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Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases

Bedeutung des Galle-Toxizität Konzeptes für die Pathogenese und Therapie von cholestatischen Lebererkrankungen

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Zusammenfassung

Störungen der Gallensekretion können auf hepatozellulärer und cholangiozellulärer Ebene eine Cholestase verursachen. Die Bildung einer "toxischen Galle" als Folge einer abnormen Gallezusammensetzung kann zu einer Schädigung der Hepatozyten und vor allem der Gallengänge führen. Die kanalikuläre Phospholipid Flippase (Mdr2/MDR3) bewerkstelligt normalerweise die biliäre Exkretion von Phospholipiden welche in weiterer Folge gemischte Mizellen mit Gallensäuren und Cholesterin bilden, und dadurch das Gallengangsepithel vor der Detergenzienwirkung der potentiell toxischen Gallensäuren schützen. Mdr2 Knockout Mäuse sind nicht in der Lage Phospholipide in die Galle zu sezernieren und entwickeln eine Gallengangsschädigung mit den makroskopischen und mikroskopischen Zeichen einer sklerosierenden Cholangitis. MDR3 Mutationen können beim Menschen ein breites Spektrum hepatobiliärer Erkrankungen verursachen, welche von der progressiven familiären intrahepatischen Cholestase beim Neugeborenen über die intrahepatische Schwangerschaftscholestase, medikamentös-induzierte Cholestasen, intrahepatische Cholelithiasis bis hin zu sklerosierenden Cholangitis und biliären Zirrhose beim Erwachsenen reichen. Andere Beispiele für eine Gallengangsschädigung als Folge einer toxischen Galle sind die Cholangiopathie im Rahmen einer zystischen Fibrose, nach Litocholsäurefütterung im Mausmodell, sowie Vanishing Bile Duct Syndrome durch Medikamente und Xenobiotika. Der therapeutische Ansatz für Cholangiopathien kann auf eine Modulation der Gallezusammensetzung im Sinne einer Reduktion der Toxizität bzw. eine Protektion des Gallengangsepithels abzielen. Die Ursodeoxycholsäure (UDCA) weist einige dieser Eigenschaften auf, zeigte jedoch in der Therapie von Cholangiopathien beim Menschen nur eine limitierte klinische Effektivität. Im Gegensatz zu UDCA, unterliegt die Seitenketten verkürzte norUDCA einem cholehepatischen Shunting und induziert eine Bikarbonat-reiche Hypercholerese. Weiters hat norUDCA anti-inflammatorische, anti-fibrotische und anti-proliferative Effekte und stimuliert die Gallensäurendetoxifikation. Geplante klinische Studien werden erst zeigen müssen ob norUDCA oder andere Seitenketten-modifizierte Gallensäuren auch beim Menschen klinisch effektiv sind. Neue Therapieansätze beinhalten auch die Möglichkeit über Kernrezeptoren wie FXR und PPARα die Gallezusammensetzung und Galletoxizität zu beeinflussen.

Summary

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, PPARα) regulating biliary phospholipid and bile acid excretion.

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  1. Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

    Michael Trauner, Peter Fickert, Emina Halilbasic & Tarek Moustafa

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  1. Michael Trauner
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  3. Emina Halilbasic
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Correspondence to Michael Trauner.

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Trauner, M., Fickert, P., Halilbasic, E. et al. Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases. Wien Med Wochenschr 158, 542–548 (2008). https://doi.org/10.1007/s10354-008-0592-1

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