Progressive familial intrahepatic cholestasis is a heterogeneous group of autosomal recessive liver disorders characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood (Alonso et al., 1994; Whitington et al., ... Progressive familial intrahepatic cholestasis is a heterogeneous group of autosomal recessive liver disorders characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood (Alonso et al., 1994; Whitington et al., 1994; Klomp et al., 2004). - Genetic Heterogeneity of Progressive Familial Intrahepatic Cholestasis PFIC is a genetically heterogeneous disorder caused by defects in the transport of bile acids. See also PFIC2 (601847), caused by mutation in a liver-specific ATP-binding cassette transporter gene (ABCB11; 603201) on chromosome 2q24, and PFIC3 (602347), caused by mutation in the class III multidrug resistance P-glycoprotein gene (ABCB4; 171060) on chromosome 7q21. PFIC1 and PFIC2 are associated with mildly elevated or normal serum levels of gamma-glutamyltransferase (GGT1; 612346), whereas PFIC3 is associated with high serum GGT1 levels and liver histology that shows portal inflammation and ductular proliferation in an early stage (Maggiore et al., 1987, 1991). There are also several phenotypically similar liver disorders that result from congenital defects in bile acid synthesis. See CBAS1 (607765).
In the Old Order Amish, Clayton et al. (1965, 1969) described a severe form of intrahepatic cholestasis leading to death in the first decade of life. The main clinical features were early onset of loose, foul-smelling stools, jaundice, ... In the Old Order Amish, Clayton et al. (1965, 1969) described a severe form of intrahepatic cholestasis leading to death in the first decade of life. The main clinical features were early onset of loose, foul-smelling stools, jaundice, hepatosplenomegaly, impaired growth with short stature, and in 4 of 6 cases, death between 17 months and 8 years. One mother had extreme pruritus without jaundice in the last trimester of each of 4 pregnancies, consistent with ICP. Two fathers had reduced maximum excretion of sulfobromophthalein. Treatment with cholestyramine, a bile-salt-sequestering exchange resin, reduced the hyperbilirubinemia. Because the bile showed an increased proportion of dihydroxy bile salts as well as the early onset of changes in the stool and the response to cholestyramine, a defect in bile salt metabolism was postulated. Kaye (1965) studied 3 sibs with intrahepatic cholestasis in which itching predated jaundice, which began by 2 or 3 years of age. One sib died at about 7 years of age and 2 were still alive at ages of about 5 and 10. Cholestyramine had no benefit. These patients were later reported by Williams et al. (1972). The same condition was probably described by Gray and Saunders (1966) in 2 sisters who died under 3 years of age and in a patient reported by Hirooka and Ohno (1968). Toussaint and Gros (1966) reported affected brothers. Landing (1972) suggested that hepatoma may be a terminal event in some patients with PFIC. De Vos et al. (1975) reported a child with Byler disease. Liver biopsy showed intrahepatic cholestasis, and electron microscopy showed interruptions of the bile canalicular membrane. The findings suggested a primary disturbance in bile acid secretion as the cause of cholestasis. Kaplinsky et al. (1980) described a brother and sister with pruritus since infancy who developed cholestatic hepatic cirrhosis early in life. Although the boy had Kayser-Fleischer rings, further studies excluded Wilson disease (277900). Determination of the concentrations and patterns of bile acids in the serum indicated a defect in bile acid transport, not bile acid synthesis. Some of the clinical features resembled those described by Jones et al. (1976). Differences from Byler disease were the absence of steatorrhea and physical retardation and survival beyond puberty in 1 sib. Nielsen et al. (1986) described Byler disease in 16 Greenland Eskimo children. Typical features included jaundice, pruritus, malnutrition, steatorrhea, osteodystrophy, short stature, and hyperbilirubinemia. Eight patients had died between the ages of 6 weeks and 3 years. The pedigrees were consistent with autosomal recessive inheritance. Liver biopsy showed nonspecific cholestatic features (Ornvold et al., 1989). Whitington et al. (1994) reported 33 patients with PFIC. Symptoms developed almost invariably before 6 months of age with severe pruritus and moderate jaundice. Serum levels of gamma-GGT and cholesterol were not elevated. Twenty-six patients had either partial biliary diversion or orthotopic liver transplantation. Seven patients died at a mean age of 3.9 years from liver failure, hepatocellular carcinoma, or complications of liver transplantation. Jacquemin et al. (1994) found that total bile acid concentration was decreased in the bile of 7 children with Byler disease compared to children with other cholestatic diseases. Total bile acid concentration in serum was similar between the 2 groups. Jacquemin et al. (1994) concluded that Byler disease is caused by a defect in primary bile acid secretion. In liver biopsies from 28 patients with PFIC and low GGT1 levels, Alonso et al. (1994) found canalicular cholestasis and disruption of the liver cell plate. Giant cell transformation was present in 56% of initial biopsies. Bile duct loss was a prominent and early finding and many biopsies had abnormal bile duct epithelium. Other features included bridging fibrosis, cirrhosis, and pseudoacinar transformation. Mallory hyaline bodies and hepatocellular carcinoma were observed in some patients with advanced cirrhosis. Bourke et al. (1996) reported familial cholestasis resembling Byler disease in 8 children in 2 sibships related as first cousins in a highly intermarried group of Irish travelers, an indigenous Irish nomadic community. The children had a history of neonatal diarrhea, sepsis, and intermittent jaundice that ultimately became permanent. They suffered from intractable pruritus and growth retardation. Despite evidence of severe cholestasis, serum gamma-glutamyltransferase and cholesterol concentrations were normal. Sweat sodium concentrations were raised in 3 children. Trauner et al. (1998) reviewed the molecular changes in the hepatocellular transport systems in patients with cholestatic disorders. PFIC1 and PFIC2 were associated with low serum gamma-glutamyltransferase concentrations; the concentration of this enzyme was high in PFIC3. Oshima et al. (1999) described 2 sibs with Byler disease and congenital sensorineural hearing loss. Klomp et al. (2000) found that liver specimens from 3 Inuit patients with PFIC showed bland canalicular cholestasis. Transmission electron microscopy showed coarsely granular bile similar to that described in Amish patients with the disorder.
In patients with PFIC1, Bull et al. (1998) identified homozygous or compound heterozygous mutations in the ATP8B1 gene (602397.0001-602397.0005).
In Inuit patients with PFIC from Greenland and Canada, Klomp et al. (2000) identified a homozygous mutation ... In patients with PFIC1, Bull et al. (1998) identified homozygous or compound heterozygous mutations in the ATP8B1 gene (602397.0001-602397.0005). In Inuit patients with PFIC from Greenland and Canada, Klomp et al. (2000) identified a homozygous mutation in the ATP8B1 gene (602397.0008). Klomp et al. (2004) identified 36 distinct mutations in the ATP8B1 gene in 39 (30%) of 130 PFIC families. Twenty-five of the mutations were detected only in 1 family.