title: Reversal of advanced fibrosis after long-term ursodeoxycholic acid therapy in a patient with residual expression of MDR3.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Servicio de Hepatología Clínica. Hospital Cosme Argerich. Buenos Aires, Argentina.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Frider
authors.affiliation: Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), Facultad de Medicina, Universidad de Buenos Aires (UBA),Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Buenos Aires, Argentina.
authors.forename: Amalia
authors.initials: A
authors.lastname: Castillo
authors.affiliation: Instituto de Investigaciones Hospital Universitario La Paz (IdiPAZ). Madrid, España.
authors.forename: Raquel
authors.initials: R
authors.lastname: Gordo-Gilart
authors.affiliation: Servicio de Hepatología Clínica. Hospital Cosme Argerich. Buenos Aires, Argentina.
authors.forename: Andrés
authors.initials: A
authors.lastname: Bruno
authors.affiliation: Servicio de Hepatología Clínica. Hospital Cosme Argerich. Buenos Aires, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Amante
authors.affiliation: Instituto de Investigaciones Hospital Universitario La Paz (IdiPAZ). Madrid, España.
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez
authors.affiliation: Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), Facultad de Medicina, Universidad de Buenos Aires (UBA),Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Buenos Aires, Argentina.
authors.forename: Verónica
authors.initials: V
authors.lastname: Mathet
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D002780:Cholestasis, Intrahepatic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D004252:DNA Mutational Analysis; D004285:Dogs; D054459:Elasticity Imaging Techniques; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D012074:Remission Induction; D012720:Severity of Illness Index; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; C095122:multidrug resistance protein 3