The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic ...liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA‐induced gut hormones, fibroblast growth factor 19 and glucagon‐like peptide 1, and the BA transport systems, apical sodium‐dependent bile acid transporter and Na+‐taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (Hepatology 2017;65:1393‐1404).
A review is presented of Gustav Paumgartner's five decades of research and practice in hepatology focusing on biliary physiology and disease. It begins with studies of the excretory function of the ...liver including hepatic uptake of indocyanine green, bilirubin, and bile acids. The implications of these studies for diagnosis and understanding of liver diseases are pointed out. From there, the path of scientific research leads to investigations of hepatobiliary bile acid transport and the major mechanisms of bile formation. The therapeutic effects of the hydrophilic bile acid, ursodeoxycholic acid, have greatly stimulated these studies. Although ursodeoxycholic acid therapy for dissolution of cholesterol gallstones and some other nonsurgical treatments of gallstones were largely superseded by surgical techniques, ursodeoxycholic acid is currently considered the mainstay of therapy of some chronic cholestatic liver diseases, such as primary biliary cirrhosis. The major mechanisms of action of ursodeoxycholic acid therapy in cholestatic liver diseases are discussed. An attempt is made to illustrate how scientific research can lead to advances in medical practice that help patients. (HEPATOLOGY 2010:51:1095–1106.)
Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a ...combination of the two. The common consequence of all forms of cholestasis is retention of bile acids and other potentially toxic compounds in the hepatooltes leading to apoptosis or necrosis of hepatocytes and eventually to chronic cholestatic liver disease. In certain cholestatic disorders there is also leakage of bile acids into the peribiliary space causing portal inflammation and fibrosis. The following pharmacological targets for treatment of intrahepatic cholestasis can be identified： stimulation of orthograde biliary secretion and retrograde secretion of bile acids and other toxic cholephils into the systemic circulation for excretion via the kidneys to reduce their retention in the hepatocytes; stimulation of the metabolism of hydrophobic bile acids and other toxic compounds to more hydrophilic, less toxic metabolites; protection of injured cholangiocytes against toxic effects of bile; inhibition of apoptosis caused by elevated levels of cytotoxic bile acids; inhibition of fibrosis caused by leakage of bile acids into the peribiliary space. The clinical results of ursodeoxcholic acid therapy of primary biliary cirrhosis may be regarded as the first success of this strategy.
In most cholestatic liver diseases the cause of the disease is not known and therapy can only be directed toward suppression of the pathogenetic processes and amelioration of the consequences of ...cholestasis. The recognition of adaptive-compensatory responses to cholestasis has become of major importance. They tend to minimize retention of bile acids and other potentially toxic solutes in the hepatocyte by limiting hepatocellular uptake, reducing bile acid synthesis, stimulating detoxification, and up-regulating alternative pathways for excretion. Some of the drugs used for the treatment of cholestatic liver diseases in an empiric way turned out to be modulators of nuclear receptors, which regulate these adaptive-compensatory responses. New drugs are being designed and tested along these lines and may be regarded as treatment opportunities of the future.
Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of cholangiocytes ...against cytotoxicity of hydrophobic bile acids, resulting from modulation of the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocytes; (2) stimulation of hepatobiliary secretion, putatively via Ca
2+- and protein kinase C-α–dependent mechanisms and/or activation of p38
MAPK and extracellular signal-regulated kinases (Erk) resulting in insertion of transporter molecules (
e.g., bile salt export pump, BSEP, and conjugate export pump, MRP2) into the canalicular membrane of the hepatocyte and, possibly, activation of inserted carriers; (3) protection of hepatocytes against bile acid–induced apoptosis, involving inhibition of mitochondrial membrane permeability transition (MMPT), and possibly, stimulation of a survival pathway. In primary biliary cirrhosis, UDCA (13-15 mg/kg/d) improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival. In primary sclerosing cholangitis, UDCA (13-20 mg/kg/d) improves serum liver chemistries and surrogate markers of prognosis, but effects on disease progression must be further evaluated. Anticholestatic effects of UDCA have also been reported in intrahepatic cholestasis of pregnancy, liver disease of cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host disease. Future efforts will focus on definition of additional clinical uses of UDCA, on optimized dosage regimens, as well as on further elucidation of mechanisms of action of UDCA at the molecular level. (H
EPATOLOGY 2002;36:525-531.)
