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Genetics of familial intrahepatic cholestasis syndromes
  1. S W C van Mil1,
  2. R H J Houwen2,
  3. L W J Klomp1
  1. 1Department of Metabolic and Endocrine Disorders, University Medical Center, Utrecht, The Netherlands
  2. 2Department of Pediatric Gastroenterology, University Medical Center, Utrecht, The Netherlands
  1. Correspondence to:
 Leo W J Klomp
 University Medical Center Utrecht, Room KC02.069.1, Lundlaan 6, 3584 EA Utrecht, The Netherlands;


Bile acids and bile salts have essential functions in the liver and in the small intestine. Their synthesis in the liver provides a metabolic pathway for the catabolism of cholesterol and their detergent properties promote the solubilisation of essential nutrients and vitamins in the small intestine. Inherited conditions that prevent the synthesis of bile acids or their excretion cause cholestasis, or impaired bile flow. These disorders generally lead to severe human liver disease, underscoring the essential role of bile acids in metabolism. Recent advances in the elucidation of gene defects underlying familial cholestasis syndromes has greatly increased knowledge about the process of bile flow. The expression of key proteins involved in bile flow is tightly regulated by transcription factors of the nuclear hormone receptor family, which function as sensors of bile acids and cholesterol. Here we review the genetics of familial cholestasis disorders, the functions of the affected genes in bile flow, and their regulation by bile acids and cholesterol.

  • ABC, ATP-binding cassette
  • AKR1D1, Δ4-3-oxosteroid-5β reductase
  • AMACR, 2-methylacyl-CoA racemase
  • ASBT, apical sodium-dependent bile salt transporter
  • ATP, adenosine triphosphate
  • BAAT, bile acid CoA:amino acid N-acyltransferase
  • BRIC, benign recurrent intrahepatic cholestasis
  • BSEP, bile salt export pump
  • C27 3β-HSD, 3β-Δ5-C27-hydroxysteroid oxidoreductase
  • CA, cholic acid
  • CDCA, chenodeoxycholic acid
  • CEA, carcinoembryonic antigen
  • CTX, cerebrotendinous xanthomatosis
  • DCA, deoxycholic acid
  • DHCA, dihydroxycholestanoic acid
  • FHCA, familial hypercholanaemia
  • FIC1, familial intrahepatic cholestasis type 1
  • FXR, farnesoid X receptor
  • GFC, Greenland familial cholestasis
  • GGT, gamma-glutamyl transpeptidase
  • GPI, glycosyl phosphatidyl inositol
  • HSD3B7, 3β-Δ5-C27-hydroxysteroid oxidoreductase
  • IBABP, ileal bile acid binding protein
  • ICP, intrahepatic cholestasis of pregnancy
  • LCA, lithocholic acid
  • LCS, lymphoedema-cholestasis syndrome
  • LXRα, liver X receptor α
  • mEH, microsomal epoxide hydrolase
  • NAICC, North American Indian childhood cirrhosis
  • NTCP, sodium-dependent taurocholate protein
  • OATP, organic anion transporter
  • PBAM, primary bile acid malabsorption
  • PC, phosphatidyl choline
  • PFIC, progressive familial intrahepatic cholestasis
  • PXR, pregnane X receptor
  • SHP, short heterodimeric partner
  • tASBT, truncated form of ASBT
  • THCA, trihydroxycholestanoic acid
  • TJP2, tight junction protein 2
  • UDCA, ursodeoxycholic acid
  • VDR, vitamin D nuclear receptor
  • bile acids
  • bile acid synthesis
  • canalicular transport
  • cholestasis
  • nuclear hormone receptor signalling

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  • Our research is supported by grant SW006 from the University Medical Center Utrecht, grant WS 98-12 from the Dutch Digestive Disease Foundation, and by a “high-potential” award from Utrecht University.

  • Competing interests: none declared