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Verkade HJ, Felzen A, Keitel V, Thompson R, Gonzales E, Strnad P, Kamath B, van Mil S. EASL Clinical Practice Guidelines on genetic cholestatic liver diseases. J Hepatol 2024; 81:303-325. [PMID: 38851996 DOI: 10.1016/j.jhep.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 04/05/2024] [Indexed: 06/10/2024]
Abstract
Genetic cholestatic liver diseases are caused by (often rare) mutations in a multitude of different genes. While these diseases differ in pathobiology, clinical presentation and prognosis, they do have several commonalities due to their cholestatic nature. These Clinical Practice Guidelines (CPGs) offer a general approach to genetic testing and management of cholestatic pruritus, while exploring diagnostic and treatment approaches for a subset of genetic cholestatic liver diseases in depth. An expert panel appointed by the European Association for the Study of the Liver has created recommendations regarding diagnosis and treatment, based on the best evidence currently available in the fields of paediatric and adult hepatology, as well as genetics. The management of these diseases generally takes place in a tertiary referral centre, in order to provide up-to-date approaches and expertise. These CPGs are intended to support hepatologists (for paediatric and adult patients), residents and other healthcare professionals involved in the management of these patients with concrete recommendations based on currently available evidence or, if not available, on expert opinion.
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Kondou H, Nakano S, Mizuno T, Bessho K, Hasegawa Y, Nakazawa A, Tanikawa K, Azuma Y, Okamoto T, Inui A, Imagawa K, Kasahara M, Zen Y, Suzuki M, Hayashi H. Clinical symptoms, biochemistry, and liver histology during the native liver period of progressive familial intrahepatic cholestasis type 2. Orphanet J Rare Dis 2024; 19:57. [PMID: 38341604 PMCID: PMC10858576 DOI: 10.1186/s13023-024-03080-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 02/05/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an ultra-rare disease caused by mutations in the ABCB11 gene. This study aimed to understand the course of PFIC2 during the native liver period. METHODS From November 2014 to October 2015, a survey to identify PFIC2 patients was conducted in 207 hospitals registered with the Japanese Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Investigators retrospectively collected clinical data at each facility in November 2018 using pre-specified forms. RESULTS Based on the biallelic pathogenic variants in ABCB11 and/or no hepatic immunohistochemical detection of BSEP, 14 Japanese PFIC2 patients were enrolled at seven facilities. The median follow-up was 63.2 [47.7-123.3] months. The median age of disease onset was 2.5 [1-4] months. Twelve patients underwent living donor liver transplantation (LDLT), with a median age at LDLT of 9 [4-57] months. Two other patients received sodium 4-phenylbutyrate (NaPB) therapy and survived over 60 months with the native liver. No patients received biliary diversion. The cases that resulted in LDLT had gradually deteriorated growth retardation, biochemical tests, and liver histology since the initial visit. In the other two patients, jaundice, growth retardation, and most of the biochemical tests improved after NaPB therapy was started, but pruritus and liver fibrosis did not. CONCLUSIONS Japanese PFIC2 patients had gradually worsening clinical findings since the initial visit, resulting in LDLT during infancy. NaPB therapy improved jaundice and growth retardation but was insufficient to treat pruritus and liver fibrosis.
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Affiliation(s)
- Hiroki Kondou
- Department of Pediatrics, Kindai University Nara Hospital, Nara, Japan
| | - Satoshi Nakano
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tadahaya Mizuno
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Hasegawa
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsuko Nakazawa
- Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Yoshihiro Azuma
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Tatsuya Okamoto
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Eastern Hospital, Kanagawa, Japan
| | - Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital and King's College London, London, UK
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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4
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Gonzales E, Gardin A, Almes M, Darmellah-Remil A, Seguin H, Mussini C, Franchi-Abella S, Duché M, Ackermann O, Thébaut A, Habes D, Hermeziu B, Lapalus M, Falguières T, Combal JP, Benichou B, Valero S, Davit-Spraul A, Jacquemin E. Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy. JHEP Rep 2023; 5:100844. [PMID: 37701337 PMCID: PMC10494458 DOI: 10.1016/j.jhepr.2023.100844] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/16/2023] [Accepted: 06/22/2023] [Indexed: 09/14/2023] Open
Abstract
Background & Aims Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease caused by biallelic variations in ABCB4. Data reporting on the impact of genotype and of response to ursodeoxycholic acid (UDCA) therapy on long-term outcomes are scarce. Methods We retrospectively describe a cohort of 38 patients with PFIC3 with a median age at last follow-up of 19.5 years (range 3.8-53.8). Results Twenty patients presented with symptoms before 1 year of age. Thirty-one patients received ursodeoxycholic acid (UDCA) therapy resulting in serum liver test improvement in 20. Twenty-seven patients had cirrhosis at a median age of 8.1 years of whom 18 received a liver transplant at a median age of 8.5 years. Patients carrying at least one missense variation were more likely to present with positive (normal or decreased) canalicular MDR3 expression in the native liver and had prolonged native liver survival (NLS; median 12.4 years [range 3.8-53.8]). In contrast, in patients with severe genotypes (no missense variation), there was no detectable canalicular MDR3 expression, symptom onset and cirrhosis occurred earlier, and all underwent liver transplantation (at a median age of 6.7 years [range 2.3-10.3]). The latter group was refractory to UDCA treatment, whereas 87% of patients with at least one missense variation displayed an improvement in liver biochemistry in response to UDCA. Biliary phospholipid levels over 6.9% of total biliary lipid levels predicted response to UDCA. Response to UDCA predicted NLS. Conclusions Patients carrying at least one missense variation, with positive canalicular expression of MDR3 and a biliary phospholipid level over 6.9% of total biliary lipid levels were more likely to respond to UDCA and to exhibit prolonged NLS. Impact and implications In this study, data show that genotype and response to ursodeoxycholic acid therapy predicted native liver survival in patients with PFIC3 (progressive familial intrahepatic cholestasis type 3). Patients carrying at least one missense variation, with positive (decreased or normal) immuno-staining for canalicular MDR3, and a biliary phospholipid level over 6.9% of total biliary lipids were more likely to respond to ursodeoxycholic acid therapy and to exhibit prolonged native liver survival.
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Affiliation(s)
- Emmanuel Gonzales
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Antoine Gardin
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Marion Almes
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Amaria Darmellah-Remil
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
| | - Hanh Seguin
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
| | - Charlotte Mussini
- Pathology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Stéphanie Franchi-Abella
- Pediatric Radiology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Mathieu Duché
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Pediatric Radiology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Oanez Ackermann
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Alice Thébaut
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Dalila Habes
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Bogdan Hermeziu
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Martine Lapalus
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | | | | | | | | | - Anne Davit-Spraul
- Biochemistry; Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Emmanuel Jacquemin
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
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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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Stindt J, Dröge C, Lainka E, Kathemann S, Pfister ED, Baumann U, Stalke A, Grabhorn E, Shagrani MA, Mozer-Glassberg Y, Hartley J, Wammers M, Klindt C, Philippski P, Liebe R, Herebian D, Mayatepek E, Berg T, Schmidt-Choudhury A, Wiek C, Hanenberg H, Luedde T, Keitel V. Cell-based BSEP trans-inhibition: A novel, non-invasive test for diagnosis of antibody-induced BSEP deficiency. JHEP Rep 2023. [DOI: 10.1016/j.jhepr.2023.100690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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Zheng Y, Zhou C, Zheng B, Hu G, Wang C, Zhou W, Lu Y, Zhang Z, Lin Q, Guo H, Jin Y, Liu Z, Tang W. Antisense oligonucleotides rescue an intronic splicing variant in the ABCB11 gene that causes progressive familial intrahepatic cholestasis type 2. Dig Liver Dis 2022; 54:1541-1547. [PMID: 35490150 DOI: 10.1016/j.dld.2022.04.002] [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: 01/11/2022] [Revised: 03/21/2022] [Accepted: 04/04/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disorder caused by variants in the ABCB11 gene encoding the bile salt export pump (BSEP). We investigated the molecular defect in a PFIC2 infant and rescued the splicing defect with antisense oligonucleotides (ASOs). METHODS Whole-exome sequencing (WES) revealed compound heterozygous variants in the ABCB11 gene in a PFIC2 patient. Liver biopsy was immunostained for BSEP. The splicing effect of the candidate variants was investigated by minigene assay. ASOs were designed to rescue aberrant splicing. RESULTS A Chinese girl of two nonconsanguineous healthy parents suffered from low glutamyl transpeptidase cholestasis and showed no response to the ursodeoxycholic acid. WES revealed that the patient was compound heterozygous for two novel variants in the ABCB11 gene: c.76+29T>G and c.390-2A>G. Liver immunohistochemistry showed the absence of BSEP. The variant c.76+29T>G was confirmed to retain 42 bp in the mature mRNA. The variant c.390-2A>G was confirmed to cause exon 6 skipping. We designed two ASOs and identified one of them that efficiently induced pseudoexon exclusion. CONCLUSION We reported two novel variants of the ABCB11 gene, c.76+29T>G and c.390-2A>G, in a PFIC2 infant, thereby expanding the genotype of PFIC2. Our findings provide evidence for ASOs as a therapeutic approach for PFIC2 patients carrying intronic variants.
