Published online Aug 7, 2017. doi: 10.3748/wjg.v23.i29.5412
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
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.
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.
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.
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.