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Mysore KR, Cheng K, Suri LA, Fawaz R, Mavis AM, Kogan-Liberman D, Mohammad S, Taylor SA. Recent advances in the management of pediatric cholestatic liver diseases. J Pediatr Gastroenterol Nutr 2025; 80:549-558. [PMID: 39840645 PMCID: PMC11961318 DOI: 10.1002/jpn3.12462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 12/19/2024] [Accepted: 12/27/2024] [Indexed: 01/23/2025]
Abstract
Pediatric cholestatic liver diseases are rare conditions that can result from multiple specific underlying etiologies. Among the most common etiologies of pediatric cholestatic liver diseases are biliary atresia, Alagille syndrome (ALGS), and inherited disorders of bile acid transport. These diseases are characterized by episodic or chronic unremitting cholestasis. Due to the chronicity of these conditions, it is imperative to optimize medical management to improve patient quality of life, provide nutritional support, and reduce bile acid toxicity in efforts to slow disease progression. Cholestatic liver diseases remain the leading cause of pediatric liver transplantation, as many underlying disease etiologies have no curative medical therapies. In the present review, we provide an update on the nutritional, medical, and surgical management of pediatric cholestatic liver diseases. As recent advances have occurred in the field with the addition of ileal bile acid transporter (IBAT) inhibitors, we also review the results from prospective clinical trials, including their strengths and limitations. While recent clinical trials have demonstrated improved pruritus using IBAT inhibitors in ALGS and progressive familial intrahepatic cholestasis, establishing medical therapies proven to slow disease progression remains an area of unmet need.
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Affiliation(s)
- Krupa R Mysore
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Katherine Cheng
- Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | | | - Rima Fawaz
- Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA
| | - Alisha M Mavis
- Department of Pediatrics, Levine Children's Hospital, Atrium Health, Charlotte, North Carolina, USA
| | - Debora Kogan-Liberman
- Department of Pediatrics, Hassenfeld Children's Hospital at NYU Langone, New York, New York, USA
| | - Saeed Mohammad
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sarah A Taylor
- Department of Pediatrics, Children's Hospital of Colorado, University of Colorado, Aurora, Colorado, USA
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Hof WFJ, de Boer JF, Verkade HJ. Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials. Expert Opin Emerg Drugs 2024; 29:305-320. [PMID: 38571480 DOI: 10.1080/14728214.2024.2336986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/27/2024] [Indexed: 04/05/2024]
Abstract
INTRODUCTION Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients. AREAS COVERED Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors. These compounds aim to reduce the pool size of bile acids by interrupting their enterohepatic circulation. Other emerging treatments in the pipeline include systemic IBAT inhibitors, synthetic bile acid derivatives, compounds targeting bile acid synthesis via the FXR/FGF axis, and chaperones/potentiators that aim to enhance the residual activity of the mutated transporters. EXPERT OPINION Substantial progress has been made in drug development for PFIC patients during the last couple of years. Although data concerning long-term efficacy are as yet only scarcely available, new therapies have demonstrated robust efficacy in a considerable fraction of patients at least on the shorter term. However, a substantial fraction of PFIC patients do not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical need for long-term effective medical, preferably non-surgical, treatment for all PFIC patients.
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Affiliation(s)
- Willemien F J Hof
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Henkjan J Verkade
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
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Koelink PJ, Gómez-Mellado VE, Duijst S, van Roest M, Meisner S, Ho-Mok KS, Frank S, Appelman BS, Bloemendaal LT, Vogel GF, van de Graaf SFJ, Bosma PJ, Oude Elferink RPJ, Wildenberg ME, Paulusma CC. The Phospholipid Flippase ATP8B1 is Involved in the Pathogenesis of Ulcerative Colitis via Establishment of Intestinal Barrier Function. J Crohns Colitis 2024; 18:1134-1146. [PMID: 38366839 PMCID: PMC11302967 DOI: 10.1093/ecco-jcc/jjae024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/30/2024] [Accepted: 02/15/2024] [Indexed: 02/18/2024]
Abstract
AIMS Patients with mutations in ATP8B1 develop progressive familial intrahepatic cholestasis type 1 [PFIC1], a severe liver disease that requires life-saving liver transplantation. PFIC1 patients also present with gastrointestinal problems, including intestinal inflammation and diarrhoea, which are aggravated after liver transplantation. Here we investigate the intestinal function of ATP8B1 in relation to inflammatory bowel diseases. METHODS ATP8B1 expression was investigated in intestinal samples of patients with Crohn's disease [CD] or ulcerative colitis [UC] as well as in murine models of intestinal inflammation. Colitis was induced in ATP8B1-deficient mice with dextran sodium sulphate [DSS] and intestinal permeability was investigated. Epithelial barrier function was assessed in ATP8B1 knockdown Caco2-BBE cells. Co-immunoprecipitation experiments were performed in Caco2-BBE cells overexpressing ATP8B1-eGFP. Expression and localization of ATP8B1 and tight junction proteins were investigated in cells and in biopsies of UC and PFIC1 patients. RESULTS ATP8B1 expression was decreased in UC and DSS-treated mice, and was associated with a decreased tight junctional pathway transcriptional programme. ATP8B1-deficient mice were extremely sensitive to DSS-induced colitis, as evidenced by increased intestinal barrier leakage. ATP8B1 knockdown cells showed delayed barrier establishment that affected Claudin-4 [CLDN4] levels and localization. CLDN4 immunohistochemistry showed a tight junctional staining in control tissue, whereas in UC and intestinal PFIC1 samples, CLDN4 was not properly localized. CONCLUSION ATP8B1 is important in the establishment of the intestinal barrier. Downregulation of ATP8B1 levels in UC, and subsequent altered localization of tight junctional proteins, including CLDN4, might therefore be an important mechanism in UC pathophysiology.
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Affiliation(s)
- Pim J Koelink
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Valentina E Gómez-Mellado
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Suzanne Duijst
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Manon van Roest
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Sander Meisner
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Kam S Ho-Mok
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Sabrina Frank
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Babette S Appelman
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Lysbeth ten Bloemendaal
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Georg F Vogel
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Stan F J van de Graaf
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Piter J Bosma
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald P J Oude Elferink
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Manon E Wildenberg
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Coen C Paulusma
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
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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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Khabou B, Kallabi F, Abdelaziz RB, Maaloul I, Aloulou H, Chehida AB, Kammoun T, Barbu V, Boudawara TS, Fakhfakh F, Khemakhem B, Sahnoun OS. Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low-GGT intrahepatic cholestasis: Genetic diagnosis and genotype-phenotype correlation assessment. Ann Hum Genet 2024; 88:194-211. [PMID: 38108658 DOI: 10.1111/ahg.12542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023]
Abstract
Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel-target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease-causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP-binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide-binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis-associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.
