Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - S. Al-Shakhshir
- National Institute for Health and Care Research (NIHR) Birmingham Liver Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - P. J. Trivedi
- National Institute for Health and Care Research (NIHR) Birmingham Liver Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - U. Baumann
- Division of Pediatric Gastroenterology, Hepatology and Liver Transplantation, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - L. Cristoferi
- Centre for Autoimmune Liver Diseases, Department of Medicina and Surgery, University of Milano-Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS San Gerardo dei Tintori, Monza, Italy
| | - J. Hov
- Norwegian PSC Research Center and Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - B. Fischler
- Department of Pediatrics, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - N. H. Hadzic
- Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College, London, United Kingdom
| | - D. Debray
- Unité d’Hépatologie Pédiatrique, Hôpital Necker-Enfants Malades, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-Immunes, Filfoie, Paris, France
| | - L. D’Antiga
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - N. Selzner
- Multiorgan Transplant Program, University of Toronto, Toronto, ON, Canada
| | - L. S. Belli
- Hepatology and Gastroenterology Unit, ASST GOM Niguarda, Milan, Italy
| | - S. Nadalin
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
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Jamil OK, Shaw D, Deng Z, Dinardi N, Fillman N, Khanna S, Krugliak Cleveland N, Sakuraba A, Weber CR, Cohen RD, Dalal S, Jabri B, Rubin DT, Pekow J. Inflammation in the proximal colon is a risk factor for the development of colorectal neoplasia in inflammatory bowel disease patients with primary sclerosing cholangitis. Therap Adv Gastroenterol 2023; 16:17562848231184985. [PMID: 37692199 PMCID: PMC10486214 DOI: 10.1177/17562848231184985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 06/12/2023] [Indexed: 09/12/2023] Open
Abstract
Background Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have an increased risk of developing colorectal neoplasia (CRN) in the proximal colon. Objectives To evaluate whether duration and severity of inflammation are linked to the development of CRN in this population. Design Retrospective, case-control chart review of patients with PSC and IBD at a tertiary care center. Methods Disease activity was scored per colonic segment at each colonoscopy prior to the first instance of observed CRN using a modified Mayo endoscopic sub-score and histologic assessment. Patients in the CRN-positive group were compared to controls that did not. Results In all, 72 PSC-IBD patients with no history of CRN were identified, 13 of whom developed CRN after at least one colonoscopy at our institution. Patients in the CRN-positive group had significantly more endoscopic (p < 0.01) and histologic (p < 0.01) inflammation in the right compared to the control group prior to the development of dysplasia. There was significantly greater endoscopic inflammation in the segment of the colon with a dysplastic lesion than other segments of the colon (p = 0.018). Patients with moderate/severe lifetime endoscopic (p = 0.02) or histologic inflammation (p = 0.04) score had a lower probability of remaining free of dysplasia during follow-up. Nearly half of the patients with dysplasia had invisible lesions found on random biopsy. Conclusions Endoscopic and histologic inflammation in the proximal colon are risk factors for CRN in patients with PSC-IBD. PSC-IBD patients frequently have subclinical inflammation, and these findings support the practice of regular assessment of disease activity and random biopsy of inflamed and uninflamed areas in patients with PSC with the goal of reducing inflammation to prevent the development of CRN.
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Affiliation(s)
- Omar K. Jamil
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Dustin Shaw
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA Digestive Diseases Research Core Center, University of Chicago Medicine, Chicago, IL, USA
| | - Zifeng Deng
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Nicholas Dinardi
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Natalie Fillman
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Shivani Khanna
- Department of Allergy and Immunology, Johns Hopkins University, Baltimore, MD, USA
| | | | - Atsushi Sakuraba
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | | | - Russell D. Cohen
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Sushila Dalal
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Bana Jabri
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA Digestive Diseases Research Core Center, University of Chicago Medicine, Chicago, IL, USA
| | - David T. Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Joel Pekow
- Inflammatory Bowel Disease Center, University of Chicago Medicine, 900 East 57th Street, MB #9, Chicago, IL 60637, USA
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11
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Waldum H, Fossmark R. Inflammation and Digestive Cancer. Int J Mol Sci 2023; 24:13503. [PMID: 37686307 PMCID: PMC10487643 DOI: 10.3390/ijms241713503] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/25/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Chronic inflammation is linked to carcinogenesis, particularly in the digestive organs, i.e., the stomach, colon, and liver. The mechanism of this effect has, however, only partly been focused on. In this review, we focus on different forms of chronic hepatitis, chronic inflammatory bowel disease, and chronic gastritis, conditions predisposing individuals to the development of malignancy. Chronic inflammation may cause malignancy because (1) the cause of the chronic inflammation is itself genotoxic, (2) substances released from the inflammatory cells may be genotoxic, (3) the cell death induced by the inflammation induces a compensatory increase in proliferation with an inherent risk of mutation, (4) changes in cell composition due to inflammation may modify function, resulting in hormonal disturbances affecting cellular proliferation. The present review focuses on chronic gastritis (Helicobacter pylori or autoimmune type) since all four mechanisms may be relevant to this condition. Genotoxicity due to the hepatitis B virus is an important factor in hepatocellular cancer and viral infection can similarly be central in the etiology and malignancy of inflammatory bowel diseases. Helicobacter pylori (H. pylori) is the dominating cause of chronic gastritis and has not been shown to be genotoxic, so its carcinogenic effect is most probably due to the induction of atrophic oxyntic gastritis leading to hypergastrinemia.
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Affiliation(s)
- Helge Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7030 Trondheim, Norway;
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12
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Yoshida H, Shiokawa M, Kuwada T, Muramoto Y, Ota S, Nishikawa Y, Maeda H, Kakiuchi N, Okamoto K, Yamazaki H, Yokode M, Nakamura T, Matsumoto S, Hirano T, Okada H, Marui S, Sogabe Y, Matsumori T, Mima A, Uza N, Eso Y, Takai A, Takahashi K, Ueda Y, Kodama Y, Chiba T, Seno H. Anti-integrin αvβ6 autoantibodies in patients with primary sclerosing cholangitis. J Gastroenterol 2023; 58:778-789. [PMID: 37310456 PMCID: PMC10366314 DOI: 10.1007/s00535-023-02006-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/31/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND Patients with primary sclerosing cholangitis (PSC) possess autoantibodies against biliary epithelial cells. However, the target molecules remain unknown. METHODS The sera of patients with PSC and controls were subjected to enzyme-linked immunosorbent assays to detect autoantibodies using recombinant integrin proteins. Integrin αvβ6 expression in the bile duct tissues was examined using immunofluorescence. The blocking activity of the autoantibodies was examined using solid-phase binding assays. RESULTS Anti-integrin αvβ6 antibodies were detected in 49/55 (89.1%) patients with PSC and 5/150 (3.3%) controls (P < 0.001), with a sensitivity and specificity of 89.1% and 96.7%, respectively, for PSC diagnosis. When focusing on the presence or absence of IBD, the proportion of the positive antibodies in PSC with IBD was 97.2% (35/36) and that in PSC alone was 73.7% (14/19) (P = 0.008). Integrin αvβ6 was expressed in bile duct epithelial cells. Immunoglobulin (Ig)G from 15/33 patients with PSC blocked integrin αvβ6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif. CONCLUSIONS Autoantibodies against integrin αvβ6 were detected in most patients with PSC; anti-integrin αvβ6 antibody may serve as a potential diagnostic biomarker for PSC.