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Affiliation(s)
- Yucan Zheng
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Chunlei Zhou
- Department of Pathology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Bixia Zheng
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Guorui Hu
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Chunli Wang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhou
- Department of Pathology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Lu
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhihua Zhang
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Qian Lin
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Hongmei Guo
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yu Jin
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhifeng Liu
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
| | - Weibing Tang
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China.
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Progressive Familial Intrahepatic Cholestasis Type 2 and Recurrence After Liver Transplantation: A Case Report. Transplant Proc 2022; 54:1370-1375. [PMID: 35718560 DOI: 10.1016/j.transproceed.2022.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/24/2022] [Accepted: 04/02/2022] [Indexed: 11/20/2022]
Abstract
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare autosomal recessive disorder caused by mutations in the ABCB11 gene. Clinical manifestations include cholestasis with low γ-glutamyltransferase (GGT), hepatosplenomegaly, and severe pruritus. Liver transplantation is required for individuals with progressive liver disease or failure of the bypass procedure and has been considered curative. However, in the case of PFIC2, although bile salt excretory pump (BSEP) deficiency is a liver-specific condition rather than a systemic disease, evidence of recurrent BSEP disease has been shown in a small proportion of allografts. We describe an unusual case of a 21-year-old individual with PFIC2 and evidence of recurrent BSEP disease after liver transplantation, with clinical and laboratory improvement after pulse therapy with methylprednisolone for 3 days and adjustment of oral immunosuppression. This case report highlights the recurrence of PFIC2 in patients post liver transplant. It also emphasizes the importance of clinical suspicion, which should be considered in cases of posttransplant cholestasis in PFIC2 patients, especially those with low γ-glutamyltransferase (GGT) and without signs of acute graft rejection. Having knowledge of the condition favors a targeted diagnostic approach and contributes to early therapeutic management and a higher success rate.
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Ibrahim SH, Kamath BM, Loomes KM, Karpen SJ. Cholestatic liver diseases of genetic etiology: Advances and controversies. Hepatology 2022; 75:1627-1646. [PMID: 35229330 DOI: 10.1002/hep.32437] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 12/14/2022]
Abstract
With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated "idiopathic" adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a "sequencing first" approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype-phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real-world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.
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Affiliation(s)
- Samar H Ibrahim
- Division of Pediatric GastroenterologyMayo ClinicRochesterMinnesotaUSA
| | - Binita M Kamath
- The Hospital for Sick ChildrenUniversity of TorontoTorontoOntarioCanada
| | - Kathleen M Loomes
- The Children's Hospital of Philadelphia and Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Saul J Karpen
- Emory University School of Medicine and Children's Healthcare of AtlantaAtlantaGeorgiaUSA
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Namgoong JM, Hwang S, Kim DY, Ahn CS, Kwon H, Ha S, Kim KM, Oh SH. Living donor liver transplantation in an infant patient with progressive familial intrahepatic cholestasis along with hepatocellular carcinoma: a case report. KOREAN JOURNAL OF TRANSPLANTATION 2022; 36:73-78. [PMID: 35769428 PMCID: PMC9235533 DOI: 10.4285/kjt.21.0007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 01/09/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease requiring liver transplantation (LT). Hepatocellular carcinoma (HCC) is very rare in infants. We present a case of living donor LT using a left lateral section graft performed in a 7-month-old female infant diagnosed with PFIC type II and HCC. No mutation on ABCB11 gene was identified. Because of progressive deterioration of liver function, living donor LT with her mother's left lateral section graft was performed. Pretransplant serum alpha-fetoprotein (AFP) level was increased to 2,740 ng/mL, but HCC was not taken into account because of its rarity. The explant liver showed micronodular liver cirrhosis, multiple infantile hemangiomas and two HCCs of 0.7 cm and 0.3 cm in size. The patient recovered uneventfully from the LT operation. This patient has been regularly followed up with abdomen ultrasonography and AFP measurement every 6 months. The patient has been continually doing well for 8 years after the LT. In conclusion, LT is currently the only effective treatment for PFIC-associated end-stage liver diseases. HCC can develop at the cirrhotic liver of any cause, thus elevation of HCC tumor markers in pediatric patients is an important clue to perform further investigation before LT.
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Affiliation(s)
- Jung-Man Namgoong
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Corresponding author: Shin Hwang Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea, Tel: +82-2-3010-3930, Fax: +82-2-3010-6701, E-mail:
| | - Dae-Yeon Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chul-Soo Ahn
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyunhee Kwon
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Suhyeon Ha
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Namgoong JM, Hwang S, Kwon H, Ha S, Kim KM, Oh SH, Hong SM. Liver transplantation in pediatric patients with progressive familial intrahepatic cholestasis: Single center experience of seven cases. Ann Hepatobiliary Pancreat Surg 2021; 26:69-75. [PMID: 34916336 PMCID: PMC8901976 DOI: 10.14701/ahbps.21-114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 11/17/2022] Open
Abstract
Backgrounds/Aims Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease requiring liver transplantation (LT). The objective of this study was to investigate the clinicopathological features and posttransplant courses of seven LT recipients with PFIC. Methods This was a retrospective single-center study of patients with PFIC who underwent LT from January 2013 to June 2020. Results Two and five patients were diagnosed with PFIC type 1 and type 2, respectively. For all seven patients, age of PFIC onset was at birth. Jaundice was present in all cases. Mean pretransplant total and direct bilirubin levels were 16.1 ± 8.1 mg/dL and 12.4 ± 6.2 mg/dL, respectively. Median patient age and body weight at LT were 10 months and 7 kg, respectively. Types of donors were mothers of patients in four and deceased donors in three. All five patients with PFIC type 2 recovered uneventfully. One patient each with PFIC type 1 underwent retransplantation due to graft failure or died due to multi-organ failure. Overall graft and patient survival rates at five years were 66.7% and 83.3%, respectively. Bile salt export pump immunohistochemical staining showed normal canalicular expression in two patients with PFIC type 1, focal loss in two patients with PFIC type 2, and total loss in three patients with PFIC type 2. Conclusions LT is currently the only effective treatment for PFIC-associated end-stage liver diseases. It is mandatory to perform regular follow-up due to the risk of complications including steatohepatitis, especially for patients with PFIC type 1.
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Affiliation(s)
- Jung-Man Namgoong
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyunhee Kwon
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Suhyeon Ha
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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12
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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13
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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 DA, Nebbia G, Arnell H, Björn Fischler, 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 JS, Li L, Durmaz Ö, Onal Z, Bunt TMG, Hansen BE, Verkade HJ. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol 2020; 73:84-93. [PMID: 32087350 DOI: 10.1016/j.jhep.2020.02.007] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 01/31/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022]
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.
