Predicting development of hepatocellular carcinoma among patients with progressive familial intrahepatic cholestasis type 2

Background and aims: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an autosomal recessive disorder due to defective bile salt export pump (BSEP) which results in cholestatic liver disease and in some cases in hepatocellular carcinoma (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 functional loss of BSEP. Methods From two participating centers, sixty-two children with PFIC2 were identified, of which seven who developed HCC were included. Clinical, genetic, histological information was collected and 3D homology modeling 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 BSEP as assessed by 3D homology modeling. Results PFIC2 was diagnosed at a mean age of 3.7 months (1-10 months) and HCC was discovered 52 months later (11-150 months). At diagnosis BSEP canalicular immunostaining was negative in 85% (6 of 7). HCC was suspected because of elevated AFP in 5 and of visualization of suspicious ultrasonographic lesion in 6 patients. In one patient HCC was discovered fortuitously after LT. Functional ability of BSEP was retained in 2 patients. These patients demonstrated clinical response to medical therapy and had mild structural alteration of BSEP on 3D modeling. Conclusion There is high incidence of HCC in PFIC2 patients (11%, 7/62). HCC can occur in presence of normal AFP and in patients with mutations that are predicted to lead to severe functional loss of BSEP.