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      Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis

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          Abstract

          AIM

          To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis (PSC) patients.

          METHODS

          Sera of 67 PSC patients [median age (range): 32 (5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin (AAA IgA/IgG) and gliadin (AGA IgA/IgG)] and for serum level of intestinal fatty acid-binding protein (I-FABP) by ELISA. Markers of lipopolysaccharide (LPS) exposure [LPS binding protein (LBP)] and various anti-microbial antibodies [anti-OMP Plus IgA and endotoxin core IgA antibody (EndoCAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99 (14-106) mo]. One hundred and fifty-three healthy subjects (HCONT) and 172 ulcerative colitis (UC) patients were the controls.

          RESULTS

          A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA IgA, AAA IgG, AGA IgA and AGA IgG, respectively. Frequencies of AAA IgA and AAA IgG ( P < 0.001, for both) and AGA IgG ( P = 0.01, for both) but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15 (1.27-20.86), P = 0.022 or for the Mayo risk score (HR = 4.24 (0.99-18.21), P = 0.052]. AAA IgA-positivity was significantly associated with higher frequency of anti-microbial antibodies ( P < 0.001 for EndoCab IgA and P = 0.012 for anti-OMP Plus IgA) and higher level of the enterocyte damage marker (median I-FABP AAA IgA pos vs neg: 365 vs 166 pg/mL, P = 0.011), but not with serum LBP level.

          CONCLUSION

          Presence of IgA type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC.

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          Primary Sclerosing Cholangitis.

          Konstantinos Lazaridis, Nicholas F LaRusso (2016)
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            Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.

            Hanns-Ulrich Marschall, Frank Lammert, Robert Krause … (2004)
            Because the mechanisms leading to bile duct damage in sclerosing cholangitis are unknown, we aimed to determine the pathogenesis of bile duct injury in multidrug resistance gene (Mdr2) (Abcb4) knockout mice (Mdr2(-/-)) as a novel model of the disease. Mdr2(-/-) and wild-type controls (Mdr2(+/+)) were studied at 2, 4, and 8 weeks of age. Liver histology, ultrastructure, immunofluorescence microscopy (to study inflammatory cells, tight junction protein ZO-1, basement membrane protein laminin, fluorescence-labeled ursodeoxycholic acid), immunohistochemistry (for alpha-smooth muscle actin, nitrotyrosine), sirius red staining, bacterial cultures of intra-abdominal organs, and polymerase chain reaction (PCR) for Helicobacter bilis DNA were compared between both genotypes. Hepatic cytokine expression was determined by reverse-transcription PCR. Bile ducts of Mdr2(-/-) showed disrupted tight junctions and basement membranes, bile acid leakage into portal tracts, induction of a portal inflammatory (CD11b, CD4-positive) infiltrate, and activation of proinflammatory (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta) and profibrogenic cytokines (transforming growth factor [TGF]-beta1). This resulted in activation of periductal myofibroblasts, leading to periductal fibrosis, separating the peribiliary plexus from bile duct epithelial cells and, finally, causing atrophy and death of the bile duct epithelium. Bacterial translocation was not increased and H. bilis was not detectable in Mdr2(-/-). Sclerosing cholangitis in Mdr2(-/-) mice is a multistep process with regurgitation of bile from leaky ducts into the portal tracts, leading to induction of periductal inflammation, followed by activation of periductal fibrogenesis, finally causing obliterative cholangitis owing to atrophy and death of bile duct epithelial cells.
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              Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management.

              John Eaton, Jayant Talwalkar, Konstantinos Lazaridis … (2013)
              Primary sclerosing cholangitis (PSC), first described in the mid-1850s, is a complex liver disease that is heterogeneous in its presentation. PSC is characterized by chronic cholestasis associated with chronic inflammation of the biliary epithelium, resulting in multifocal bile duct strictures that can affect the entire biliary tree. Chronic inflammation leads to fibrosis involving the hepatic parenchyma and biliary tree, which can lead to cirrhosis and malignancy. The etiology of PSC is not fully understood, which in part explains the lack of effective medical therapy for this condition. However, we have begun to better understand the molecular pathogenesis of PSC. The recognition of specific clinical subtypes and their pattern of progression could improve phenotypic and genotypic classification of the disease. We review our current understanding of this enigmatic disorder and discuss important topics for future studies. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
              Article 0 comments Cited 109 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): World J Gastroenterol
                Journal ID (iso-abbrev): World J. Gastroenterol
                Journal ID (publisher-id): WJG
                Title: World Journal of Gastroenterology
                Publisher: Baishideng Publishing Group Inc
                ISSN (Print): 1007-9327
                ISSN (Electronic): 2219-2840
                Publication date (Print): 7 August 2017
                Publication date (Electronic): 7 August 2017
                Volume: 23
                Issue: 29
                Pages: 5412-5421
                Affiliations
                Tamas Tornai, Zsuzsanna Vitalis, Istvan Tornai, Eszter Palyu, Maria Papp, Institute of Internal Medicine, Department of Gastroenterology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary, H-4032 Debrecen, Hungary
                David Tornai, Peter Antal-Szalmas, Department of Laboratory Medicine, University of Debrecen, Faculty of Medicine Debrecen, Hungary, H-4032 Debrecen, Hungary
                Gary L Norman, Zakera Shums, Inova Diagnostics, Inc., San Diego, CA 92131, United States
                Gabor Veres, Antal Dezsofi, 1 st Department of Pediatrics, Semmelweis University, H-1083 Budapest, Hungary
                Gabriella Par, Alajos Par, 1 st Department of Medicine, University of Pecs, H-7624 Pecs, Hungary
                Peter Orosz, Gastroenterology Department of Medicine, Borsod-Abauj Zemplen County Hospital, H-3526 Miskolc, Hungary
                Ferenc Szalay, Peter Laszlo Lakatos, 1 st Department of Medicine, Semmelweis University, H-1083 Budapest, Hungary
                Author notes

                Author contributions: Papp M, Tornai I and Antal-Szamas P designed research; Papp M, Tornai T, Tornai D, Palyu E, Vitalis Z, Norman GL, Shums Z, Veres G, Dezsofi A, Par G, Par A, Orosz P, Szalay F and Lakatos PL performed research; Papp M and Tornai T analyzed data; Papp M and Tornai T wrote paper.

                Supported by Research Grant of National Research Development and Innovation Office, No. K115818/2015/1; János Bólyai Research Scholarship of Hungarian Academy of Sciences to Papp M; and the New National Excellence Program of the Ministry of Human Capacities, No. ÚNKP-16-3 to Tornai T

                Correspondence to: Maria Papp, MD, PhD, Institute of Internal Medicine, Department of Gastroenterology, University of Debrecen, Faculty of Medicine, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. papp.maria@ 123456med.unideb.hu

                Telephone: +36-52-255152 Fax: +36-52-255152

                Article
                Other ID: jWJG.v23.i29.pg5412
                DOI: 10.3748/wjg.v23.i29.5412
                PMC ID: 5550791
                PubMed ID: 28839442
                SO-VID: 7c7d696e-b87d-482a-8898-2b5d82bebfd6
                Copyright © ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
                License:

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                Date received : 27 March 2017
                Date revision received : 9 May 2017
                Date accepted : 18 June 2017
                Categories
                Subject: Observational Study

                Keywords: primary sclerosing cholangitis,gut barrier dysfunction,intestinal fatty acid-binding protein,anti-f-actin antibody,anti-gliadin antibody
                Data availability:
                Keywords: primary sclerosing cholangitis, gut barrier dysfunction, intestinal fatty acid-binding protein, anti-f-actin antibody, anti-gliadin antibody

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