Cholestatic liver diseases

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Wien Med Wochenschr. 2008 Oct;158(19-20):542-548.

Lessons from the toxic bile concept for the pathogenesis and

treatment of cholestatic liver diseases.

Trauner M, Fickert P, Halilbasic E, Moustafa T

Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Internal Medicine,

Medical University of Graz, Graz, Austria, michael.trauner@meduni-

graz.at.

Alterations in bile secretion at the hepatocellular and

cholangiocellular levels may cause cholestasis. Formation of 'toxic

bile' may be the consequence of abnormal bile composition and can

result in hepatocellular and/or bile duct injury. The canalicular

phospholipid flippase (Mdr2/MDR3) normally mediates biliary excretion

of phospholipids, which normally form mixed micelles with bile acids

and cholesterol to protect the bile duct epithelium from the

detergent properties of bile acids. Mdr2 knockout mice are not

capable of excreting phospholipids into bile and spontaneously

develop bile duct injury with macroscopic and microscopic features

closely resembling human sclerosing cholangitis. MDR3 mutations have

been linked to a broad spectrum of hepatobiliary disorders in humans

ranging from progressive familial intrahepatic cholestasis in

neonates to intrahepatic cholestasis of pregnancy, drug-induced

cholestasis, intrahepatic cholelithiasis, sclerosing cholangitis and

biliary cirrhosis in adults. Other examples for bile injury due to

the formation of toxic bile include the cholangiopathy seen in cystic

fibrosis, after lithocholate feeding (in mice) and vanishing bile

duct syndromes induced by drugs and xenobiotics. Therapeutic

strategies for cholangiopathies may target bile composition/toxicity

and the affected bile duct epithelium itself, and ideally should also

have anti-cholestatic, anti-fibrotic and anti-neoplastic properties.

Ursodeoxycholic acid (UDCA) shows some of these properties, but is of

limited efficacy in the treatment of human cholangiopathies. By

contrast to UDCA, its side chain-shortened homologue norUDCA

undergoes cholehepatic shunting leading to a bicarbonate-rich

hypercholeresis. Moreover, norUDCA has anti-inflammatory, anti-

fibrotic and anti-proliferative effects, and stimulates bile acid

detoxification. Upcoming clinical trials will have to demonstrate

whether norUDCA or other side chain-modified bile acids are also

clinically effective in humans. Finally, drugs for the treatment of

cholangiopathies may target bile toxicity via nuclear receptors (FXR,

PPARalpha) regulating biliary phospholipid and bile acid excretion.

PMID: 18998069.

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> Wien Med Wochenschr. 2008 Oct;158(19-20):542-548.

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> Lessons from the toxic bile concept for the pathogenesis and

> treatment of cholestatic liver diseases.

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