Cholestatic liver disease: pathophysiology and therapeutic options

Abstract

Cholestasis results from defective canalicular secretion of bile or obstruction to bile flow distal to the canaliculus. In early primary biliary cirrhosis, bile secretion continues, because of the secretory pressure of bile or because some ductules are not obstructed. With complete cholestasis, a bile acid deficiency occurs in the small intestinal lumen leading to lipid maldigestion and fat-soluble vitamin malabsorption. Bacterial proliferation, bacterial translocation to lymph nodes and endotoxemia may also occur leading to an acute phase reaction. Retention of bile acids in the hepatocyte leads to apoptosis. Accumulation of bile acids in the systemic circulation leads to pruritus, and may contribute to endothelial injury in the lungs and kidney. Early attempts to mimic hepatic excretory function by hemoperfusion over adsorbent columns were unsuccessful for a variety of reasons. Extracorporeal dialysis against albumin offers promise of a realistic albeit partial simulation of hepatic excretory function.

Reversibility of Caspase Activation and Its Role during Glycochenodeoxycholate-induced Hepatocyte Apoptosis

“…Accumulation of bile acids induces hepatocyte apoptosis and necrosis (29). Our study demonstrated that low dosages (50 M) of GCDC caused hepatocyte apoptosis, not necrosis.…”

Essential roles of bile acids and their nuclear receptors, FXR and PXR, in the cholestatic liver disease

“…Cholestatic liver disease is an impaired bile formation condition in which bile flows into gall bladder, resulting in hepatic accumulation of bile acids (BAs), cholesterol and bilirubin (Trauner et al 1998;Hofmann 2002;Zollner & Trauner 2009;Jonker et al 2012). Accumulation of hydrophobic BAs results in the production of reactive oxidative species (ROS), leading to progressive liver disease with eventually cirrhosis (Copple et al 2010).…”

Game and Players: Mitochondrial Apoptosis and the Therapeutic Potential of Ursodeoxycholic Acid

“…In contrast, apoptosis represents the execution of a death program often initiated by specific stimuli. Nevertheless, it is important to note that, in certain occasions, rather than separate entities, apoptosis and necrosis are frequently the consequence of the same initiating factors and signaling pathways, representing extremes on a continuum of cell death (Bull et al, 1983;Hofmann, 2002).…”

“…In contrast, apoptosis represents the execution of a death program often initiated by specific stimuli. Nevertheless, it is important to note that, in certain occasions, rather than separate entities, apoptosis and necrosis are frequently the consequence of the same initiating factors and signaling pathways, representing extremes on a continuum of cell death (Bull et al, 1983;Hofmann, 2002).Apoptosis is an active mechanism by which metazoan organisms quickly eliminate cells in response 124 Solá et alThe molecular mechanisms of programmed cell death are highly conserved throughout evolution. Studies in Caenorhabditis elegans (C. elegans) have demonstrated that cell demise is carried out by specific cellular pathways (Hall et al, 1997), suggesting that it may be more "programmed" than initially thought.…”