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

Nat Course Prognosis PFIC Effect B; Daan B. E. van Wessel; Richard J. Thompson; Emmanuel Gonzales; Irena Jankowska; Benjamin L. Shneider; Etienne Sokal; Tassos Grammatikopoulos; Agustina Kadaristiana; Emmanuel Jacquemin; Anne Spraul; Patryk Lipinski; Piotr Czubkowski; Nathalie Rock; Mohammad Shagrani; Dieter Broering; Talal Algoufi; Nejat Mazhar; Emanuele Nicastro; Deirdre Kelly; Gabriella Nebbia; Henrik Arnell; Bjorn Fischler; Jan B. F. Hulscher; Daniele Serranti; Cigdem Arikan; Dominique Debray; Florence Lacaille; Cristina Goncalves; Loreto Hierro; Gema Munoz Bartolo; Yael Mozer-Glassberg; Amer Azaz; Jernej Brecelj; Antal Dersofi; Pier Luigi Calvo; Dorothee Krebs-Schmitt; Steffen Hartleif; Wendy L. van der Woerd; Jian-She Wang; Li-ting Li; Ozlem Durmaz; Nanda Kerkar; Marianne Horby Jorgensen; Ryan Fischer; Carolina Jimenez-Rivera; Seema Alam; Mara Cananzi; Noemie Laverdure; Cristina Targa Ferreira; Henkjan J. Verkade

doi:10.1002/hep.31787

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

Nat Course Prognosis PFIC Effect B, Daan B. E. van Wessel, Richard J. Thompson, Emmanuel Gonzales, Irena Jankowska, Benjamin L. Shneider, Etienne Sokal, Tassos Grammatikopoulos, Agustina Kadaristiana, Emmanuel Jacquemin, Anne Spraul, Patryk Lipinski, Piotr Czubkowski, Nathalie Rock, Mohammad Shagrani, Dieter Broering, Talal Algoufi, Nejat Mazhar, Emanuele Nicastro, Deirdre KellyGabriella Nebbia, Henrik Arnell, Bjorn Fischler, Jan B. F. Hulscher, Daniele Serranti, Cigdem Arikan, Dominique Debray, Florence Lacaille, Cristina Goncalves, Loreto Hierro, Gema Munoz Bartolo, Yael Mozer-Glassberg, Amer Azaz, Jernej Brecelj, Antal Dersofi, Pier Luigi Calvo, Dorothee Krebs-Schmitt, Steffen Hartleif, Wendy L. van der Woerd, Jian-She Wang, Li-ting Li, Ozlem Durmaz, Nanda Kerkar, Marianne Horby Jorgensen, Ryan Fischer, Carolina Jimenez-Rivera, Seema Alam, Mara Cananzi, Noemie Laverdure, Cristina Targa Ferreira, Henkjan J. Verkade^*

^*Corresponding author for this work

Center for Liver, Digestive and Metabolic Diseases (CLDM)

Research output: Contribution to journal › Article › Academic › peer-review

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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 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.

Original language	English
Pages (from-to)	892-906
Number of pages	15
Journal	Hepatology
Volume	74
Issue number	2
Early online date	13-Jul-2021
DOIs	https://doi.org/10.1002/hep.31787
Publication status	Published - Aug-2021

Keywords

FAMILIAL INTRAHEPATIC CHOLESTASIS
SALT EXPORT PUMP
ABCB11 MUTATIONS
ATP8B1 GENE
TYPE-1
PFIC1
EXPRESSION
CHILDREN
DISEASE

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Nat Course Prognosis PFIC Effect B, van Wessel, D. B. E., Thompson, R. J., Gonzales, E., Jankowska, I., Shneider, B. L., Sokal, E., Grammatikopoulos, T., Kadaristiana, A., Jacquemin, E., Spraul, A., Lipinski, P., Czubkowski, P., Rock, N., Shagrani, M., Broering, D., Algoufi, T., Mazhar, N., Nicastro, E., ... Verkade, H. J. (2021). Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency. Hepatology, 74(2), 892-906. https://doi.org/10.1002/hep.31787

@article{b46387194d444316b2ec3f57c36ffddb,

title = "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 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.",

keywords = "FAMILIAL INTRAHEPATIC CHOLESTASIS, SALT EXPORT PUMP, ABCB11 MUTATIONS, ATP8B1 GENE, TYPE-1, PFIC1, EXPRESSION, CHILDREN, DISEASE",

