Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

doi:10.1016/j.jhepr.2022.100626

. 2022 Nov 16;5(2):100626.

doi: 10.1016/j.jhepr.2022.100626. eCollection 2023 Feb.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Antonia Felzen¹, Daan B E van Wessel¹, Emmanuel Gonzales^{2

3

4}, Richard J Thompson⁵, Irena Jankowska^{3

6}, Benjamin L Shneider^{7

8}, Etienne Sokal^{3

9}, Tassos Grammatikopoulos⁵, Agustina Kadaristiana⁵, Emmanuel Jacquemin^{2

3

4}, Anne Spraul^{4

10}, Patryk Lipiński^{3

6}, Piotr Czubkowski^{3

6}, Nathalie Rock¹¹, Mohammad Shagrani^{12

13}, Dieter Broering¹², Emanuele Nicastro¹⁴, Deirdre Kelly^{3

15}, Gabriella Nebbia¹⁶, Henrik Arnell^{3

17}, Björn Fischler^{3

17}, Jan B F Hulscher^{3

18}, Daniele Serranti¹⁹, Cigdem Arikan²⁰, Esra Polat²¹, Dominique Debray^{3

22}, Florence Lacaille^{3

22}, Cristina Goncalves^{3

23}, Loreto Hierro^{3

24}, Gema Muñoz Bartolo^{3

24}, Yael Mozer-Glassberg²⁵, Amer Azaz²⁶, Jernej Brecelj^{27

28}, Antal Dezsőfi²⁹, Pier Luigi Calvo³⁰, Enke Grabhorn³¹, Steffen Hartleif^{3

32}, Wendy J van der Woerd³³, Binita M Kamath^{7

34}, Jian-She Wang³⁵, Liting Li³⁵, Özlem Durmaz³⁶, Nanda Kerkar³⁷, Marianne Hørby Jørgensen^{3

38}, Ryan Fischer³⁹, Carolina Jimenez-Rivera⁴⁰, Seema Alam⁴¹, Mara Cananzi^{3

42}, Noemie Laverdure⁴³, Cristina Targa Ferreira⁴⁴, Felipe Ordoñez Guerrero⁴⁵, Heng Wang⁴⁶, Valerie Sency⁴⁶, Kyung Mo Kim⁴⁷, Huey-Ling Chen⁴⁸, Elisa de Carvalho⁴⁹, Alexandre Fabre^{50