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Affiliation(s)
- Boudour Khabou
- Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia
| | - Fakhri Kallabi
- Molecular and Human Genetics Laboratory, Faculty of Medicine, University of Sfax, Sfax, Tunisia
| | - Rim Ben Abdelaziz
- Department of Pediatrics, Hospital La Rabta, Tunis, Tunisia
- Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Ines Maaloul
- Department of Pediatrics, University Hospital Hedi Chaker, Sfax, Tunisia
| | - Hajer Aloulou
- Department of Pediatrics, University Hospital Hedi Chaker, Sfax, Tunisia
| | | | - Thouraya Kammoun
- Department of Pediatrics, University Hospital Hedi Chaker, Sfax, Tunisia
| | - Veronique Barbu
- LCBGM, Medical Biology and Pathology Department, APHP, HUEP, St Antoine Hospital, Sorbonne University, Paris, France
| | | | - Faiza Fakhfakh
- Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia
| | - Bassem Khemakhem
- Plant Biotechnology Laboratory, Faculty of Sciences, Sfax University, Sfax, Tunisia
| | - Olfa Siala Sahnoun
- Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia
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Wakasa K, Tamura R, Osaka S, Takei H, Asai A, Nittono H, Kusuhara H, Hayashi H. Rapid in vivo evaluation system for cholestasis-related genes in mice with humanized bile acid profiles. Hepatol Commun 2024; 8:e0382. [PMID: 38517206 PMCID: PMC10962888 DOI: 10.1097/hc9.0000000000000382] [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: 07/24/2023] [Accepted: 12/05/2023] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND Pediatric cholestatic liver diseases (Ped-CLD) comprise many ultrarare disorders with a genetic basis. Pharmacologic therapy for severe cases of Ped-CLD has not been established. Species differences in bile acid (BA) metabolism between humans and rodents contribute to the lack of phenocopy of patients with Ped-CLD in rodents and hinder the development of therapeutic strategies. We aimed to establish an efficient in vivo system to understand BA-related pathogenesis, such as Ped-CLD. METHODS We generated mice that express spCas9 specifically in the liver (L-Cas9Tg/Tg [liver-specific Cas9Tg/Tg] mice) and designed recombinant adeno-associated virus serotype 8 encoding small-guide RNA (AAV8 sgRNA) targeting Abcc2, Abcb11, and Cyp2c70. In humans, ABCC2 and ABCB11 deficiencies cause constitutional hyperbilirubinemia and most severe Ped-CLD, respectively. Cyp2c70 encodes an enzyme responsible for the rodent-specific BA profile. Six-week-old L-Cas9Tg/Tg mice were injected with this AAV8 sgRNA and subjected to biochemical and histological analysis. RESULTS Fourteen days after the injection with AAV8 sgRNA targeting Abcc2, L-Cas9Tg/Tg mice exhibited jaundice and phenocopied patients with ABCC2 deficiency. L-Cas9Tg/Tg mice injected with AAV8 sgRNA targeting Abcb11 showed hepatomegaly and cholestasis without histological evidence of liver injury. Compared to Abcb11 alone, simultaneous injection of AAV8 sgRNA for Abcb11 and Cyp2c70 humanized the BA profile and caused higher transaminase levels and parenchymal necrosis, resembling phenotypes with ABCB11 deficiency. CONCLUSIONS This study provides proof of concept for efficient in vivo assessment of cholestasis-related genes in humanized bile acid profiles. Our platform offers a more time- and cost-effective alternative to conventional genetically engineered mice, increasing our understanding of BA-related pathogenesis such as Ped-CLD and expanding the potential for translational research.
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Affiliation(s)
- Kihiro Wakasa
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Ryutaro Tamura
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Shuhei Osaka
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Hajime Takei
- Junshin Clinic Bile Acid Institute, Tokyo, Japan
| | - Akihiro Asai
- Department of Gastroenterology, and Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | | | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
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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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Sutton H, Karpen SJ, Kamath BM. Pediatric Cholestatic Diseases: Common and Unique Pathogenic Mechanisms. ANNUAL REVIEW OF PATHOLOGY 2024; 19:319-344. [PMID: 38265882 DOI: 10.1146/annurev-pathmechdis-031521-025623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2024]
Abstract
Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert. Bile acid (BA) synthesis and excretion, the formation and flow of bile, and the enterohepatic reuptake of BAs all function to maintain the circulation of BAs, a key molecule in lipid digestion, metabolic and cellular signaling, and, as discussed in the review, a crucial mediator in the pathogenesis of cholestasis. Disruption of one or several of these steps can result in the accumulation of toxic BAs in bile ducts and hepatocytes leading to inflammation, fibrosis, and, over time, biliary and hepatic cirrhosis. Biliary atresia, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and Alagille syndrome are four of the most common pediatric cholestatic conditions. Through understanding the commonalities and differences in these diseases, the important cellular mechanistic underpinnings of cholestasis can be greater appreciated.
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Affiliation(s)
- Harry Sutton
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
| | - Saul J Karpen
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Binita M Kamath
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
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McKiernan P, Bernabeu JQ, Girard M, Indolfi G, Lurz E, Trivedi P. Opinion paper on the diagnosis and treatment of progressive familial intrahepatic cholestasis. JHEP Rep 2024; 6:100949. [PMID: 38192535 PMCID: PMC10772241 DOI: 10.1016/j.jhepr.2023.100949] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/10/2023] [Accepted: 10/17/2023] [Indexed: 01/10/2024] Open
Abstract
Background & Aims Progressive familial intrahepatic cholestasis (PFIC) relates to a group of rare, debilitating, liver disorders which typically present in early childhood, but have also been reported in adults. Without early detection and effective treatment, PFIC can result in end-stage liver disease. The aim of the paper was to put forward recommendations that promote standardisation of the management of PFIC in clinical practice. Methods A committee of six specialists came together to discuss the challenges faced by physicians in the management of PFIC. The committee agreed on two key areas where expert guidance is required to optimise care: (1) how to diagnose and treat patients with a clinical presentation of PFIC in the absence of clear genetic test results/whilst awaiting results, and (2) how to monitor disease progression and response to treatment. A systematic literature review was undertaken to contextualise and inform the recommendations. Results An algorithm was developed for the diagnosis and treatment of children with suspected PFIC. The algorithm recommends the use of licensed inhibitors of ileal bile acid transporters as the first-line treatment for patients with PFIC and suggests that genetic testing be used to confirm genotype whilst treatment is initiated in patients in whom PFIC is suspected. The authors recommend referring patients to an experienced centre, and ensuring that monitoring includes measurements of pruritus, serum bile acid levels, growth, and quality of life following diagnosis and during treatment. Conclusions The algorithm presented within this paper offers guidance to optimise the management of paediatric PFIC. The authors hope that these recommendations will help to standardise the management of PFIC in the absence of clear clinical guidelines. Impact and implications This opinion paper outlines a consistent approach to the contemporaneous diagnosis, monitoring, referral and management of children with progressive familial intrahepatic cholestasis. This should assist physicians given the recent developments in genetic diagnosis and the availability of effective drug therapy. This manuscript will also help to raise awareness of current developments and educate health planners on the place for new drug therapies in progressive familial intrahepatic cholestasis.
