Introduction: Progressive familial intrahepatic cholestasis (PFIC) is a rare autosomal recessive disease that affects bile acid transport leading to clinical manifestations ranging from varying levels of cholestasis with severe pruritis to overt liver failure.  There are several subtypes of PFIC, with newer variants being recently identified.  PFIC 2 specifically has been associated with the development of hepatocellular carcinoma (HCC).  In patients with medically refractory disease, liver failure, or HCC, transplantation is the only curative option.  Herein we report the largest single center series of liver transplantation for PFIC, with a particular focus on malignancy risk. 
Methods: We conducted a retrospective review of a prospectively collected database of all pediatric liver transplant patients performed at a large, single center between 1990 and 2022.  Patients transplanted for a primary diagnosis of PFIC were included in the study.
Results: We identified 16 patients who underwent liver transplant for PFIC (Type 1=2, Type 2=8, Type 3=4, Type 4=2).  Confirmatory genetic testing was performed for all patients.  Six patients (38%) were diagnosed by age 1, and 15 (94%) by age 3.  Surgical biliary diversion was performed in 7 (44%) patients for treatment of severe pruritis.  Average age at transplant was 6.5 years (range 9 months-14 years).  Deceased donor allografts were used in 15 (94%) patients (14 whole organ, 1 left lateral segment) and 1 patient received a live donor graft.  Two patients had suspected HCC pretransplant: 1 with PFIC 2 and 1 with PFIC 3.  Both were diagnosed with surveillance MRI and markedly elevated alpha fetoprotein (AFP) levels. The PFIC 2 patient had a single 2.9cm and lesion and an AFP level of 6441ng/mL from a normal baseline and the PFIC 3 patient had 2 lesions: 1.6 and 2.0cm and an AFP level of 6115ng/mL from a normal baseline.  Both patients underwent transarterial chemoembolization as a bridge to transplant.  HCC was confirmed on explant pathology.  Serum AFP levels rapidly returned to normal post-transplantation and remain so to date. Currently, 14 (88%) patients remain alive post-transplant with a functioning liver graft (median follow up 6 years (range 0-21 years)).  One patient underwent retransplant 19 years after initial transplant for chronic rejection. 
Conclusions: PFIC is a rare genetic disorder resulting in liver failure that can be treated with liver transplant with excellent long-term outcomes.  The occurrence of HCC with PFIC has previously been reported to be confined to patients with PFIC 2.  We describe the presence of histologically proven HCC in a patient with genetically confirmed PFIC 3.  While rare, ALL patients with PFIC should undergo malignancy screening with serial AFP levels and/or cross-sectional imaging as the risk may be higher than realized in this special subset of patients.