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Affiliation(s)
- Daan B E van Wessel
- Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, The Netherlands
| | | | - Emmanuel Gonzales
- Service d'Hépatologie et de Transplantation Hépatique Pédiatriques, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris Saclay, Inserm UMR-S 1174, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Irena Jankowska
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Etienne Sokal
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Université; Catholique de Louvain, Cliniques St Luc, Brussels, Belgium
| | | | | | - Emmanuel Jacquemin
- Service d'Hépatologie et de Transplantation Hépatique Pédiatriques, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris Saclay, Inserm UMR-S 1174, France
| | - Anne Spraul
- 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 Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Piotr Czubkowski
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Nathalie Rock
- Université; Catholique de Louvain, Cliniques St Luc, Brussels, Belgium
| | - Mohammad Shagrani
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; Alfaisal University, College of Medicine, Riyadh, Saudi Arabia
| | - Dieter Broering
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Talal Algoufi
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Nejat Mazhar
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Emanuele Nicastro
- Pediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Deirdre A 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 Digestive Diseases, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Björn Fischler
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Digestive Diseases, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Jan B F Hulscher
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Paediatric Surgery, University Medical Centre Groningen, Groningen, The Netherlands
| | - Daniele Serranti
- Paediatric and Liver Unit, Meyer Children's University Hospital of Florence
| | - Cigdem Arikan
- Koc University School of Medicine, Paediatric GI and Hepatology Liver Transplantation Centre, Kuttam System in Liver Medicine, Istanbul, Turkey
| | - Esra Polat
- Hospital Umraniye Training and Research Hospital, Istanbul, Turkey
| | - Dominique Debray
- Unité; d'hépatologie Pédiatrique et Transplantation, Hôpital Necker, Paris, France
| | - Florence Lacaille
- Unité; d'hépatologie Pédiatrique et Transplantation, Hôpital Necker, Paris, France
| | - Cristina Goncalves
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Coimbra University Hospital Center, Coimbra, Portugal
| | - Loreto Hierro
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Liver Service, La Paz University Hospital, Madrid, Spain
| | - Gema Muñoz Bartolo
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Liver Service, La Paz University Hospital, Madrid, Spain
| | - Yael Mozer-Glassberg
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Centre of Israel
| | - Amer Azaz
- 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 Paediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Antal Dezsőfi
- 1st Department of Paediatrics, 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, Torino, Italy
| | - Enke Grabhorn
- Klinik Für Kinder- Und Jugendmedizin, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany
| | - Ekkehard Sturm
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER); University Children's Hospital Tübingen, Tübingen, Germany
| | - Wendy J van der Woerd
- Wilhelmina Children's Hospital, University Medical Centre Utrecht, Paediatric Gastroenterology, Hepatology and Nutrition, Utrecht, The Netherlands
| | - Binita M Kamath
- 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
- Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Zerrin Onal
- Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Ton M G Bunt
- Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, The Netherlands
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, University Health Network, Canada; IHPME, University of Toronto, Canada
| | - Henkjan J Verkade
- Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
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14
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Quintero J, Juamperez J, Gonzales E, Julio E, Mercadal-Hally M, Collado-Hilly M, Marín-Sánchez A, Charco R. Successful Treatment with Rituximab and Immunoadsorption for an Auto-Antibody Induced Bile Salt Export Pump Deficiency in a Liver Transplanted Patient. Pediatr Gastroenterol Hepatol Nutr 2020; 23:174-179. [PMID: 32206630 PMCID: PMC7073374 DOI: 10.5223/pghn.2020.23.2.174] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022] Open
Abstract
We present an 8 years old girl who was diagnosed at 6 months of age of Progressive Familial Intrahepatic Cholestasis type 2. Although liver transplantation (LT) was classically considered curative for these patients, cholestasis recurrence with normal gamma-glutamyl transpeptidase (GGT), mediated by anti-bile salt export pump (BSEP) antibodies after LT (auto-antibody Induced BSEP Deficiency, AIBD) has been recently reported. Our patient underwent LT at 14 months. During her evolution, patient presented three episodes of acute rejection. Seven years after the LT, the patient presented pruritus with cholestasis and elevation of liver enzymes with persistent normal GGT. Liver biopsy showed intrahepatic cholestasis and giant-cell transformation with very low BSEP activity. Auto-antibodies against BSEP were detected therefore an AIBD was diagnosed. She was treated with Rituximab and immunoadsorption with resolution of the AIBD. As a complication of the treatment she developed a pneumocystis infection successfully treated with corticoids, cotrimoxazol and anidulafungin.
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Affiliation(s)
- Jesús Quintero
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Javier Juamperez
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Emmanuel Gonzales
- Inserm Unité Mixte de Recherche 1193, Université Paris-Saclay, Orsay France
| | - Ecaterina Julio
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Maria Mercadal-Hally
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | | | - Ana Marín-Sánchez
- Department of Immunology, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Ramon Charco
- Department of HPB Surgery and Trasplant, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
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15
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Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis. Sci Rep 2019; 9:17075. [PMID: 31745229 PMCID: PMC6863819 DOI: 10.1038/s41598-019-53628-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 11/04/2019] [Indexed: 12/11/2022] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0-3.0;P = 0.003) and 2.4-fold (95% CI, 1.7-3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.
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16
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Alloimmunity and Cholestasis After Liver Transplantation in Children With Progressive Familial Intrahepatic Cholestasis. J Pediatr Gastroenterol Nutr 2019; 68:169-174. [PMID: 30664572 DOI: 10.1097/mpg.0000000000002200] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Bile salt export pump (BSEP) deficiency is an important reason for chronic cholestasis leading to liver transplantation (LT) in early childhood. The underlying pathology is a dysfunction of BSEP due to various mutations in the ABCB11 gene. Cases of clinical recurrence after LT due to alloantibodies directed against BSEP (antibody-induced BSEP deficiency [AIBD]) have been reported. Most of these patients could be controlled by intensified immunosuppression. METHODS We here report on 3 children with BSEP-deficiency and end-stage liver disease, which developed AIBD after LT refractory to extensive immunosuppressive and immunomodulatory treatments; retransplantation was necessary in all 3 patients. In 1 patient, a stem cell transplantation was performed successfully. RESULTS AIBD seems to be induced by triggering factors such as initial impaired graft function or infections after LT. CONCLUSIONS The underlying mutation may play a role in this process. Intensifying immunosuppression may be able to control AIBD, but some cases seem to be refractory to treatment and require retransplantation. Stem cell transplantation may provide a new therapeutic option for cases refractory to conservative treatment.
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17
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Brinkert F, Pukite I, Krebs-Schmitt D, Briem-Richter A, Stindt J, Häussinger D, Keitel V, Müller I, Grabhorn E. Allogeneic haematopoietic stem cell transplantation eliminates alloreactive inhibitory antibodies after liver transplantation for bile salt export pump deficiency. J Hepatol 2018; 69:961-965. [PMID: 29935200 DOI: 10.1016/j.jhep.2018.06.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 05/29/2018] [Accepted: 06/05/2018] [Indexed: 12/12/2022]
Abstract
Progressive familial intrahepatic cholestasis 2 is an autosomal-recessive disorder caused by mutations in the ABCB11 gene, which encodes the bile salt export pump (BSEP). Recurrence of BSEP deficiency after liver transplantation is caused by the development of anti-BSEP antibodies. Antibody-induced BSEP deficiency is typically treated by increasing immunosuppressive therapy. We report, in a child, the first case of allogeneic haematopoietic stem cell transplantation for antibody-induced BSEP deficiency that was refractory to intensive pharmacological immunosuppression and immunoadsorption. After haematopoietic stem cell transplantation, anti-BSEP antibodies were cleared from the patient's serum and later from the canalicular space of the liver graft.
