Cholestasis, Progressive Familial Intrahepatic, 3

A number sign (#) is used with this entry because of evidence that progressive familial intrahepatic cholestasis-3 (PFIC3) is caused by mutation in the gene encoding the class III multidrug resistance (MDR3) P-glycoprotein (ABCB4; 171060).

For a general phenotypic description and a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600).

Clinical Features

De Vree et al. (1998) reported 2 unrelated patients with PFIC3. The first patient was a Turkish boy, born of consanguineous parents, who had recurrent bouts of jaundice from the age of 3 months, when he presented with severe icterus, diarrhea, fever, and pruritus. At the age of 3 years, he showed hepatosplenomegaly, elevated serum liver enzymes, increased gamma-glutamyltransferase (GGT1; 612346) activity (6 times normal), and a high serum bile acid concentration (50 times normal). Liver biopsy showed nonspecific portal inflammation, extensive portal fibrosis, and cirrhosis. There was no response to treatment with ursodeoxycholate (UDCA). Orthotopic liver transplantation was performed at the age of 3.5 years. The second patient was a North African boy, born of first-cousin parents, who had recurrent episodes of severe pruritus from the age of 8 months. At age 3 years, he had hepatosplenomegaly, elevated serum GGT1 activity (38 times normal), and increased serum bile acids (16 times normal), whereas other liver enzymes were only mildly elevated. Liver histology showed ductular proliferation and extensive portal fibrosis. Liver transplantation was performed at the age of 9 years. The mother of the affected child experienced recurrent episodes of intrahepatic cholestasis of pregnancy (ICP3; 614972).

Deleuze et al. (1996) found lack of MDR3 (ABCB4) mRNA in the livers of patients with PFIC and increased serum GGT1 levels.

Molecular Genetics

In 2 unrelated patients with PFIC and high serum GGT1, de Vree et al. (1998) identified 2 different homozygous mutations in the ABCB4 gene (171060.0001; 171060.0002).

In a patient with severe PFIC3 requiring liver transplant at the age of 6 years, Jacquemin et al. (1999) identified a homozygous mutation in the ABCB4 gene (171060.0003). Six women in the family with intrahepatic cholestasis of pregnancy were heterozygous for the mutation.

Degiorgio et al. (2007) identified 29 distinct mutations in the ABCB4 gene, including 25 novel mutations (see, e.g., 171060.0009; 171060.0010), in 18 probands with PFIC3. The findings indicated high allelic variability in the disorder with a high prevalence of mutations in exon 17 of the ABCB4 gene.

Nomenclature

Hadchouel (1998) questioned the designation PFIC3 for this type of cholestasis. Noting that there are at least 2 other types of PFIC, she suggested that PFIC3 should be referred to as 'MDR3 deficiency.'