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Affiliation(s)
- Patrick McKiernan
- Liver Unit and Small Bowel Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Jesus Quintero Bernabeu
- Pediatric Hepatology and Liver Transplant Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Muriel Girard
- Pediatric Hepatology Unit, Hôpital Necker-Enfants Malades, and Université Paris Cité, Paris, France
| | - Giuseppe Indolfi
- Paediatric and Liver Unit, Meyer Children's Hospital IRCCS, Florence, Italy
- Department NEUROFARBA, University of Florence, Florence, Italy
| | - Eberhard Lurz
- Dr. von Hauner Children’s Hospital, LMU Munich University Hospital, Munich, Germany
| | - Palak Trivedi
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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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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Cheng K, Rosenthal P. Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis. Hepatol Commun 2023; 7:e0314. [PMID: 38055640 PMCID: PMC10984671 DOI: 10.1097/hc9.0000000000000314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/12/2023] [Indexed: 12/08/2023] Open
Abstract
Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis.
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Affiliation(s)
- Katherine Cheng
- Department of Pediatrics Gastroenterology, Hepatology and Nutrition, University of California San Francisco, San Francisco, California, USA
| | - Philip Rosenthal
- Department of Pediatrics Gastroenterology, Hepatology and Nutrition, University of California San Francisco, San Francisco, California, USA
- Department of Surgery, University of California, San Francisco, San Francisco, California, USA
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12
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Tamura R, Sabu Y, Mizuno T, Mizuno S, Nakano S, Suzuki M, Abukawa D, Kaji S, Azuma Y, Inui A, Okamoto T, Shimizu S, Fukuda A, Sakamoto S, Kasahara M, Takahashi S, Kusuhara H, Zen Y, Ando T, Hayashi H. Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis. Nat Commun 2023; 14:6763. [PMID: 37990006 PMCID: PMC10663612 DOI: 10.1038/s41467-023-42424-x] [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: 06/09/2023] [Accepted: 10/11/2023] [Indexed: 11/23/2023] Open
Abstract
Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.
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Affiliation(s)
- Ryutaro Tamura
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Yusuke Sabu
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Tadahaya Mizuno
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center and Trans-Border Medical Research Center, University of Tsukuba, Ibaraki, Japan
| | - Satoshi Nakano
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Daiki Abukawa
- Department of Gastroenterology and Hepatology, Miyagi Children's Hospital, Miyagi, Japan
| | - Shunsaku Kaji
- Department of Pediatrics, Tsuyama-Chuo Hospital, Okayama, Japan
| | - Yoshihiro Azuma
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Eastern Hospital, Kanagawa, Japan
| | - Tatsuya Okamoto
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Seiichi Shimizu
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Akinari Fukuda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center and Trans-Border Medical Research Center, University of Tsukuba, Ibaraki, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital & King's College London, London, UK
| | - Tomohiro Ando
- Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.
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13
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Thompson RJ, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, D’Antiga L, Di Giorgio A, Durmaz Ö, Gonzalès E, Grammatikopoulos T, Gupte G, Hardikar W, Houwen RH, Kamath BM, Karpen SJ, Lacaille F, Lachaux A, Lainka E, Loomes KM, Mack CL, Mattsson JP, McKiernan P, Ni Q, Özen H, Rajwal SR, Roquelaure B, Shteyer E, Sokal E, Sokol RJ, Soufi N, Sturm E, Tessier ME, van der Woerd WL, Verkade HJ, Vittorio JM, Wallefors T, Warholic N, Yu Q, Horn P, Kjems L. Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis. JHEP Rep 2023; 5:100782. [PMID: 37456676 PMCID: PMC10338319 DOI: 10.1016/j.jhepr.2023.100782] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 03/28/2023] [Accepted: 04/16/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND & AIMS PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. METHODS PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). RESULTS In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 μmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 μmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. CONCLUSIONS Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. CLINICAL TRIALS REGISTRATION This study is registered at ClinicalTrials.gov (NCT03659916). IMPACT AND IMPLICATIONS Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.
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Affiliation(s)
| | - Reha Artan
- Department of Pediatric Gastroenterology, Akdeniz University, Antalya, Turkey
| | - Ulrich Baumann
- Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
| | - Pier Luigi Calvo
- Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliera-Città della Salute e della Scienza di Torino, Turin, Italy
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disorders, and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Buket Dalgic
- Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Lorenzo D’Antiga
- Pediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Angelo Di Giorgio
- Pediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Özlem Durmaz
- Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Emmanuel Gonzalès
- Hépatologie et Transplantation Hépatique Pédiatriques, Centre de Référence de l’Atrésie des Voies Biliaires et des Cholestases Génétiques, FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Hépatinov, Inserm U 1193, Paris, France
| | - Tassos Grammatikopoulos
- Institute of Liver Studies, King’s College London, London, UK
- Pediatric Liver, GI, and Nutrition Center and MowatLabs, King’s College Hospital NHS Trust, London, UK
| | - Girish Gupte
- Liver Unit and Small Bowel Transplantation, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
| | - Winita Hardikar
- Department of Gastroenterology, Royal Children's Hospital, Melbourne, Australia
| | - Roderick H.J. Houwen
- Department of Pediatric Gastroenterology at the Wilhelmina Children’s Hospital and University Medical Center, Utrecht, The Netherlands
| | - Binita M. Kamath
- Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada
| | - Saul J. Karpen
- Pediatrics Department, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Florence Lacaille
- Pediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France
| | - Alain Lachaux
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service D’hépatogastoentérologie et Nutrition Pédiatrique, Lyon, France
| | - Elke Lainka
- Department of Pediatric Gastroenterology, Hepatology, and Liver Transplantation, University Children’s Hospital, Essen, Germany
| | - Kathleen M. Loomes
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Cara L. Mack
- Pediatric Gastroenterology, Hepatology, & Nutrition, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Patrick McKiernan
- Liver Unit and Small Bowel Transplantation, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
| | | | - Hasan Özen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Sanjay R. Rajwal
- Children’s Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds Children’s Hospital, Leeds, UK
| | | | - Eyal Shteyer
- Faculty of Medicine, Hebrew University of Jerusalem, Juliet Keidan Department of Pediatric Gastroenterology, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Etienne Sokal
- Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium
| | - Ronald J. Sokol
