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Semin Liver Dis 2010; 30(2): 117-124
DOI: 10.1055/s-0030-1253221
© Thieme Medical Publishers

Progressive Familial Intrahepatic Cholestasis Type 1

Coen C. Paulusma1 , Ronald P.J. Oude Elferink1 , Peter L.M Jansen1
  • 1Tytgat Institute of Liver and Gastrointestinal Research and Department of Gastroenterology and Liver Disease, Academic Medical Center, Amsterdam, The Netherlands
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Publication History

Publication Date:
26 April 2010 (online)

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ABSTRACT

Progressive familial intrahepatic cholestasis type 1 is a rare genetic liver disease that presents in the first year of life. Bile salts are elevated and these patients are often jaundiced. Despite the cholestasis, serum gamma-glutamyltransferase activity is normal or reduced. Pruritus is a major symptom in these patients. Partial external biliary diversion is helpful in several patients as it reduces the pruritus and postpones or even avoids liver transplantation. The disease is caused by mutations in the gene ATP8B1 that preclude the normal expression of ATP8B1. ATP8B1 is a protein that acts as a lipid flippase, transporting phosphatidylserine from the exoplasmic to the cytoplasmic leaflet of the canalicular membrane of hepatocytes. The authors have shown that the canalicular membrane of ATP8B1-deficient hepatocytes is less stable as evidenced by enhanced extraction of membrane constituents by bile salts. Recent evidence suggests membrane instability in ATP8B1-deficient hair cells of the ear, providing an explanation for hearing loss in ATP8B1 deficiency. Although the exact etiology of cholestasis is incompletely understood, it is hypothesized that ATP8B1 deficiency results in enhanced cholesterol extraction from the canalicular membrane, which impairs the function of the bile salt export pump (BSEP), resulting in cholestasis. Mutations in ATP8B1 also cause benign recurrent intrahepatic cholestasis, a milder variant of the disease characterized by episodes of cholestasis. The onset and resolution of the cholestatic episodes in these patients is still not well understood.

KEYWORDS

Progressive familial intrahepatic cholestasis - benign recurrent intrahepatic cholestasis - intrahepatic cholestasis of pregnancy - partial external biliary diversion - ATP8B1 - bile salt export pump - farnesoid X-receptor

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Peter L.M JansenM.D. Ph.D. 

Department of Gastroenterology and Liver Disease, Academic Medical Center

Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Email: p.l.jansen@amc.uva.nl

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