51}, Jesus Quintero Bernabeu^{3

52}, Aglaia Zellos⁵³, Estella M Alonso^{8

54}, Ronald J Sokol^{8

55}, Frederick J Suchy^{8

55}, Kathleen M Loomes^{8

56}, Patrick J McKiernan^{8

57}, Philip Rosenthal^{8

58}, Yumirle Turmelle^{8

59}, Simon Horslen^{8

57}, Kathleen Schwarz^{8

60}, Jorge A Bezerra^{8

61}, Kasper Wang^{8

62}, Bettina E Hansen^{63

64

65}, Henkjan J Verkade^{1

3}; NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium

Affiliations

¹ Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands.
² Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Paris, France.
³ European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
⁴ INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France.
⁵ Institute of Liver Studies, King's College London, London, United Kingdom.
⁶ Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
⁷ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁸ Childhood Liver Disease Research Network (ChiLDReN).
⁹ Pediatric Gastorenterology and Hepatology, Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium.
¹⁰ Service de Biochemie, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris-Saclay, Inserm UMR-S 1174, France.
¹¹ Pediatric Gastroenterology, Hepatology and Nutrition Unit, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Switzerland.
¹² Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
¹³ Alfaisal University, College of Medicine, Riyadh, Saudi Arabia.
¹⁴ Pediatric Hepatology, Gastroenterology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy.
¹⁵ Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom.
¹⁶ Servizio Di Epatologia e Nutrizione Pediatrica, Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
¹⁷ Pediatric Gastroenterology Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
¹⁸ Pediatric Surgery, University Medical Center Groningen, Groningen, the Netherlands.
¹⁹ Pediatric and Liver Unit, Meyer Children's University Hospital of Florence, Florence, Italy.
²⁰ Koc University School of Medicine, Pediatric GI and Hepatology Liver Transplantation Center, Kuttam System in Liver Medicine, Istanbul, Turkey.
²¹ Pediatric Gastroenterology, Sancaktepe Training and Research Hospital, Istanbul, Turkey.
²² Gastroenterology-Hepatology-Nutrition Unit, APHP-Necker Enfants Malades University Hospital, Paris, France.
²³ Previously Coimbra University Hospital Center, Coimbra, Portugal, Now Pediatric Gastroenterology/Hepatology Center Lisbon, Portugal.
²⁴ Service of Pediatric Hepatology and Transplantation, Children's Hospital La Paz, La Paz University Hospital, Madrid, Spain.
²⁵ Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
²⁶ Pediatric Gastroenterology, Hepatology and Nutrition, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.
²⁷ Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, and Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
²⁸ Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
²⁹ Department of Pediatrics, Semmelweis University, Budapest, Hungary.
³⁰ Pediatic Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città Della Salute e Della Scienza University Hospital, Turin, Italy.
³¹ Pediatric Hepatology and Liver Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
³² Pediatric Gastroenterology and Hepatology, University Children's Hospital Tυ¨bingen, University Medical Center Tυ¨bingen, Tυ¨bingen, Germany.
³³ Pediatric Gastroenterology, Hepatology and Nutrition, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
³⁴ Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada.
³⁵ Children's Hospital of Fudan University, Shanghai, China.
³⁶ Department of Child Health and Diseases, Gastroenterology, Hepatology and Nutrition, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
³⁷ Pediatric Gastroenterology, Hepatology and Nutrition, University of Rochester Medical Center, Rochester, NY, USA.
³⁸ Department of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark.
³⁹ Pediatric Gastroenterology, Hepatology and Nutrition, Children's Mercy Hospital, Kansas City, MO, USA.
⁴⁰ Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.
⁴¹ Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
⁴² Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy.
⁴³ Service de Gastroentérologie, Hépatologie et Nutrition Pédiatriques, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Lyon, France.
⁴⁴ Pediatric Gastroenterology, Hospital da Criança Santo Antônio, Porto Allegre, Brazil.
⁴⁵ Pediatric Gastroenterology and Hepatology, Fundación Cardioinfantil Instituto de Cardiologia, Bogotá, Colombia.
⁴⁶ DDC Clinic - Center for Special Needs Children, Adolescent Medicine and Pediatrics, Middlefield, OH, USA.
⁴⁷ Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, South Korea.
⁴⁸ Division of Pediatric Gastroenterology, Hepatology and Nutrition, National Taiwan University Children's Hospital, Taipei, Taiwan.
⁴⁹ Pediatric Gastroenterology and Hepatology, Brasília Children's Hospital, Brasilia, Brazil.
⁵⁰ INSERM, MMG, Aix Marseille University, Marseille, France.
⁵¹ Service de Pédiatrie Multidisciplinaire, Timone Enfant, Marseille, France.
⁵² Pediatric Hepatology and Liver Transplant Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁵³ First Department of Pediatrics, Aghia Sophia Children's Hospital, National and Kapodistrian University of Athens, Greece.
⁵⁴ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
⁵⁵ Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
⁵⁶ Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁵⁷ Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁵⁸ Department of Pediatrics and Surgery, UCSF Benioff Children's Hospital, University of California San Francisco School of Medicine, San Francisco, CA, USA.
⁵⁹ Section of Hepatology, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
⁶⁰ Division of Pediatric Gastroenterology, University of California San Diego, Rady Children's Hospital San Diego, CA, USA.
⁶¹ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶² Division of General Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁶³ Toronto Center for Liver Disease, University Health Network, Toronto, Canada.
⁶⁴ IHPME, University of Toronto, Toronto, Canada.
⁶⁵ Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

PMID: 36687469
PMCID: PMC9852554
DOI: 10.1016/j.jhepr.2022.100626

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Antonia Felzen et al. JHEP Rep. 2022.