- University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, CO, USA
| | - Nisreen Soufi
- Pediatrics Department, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Ekkehard Sturm
- Pediatric Gastroenterology and Hepatology, University Children’s Hospital Tübingen, Tübingen, Germany
| | - Mary Elizabeth Tessier
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX, USA
| | - Wendy L. van der Woerd
- Department of Pediatric Gastroenterology at the Wilhelmina Children’s Hospital and University Medical Center, Utrecht, The Netherlands
| | - Henkjan J. Verkade
- Department of Pediatrics, University of Groningen, Beatrix Children’s Hospital/University Medical Center Groningen, Groningen, The Netherlands
| | - Jennifer M. Vittorio
- Department of Surgery, Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY, USA
| | | | | | - Qifeng Yu
- Albireo Pharma, Inc., Boston, MA, USA
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14
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Kavallar AM, Messner F, Scheidl S, Oberhuber R, Schneeberger S, Aldrian D, Berchtold V, Sanal M, Entenmann A, Straub S, Gasser A, Janecke AR, Müller T, Vogel GF. Internal Ileal Diversion as Treatment for Progressive Familial Intrahepatic Cholestasis Type 1-Associated Graft Inflammation and Steatosis after Liver Transplantation. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9121964. [PMID: 36553407 PMCID: PMC9777440 DOI: 10.3390/children9121964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Progressive Familial Intrahepatic cholestasis type I (PFIC1) is a rare congenital hepatopathy causing cholestasis with progressive liver disease. Surgical interruption of the enterohepatic circulation, e.g., surgical biliary diversion (SBD) can slow down development of liver cirrhosis. Eventually, end stage liver disease necessitates liver transplantation (LT). PFIC1 patients might develop diarrhea, graft steatosis and inflammation after LT. SBD after LT was shown to be effective in the alleviation of liver steatosis and graft injury. CASE REPORT Three PFIC1 patients received LT at the ages of two, two and a half and five years. Shortly after LT diarrhea and graft steatosis was recognized, SBD to the terminal ileum was opted to prevent risk for ascending cholangitis. After SBD, inflammation and steatosis was found to be reduced to resolved, as seen by liver biochemistry and ultrasounds. Diarrhea was reported unchanged. CONCLUSION We present three PFIC1 cases for whom SBD to the terminal ileum successfully helped to resolve graft inflammation and steatosis.
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Affiliation(s)
- Anna M. Kavallar
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Franka Messner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Stefan Scheidl
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Denise Aldrian
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Valeria Berchtold
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Murat Sanal
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Andreas Entenmann
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Simon Straub
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Anna Gasser
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Andreas R. Janecke
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Institute of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Thomas Müller
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Georg F. Vogel
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Correspondence: ; Tel.: +43-(0)-512-504-23501; Fax: +43-(0)-512-504-23491
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15
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Felzen A, van Wessel DB, Gonzales E, Thompson RJ, Jankowska I, Shneider BL, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipiński P, Czubkowski P, Rock N, Shagrani M, Broering D, Nicastro E, Kelly D, Nebbia G, Arnell H, Fischler B, Hulscher JB, 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, Hartleif S, van der Woerd WJ, Kamath BM, Wang JS, Li L, Durmaz Ö, Kerkar N, Jørgensen MH, Fischer R, Jimenez-Rivera C, Alam S, Cananzi M, Laverdure N, Ferreira CT, Guerrero FO, Wang H, Sency V, Kim KM, Chen HL, de Carvalho E, Fabre A, Bernabeu JQ, Zellos A, Alonso EM, Sokol RJ, Suchy FJ, Loomes KM, McKiernan PJ, Rosenthal P, Turmelle Y, Horslen S, Schwarz K, Bezerra JA, Wang K, Hansen BE, Verkade HJ, the NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. JHEP Rep 2022; 5:100626. [PMID: 36687469 PMCID: PMC9852554 DOI: 10.1016/j.jhepr.2022.100626] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/07/2022] [Accepted: 10/24/2022] [Indexed: 11/17/2022] Open
Abstract
Background & Aims Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.
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Key Words
- ABCB11, ATP-binding cassette, sub-family B member 11
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- BSEP
- BSEP, bile salt export pump
- ChiLDReN, Childhood Liver Disease Research Network
- GGT, gamma-glutamyltransferase
- HCC, hepatocellular carcinoma
- LTx, liver transplantation
- NAPPED, NAtural course and Prognosis of PFIC and Effect of biliary Diversion
- NLS, native liver survival
- PFIC2
- PFIC2, progressive familial intrahepatic cholestasis type 2
- PPTM, predicted protein truncating mutation
- REDCap, Research Electronic Data Capture
- TSB, total serum bilirubin
- UDCA, ursodeoxycholic acid
- compound heterozygosity
- genotype
- interruption of the enterohepatic circulation
- phenotype
- sBAs, serum bile acids
- siEHC, surgical interruption of the enterohepatic circulation
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Affiliation(s)
- Antonia Felzen
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands
| | - Daan B.E. van Wessel
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands
| | - Emmanuel Gonzales
- Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Paris, France,European Reference Network on Hepatological Diseases (ERN RARE-LIVER),INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France
| | | | - Irena Jankowska
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Benjamin L. Shneider
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA,Childhood Liver Disease Research Network (ChiLDReN)
| | - Etienne Sokal
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Gastorenterology and Hepatology, Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium
| | | | | | - Emmanuel Jacquemin
- Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Paris, France,European Reference Network on Hepatological Diseases (ERN RARE-LIVER),INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France
| | - Anne Spraul
- INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France,Service de Biochemie, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris-Saclay, Inserm UMR-S 1174, France
| | - Patryk Lipiński
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Piotr Czubkowski
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Nathalie Rock
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Switzerland
| | - Mohammad Shagrani
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia,Alfaisal University, College of Medicine, Riyadh, Saudi Arabia
| | - Dieter Broering
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Emanuele Nicastro
- Pediatric Hepatology, Gastroenterology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Deirdre Kelly
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom
| | - Gabriella Nebbia
- Servizio Di Epatologia e Nutrizione Pediatrica, Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Henrik Arnell
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Gastroenterology Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Björn Fischler
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Gastroenterology Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Jan B.F. Hulscher
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Daniele Serranti
