Cholestatic Liver Diseases from Child to Adult: The Diversity of MDR3 Disease

Zusammenfassung

Die Phospholipidfloppase MDR3 (Gensymbol: ABCB4) findet sich in der kanalikulären Hepatozytenmembran und mediiert die biliäre Sekretion von Phosphatidylcholin, welches für die Bildung gemischter Mizellen benötigt wird. Es sind zahlreiche Mutationen von MDR3 bekannt, die cholestatische Lebererkrankungen unterschiedlichen Schweregrads verursachen. Hierzu gehören die progressive familiäre intrahepatische Cholestase Typ 3 (PFIC-3), die intrahepatische Schwangerschaftscholestase (ICP) und das low phospholipid associated cholelithiasis Syndrom (LPAC). In dieser Arbeit berichten wir über 4 neue (S1076N; L 23Hfs16X; c.286 + 1G > A; Q 1181E) und eine bekannte (S27G) MDR3-Mutation bei 8 Patienten aus 3 Familien. Die Patienten präsentierten sich mit einem großen Spektrum an Lebererkrankungen. Die klinische Präsentation, spezifische Laborbefunde und eine richtungweisende Familienanamnese waren ausschlaggebend für die Identifikation des genetischen Hintergrunds der Erkrankungen. Die Fälle zeigen zudem, dass ein und dieselbe Mutation mit unterschiedlich starker Ausprägung und Progression der Erkrankung verbunden sein kann.

Abstract

The phospholipidfloppase MDR3 (gene symbol: ABCB4) is expressed in the canalicular membrane of hepatocytes and mediates the biliary excretion of phosphatidylcholine, which is required for the formation of mixed micelles in bile. Several mutations of ABCB4 have been identified, which cause cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 3 (PFIC-3), intrahepatic cholestasis of pregnancy (ICP) and the low phospholipid associated cholelithiasis syndrome (LPAC). Here, we report on four new (S1076N; L 23Hfs16X; c.286 + 1G > A; Q 1181E) and one known (S27G) MDR3 mutations in eight patients of three families. The patients presented with a wide spectrum of liver diseases. The clinical presentation and decisive laboratory findings or the association to a trend-setting family history led to the identification of the genetic background in these patients. Even the same mutation may be associated with varying disease progression.

Schlüsselwörter

Leber - Cholestase - Phosphatidylcholin - Phospholipidfloppase - ABC-Transporter - gamma-Glutamyltransferase

Key words

liver - cholestasis - phosphatidylcholine - phospholipidfloppase - ABC transporter - gamma-glutamyl transferase

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