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MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease

Muriel Girard1, Florence Lacaille, Virginie Verkarre

  • 1Department of Pediatric Gastroenterology and Hepatology, Necker Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes-Sorbonne Cité, Paris, France; INSERM, UMR 781, Université Paris Descartes-Sorbonne Cité, Institut Imagine, Paris, France.

Hepatology (Baltimore, Md.)
|December 31, 2013
PubMed
Abstract

Insights

Microvillous inclusion disease (MVID), caused by MYO5B gene mutations, can lead to a progressive liver disease resembling PFIC. Impaired MYO5B function disrupts bile flow and increases bile acid absorption, impacting MVID patient outcomes.

Area of Science:

  • Hepatology
  • Gastroenterology
  • Genetics

Background:

  • Microvillous inclusion disease (MVID) is a congenital enterocyte disorder linked to MYO5B gene mutations.
  • MVID often causes intractable diarrhea, frequently requiring intestinal transplantation (ITx).
  • A subset of MVID patients develop a progressive cholestatic liver disease, similar to progressive familial intrahepatic cholestasis (PFIC).

Purpose of the Study:

  • To investigate the mechanisms by which MYO5B mutations contribute to hepatic biliary dysfunction and cholestasis in MVID patients.
  • To analyze clinical features, outcomes, and liver histology in MVID patients with cholestasis.
  • To identify potential therapeutic strategies for MVID-associated cholestasis.

Main Methods:

  • Review of clinical and biological data from 28 MVID patients, focusing on 8 with liver disease.
  • Analysis of pretransplant liver biopsies using immunostaining and electron microscopy.
  • Genetic analysis to rule out mutations in known cholestasis genes (ABCB11/BSEP, ATP8B1/FIC1).

Main Results:

  • Cholestasis occurred before or after ITx, characterized by jaundice, pruritus, and elevated bile acids with normal GGT.
  • Liver histology revealed canalicular cholestasis, fibrosis, and ultrastructural bile canaliculi abnormalities.
  • Immunohistochemistry showed abnormal distribution of MYO5B, RAB11A, and BSEP in hepatocytes, suggesting impaired apical recycling and BSEP targeting.
  • Interruption of enterohepatic bile acid cycling provided the most effective long-term remission.

Conclusions:

  • MVID patients are susceptible to a PFIC-like liver disease that can negatively impact outcomes post-ITx.
  • Cholestasis in MVID arises from impaired MYO5B/RAB11A apical recycling, defective BSEP targeting, and increased ileal bile acid absorption.
  • Combined liver-intestinal transplantation should be considered for MVID patients with severe cholestasis, as it can worsen after ITx.

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