Cholestasis, Progressive Familial Intrahepatic, 2

A number sign (#) is used with this entry because of evidence that progressive familial intrahepatic cholestasis-2 (PFIC2) is caused by homozygous or compound heterozygous mutation in the ABCB11 gene (603201), which encodes a liver-specific ATP-binding cassette (ABC) transporter, on chromosome 2q31.

Benign recurrent intrahepatic cholestasis-2 (BRIC2; 605479) is an allelic disorder.

For a phenotypic description and a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (211600).

Clinical Features

Sandor et al. (1976) described brother and sister with 'giant cell hepatitis' in infancy. The male died of a rare primary hepatic cancer; the female died of cirrhosis and hepatic coma. In studying archival material from the family reported by Sandor et al. (1976), Knisely et al. (2006) determined that the sibs had PFIC2 resulting from mutation in the ABCB11 gene. Knisely et al. (2006) studied 10 additional patients with PFIC in whom hepatocellular carcinoma was diagnosed between the ages of 13 and 52 months. Archival material was retrieved for study, and leukocytes on patients and parents were studied when available. BSEP deficiency was demonstrated by immunohistochemical analysis, and 13 different mutations in the ABCB11 gene were identified in all patients in whom leukocyte DNA could be studied; these mutations were confirmed in the parents. Knisely et al. (2006) concluded that PFIC caused by mutations in the ABCB11 gene increases the risk of hepatocellular carcinoma in early life.

Clinical Management

Jara et al. (2009) reported 3 unrelated patients with PFIC2, confirmed by genetic analysis, who underwent liver transplantation and developed recurrence of the disorder between 2 and 12 years later. In all cases, increased immunosuppression resulted in resolution of the symptoms. Serum samples from all patients showed high titers of polyclonal antibodies that reacted against bile salt export pump (BSEP) protein, encoded by the ABCB11 gene. The antibodies were shown in vitro to interfere with BSEP-mediated bile transport function and with bile acid secretion in rats in vivo. In conclusion, the patients represented phenotypic recurrence of severe BSEP deficiency resulting from antibody-mediated blockade of BSEP in grafts. It was not known whether the patients had circulating antibodies prior to transplant, but Jara et al. (2009) hypothesized that the antibodies probably developed after transplantation in response to foreign BSEP.

Mapping

By homozygosity mapping and linkage analysis of 6 Middle Eastern kindreds with PFIC, Strautnieks et al. (1997, 1997) mapped a second locus for PFIC, termed PFIC2, to chromosome 2q24 (maximum lod score of 7.1). One pedigree was unlinked, suggesting the existence of a third locus.

Arnell et al. (1997) studied 8 Swedish families with progressive familial intrahepatic cholestasis (PFIC) and excluded linkage to 18q21-q22, providing further evidence for genetic heterogeneity in this disorder.

Molecular Genetics

In patients with PFIC2, Strautnieks et al. (1998) identified 10 different mutations in the ABCB11 gene (see, e.g., 603201.0001-603201.0004).

Using immunohistochemistry, Jansen et al. (1999) found absence of the BSEP protein in 16 of 28 liver biopsy samples from patients with PFIC. All 10 of the BSEP-negative patients tested were found to have mutations in the ABCB11 gene. Six patients had heterozygous mutations, and Jansen et al. (1999) suggested that the second disease-causing mutations had not yet been identified.