Progressive familial intrahepatic cholestasis and related disorders
By Emmanuel Jacquemin, M. D., Ph. D.
Hepatology Unit, Department of Pediatrics, and INSERM U 347, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
Last update: 03 January 2001
Progressive familial intrahepatic cholestasis (PFIC) is an heterogeneous group of autosomal recessive liver disorders of childhood in which cholestasis of hepatocellular origin often presents in the neonatal period or the first year of life and leads to death from liver failure at ages ranging from infancy to adolescence. Recent molecular and genetic studies have allowed the identification of genes responsible for three types of PFIC and have shown that PFIC was related to mutations in hepatocellular transport system genes involved in bile formation (see figure). Liver diseases resembling PFIC that have been identified as inborn errors in primary bile acid synthesis are not considered in this chapter.
The first type, called PFIC1 is caused by mutations in the FIC1 gene. In patients belonging to the Byler kindred, the disease is called Byler disease. This gene which encodes a P-type ATPase is also mutated in the milder phenotype, benign recurrent intrahepatic cholestasis (BRIC) and in Greenland familial cholestasis. The function of this P-type ATPase is unknown but it could be an aminophospholipid transporter responsible for maintening the enrichment of phosphatidylserine and phosphatidylethanolamine on the inner leaflet of the plasma membrane in comparison of the outer leaflet. How mutations in this protein cause cholestasis is unclear, but it is thought to be involved in the enterohepatic cycling of bile salts.
The second type, called PFIC2 (previously called Byler syndrome and recently named BSEP deficiency) is caused by mutations in the BSEP gene (also designated ABCB11). Byler syndrome has been defined as a disease similar to Byler disease but occuring in patients not belonging to the Byler family. The BSEP gene encodes the ATP-dependent canalicular bile salt export pump (BSEP) of human liver. Mutations in this protein is responsible for the decreased biliary bile salt secretion described in affected patients, leading to accumulation of bile salts inside the hepatocyte and ongoing severe hepatocellular damage. Despite cholestasis, patients with PFIC1 and PFIC2 have normal serum gamma-glutamyltransferase (GGT) activity. Liver histology is characterized by the absence of a true ductular proliferation with only periportal biliary metaplasia of hepatocytes.
The third type of PFIC, called PFIC3, can be distinguished from the other types by a high serum GGT activity and liver histology which shows ductular proliferation and inflammatory infiltrate in the early stages despite patency of intra and extrahepatic bile ducts. We have reported in several patients that a genetic defect in the MDR3 gene (also designated ABCB4) underlies PFIC3 which shares histological and biochemical (low biliary phospholipid level) features with mice with a homozygous disruption of the mdr2 gene. Class III Multidrug Resistance (MDR) P-glycoproteins (P-gp), mdr2 in mice and MDR3 in human, are phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion and are predominantly, if not exclusively, expressed in the canalicular membrane of the hepatocyte.
The link between PFIC and intrahepatic cholestasis of pregnancy (ICP) has been made when we have found, within the families of two different children with PFIC3, each child having a distinct nonsense homozygous MDR3 mutation, that heterozygous women had experienced typical recurrent episodes of ICP. These familial observations provide arguments for a genetic basis of ICP. It is likely that the heterozygous state for a MDR3 gene defect represents a genetic predisposition in these families, since cholestasis was not present in every pregnancy in these women. Associated non genetic factors, such as female sex hormones and metabolites, could modify MDR3 heterozygous state expressivity directly by decreasing normal allele expression or indirectly by impairing the function of transport systems involved in bile secretion. Such events could favour the transient decompensation of the heterozygous state for a MDR3 gene defect during pregnancy leading to ICP. As for PFIC3, cholestasis would result from the toxicity of bile in which detergent bile salts are not inactivated by phospholipids. While heterozygous mdr2 (+/-) mice, with a maximal phospholipid secretion of 60% of controls do not develop liver disease, the appearance of liver injury in a heterozygous patient could be expected because in humans the bile salt pool is much more hydrophobic than in mice. This may justify to search for a MDR3 gene mutation in ICP, particularly if serum GGT activity is high. Indeed, since our initial publication, another case of ICP with high serum GGT activity has been reported in a woman harboring an heterozygous MDR3 missense mutation with no known family history of PFIC. These new discoveries on molecular mechanisms of bile secretion also raise the issue whether a heterozygous woman for a FIC1 or BSEP defect may be at risk for ICP. Indeed, in the original report of Byler's disease, the mother of an affected child had experienced several episodes of ICP. Furthermore, BRIC and ICP have been reported in a single kindred suggesting that both cholestatic syndromes may be inter-related. It is hypothesized that FIC1 or BSEP genes could be involved in ICP with normal serum GGT activity.
For patients with PFIC, oral administration of ursodeoxycholic acid and surgical partial external biliary diversion may represent alternatives to liver transplantation. In the future, other therapies such as cell and gene therapies, might represent an alternative to liver transplantation.
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