- Pediatric and Liver Unit, Meyer Children’s University Hospital of Florence, Florence, Italy
| | - Cigdem Arikan
- Koc University School of Medicine, Pediatric GI and Hepatology Liver Transplantation Center, Kuttam System in Liver Medicine, Istanbul, Turkey
| | - Esra Polat
- Pediatric Gastroenterology, Sancaktepe Training and Research Hospital, Istanbul, Turkey
| | - Dominique Debray
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology-Hepatology-Nutrition Unit, APHP-Necker Enfants Malades University Hospital, Paris, France
| | - Florence Lacaille
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology-Hepatology-Nutrition Unit, APHP-Necker Enfants Malades University Hospital, Paris, France
| | - Cristina Goncalves
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Previously Coimbra University Hospital Center, Coimbra, Portugal, Now Pediatric Gastroenterology/Hepatology Center Lisbon, Portugal
| | - Loreto Hierro
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Service of Pediatric Hepatology and Transplantation, Children's Hospital La Paz, La Paz University Hospital, Madrid, Spain
| | - Gema Muñoz Bartolo
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Service of Pediatric Hepatology and Transplantation, Children's Hospital La Paz, La Paz University Hospital, Madrid, Spain
| | - Yael Mozer-Glassberg
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Amer Azaz
- Pediatric Gastroenterology, Hepatology and Nutrition, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | - Jernej Brecelj
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, and Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Antal Dezsőfi
- Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Pier Luigi Calvo
- Pediatic Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città Della Salute e Della Scienza University Hospital, Turin, Italy
| | - Enke Grabhorn
- Pediatric Hepatology and Liver Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Steffen Hartleif
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Gastroenterology and Hepatology, University Children’s Hospital Tυ¨bingen, University Medical Center Tυ¨bingen, Tυ¨bingen, Germany
| | - Wendy J. van der Woerd
- Pediatric Gastroenterology, Hepatology and Nutrition, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Binita M. Kamath
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA,Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
| | - Jian-She Wang
- Children’s Hospital of Fudan University, Shanghai, China
| | - Liting Li
- Children’s Hospital of Fudan University, Shanghai, China
| | - Özlem Durmaz
- Department of Child Health and Diseases, Gastroenterology, Hepatology and Nutrition, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Nanda Kerkar
- Pediatric Gastroenterology, Hepatology and Nutrition, University of Rochester Medical Center, Rochester, NY, USA
| | - Marianne Hørby Jørgensen
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Department of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
| | - Ryan Fischer
- Pediatric Gastroenterology, Hepatology and Nutrition, Children's Mercy Hospital, Kansas City, MO, USA
| | - Carolina Jimenez-Rivera
- Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada
| | - Seema Alam
- Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Mara Cananzi
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women’s and Children’s Health, University Hospital of Padova, Padova, Italy
| | - Noemie Laverdure
- Service de Gastroentérologie, Hépatologie et Nutrition Pédiatriques, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Lyon, France
| | | | - Felipe Ordoñez Guerrero
- Pediatric Gastroenterology and Hepatology, Fundación Cardioinfantil Instituto de Cardiologia, Bogotá, Colombia
| | - Heng Wang
- DDC Clinic - Center for Special Needs Children, Adolescent Medicine and Pediatrics, Middlefield, OH, USA
| | - Valerie Sency
- DDC Clinic - Center for Special Needs Children, Adolescent Medicine and Pediatrics, Middlefield, OH, USA
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, South Korea
| | - Huey-Ling Chen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Elisa de Carvalho
- Pediatric Gastroenterology and Hepatology, Brasília Children's Hospital, Brasilia, Brazil
| | - Alexandre Fabre
- INSERM, MMG, Aix Marseille University, Marseille, France,Service de Pédiatrie Multidisciplinaire, Timone Enfant, Marseille, France
| | - Jesus Quintero Bernabeu
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Hepatology and Liver Transplant Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Aglaia Zellos
- First Department of Pediatrics, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, Greece
| | - Estella M. Alonso
- Childhood Liver Disease Research Network (ChiLDReN),Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA
| | - Ronald J. Sokol
- Childhood Liver Disease Research Network (ChiLDReN),Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | - Frederick J. Suchy
- Childhood Liver Disease Research Network (ChiLDReN),Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | - Kathleen M. Loomes
- Childhood Liver Disease Research Network (ChiLDReN),Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Patrick J. McKiernan
- Childhood Liver Disease Research Network (ChiLDReN),Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Philip Rosenthal
- Childhood Liver Disease Research Network (ChiLDReN),Department of Pediatrics and Surgery, UCSF Benioff Children's Hospital, University of California San Francisco School of Medicine, San Francisco, CA, USA
| | - Yumirle Turmelle
- Childhood Liver Disease Research Network (ChiLDReN),Section of Hepatology, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA
| | - Simon Horslen
- Childhood Liver Disease Research Network (ChiLDReN),Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kathleen Schwarz
- Childhood Liver Disease Research Network (ChiLDReN),Division of Pediatric Gastroenterology, University of California San Diego, Rady Children's Hospital San Diego, CA, USA
| | - Jorge A. Bezerra
- Childhood Liver Disease Research Network (ChiLDReN),Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Kasper Wang
- Childhood Liver Disease Research Network (ChiLDReN),Division of General Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Bettina E. Hansen
- Toronto Center for Liver Disease, University Health Network, Toronto, Canada,IHPME, University of Toronto, Toronto, Canada,Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Henkjan J. Verkade
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands,European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Corresponding author. Address: Pediatric Gastroenterology & Hepatology, Department of Pediatrics, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands. Tel.: +31 50 3614147, fax: +31 50 361 1704
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Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, D'Antiga L, Durmaz Ö, Fischler B, Gonzalès E, Grammatikopoulos T, Gupte G, Hardikar W, Houwen RHJ, Kamath BM, Karpen SJ, Kjems L, Lacaille F, Lachaux A, Lainka E, Mack CL, Mattsson JP, McKiernan P, Özen H, Rajwal SR, Roquelaure B, Shagrani M, Shteyer E, Soufi N, Sturm E, Tessier ME, Verkade HJ, Horn P. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2022; 7:830-842. [PMID: 35780807 DOI: 10.1016/s2468-1253(22)00093-0] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 03/14/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 μg/kg, or odevixibat 120 μg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 μmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 μg/kg per day (n=23), or odevixibat 120 μg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 μg/kg per day group and 52% in the 120 μg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 μg/kg per day group and four in the 120 μg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING Albireo Pharma.