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Affiliation(s)
- Hiroyuki Yoshida
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masahiro Shiokawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Takeshi Kuwada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuya Muramoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Sakiko Ota
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshihiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirona Maeda
- Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
| | - Nobuyuki Kakiuchi
- Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
| | - Kanako Okamoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hajime Yamazaki
- Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masataka Yokode
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeharu Nakamura
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shimpei Matsumoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Hirano
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Okada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Saiko Marui
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuko Sogabe
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomoaki Matsumori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Atsushi Mima
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuji Eso
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ken Takahashi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshihide Ueda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Kansai Electric Power Hospital, Osaka, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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13
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Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023; 20:135-154. [PMID: 36352157 DOI: 10.1038/s41575-022-00690-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut-liver axis owing to the close association between liver disease and colonic inflammation. It is well established that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut-liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut-liver axis.
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Affiliation(s)
- Johannes R Hov
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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14
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Mikolajczyk AE, Cohen NA, Watson S, Ackerman M, Goeppinger SR, Hart J, Turner JR, Rubin DT. Assessment of the Degree of Variation of Histologic Inflammation in Ulcerative Colitis. Inflamm Bowel Dis 2023; 29:222-227. [PMID: 35436339 PMCID: PMC10686247 DOI: 10.1093/ibd/izac070] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Treatment of ulcerative colitis (UC) now includes mucosal healing. Adoption of histologic end points is hindered by a lack of evidence guiding optimal sampling, interpretation, and reproducibility of results. METHODS We analyzed biopsy fragments from colonoscopies in 92 patients with UC. Fragments were scored using 6-point histologic inflammatory activity (HIA) scale. Variability was determined using ordinal representations of HIA scores. The most frequently observed score and percentage of biopsy fragments with that score were determined for each biopsy, each segment, and across all 3 segments for each colonoscopy. Mean percentages and 95% confidence intervals (CIs) were calculated. RESULTS We reviewed 1802 biopsy fragments. The mean percentages of intrasegment biopsy fragments with the same HIA score were 85.5% (95% CI, 80.9% to 92.9%), 79.6% (95% CI, 76.0% to 87.3%), and 82.7% (95% CI, 79.1% to 90.0%) for the rectum, left colon, and right colon, respectively. The mean percentage of intersegment biopsy fragments with the same HIA score was 70.2% (95% CI, 65.7% to 82.5%). The mean percentages of intrabiopsy fragments with the same HIA score were 83.3% (95% CI, 77.6% to 93.5%), 83.6% (95% CI, 80.1% to 89.7%), and 90.2% (95% CI, 87.6% to 94.7%) for the rectum, left colon, and right colon, respectively. All 3 analyses revealed increased variation when a greater degree of histologic inflammation was present in the biopsies (mean HIA score ≥2). CONCLUSIONS We found minimal variability between degree of inflammation among biopsy fragments within and among different colorectal segments in UC, suggesting that even a single biopsy would adequately reflect the inflammation of the entire colorectum. These findings have significant implications for the use of histology as a clinical target and trial end point in UC.
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Affiliation(s)
- Adam E Mikolajczyk
- University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, IL, United States
| | - Nathaniel A Cohen
- University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, IL, United States
| | - Sydeaka Watson
- University of Chicago Medicine, Department of Health Studies, Chicago, IL, United States
| | - Max Ackerman
- University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, IL, United States
| | - Sarah R Goeppinger
- University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, IL, United States
| | - John Hart
- University of Chicago Medicine, Department of Pathology, Chicago, IL, United States
| | - Jerrold R Turner
- Brigham and Women’s Hospital, Department of Pathology, Chicago, IL, United States
| | - David T Rubin
- University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, IL, United States
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15
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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16
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Laredo V, García-Mateo S, Martínez-Domínguez SJ, López de la Cruz J, Gargallo-Puyuelo CJ, Gomollón F. Risk of Cancer in Patients with Inflammatory Bowel Diseases and Keys for Patient Management. Cancers (Basel) 2023; 15:871. [PMID: 36765829 PMCID: PMC9913122 DOI: 10.3390/cancers15030871] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023] Open
Abstract
Chronic inflammation in patients with Inflammatory Bowel Disease (IBD) leads to an increased risk of colorectal cancer, small bowel cancer, intestinal lymphoma and cholangiocarcinoma. However, treatments for IBD have also been associated with an increased risk of neoplasms. Patients receiving Thiopurines (TPs) have an increased risk of hematologic malignancies, non-melanoma skin cancer, urinary tract neoplasms and cervical cancer. Anti-TNFs have been associated with a higher risk of neoplasms, mainly lymphomas and melanomas; however, the data are controversial, and some recent studies do not confirm the association. Nevertheless, other biologic agents, such as ustekinumab and vedolizumab, have not shown an increased risk of any neoplasm to date. The risk of malignancies with tofacitinib exists, but its magnitude and relationship with previous treatment with TPs is not defined, so more studies from daily clinical practice are needed. Although biologic therapy seems to be safe for patients with current cancer or a prior history of cancer, as has been demonstrated in other chronic inflammatory conditions, prospective studies in this specific population are needed. Until that time, it is crucial to manage such conditions via the combined clinical expertise of the gastroenterologist and oncologist.
