Primary
sclerosing cholangitis (PSC) is the classical hepatobiliary
manifestation of IBD. This clinical association is linked pathologically
to the recruitment of mucosal T cells to the liver, via vascular
adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to
examine the expression, function and enzymatic activation of the
ectoenzyme VAP-1 in patients with PSC.

We
examined VAP-1 expression in patients with PSC, correlated levels with
clinical characteristics and determined the functional consequences of
enzyme activation by specific enzyme substrates on hepatic endothelium.

The
intrahepatic enzyme activity of VAP-1 was elevated in PSC versus
immune-mediated disease controls and non-diseased liver (p<0.001).
The adhesion of gut-tropic α4β7⁺lymphocytes to hepatic
endothelial cells in vitro under flow was attenuated by 50% following
administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a
number of natural VAP-1 substrates tested, cysteamine-which can be
secreted by inflamed colonic epithelium and gut bacteria-was the most
efficient (yielded the highest enzymatic rate) and efficacious in its
ability to induce expression of functional mucosal addressin cell
adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated
patient cohort with PSC, elevated serum soluble (s)VAP-1 levels
predicted poorer transplant-free survival for patients, independently
(HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence
of liver cirrhosis.

VAP-1
expression is increased in PSC, facilitates adhesion of gut-tropic
lymphocytes to liver endothelium in a substrate-dependent manner, and
elevated levels of its circulating form predict clinical outcome in
patients.