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Hereditäre Defekte hepatobiliärer Transportproteine

Hereditary defects of hepatobiliary transport proteins

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Zusammenfassung

Eine gestörte Funktion hepatobiliärer Transportproteine kann zu schweren hereditären cholestatischen Leberkrankheiten führen. Die progressive familiäre intrahepatische Cholestase (PFIC) manifestiert sich im frühen Kindesalter. Varianten des FIC1-Aminophospholipidtransporters (ATP8B1-Gen) verursachen sowohl die PFIC1 als auch die benigne rekurrente intrahepatische Cholestase vom Typ 1 (BRIC1). Ein Funktionsverlust der Gallensäuren-Effluxpumpe BSEP (ABCB11) führt zu PFIC2 oder BRIC2. Eine häufige BSEP-Variante, der V444A-Polymorphismus, wird häufig bei verschiedenen Arten von Cholestase gefunden, u. a. bei medikamentös induzierten Leberschäden. Schließlich führt die Dysfunktion des „multidrug resistance gene product 3“ (MDR3, ABCB4) zu PFIC3, die mit niedrigen biliären Phospholipiden und – aufgrund von Gallengangsschädigungen – hohen GGT-Konzentrationen im Serum einhergeht. Alle drei Transportergene sind auch mit gewissen Formen der intrahepatischen Schwangerschaftscholestase assoziiert. Die Behandlungsoptionen umfassen die Gabe von Ursodeoxycholsäure (UDCA) bei milderen Verlaufsformen bis hin zur Lebertransplantation bei schweren pädiatrischen cholestatischen Leberkrankheiten.

Abstract

Defects in transport proteins that are expressed at the hepatocyte canalicular membrane can cause severe impairment of hepatobiliary transport processes. Progressive familial intrahepatic cholestasis (PFIC) typically manifests in early childhood. Genetic variants in the aminophospholipid transporter FIC1 (ATP8B1 gene) cause PFIC1, characterized by elevated serum bile acids but normal or only mildly elevated gamma-GT levels. Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is also caused by ATP8B1 mutations. Defects in the function of the bile salt efflux pump (BSEP; ABCB11) cause PFIC2 or BRIC2, depending on the degree of BSEP impairment. A common BSEP variant, the V444A polymorphism, is commonly found in various types of cholestatic liver injury, including drug-induced liver injury. Finally, dysfunction of the multidrug resistance gene product MDR3 (ABCB4) leads to PFIC3, characterized by low biliary phospholipids and high gamma-GT levels in serum due to bile duct injury. All three transporter genes are also associated with intrahepatic cholestasis of pregnancy. Treatment options include ursodeoxycholic acid for milder forms and liver transplantation for severe pediatric cases.

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  1. Klinik für Klinische Pharmakologie und Toxikologie, UniversitätsSpital Zürich, Rämistr. 100, 8091, Zürich, Schweiz

    J. Mwinyi &  G.A. Kullak-Ublick

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Correspondence to G.A. Kullak-Ublick.

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Mwinyi, J., Kullak-Ublick, G. Hereditäre Defekte hepatobiliärer Transportproteine. Gastroenterologe 5, 39–48 (2010). https://doi.org/10.1007/s11377-009-0345-8

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