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Affiliation(s)
- Viviana Laredo
- Department of Gastroenterology, Lozano Blesa University Hospital, 50009 Zaragoza, Spain
- Aragón Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
- School of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Sandra García-Mateo
- Department of Gastroenterology, Lozano Blesa University Hospital, 50009 Zaragoza, Spain
- Aragón Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
- School of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Samuel J. Martínez-Domínguez
- Department of Gastroenterology, Lozano Blesa University Hospital, 50009 Zaragoza, Spain
- Aragón Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
- School of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Julia López de la Cruz
- Department of Gastroenterology, Lozano Blesa University Hospital, 50009 Zaragoza, Spain
- Aragón Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
| | - Carla J. Gargallo-Puyuelo
- Department of Gastroenterology, Lozano Blesa University Hospital, 50009 Zaragoza, Spain
- Aragón Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
- School of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Fernando Gomollón
- Department of Gastroenterology, Lozano Blesa University Hospital, 50009 Zaragoza, Spain
- Aragón Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
- School of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
- CIBER for Liver and Digestive Diseases (CIBERehd), 28029 Madrid, Spain
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17
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Zhang R, Lauwers GY, Choi WT. Increased Risk of Non-conventional and Invisible Dysplasias in Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Disease. J Crohns Colitis 2022; 16:1825-1834. [PMID: 35771958 DOI: 10.1093/ecco-jcc/jjac090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Patients with primary sclerosing cholangitis and inflammatory bowel disease [termed PSC-IBD] have a higher risk of developing colorectal neoplasia than those with IBD alone. The mechanism by which concomitant PSC increases the risk of colorectal neoplasia remains unknown. Seven distinct non-conventional dysplastic subtypes have been recently described in IBD, including crypt cell dysplasia, hypermucinous dysplasia, goblet cell-deficient dysplasia, dysplasia with increased Paneth cell differentiation [DPD], sessile serrated lesion [SSL]-like dysplasia, traditional serrated adenoma [TSA]-like dysplasia, and serrated dysplasia, not otherwise specified [NOS]. Despite the lack of high-grade morphological features, crypt cell, hypermucinous, and goblet cell-deficient dysplasias often show molecular features characteristic of advanced neoplasia [i.e. aneuploidy and KRAS mutations] and are more frequently associated with advanced neoplasia than conventional dysplasia on follow-up. We aimed to characterise clinicopathological features of dysplasia found in PSC-IBD patients. METHODS A cohort of 173 PSC-IBD patients were analysed. All dysplastic lesions were subtyped as either conventional or non-conventional dysplasia. The clinicopathological features of PSC-IBD patients with neoplasia were also compared with those of non-PSC IBD patients with neoplasia. RESULTS There were 109 [63%] men and 64 [37%] women, with a mean age of 26 years at IBD diagnosis and a long history of IBD [mean duration: 14 years]. Ulcerative colitis was the most common IBD subtype [80%], and the majority of patients [92%] had a history of pancolitis. A total of 153 dysplastic lesions were detected in 54 [31%] patients, 35 [65%] of whom had multifocal dysplasia. One additional patient presented with colorectal cancer [CRC] without a history of dysplasia. Dysplasia was often non-conventional [n = 93; 61%], endoscopically/grossly invisible [n = 101; 66%], and right/proximal-sided [n = 90; 59%]. All seven non-conventional subtypes were identified, including 46 [30%] crypt cell dysplasia, 23 [15%] hypermucinous dysplasia, 12 [8%] goblet cell-deficient dysplasia, seven [5%] DPD, three [2%] TSA-like dysplasia, one [1%] SSL-like dysplasia, and one [1%] serrated dysplasia NOS. Follow-up information was available for 86 lesions, of which 32 [37%] were associated with subsequent detection of advanced neoplasia [high-grade dysplasia or CRC] within a mean follow-up time of 55 months. PSC-IBD patients with neoplasia were more likely to have pancolitis [98%, p = 0.039] and a longer IBD duration [mean: 17 years, p = 0.021] than those without neoplasia [89% and 12 years, respectively]. When compared with a cohort of non-PSC IBD patients with neoplasia, the PSC-IBD group with neoplasia was more often associated with non-conventional [61%, p <0.001], invisible [66%, p <0.001], and right/proximal-sided [59%, p = 0.045] dysplasias [vs 25%, 21%, and 47%, respectively, for the non-PSC IBD group]. The rate of advanced neoplasia was nearly 2-fold higher in the PSC-IBD group [37%] compared with the non-PSC IBD group [22%] [p = 0.035]. CONCLUSIONS Nearly a third of PSC-IBD patients developed dysplasia, which is often associated with non-conventional dysplastic features, invisible endoscopic/gross appearance, right/proximal-sided colon, multifocality, and advanced neoplasia on follow-up. These findings underscore the importance of recognising these non-conventional subtypes by practising pathologists and the need for careful and frequent endoscopic surveillance, with random biopsies, in PSC-IBD patients.
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Affiliation(s)
- Ruth Zhang
- University of California at San Francisco, Department of Pathology, San Francisco, CA, USA
| | - Gregory Y Lauwers
- H. Lee Moffitt Cancer Center and Research Institute, Department of Pathology, Tampa, FL, USA
| | - Won-Tak Choi
- University of California at San Francisco, Department of Pathology, San Francisco, CA, USA
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18
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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19
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Colorectal Cancer in Ulcerative Colitis: Mechanisms, Surveillance and Chemoprevention. Curr Oncol 2022; 29:6091-6114. [PMID: 36135048 PMCID: PMC9498229 DOI: 10.3390/curroncol29090479] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/14/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
Patients with ulcerative colitis (UC) are at a two- to three-fold increased risk of developing colorectal cancer (CRC) than the general population based on population-based data. UC-CRC has generated a series of clinical problems, which are reflected in its worse prognosis and higher mortality than sporadic CRC. Chronic inflammation is a significant contributor to the development of UC-CRC, so comprehending the relationship between the proinflammatory factors and epithelial cells together with downstream signaling pathways is the core to elucidate the mechanisms involved in developing of CRC. Clinical studies have shown the importance of early prevention, detection and management of CRC in patients with UC, and colonoscopic surveillance at regular intervals with multiple biopsies is considered the most effective way. The use of endoscopy with targeted biopsies of visible lesions has been supported in most populations. In contrast, random biopsies in patients with high-risk characteristics have been suggested during surveillance. Some of the agents used to treat UC are chemopreventive, the effects of which will be examined in cancers in UC in a population-based setting. In this review, we outline the current state of potential risk factors and chemopreventive recommendations in UC-CRC, with a specific focus on the proinflammatory mechanisms in promoting CRC and evidence for personalized surveillance.
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Nguyen ED, Wang D, Lauwers GY, Choi WT. Increased Histologic Inflammation is an Independent Risk Factor for Non-Conventional Dysplasia in Ulcerative Colitis. Histopathology 2022; 81:644-652. [PMID: 35942654 DOI: 10.1111/his.14765] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/18/2022] [Accepted: 08/05/2022] [Indexed: 11/28/2022]
Abstract
AIMS Several types of non-conventional dysplasia have been described in inflammatory bowel disease. Hypermucinous, goblet cell deficient, and crypt cell dysplasias are considered high-risk subtypes, as they often have molecular features of advanced neoplasia (e.g., aneuploidy) and are more frequently associated with advanced neoplasia than conventional dysplasia. This study investigated if increased colonic inflammation is a risk factor for non-conventional dysplasia. METHODS AND RESULTS A cohort of 125 patients with ulcerative colitis (UC)-associated dysplasia were analyzed and compared with 50 control UC patients without a history of neoplasia. For each patient, all biopsies prior to the initial detection of dysplasia were scored using a 4-point inflammatory activity score. Both mean and maximum scores from all biopsies taken during each colonoscopy were derived. Inflammation burden was calculated by multiplying average maximum score between each pair of surveillance episodes by length of surveillance interval in years. The average scores of all colonoscopies were used to calculate overall mean, maximum, and inflammation burden scores. In multivariate analyses, higher maximum (odds ratio [OR] 3.4) and inflammation burden (OR 4.2) scores were significantly associated with the detection of dysplasia (p < 0.05). Similarly, higher mean and maximum scores increased the odds of non-conventional dysplasia by 2.7 and 4.9, respectively (p < 0.05). There was a stronger association between these two scores and high-risk subtypes (ORs 4.0 and 7.5, respectively, p < 0.05). CONCLUSIONS The risk of non-conventional dysplasia is significantly associated with increased inflammation, which may contribute to its higher rates of aneuploidy and malignancy.