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Affiliation(s)
| | - Henrik Arnell
- Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Reha Artan
- Department of Paediatric Gastroenterology, Akdeniz University, Antalya, Turkey
| | - Ulrich Baumann
- Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
| | - Pier Luigi Calvo
- Paediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Buket Dalgic
- Department of Paediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Lorenzo D'Antiga
- Department of Paediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Özlem Durmaz
- Istanbul University Istanbul Faculty of Medicine, Department of Paediatric Gastroenterology and Hepatology, Istanbul, Turkey
| | - Björn Fischler
- Department of Paediatrics, CLINTEC, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Emmanuel Gonzalès
- Hépatologie et Transplantation Hépatique Pédiatriques, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Hépatinov, Inserm U1193, Paris, France
| | - Tassos Grammatikopoulos
- Institute of Liver Studies, King's College London, London, UK; Paediatric Liver, GI and Nutrition Centre and MowatLabs, King's College Hospital NHS Trust, London, UK
| | - Girish Gupte
- Liver Unit and Small Bowel Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Winita Hardikar
- Department of Gastroenterology, Royal Children's Hospital, Melbourne, VIC, Australia
| | - Roderick H J Houwen
- Department of Paediatric Gastroenterology, Wilhelmina Children's Hospital and University Medical Centre, Utrecht, Netherlands
| | - Binita M Kamath
- Department of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada
| | - Saul J Karpen
- Paediatrics Department, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA
| | | | - Florence Lacaille
- Paediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France
| | - Alain Lachaux
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service D'hépatogastoentérologie et Nutrition Pédiatrique, Lyon, France
| | - Elke Lainka
- Children's Hospital, Department of Paediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany
| | - Cara L Mack
- Paediatrics Department, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | | | - Patrick McKiernan
- Liver Unit and Small Bowel Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Hasan Özen
- Division of Paediatric Gastroenterology, Hepatology, and Nutrition, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Sanjay R Rajwal
- Children's Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK
| | - Bertrand Roquelaure
- APHM, Service de Pédiatrie Multidisciplinaire, Hôpital de la Timone Enfants, Marseille, France
| | - Mohammad Shagrani
- Department of Liver and SB Transplant and Hepatobiliary-Paediatric Surgery, King Faisal Specialist Hospital and Research Centre-Organ Transplant Centre and College Of Medicine-Alfaisal University, Riyadh, Saudi Arabia
| | - Eyal Shteyer
- Faculty of Medicine, Hebrew University of Jerusalem, Juliet Keidan Department of Paediatric Gastroenterology, Shaare Zedek Medical Centre, Jerusalem, Israel
| | - Nisreen Soufi
- Paediatrics Department, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Ekkehard Sturm
- Paediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Mary Elizabeth Tessier
- Department of Paediatrics, Section of Paediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine-Texas Children's Hospital, Houston, TX, USA
| | - Henkjan J Verkade
- Department of Paediatrics, University of Groningen, Beatrix Children's Hospital-University Medical Centre Groningen, Groningen, Netherlands
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Abstract
Bile acid transport is a complex physiologic process, of which disruption at any step can lead to progressive intrahepatic cholestasis (PFIC). The first described PFIC disorders were originally named as such before identification of a genetic cause. However, advances in clinical molecular genetics have led to the identification of additional disorders that can cause these monogenic inherited cholestasis syndromes, and they are now increasingly referred to by the affected protein causing disease. The list of PFIC disorders is expected to grow as more causative genes are discovered. Here forth, we present a comprehensive overview of known PFIC disorders.
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Affiliation(s)
- Sara Hassan
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. https://twitter.com/SaraHassanMD
| | - Paula Hertel
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA.
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18
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Martínez-García J, Molina A, González-Aseguinolaza G, Weber ND, Smerdou C. Gene Therapy for Acquired and Genetic Cholestasis. Biomedicines 2022; 10:biomedicines10061238. [PMID: 35740260 PMCID: PMC9220166 DOI: 10.3390/biomedicines10061238] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 11/16/2022] Open
Abstract
Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.
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Affiliation(s)
- Javier Martínez-García
- Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, 31008 Pamplona, Spain; (J.M.-G.); (A.M.); (G.G.-A.)
| | - Angie Molina
- Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, 31008 Pamplona, Spain; (J.M.-G.); (A.M.); (G.G.-A.)
| | - Gloria González-Aseguinolaza
- Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, 31008 Pamplona, Spain; (J.M.-G.); (A.M.); (G.G.-A.)
- Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain
- Vivet Therapeutics S.L., 31008 Pamplona, Spain
| | - Nicholas D. Weber
- Vivet Therapeutics S.L., 31008 Pamplona, Spain
- Correspondence: (N.D.W.); (C.S.); Tel.: +34-948194700 (N.D.W. & C.S.)
| | - Cristian Smerdou
- Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, 31008 Pamplona, Spain; (J.M.-G.); (A.M.); (G.G.-A.)
- Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain
- Correspondence: (N.D.W.); (C.S.); Tel.: +34-948194700 (N.D.W. & C.S.)
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19
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Öztürk H, Sarı S, Sözen H, Eğritaş Gürkan Ö, Dalgıç B, Dalgıç A. Long-Term Outcomes of Patients With Progressive Familial Intrahepatic Cholestasis After Biliary Diversion. EXP CLIN TRANSPLANT 2022; 20:76-80. [PMID: 35570606 DOI: 10.6002/ect.pediatricsymp2022.o26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Progressive familial intrahepatic cholestasis is a heterogeneous group of genetic disorders characterized by disrupted bile homeostasis. Patients with this disease typically present with cholestasis and pruritus early in life and often progress to end-stage liver disease. The clinical symptoms that patients with progressive familial intrahepatic cholestasis encounter are usually refractory to medical treatment. Although the effects of biliary diversion surgery on native liver survival are not exactly known, this procedure may provide a positive impact on pruritus and laboratory parameters in these patients. MATERIALS AND METHODS We retrospectively evaluated the clinical and laboratory characteristics of patients with progressive familial intrahepatic cholestasis who underwent partial external biliary diversion between 2002 and 2020 at our center. Diagnosis of progressive familial intrahepatic cholestasis was made by clinical, biochemical, and histopathological characteristics as well as genetic testing. RESULTS Nine patients were included in the study. Five patients required liver transplant during follow-up, with 4 having liver transplant as a result of endstage liver disease (median interval of 5 years). In 1 patient, partial external biliary diversion was performed 1.5 years after liver transplant for severe diarrhea, metabolic acidosis, and hepatic steatosis. Four patients did not require liver transplant during follow-up (median follow-up time of 7.6 years). Pruritus responded well to partial external biliary diversion in all patients. Among laboratory values evaluated 6 months after biliary diversion, only albumin showed significant improvement. CONCLUSIONS Partial external biliary diversion had favorable results on long-term follow-up. This procedure can provide the relief of pruritus and delay the requirement for liver transplant in patients with progressive familial intrahepatic cholestasis. In our view, partial external biliary diversion should be considered the first-line surgical management for patients with this disease.
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Affiliation(s)
- Hakan Öztürk
- From the Department of Pediatric Gastroenterology, Gazi University, Ankara, Turkey
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20
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Pfister ED, Dröge C, Liebe R, Stalke A, Buhl N, Ballauff A, Cantz T, Bueltmann E, Stindt J, Luedde T, Baumann U, Keitel V. Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review. Liver Int 2022; 42:1084-1096. [PMID: 35184362 DOI: 10.1111/liv.15200] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity. METHODS We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. RESULTS Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. CONCLUSION The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.