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Affiliation(s)
- Florian Brinkert
- University Children's Hospital, Pediatric Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Ieva Pukite
- University Children's Hospital Riga, Riga, Latvia
| | - Dorothee Krebs-Schmitt
- University Children's Hospital, Pediatric Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Briem-Richter
- University Children's Hospital, Pediatric Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
| | - Ingo Müller
- Division for Pediatric Stem Cell Transplantation and Immunology, Clinic for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Enke Grabhorn
- University Children's Hospital, Pediatric Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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18
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Liu Y, Sun LY, Zhu ZJ, Wei L, Qu W, Zeng ZG. Liver Transplantation for Progressive Familial Intrahepatic Cholestasis. Ann Transplant 2018; 23:666-673. [PMID: 30250015 PMCID: PMC6248029 DOI: 10.12659/aot.909941] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that disrupts the genes for bile formation. Liver transplantation (LT) is the only effective treatment for PFIC patients with end-stage liver disease. We describe our experience in terms of clinical characteristics, complications, and outcome of LT for PFIC. CASE REPORT The data of 5 pediatric PFIC patients recipients (3 PFIC1, 1 PFIC2, and 1 PFIC3) who received LT at our Liver Transplant Center from June 2013 to February 2017 were retrospectively analyzed. Four patients received liver transplantation from donation after cardiac death (DCD) donors. One patient received a living donor liver transplantation (LDLT). All the LT recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF). Diarrhea did not improve in 2 PFIC1 patients after LT, and they both developed steatohepatitis several months after LT. The other PFIC1 patient received ABO blood group incompatible LT and developed biliary complications and a severe Epstein-Barr virus infection; this patient underwent endoscopic retrograde cholangiopancreatography. She recovered after treatment with ganciclovir and reduction of tacrolimus dosage. The PFIC2 patient had abnormal liver function 19 months after LT, and recovered after administration of increased dosage of immunosuppressant agents. Liver function in the PFIC3 patient was normal during 2-year follow-up. CONCLUSIONS Liver transplantation is an effective treatment in PFIC patients. However, PFIC1 patients may develop aggravated diarrhea and steatohepatitis after LT. PFIC2 and PFIC3 patients have good outcomes after LT.
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Affiliation(s)
- Ying Liu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland)
| | - Li-Ying Sun
- Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).,Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China (mainland)
| | - Zhi-Jun Zhu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).,Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China (mainland)
| | - Lin Wei
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland)
| | - Wei Qu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland)
| | - Zhi-Gui Zeng
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland)
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19
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Chan KM, Cheng CH, Wu TH, Lee CF, Wu TJ, Chou HS, Lee WC. De Novo Endotoxin-Induced Production of Antibodies against the Bile Salt Export Pump Associated with Bacterial Infection following Major Hepatectomy. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6197152. [PMID: 29850541 PMCID: PMC5937615 DOI: 10.1155/2018/6197152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 02/01/2018] [Accepted: 03/18/2018] [Indexed: 01/25/2023]
Abstract
BACKGROUND Clinically severe infection-related inflammation after major liver resection may cause hyperbilirubinemia. This study aims to clarify the impact of bacterial infection and endotoxins on the hepatobiliary transporter system and to explore possible mechanisms of endotoxin-related postoperative hyperbilirubinemia. METHOD Mice that underwent major hepatectomy with removal of at least 70% of liver volume were exposed to lipopolysaccharide (LPS) at different dosages. Subsequently, hepatobiliary transporter compounds related to bile salt excretion were further investigated. RESULTS The expression of genes related to hepatobiliary transporter compounds was not significantly different in the liver tissue of mice after major hepatectomy and LPS exposure. However, bile salt export pump (BSEP) protein expression within the liver tissue of mice treated with LPS after major hepatectomy was relatively weaker and was even further reduced in the high-dose LPS group. The formation of antibodies against the BSEP in response to endotoxin exposure was also detected. CONCLUSION This study illustrates a possible mechanism whereby the dysfunction of hepatobiliary transporter systems caused by endotoxin-induced autoantibodies may be involved in the development of postoperative jaundice associated with bacterial infection after major hepatectomy.
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Affiliation(s)
- Kun-Ming Chan
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chih-Hsien Cheng
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Tsung-Han Wu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chen-Fang Lee
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ting-Jung Wu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Hong-Shiue Chou
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wei-Chen Lee
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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Cholestasis After Pediatric Liver Transplantation-Recurrence of a Progressive Familial Intrahepatic Cholestasis Phenotype as a Rare Differential Diagnosis: A Case Report. Transplant Proc 2018; 49:1628-1633. [PMID: 28838453 DOI: 10.1016/j.transproceed.2017.06.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 06/16/2017] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Nonobstructive cholestasis after pediatric liver transplantation is a common diagnostic and therapeutic dilemma. We describe a girl with neonatal cholestasis because of progressive familial intrahepatic cholestasis 2 (PFIC-2) and presence of a homozygous splice site mutation in the ABCB11 gene. Liver transplantation was performed because of end-stage liver disease at the age of 6. Cholestasis with normal gamma-glutamyl transferase (GGT) developed 8 years after liver transplantation. A liver biopsy showed canalicular cholestasis and giant cell hepatitis without evidence of rejection, mimicking PFIC-2. Immunofluorescence staining of normal human liver sections with patient's serum revealed reactivity toward a canalicular epitope, which could be identified as bile salt export pump (BSEP) using BSEP-yellow fluorescent protein (YFP) transfected cells. Our patient developed a recurrence of a PFIC-2 phenotype due to production of antibodies against BSEP (alloimmune BSEP disease [AIBD]). Intensification of immunosuppressive therapy as well as antibody treatment with plasmapheresis and Rituximab were initiated, leading to stabilization of the clinical condition and depletion of anti-BSEP antibodies in serum. However, after 1 year liver transplantation was necessary again because of end-stage liver insufficiency. Afterward, immunomodulatory treatment consisted of tacrolimus, mycophenolate mofetil, prednisone, immunoadsorption, and high-dose immunoglobulin therapy (1 g/kg/d). CONCLUSION Cholestasis after liver transplantation may indicate an AIBD with a PFIC-2 phenotype. Besides enhancement of immunosuppressive therapy, an antibody depletion with plasmapheresis, immunoadsorption, immunoglobulins, and B-cell depletion represents a therapeutic option.
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Imagawa K, Hayashi H, Sabu Y, Tanikawa K, Fujishiro J, Kajikawa D, Wada H, Kudo T, Kage M, Kusuhara H, Sumazaki R. Clinical phenotype and molecular analysis of a homozygous ABCB11 mutation responsible for progressive infantile cholestasis. J Hum Genet 2018; 63:569-577. [PMID: 29507376 DOI: 10.1038/s10038-018-0431-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 02/02/2018] [Accepted: 02/07/2018] [Indexed: 01/26/2023]
Abstract
The bile salt export pump (BSEP) plays an important role in biliary secretion. Mutations in ABCB11, the gene encoding BSEP, induce progressive familial intrahepatic cholestasis type 2 (PFIC2), which presents with severe jaundice and liver dysfunction. A less severe phenotype, called benign recurrent intrahepatic cholestasis type 2, is also known. About 200 missense mutations in ABCB11 have been reported. However, the phenotype-genotype correlation has not been clarified. Furthermore, the frequencies of ABCB11 mutations differ between Asian and European populations. We report a patient with PFIC2 carrying a homozygous ABCB11 mutation c.386G>A (p.C129Y) that is most frequently reported in Japan. The pathogenicity of BSEPC129Y has not been investigated. In this study, we performed the molecular analysis of this ABCB11 mutation using cells expressing BSEPC129Y. We found that trafficking of BSEPC129Y to the plasma membrane was impaired and that the expression of BSEPC129Y on the cell surface was significantly lower than that in the control. The amount of bile acids transported via BSEPC129Y was also significantly lower than that via BSEPWT. The transport activity of BSEPC129Y may be conserved because the amount of membrane BSEPC129Y corresponded to the uptake of taurocholate into membrane vesicles. In conclusion, we demonstrated that c.386G>A (p.C129Y) in ABCB11 was a causative mutation correlating with the phenotype of patients with PFIC2, impairment of biliary excretion from hepatocytes, and the absence of canalicular BSEP expression in liver histological assessments. Mutational analysis in ABCB11 could facilitate the elucidation of the molecular mechanisms underlying the development of intrahepatic cholestasis.
