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Wischlen E, Laverdure N, Erard D, Rohmer B, Boillot O, Dubois R, Lachaux A, Collardeau-Frachon S, Hervieu V, Dumortier J. Iterative antibody-induced bile salt export pump deficiency after successive liver transplantations successfully treated with plasmapheresis and rituximab. Clin Res Hepatol Gastroenterol 2023; 47:102139. [PMID: 37187258 DOI: 10.1016/j.clinre.2023.102139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 05/05/2023] [Accepted: 05/10/2023] [Indexed: 05/17/2023]
Abstract
Post-transplantation evolution of progressive familial intrahepatic cholestasis type 2 patients can be complicated by antibody-induced bile salt export pump deficiency (AIBD). There is no consensus on its management. We describe a patient who presented two episodes, 9 years apart. The first episode was refractory to plasmapheresis and intravenous immunoglobulin (IVIG) started 2 months after AIBD onset, leading to graft loss. The second episode responded to plasmapheresis, IVIG and rituximab initiated less than 2 weeks after the beginning of symptoms, allowing for long-term recovery. This case suggests that intensive treatment with minimum delay after symptoms onset could sponsor a better evolution.
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Affiliation(s)
- Emma Wischlen
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Département d'Hépatogastroentérologie et Nutrition Pédiatrique, and Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques.
| | - Noémie Laverdure
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Département d'Hépatogastroentérologie et Nutrition Pédiatrique, and Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques
| | - Domitille Erard
- Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Service d'Hépatogastroentérologie
| | - Barbara Rohmer
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Département d'Hépatogastroentérologie et Nutrition Pédiatrique, and Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques
| | - Olivier Boillot
- Hospices civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives; Université Claude Bernard Lyon 1
| | - Rémi Dubois
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de chirurgie uro-viscérale, thoracique et de transplantation de l'enfant
| | - Alain Lachaux
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Département d'Hépatogastroentérologie et Nutrition Pédiatrique, and Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques; Université Claude Bernard Lyon 1
| | - Sophie Collardeau-Frachon
- Université Claude Bernard Lyon 1; Hospices civils de Lyon, Groupement Hospitalier Est, Service d'Anatomie Pathologique, Lyon, France
| | - Valérie Hervieu
- Université Claude Bernard Lyon 1; Hospices civils de Lyon, Groupement Hospitalier Est, Service d'Anatomie Pathologique, Lyon, France
| | - Jérôme Dumortier
- Hospices civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives; Université Claude Bernard Lyon 1
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Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, D'Antiga L, Durmaz Ö, Fischler B, Gonzalès E, Grammatikopoulos T, Gupte G, Hardikar W, Houwen RHJ, Kamath BM, Karpen SJ, Kjems L, Lacaille F, Lachaux A, Lainka E, Mack CL, Mattsson JP, McKiernan P, Özen H, Rajwal SR, Roquelaure B, Shagrani M, Shteyer E, Soufi N, Sturm E, Tessier ME, Verkade HJ, Horn P. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2022; 7:830-842. [PMID: 35780807 DOI: 10.1016/s2468-1253(22)00093-0] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 03/14/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 μg/kg, or odevixibat 120 μg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 μmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 μg/kg per day (n=23), or odevixibat 120 μg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 μg/kg per day group and 52% in the 120 μg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 μg/kg per day group and four in the 120 μg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING Albireo Pharma.
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Affiliation(s)
| | - Henrik Arnell
- Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Reha Artan
- Department of Paediatric Gastroenterology, Akdeniz University, Antalya, Turkey
| | - Ulrich Baumann
- Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
| | - Pier Luigi Calvo
- Paediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Buket Dalgic
- Department of Paediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Lorenzo D'Antiga
- Department of Paediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Özlem Durmaz
- Istanbul University Istanbul Faculty of Medicine, Department of Paediatric Gastroenterology and Hepatology, Istanbul, Turkey
| | - Björn Fischler
- Department of Paediatrics, CLINTEC, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Emmanuel Gonzalès
- Hépatologie et Transplantation Hépatique Pédiatriques, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Hépatinov, Inserm U1193, Paris, France
| | - Tassos Grammatikopoulos
- Institute of Liver Studies, King's College London, London, UK; Paediatric Liver, GI and Nutrition Centre and MowatLabs, King's College Hospital NHS Trust, London, UK
| | - Girish Gupte
- Liver Unit and Small Bowel Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Winita Hardikar
- Department of Gastroenterology, Royal Children's Hospital, Melbourne, VIC, Australia
| | - Roderick H J Houwen
- Department of Paediatric Gastroenterology, Wilhelmina Children's Hospital and University Medical Centre, Utrecht, Netherlands
| | - Binita M Kamath
- Department of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada
| | - Saul J Karpen
- Paediatrics Department, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA
| | | | - Florence Lacaille
- Paediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France
| | - Alain Lachaux
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service D'hépatogastoentérologie et Nutrition Pédiatrique, Lyon, France
| | - Elke Lainka
- Children's Hospital, Department of Paediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany
| | - Cara L Mack
- Paediatrics Department, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | | | - Patrick McKiernan
- Liver Unit and Small Bowel Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Hasan Özen
- Division of Paediatric Gastroenterology, Hepatology, and Nutrition, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Sanjay R Rajwal
- Children's Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK
| | - Bertrand Roquelaure
- APHM, Service de Pédiatrie Multidisciplinaire, Hôpital de la Timone Enfants, Marseille, France
| | - Mohammad Shagrani
- Department of Liver and SB Transplant and Hepatobiliary-Paediatric Surgery, King Faisal Specialist Hospital and Research Centre-Organ Transplant Centre and College Of Medicine-Alfaisal University, Riyadh, Saudi Arabia
| | - Eyal Shteyer
- Faculty of Medicine, Hebrew University of Jerusalem, Juliet Keidan Department of Paediatric Gastroenterology, Shaare Zedek Medical Centre, Jerusalem, Israel
| | - Nisreen Soufi
- Paediatrics Department, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Ekkehard Sturm
- Paediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Mary Elizabeth Tessier
- Department of Paediatrics, Section of Paediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine-Texas Children's Hospital, Houston, TX, USA
| | - Henkjan J Verkade
- Department of Paediatrics, University of Groningen, Beatrix Children's Hospital-University Medical Centre Groningen, Groningen, Netherlands
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Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019; 11:450-463. [PMID: 31183005 PMCID: PMC6547292 DOI: 10.4254/wjh.v11.i5.450] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/19/2019] [Accepted: 04/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.
AIM To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.
METHODS We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.
RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.
CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (ATP8B1), BSEP (ABCB11), and MDR3 (ABCB4) transporter deficiencies, as well as more recently described gene mutations -- TJP2 (TJP2), FXR (NR1H4), MYO5B (MYO5B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.
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Affiliation(s)
- Sarah AF Henkel
- Division of Gastroenterology, Hepatology, and Nutrition, Emory School of Medicine, Atlanta, GA 30322, United States
| | - Judy H Squires
- Department of Radiology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Mary Ayers
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Armando Ganoza
- Division of Pediatric Transplantation, Department of Surgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Patrick Mckiernan
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - James E Squires
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
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