Article Text
Abstract
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 (γ-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 γ-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 31P 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.
- ICP, intrahepatic cholestasis of pregnancy
- PFIC, progressive familial intrahepatic cholestasis
- BRIC, benign recurrent intrahepatic cholestasis
- MRS, magnetic resonance spectroscopy
- γ-GT, gamma-glutamyl transpeptidase
- NTP, nucleotide or nucleoside triphosphate
- PME, phosphomonoester
- PDE, phosphodiester
- GPC, glycerophosphorylcholine
- GPE, glycerophosphorylethanolamine
- ABC, ATP binding cassette
- PCR, polymerase chain reaction
- IQR, interquartile range
- bile
- liver
- magnetic resonance spectroscopy
- intrahepatic cholestasis of pregnancy
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- ICP, intrahepatic cholestasis of pregnancy
- PFIC, progressive familial intrahepatic cholestasis
- BRIC, benign recurrent intrahepatic cholestasis
- MRS, magnetic resonance spectroscopy
- γ-GT, gamma-glutamyl transpeptidase
- NTP, nucleotide or nucleoside triphosphate
- PME, phosphomonoester
- PDE, phosphodiester
- GPC, glycerophosphorylcholine
- GPE, glycerophosphorylethanolamine
- ABC, ATP binding cassette
- PCR, polymerase chain reaction
- IQR, interquartile range
Footnotes
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Conflict of interest: None declared.
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This study was presented in part as an oral presentation at the British Society of Gastroenterology Annual Meeting, Glasgow 2004.