ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): Phenotypic differences between PFIC1 and PFIC2 and natural history

Authors

  • Anne Davit-Spraul,

    1. Biochemistry Unit, Hôpital Bicêtre, Assistance Publique, Hôpitaux de Paris, Paris, France
    Search for more papers by this author
  • Monique Fabre,

    1. Pathology Unit, Hôpital Bicêtre, Assistance Publique, Hôpitaux de Paris, Paris, France
    2. Faculty of Medicine Paris-Sud 11, University Paris, Paris, France
    Search for more papers by this author
  • Sophie Branchereau,

    1. Pediatric Surgery Unit, Hôpital Bicêtre, Assistance Publique, Hôpitaux de Paris, Paris, France
    Search for more papers by this author
  • Christiane Baussan,

    1. Biochemistry Unit, Hôpital Bicêtre, Assistance Publique, Hôpitaux de Paris, Paris, France
    Search for more papers by this author
  • Emmanuel Gonzales,

    1. Faculty of Medicine Paris-Sud 11, University Paris, Paris, France
    2. Pediatric Hepatology Unit and National Reference Centre for Biliary Atresia, Hôpital Bicêtre, Assistance Publique, Hôpitaux de Paris, Paris, France
    3. INSERM U757, University Paris 11, Orsay, France
    Search for more papers by this author
  • Bruno Stieger,

    1. Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland
    Search for more papers by this author
  • Olivier Bernard,

    1. Faculty of Medicine Paris-Sud 11, University Paris, Paris, France
    2. Pediatric Hepatology Unit and National Reference Centre for Biliary Atresia, Hôpital Bicêtre, Assistance Publique, Hôpitaux de Paris, Paris, France
    Search for more papers by this author
  • Emmanuel Jacquemin

    Corresponding author
    1. Faculty of Medicine Paris-Sud 11, University Paris, Paris, France
    2. Pediatric Hepatology Unit and National Reference Centre for Biliary Atresia, Hôpital Bicêtre, Assistance Publique, Hôpitaux de Paris, Paris, France
    3. INSERM U757, University Paris 11, Orsay, France
    • Service d'Hépatologie Pédiatrique, Hôpital Bicêtre, 78, rue du Général Leclerc, Le Kremlin-Bicêtre, 94275 cedex, France
    Search for more papers by this author
    • fax: +33 1 45 21 28 16


  • Supported by Assistance Publique, Hôpitaux de Paris and Ministère de la Santé (Paris, France); grants: Innovations Technologiques 2002/2003, Progrès Médical 2004/2005 and DHOS 2005/2006.

  • Potential conflict of interest: Nothing to report. Additional Supporting Information may be found in the online version of this article.

Abstract

Progressive familial intrahepatic cholestasis (PFIC) types 1 and 2 are characterized by normal serum gamma-glutamyl transferase (GGT) activity and are due to mutations in ATP8B1 (encoding FIC1) and ABCB11 (encoding bile salt export pump [BSEP]), respectively. Our goal was to evaluate the features that may distinguish PFIC1 from PFIC2 and ease their diagnosis. We retrospectively reviewed charts of 62 children with normal-GGT PFIC in whom a search for ATP8B1 and/or ABCB11 mutation, liver BSEP immunostaining, and/or bile analysis were performed. Based on genetic testing, 13 patients were PFIC1 and 39 PFIC2. The PFIC origin remained unknown in 10 cases. PFIC2 patients had a higher tendency to develop neonatal cholestasis. High serum alanine aminotransferase and alphafetoprotein levels, severe lobular lesions with giant hepatocytes, early liver failure, cholelithiasis, hepatocellular carcinoma, very low biliary bile acid concentration, and negative BSEP canalicular staining suggest PFIC2, whereas an absence of these signs and/or presence of extrahepatic manifestations suggest PFIC1. The PFIC1 and PFIC2 phenotypes were not clearly correlated with mutation types, but we found tendencies for a better prognosis and response to ursodeoxycholic acid (UDCA) or biliary diversion (BD) in a few children with missense mutations. Combination of UDCA, BD, and liver transplantation allowed 87% of normal-GGT PFIC patients to be alive at a median age of 10.5 years (1-36), half of them without liver transplantation. Conclusion: PFIC1 and PFIC2 differ clinically, biochemically, and histologically at presentation and/or during the disease course. A small proportion of normal-GGT PFIC is likely not due to ATP8B1 or ABCB11 mutations. (HEPATOLOGY 2010)

Ancillary