Copyright
©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis
Tamas Tornai, Eszter Palyu, Zsuzsanna Vitalis, Istvan Tornai, David Tornai, Peter Antal-Szalmas, Gary L Norman, Zakera Shums, Gabor Veres, Antal Dezsofi, Gabriella Par, Alajos Par, Peter Orosz, Ferenc Szalay, Peter Laszlo Lakatos, Maria Papp
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, 1st Department of Pediatrics, Semmelweis University, H-1083 Budapest, Hungary
Gabriella Par, Alajos Par, 1st 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, 1st Department of Medicine, Semmelweis University, H-1083 Budapest, Hungary
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
Institutional review board statement: The study protocol was approved by the Regional and Institutional Research Ethics Committee of University of Debrecen and the National Scientific and Research Ethics Committee (DEOEC-RKEB/IKEB 5306-9/2011, 3515-2011, 3885/2012/EKU [60/PI/2012], 3880/2012/EKU [59/PI/2012], 9485-1/2016/EKU ad 167/2016).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrolment.
Conflict-of-interest statement: Gary L Norman and Zakera Shums are employees of Inova Diagnostics.
Data sharing statement: No additional data are available.
Open-Access: 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. See: http://creativecommons.org/licenses/by-nc/4.0/
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@med.unideb.hu
Telephone: +36-52-255152 Fax: +36-52-255152
Received: March 27, 2017
Peer-review started: March 29, 2017
First decision: April 26, 2017
Revised: May 9, 2017
Accepted: June 18, 2017
Article in press: June 19, 2017
Published online: August 7, 2017
Processing time: 133 Days and 3.9 Hours
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-FABPAAA IgA posvsneg: 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.
Core tip: Importance of gut-liver interaction in the pathogenesis of primary sclerosing cholangitis (PSC) has been certified by a variety of clinical and experimental evidences. Clinical manifestations and progression of the disease are heterogeneous. No reliable biomarkers have been identified to this point that is able to predict the pace of progression. In the present, prospective follow-up study, we evaluated the clinical importance of novel serological markers related to gut barrier function in the prediction of progressive disease course in a cohort of PSC patients. IgA type anti-F-actin antibody was identified as a novel serologic marker during the prognostic work-up of PSC. Presence of anti-F-actin IgA identified PSC patients with progressive disease course and was associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC.
