BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) affects approximately 0.7% of pregnancies in the UK and is associated with prematurity, fetal distress, and intrauterine death. Homozygous mutations in the ATP8B1 gene cause cholestasis with a normal serum gamma-glutamyl transpeptidase (gamma-GT), and have been reported in two forms of cholestasis: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC). AIMS: To establish whether mutations in ATP8B1 are associated with ICP in British cases PATIENTS: Sixteen well phenotyped women with ICP without raised gamma-GT were selected for sequence analysis. Subsequently, 182 patients and 120 controls were examined for the presence of the variants detected. METHODS: All coding exons were sequenced in 16 cases. Eight ICP cases, including two women carrying a mutation, were investigated using in vivo hepatic (31)P magnetic resonance spectroscopy (MRS) RESULTS: Two heterozygous ATP8B1 transitions (208G>A and 2599C>T) that resulted in amino acid substitutions were identified; 208G>A was identified in three cases. MRS revealed an increased phosphodiester signal (Mann-Whitney U test, p = 0.03) and a decreased phosphomonoester/phosphodiester ratio (p = 0.04) in ICP cases compared with controls. CONCLUSIONS: We were able to demonstrate ATP8B1 mutations in ICP. MRS studies suggest that susceptibility to ICP is associated with a relative rise in biliary phospholipid. These data also suggest that MRS may be used for non-invasive assessment of the liver and biliary constituents in cholestasis.
BACKGROUND:Intrahepatic cholestasis of pregnancy (ICP) affects approximately 0.7% of pregnancies in the UK and is associated with prematurity, fetal distress, and intrauterine death. Homozygous mutations in the ATP8B1 gene cause cholestasis with a normal serum gamma-glutamyl transpeptidase (gamma-GT), and have been reported in two forms of cholestasis: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC). AIMS: To establish whether mutations in ATP8B1 are associated with ICP in British cases PATIENTS: Sixteen well phenotyped women with ICP without raised gamma-GT were selected for sequence analysis. Subsequently, 182 patients and 120 controls were examined for the presence of the variants detected. METHODS: All coding exons were sequenced in 16 cases. Eight ICP cases, including two women carrying a mutation, were investigated using in vivo hepatic (31)P magnetic resonance spectroscopy (MRS) RESULTS: Two heterozygous ATP8B1 transitions (208G>A and 2599C>T) that resulted in amino acid substitutions were identified; 208G>A was identified in three cases. MRS revealed an increased phosphodiester signal (Mann-Whitney U test, p = 0.03) and a decreased phosphomonoester/phosphodiester ratio (p = 0.04) in ICP cases compared with controls. CONCLUSIONS: We were able to demonstrate ATP8B1 mutations in ICP. MRS studies suggest that susceptibility to ICP is associated with a relative rise in biliary phospholipid. These data also suggest that MRS may be used for non-invasive assessment of the liver and biliary constituents in cholestasis.
Authors: Maya K Leabman; Conrad C Huang; Joseph DeYoung; Elaine J Carlson; Travis R Taylor; Melanie de la Cruz; Susan J Johns; Doug Stryke; Michiko Kawamoto; Thomas J Urban; Deanna L Kroetz; Thomas E Ferrin; Andrew G Clark; Neil Risch; Ira Herskowitz; Kathleen M Giacomini Journal: Proc Natl Acad Sci U S A Date: 2003-04-28 Impact factor: 11.205
Authors: L W Klomp; L N Bull; A S Knisely; M A van Der Doelen; J A Juijn; R Berger; S Forget; I M Nielsen; H Eiberg; R H Houwen Journal: Hepatology Date: 2000-12 Impact factor: 17.425
Authors: E Jacquemin; J M De Vree; D Cresteil; E M Sokal; E Sturm; M Dumont; G L Scheffer; M Paul; M Burdelski; P J Bosma; O Bernard; M Hadchouel; R P Elferink Journal: Gastroenterology Date: 2001-05 Impact factor: 22.682
Authors: P H Dixon; N Weerasekera; K J Linton; O Donaldson; J Chambers; E Egginton; J Weaver; C Nelson-Piercy; M de Swiet; G Warnes; E Elias; C F Higgins; D G Johnston; M I McCarthy; C Williamson Journal: Hum Mol Genet Date: 2000-05-01 Impact factor: 6.150
Authors: D K Menon; J Sargentoni; S D Taylor-Robinson; J D Bell; I J Cox; D J Bryant; G A Coutts; K Rolles; A K Burroughs; M Y Morgan Journal: Hepatology Date: 1995-02 Impact factor: 17.425
Authors: S D Taylor-Robinson; J Sargentoni; J D Bell; N Saeed; K K Changani; B R Davidson; K Rolles; A K Burroughs; H J Hodgson; C S Foster; I J Cox Journal: Liver Date: 1997-08
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