Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases

Abstract

Ursodeoxycholic acid (ursodiol) is a non‐toxic, hydrophilic bile acid used to treat predominantly cholestatic liver disorders. Better understanding of the cellular and molecular mechanisms of action of ursodeoxycholic acid has helped to elucidate its cytoprotective, anti‐apoptotic, immunomodulatory and choleretic effects. Ursodeoxycholic acid prolongs survival in primary biliary cirrhosis and it improves biochemical parameters of cholestasis in various other cholestatic disorders including primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cystic fibrosis and total parenteral nutrition‐induced cholestasis. However, a positive effect on survival remains to be established in these diseases. Ursodeoxycholic acid is of unproven efficacy in non‐cholestatic disorders such as acute rejection after liver transplantation, non‐alcoholic steatohepatitis, alcoholic liver disease and chronic viral hepatitis. This review outlines the present knowledge of the modes of action of ursodeoxycholic acid, and presents data from clinical trials on its use in chronic liver diseases.

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

“…31,42 Moreover, statins have been shown to stimulate biliary excretion of phospholipids 34,35 that may further protect bile ducts from immunomediated injury in PBC. 43,44 This may be explained by activation of the nuclear peroxisome proliferator-activated receptor-␣, 45 which is predicted to modulate biliary bile acid/phospholipid ratio via increased biliary phospholipid secretion and increased cholangiocellular reabsorption of biliary bile acids, 31,46 resulting in less aggressive bile.…”

Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver

“…7 After anesthesia with sodium pentobarbital (50 mg/kg body wt i.p. ), preparation and cannulation of the portal vein, rat livers were perfused with Krebs-Ringer bicarbonate solution at 371C (KRB: NaCl 118 mmol/l, KCl 4.8 mmol/l, NaHCO 3 25 mmol/l, KH 2 PO 4 1.2 mmol/l, MgSO 4 1.2 mmol/l, CaCl 2 1.9 mmol/l, D-glucose 5.5 mmol/l, pH 7.4; gassed with 95% O 2 /5% CO 2 by an oxygenator) at a constant flow rate of 3.5 ml/min/g liver. Livers were then preloaded with horseradish peroxidase (HRP, 0.05 mg/ml) for 25 min in a recirculating KRB perfusion (32 ml/min) containing 1 g/dl bovine serum albumin (BSA) to avoid adherence of HRP to glassware and tubing and protect livers against potential accumulating toxins during recirculation.…”

“…However, post-translational stimulation of hepatobiliary secretion by activation of complex intracellular signaling pathways is regarded as one key mechanism of action of UDCA in cholestasis. [1][2][3][4][5][6] We have recently reported that the cholestatic bile acid taurolithocholic acid (TLCA) reduces the density of the apical conjugate export pump, Mrp2 (ABCC2), in canalicular membranes of rat livers and markedly impairs organic anion secretion into bile, 7 in part by phosphatidylinositol 3-kinase (PI3K)-dependent mechanisms. 8 The taurine conjugate of UDCA (TUDCA) reversed the cholestatic effect of TLCA on bile formation, normalized Mrp2 density in canalicular membranes of cholestatic hepatocytes, and stimulated organic anion secretion into bile in part by protein kinase C (PKC)-dependent mechanisms.…”

“…1 Anticholestatic effects of UDCA are also observed in experimental models of cholestasis [1][2][3][4][5][6] The mechanisms of action of UDCA are incompletely understood so far. However, post-translational stimulation of hepatobiliary secretion by activation of complex intracellular signaling pathways is regarded as one key mechanism of action of UDCA in cholestasis.…”

A prospective, multicentre, observational study of patients with chronic cholestatic liver diseases receiving Udiliv and reg; in India: splendid study

“…It prolongs survival in primary biliary cirrhosis and improves biochemical parameters of cholestasis in other underlying etiologies of chronic cholestasis including PSC, IHC of pregnancy, cystic fibrosis and total parenteral nutrition-induced cholestasis. There is also encouraging evidence supporting the use of UDCA in the treatment of alcoholic liver disease (ALD) 12 , nonalcoholic fatty liver disease (NAFLD) 13 , viral hepatitis 14 , gall stones 15 , and drug-or total parenteral nutrition (TPN)-induced cholestasis. 16 It is believed that the profile of CCLD in India is different from the West with respect to etio-pathogenesis and clinical presentation.…”