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Affiliation(s)
- Eric D Nguyen
- University of California at San Francisco, Department of Pathology, San Francisco, CA, 94143, USA
| | - Dongliang Wang
- SUNY Upstate Medical University, Department of Public Health and Preventive Medicine, Syracuse, NY, 13210, USA
| | - Gregory Y Lauwers
- H. Lee Moffitt Cancer Center and Research Institute, Department of Pathology, Tampa, FL, 33612, USA
| | - Won-Tak Choi
- University of California at San Francisco, Department of Pathology, San Francisco, CA, 94143, USA
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21
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Akiyama S, Fukuda S, Steinberg JM, Suzuki H, Tsuchiya K. Characteristics of inflammatory bowel diseases in patients with concurrent immune-mediated inflammatory diseases. World J Gastroenterol 2022; 28:2843-2853. [PMID: 35978883 PMCID: PMC9280738 DOI: 10.3748/wjg.v28.i25.2843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/10/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are more likely to have concurrent immune-mediated inflammatory diseases (IMIDs) than those without IBD. IMIDs have been observed to alter the phenotype and outcomes of IBD in recent studies. Several studies have found that IBD patients with concurrent IMIDs may have more extensive or severe disease phenotypes, and are considered to be at increased risk of requiring biologics and IBD-related surgeries, suggesting that having multiple IMIDs is a poor prognostic factor for IBD. Furthermore, IBD patients with primary sclerosing cholangitis and Takayasu arteritis are reported to have unique endoscopic phenotypes, suggesting concurrent IMIDs can influence IBD phenotype with specific intestinal inflammatory distributions. In this review, we discuss the pathogenesis, disease phenotypes, and clinical outcomes in IBD patients with concomitant IMIDs.
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Affiliation(s)
- Shintaro Akiyama
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Soma Fukuda
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Joshua M Steinberg
- Inflammatory Bowel Disease, Gastroenterology of the Rockies, Denver, CO 80218, United States
| | - Hideo Suzuki
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
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22
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Núñez F P, Quera R, Rubin DT. Endoscopic colorectal cancer surveillance in inflammatory bowel disease: Considerations that we must not forget. World J Gastrointest Endosc 2022; 14:85-95. [PMID: 35316980 PMCID: PMC8908328 DOI: 10.4253/wjge.v14.i2.85] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/02/2021] [Accepted: 01/23/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic immune-mediated inflammatory disease that primarily affects the gastrointestinal tract and is characterized by periods of activity and remission. The inflammatory activity of the disease involving the colon and rectum increases the risk of colorectal cancer (CRC) over the years. Although prevention strategies are evolving, regular surveillance for early detection of neoplasia as a secondary prevention strategy is paramount in the care of IBD patients. In this review article, we discuss the current evidence of the risks of developing CRC and evaluate the best available strategies for screening and surveillance, as well as future opportunities for cancer prevention.
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Affiliation(s)
- Paulina Núñez F
- Universidad de los Andes, Digestive Disease Center, Inflammatory Bowel Disease Program, Clinica, Santiago 7620157, RM, Chile
- Department of Gastroenterology, Hospital San Juan de Dios. Universidad de Chile, Santiago 7701230, RM, Chile
| | - Rodrigo Quera
- Universidad de los Andes, Digestive Disease Center, Inflammatory Bowel Disease Program, Clinica, Santiago 7620157, RM, Chile
| | - David T Rubin
- Medicine Inflammatory Bowel Disease Center, University of Chicago, Chicago, IL 60637, United States
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23
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Ranasinghe R, Mathai M, Zulli A. A synopsis of modern - day colorectal cancer: Where we stand. Biochim Biophys Acta Rev Cancer 2022; 1877:188699. [DOI: 10.1016/j.bbcan.2022.188699] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/30/2022] [Accepted: 02/14/2022] [Indexed: 02/07/2023]
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24
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Popa IV, Burlacu A, Gavrilescu O, Dranga M, Prelipcean CC, Mihai C. A new approach to predict ulcerative colitis activity through standard clinical–biological parameters using a robust neural network model. Neural Comput Appl 2021. [DOI: 10.1007/s00521-021-06055-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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25
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Characteristic features of ulcerative colitis with concomitant primary sclerosing cholangitis. PRZEGLAD GASTROENTEROLOGICZNY 2021; 16:184-187. [PMID: 34584578 PMCID: PMC8456759 DOI: 10.5114/pg.2021.108983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 01/30/2021] [Indexed: 11/17/2022]
Abstract
Ulcerative colitis is a chronic inflammatory bowel disease of the colon. The most frequent symptoms include bloody diarrhoea with rectal urgency and tenesmus. It is often complicated by the presence of primary sclerosing cholangitis, a chronic, cholestatic liver disease, characterised by the inflammation and fibrosis of bile ducts. The presence of primary sclerosing cholangitis seems to alter the course of ulcerative colitis, changing its natural course.
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26
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The characteristics of pediatric ulcerative colitis with primary sclerosing cholangitis: A single-center study in Taiwan. Pediatr Neonatol 2021; 62:483-490. [PMID: 34074613 DOI: 10.1016/j.pedneo.2021.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 01/17/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is often associated with ulcerative colitis (UC). We investigated the clinical characteristics of pediatric UC patients with and without PSC. METHODS We retrospectively recruited children with UC, with and without PSC, from 2006 to 2017 in a tertiary center in Taiwan. The clinical data of the patients, including clinical and endoscopic UC severity scores, medications, and laboratory parameters, were analyzed. RESULTS We recruited five children with PSC-UC (PSC-UC group), and 26 with UC alone (non-PSC UC group) in this retrospective analysis. Among the patients with PSC-UC, four (80%) were compatible with definite or probable autoimmune sclerosing cholangitis (ASC). The UC Endoscopic Index of Severity (5.00 vs. 9.00, P = 0.003) and Mayo score (4.00 vs. 8.00, P = 0.014) were significantly lower in the PSC-UC group than the non-PSC UC group. The prevalence of immunomodulator use was significantly higher in the PSC-UC than the non-PSC UC group (100% vs. 42.3%, P = 0.043), but there was no difference regarding steroids, mesalamine, or biologics. At the end of the study, significantly fewer patients were steroid-free in the PSC-UC than the non-PSC UC group (20.0% vs. 84.6%, P = 0.010). CONCLUSIONS Pediatric patients with PSC-UC had less severe colitis than those with UC alone in terms of the clinical activity index and endoscopic severity index, but they were more likely to need an immunomodulator and less likely to be steroid-free in the long term, for the control of liver disease.
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27
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The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies. Int J Mol Sci 2021; 22:ijms22136975. [PMID: 34203536 PMCID: PMC8268159 DOI: 10.3390/ijms22136975] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.
