Περίληψη:
BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1
(ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1)
deficiency, or progressive familial intrahepatic cholestasis type 1. 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 insights by using the largest genetically
defined cohort of patients with FIC1 deficiency to date.
APPROACH AND RESULTS: 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 PPTMs), 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 18 years. NLS was comparable among FIC1-A, FIC1-B, and
FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P =
0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years:
65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were
negatively associated with NLS (NLS at age 10 years, sBAs < 194 mu
mol/L: 49% vs. sBAs >= 194 mu mol/L: 15%; P = 0.03). SBD decreased
sBAs (230 [125-282] to 74 [11-177] mu mol/L; P = 0.005). SBD (HR
0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65
mu mol/L (P = 0.05) tended to be associated with improved NLS.
CONCLUSIONS: Less than half of patients with FIC1 deficiency 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.
Συγγραφείς:
van Wessel, Daan B. E.
Thompson, Richard J.
Gonzales, Emmanuel
and Jankowska, Irena
Shneider, Benjamin L.
Sokal, Etienne and
Grammatikopoulos, Tassos
Kadaristiana, Agustina
Jacquemin,
Emmanuel
Spraul, Anne
Lipinski, Patryk
Czubkowski, Piotr and
Rock, Nathalie
Shagrani, Mohammad
Broering, Dieter
Algoufi,
Talal
Mazhar, Nejat
Nicastro, Emanuele
Kelly, Deirdre and
Nebbia, Gabriella
Arnell, Henrik
Fischler, Bjorn
Hulscher,
Jan B. F.
Serranti, Daniele
Arikan, Cigdem
Debray, Dominique
and Lacaille, Florence
Goncalves, Cristina
Hierro, Loreto and
Bartolo, Gema Munoz
Mozer-Glassberg, Yael
Azaz, Amer and
Brecelj, Jernej
Dezsofi, Antal
Calvo, Pier Luigi and
Krebs-Schmitt, Dorothee
Hartleif, Steffen
van der Woerd, Wendy
L.
Wang, Jian-She
Li, Li-Ting
Durmaz, Ozlem
Kerkar,
Nanda
Jorgensen, Marianne Horby
Fischer, Ryan and
Jimenez-Rivera, Carolina
Alam, Seema
Cananzi, Mara and
Laverdure, Noemie
Ferreira, Cristina Targa
Ordonez, Felipe and
Wang, Heng
Sency, Valerie
Kim, Kyung Mo
Chen, Huey-Ling and
Carvalho, Elisa
Fabre, Alexandre
Bernabeu, Jesus Quintero and
Alonso, Estella M.
Sokol, Ronald J.
Suchy, Frederick J. and
Loomes, Kathleen M.
McKiernan, Patrick J.
Rosenthal, Philip and
Turmelle, Yumirle
Rao, Girish S.
Horslen, Simon
Kamath,
Binita M.
Rogalidou, Maria
Karnsakul, Wikrom W.
Hansen,
Bettina
Verkade, Henkjan J.
Nat Course Prognosis PFIC Effect B
