Advances in familial and congenital cholestatic diseases. Clinical and diagnostic implications.

Recent progress in liver cell biology and molecular genetics revealed that a number of familial and congenital cholestatic disorders are caused by mutations in genes coding for hepatobiliary-transporter or for signalling proteins involved in morphogenesis. The status of the field is reviewed in the light of its impact on current diagnostic and clinical practice. The heterogeneous progressive familial intrahepatic cholestasis can now be separated into different genetic diseases. FIC1-defective progressive familial intrahepatic cholestasis (previously Byler disease) is determined by mutations in the FIC1 gene, coding for P-type ATPases of unknown physiological function, while a second form (bile salt export pump defective progressive familial intrahepatic cholestatis) is caused by a defective function of the canalicular bile salt export pump. Furthermore, a group of progressive familial intrahepatic cholestasis patients with high serum gamma glutamyltranspeptidase have mutations in the gene (PGY3) coding for the MDR3 protein, a canalicular ATP-dependent phopshatidylcholine translocator. Recurrent intrahepatic cholestasis (previously benign recurrent cholestasis), is also linked to specific mutations in the FIC1 gene. Finally, in Alagille syndrome, mutations in the JAG1 gene cause deficiency Jagged 1, a ligand for Notch 1, a receptor determining cell fate during early embryogenesis. Diagnosis of Alagille syndrome, a condition that should be suspected in all patients with unexplained cholestasis, will thus be confirmed by genetic analysis for mutations of JAG1. In children with cholestasis and low serum bile acid levels, an inborn error of bile acid synthesis should be excluded by urinary bile acid analysis by means of fast atom bombardment-ionization mass-spectrometry. In contrast, in children with cholestasis and high serum bile acid concentrations, a high serum gamma glutamyltranspeptidase value would indicate MDR3 deficiency, which should be excluded through biliary phospholipid determination and genetic analysis of PGY3 gene. Finally, in those children with cholestasis, high serum bile acids and low gamma glutamyltranspeptidase activity, analysis of mutation in FIC1 and bile salt export pump genes may lead to the diagnosis of progressive familial intrahepatic cholestasis either from bile salt export pump or FIC1 deficiency.