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Affiliation(s)
- Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan. .,Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
| | - Yusuke Sabu
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Jun Fujishiro
- Department of Pediatric Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daigo Kajikawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Hiroki Wada
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Toyoichiro Kudo
- Department of Pediatrics, Mito Saiseikai General Hospital, Ibaraki, Japan
| | - Masayoshi Kage
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Ryo Sumazaki
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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23
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Post-transplant Recurrent Bile Salt Export Pump Disease: A Form of Antibody-mediated Graft Dysfunction and Utilization of C4d. J Pediatr Gastroenterol Nutr 2017; 65:364-369. [PMID: 28945205 DOI: 10.1097/mpg.0000000000001653] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Recurrent bile salt export pump (rBSEP) disease has been reported in progressive familial intrahepatic cholestasis type 2 (PFIC2) patients following liver transplantation (LT) and is often refractory to standard anti-cellular rejection immunosuppressants. The mechanism of rBSEP disease is proposed to be a form of type II hypersensitivity reaction with de novo anti-BSEP antibodies blocking the function of allograft BSEP. Utilization of C4d has not been evaluated in rBSEP. We describe a girl with 3 episodes of rBSEP with severe pruritus at 8.9, 10.3, and 11.0 years post-LT, respectively. Patient's serum reacted with normal liver canaliculi by indirect immunofluorescence (IF), whereas patient's liver showed canalicular immunoglobulin G deposition. The histologic features of all 3 liver biopsies recapitulate PFIC2 with cholestatic giant cell hepatitis. Canalicular BSEP expression was not detected in areas of feathery degeneration by immunohistochemistry, but was retained in morphologically normal liver. By direct IF, C4d showed diffuse sinusoidal staining in the third biopsy. Patient responded well to rituximab with or without intravenous immunoglobulin with subsiding symptoms and normalization of serum bile acid levels. In conclusion, rBSEP disease should be considered in the differential diagnosis when evaluating for rejection in a PFIC2 patient post-LT presenting with pruritus. A portion of liver core may be snap frozen in OCT medium for possible direct IF for C4d, that can serve as a surrogate marker for complement activation and antibody-mediated graft dysfunction.
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Generation of a bile salt export pump deficiency model using patient-specific induced pluripotent stem cell-derived hepatocyte-like cells. Sci Rep 2017; 7:41806. [PMID: 28150711 PMCID: PMC5288783 DOI: 10.1038/srep41806] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 11/23/2016] [Indexed: 12/16/2022] Open
Abstract
Bile salt export pump (BSEP) plays an important role in hepatic secretion of bile acids and its deficiency results in severe cholestasis and liver failure. Mutation of the ABCB11 gene encoding BSEP induces BSEP deficiency and progressive familial intrahepatic cholestasis type 2 (PFIC2). Because liver transplantation remains standard treatment for PFIC2, the development of a novel therapeutic option is desired. However, a well reproducible model, which is essential for the new drug development for PFIC2, has not been established. Therefore, we attempted to establish a PFIC2 model by using iPSC technology. Human iPSCs were generated from patients with BSEP-deficiency (BD-iPSC), and were differentiated into hepatocyte-like cells (HLCs). In the BD-iPSC derived HLCs (BD-HLCs), BSEP was not expressed on the cell surface and the biliary excretion capacity was significantly impaired. We also identified a novel mutation in the 5'-untranslated region of the ABCB11 gene that led to aberrant RNA splicing in BD-HLCs. Furthermore, to evaluate the drug efficacy, BD-HLCs were treated with 4-phenylbutyrate (4PBA). The membrane BSEP expression level and the biliary excretion capacity in BD-HLCs were rescued by 4PBA treatment. In summary, we succeeded in establishing a PFIC2 model, which may be useful for its pathophysiological analysis and drug development.
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25
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Lemoine C, Bhardwaj T, Bass LM, Superina RA. Outcomes following partial external biliary diversion in patients with progressive familial intrahepatic cholestasis. J Pediatr Surg 2017; 52:268-272. [PMID: 27916445 DOI: 10.1016/j.jpedsurg.2016.11.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 11/08/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND/PURPOSE PFIC is a family of bile acid (BA) transport disorders that may result in serious liver disease requiring transplantation. We reviewed our experience with PEBD as a method to improve liver function and avoid transplantation. METHODS All patients with PFIC were reviewed. Outcomes included changes in serum BA, conversion to ileal bypass (IB), and survival without transplantation. Statistics were obtained using paired t-test and Wilcoxon test. RESULTS Thirty-five patients with PFIC were identified. Data were available in 24. Twenty-four children (12 males) underwent PEBD: 10 PFIC-1, 13 PFIC-2, and one PFIC-3. BA levels decreased in PFIC-1 patients (1724±3215 to 11±6μmol/L, P=0.03) and in the single PFIC-3 patient (821 to 11.2μmol/L), but not significantly in PFIC-2 patients (193±99 to 141±118μmol/L, P=0.15). Seven patients were converted to IB. There were no significant changes in BA levels following conversion. Five-year transplant-free survival was 100% in PFIC-1 and PFIC-3, but only 38% (5/13) in PFIC-2 (P=0.004). CONCLUSION PEBD is an effective procedure to reduce total BA levels and improve symptoms in PFIC patients. However, it appears to be less efficacious in the PFIC-2 group. The higher BA levels could contribute to ongoing liver damage, and thus a higher transplant rate in PFIC-2 patients. LEVEL OF EVIDENCE Level IV.
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Affiliation(s)
- Caroline Lemoine
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
| | - Tanya Bhardwaj
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
| | - Lee M Bass
- Division of Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
| | - Riccardo A Superina
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA.
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Kubitz R, Dröge C, Kluge S, Stindt J, Stross C, Häussinger D, Flechtenmacher C, Wenning D, Teufel U, Schmitt CP, Engelmann G. High affinity anti-BSEP antibodies after liver transplantation for PFIC-2 - Successful treatment with immunoadsorption and B-cell depletion. Pediatr Transplant 2016; 20:987-993. [PMID: 27368585 DOI: 10.1111/petr.12751] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/06/2016] [Indexed: 01/22/2023]
Abstract
PFIC due to BSEP mutations (PFIC type 2) often necessitates OLT. It has recently been recognized that some PFIC-2 patients develop phenotypic disease recurrence post-OLT due to the appearance of anti-BSEP antibodies. Here, we describe a boy who became cholestatic four yr after OLT during modification of immunosuppression. Canalicular antibody deposits were detected in biopsies of the transplant and antibodies specifically reacting with BSEP were identified at high titers in his serum. These antibodies bound extracellular epitopes of BSEP and inhibited BS transport and were assumed to cause disease recurrence. Consequently, anti-BSEP antibody depletion was pursued by IA and B-cell depletion by anti-CD20 antibodies (rituximab) along with a switch of immunosuppression. This treatment resulted in prolonged relief of symptoms. Depletion of pathogenic anti-BSEP antibodies causing AIBD after OLT in PFIC-2 patients should be considered as a central therapeutic goal.
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Affiliation(s)
- Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Stefanie Kluge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Claudia Stross
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | | | - Daniel Wenning
- Department of General Paediatrics, Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
| | - Ulrike Teufel
- Department of General Paediatrics, Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
| | - Claus Peter Schmitt
- Department of General Paediatrics, Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
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Masahata K, Uehara S, Ibuka S, Nakahata K, Hasegawa Y, Kondou H, Kubitz R, Ueno T. Recurrence of Progressive Familial Intrahepatic Cholestasis Type 2 Phenotype After Living-donor Liver Transplantation: A Case Report. Transplant Proc 2016; 48:3156-3162. [DOI: 10.1016/j.transproceed.2016.02.067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 02/08/2016] [Accepted: 02/24/2016] [Indexed: 10/20/2022]
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28
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Sonthalia N, Jain SS, Pawar VB, Zanwar VG, Surude RG, Rathi PM, Munde KK, Bavdekar S. A Child with Debilitating Pruritus. Clin Pract 2016; 6:865. [PMID: 28028430 PMCID: PMC5136740 DOI: 10.4081/cp.2016.865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/28/2016] [Accepted: 09/22/2016] [Indexed: 11/23/2022] Open
Abstract
We describe a case of two-year-old boy presenting with debilitating pruritus, patchy alopecia and jaundice since the age of 6 months. On evaluation he had intrahepatic cholestasis with persistently raised serum alkaline phosphatase, normal Gamma glutamyl transferase and raised serum bile acid levels. His liver biopsy showed bland cholestasis and electron microscopy showed granular bile suggestive of progressive familial intrahepatic cholestasis type I. Medical therapy with ursodeoxycholic acid, cholestyramine, rifampicin with nutritional modification was successful in alleviating the symptoms and correcting the nutritional status. To our knowledge this is only the sixth case of progressive familial intrahepatic cholestasis type I reported from India. Herein we discuss the diagnostic and therapeutic hurdles that one encounters in managing progressive familial intrahepatic cholestasis and also review the literature regarding this rare disorder.
