BACKGROUND AND AIMS Progressive familial inrahepatic cholestasis type 2 (PFIC2) is an autosomal recessive disorder with defective bile salt export pump (BESP) which results in cholestatic liver disease in 15% - hepatocellular carinoma (HCC). As intra-hepatocytic bile accumulation is considered to be the driver of oncogenesis in PFIC2, we hypothesized that risk of HCC would correlate to capability of BESP. METHODS From two participating centers, sixty-two childeren with PFIC2 were identiefied, of which seven who developed HCC were included. Clinical, genetic, histological information was collected and 3D homology modelling was done to determine the severity of structural alterations in BSEP. Functional ability of BSEP was assessed by the clinical response to medical therapy and severity of structural change in the BESP as assesed by 3D homology modelling. RESULTS PFIC2 was diagnosed at a mean of 3.7 months (1-10months) and HCC was discovered 52 months later (11-150months). At diagnosis BESP was absent in 85% (6 of 7) while one had canalicular localization. The diagnosis features of HCC were elevated AFP in 71% (5 àf 7) and ultrasound characteristics in 85% (6 of 7). Functional ability of BSEP was related in 28% (2 to 7). These both demonstrated clinical response to medical therapy and had mild structural alteration of BSEP on 3D modelling CONCLUSIONS There is a high incidence of HCC in PFIC2, and can occur in presence of normal AFP. The functional capability of BSEP can be predicted by structural modelling and does not correlate to risk of oncogenesis
