JHEP Reports (Feb 2023)
Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency
- Antonia Felzen,
- Daan B.E. van Wessel,
- Emmanuel Gonzales,
- Richard J. Thompson,
- 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,
- Emanuele Nicastro,
- Deirdre Kelly,
- Gabriella Nebbia,
- Henrik Arnell,
- Björn 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,
- Steffen Hartleif,
- Wendy J. van der Woerd,
- Binita M. Kamath,
- Jian-She Wang,
- Liting Li,
- Özlem Durmaz,
- Nanda Kerkar,
- Marianne Hørby Jørgensen,
- Ryan Fischer,
- Carolina Jimenez-Rivera,
- Seema Alam,
- Mara Cananzi,
- Noemie Laverdure,
- Cristina Targa Ferreira,
- Felipe Ordoñez Guerrero,
- Heng Wang,
- Valerie Sency,
- Kyung Mo Kim,
- Huey-Ling Chen,
- Elisa de Carvalho,
- Alexandre Fabre,
- Jesus Quintero Bernabeu,
- Aglaia Zellos,
- Estella M. Alonso,
- Ronald J. Sokol,
- Frederick J. Suchy,
- Kathleen M. Loomes,
- Patrick J. McKiernan,
- Philip Rosenthal,
- Yumirle Turmelle,
- Simon Horslen,
- Kathleen Schwarz,
- Jorge A. Bezerra,
- Kasper Wang,
- Bettina E. Hansen,
- Henkjan J. Verkade
Affiliations
- Antonia Felzen
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands
- Daan B.E. van Wessel
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands
- Emmanuel Gonzales
- 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; European Reference Network on Hepatological Diseases (ERN RARE-LIVER); INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France
- Richard J. Thompson
- Institute of Liver Studies, King's College London, London, United Kingdom
- Irena Jankowska
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
- Benjamin L. Shneider
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Childhood Liver Disease Research Network (ChiLDReN)
- Etienne Sokal
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Gastorenterology and Hepatology, Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium
- Tassos Grammatikopoulos
- Institute of Liver Studies, King's College London, London, United Kingdom
- Agustina Kadaristiana
- Institute of Liver Studies, King's College London, London, United Kingdom
- Emmanuel Jacquemin
- 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; European Reference Network on Hepatological Diseases (ERN RARE-LIVER); INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France
- Anne Spraul
- INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France; Service de Biochemie, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris-Saclay, Inserm UMR-S 1174, France
- Patryk Lipiński
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
- Piotr Czubkowski
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
- Nathalie Rock
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Switzerland
- Mohammad Shagrani
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Alfaisal University, College of Medicine, Riyadh, Saudi Arabia
- Dieter Broering
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
- Emanuele Nicastro
- Pediatric Hepatology, Gastroenterology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy
- Deirdre Kelly
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom
- Gabriella Nebbia
- Servizio Di Epatologia e Nutrizione Pediatrica, Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Henrik Arnell
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Gastroenterology Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
- Björn Fischler
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Gastroenterology Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
- Jan B.F. Hulscher
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Surgery, University Medical Center Groningen, Groningen, the Netherlands
- Daniele Serranti
- Pediatric and Liver Unit, Meyer Children’s University Hospital of Florence, Florence, Italy
- Cigdem Arikan
- Koc University School of Medicine, Pediatric GI and Hepatology Liver Transplantation Center, Kuttam System in Liver Medicine, Istanbul, Turkey
- Esra Polat
- Pediatric Gastroenterology, Sancaktepe Training and Research Hospital, Istanbul, Turkey
- Dominique Debray
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Gastroenterology-Hepatology-Nutrition Unit, APHP-Necker Enfants Malades University Hospital, Paris, France
- Florence Lacaille
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Gastroenterology-Hepatology-Nutrition Unit, APHP-Necker Enfants Malades University Hospital, Paris, France
- Cristina Goncalves
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Previously Coimbra University Hospital Center, Coimbra, Portugal, Now Pediatric Gastroenterology/Hepatology Center Lisbon, Portugal
- Loreto Hierro
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Service of Pediatric Hepatology and Transplantation, Children's Hospital La Paz, La Paz University Hospital, Madrid, Spain
- Gema Muñoz Bartolo
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Service of Pediatric Hepatology and Transplantation, Children's Hospital La Paz, La Paz University Hospital, Madrid, Spain
- Yael Mozer-Glassberg
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- Amer Azaz
- Pediatric Gastroenterology, Hepatology and Nutrition, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
- Jernej Brecelj
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, and Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Antal Dezsőfi