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28
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Attauabi M, Zhao M, Bendtsen F, Burisch J. Systematic Review with Meta-analysis: The Impact of Co-occurring Immune-mediated Inflammatory Diseases on the Disease Course of Inflammatory Bowel Diseases. Inflamm Bowel Dis 2021; 27:927-939. [PMID: 32628745 DOI: 10.1093/ibd/izaa167] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Patients with inflammatory bowel diseases (IBDs) are at risk of developing a variety of other immune-mediated inflammatory diseases (IMIDs). The influence of co-occurring IMIDs on the disease course of IBD remains unknown. The aim of this study was therefore to conduct a systematic review and meta-analysis of the impact of IMIDs on phenotypic presentation and outcome in patients with IBD. METHODS PubMed and Embase were searched from their earliest records through December 2018 and updated in October 2019 for studies reporting proportions or ratios of IBD-related disease outcomes in patients with and without co-occurring IMIDs. Meta-analyses were performed to estimate summary proportions and risks of the main outcomes. PRISMA guidelines were used, and study quality was assessed according to the Newcastle-Ottawa Scale. RESULTS A total of 93 studies were identified, comprising 16,064 IBD patients with co-occurring IMIDs and 3,451,414 IBD patients without IMIDs. Patients with IBD and co-occurring IMIDs were at increased risk of having extensive colitis or pancolitis (risk ratio, 1.38; 95% Cl, 1.25-1.52; P < 0.01, I2 = 86%) and receiving IBD-related surgeries (risk ratio, 1.17; 95% Cl, 1.01-1.36; P = 0.03; I2 = 85%) compared with patients without IMIDs. Co-occurrence of IMIDs other than primary sclerosing cholangitis in patients with IBD was associated with an increased risk of receiving immunomodulators (risk ratio, 1.15; 95% Cl, 1.06-1.24; P < 0.01; I2 = 60%) and biologic therapies (risk ratio, 1.19; 95% Cl, 1.08-1.32; P < 0.01; I2 = 53%). CONCLUSION This meta-analysis found that the presence of co-occurring IMIDs influences the disease course of IBD, including an increased risk of surgery and its phenotypical expression.
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Affiliation(s)
- Mohamed Attauabi
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mirabella Zhao
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Johan Burisch
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
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29
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Moderate-to-severe Endoscopic Inflammation is Frequent After Clinical Remission in Pediatric Ulcerative Colitis. J Pediatr Gastroenterol Nutr 2021; 72:569-573. [PMID: 33346576 DOI: 10.1097/mpg.0000000000003018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Pediatric ulcerative colitis (UC) is characterized by low sustained remission rates and frequent extension of disease even if clinical remission is obtained with therapy. Moderate-to-severe endoscopic activity is a risk factor for relapse while prospective evidence regarding early mucosal healing or persistence of inflammation after remission in children is not available. Our aim was to evaluate if significant inflammation is common after clinical remission and could explain the high relapse rate in pediatric UC. METHODS Pediatric UC patients with clinical remission, defined as pediatric UC activity index (PUCAI) scores <10, were prospectively assessed for mucosal healing by endoscopy 3 to 5 months after remission was documented. Mayo score was assessed for each segment by a blinded adult gastroenterologist using central reading. Symptomatic patients before sigmoidoscopy were excluded. Sustained remission was assessed retrospectively at 18 months follow-up. RESULTS Forty-two children were screened, 28 children in continuous clinical remission at time of sigmoidoscopy were included. Mayo 0 was present in 12/28 (42.86%), Mayo 1 in 2/28 (7.1%) and Mayo 2 to 3 in 14/28 (50.0%) endoscopies. Among 23 patients with follow-up through 18 months, remission was sustained in 6/12 (50.0%) with Mayo score 0 to 1 versus 2/11 (18.18%) of patients with Mayo 2 and 3. CONCLUSIONS Over 50% of children assessed for mucosal healing 3 to 5 months after clinical remission is obtained, have endoscopic disease, primarily moderate-to-severe Mayo 2 to 3 inflammation, which was associated with lower sustained remission.
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30
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Shen B. Oral vancomycin in the treatment of primary sclerosing cholangitis-associated pouchitis. Gastroenterol Rep (Oxf) 2021; 9:274-275. [PMID: 34316379 PMCID: PMC8309678 DOI: 10.1093/gastro/goab004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/15/2020] [Accepted: 08/31/2020] [Indexed: 11/24/2022] Open
Affiliation(s)
- Bo Shen
- Center for Inflammatory Bowel Disease, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA
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31
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Little R, Wine E, Kamath BM, Griffiths AM, Ricciuto A. Gut microbiome in primary sclerosing cholangitis: A review. World J Gastroenterol 2020; 26:2768-2780. [PMID: 32550753 PMCID: PMC7284173 DOI: 10.3748/wjg.v26.i21.2768] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/27/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and stricturing. Exploration of the pathogenesis of PSC in light of its association with inflammatory bowel disease (IBD) and the “gut-liver” axis is an emerging area of interest. A growing number of studies have begun to elucidate the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSC-IBD. Studies of the fecal microbiota have highlighted enriched levels of certain species, including Veillonella, Streptococcus and Enterococcus, among others. A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated. For example, Klebsiella pneumoniae strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses. Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites, including bile acids (BAs), which function as signaling molecules with important gut and hepatic effects. An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and fecal microbial transplantation. Some of these have already shown some preliminary evidence of benefit. Despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations. In this review, we summarize studies that have investigated the microbiome in PSC and PSC-IBD as well as putative mechanisms, including the potential role of metabolites, such as BAs. We then briefly review the evidence for interventions with microbe-altering properties for treating PSC.
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Affiliation(s)
- Rebecca Little
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Eytan Wine
- Division of Pediatric Gastroenterology and Nutrition, 7-142H Katz Group – Rexall Centre, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Anne M Griffiths
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Amanda Ricciuto
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
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Primary Sclerosing Cholangitis in Children With Inflammatory Bowel Diseases Is Associated With Milder Clinical Activity But More Frequent Subclinical Inflammation and Growth Impairment. Clin Gastroenterol Hepatol 2020; 18:1509-1517.e7. [PMID: 31493578 DOI: 10.1016/j.cgh.2019.08.048] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 07/29/2019] [Accepted: 08/16/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Although inflammatory bowel diseases (IBD) associated with primary sclerosing cholangitis (PSC) have been well characterized in adults, there have been few pediatric studies, and these were small and produced conflicting results. We investigated features of PSC-IBD in children, compared with children with IBD without PSC. METHODS We performed a retrospective study of 74 children with PSC-IBD, diagnosed from 2000 through 2018, who were each matched with 2 children with ulcerative colitis or IBD-unclassified (controls) based on sex, date of birth, and type of IBD. We compared IBD distribution and clinical activity (remission, medication use, hospitalization, or colectomy) and patient growth between groups. Data were extracted from each hospital contact and analyzed using mixed effects analyses or Cox proportional hazards regression, adjusting for time-dependent medication exposure. RESULTS Higher proportions of children with PSC-IBD had backwash ileitis, pancolitis, and rectal sparing, and more severe right-sided disease, than controls (P < .05). Patients with PSC-IBD were more likely to be treated with only 5-ASA, compared with controls (odds ratio [OR], 3.04; 95% CI, 1.44-6.41) and to have IBD in clinical remission (OR, 2.94; 95% CI, 1.78-4.87). Risk of colectomy or treatment with a biologic agent was lower in patients with PSC-IBD than controls (hazard ratio, 0.24; 95% CI, 0.12-0.52). However, determination of IBD severity based on symptoms underestimated severity based on endoscopic activity in patients with PSC-IBD. Among patients with IBD in clinical remission, those with PSC were less likely to have endoscopic remission (OR, 0.44; 95% CI, 0.20-0.96). Patients with PSC-IBD were shorter and had lower weight over time, compared with controls. CONCLUSIONS In a retrospective study, we found that features of IBD differed between children with vs without PSC, similar to adults. Despite the mild clinical activity of IBD in patients with PSC, lack of symptoms does not always indicate lack of mucosal inflammation. Children with PSC-IBD have greater growth impairments compared with children with ulcerative colitis or IBD-unclassified.