. 2022 Nov 16;5(2):100626.

doi: 10.1016/j.jhepr.2022.100626. eCollection 2023 Feb.

Authors

Affiliations

¹ Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands.
² Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Paris, France.
³ European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
⁴ INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France.
⁵ Institute of Liver Studies, King's College London, London, United Kingdom.
⁶ Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
⁷ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁸ Childhood Liver Disease Research Network (ChiLDReN).
⁹ Pediatric Gastorenterology and Hepatology, Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium.
¹⁰ Service de Biochemie, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris-Saclay, Inserm UMR-S 1174, France.
¹¹ Pediatric Gastroenterology, Hepatology and Nutrition Unit, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Switzerland.
¹² Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
¹³ Alfaisal University, College of Medicine, Riyadh, Saudi Arabia.
¹⁴ Pediatric Hepatology, Gastroenterology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy.
¹⁵ Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom.
¹⁶ Servizio Di Epatologia e Nutrizione Pediatrica, Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
¹⁷ Pediatric Gastroenterology Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
¹⁸ Pediatric Surgery, University Medical Center Groningen, Groningen, the Netherlands.
¹⁹ Pediatric and Liver Unit, Meyer Children's University Hospital of Florence, Florence, Italy.
²⁰ Koc University School of Medicine, Pediatric GI and Hepatology Liver Transplantation Center, Kuttam System in Liver Medicine, Istanbul, Turkey.
²¹ Pediatric Gastroenterology, Sancaktepe Training and Research Hospital, Istanbul, Turkey.
²² Gastroenterology-Hepatology-Nutrition Unit, APHP-Necker Enfants Malades University Hospital, Paris, France.
²³ Previously Coimbra University Hospital Center, Coimbra, Portugal, Now Pediatric Gastroenterology/Hepatology Center Lisbon, Portugal.
²⁴ Service of Pediatric Hepatology and Transplantation, Children's Hospital La Paz, La Paz University Hospital, Madrid, Spain.
²⁵ Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
²⁶ Pediatric Gastroenterology, Hepatology and Nutrition, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.
²⁷ Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, and Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
²⁸ Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
²⁹ Department of Pediatrics, Semmelweis University, Budapest, Hungary.
³⁰ Pediatic Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città Della Salute e Della Scienza University Hospital, Turin, Italy.
³¹ Pediatric Hepatology and Liver Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
³² Pediatric Gastroenterology and Hepatology, University Children's Hospital Tυ¨bingen, University Medical Center Tυ¨bingen, Tυ¨bingen, Germany.
³³ Pediatric Gastroenterology, Hepatology and Nutrition, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
³⁴ Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada.
³⁵ Children's Hospital of Fudan University, Shanghai, China.
³⁶ Department of Child Health and Diseases, Gastroenterology, Hepatology and Nutrition, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
³⁷ Pediatric Gastroenterology, Hepatology and Nutrition, University of Rochester Medical Center, Rochester, NY, USA.
³⁸ Department of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark.
³⁹ Pediatric Gastroenterology, Hepatology and Nutrition, Children's Mercy Hospital, Kansas City, MO, USA.
⁴⁰ Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.
⁴¹ Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
⁴² Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy.
⁴³ Service de Gastroentérologie, Hépatologie et Nutrition Pédiatriques, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Lyon, France.
⁴⁴ Pediatric Gastroenterology, Hospital da Criança Santo Antônio, Porto Allegre, Brazil.
⁴⁵ Pediatric Gastroenterology and Hepatology, Fundación Cardioinfantil Instituto de Cardiologia, Bogotá, Colombia.
⁴⁶ DDC Clinic - Center for Special Needs Children, Adolescent Medicine and Pediatrics, Middlefield, OH, USA.
⁴⁷ Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, South Korea.
⁴⁸ Division of Pediatric Gastroenterology, Hepatology and Nutrition, National Taiwan University Children's Hospital, Taipei, Taiwan.
⁴⁹ Pediatric Gastroenterology and Hepatology, Brasília Children's Hospital, Brasilia, Brazil.
⁵⁰ INSERM, MMG, Aix Marseille University, Marseille, France.
⁵¹ Service de Pédiatrie Multidisciplinaire, Timone Enfant, Marseille, France.
⁵² Pediatric Hepatology and Liver Transplant Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁵³ First Department of Pediatrics, Aghia Sophia Children's Hospital, National and Kapodistrian University of Athens, Greece.
⁵⁴ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
⁵⁵ Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
⁵⁶ Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁵⁷ Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁵⁸ Department of Pediatrics and Surgery, UCSF Benioff Children's Hospital, University of California San Francisco School of Medicine, San Francisco, CA, USA.
⁵⁹ Section of Hepatology, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
⁶⁰ Division of Pediatric Gastroenterology, University of California San Diego, Rady Children's Hospital San Diego, CA, USA.
⁶¹ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶² Division of General Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁶³ Toronto Center for Liver Disease, University Health Network, Toronto, Canada.
⁶⁴ IHPME, University of Toronto, Toronto, Canada.
⁶⁵ Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

