Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency

Abstract

Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs <194 µmol/L: 49% versus sBAs ≥194 µmol/L: 15%; P=0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P=0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P=0.06) and post-SBD sBA concentrations <65μmol/L (P=0.05) tended to be associated with improved NLS. Conclusion:Less than half of FIC1 deficiency patients reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Long‐term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience

“…Procedures including partial external biliary diversion, partial internal biliary diversion, and ileal exclusion can interrupt the natural history of PFIC1 progression and generally, though not uniformly, can provide some clinical improvement 8,21,25 . Long‐term follow‐up data after diversion for PFIC1 remain largely under reported; however, available data show that the majority will still require LT 5,8,21,25,26 . Indeed, in 2 of 7 patients in our cohort, PEBD preceded transplant with the time from diversion to LT being approximately 2 years for each patient.…”

“…This may in part be due to the genetic homogeneity of our cohort. Notably, while recent reports with other PFIC disorders demonstrate that the genotype can associate with clinical outcomes and the success of therapeutic interventions, 35 these findings have not been shown to be reproduced in PFIC1 populations 26 . Other considerations are the genetic constitution of the donor grafts.…”

Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review

“…While OLT cures the cholestatic phenotype, failure to catch up on growth deficiency, development of fatty liver disease and exacerbation of diarrhoea hamper the positive effects of OLT. 23,32,34 Following OLT, the FIC1 disease patient (case 1) did not develop hearing impairment or fatty liver disease but suffered from persistent diarrhoea and failure to catch up on stature growth.…”

“…Native liver survival into adulthood has not been described for NR1H4-associated PFIC, and is observed in less than 50% for most ATP8B1-and ABCB11-associated PFIC patients carrying mutations leading to protein truncation or non-functional proteins. 8,23,24 While animal models of ABCB4associated PFIC have been successfully treated with gene therapy or synthetic ABCB4 mRNA, [25][26][27] orthotopic liver transplantation (OLT) represents the only curative treatment available to date. In a subgroup of patients, long-term remission can be achieved by partial biliary diversion (PBD) or, in the future, possibly also by pharmacological intervention using inhibitors of the ileal bile acid transporter (IBAT) also known as apical sodium-dependent bile acid transporter (ASBT, SLC10A2).…”

“…patients presenting with biallelic (homozygous or compound heterozygous) pathogenic ATP8B1 variants 30–33 . A recent multicentre study of 130 patients found no correlation between the severity of the genetic lesion, expressed as the presence of predicted protein‐truncating mutations (PPTMs), and the natural history or prognosis of FIC1 deficiency 23 . In a study comparing 42 patients with FIC1 disease to 60 patients with bile salt export pump (BSEP) disease, the outcome following OLT remained unsatisfactory in many FIC1 disease patients, mainly because of extrahepatic manifestations 30,34 .…”