Reversal of advanced fibrosis after long-term ursodeoxycholic acid therapy in a patient with residual expression of MdR3

• Published in: Annals of hepatology 2015-09, Vol.14 (5), p.745-751
• Main Authors: Frider, Bernardo, Castillo, Amalia, Gordo-Gilart, Raquel, Bruno, Andrés, Amante, Marcelo, Alvarez, Luis, Mathet, Verónica
• Format: Article
• Language: English
• Subjects: ABCB4; Animals; ATP Binding Cassette Transporter, Sub-Family B - deficiency; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; Cholagogues and Choleretics - therapeutic use; Cholestasis; Cholestasis, Intrahepatic - diagnosis; Cholestasis, Intrahepatic - drug therapy; Cholestasis, Intrahepatic - genetics; DNA Mutational Analysis; Dogs; Elasticity Imaging Techniques; Gastroenterology and Hepatology; Genetic Predisposition to Disease; HEK293 Cells; Humans; Immunohistochemistry; Liver Cirrhosis - diagnosis; Liver Cirrhosis - drug therapy; Liver Cirrhosis - genetics; Madin Darby Canine Kidney Cells; Male; Mutation, Missense; PFIC-3; Phenotype; Remission Induction; Severity of Illness Index; Time Factors; Transfection; Treatment Outcome; Ursodeoxycholic Acid - therapeutic use; Young Adult
• ISSN: 1665-2681
• DOI: 10.1016/S1665-2681(19)30771-9

AbstractIntroduction. Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a severe liver disorder associated with inherited dysfunction of multidrug resistance protein 3 (MDR3/ABCB4), which functions as a phospholipid floppase, translocating phosphatidylcholine from the inner to the outer hemileaflet of the canalicular membrane of hepatocytes. MDR3 deficiency results in a disbalanced bile which may damage the luminal membrane of cells of the hepatobiliary system. We evaluated clinical, biochemical and histological improvement in a genetically proven PFIC-3 patient after long-term ursodeoxycholic acid (UDCA) administration. Material and methods. A PFIC-3 patient and a relative with cholestatic liver disease were studied. Hepatic MDR3 expression was analyzed by immunohistochemistry and ABCB4 mutations were identified. The effect of the mutations on MDR3 expression and subcellular localization was studied in vitro. Results. A 23-year-old man presented cholestasis with severe fibrosis and incomplete cirrhosis. Canalicular staining for MDR3 was faint. Sequence analysis of ABCB4 revealed two missense mutations that reduce drastically protein expression levels. After 9 years of treatment with UDCA disappearance of fibrosis and cirrhosis was achieved. Conclusion. These data indicate that fibrosis associated with MDR3 deficiency can be reversed by long-term treatment with UDCA, at least when there is residual expression of the protein.