Dataset Information

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.

SUBMITTER: van Wessel DBE

PROVIDER: S-EPMC8456904 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

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

van Wessel Daan B E DBE Thompson Richard J RJ Gonzales Emmanuel E Jankowska Irena I Shneider Benjamin L BL Sokal Etienne E Grammatikopoulos Tassos T Kadaristiana Agustina A Jacquemin Emmanuel E Spraul Anne A Lipiński Patryk P Czubkowski Piotr P Rock Nathalie N Shagrani Mohammad M Broering Dieter D Algoufi Talal T Mazhar Nejat N Nicastro Emanuele E Kelly Deirdre D Nebbia Gabriella G Arnell Henrik H Fischler Björn B Hulscher Jan B F JBF Serranti Daniele D Arikan Cigdem C Debray Dominique D Lacaille Florence F Goncalves Cristina C Hierro Loreto L Muñoz Bartolo Gema G Mozer-Glassberg Yael Y Azaz Amer A Brecelj Jernej J Dezsőfi Antal A Luigi Calvo Pier P Krebs-Schmitt Dorothee D Hartleif Steffen S van der Woerd Wendy L WL Wang Jian-She JS Li Li-Ting LT Durmaz Özlem Ö Kerkar Nanda N Hørby Jørgensen Marianne M Fischer Ryan R Jimenez-Rivera Carolina C Alam Seema S Cananzi Mara M Laverdure Noémie N Targa Ferreira Cristina C Ordonez Felipe F Wang Heng H Sency Valerie V Mo Kim Kyung K Chen Huey-Ling HL Carvalho Elisa E Fabre Alexandre A Quintero Bernabeu Jesus J Alonso Estella M EM Sokol Ronald J RJ Suchy Frederick J FJ Loomes Kathleen M KM McKiernan Patrick J PJ Rosenthal Philip P Turmelle Yumirle Y Rao Girish S GS Horslen Simon S Kamath Binita M BM Rogalidou Maria M Karnsakul Wikrom W WW Hansen Bettina B Verkade Henkjan J HJ

Hepatology (Baltimore, Md.) 20210713 2

<h4>Background and aims</h4>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 ...[more]

PMID: 33666275

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Project description:AimTo investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency.MethodsMutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney (HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization. Bile acid profiles of patient and control bile samples were generated by ultra-performance liquid chromatography-tandem mass spectrometry. Wild-type and mutant BSEP transport of [3H]-labeled taurocholate (TC) and taurochenodeoxycholate (TCDC) was assessed by vesicular transport assays.ResultsA girl (at 2 mo) presented with pruritus, jaundice and elevated serum bile salts (BS). PEBD stabilized liver function and prevented liver transplantation. She was heterozygous for the BSEP deletion p.T919del and the nonsense mutation p.R1235X. At the age of 17 years relative amounts of conjugated BS in her bile were normal, while total BS were less than 3% as compared to controls. An unrelated boy (age 1.5 years) presenting with severe pruritus and elevated serum BS was heterozygous for the same nonsense and another missense mutation, p.G1032R. PEBD failed to alleviate pruritus, eventually necessitating liver transplantation. BS concentration in bile was about 5% of controls. BS were mainly unconjugated with an unusual low amount of chenodeoxycholate derivatives (< 5%). The patients' native liver biopsies showed canalicular BSEP expression. Both BSEP p.T919del and p.G1032R were localized in the plasma membrane in HEK293 cells. In vitro transport assays showed drastic reduction of transport by both mutations. Using purified recombinant BSEP as quantifiable reference, per-molecule transport rates for TC and TCDC were determined to be 3 and 2 BS molecules per wild-type BSEP transporter per minute, respectively.ConclusionIn summary, our findings suggest that residual function of BSEP as well as substrate specificity influence the therapeutic effectiveness of PEBD in progressive familial intrahepatic cholestasis type 2 (PFIC-2).

Dataset Information

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

Background and aims

Approach and results

Conclusions

Publications

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

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