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

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 Lipiński; Piotr Czubkowski; Nathalie Rock; Mohammad Shagrani; Dieter Broering; Talal Algoufi; Nejat Mazhar; Emanuele Nicastro; Deirdre Kelly; Gabriella Nebbia; Henrik Arnell; Björn Fischler; Jan B F Hulscher; Daniele Serranti; Cigdem Arikan; Dominique Debray; Florence Lacaille; Cristina Goncalves; Loreto Hierro; Gema Muñoz Bartolo; Yael Mozer-Glassberg; Amer Azaz; Jernej Brecelj; Antal Dezsőfi; Pier Luigi Calvo; Dorothee Krebs-Schmitt; Steffen Hartleif; Wendy L van der Woerd; Jian-She Wang; Li-Ting Li; Özlem Durmaz; Nanda Kerkar; Marianne Hørby Jørgensen; Ryan Fischer; Carolina Jimenez-Rivera; Seema Alam; Mara Cananzi; Noémie Laverdure; Cristina Targa Ferreira; Felipe Ordonez; Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium

doi:10.1002/hep.31787

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

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 Lipiński, Piotr Czubkowski, Nathalie Rock, Mohammad Shagrani, Dieter Broering, Talal Algoufi, Nejat Mazhar, Emanuele Nicastro, Deirdre Kelly, Gabriella NebbiaHenrik Arnell, Björn Fischler, Jan B F Hulscher, Daniele Serranti, Cigdem Arikan, Dominique Debray, Florence Lacaille, Cristina Goncalves, Loreto Hierro, Gema Muñoz Bartolo, Yael Mozer-Glassberg, Amer Azaz, Jernej Brecelj, Antal Dezsőfi, Pier Luigi Calvo, Dorothee Krebs-Schmitt, Steffen Hartleif, Wendy L van der Woerd, Jian-She Wang, Li-Ting Li, Özlem Durmaz, Nanda Kerkar, Marianne Hørby Jørgensen, Ryan Fischer, Carolina Jimenez-Rivera, Seema Alam, Mara Cananzi, Noémie Laverdure, Cristina Targa Ferreira, Felipe Ordonez, Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium

Afdeling for Børn og Unge

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.

Originalsprog	Engelsk
Tidsskrift	Hepatology (Baltimore, Md.)
Vol/bind	74
Udgave nummer	2
Sider (fra-til)	892-906
Antal sider	15
ISSN	0270-9139
DOI	https://doi.org/10.1002/hep.31787
Status	Udgivet - aug. 2021

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10.1002/hep.31787

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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., Lipiński, P., Czubkowski, P., Rock, N., Shagrani, M., Broering, D., Algoufi, T., Mazhar, N., Nicastro, E., Kelly, D., ... Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium (2021). Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency. Hepatology (Baltimore, Md.), 74(2), 892-906. https://doi.org/10.1002/hep.31787

van Wessel, DBE, Thompson, RJ, Gonzales, E, Jankowska, I, Shneider, BL, Sokal, E, Grammatikopoulos, T, Kadaristiana, A, Jacquemin, E, Spraul, A, Lipiński, 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, Muñoz Bartolo, G, Mozer-Glassberg, Y, Azaz, A, Brecelj, J, Dezsőfi, A, Luigi Calvo, P, Krebs-Schmitt, D, Hartleif, S, van der Woerd, WL, Wang, J-S, Li, L-T, Durmaz, Ö, Kerkar, N, Hørby Jørgensen, M, Fischer, R, Jimenez-Rivera, C, Alam, S, Cananzi, M, Laverdure, N, Targa Ferreira, C, Ordonez, F & Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium 2021, 'Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency', Hepatology (Baltimore, Md.), bind 74, nr. 2, s. 892-906. https://doi.org/10.1002/hep.31787

@article{83bd6d10e1b2453a88e3924dbe85dcaa,

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 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.",

keywords = "Adenosine Triphosphatases/deficiency, Adolescent, Bile Acids and Salts/blood, Bile Ducts, Intrahepatic/surgery, Child, Child, Preschool, Cholestasis, Intrahepatic/blood, Codon, Nonsense, Female, Follow-Up Studies, Humans, Infant, Liver Transplantation/statistics & numerical data, Male, Prognosis, Prospective Studies, Retrospective Studies, Risk Assessment/methods, Survival Analysis, Treatment Outcome, Young Adult",

author = "{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 Lipi{\'n}ski 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 Bj{\"o}rn 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 {Mu{\~n}oz Bartolo}, Gema and Yael Mozer-Glassberg and Amer Azaz and Jernej Brecelj and Antal Dezs{\H o}fi and {Luigi Calvo}, Pier and Dorothee Krebs-Schmitt and Steffen Hartleif and {van der Woerd}, {Wendy L} and Jian-She Wang and Li-Ting Li and {\"O}zlem Durmaz and Nanda Kerkar and {H{\o}rby J{\o}rgensen}, Marianne and Ryan Fischer and Carolina Jimenez-Rivera and Seema Alam and Mara Cananzi and No{\'e}mie Laverdure and {Targa Ferreira}, Cristina and Felipe Ordonez and {Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium}",

note = "{\textcopyright} The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.",

year = "2021",

month = aug,

doi = "10.1002/hep.31787",

language = "English",

volume = "74",

pages = "892--906",

journal = "Hepatology (Baltimore, Md.)",

issn = "0270-9139",

publisher = "Wiley",

number = "2",

}

TY - JOUR

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

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 - Lipiński, 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, Björn

AU - Hulscher, Jan B F

AU - Serranti, Daniele

AU - Arikan, Cigdem

AU - Debray, Dominique

AU - Lacaille, Florence

AU - Goncalves, Cristina

AU - Hierro, Loreto

AU - Muñoz Bartolo, Gema

AU - Mozer-Glassberg, Yael

AU - Azaz, Amer

AU - Brecelj, Jernej

AU - Dezsőfi, Antal

AU - Luigi Calvo, Pier

AU - Krebs-Schmitt, Dorothee

AU - Hartleif, Steffen

AU - van der Woerd, Wendy L

AU - Wang, Jian-She

AU - Li, Li-Ting

AU - Durmaz, Özlem

AU - Kerkar, Nanda

AU - Hørby Jørgensen, Marianne

AU - Fischer, Ryan

AU - Jimenez-Rivera, Carolina

AU - Alam, Seema

AU - Cananzi, Mara

AU - Laverdure, Noémie

AU - Targa Ferreira, Cristina

AU - Ordonez, Felipe

AU - Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium

N1 - © The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

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 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.

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 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.

KW - Adenosine Triphosphatases/deficiency

KW - Adolescent

KW - Bile Acids and Salts/blood

KW - Bile Ducts, Intrahepatic/surgery

KW - Child

KW - Child, Preschool

KW - Cholestasis, Intrahepatic/blood

KW - Codon, Nonsense

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Infant

KW - Liver Transplantation/statistics & numerical data

KW - Male

KW - Prognosis

KW - Prospective Studies

KW - Retrospective Studies

KW - Risk Assessment/methods

KW - Survival Analysis

KW - Treatment Outcome

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85110180026&partnerID=8YFLogxK

U2 - 10.1002/hep.31787

DO - 10.1002/hep.31787

M3 - Journal article

C2 - 33666275

SN - 0270-9139

VL - 74

SP - 892

EP - 906

JO - Hepatology (Baltimore, Md.)

JF - Hepatology (Baltimore, Md.)

IS - 2

ER -

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

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