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Affiliation(s)
- Eva-Doreen Pfister
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
| | - Roman Liebe
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Amelie Stalke
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Nicole Buhl
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Antje Ballauff
- Department of Paediatrics, Helios Hospital, Krefeld, Germany
| | - Tobias Cantz
- Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Eva Bueltmann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
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21
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Huang Y, Luo EP, Li M, Yang J, Gan JH, Zhao WF. Two novel ATP8B1 mutations involved in progressive familial intrahepatic cholestasis type 1 that is ameliorated by rifampicin: A case report. J Dig Dis 2022; 23:124-129. [PMID: 34985190 PMCID: PMC9304250 DOI: 10.1111/1751-2980.13078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 11/17/2021] [Accepted: 12/31/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Yan Huang
- Department of Infectious DiseasesFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Er Ping Luo
- Department of Infectious DiseasesFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Min Li
- Department of DermatologyFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Jing Yang
- Department of NephrologyFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Jian He Gan
- Department of Infectious DiseasesFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Wei Feng Zhao
- Department of Infectious DiseasesFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
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22
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Bolia R, Goel AD, Sharma V, Srivastava A. Biliary diversion in progressive familial intrahepatic cholestasis: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2022; 16:163-172. [PMID: 35051344 DOI: 10.1080/17474124.2022.2032660] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Biliary diversion (BD) is indicated in progressive familial intrahepatic cholestasis (PFIC) with refractory pruritus. Three types-partial external biliary drainage (PEBD), partial internal biliary drainage (PIBD), and ileal exclusion (IE) are described, with no consensus about the relative efficacy of these procedures. METHODS PubMed, Scopus, and Google Scholar were searched for publications on PFIC and BD. Improvement in pruritus, serum bile acid (BA), and need for liver transplantation (LT) were compared between the various BD procedures. RESULTS 25 studies [424 children (PEBD-301, PIBD-93, IE-30)] were included. Pruritus resolved in 59.5% [PIBD:72% (95%CI 43-96%), PEBD:57% (95%CI 43-71%) and IE:48% (95%CI 14-82%)] cases. Significant overlap in confidence intervals indicated no significant differences. Absolute decrease in BA (AUROC-0.72) and bilirubin (AUROC-0.69) discriminated responders and non-responders. Eventually, 27% required LT: PIBD 10.7%, PEBD32%, IE 27%. The post-operative BA (AUROC-0.9) and bilirubin (AUROC-0.85) determined need for LT. Complications were commoner in PEBD than PIBD (38% vs 21.8%: p=0.02). CONCLUSION 59.5% children have pruritus relief after BD and 27% need LT. PIBD has lower complications and LT requirement than PEBD. However, this requires cautious interpretation as the 2 groups differed in PFIC type and follow-up duration.
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Affiliation(s)
- Rishi Bolia
- Division of Paediatric Gastroenterology, Department of Paediatrics, All India Institute of Medical Sciences, Rishikesh, India
| | - Akhil Dhanesh Goel
- Department of Community and Family Medicine, All India Institute of Medical Sciences, Jodhpur, India
| | - Vishakha Sharma
- Division of Paediatric Gastroenterology, Department of Paediatrics, All India Institute of Medical Sciences, Rishikesh, India
| | - Anshu Srivastava
- Department of Paediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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23
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Alam S, Lal BB. Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies. World J Hepatol 2022; 14:98-118. [PMID: 35126842 PMCID: PMC8790387 DOI: 10.4254/wjh.v14.i1.98] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/17/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Recent evidence points towards the role of genotype to understand the phenotype, predict the natural course and long term outcome of patients with progressive familial intrahepatic cholestasis (PFIC). Expanded role of the heterozygous transporter defects presenting late needs to be suspected and identified. Treatment of pruritus, nutritional rehabilitation, prevention of fibrosis progression and liver transplantation (LT) in those with end stage liver disease form the crux of the treatment. LT in PFIC has its own unique issues like high rates of intractable diarrhoea, growth failure; steatohepatitis and graft failure in PFIC1 and antibody-mediated bile salt export pump deficiency in PFIC2. Drugs inhibiting apical sodium-dependent bile transporter and adenovirus-associated vector mediated gene therapy hold promise for future.
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Affiliation(s)
- Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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24
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Rodríguez BM, Busoms CM, Sampol LM, Romero RG, Rivero GC, Martín de Carpi J. Heterozygous mutations of ATP8B1, ABCB11 and ABCB4 cause mild forms of Progressive Familial Intrahepatic Cholestasis in a pediatric cohort. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45:585-592. [PMID: 34942279 DOI: 10.1016/j.gastrohep.2021.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 11/29/2021] [Accepted: 12/03/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Heterozygous defects in genes implicated in Progressive Familial Intrahepatic Cholestasis have been described in milder forms of cholestatic diseases. Our aim is to describe clinical, laboratory and imaging characteristics as well as treatment and outcome of a cohort of pediatric patients with heterozygous mutations in ATP8B1, ABCB11 or ABCB4. PATIENTS AND METHODS We present a retrospective descriptive study including pediatric patients with at least one heterozygosis defect in ATP8B1, ABCB11 or ABCB4 diagnosed after a cholestatic episode. Clinical, diagnostic and outcome data were collected including gene analysis (panel of PFIC NextGeneDx®). RESULTS 7 patients showed a heterozygous mutation: 3 patients in ABCB4, 1 in ABCB11, 2 in ABCB4 and ABCB11 and 1 in ATP8B1. The median onset age was 5.5 years with a median time of follow-up of 6 years. The initial presentation was pruritus followed by asymptomatic hypertransaminasemia and persistent cholestasis. Two patients had family history of gallbladder stones and mild hepatitis. All showed elevated transaminases and bile acids, high gamma glutamyl-transferase (GGT) in 3 and conjugated bilirubin in 2 patients. Liver biopsy showed inflammatory infiltrate or mild fibrosis with normal immunohistochemistry. All patients were treated with ursodeoxycholic acid, two patients requiring the addition of resincholestyramine. During follow-up, 3 patients suffered limited relapses of pruritus. No disease progression was observed. CONCLUSION Heterozygous mutations in genes coding proteins of the hepatocellular transport system can cause cholestatic diseases with great phenotypic variability. The presence of repeated episodes of hypertransaminasemia or cholestasis after a trigger should force us to rule out the presence of these heterozygous mutations in genes involved in CIFP.
