Genotype correlates with the natural history of severe bile salt export pump deficiency

Daan B E van Wessel; Richard J Thompson; Emmanuel Gonzales; Irena Jankowska; 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; Bjo Rn Fischler; Jan B F Hulscher; Daniele Serranti; Cigdem Arikan; Esra Polat; Dominique Debray; Florence Lacaille; Cristina Goncalves; Loreto Hierro; Gema Muñoz Bartolo; Yael Mozer-Glassberg; Amer Azaz; Jernej Brecelj; Antal Dezsőfi; Pier Luigi Calvo; Enke Grabhorn; Ekkehard Sturm; Wendy J van der Woerd; Binita M Kamath; Jian-She Wang; Liting Li; Özlem Durmaz; Zerrin Onal; Ton Mg Bunt; Bettina Hansen; Henkjan J Verkade

doi:10.1016/j.jhep.2020.02.007

Genotype correlates with the natural history of severe bile salt export pump deficiency

Daan B E van Wessel, Richard J Thompson, Emmanuel Gonzales, Irena Jankowska, 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 ArnellBjo Rn Fischler, Jan B F Hulscher, Daniele Serranti, Cigdem Arikan, Esra Polat, Dominique Debray, Florence Lacaille, Cristina Goncalves, Loreto Hierro, Gema Muñoz Bartolo, Yael Mozer-Glassberg, Amer Azaz, Jernej Brecelj, Antal Dezsőfi, Pier Luigi Calvo, Enke Grabhorn, Ekkehard Sturm, Wendy J van der Woerd, Binita M Kamath, Jian-She Wang, Liting Li, Özlem Durmaz, Zerrin Onal, Ton Mg Bunt, Bettina Hansen, 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 & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27–0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. Lay summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Original language	English
Pages (from-to)	84-93
Number of pages	10
Journal	Journal of Hepatology
Volume	73
Issue number	1
Early online date	19-Feb-2020
DOIs	https://doi.org/10.1016/j.jhep.2020.02.007
Publication status	Published - Jul-2020

Keywords

Severe BSEP deficiency
PFIC2
ABCB11
Natural history
Surgical biliary diversion
FAMILIAL INTRAHEPATIC CHOLESTASIS
EXTERNAL BILIARY DIVERSION
SURGICAL-MANAGEMENT
ABCB11 MUTATIONS
CHILDREN
LIVER
TYPE-2
BSEP
EXPRESSION
OUTCOMES

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Genotype correlates with the natural history of severe bile salt export pump deficiency
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van Wessel, D. B. E., Thompson, R. J., Gonzales, E., Jankowska, I., 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., ... Verkade, H. J. (2020). Genotype correlates with the natural history of severe bile salt export pump deficiency. Journal of Hepatology, 73(1), 84-93. https://doi.org/10.1016/j.jhep.2020.02.007

@article{d0771851206448e09ed1952ecd7bfac0,

title = "Genotype correlates with the natural history of severe bile salt export pump deficiency",

abstract = "Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27–0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. Lay summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.",

keywords = "Severe BSEP deficiency, PFIC2, ABCB11, Natural history, Surgical biliary diversion, FAMILIAL INTRAHEPATIC CHOLESTASIS, EXTERNAL BILIARY DIVERSION, SURGICAL-MANAGEMENT, ABCB11 MUTATIONS, CHILDREN, LIVER, TYPE-2, BSEP, EXPRESSION, OUTCOMES",

author = "{van Wessel}, {Daan B E} and Thompson, {Richard J} and Emmanuel Gonzales and Irena Jankowska 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 Fischler, {Bjo Rn} and Hulscher, {Jan B F} and Daniele Serranti and Cigdem Arikan and Esra Polat 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 Calvo, {Pier Luigi} and Enke Grabhorn and Ekkehard Sturm and {van der Woerd}, {Wendy J} and Kamath, {Binita M} and Jian-She Wang and Liting Li and {\"O}zlem Durmaz and Zerrin Onal and Bunt, {Ton Mg} and Bettina Hansen and Verkade, {Henkjan J}",

note = "Copyright {\textcopyright} 2020. Published by Elsevier B.V.",

year = "2020",

month = jul,

doi = "10.1016/j.jhep.2020.02.007",

language = "English",

volume = "73",

pages = "84--93",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "ELSEVIER SCIENCE BV",

number = "1",

}

van Wessel, DBE, Thompson, RJ, Gonzales, E, Jankowska, I, 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, BR, Hulscher, JBF, Serranti, D, Arikan, C, Polat, E, Debray, D, Lacaille, F, Goncalves, C, Hierro, L, Muñoz Bartolo, G, Mozer-Glassberg, Y, Azaz, A, Brecelj, J, Dezsőfi, A, Calvo, PL, Grabhorn, E, Sturm, E, van der Woerd, WJ, Kamath, BM, Wang, J-S, Li, L, Durmaz, Ö, Onal, Z, Bunt, TM, Hansen, B & Verkade, HJ 2020, 'Genotype correlates with the natural history of severe bile salt export pump deficiency', Journal of Hepatology, vol. 73, no. 1, pp. 84-93. https://doi.org/10.1016/j.jhep.2020.02.007

TY - JOUR

T1 - Genotype correlates with the natural history of severe bile salt export pump deficiency

AU - van Wessel, Daan B E

AU - Thompson, Richard J

AU - Gonzales, Emmanuel

AU - Jankowska, Irena

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, Bjo Rn

AU - Hulscher, Jan B F

AU - Serranti, Daniele

AU - Arikan, Cigdem

AU - Polat, Esra

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 - Calvo, Pier Luigi

AU - Grabhorn, Enke

AU - Sturm, Ekkehard

AU - van der Woerd, Wendy J

AU - Kamath, Binita M

AU - Wang, Jian-She

AU - Li, Liting

AU - Durmaz, Özlem

AU - Onal, Zerrin

AU - Bunt, Ton Mg

AU - Hansen, Bettina

AU - Verkade, Henkjan J

PY - 2020/7

Y1 - 2020/7

N2 - Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27–0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. Lay summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

AB - Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27–0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. Lay summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

KW - Severe BSEP deficiency

KW - PFIC2

KW - ABCB11

KW - Natural history

KW - Surgical biliary diversion

KW - FAMILIAL INTRAHEPATIC CHOLESTASIS

KW - EXTERNAL BILIARY DIVERSION

KW - SURGICAL-MANAGEMENT

KW - ABCB11 MUTATIONS

KW - CHILDREN

KW - LIVER

KW - TYPE-2

KW - BSEP

KW - EXPRESSION

KW - OUTCOMES

U2 - 10.1016/j.jhep.2020.02.007

DO - 10.1016/j.jhep.2020.02.007

M3 - Article

C2 - 32087350

SN - 0168-8278

VL - 73

SP - 84

EP - 93

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 1

ER -

Genotype correlates with the natural history of severe bile salt export pump deficiency

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