ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy

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 P-31 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.