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Affiliation(s)
- Nikhil Sonthalia
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Samit S Jain
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Vinay B Pawar
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Vinay G Zanwar
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Ravindra G Surude
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Pravin M Rathi
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Kshitij K Munde
- Department of Pediatric Medicine; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Sandeep Bavdekar
- Department of Pediatric Medicine; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
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29
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Agarwal S, Lal BB, Rawat D, Rastogi A, Bharathy KG, Alam S. Progressive Familial Intrahepatic Cholestasis (PFIC) in Indian Children: Clinical Spectrum and Outcome. J Clin Exp Hepatol 2016; 6:203-208. [PMID: 27746616 PMCID: PMC5052402 DOI: 10.1016/j.jceh.2016.05.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/06/2016] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE To study the clinical and laboratory profile of children with progressive familial intrahepatic cholestasis (PFIC) and evaluate their outcome. METHODS The study is a retrospective review of all cases diagnosed with PFIC between January 2011 and July 2015. All children underwent histopathological examination and immunostaining. Management was done as per institute's protocol. RESULTS There were a total of 24 PFIC cases (PFIC 1-2, PFIC 2-19, PFIC 3-3). Eleven presented as neonatal cholestasis, whereas 13 others presented after 6 months of life. Median age of presentation in PFIC 2 was 5.5 months with a time lag of 13 months in diagnosis. PFIC 1 and 2 presented in infancy, whereas PFIC 3 presented late. Familial clustering was seen in 12 of 24 cases. Pruritus resolved with medical management in two-thirds of cases, 3 cases required biliary diversion (BD) with dramatic improvement. One child improved after liver transplantation. CONCLUSIONS PFIC accounts for 8% of neonatal cholestasis and 34% of cholestasis in older children with PFIC 2 being the commonest subtype. Medical therapy is successful in majority. Partial internal BD should be offered to non-cirrhotic low gamma glutamyl transferase PFIC with intractable pruritus. Progression to cirrhosis may be prevented or delayed by early diagnosis and timely intervention.
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Key Words
- BD, biliary diversion
- BSEP, bile salt export pump
- DDLT, deceased donor liver transplantation
- ESLD, end stage liver disease
- GGT, gamma glutamyl transferase
- HE, hepatic encephalopathy
- ICP, intrahepatic cholestasis of pregnancy
- LFT, liver functions test
- LT, liver transplantation
- MDR3, multi drug resistant protein 3
- NCS, neonatal cholestasis syndrome
- PEBD, partial external biliary diversion
- PFIC, progressive familial intrahepatic cholestasis
- PIBD, partial internal biliary diversion
- UDCA, ursodeoxycholic acid
- biliary diversion
- gamma-glutamyl transferase
- immunostaining
- neonatal cholestasis
- pruritus
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Affiliation(s)
- Sajan Agarwal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Dinesh Rawat
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Kishore G.S. Bharathy
- Department of HPB Surgery, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India,Address for correspondence: Seema Alam, Professor & Head, Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India. Tel.: +91 9540951008.Department of Pediatric Hepatology, Institute of Liver and Biliary SciencesNew DelhiIndia
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30
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Oishi K, Arnon R, Wasserstein MP, Diaz GA. Liver transplantation for pediatric inherited metabolic disorders: Considerations for indications, complications, and perioperative management. Pediatr Transplant 2016; 20:756-69. [PMID: 27329540 PMCID: PMC5142218 DOI: 10.1111/petr.12741] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/18/2016] [Indexed: 12/13/2022]
Abstract
LT is an effective therapeutic option for a variety of IEM. This approach can significantly improve the quality of life of patients who suffer from severe disease manifestations and/or life-threatening metabolic decompensations despite medical/dietary management. Due to the significant risks for systemic complications from surgical stressors, careful perioperative management is vital. Even after LT, some disorders require long-term dietary restriction, medical management, and monitoring of metabolites. Successful liver transplant for these complex disorders can be achieved with disease- and patient-specific strategies using a multidisciplinary approach. In this article, we review indications, complications, perioperative management, and long-term follow-up recommendations for IEM that are treatable with LT.
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Affiliation(s)
- Kimihiko Oishi
- Departments of Pediatrics, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Ronen Arnon
- Departments of Pediatrics, Pediatric Gastroenterology and Hepatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, The Recanati / Miller Transplantation Institute, Mount Sinai Medical Center, New York, NY10029
| | - Melissa P. Wasserstein
- Departments of Pediatrics, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - George A. Diaz
- Departments of Pediatrics, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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31
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Mehl A, Bohorquez H, Serrano MS, Galliano G, Reichman TW. Liver transplantation and the management of progressive familial intrahepatic cholestasis in children. World J Transplant 2016; 6:278-290. [PMID: 27358773 PMCID: PMC4919732 DOI: 10.5500/wjt.v6.i2.278] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 02/24/2016] [Accepted: 03/14/2016] [Indexed: 02/05/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile results in progressive liver damage, and if left untreated leads to end stage liver disease and death. Patients often present with worsening jaundice and pruritis within the first few years of life. Many of these patients will progress to end stage liver disease and require liver transplantation. The role and timing of liver transplantation still remains debated especially in the management of PFIC1. In those patients who are appropriately selected, liver transplantation offers an excellent survival benefit. Appropriate timing and selection of patients for liver transplantation will be discussed, and the short and long term management of patients post liver transplantation will also be described.
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32
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Stindt J, Kluge S, Dröge C, Keitel V, Stross C, Baumann U, Brinkert F, Dhawan A, Engelmann G, Ganschow R, Gerner P, Grabhorn E, Knisely AS, Noli KA, Pukite I, Shepherd RW, Ueno T, Schmitt L, Wiek C, Hanenberg H, Häussinger D, Kubitz R. Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency. Hepatology 2016; 63:524-37. [PMID: 26516723 DOI: 10.1002/hep.28311] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 10/27/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody-induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC-2 patients who suffered from phenotypic disease recurrence post-OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G-class BSEP-reactive antibodies in these patients. In all cases, the N-terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C-terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle-based functional assay, transport inhibition by anti-BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG. CONCLUSIONS PFIC-2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post-OLT. The antibody response is polyclonal, targeting both extra- and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis.