PMID: 36687469
PMCID: PMC9852554
DOI: 10.1016/j.jhepr.2022.100626

Abstract

Background & aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship.

Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS.

Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001).

Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment.

Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Keywords: ABCB11, ATP-binding cassette, sub-family B member 11; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSEP; BSEP, bile salt export pump; ChiLDReN, Childhood Liver Disease Research Network; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma; LTx, liver transplantation; NAPPED, NAtural course and Prognosis of PFIC and Effect of biliary Diversion; NLS, native liver survival; PFIC2; PFIC2, progressive familial intrahepatic cholestasis type 2; PPTM, predicted protein truncating mutation; REDCap, Research Electronic Data Capture; TSB, total serum bilirubin; UDCA, ursodeoxycholic acid; compound heterozygosity; genotype; interruption of the enterohepatic circulation; phenotype; sBAs, serum bile acids; siEHC, surgical interruption of the enterohepatic circulation.

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Conflict of interest statement

Antonia Felzen [MD/PhD scholarship University of Groningen], Daan B.E. van Wessel [MD/PhD scholarship University of Groningen], Emmanuel M. Gonzales [Consultant for CTRS, Vivet Therapeutics, Mirum Pharmaceuticals and Albireo], Richard J. Thompson [Consultant for Shire, Albireo, Mirum Pharmaceuticals, Horizon Pharmaceuticals, Sana Biotechnology, GenerationBio, Retrophin and Qing Bile Therapeutics], Irena Jankowska [Nothing to disclose], Benjamin L. Shneider [Nothing to disclose], Etienne Sokal [Founder, board director and Chairman of the Scientific & Medical advisor board of Promethera Biosciences; consultant Johnson&Johnson], Tassos Grammatikopoulos [Consultant for Albireo], Agustina Kadaristiana [Nothing to disclose], Emmanuel Jacquemin [Consultant for CTRS and Vivet Therapeutics], Anne Spraul [Nothing to disclose], Patryk Lipiński [Nothing to disclose], Piotr Czubkowski [Nothing to disclose], Nathalie Rock [Nothing to disclose], Mohammad Shagrani [Nothing to disclose], Dieter Broering [Nothing to disclose], Emanuele Nicastro [Nothing to disclose] Deirdre Kelly [Consultant for Albireo], Gabriela Nebbia [Nothing to disclose], Henrik Arnell [Consultant for Albireo and Mirum Pharmaceuticals], Bjorn Fischler [Attended one advisory board meeting with Albireo in 2016], Jan Hulscher [Nothing to disclose], Daniele Serranti [Nothing to disclose], Cigdem Arikan [Nothing to disclose], Esra Polat [Nothing to disclose], Dominique Debray [Consultant for Alexion and Orphalan pharmaceuticals], Florence Lacaille [Nothing to disclose], Cristina Goncalves [Nothing to disclose], Loreto Hierro [Nothing to disclose], Gema Munoz Bartolo [Nothing to disclose], Yael Mozer- Glassberg [Nothing to disclose], Amer Azaz [Nothing to disclose], Jernej Brecelj [Nothing to disclose], Antal Dezsofi [Nothing to disclose], Pier Luigi Calvo [Nothing to disclose], Enke Grabhorn [Nothing to disclose], Ekkehard Sturm [Nothing to disclose] Wendy van der Woerd [Nothing to disclose], Binita Kamath [Consultant for Mirum Pharmaceuticals, Shire and DCI], Jian-She Wang [Nothing to disclose], Liting Li [Nothing to disclose], Özlem Durmaz [Nothing to disclose], Nanda Kerkar [Nothing to disclose], Marianne Hørby Jørgensen [Nothing to disclose], Ryan Fischer [Consultant for Albireo and Mirum Pharmaceuticals], Carolina Jimenez-Rivera [Nothing to disclose], Seema Alam [Nothing to disclose], Mara Cananzi [Attended one advisory board meeting with Albireo, Mirum Pharmaceuticals and Nestlè; consultant for CTRS], Noemie Laverdure [Consultant for Abbvie], Cristina Targa Ferreira [Nothing to disclose], Felipe Ordoñez Guerrero [Nothing to disclose], Heng Wang [Nothing to disclose], Valerie Sency [Nothing to disclose], Kyungmo Kim [Nothing to disclose], Huey-Ling Chen [Nothing to disclose], Elisa de Carvalho [Nothing to disclose], Alexandre Fabre [Nothing to disclose], Jesus Quintero Bernabeu [Nothing to disclose], Aglaia Zellos [Nothing to disclose], Estella M. Alonso [Nothing to disclose], Ronald J. Sokol [Consultant for Albireo and Mirum Pharmaceuticals], Frederick J. Suchy [Nothing to disclose], Kathleen M. Loomes [Consultant for Albireo, Mirum and Travere Therapeutics], Patrick J. McKiernan [Consultant for Albireo], Philip Rosenthal [Grant/Research Support by Gilead, AbbVie, Merck, Albireo, Mirum Pharmaceuticals, Arrowhead and Travere; consultant for Gilead, AbbVie, Audentes, Dicerna, Albireo, Mirum Pharmaceuticals, Travere, Takeda, Encoded, BioMarin, MedinCell and Ambys], Yumirle Turmelle [Nothing to disclose], Simon Horslen [Grant/Research support from Mirum Pharmaceuticals], Kathleen Schwarz [Grant support from Gilead, Albireo and the Global Alagille Syndrome Alliance; consultant for Mirum Pharmaceuticals, Up to Date and Sarepta], Jorge A. Bezerra [Grant support from Gilead and Albireo], Kasper Wang [Nothing to disclose], Bettina Hansen [Unrestricted grant support from Cymabay, Intercept, Calliditas, Mirum Pharmaceuticals and Albireo; consultant for Mirum Pharmaceuticals, Albireo AB, Chemomab, Calliditas, Intercept, Cyma Bay,], Henkjan J. Verkade [Consultant for Danone/Nutricia Research, Ausnutria BV, Albireo AB, Mirum Parmaceuticals, Intercept and Vivet]. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

**Fig. 1**
Flowchart of patient inclusion from NAPPED database. Genotype category explained under methods section. BSEP, bile salt export pump; NAPPED, NAtural course and Prognosis of PFIC and Effect of biliary Diversion.

**Fig. 2**
Observed native liver survival over time in patients with a BSEP1/1, BSEP1/3 and BSEP3/3 genotype. (A) All patients. (B) Patients without siEHC during follow-up, patients with siEHC are censored at time of siEHC. (C) Patients after they had siEHC. Genotypic categorization of BSEP1/1, BSEP1/3 and BSEP3/3 groups is defined in the methods section. Log-rank tests. BSEP, bile salt export pump; siEHC, surgical interruption of the enterohepatic circulation.

