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.