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Affiliation(s)
- Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Stefanie Kluge
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Claudia Stross
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Ulrich Baumann
- Pediatric Gastroenterology and Hepatology, Department for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Florian Brinkert
- Pediatric Hepatology and Liver Transplantation, Transplantation Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anil Dhawan
- Pediatric Liver Center, King's College Hospital, London, United Kingdom
| | - Guido Engelmann
- Department of General Pediatrics, Heidelberg University Hospital, Heidelberg, Germany.,Pediatric Clinic, Lukaskrankenhaus GmbH, Neuss, Germany
| | - Rainer Ganschow
- Pediatric Hepatology and Liver Transplantation, Transplantation Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Clinic of General Pediatrics, University Hospital, Bonn, Germany
| | - Patrick Gerner
- Department for Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Clinic for Pediatrics II, University Children's Hospital Essen, University Duisburg-Essen, Essen, Germany.,Children's Hospital, Albert Ludwigs University, Freiburg, Germany
| | - Enke Grabhorn
- Pediatric Hepatology and Liver Transplantation, Transplantation Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - A S Knisely
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Khalid A Noli
- Clinical Laboratory Services Division, Dhahran Health Center, Dhahran, Saudi Arabia
| | - Ieva Pukite
- Latvian Center of Pediatric Gastroenterology/Hepatology, University Children's Hospital, Riga, Latvia
| | - Ross W Shepherd
- Texas Children's Hospital Liver Center, Baylor College of Medicine, Gastroenterology, Houston, TX
| | - Takehisa Ueno
- Pediatric Surgery/Pediatric Liver and GI Transplant, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University, Düsseldorf, Germany
| | - Constanze Wiek
- Department of Otorhinolaryngology (ENT), Heinrich Heine University School of Medicine, Düsseldorf, Germany
| | - Helmut Hanenberg
- Department of Otorhinolaryngology (ENT), Heinrich Heine University School of Medicine, Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.,Medical Clinic I, Bethanien Hospital, Moers, Germany
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Kubitz R, Dröge C, Kluge S, Stross C, Walter N, Keitel V, Häussinger D, Stindt J. Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis. Clin Rev Allergy Immunol 2016; 48:273-84. [PMID: 25342496 DOI: 10.1007/s12016-014-8457-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Severe cholestasis may result in end-stage liver disease with the need of liver transplantation (LTX). In children, about 10 % of LTX are necessary because of cholestatic liver diseases. Apart from bile duct atresia, three types of progressive familial intrahepatic cholestasis (PFIC) are common causes of severe cholestasis in children. The three subtypes of PFIC are defined by the involved genes: PFIC-1, PFIC-2, and PFIC-3 are due to mutations of P-type ATPase ATP8B1 (familial intrahepatic cholestasis 1, FIC1), the ATP binding cassette transporter ABCB11 (bile salt export pump, BSEP), or ABCB4 (multidrug resistance protein 3, MDR3), respectively. All transporters are localized in the canalicular membrane of hepatocytes and together mediate bile salt and phospholipid transport. In some patients with PFIC-2 disease, recurrence has been observed after LTX, which mimics a PFIC phenotype. It could be shown by several groups that inhibitory anti-BSEP antibodies emerge, which most likely cause disease recurrence. The prevalence of severe BSEP mutations (e.g., splice site and premature stop codon mutations) is very high in this group of patients. These mutations often result in the complete absence of BSEP, which likely accounts for an insufficient auto-tolerance against BSEP. Although many aspects of this "new" disease are not fully elucidated, the possibility of anti-BSEP antibody formation has implications for the pre- and posttransplant management of PFIC-2 patients. This review will summarize the current knowledge including diagnosis, pathomechanisms, and management of "autoimmune BSEP disease."
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Affiliation(s)
- Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany,
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Harmancı Ö, Ensaroğlu F, Özçay F, Öcal S, Korkmaz M, Özdemir BH, Selçuk H, Moray G, Haberal M. Late-Onset Drug-Induced Cholestasis in a Living-Related Liver Transplant Donor With Progressive Familial Intrahepatic Cholestasis. EXP CLIN TRANSPLANT 2015; 13 Suppl 3:107-9. [PMID: 26640927 DOI: 10.6002/ect.tdtd2015.p62] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
We present a rare case of progressive familial intrahepatic cholestasis within a family. A 34-yearold female became a living-related liver transplant donor for her son, who had the disease. Nine years after the transplant, the mother developed severe intrahepatic cholestasis, for which she was evaluated after using an oral contraceptive drug. She presented with jaundice, pruritus, and increased bilirubin levels, together with elevated gamma glutamyl transferase and alkaline phosphatase levels. A liver biopsy revealed findings consistent with intrahepatic cholestasis. However, despite follow-up management and cessation of the insulting drug, her total bilirubin count continuously increased to 20 mg/dL and was accompanied by intractable pruritus. A total of 9 plasmapheresis sessions were performed, and she was started on a regimen of ursodeoxycholic acid (13 mg/kg/d) and cholestyramine (4 g, 3 times daily). The clinical and laboratory picture dramatically improved following cessation of the oral contraceptive, plasmapheresis sessions, and drug treatment. The patient's cholestasis normalized within 3 months, and she recovered uneventfully. A genetic analysis of the whole family revealed that both parents were heterozygous for the mutation c.124G>A in ABCB11, and the son was homozygous for this mutation. These findings supported varying degrees of bile salt export pump deficiency in the family members. Defective bile salt excretory system function can result in a wide spectrum of clinical presentations, ranging from progressive familial intrahepatic cholestasis requiring liver transplant to late-onset drug-induced cholestasis. Our findings suggest that, in a heterozygous carrier of a progressive familial intrahepatic cholestasis mutation, drug-induced cholestasis is responsive to treatment, after which the clinical picture can normalize within 3 months.
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Affiliation(s)
- Özgür Harmancı
- From the Department of Gastroenterology, Baskent University Faculty of Medicine, Ankara, Turkey
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Anti-CD20 Monoclonal Antibody Therapy in Functional Bile Salt Export Pump Deficiency After Liver Transplantation. J Pediatr Gastroenterol Nutr 2015; 60:e50-3. [PMID: 24231640 DOI: 10.1097/mpg.0000000000000238] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Kubitz R, Dröge C, Kluge S, Stindt J, Häussinger D. Genetic variations of bile salt transporters. DRUG DISCOVERY TODAY. TECHNOLOGIES 2015; 12:e55-67. [PMID: 25027376 DOI: 10.1016/j.ddtec.2014.03.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Bile salt transporters directly or indirectly influence biological processes through physicochemical or signalling properties of bile salts. The coordinated action of uptake and efflux transporters in polarized epithelial cells of the liver, biliary tree, small intestine and kidney determine bile salt concentrations in different compartments of the body. Genetic variations of bile salt transporters lead to clinical relevant phenotypes of varying severity ranging from a predisposition for drug-induced liver injury to rapidly progressing end-stage liver disease. This review focuses on the impact of genetic variations of bile salt transporters including BSEP, NTCP, ASBT and OSTα/β and discusses approaches for transporter analysis.
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Soroka CJ, Boyer JL. Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations. Mol Aspects Med 2014; 37:3-14. [PMID: 23685087 PMCID: PMC3784619 DOI: 10.1016/j.mam.2013.05.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 04/25/2013] [Accepted: 05/07/2013] [Indexed: 12/17/2022]
Abstract
The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of dietary fats. Mutations in BSEP are associated with cholestatic diseases such as progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy. Development of clinical therapies for these conditions necessitates a clear understanding of the cell biology of biosynthesis, trafficking, and transcriptional and translational regulation of BSEP. This chapter will focus on the molecular and cell biological aspects of this critical hepatic membrane transporter.
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Affiliation(s)
- Carol J Soroka
- Yale University School of Medicine, Department of Internal Medicine, New Haven, CT 06520, United States.
| | - James L Boyer
- Yale University School of Medicine, Department of Internal Medicine, New Haven, CT 06520, United States.
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Agrawal S, Dhiman RK. Hepatobiliary quiz-10 (2014). J Clin Exp Hepatol 2014; 4:184-7. [PMID: 25755558 PMCID: PMC4188822 DOI: 10.1016/j.jceh.2014.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
| | - Radha K. Dhiman
- Address for correspondence. Radha K. Dhiman, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
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Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014; 4:25-36. [PMID: 25755532 PMCID: PMC4017198 DOI: 10.1016/j.jceh.2013.10.005] [Citation(s) in RCA: 179] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 10/31/2013] [Indexed: 12/12/2022] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types-PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.
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Key Words
- ABC, ATP binding cassette
- ASBT, apical sodium bile salt transporter
- ATP, adenosine triphosphate
- ATPase, adenosine triphosphatase
- BRIC, benign recurrent intrahepatic cholestasis
- BSEP, bile salt exporter protein
- CFTR, cystic fibrosis transmembrane conductance regulator
- CYP, cytochrome P
- DNA, deoxyribonucleic acid
- ERAD, endoplasmic reticulum associated degradation
- ESLD, end stage liver disease
- FIC1, familial intrahepatic cholestasis protein 1
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- IB, ileal bypass
- ICP, intrahepatic cholestasis of pregnancy
- LT, liver transplant
- MARS, Molecular Adsorbent Recirculating System
- MDR, multidrug resistance protein
- MRCP, magnetic resonance cholangiopancreaticography
- PBD, partial biliary drainage
- PEBD, partial external biliary drainage
- PFIC, progressive familial intrahepatic cholestasis
- PIBD, partial internal biliary drainage
- PPAR, peroxisome proliferator activator receptor
- UDCA, ursodeoxycholic acid
- bile secretion
- children
- cholestasis
- familial
- mRNA, messenger ribonucleic acid
- pGp, p-glycoprotein
- pruritus
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Affiliation(s)
- Anshu Srivastava
- Address for correspondence: Anshu Srivastava, Associate Professor, Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India. Tel.: +91 522 2495212, +91 9935219497 (mobile); fax: +91 522 2668017.