author = "{Nat Course Prognosis PFIC Effect B} and {van Wessel}, {Daan B. E.} and Thompson, {Richard J.} and Emmanuel Gonzales and Irena Jankowska and Shneider, {Benjamin L.} and Etienne Sokal and Tassos Grammatikopoulos and Agustina Kadaristiana and Emmanuel Jacquemin and Anne Spraul and Patryk Lipinski and Piotr Czubkowski and Nathalie Rock and Mohammad Shagrani and Dieter Broering and Talal Algoufi and Nejat Mazhar and Emanuele Nicastro and Deirdre Kelly and Gabriella Nebbia and Henrik Arnell and Bjorn Fischler and Hulscher, {Jan B. F.} and Daniele Serranti and Cigdem Arikan and Dominique Debray and Florence Lacaille and Cristina Goncalves and Loreto Hierro and {Munoz Bartolo}, Gema and Yael Mozer-Glassberg and Amer Azaz and Jernej Brecelj and Antal Dersofi and Calvo, {Pier Luigi} and Dorothee Krebs-Schmitt and Steffen Hartleif and {van der Woerd}, {Wendy L.} and Jian-She Wang and Li-ting Li and Ozlem Durmaz and Nanda Kerkar and Jorgensen, {Marianne Horby} and Ryan Fischer and Carolina Jimenez-Rivera and Seema Alam and Mara Cananzi and Noemie Laverdure and Ferreira, {Cristina Targa} and Verkade, {Henkjan J.}",

year = "2021",

month = aug,

doi = "10.1002/hep.31787",

language = "English",

volume = "74",

pages = "892--906",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Wiley",

number = "2",

}

Nat Course Prognosis PFIC Effect B, van Wessel, DBE, Thompson, RJ, Gonzales, E, Jankowska, I, Shneider, BL, Sokal, E, Grammatikopoulos, T, Kadaristiana, A, Jacquemin, E, Spraul, A, Lipinski, P, Czubkowski, P, Rock, N, Shagrani, M, Broering, D, Algoufi, T, Mazhar, N, Nicastro, E, Kelly, D, Nebbia, G, Arnell, H, Fischler, B, Hulscher, JBF, Serranti, D, Arikan, C, Debray, D, Lacaille, F, Goncalves, C, Hierro, L, Munoz Bartolo, G, Mozer-Glassberg, Y, Azaz, A, Brecelj, J, Dersofi, A, Calvo, PL, Krebs-Schmitt, D, Hartleif, S, van der Woerd, WL, Wang, J-S, Li, L, Durmaz, O, Kerkar, N, Jorgensen, MH, Fischer, R, Jimenez-Rivera, C, Alam, S, Cananzi, M, Laverdure, N, Ferreira, CT & Verkade, HJ 2021, 'Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency', Hepatology, vol. 74, no. 2, pp. 892-906. https://doi.org/10.1002/hep.31787

TY - JOUR

T1 - Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency

AU - Nat Course Prognosis PFIC Effect B

AU - van Wessel, Daan B. E.

AU - Thompson, Richard J.

AU - Gonzales, Emmanuel

AU - Jankowska, Irena

AU - Shneider, Benjamin L.

AU - Sokal, Etienne

AU - Grammatikopoulos, Tassos

AU - Kadaristiana, Agustina

AU - Jacquemin, Emmanuel

AU - Spraul, Anne

AU - Lipinski, Patryk

AU - Czubkowski, Piotr

AU - Rock, Nathalie

AU - Shagrani, Mohammad

AU - Broering, Dieter

AU - Algoufi, Talal

AU - Mazhar, Nejat

AU - Nicastro, Emanuele

AU - Kelly, Deirdre

AU - Nebbia, Gabriella

AU - Arnell, Henrik

AU - Fischler, Bjorn

AU - Hulscher, Jan B. F.

AU - Serranti, Daniele

AU - Arikan, Cigdem

AU - Debray, Dominique

AU - Lacaille, Florence

AU - Goncalves, Cristina

AU - Hierro, Loreto

AU - Munoz Bartolo, Gema

AU - Mozer-Glassberg, Yael

AU - Azaz, Amer

AU - Brecelj, Jernej

AU - Dersofi, Antal

AU - Calvo, Pier Luigi

AU - Krebs-Schmitt, Dorothee

AU - Hartleif, Steffen

AU - van der Woerd, Wendy L.

AU - Wang, Jian-She

AU - Li, Li-ting

AU - Durmaz, Ozlem

AU - Kerkar, Nanda

AU - Jorgensen, Marianne Horby

AU - Fischer, Ryan

AU - Jimenez-Rivera, Carolina

AU - Alam, Seema

AU - Cananzi, Mara

AU - Laverdure, Noemie

AU - Ferreira, Cristina Targa

AU - Verkade, Henkjan J.

PY - 2021/8

Y1 - 2021/8

N2 - 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.

AB - 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.

KW - FAMILIAL INTRAHEPATIC CHOLESTASIS

KW - SALT EXPORT PUMP

KW - ABCB11 MUTATIONS

KW - ATP8B1 GENE

KW - TYPE-1

KW - PFIC1

KW - EXPRESSION

KW - CHILDREN

KW - DISEASE

U2 - 10.1002/hep.31787

DO - 10.1002/hep.31787

M3 - Article

SN - 0270-9139

VL - 74

SP - 892

EP - 906

JO - Hepatology

JF - Hepatology

IS - 2

ER -

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

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