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

Abstract

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 µmol/L: 49% vs. 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 < 65 μmol/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.

Fig. 1

Flowchart of patient inclusion from the NAPPED database and subsequent categorization based on genotype. *Either only one mutation in ATP8B1, ATP8B1 mutations of no (known) clinical consequence, mutations in ABCB11/TJP2, or participation in investigational drug trials. ^sEpisodic cholestasis and/or pruritus and transient hepatocellular damage. ^†Splice site, frameshift due to deletion or insertion, nonsense, or duplication.

Fig. 2

Proportion of all patients alive with native liver with a surgical diversion over time (A) and proportion of patients alive with native liver (B) in all patients.

Fig. 3

Proportion of patients with a surgical diversion (A) and proportion of patients alive with native liver (B) in patients without PPTMs (FIC1‐A), with one PPTM (FIC1‐B), or two PPTMs (FIC1‐C).

Fig. 4

Pre‐SBD and post‐SBD biochemistry: sBAs (A), TSB (B), ALT (C), and AST (D) in patients with FIC1‐A (filled circles), FIC1‐B (open circles), and FIC1‐C (triangles) genotypes for whom paired data were available.

Fig. 5

Observed native liver survival (x axis) in all patients with an FIC1 genotype, who underwent SBD (n = 62) or not (n = 68). The clock‐reset approach allows visualization of native liver survival up to SBD (solid line, all patients) and after SBD (dotted line, only patients who underwent SBD). The estimated HR is achieved by Cox regression, with SBD as a time‐dependent risk factor, adjusted for genotype, sex, and birth year.

Fig. 6

NLS after SBD in patients with an FIC1‐A (no truncating mutations), an FIC1‐B (one truncating mutation), or an FIC1‐C (two truncating mutations) genotype.

Fig. 7

NLS after SBD in patients with a sBA concentration of < 65 umol/L versus ≥ 65 umol/L.