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Van Der Have M, Oldenburg B. Is Ulcerative Colitis Associated With Primary Sclerosing Cholangitis an Undertreated Condition? Inflamm Bowel Dis 2020; 26:780-781. [PMID: 31626699 DOI: 10.1093/ibd/izz211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Indexed: 12/29/2022]
Abstract
Wang et al. report that ulcereative colitis–primary sclerosing cholangitis (UC-PSC) patients less commonly receive corticosteroids and anti-TNFα therapy, despite having more pancolonic involvement compared with UC. Whether UC-PSC is an undertreated condition will be discussed in this editorial.
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Affiliation(s)
- Mike Van Der Have
- Department Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Bas Oldenburg
- Department Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
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34
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Vessby J, Lampinen M, Åberg M, Rorsman F, Siegbahn A, Wanders A, Carlson M. Tissue factor in ulcerative colitis, with and without concomitant primary sclerosing cholangitis. Ups J Med Sci 2019; 124:238-245. [PMID: 31774347 PMCID: PMC6968534 DOI: 10.1080/03009734.2019.1689209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background: Ulcerative colitis (UC) in patients with the severe disease primary sclerosing cholangitis (PSC) constitutes a distinct clinical phenotype (PSC-UC) with a high incidence of colorectal cancer. Today, PSC-UC diagnosis is built on clinical observations only. Tissue factor (TF) has a potential use in UC diagnostics, and also in colorectal cancer prognostication. Here we evaluate TF expression in an inflammatory bowel disease (IBD) cohort, with special focus on differences between UC and PSC-UC patients.Materials and methods: Colonic biopsies from UC (n = 23), PSC (n = 24), and healthy controls (n = 11) were stained for TF by immunohistochemistry. Mononuclear cell contribution to TF expression was verified using flow cytometry.Results: TF was distributed at three distinct colonic locations: in subepithelial pericryptal sheath cells, in mononuclear cells, and in the intestinal stroma. In contrast to UC-where inflammation was accompanied with TF up-regulation-PSC-UC activity remained low during inflammation. Stromal TF positivity was found exclusively in ongoing inflammation.Conclusion: Our study provides additional support for a divergent pathogenesis in PSC-UC, with an inflammatory environment that differs from classical UC. Stromal TF emerges as a new marker of colonic inflammation.
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Affiliation(s)
- Johan Vessby
- Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden
| | - Maria Lampinen
- Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden
| | - Mikael Åberg
- Department of Medical Sciences, Clinical Chemistry and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Fredrik Rorsman
- Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden
| | - Agneta Siegbahn
- Department of Medical Sciences, Clinical Chemistry and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Alkwin Wanders
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Marie Carlson
- Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden
- CONTACT Marie Carlson Gastroenterology Research Group, Department of Medical Sciences, University Hospital Akademiska, S-751 85 Uppsala, Sweden
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Stokkeland K, Höijer J, Bottai M, Söderberg-Löfdal K, Bergquist A. Statin Use Is Associated With Improved Outcomes of Patients With Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol 2019; 17:1860-1866.e1. [PMID: 30448601 DOI: 10.1016/j.cgh.2018.11.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/09/2018] [Accepted: 11/02/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is increasing evidence that statins can benefit patients with chronic liver diseases, but their effects have not been studied in patients with primary sclerosing cholangitis (PSC). We performed a nationwide study in Sweden to determine the effects of exposure to drugs, including statins, in patients with PSC. METHODS We studied a population-based cohort of patients in Sweden with PSC and concomitant ulcerative colitis or Crohn's disease from 2005 through 2014 (n = 2914), followed through 2016. We collected analyzed data from the patient register, the prescribed drug register, the death certificate register and the cancer register. We calculated risk or death, liver transplantation, bleeding of esophageal varices, and cancer in relation to drug exposure. RESULTS The mean age of patients at the time of diagnosis with PSC was 41.4 years (inter-quartile range [IQR], 25.6-56.1 years). The total follow-up time was 11769 person-years, during which 3.4% of patients received liver transplants and 19.9% died. Proportions of patients exposed to drugs were: ursodeoxycholic acid, 60.2%; 5-aminosalicylic acid, 74.4%; azathioprine or mercaptopurins, 33.7%; and statins, 13.9%. Statin use was associated with a reduced risk of all-cause mortality (hazard ratio [HR], 0.68; 95% CI, 0.54-0.88) and death or liver transplantation (HR, 0.50; 95% CI, 0.28-0.66). Use of azathioprine was also associated with reduced mortality (HR, 0.66; 95% CI, 0.52-0.84) and risk of death or liver transplantation (HR, 0.65; 95% CI, 0.50-0.83). Exposure to ursodeoxycholic acid did not affect mortality (HR, 1.04; 95% CI, 0.87-1.25). CONCLUSION In a population-based cohort of patients in Sweden with PSC, we associated use of statins and azathioprine with decreased risks of death and death or liver transplantation. Exposure to ursodeoxycholic acid was not associated with reduced mortality.
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Affiliation(s)
- Knut Stokkeland
- Department of Medicine, Visby Hospital, Visby, Sweden; Department of Medicine Huddinge, Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Stockholm, Sweden
| | - Jonas Höijer
- Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Matteo Bottai
- Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Karin Söderberg-Löfdal
- Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Annika Bergquist
- Department of Medicine Huddinge, Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Stockholm, Sweden; Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.
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Shen M, Meng L. Peripheral blood miR-372 as a biomarker for ulcerative colitis via direct targeting of NLRP12. Exp Ther Med 2019; 18:1486-1492. [PMID: 31363381 DOI: 10.3892/etm.2019.7707] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 09/28/2018] [Indexed: 12/15/2022] Open
Abstract
The present study aimed to investigate the expression pattern and underlying mechanism of microRNA-372 (miR-372) in the progression of ulcerative colitis (UC). Reverse transcription-quantitative polymerase chain reaction was used to measure miR-372 expression levels in the blood and colonic mucosa tissue samples from patients with UC. The present study demonstrated that levels of miR-372 were significantly increased in the blood and colonic mucosa tissue samples from patients with UC compared with healthy controls. Furthermore, the level of serum miR-372 was positively correlated with the level of serum c-reactive protein. Receiver operating characteristic analysis indicated that levels of miR-372 detected in serum and tissue samples could be used to screen for patients with UC from healthy controls. These results indicated a potential role of miR-372 as a diagnostic marker and therapeutic target for patients with UC. Furthermore, a conserved miR-372 binding site in the 3'untranslated region of the NLR family pyrin domain containing 12 (NLRP12) was identified. Dual luciferase assay demonstrated that overexpression of miR-372 significantly reduced the relative luciferase activity of pmirGLO-NLRP12-3'UTR compared with control pmirGLO. In addition, western blot analysis indicated that overexpression of miR-372 significantly decreased the protein expression level of NLRP12. Therefore it was hypothesized that miR-372 may promote the progression of UC by suppressing NLRP12 protein expression and thereby inducing the excessive production of inflammatory cytokines. In conclusion, high levels of miR-372 detected in peripheral blood samples may serve a role as a potential biomarker to screen potential patients with UC from healthy controls.
