4.8 Article

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

期刊

HEPATOLOGY
卷 74, 期 2, 页码 892-906

出版社

WILEY
DOI: 10.1002/hep.31787

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资金

  1. NCATS NIH HHS [UL1 TR000003, UL1 TR002535, UL1 TR001872] Funding Source: Medline
  2. NIDDK NIH HHS [U01 DK062500, U01 DK062466, U01 DK103149, U01 DK062481, U01 DK062431, U01 DK062453, U01 DK084536] Funding Source: Medline

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This study utilized the largest genetically defined cohort of patients with FIC1 deficiency to date, revealing that less than half of patients reach adulthood with native liver function; the number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency; sBA concentrations provide limited prognostic information on long-term NLS.
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.

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