Angiogenesis: a new surrogate histopathological marker is capable of differentiating between mild and significant portal hypertension

Abstract

Aim: Angiogenesis is considered an important pathophysiological feature of portal hypertension. We investigated the ability of angiogenesis, as CD34-positive microvessel density (MVD), to differentiate portal pressure in a CCl 4-induced rat cirrhosis model. Methods: Cirrhosis was induced by intraperitoneal injection of carbon tetrachloride in 46 male adult Sprague-Dawley rats. A catheter connected to a highly sensitive pressure transducer was inserted into the portal vein to continuously record portal pressure. Fibrosis area, nodule size and MVD were assessed by image morphometry. Results: Of 42 rats in which portal pressure was measured successfully, 27 (64%) had portal pressure ≥10 mmHg, defined as significant portal hypertension. MVD was 4.5-fold higher and fibrosis area 13.0-fold higher in rats with significant portal hypertension than in rats with portal pressure <10 mmHg. Portal pressure was significantly correlated with MVD (r=0.491, p<0.001) and fibrosis area (r=0.545, p﹤ 0.001) in all animals, but only MVD correlated with portal pressure (r=0.731 p<0.001) in rats with significant portal hypertension. The area under receiver operating characteristic curve for MVD in all rats was 0.953 (95% CI: 0.875-1.031) and optimum cutoff for MVD was 18/mm2, with 96.3% sensitivity and 93.3% specificity. Conclusions: We found that MVD, measured by CD34 immunostaining, was better able than the fibrosis area to discriminate significant portal hypertension in rats, suggesting that MVD could be a surrogate marker for portal hypertension in patients with liver diseases.