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Affiliation(s)
- Mengdie Shen
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Li'Na Meng
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
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Núñez F P, Quera P R, Gomollón F. Primary sclerosing cholangitis and inflammatory bowel disease: Intestine-liver interrelation. GASTROENTEROLOGIA Y HEPATOLOGIA 2019; 42:316-325. [PMID: 30948141 DOI: 10.1016/j.gastrohep.2019.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 02/05/2019] [Accepted: 02/06/2019] [Indexed: 02/08/2023]
Abstract
The association between inflammatory bowel disease (IBD) and primary sclerosing cholangitis should be considered a distinct clinical entity. This association involves genetic abnormalities, epidemiological factors (more common in men, with no a geographical pattern) and, commonly, subclinical inflammation, predominance of the right colon (endoscopic and histological), backwash ileitis and rectal sparing. Furthermore, there is an increased risk of colorectal cancer and cholangiocarcinoma. The aim of this review is to show how IBD influences the progression of this entity, transplantation requirements and recurrence. We also discuss the current evidence on the use of biological therapy in this group of patients.
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Affiliation(s)
- Paulina Núñez F
- Fellow Programa Enfermedad Inflamatoria Universidad de Chile-Clínica Las Condes. Servicio de Gastroenterología, Hospital San Juan de Dios, Santiago, Chile.
| | - Rodrigo Quera P
- Programa Enfermedad Inflamatoria; Servicio de Gastroenterología, Clínica Las Condes, Santiago, Chile
| | - Fernando Gomollón
- Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa, IIS Aragón, Ciberehd, Zaragoza, España
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38
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Abstract
Ulcerative colitis (UC) is an idiopathic inflammatory disorder. These guidelines indicate the preferred approach to the management of adults with UC and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. In instances where the evidence was not appropriate for GRADE, but there was consensus of significant clinical merit, "key concept" statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not only, approach to clinical scenarios.
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Affiliation(s)
- David T Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA, USA
| | - Corey A Siegel
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
| | - Bryan G Sauer
- Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Millie D Long
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
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39
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Fousekis FS, Theopistos VI, Mitselos IV, Skamnelos A, Kavvadias A, Katsanos KH, Christodoulou DK. Specific Features of Patients With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis. J Clin Med Res 2019; 11:81-88. [PMID: 30700999 PMCID: PMC6340671 DOI: 10.14740/jocmr3680] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 11/20/2018] [Indexed: 12/12/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic and progressive disease of the biliary tract. PSC is strongly associated with inflammatory bowel disease (IBD), mainly with ulcerative colitis, and most PSC patients have underlying IBD. The pathophysiological interactions between IBD and PSC are unclear, although it seems that the patients with IBD and PSC have a distinct phenotype. IBD with coexisting PSC is more extensive and is characterized by milder activity compared to IBD alone. The coexistence of PSC increases the risk for colorectal cancer in IBD patients and lifelong annual surveillance colonoscopy is recommended. Also, liver transplantation (LT) for PSC may affect the course of IBD. In addition, the management of IBD after LT includes many specific problems. On the other hand, the effect of IBD on the natural history of PSC appears to be milder. However, IBD may increase the risk of postsurgical complications after LT and is a risk factor for recurrent PSC after LT. Overall, the coexistence of IBD with PSC changes the management, natural history and prognosis of both diseases.
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Affiliation(s)
- Fotios S. Fousekis
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Vasileios I. Theopistos
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Ioannis V. Mitselos
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Alexandros Skamnelos
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Athanasios Kavvadias
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Konstantinos H. Katsanos
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Dimitrios K. Christodoulou
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
- Corresponding Author: Dimitrios K. Christodoulou, Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina 45100, Greece.
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40
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Floreani A, De Martin S, Secchi MF, Cazzagon N. Extrahepatic autoimmunity in autoimmune liver disease. Eur J Intern Med 2019; 59:1-7. [PMID: 30360943 DOI: 10.1016/j.ejim.2018.10.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 10/16/2018] [Indexed: 02/07/2023]
Abstract
The most important autoimmune liver disease include: autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. In general, about one in three patients with an autoimmune liver disease have a concomitant extrahepatic autoimmune disease, which may include rheumatological, endocrinological, gastrointestinal, pulmonary or dermatological conditions. The pathogenesis of these conditions includes the production of both innate and adaptive immune responses targeting cholangiocytes as well as different extrahepatic tissues. In this sense, extrahepatic autoimmunity represent a continuous spectrum of autoimmunity involving liver and extrahepatic tissues. This review aims to focus the clinical and pathophysiological aspects of extrahepatic autoimmunity associated to autoimmune liver diseases.
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Affiliation(s)
- Annarosa Floreani
- Dept of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Italy.
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Maria Francesca Secchi
- Dept of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Italy
| | - Nora Cazzagon
- Dept of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Italy
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41
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Trivedi PJ, Reece J, Laing RW, Slaney E, Cooney R, Gunson BK, Kamarajah SK, Pinkney T, Thompson F, Muiesan P, Schlegel A, Hirschfield GM, Iqbal T, Ferguson J. The impact of ileal pouch-anal anastomosis on graft survival following liver transplantation for primary sclerosing cholangitis. Aliment Pharmacol Ther 2018; 48:322-332. [PMID: 29882252 DOI: 10.1111/apt.14828] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 03/25/2018] [Accepted: 05/08/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Liver transplantation is the only life-extending intervention for primary sclerosing cholangitis (PSC). Given the co-existence with colitis, patients may also require colectomy; a factor potentially conferring improved post-transplant outcomes. AIM To determine the impact of restorative surgery via ileal pouch-anal anastomosis (IPAA) vs retaining an end ileostomy on liver-related outcomes post-transplantation. METHODS Graft survival was evaluated across a prospectively accrued transplant database, stratified according to colectomy status and type. RESULTS Between 1990 and 2016, 240 individuals with PSC/colitis underwent transplantation (cumulative 1870 patient-years until first graft loss or last follow-up date), of whom 75 also required colectomy. A heightened incidence of graft loss was observed for the IPAA group vs those retaining an end ileostomy (2.8 vs 0.4 per 100 patient-years, log-rank P = 0.005), whereas rates between IPAA vs no colectomy groups were not significantly different (2.8 vs 1.7, P = 0.1). In addition, the ileostomy group experienced significantly lower graft loss rates vs. patients retaining an intact colon (P = 0.044). The risks conferred by IPAA persisted when taking into account timing of colectomy as related to liver transplantation via time-dependent Cox regression analysis. Hepatic artery thrombosis and biliary strictures were the principal aetiologies of graft loss overall. Incidence rates for both were not significantly different between IPAA and no colectomy groups (P = 0.092 and P = 0.358); however, end ileostomy appeared protective (P = 0.007 and 0.031, respectively). CONCLUSION In PSC, liver transplantation, colectomy + IPAA is associated with similar incidence rates of hepatic artery thrombosis, recurrent biliary strictures and re-transplantation compared with no colectomy. Colectomy + end ileostomy confers more favourable graft outcomes.
