Angiopoietin 1 and angiopoietin 2 are associated with medial thickening of hepatic arterial branches in biliary atresia

Abstract

Background: Biliary atresia (BA) is an infantile disorder characterized by progressive sclerosing cholangiopathy leading to biliary obstruction. First-line treatment of BA is hepatoportoenterostomy, the prognosis of which is related to age at surgery and to histological variables such as extent of fibrosis and ductular reaction. Hepatic arterial medial thickening (MT) suggests an arteriopathy in BA pathogenesis. We evaluated the expression of angiopoietin (ANGPT)/tyrosine kinase with immunoglobulin-like and epidermal growth factorlike domains 2 (TIE2) system in liver samples obtained from patients with BA, correlating it with MT, variables associated with disease severity, and postoperative prognosis. Methods: ANGPT1, ANGPT2, and TIE2 expression levels were assessed by quantitative PCR in liver samples obtained from BA patients (n = 23) at portoenterostomy and age-matched infants with intrahepatic cholestasis (IHC; n = 7). Histological variables were morphometrically assessed. results: ANGPT1 and ANGPT2 were overexpressed in BA in comparison with IHC (P = 0.024 and P = 0.029, respectively). In BA, ANGPTs expression was positively correlated with MT (ANGPT1: r s = 0.59, P = 0.013; ANGPT2: r s = 0.52, P = 0.032), not with the variables associated with disease severity. TIE2 and ANGPTs expression levels were negatively correlated (ANGPT1: r s = −0.73, P < 0.001; ANGPT2: r s = −0.54, P = 0.007). conclusion: In BA, there is overexpression of both ANGPT1 and ANGPT2, which is correlated with MT but not with age at portoenterostomy or with the histological variables associated with disease severity at the time of procedure. Biliary atresia (BA) is an infantile hepatobiliary disorder characterized by the obstruction of bile ducts associated with a progressive sclerosing cholangiopathy. The primary treatment for BA is a hepatoportoenterostomy, which should be performed as soon as possible, because its chances of longterm success decrease when the age at surgery increases (1). In addition to age at portoenterostomy, histological findings observed in biopsies collected at the time of the procedure, such as the extents of fibrosis and ductular reaction, represent variables associated with disease severity and can help foresee the postoperative outcomes (2).Regardless of portoenterostomy, BA induces cirrhosis by the continuous sclerosing cholangiopathy process, thus making this entity the leading cause of liver transplantation in children.The etiology of such a cholangiopathy remains elusive, and BA seems to represent more a phenotype than a unique disease. Our group is interested in the putative role of an arteriopathy in the development of BA because there are arteriographic (3), ultrasonographic (4-6), computed tomographic (7), histological (8), and immunohistochemical (9) evidences of medial thickening (MT) in hepatic artery branches owing to a vascular remodeling associated with hypoxia-ischemia in the portal tracts and porta hepatis. Knowledge on the behavior of angiogenic molecules in the liver of the affected patients...

Expression of vascular endothelial growth factor A in liver tissues of infants with biliary atresia

“…The relation between the simultaneous increased expression of VEGF-A in BDs and AWs in liver tissues as well as presence of subcapsular hepatic flow in the BA group, and absence of this relation in the non-BA group in the current study supports the putative role of an arteriopathy in the development of BA [18].…”

Oxidative stress and cell damage in a model of precancerous lesions and advanced hepatocellular carcinoma in rats

“…Ten images from each slide were captured from randomly selected high-power fields (200× magnification) containing the conjunctive tissue area positive. Morphometric assessment of the percentage of the ratios of conjunctive tissue relative to whole liver were performed using the Adobe Photoshop CS5 Extended 10.0 (Adobe Systems, San Jose, CA), according to the protocol described by Souza et al [13] .…”

Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes

“…53,54 Although limited data support this mechanism, it is possible that arterial changes might be driven by primary growth signals, or represent a response to a diseased micro-environment that might be rich in growth-promoting signals that favour angiogenesis. 55,56 …”