Alterations in Tight Junctions Differ Between Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Abstract

Tight junctions (TJ) of biliary epithelial cells (BEC) and hepatocytes prevent bile regurgitation from the biliary tract. Alterations in these TJs may participate in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We examined the localization of 2 TJ proteins, ZO-1 and 7H6, in these diseases. Frozen sections from livers of PBC, PSC, extrahepatic cholestasis (Ex-C), and hepatitis C-associated cirrhosis (LC-C), as well as histologically normal livers, were processed for double-fluorescence immunohistochemistry. In controls and cirrhosis, 7H6 and ZO-1 colocalized surrounding the luminal space of the bile ducts and outlined the bile canalicular spaces between hepatocytes. In untreated PBC, immunostaining for ZO-1 in BEC of bile ducts 40 to 80 m in diameter was preserved, but that for 7H6 was diminished to absent. In PBC treated with ursodeoxycholic acid (UDCA), immunostaining for 7H6 was well preserved. In PSC as well as in Ex-C, immunostaining for both 7H6 and ZO-1 was well preserved in bile ducts. In hepatocytes, ZO-1 showed preserved immunoreactivity, but immunostaining for 7H6 frequently disappeared. The percentage of bile ducts with immunostaining for 7H6 in all bile ducts with immunostaining for ZO-1 was significantly reduced in PBC compared with that in control, LC-C, Ex-C, and PSC (all P < .0001). Substantial alteration in the TJ protein occurs predominantly in bile ducts in PBC and in hepatocytes in PSC, suggesting increased paracellular permeability along different paracellular routes for bile regurgitation in these chronic cholestatic liver diseases. (HEPATOLOGY 2001;33: 1460-1468.)Primary biliary cirrhosis (PBC), a chronic cholestatic liver disease characterized by immune-mediated bile duct destruction, shows elevated serum concentrations of bile acids, alkaline phosphatase, ␥-glutamyl transpeptidase, and, in advanced stages, bilirubin. 1 In cholestasis, elevations of these substances in blood result at least in part from regurgitation of bile constituents into blood. 2 Previous ultrastructural studies demonstrated not only degenerated or apoptotic biliary cells, but also separation of those cells associated with reduced intercellular digitation in PBC. Electron-dense deposits are often shown between the multilayered basement membrane and in lateral intercellular spaces of damaged bile ducts, which are surrounded by infiltrating macrophages containing neutral fats. These findings strongly suggested increased biliary epithelial permeability in PBC, resulting in bile leakage from the luminal space of bile ducts to the periductal area. [3][4][5][6] Because the tight junction (TJ) of biliary epithelial cells (BEC) is the only intercellular barrier between the luminal space and the portal area, the functional integrity of TJ is crucial in preventing paracellular leakage of bile constituents. In several clinical forms of cholestasis and in cholestatic models, distinct functional and morphologic alterations of TJ have been described in hepatoc...

Hepatitis C virus envelope components alter localization of hepatocyte tight junction–associated proteins and promote occludin retention in the endoplasmic reticulum†

“…8 In intrahepatic cholestasis, alterations of tight and gap junctional functions are frequently observed, which results in impaired intercellular communication and leaky canalicular structures. [9][10][11] Although the changes in gap junctions and TJs had been considered independent of each other, recent findings have shown that ZO-1 and occludin bind to connexins, which raises the possibility of either coordinate or reciprocal regulation of macromolecular complexes containing gap and TJ proteins. 24 The effects of HCV on gap junctions are currently being studied in our laboratory.…”

“…Cholestatic hepatocytes show alterations of TJ functions, resulting in a deteriorated "barrier" function. [9][10][11] Recurrence of HCV infection after liver orthotopic transplantation is commonly associated with a rapid progression of a cholestatic form of hepatitis and leads to accelerated graft failure and death. 12 On recurrence, serum concentrations of HCV RNA may reach 10 to 20 times pretransplantation values, and high HCV protein expression in the transplanted liver is associated with the development of acute and chronic hepatitis.…”

Rapid-onset Primary Biliary Cirrhosis Resembling Drug-induced Liver Injury

“…Its multifarious pharmacological effects such as bile excretion-accelerating effect and liver cell-protecting effect are well known (13,14). Recently, the anti-apoptotic effect of UDCA has also been elucidated (15,16).…”

Selective Na+/H+ exchange inhibition by cariporide reduces liver fibrosis in the rat

“…Furthermore, it has been shown that inhibition of the Na ϩ /H ϩ exchanger is associated with a reduction in cholangiocyte functional activity 47 and ductal bile flow. 48 Therefore, cariporide could exert its positive effects in several ways: (1) by reducing bile flow, thus reducing the intraductal pressure that is commonly associated with an alteration of paracellular permeability, toxic compound spillover, and hepatocyte damage 49 ; (2) by reducing fibrosis and consequently intraductal pressure; and (3) by preventing the ductular reaction induced by BDL. In fact, ductular reaction is considered to be protective in a cholestatic condition, but it resolves in parenchymal damage when the obstacle to bile flow remains.…”