Expression of connective tissue growth factor in the human liver with idiopathic portal hypertension

Abstract

Idiopathic portal hypertension (IPH) is a disorder of unknown etiology, clinically associated with portal hypertension in the absence of cirrhosis. This study was designed to delineate the characteristics of IPH RNA expression in liver specimens from patients with IPH. Liver specimens from patients with IPH and patients without liver diseases underwent cDNA expression analysis and in situ hybridization studies. Connective tissue growth factor (CTGF) levels in serum were examined in 76 patients with IPH, 84 patients with hepatitis C virus infection (including those with cirrhosis), and 38 healthy volunteers. Among 588 genes sorted on macroarray, seven up-regulated genes, including CTGF, were detected. In situ hybridization studies showed that positive reactions for CTGF mRNA were most intense in the epithelial cells of proliferating bile ducts within portal tracts in patients with IPH. In the liver parenchyma, there was no appreciable staining of hepatocytes, sinusoidal endothelial cells, or hepatic stellate cells (HSCs), and there were few positive signals for CTGF mRNA in normal liver. The serum CTGF level in patients with IPH was significantly higher than the value in healthy volunteers. Six (8%) of the 76 patients with IPH had serum CTGF levels greater than 80 ng/mL, far exceeding the level of any patient with cirrhosis. In conclusion, overexpression of CTGF is one of the most important features of IPH.

Figures

Figure 1

cDNA expression on macroarray analysis. One gene appeared as two spots on the membrane. Seven overexpressed genes were identified as shown above.

Figure 2

Histological examination of liver with IPH. (A) An enlarged portal tract containing proliferating bile ducts. Hematoxylin and eosin stain, x100. (B) Collagen fibers are seen in the fibrous portal tract. Azan stain, x40. (C–H) In situ hybridization shows positive signals for connective tissue growth factor (CTGF) mRNA in the epithelial cells of bile ducts (arrow), endothelial cells of portal tracts, and myofibroblasts (arrowhead) (C, x100 and D–H, x400). P, portal tract; B, bile duct; H, hepatocyte; S, sinusoid; E, endothelial cell; *, lumen.

Figure 3

Serum levels of CTGF in patients with IPH, patients with HCV, and healthy volunteers (control). Patients with HCV were divided in four groups according to the stage of hepatic fibrosis: F1, periportal fibrous expansion; F2, porto-portal septa; F3, porto-central septa; and F4, cirrhosis. * means significantly higher than the control value.