Taurolithocholic acid (TLCA) is a potent cholestatic agent. Our recent work suggested that TLCA impairs hepatobiliary exocytosis,
insertion of transport proteins into apical hepatocyte membranes, and ...bile flow by protein kinase Cε (PKCε)-dependent mechanisms.
Products of phosphatidylinositol 3-kinases (PI3K) stimulate PKCε. We studied the role of PI3K for TLCA-induced cholestasis
in isolated perfused rat liver (IPRL) and isolated rat hepatocyte couplets (IRHC). In IPRL, TLCA (10 μmol/liter) impaired
bile flow by 51%, biliary secretion of horseradish peroxidase, a marker of vesicular exocytosis, by 46%, and the Mrp2 substrate,
2,4-dinitrophenyl- S -glutathione, by 95% and stimulated PI3K-dependent protein kinase B, a marker of PI3K activity, by 154% and PKCε membrane
binding by 23%. In IRHC, TLCA (2.5 μmol/liter) impaired canalicular secretion of the fluorescent bile acid, cholylglycylamido
fluorescein, by 50%. The selective PI3K inhibitor, wortmannin (100 nmol/liter), and the anticholestatic bile acid tauroursodeoxycholic
acid (TUDCA, 25 μmol/liter) independently and additively reversed the effects of TLCA on bile flow, exocytosis, organic anion
secretion, PI3K-dependent protein kinase B activity, and PKCε membrane binding in IPRL. Wortmannin also reversed impaired
bile acid secretion in IRHC. These data strongly suggest that TLCA exerts cholestatic effects by PI3K- and PKCε-dependent
mechanisms that are reversed by tauroursodeoxycholic acid in a PI3K-independent way.
New insights into the molecular mechanisms of bile formation and cholestasis have provided new concepts for pharmacotherapy of cholestatic liver diseases. The major aim in all forms of cholestasis is ...the reduction of hepatocellular retention of bile acids and other potentially toxic constituents of bile. Reduction of hepatocellular retention may be achieved by drugs that stimulate hepatocellular secretion via the canalicular route into the bile or via the alternative route across the basolateral membrane into the blood, and by drugs that stimulate the hepatocellular metabolism of hydrophobic bile acids to hydrophilic, less toxic metabolites. In cholestatic liver diseases that start with an injury of the biliary epithelium (e.g., primary biliary cirrhosis; PBC), protection of the cholangiocytes against the toxic effects of hydrophobic bile acids is most important. When hepatocellular retention of bile acids has occurred, the inhibition of bile acid‐induced apoptosis becomes another target of therapy. Ursodeoxycholic acid protects the biliary epithelium by reducing the toxicity of bile, stimulates hepatobiliary secretion by upregulating transporters and inhibits apoptosis. It is the mainstay of therapy in PBC but of benefit also in a number of other cholestatic liver diseases. New drugs such as 6‐ethyl‐chenodeoxycholic acid and 24‐nor‐ursodeoxycholic acid are being evaluated for the treatment of cholestatic liver diseases.
Background: Endoscopic extraction of bile duct stones after sphincterotomy has a success rate of up to 95%. Failures occur in patients with extremely large stones, intrahepatic stones, and bile duct ...strictures. This study examined the efficacy and the safety of extracorporeal shock-wave lithotripsy in a large cohort of patients in whom routine endoscopic measures including mechanical lithotripsy had failed to extract bile duct stones. Methods: Out of 1587 consecutive patients, endoscopic stone extraction including mechanical lithotripsy was unsuccessful in 313 (20%). These 313 patients (64% women, median age, 73 years) underwent high-energy extracorporeal shock-wave lithotripsy. Stone targeting was performed fluoroscopically (99%) or by ultrasonography (1%). Results: Complete clearance of bile duct calculi was achieved in 281 (90%) patients. In 80% of the patients, the fragments were extracted endoscopically after shock-wave therapy; spontaneous passage was observed in 10%. For patients with complete clearance compared with those without there were no differences with regard to size or number of the stones, intrahepatic or extrahepatic stone location, presence or absence of bile duct strictures, or type of lithotripter. Cholangitis (n = 4) and acute cholecystitis (n = 1) were the rare adverse effects. Conclusions: In patients with bile duct calculi that are difficult to extract endoscopically, high-energy extracorporeal shock-wave lithotripsy is a safe and effective therapy regardless of stone size, stone location, or the presence of bile duct stricture. (Gastrointest Endosc 2001;53:27-32.)
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