ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy.

[benign recurrent intrahepatic cholestasis]

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 ATP 8 B 1 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 (PFIC 1 ) and benign recurrent intrahepatic cholestasis (BRIC ).To establish whether mutations in ATP 8 B 1 are associated with ICP in British casesSixteen 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 .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 ATP 8 B 1 transitions (208 G >A and 2599 C >T ) that resulted in amino acid substitutions were identified ; 208 G >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 .We were able to demonstrate ATP 8 B 1 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 .

Diseases
Validation

Diseases presenting "prematurity" symptom

benign recurrent intrahepatic cholestasis

classical phenylketonuria

homocystinuria without methylmalonic aciduria

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