Progressive Familial Intrahepatic Cholestasis

Jacquemin, Emmanuel

doi:10.1016/s1089-3261(05)70139-2

Cited by 89 publications

(60 citation statements)

References 64 publications

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“…The first two types, PFIC1 and 2, share common phenotypic features, including normal or nearly normal serum ␥-glutamyl transpeptidase activity and little bile duct proliferation, that are unusual in other types of cholestatic liver diseases. 1 In PFIC2, mutations affect the ABCB11 gene, which encodes a bile salt transporter, the canalicular bile salt export pump (BSEP). 2 Thus, a defect in the extrusion of bile salts across the canalicular membrane of hepatocytes is the primary cause of cholestasis in PFIC2.…”

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

“…17 To better define at which level ATP8B1 contributes to the regulation of bile secretion, we examined its expression in human hepatocytes, bile duct and gallbladder epithelial cells. To determine whether ATP8B1 deficiency may affect biliary functions in hepatocytes or in cholangiocytes, we examined the expression of genes involved in different aspects of bile secretion: (1) in the liver of patients with PFIC1 as compared to a normal liver and to the liver of patients with other cholestatic liver diseases (PFIC2 and biliary atresia), and (2) in a biliary epithelial cell line in which ATP8B1 endogenous expression was invalidated by small interfering RNA (siRNA).…”

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

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Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

et al. 2006

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Recent reports in patients with PFIC1 have indicated that a gene defect in ATP8B1 could cause deregulations in bile salt transporters through decreased expression and/or activity of FXR. This study aimed to: (1) define ATP8B1 expression in human hepatobiliary cell types, and (2) determine whether ATP8B1 defect affects gene expressions related to bile secretion in these cells. ATP8B1 expression was detected by RT-PCR in hepatocytes and cholangiocytes isolated from normal human liver and gallbladder. ATP8B1 mRNA levels were 20-and 200-fold higher in bile duct and gallbladder epithelial cells, respectively, than in hepatocytes. RT-PCR analyses of the liver from two patients with PFIC1, one with PFIC2, one with biliary atresia, showed that, compared to normal liver, hepatic expressions of FXR, SHP, CYP7A1, ASBT were decreased at least by 90% in all cholestatic disorders. In contrast, NTCP transcripts were less decreased (by <30% vs. 97%) in PFIC1 as compared with other cholestatic disorders, while BSEP transcripts, in agreement with BSEP immunohistochemical signals, were normal or less decreased (by 50% vs. 97%). CFTR hepatic expression was decreased (by 80%), exclusively in PFIC1, while bile duct mass was not reduced, as ascertained by cytokeratin-19 immunolabeling. In Mz-ChA-2 human biliary epithelial cells, a significant decrease in CFTR expression was associated with ATP8B1 invalidation by siRNA. In conclusion, cholangiocytes are a major site of ATP8B1 hepatobiliary expression. A defect of ATP8B1 along with CFTR downregulation can impair the contribution of these cells to bile secretion, and potentially explain the extrahepatic cystic fibrosis-like manifestations that occur in PFIC1. (HEPATOLOGY 2006;43:1125-1134 P rogressive familial intrahepatic cholestasis (PFIC) represents a heterogeneous group of inherited disorders, in which cholestasis starts in infancy and generally leads to liver failure in childhood. Three types of PFIC, caused by mutations in three separate genes, are currently recognized. The first two types, PFIC1 and 2, share common phenotypic features, including normal or nearly normal serum ␥-glutamyl transpeptidase activity and little bile duct proliferation, that are unusual in other types of cholestatic liver diseases. 1 In PFIC2, mutations affect the ABCB11 gene, which encodes a bile salt transporter, the canalicular bile salt export pump (BSEP). 2 Thus, a defect in the extrusion of bile salts across the canalicular membrane of hepatocytes is the primary cause of cholestasis in PFIC2. In PFIC1, mutations affect the ATP8B1 gene, which encodes a protein also called FIC1. 3 ATP8B1 protein belongs to a subfamily of P-type adenosine triphosphatases. Two members of this subfamily including ATP8B1 have been reported to mediate aminophospholipid translocation in plasma membranes. 4,5 The physiological function of ATP8B1 protein and the mechanisms by which ATP8B1 deficiency leads to PFIC1 disease remain poorly understood. It was previously shown that ATP8B1 is expressed in different tissues such as th...

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Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

et al. 2006

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“…Supplementation with UDCA may be enough to decrease bile toxicity beneath a critical threshold level in this subset of patients 23 .…”

Section: Treatmentmentioning

confidence: 99%

“…• Responders to UDCA likely have missense mutations, with a partial defect allowing for some residual phospholipids secretion into bile 22,23 . Supplementation with UDCA may be enough to decrease bile toxicity beneath a critical threshold level in this subset of patients 23 .…”

Section: Treatmentmentioning

confidence: 99%

The multiple facets of ABCB4 (MDR3) deficiency

Sundaram

Sokol²

2007

Curr Treat Options Gastro

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“…PFIC yenidoğan döneminde başlayıp genellikle ilk dekadda siroza ilerleyen kronik kolestazla giden bir hastalıktır. Ortalama başlangıç yaşı 3 ay olup bazı hastalar sarılığı daha ileri dönemlerde geliştirebilirler (2,3). Hastalığın patogenezinden safra kanalcıkları düzeyinde safra asidi transportunun bozukluğu sorumlu tutulmaktadır.…”

Section: Introductionunclassified