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Lin HC, Alvarez L, Laroche G, Melin-Aldana H, Pfeifer K, Schwarz K, Whitington PF, Alonso EM, Ekong UD. Rituximab as therapy for the recurrence of bile salt export pump deficiency after liver transplantation. Liver Transpl 2013; 19:1403-10. [PMID: 24115678 DOI: 10.1002/lt.23754] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 09/08/2013] [Indexed: 12/14/2022]
Abstract
Progressive familial intrahepatic cholestasis type 2 (PFIC2) results from recessive mutations in the adenosine triphosphate-binding cassette B11 gene, which encodes for bile salt export pump (BSEP). Liver transplantation (LT) is offered to PFIC2 patients with end-stage liver disease. Reports have described recurrent cholestasis in PFIC2 patients after transplantation, and this has been associated with immunoglobulin G antibodies to BSEP. High-titer anti-BSEP antibodies appear to correlate with episodes of cholestatic graft dysfunction. There is no established paradigm for treating antibody-mediated posttransplant BSEP disease. It appears to be refractory to changes in immunosuppressant medications that would typically be effective in treating allograft rejection. Taking what is known about its pathophysiology, we designed a treatment consisting of rituximab, a chimeric monoclonal anti-CD20 antibody, in combination with intravenous immunoglobulin and plasmapheresis. Using this approach, we report the successful management of 2 patients with antibody-mediated recurrence of PFIC2 after LT.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 11
- ATP-Binding Cassette Transporters/deficiency
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/immunology
- Antibodies/blood
- Antibodies, Monoclonal, Murine-Derived/therapeutic use
- Biopsy
- Cholestasis, Intrahepatic/blood
- Cholestasis, Intrahepatic/diagnosis
- Cholestasis, Intrahepatic/genetics
- Cholestasis, Intrahepatic/immunology
- Cholestasis, Intrahepatic/surgery
- Genetic Predisposition to Disease
- Humans
- Immunoglobulin G/blood
- Immunoglobulins, Intravenous/therapeutic use
- Immunosuppressive Agents/therapeutic use
- Infant
- Liver Transplantation
- Male
- Phenotype
- Plasmapheresis
- Recurrence
- Rituximab
- Time Factors
- Treatment Outcome
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Affiliation(s)
- Henry C Lin
- Departments of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
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Abstract
PURPOSE OF REVIEW There is increasing evidence to suggest that antibody-mediated mechanisms play a role in the pathogenesis of liver allograft rejection. This article will review the pathology of antibody-mediated rejection (AMR) focusing on recent studies which have improved our understanding of the clinicopathological features and diagnostic approaches. RECENT FINDINGS Recent studies have investigated the patterns of immunohistochemical staining for C4d as a tissue marker of AMR in posttransplant biopsies, and have correlated these findings with other histopathological changes and with the presence of donor-specific antibodies (DSAs). These studies have highlighted the diagnostic applications and limitations of C4d immunostaining. They have also emphasized the importance of using strict criteria for defining 'pure' AMR in the liver allograft - that is, graft dysfunction associated with compatible histological findings (typically resembling biliary obstruction), the presence of DSAs and diffusely positive staining for C4d. SUMMARY Pure AMR is relatively uncommon in ABO-compatible grafts - it should be diagnosed on the basis of strict criteria and requires treatment with antibody-depleting immunosuppression. C4d immunostaining in isolation has limited diagnostic value. However, the presence of diffuse C4d immunostaining (involving endothelium or stroma in >50% of portal tracts or sinusoids) suggests a significant component of antibody-mediated graft damage. In a person with suggestive histological features, this finding should prompt testing for DSAs. Even in the absence of typical histological features of AMR, the combined presence of DSAs and diffuse C4d positivity is associated with more frequent or severe acute and chronic rejection, which may also warrant treatment with antibody-depleting immunosuppression.
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The bile salt export pump (BSEP) in health and disease. Clin Res Hepatol Gastroenterol 2012; 36:536-53. [PMID: 22795478 DOI: 10.1016/j.clinre.2012.06.006] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 05/29/2012] [Accepted: 06/06/2012] [Indexed: 02/04/2023]
Abstract
The bile salt export pump (BSEP) is the major transporter for the secretion of bile acids from hepatocytes into bile in humans. Mutations of BSEP are associated with cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 2 (PFIC-2), benign recurrent intrahepatic cholestasis type 2 (BRIC-2) and genetic polymorphisms are linked to intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). Detailed analysis of these diseases has considerably increased our knowledge about physiology and pathophysiology of bile secretion in humans. This review focuses on expression, localization, and function, short- and long-term regulation of BSEP as well as diseases association and treatment options for BSEP-associated diseases.
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Abstract
Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and in ABCB11 encoding bile salt export pump (BSEP) protein, respectively. Defects in ABCB4, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy and specific targeted pharmacotherapy may represent alternative treatments in the future.
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Affiliation(s)
- Emmanuel Jacquemin
- Pediatric Hepatology and Liver Transplantation Unit, and Reference Centre for Rare Liver Diseases, Bicêtre Hospital, AP-HP, 78 rue du général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France.
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What is the long-term outcome of the liver allograft? J Hepatol 2011; 55:702-717. [PMID: 21426919 DOI: 10.1016/j.jhep.2011.03.005] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Revised: 03/11/2011] [Accepted: 03/13/2011] [Indexed: 12/11/2022]
Abstract
With improved long-term survival following liver transplantation (LT), issues relating to the assessment of the liver allograft in long-term survivors are becoming increasingly relevant. Histological abnormalities are commonly present in late post-transplant biopsies, including protocol biopsies from patients who appear to be well with good graft function. Recurrent disease is the commonest recognised cause of abnormal graft histology, but may be modified by the effects of immunosuppression or interactions with other graft complications, resulting in complex or atypical changes. Other abnormalities seen in late post-transplant biopsies include rejection (which often has different appearances to those seen in the post-transplant period), de novo disease, "idiopathic" post-transplant hepatitis (IPTH) and nodular regenerative hyperplasia. In many cases graft dysfunction has more than one cause and liver biopsy may help to identify the predominant cause of graft damage. Problems exist with the terminology used to describe less well understood patterns of graft injury, but there is emerging evidence to suggest that late rejection, de novo autoimmune hepatitis and IPTH may all be part of an overlapping spectrum of immune-mediated injury occurring in the late post-transplant liver allograft. Careful clinico-pathological correlation is very important and the wording of the biopsy report should take into account therapeutic implications, particularly whether changes in immunosuppression may be indicated. This article will provide an overview of the main histological changes occurring in long-term survivors post-LT, focusing on areas where the assessment of late post-transplant biopsies is most relevant clinically.
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Deng YN, Wang LL, Tang Q, Chen XQ, Chen P, Shan QW, Lian SJ, Yun X. Association between BSEP V444A polymorphism and risk of idiopathic neonatal hepatitis/cholestasis. Shijie Huaren Xiaohua Zazhi 2011; 19:38-43. [DOI: 10.11569/wcjd.v19.i1.38] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the association between the V444A polymorphism in the bile salt export pump (BSEP) gene and the risk of idiopathic neonatal hepatitis/cholestasis.
METHODS: Eighty-one infants with idiopathic hepatitis/cholestasis (case group) and 48 healthy infants without intrahepatic cholestasis (control group) were included in this study. The V444A polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
RESULTS: There are three V444A genotypes: AA homozygote, GA heterozygote, and GG homozygote. The frequencies of AA and AG and GG genotypes were 0.6%, 4.9% and 44.4% in the case group and 14.6%, 62.5% and 22.9% in the control group, respectively, with a significant difference between the two groups (P = 0.019). The distribution of GG genotype was significantly different between the two groups (P < 0.05, OR = 2.691, 95%CI: 1.205-6.008). The risk of suffering from idiopathic intrahepatic cholestasis in G allele carriers was 1.951 times higher than that in A allele carriers (OR = 1.951, 95%CI: 1.56-3.291).
CONCLUSION: The G allele of the BSEP V444A G polymorphism may be a risk factor for idiopathic intrahepatic cholestasis in infants.
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