Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis

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The prospective translational study ‘Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis’ (DOI: 10.1136/gutjnl-2016-311739) was published 2017 by Jendrek et al. in Gut. The authors demonstrated that IgA type antibodies against glycoprotein 2 (anti-GP2 IgA), a protein involved in mucosal immunity, are predictive for development of cholangiocarcinoma and death in patients with PSC. Anti-GP2-IgA would therefore represent the first biomarker for PSC-associated cholangiocarcinoma, which is the most important medical complication in PSC. This finding may significantly change the routine surveillance of patients with PSC.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown aetiology.1 The hallmarks of PSC are inflammation and scarring of the intra- and/or extrahepatic bile ducts which result in progressive bile duct strictures. PSC patients suffer from inflammatory bowel disease (IBD) in up to 80%.2 PSC poses a significant medical burden with a high mortality rate, which is largely explained by the high incidence of cholangiocarcinoma (CCA) as well as gallbladder- and colorectal cancer.3 Currently, liver transplantation is the only “curative” therapy available for PSC.

In the general population, CCA is rare. However, in PSC patients, CCA represents the complication with the highest frequency and mortality, occurring at a life time incidence of around 15%.4 In advanced stages, the prognosis for CCA is dismal. Therefore, regular surveillance is mandatory.5 Despite regular follow-up by ultrasound and magnetic-resonance imaging, in many patients CCA is not detected until an advanced disease stage. Unfortunately, no biomarker exists to estimate the patient’s individual risk for CCA. Such a biomarker would provide physicians with a potentially life-saving tool for early and prioritized decision for liver transplantation.

In their study, Jendrek et al.6 investigated the prevalence and prognostic value of a subclass of “pancreatic autoantibodies”, IgA antibodies against glycoprotein 2 (anti-GP2 IgA), in patients with PSC. Previously, anti-GP2 IgA have been detected in patients with complicated phenotypes of Crohn’s disease, an IBD which shares a considerable overlap with PSC regarding genotype and phenotype. The study design by Jendrek et al. included two parts: In an exploration phase, the authors tested sera for the presence of pancreatic autoantibodies from n=138 patients with well-characterized PSC as well as from n=52 healthy controls and n=62 patients with ulcerative colitis without PSC. In a validation phase, the authors investigated sera from n=180 patients with PSC, as well as from patients with sporadic CCA (n=56), secondary sclerosing cholangitis (SSC; n=20) and autoimmune hepatitis (n=18). The patients received follow-up over a median time of 3.5 years (range, 0─8.83) from the date of serum collection. Various clinical variables were assessed prospectively.

Anti-GP2 IgA occurred frequently in patients with PSC and SSC (about 50%, respectively, irrespective of the presence of IBD) as well as in patients with sporadic CCA (36%). Anti-GP2 IgA were associated with poor survival of PSC patients in both cohorts (log-rank test; p=0.016 and p=0.018), which was primarily attributed to CCA manifestation. A meta-analysis of both cohorts indicated a cumulative odds ratio of 5.0 for CCA in PSC patients being positive for anti-GP2 IgA. This association was independent from age, disease duration and bilirubin levels.

To conclude, anti-GP2 IgA may serve as a novel biomarker to stratify the prognostic risk of patients with sclerosing bile duct disease. Particularly, presence of anti-GP2 IgA in patients in PSC may serve as a predictor of CCA. Anti-GP2 IgA may complement existing tools, such as the Model-of-End-stage-Liver-Disease Score, in order to prioritize PSC patients for liver transplantation. Interestingly, GP2 is involved in mucosal immune responses against gut bacteria.7 Therefore, the clinical association uncovered in the present study may open new avenues for the study of putative bacterial pathogens in PSC aetiology.

Timur Liwinski
I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Contact: t.liwinski@uke.de

References

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  2. Loftus EV, Harewood GC, Loftus CG, et al., PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54:91-96.
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  6. Jendrek ST, Gotthardt D, Nitzsche T, et al., Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis. Gut 2017; 66:137-144. doi: 10.1136/gutjnl-2016-311739.
  7. Yu S, Lowe AW., The pancreatic zymogen granule membrane protein, GP2, binds Escherichia coli type 1 Fimbriae. BMC Gastroenterol 2009; 9:58. doi:10.1186/1471-230×-9-58.