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Affiliation(s)
- P J Trivedi
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK.,Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - J Reece
- Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | - R W Laing
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | - E Slaney
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | - R Cooney
- Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | - B K Gunson
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | - S K Kamarajah
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - T Pinkney
- Department of Colorectal Surgery, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | - F Thompson
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - P Muiesan
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | - A Schlegel
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK.,Swiss HPB and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | - G M Hirschfield
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - T Iqbal
- Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK
| | - J Ferguson
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, UK
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42
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Symptoms Do Not Correlate With Findings From Colonoscopy in Children With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol 2018; 16:1098-1105.e1. [PMID: 29378308 DOI: 10.1016/j.cgh.2018.01.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 01/09/2018] [Accepted: 01/12/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Approximately 75% of children with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). IBD in patients with PSC (PSC-IBD) often has a unique phenotype, including a mild clinical course, yet it is associated with an increased risk of colorectal cancer compared with colonic IBD without PSC. We investigated whether subclinical endoscopic and histologic inflammation could account for the increased risk of colorectal cancer in patients with PSC-IBD, and whether these patients have increased fecal levels of calprotectin, a marker of inflammation. METHODS We performed a prospective study of children (age, <18 y) with colonic IBD with and without PSC who underwent colonoscopy from February 1, 2016, through March 31, 2017, at the Hospital for Sick Children in Toronto, Canada. We collected pediatric ulcerative colitis activity index (PUCAI) scores (to measure symptoms) and fecal levels of calprotectin from 37 children with PSC-IBD and 50 children with only IBD (controls; UC or IBD-unclassified). Colonoscopies were scored using the Mayo endoscopic subscore and the UC Endoscopic Index of Severity (UCEIS) scores, and histologic activity was graded. Among patients in clinical remission, endoscopic scores and the odds of active endoscopic disease (based on a UCEIS score ≥1) were compared between patients with and without PSC in univariate and multivariable analyses. Correlations between activity markers were compared between groups. The ability of fecal calprotectin to identify mucosal healing in patients with PSC-IBD was assessed using receiver operating characteristic curve analyses. Analogous analyses were performed for histologic activity. RESULTS Patients with PSC-IBD in clinical remission had higher endoscopic scores and greater odds of active endoscopic disease than controls (odds ratio, 5.9; 95% CI, 1.6-21.5). There was a higher degree of correlation between PUCAI and UCEIS scores in controls (r = 0.82) than in patients with PSC-IBD (r = 0.51; P = .01). Fecal levels of calprotectin correlated with UCEIS in patients with PSC-IBD (r = 0.84) and controls (r = 0.82; P = .80). Fecal levels of calprotectin identified mucosal healing in patients with PSC-IBD with an area under the receiver operating characteristic curve of 0.94 (optimal cut-point, 93 μg/g; 100% sensitivity and 92% specificity). Histologic activity scores and the odds of active histologic disease were also greater in patients in clinical remission with PSC-IBD than controls. CONCLUSIONS Children with PSC-IBD in clinical remission, based on PUCAI scores, have a significantly higher risk of active endoscopic and histologic disease than children with colitis without PSC. Fecal levels of calprotectin correlate with endoscopic findings in pediatric patients with PSC-IBD; levels below 93 μg/g are associated with mucosal healing.
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43
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Abstract
PURPOSE OF REVIEW To review the characteristics of IBD and PSC that occur in association, as well as their reciprocal influences on disease evolution, in adult and pediatric populations. RECENT FINDINGS IBD co-existing with PSC is genetically and clinically distinct from IBD alone. It is frequently characterized by pancolitis, rectal sparing, and possibly backwash ileitis, as well as a threefold increased risk of colorectal dysplasia. Adults and children with colitis and PSC appear to be at increased risk of active endoscopic and histologic disease in the absence of symptoms compared to individuals without PSC. PSC occurring with Crohn's disease has been observed to be less severe than PSC co-existing with ulcerative colitis, independent of its association with small duct disease. Recent studies suggest that colectomy is associated with a decreased risk of recurrent PSC after liver transplantation, challenging the traditional teaching that PSC and IBD evolve independently. While much about the gut-liver axis in PSC-IBD remains poorly understood, the IBD associated with PSC has a unique phenotype, of which subclinical inflammation is an important component. Additional research is needed to characterize further the potentially protective role of colectomy against recurrent PSC post-liver transplantation and to investigate the influence of IBD control and/or colectomy on PSC progression.
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Affiliation(s)
- Amanda Ricciuto
- Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, M5G1X8, Canada.
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, M5G1X8, Canada
| | - Anne M Griffiths
- Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, M5G1X8, Canada
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44
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Christensen B, Micic D, Gibson PR, Yarur A, Bellaguarda E, Corsello P, Gaetano JN, Kinnucan J, Rao VL, Reddy S, Singh S, Pekow J, Rubin DT. Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease. Aliment Pharmacol Ther 2018; 47:753-762. [PMID: 29377235 PMCID: PMC5821055 DOI: 10.1111/apt.14525] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 10/16/2017] [Accepted: 12/29/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Blocking of lymphocyte trafficking to bile ducts is a potential mechanism to alter the disease course of patients with primary sclerosing cholangitis (PSC). AIM To describe the effect of the α4 β7 integrin antibody, vedolizumab, on liver biochemistry and disease activity in patients with PSC and inflammatory bowel disease (IBD). METHODS This is a retrospective multi-centre study of adult patients with a diagnosis of both IBD and PSC. The primary outcome was change in serum alkaline phosphatase level at weeks 14 and 30. Secondary outcomes included changes in other liver biochemistries and in clinical outcomes for the bowel disease. A safety analysis for adverse events was performed. RESULTS Thirty-four patients (16 Crohn's disease, 18 ulcerative colitis) were included. Nine (26%) had a history of liver transplant. Median follow-up on vedolizumab was 9 months (IQR: 7-16). There was no overall change in serum alkaline phosphatase level with vedolizumab therapy (median 268 [IQR: 105-551] IU/L at baseline versus 249 [IQR: 183-634] IU/L, P = 0.99 at week 30). No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30. Clinical remission was achieved at week 30 in 55% of Crohn's disease and 29% of ulcerative colitis patients. Seven (21%) patients ceased vedolizumab; six patients stopped therapy due to persistent IBD activity and one for worsening of liver biochemistries. CONCLUSION Vedolizumab treatment in patients with PSC and IBD did not improve liver biochemistry but was associated with improvement in bowel disease and a favourable safety profile.
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Affiliation(s)
- Britt Christensen
- Alfred Hospital and Monash University, Melbourne, Australia,Royal Melbourne Hospital, Melbourne, Australia
| | - Dejan Micic
- Northwestern University Feinberg School of Medicine, Chicago, IL, 60611
| | | | - Andres Yarur
- Medical College of Wisconsin, Division of Gastroenterology and Hepatology, Milwaukee, WI 53226
| | | | - Paul Corsello
- University of Michigan Health System, Ann Arbor, MI, 48109
| | - John N. Gaetano
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL 60637
| | - Jami Kinnucan
- University of Michigan Health System, Ann Arbor, MI, 48109
| | - Vijaya L. Rao
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL 60637
| | - Shilpa Reddy
- Northwestern University Feinberg School of Medicine, Chicago, IL, 60611
| | - Samrath Singh
- Medical College of Wisconsin, Division of Gastroenterology and Hepatology, Milwaukee, WI 53226
| | - Joel Pekow
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL 60637
| | - David T. Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL 60637
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