**Fig. 3**
Observed proportion of liver transplants in patients that did not undergo siEHC during follow-up. Genotypic categorization of BSEP1/1, BSEP1/3 and BSEP3/3 groups is defined in the methods section. Log-rank tests. BSEP, bile salt export pump; siEHC, surgical interruption of the enterohepatic circulation.

**Fig. 4**
Observed proportion of liver transplants in patients that did undergo siEHC during follow-up. Genotypic categorization of BSEP1/1, BSEP1/3 and BSEP3/3 groups is defined in the methods section. Median age at siEHC was 2.9 years in BSEP1/1, 1.8 years in BSEP1/3 and 2.5 years in BSEP3/3. Log-rank tests. BSEP, bile salt export pump; siEHC, surgical interruption of the enterohepatic circulation.

**Fig. 5**
Serum bile acids prior to and after siEHC in patients with a BSEP1/1, BSEP1/3 and BSEP3/3 genotype. Wilcoxon signed-rank test. Bars represent median and IQR. BSEP, bile salt export pump; siEHC, surgical interruption of the enterohepatic circulation.

**Fig. 6**
Observed native liver survival after siEHC, stratified for post-surgical sBA cut-offs. In all available patients (BSEP1/1, BSEP1/3 and BSEP3/3) with a relative decrease in sBAs of < or ≥75%. Log-rank tests. sBAs, serum bile acids; siEHC, surgical interruption of the enterohepatic circulation.

**Fig. 7**
Observed proportion of patients with hepatocellular carcinoma per genotypic category. Genotypic categorization of BSEP1/1, BSEP1/3 and BSEP3/3 groups is defined in the methods section. Log-rank tests. BSEP, bile salt export pump.

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References

1. Noe J., Stieger B., Meier P.J. Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology. 2002;123(5):1659–1666. - PubMed
1. Thompson R., Strautnieks S. BSEP: function and role in progressive familial intrahepatic cholestasis. Semin Liver Dis. 2001;21(4):545–550. - PubMed
1. Davit-Spraul A., Fabre M., Branchereau S., Baussan C., Gonzales E., Stieger B., et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51(5):1645–1655. - PubMed
1. Pawlikowska L., Strautnieks S., Jankowska I., Czubkowski P., Emerick K., Antoniou A., et al. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010;53(1):170–178. - PMC - PubMed
1. van Wessel D.B.E., Thompson R.J., Gonzales E., Jankowska I., Sokal E., Grammatikopoulos T., et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020;73(1):84–93. - PubMed

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[1] Noe J., Stieger B., Meier P.J. Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology. 2002;123(5):1659–1666. - PubMed

[2] Noe J., Stieger B., Meier P.J. Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology. 2002;123(5):1659–1666. - PubMed

[3] Thompson R., Strautnieks S. BSEP: function and role in progressive familial intrahepatic cholestasis. Semin Liver Dis. 2001;21(4):545–550. - PubMed

[4] Thompson R., Strautnieks S. BSEP: function and role in progressive familial intrahepatic cholestasis. Semin Liver Dis. 2001;21(4):545–550. - PubMed

[5] Davit-Spraul A., Fabre M., Branchereau S., Baussan C., Gonzales E., Stieger B., et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51(5):1645–1655. - PubMed

[6] Davit-Spraul A., Fabre M., Branchereau S., Baussan C., Gonzales E., Stieger B., et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51(5):1645–1655. - PubMed

[7] Pawlikowska L., Strautnieks S., Jankowska I., Czubkowski P., Emerick K., Antoniou A., et al. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010;53(1):170–178. - PMC - PubMed

[8] Pawlikowska L., Strautnieks S., Jankowska I., Czubkowski P., Emerick K., Antoniou A., et al. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010;53(1):170–178. - PMC - PubMed

[9] van Wessel D.B.E., Thompson R.J., Gonzales E., Jankowska I., Sokal E., Grammatikopoulos T., et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020;73(1):84–93. - PubMed

[10] van Wessel D.B.E., Thompson R.J., Gonzales E., Jankowska I., Sokal E., Grammatikopoulos T., et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020;73(1):84–93. - PubMed

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Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

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Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

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