- Department of Pediatrics, Semmelweis University, Budapest, Hungary
- Pier Luigi Calvo
- Pediatic Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città Della Salute e Della Scienza University Hospital, Turin, Italy
- Enke Grabhorn
- Pediatric Hepatology and Liver Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany
- Steffen Hartleif
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Gastroenterology and Hepatology, University Children’s Hospital Tυ¨bingen, University Medical Center Tυ¨bingen, Tυ¨bingen, Germany
- Wendy J. van der Woerd
- Pediatric Gastroenterology, Hepatology and Nutrition, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
- Binita M. Kamath
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
- Jian-She Wang
- Children’s Hospital of Fudan University, Shanghai, China
- Liting Li
- Children’s Hospital of Fudan University, Shanghai, China
- Özlem Durmaz
- Department of Child Health and Diseases, Gastroenterology, Hepatology and Nutrition, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
- Nanda Kerkar
- Pediatric Gastroenterology, Hepatology and Nutrition, University of Rochester Medical Center, Rochester, NY, USA
- Marianne Hørby Jørgensen
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Department of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
- Ryan Fischer
- Pediatric Gastroenterology, Hepatology and Nutrition, Children's Mercy Hospital, Kansas City, MO, USA
- Carolina Jimenez-Rivera
- Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada
- Seema Alam
- Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
- Mara Cananzi
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); 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
- Noemie Laverdure
- Service de Gastroentérologie, Hépatologie et Nutrition Pédiatriques, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Lyon, France
- Cristina Targa Ferreira
- Pediatric Gastroenterology, Hospital da Criança Santo Antônio, Porto Allegre, Brazil
- Felipe Ordoñez Guerrero
- Pediatric Gastroenterology and Hepatology, Fundación Cardioinfantil Instituto de Cardiologia, Bogotá, Colombia
- Heng Wang
- DDC Clinic - Center for Special Needs Children, Adolescent Medicine and Pediatrics, Middlefield, OH, USA
- Valerie Sency
- DDC Clinic - Center for Special Needs Children, Adolescent Medicine and Pediatrics, Middlefield, OH, USA
- Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, South Korea
- Huey-Ling Chen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, National Taiwan University Children's Hospital, Taipei, Taiwan
- Elisa de Carvalho
- Pediatric Gastroenterology and Hepatology, Brasília Children's Hospital, Brasilia, Brazil
- Alexandre Fabre
- INSERM, MMG, Aix Marseille University, Marseille, France; Service de Pédiatrie Multidisciplinaire, Timone Enfant, Marseille, France
- Jesus Quintero Bernabeu
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Hepatology and Liver Transplant Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Aglaia Zellos
- First Department of Pediatrics, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, Greece
- Estella M. Alonso
- Childhood Liver Disease Research Network (ChiLDReN); Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA
- Ronald J. Sokol
- Childhood Liver Disease Research Network (ChiLDReN); Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
- Frederick J. Suchy
- Childhood Liver Disease Research Network (ChiLDReN); Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
- Kathleen M. Loomes
- Childhood Liver Disease Research Network (ChiLDReN); Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Patrick J. McKiernan
- Childhood Liver Disease Research Network (ChiLDReN); Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
- Philip Rosenthal
- Childhood Liver Disease Research Network (ChiLDReN); Department of Pediatrics and Surgery, UCSF Benioff Children's Hospital, University of California San Francisco School of Medicine, San Francisco, CA, USA
- Yumirle Turmelle
- Childhood Liver Disease Research Network (ChiLDReN); Section of Hepatology, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA
- Simon Horslen
- Childhood Liver Disease Research Network (ChiLDReN); Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
- Kathleen Schwarz
- Childhood Liver Disease Research Network (ChiLDReN); Division of Pediatric Gastroenterology, University of California San Diego, Rady Children's Hospital San Diego, CA, USA
- Jorge A. Bezerra
- Childhood Liver Disease Research Network (ChiLDReN); Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Kasper Wang
- Childhood Liver Disease Research Network (ChiLDReN); Division of General Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Bettina E. Hansen
- Toronto Center for Liver Disease, University Health Network, Toronto, Canada; IHPME, University of Toronto, Toronto, Canada; Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
- Henkjan J. Verkade
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Corresponding author. Address: Pediatric Gastroenterology & Hepatology, Department of Pediatrics, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands. Tel.: +31 50 3614147, fax: +31 50 361 1704
- Journal volume & issue
-
Vol. 5,
no. 2
p. 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.
