Biomaterial Database

MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease. 2014

Muriel Girard, and Florence Lacaille, and Virginie Verkarre, and Raphael Mategot, and Gerard Feldmann, and Alain Grodet, and Frédérique Sauvat, and Sabine Irtan, and Anne Davit-Spraul, and Emmanuel Jacquemin, and Frank Ruemmele, and Dominique Rainteau, and Olivier Goulet, and Virginie Colomb, and Christophe Chardot, and Alexandra Henrion-Caude, and Dominique Debray

Department 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.

Microvillous inclusion disease (MVID) is a congenital disorder of the enterocyte related to mutations in the MYO5B gene, leading to intractable diarrhea often necessitating intestinal transplantation (ITx). Among our cohort of 28 MVID patients, 8 developed a cholestatic liver disease akin to progressive familial intrahepatic cholestasis (PFIC). Our aim was to investigate the mechanisms by which MYO5B mutations affect hepatic biliary function and lead to cholestasis in MVID patients. Clinical and biological features and outcome were reviewed. Pretransplant liver biopsies were analyzed by immunostaining and electron microscopy. Cholestasis occurred before (n = 5) or after (n = 3) ITx and was characterized by intermittent jaundice, intractable pruritus, increased serum bile acid (BA) levels, and normal gamma-glutamyl transpeptidase activity. Liver histology showed canalicular cholestasis, mild-to-moderate fibrosis, and ultrastructural abnormalities of bile canaliculi. Portal fibrosis progressed in 5 patients. No mutation in ABCB11/BSEP or ATP8B1/FIC1 genes were identified. Immunohistochemical studies demonstrated abnormal cytoplasmic distribution of MYO5B, RAB11A, and BSEP in hepatocytes. Interruption of enterohepatic BA cycling after partial external biliary diversion or graft removal proved the most effective to ensure long-term remission. CONCLUSIONS MVID patients are at risk of developing a PFIC-like liver disease that may hamper outcome after ITx. Our results suggest that cholestasis in MVID patients results from (1) impairment of the MYO5B/RAB11A apical recycling endosome pathway in hepatocytes, (2) altered targeting of BSEP to the canalicular membrane, and (3) increased ileal BA absorption. Because cholestasis worsens after ITx, indication of a combined liver ITx should be discussed in MVID patients with severe cholestasis. Future studies will need to address more specifically the effect of MYO5B dysfunction in BA homeostasis.

UI	MeSH Term	Description	Entries
D007223	Infant	A child between 1 and 23 months of age.	Infants
D008286	Malabsorption Syndromes	General term for a group of MALNUTRITION syndromes caused by failure of normal INTESTINAL ABSORPTION of nutrients.	Malabsorption Syndrome,Syndrome, Malabsorption,Syndromes, Malabsorption
D008297	Male		Males
D008871	Microvilli	Minute projections of cell membranes which greatly increase the surface area of the cell.	Brush Border,Striated Border,Border, Brush,Border, Striated,Borders, Brush,Borders, Striated,Brush Borders,Microvillus,Striated Borders
D009081	Mucolipidoses	A group of inherited metabolic diseases characterized by the accumulation of excessive amounts of acid mucopolysaccharides, sphingolipids, and/or glycolipids in visceral and mesenchymal cells. Abnormal amounts of sphingolipids or glycolipids are present in neural tissue. INTELLECTUAL DISABILITY and skeletal changes, most notably dysostosis multiplex, occur frequently. (From Joynt, Clinical Neurology, 1992, Ch56, pp36-7)	Cherry Red Spot Myoclonus Syndrome,Ganglioside Sialidase Deficiency Disease,I-Cell Disease,Lipomucopolysaccharidosis,Mucolipidosis,Myoclonus Cherry Red Spot Syndrome,Pseudo-Hurler Polydystrophy,Sialidosis,Cherry Red Spot-Myoclonus Syndrome,Deficiency Disease, Ganglioside Sialidase,Glycoprotein Neuraminidase Deficiency,Inclusion Cell Disease,Mucolipidosis I,Mucolipidosis II,Mucolipidosis III,Mucolipidosis III Alpha Beta,Mucolipidosis IIIa,Mucolipidosis IV,Mucolipidosis Type 1,Mucolipidosis Type I,Mucolipidosis Type II,Mucolipidosis Type III,Mucolipidosis Type IV,Myoclonus-Cherry Red Spot Syndrome,Psuedo-Hurler Disease,Sialolipidosis,Type I Mucolipidosis,Type II Mucolipidosis,Type III Mucolipidosis,Type IV Mucolipidosis,Deficiencies, Glycoprotein Neuraminidase,Deficiency, Glycoprotein Neuraminidase,Glycoprotein Neuraminidase Deficiencies,I Cell Disease,I-Cell Diseases,Inclusion Cell Diseases,Lipomucopolysaccharidoses,Mucolipidoses, Type I,Mucolipidoses, Type II,Mucolipidoses, Type III,Mucolipidoses, Type IV,Mucolipidosis, Type I,Mucolipidosis, Type II,Mucolipidosis, Type III,Mucolipidosis, Type IV,Polydystrophy, Pseudo-Hurler,Pseudo Hurler Polydystrophy,Psuedo Hurler Disease,Psuedo-Hurler Diseases,Sialidoses,Sialolipidoses,Type I Mucolipidoses,Type II Mucolipidoses,Type III Mucolipidoses,Type IV Mucolipidoses
D011992	Endosomes	Cytoplasmic vesicles formed when COATED VESICLES shed their CLATHRIN coat. Endosomes internalize macromolecules bound by receptors on the cell surface.	Receptosomes,Endosome,Receptosome
D002675	Child, Preschool	A child between the ages of 2 and 5.	Children, Preschool,Preschool Child,Preschool Children
D002779	Cholestasis	Impairment of bile flow due to obstruction in small bile ducts (INTRAHEPATIC CHOLESTASIS) or obstruction in large bile ducts (EXTRAHEPATIC CHOLESTASIS).	Bile Duct Obstruction,Biliary Stasis,Bile Duct Obstructions,Biliary Stases,Cholestases,Duct Obstruction, Bile,Duct Obstructions, Bile,Obstruction, Bile Duct,Obstructions, Bile Duct,Stases, Biliary,Stasis, Biliary
D003968	Diarrhea, Infantile	DIARRHEA occurring in infants from newborn to 24-months old.	Infantile Diarrhea,Diarrheas, Infantile,Infantile Diarrheas
D005260	Female		Females