The Natural Course of FIC1 Deficiency: Results from the Napped-Consortium

Abstract

Background: Severe deficiency of FIC1 (FIC1-def) is due to mutations in the ATP8B1gene, and is responsible for progressive familial intrahepatic cholestasis type 1. The ATP8B1encodes the FIC1-protein, which functions as an minophospholipid translocase. Because of secondary impaired biliary bile salt secretion, patients typically present with pruritus and low gamma-GT cholestasis in early childhood. FIC1 is also expressed in other tissues, such as pancreas and intestine, and extrahepatic manifestations may occur in FIC1-def patients. Ursodeoxycholic acid or surgical biliary diversion (SBD) techniques might be beneficial for some patients, yet many patients require liver transplantation(LTx) at some stage. We aim to better understand the natural course of FIC1-def and the efficacy of interventions. Therefore, we have set up an extensive international consortium, “NAPPED” (NAtural course and Prognosis of PFIC and Effect of biliary Diversion). Methods: We present retrospective follow up data on individual patients from 22 centers in Europe, North-America, Asia and Australia. All patients were either compound heterozygous or homozygous for disease associated mutations in the ATP8B1gene. We used time-dependent Cox regression for native liver survival (NLS), adjusted for gender and birth year, in patients that had undergone SBD (SBD+ve) or not (SBD-ve). Continuous variables are expressed as median [range]. Results: We included 46 FIC1-def patients (predominately males, 76%; P<0.001). Age at first visit was 0.5 [0-16.8] years. Use of ursodeoxycholic acid prior to first visit was 39%. Age at last follow up was 5.4 [0.25-27.8] years. Overall SBD rates at five/ten years of age were 37/43%, for males (36/45%) and females (50/50%, respectively; p=0.15). SBD rates in compound heterozygous and homozygous patients were 34/34% and 37/45%, respectively (p=0.29). Overall five/ten-year NLS was 74/46%. Five/ten-year NLS in males and females was 71/49% and 88/58%, respectively (p=0.87). NLS in compound heterozygous and homozygous patients was 78/33% and 72/52%, respectively (p=0.61). NLS did not differ significantly between SBD+ve patients and SBD-ve patients [HR=1.16; 95%CI(0.33-4.01); p=.82]. HCC was not encountered in any patient during follow-up, in contrast to observations in other cholestatic diseases. Mortality prior to LTx was 2%. The observed NLS at 18 years of age was 46%. Conclusion: Our large global cohort of this extremely rare condition allows to address genotype - phenotype relationships in FIC-1 deficiency and to study the natural course of diseases. Our data indicate that mortality is relatively low and that the vast majority of patients reaches adulthood, with native or transplanted liver, and thus becomes an important, relatively new patient entity for adult hepatology practice