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Affiliation(s)
- Beatriz Mínguez Rodríguez
- Department of Gastroenterology, Hepatology and Nutrition. Sant Joan de Déu Hospital, Barcelona, Spain.
| | - Cristina Molera Busoms
- Department of Gastroenterology, Hepatology and Nutrition. Sant Joan de Déu Hospital, Barcelona, Spain.
| | | | - Ruth García Romero
- Unit of Paediatric Gastroenterology, Hepatology and Nutrition. Miguel Servet Hospital, Zaragoza, Spain.
| | - Gemma Colomé Rivero
- Department of Paediatric Gastroenterology. Nens Hospital of Barcelona, Barcelona, Spain.
| | - Javier Martín de Carpi
- Department of Gastroenterology, Hepatology and Nutrition. Sant Joan de Déu Hospital, Barcelona, Spain.
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25
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Henkel SAF, Salgado CM, Reyes-Mugica M, Soltys KA, Strauss K, Mazariegos GV, Squires RH, McKiernan PJ, Zhang X, Squires JE. Long-term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience. Pediatr Transplant 2021; 25:e14108. [PMID: 34339082 DOI: 10.1111/petr.14108] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/26/2021] [Accepted: 07/23/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. METHODS We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. RESULTS Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. CONCLUSION We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.
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Affiliation(s)
- Sarah A F Henkel
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Claudia M Salgado
- Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Miguel Reyes-Mugica
- Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kyle A Soltys
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kevin Strauss
- Clinic for Special Children, Strasburg, PA, USA.,Department of Pediatrics, Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA
| | - George V Mazariegos
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Robert H Squires
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Patrick J McKiernan
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Xingyu Zhang
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - James E Squires
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
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26
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Felzen A, Verkade HJ. The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments. Eur J Med Genet 2021; 64:104317. [PMID: 34478903 DOI: 10.1016/j.ejmg.2021.104317] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/11/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023]
Abstract
The Progressive Familial Intrahepatic Cholestasis (PFIC) disease spectrum encompasses a variety of genetic diseases that affect the bile production and the secretion of bile acids. Typically, the first presentation of these diseases is in early childhood, frequently followed by a severe course necessitating liver transplantation before adulthood. Except for transplantation, treatment modalities have been rather limited and frequently only aim at the symptoms of cholestasis, such as cholestatic pruritus. In recent years, progress has been made in understanding the pathophysiology of these diseases and new treatment modalities have been emerging. Herewith we summarize the latest developments in the field and formulate the current key questions and opportunities for further progress.
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Affiliation(s)
- Antonia Felzen
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands
| | - Henkjan J Verkade
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands.
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27
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Baumann U, Sturm E, Lacaille F, Gonzalès E, Arnell H, Fischler B, Jørgensen MH, Thompson RJ, Mattsson JP, Ekelund M, Lindström E, Gillberg PG, Torfgård K, Soni PN. Effects of odevixibat on pruritus and bile acids in children with cholestatic liver disease: Phase 2 study. Clin Res Hepatol Gastroenterol 2021; 45:101751. [PMID: 34182185 DOI: 10.1016/j.clinre.2021.101751] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 05/05/2021] [Accepted: 06/02/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE Ileal bile acid transporter inhibition is a novel therapeutic concept for cholestatic pruritus and cholestatic liver disease progression. Odevixibat, a potent, selective, reversible ileal bile acid transporter inhibitor, decreases enteric bile acid reuptake with minimal systemic exposure. Oral odevixibat safety, tolerability, and efficacy in pediatric patients with cholestatic liver disease and pruritus were evaluated. PATIENTS AND METHODS In this phase 2, open-label, multicenter study, children received 10‒200 μg/kg oral odevixibat daily for 4 weeks. Changes in serum bile acid levels (primary efficacy endpoint), pruritus, and sleep disturbance were explored. RESULTS Twenty patients were enrolled (8 females; 1‒17 years; 4 re-entered at a different dose). Diagnoses included progressive familial intrahepatic cholestasis (n = 13; 3 re-entries), Alagille syndrome (n = 6), biliary atresia (n = 3), and other intrahepatic cholestasis causes (n = 2; 1 re-entry). Mean baseline serum bile acid levels were high (235 µmol/L; range, 26‒564) and were reduced in the majority (-123.1 μmol/L; range, -394 to 14.5, reflecting reductions of up to 98%). Patient-reported diary data documented improved pruritus (3 scales) and sleep. With 100 μg/kg, mean (SEM) decrease was 2.8 (1.1) points for pruritus (visual analogue itch scale 0-10) and 2.9 (0.9) points for sleep disturbance (Patient-Oriented Scoring Atopic Dermatitis scale 0-10). Reduced pruritus correlated significantly with reduced serum bile acids (P ≤ 0.007). Significant correlations were also observed between autotaxin levels and pruritus. All patients completed the study. No serious adverse events were treatment related; most adverse events, including increased transaminases, were transient. CONCLUSIONS Orally administered odevixibat was well tolerated, reduced serum bile acids, and improved pruritus and sleep disturbance in children with cholestatic diseases.
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Affiliation(s)
- Ulrich Baumann
- Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
| | - Ekkehard Sturm
- Pediatric Gastroenterology and Hepatology, University Children's Hospital Tuebingen, Tuebingen, Germany
| | - Florence Lacaille
- Pediatric Gastroenterology-Hepatology-Nutrition, Necker-Enfants Malades Hospital, Paris, France
| | - Emmanuel Gonzalès
- Hépatologie et Transplantation Hépatique Pédiatriques, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Hépatinov, Inserm U 1193, Paris, France
| | - Henrik Arnell
- Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Womens and Childrens Health, Karolinska Institutet, Stockholm, Sweden
| | - Björn Fischler
- Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Womens and Childrens Health, Karolinska Institutet, Stockholm, Sweden
| | | | - Richard J Thompson
- Institute of Liver Studies, King's College London, London, United Kingdom
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28
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Bjørnland K, Hukkinen M, Gatzinsky V, Arnell H, Pakarinen MP, Almaas R, Svensson JF. Partial Biliary Diversion May Promote Long-Term Relief of Pruritus and Native Liver Survival in Children with Cholestatic Liver Diseases. Eur J Pediatr Surg 2021; 31:341-346. [PMID: 32707578 DOI: 10.1055/s-0040-1714657] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Rare cholestatic liver diseases may cause debilitating pruritus in children. Partial biliary diversion (PBD) may relieve pruritus and postpone liver transplantation which is the only other alternative when conservative treatment fails. The aim was to report long-term outcome after PBD in a population of 26 million people during a 25-year period. MATERIALS AND METHODS This is an international, multicenter retrospective study reviewing medical journals. Complications were graded according to the Clavien-Dindo classification system. RESULTS Thirty-three patients, 14 males, underwent PBD at a median of 1.5 (0.3-13) years at four Nordic pediatric surgical centers. Progressive familial intrahepatic cholestasis was the most common underlying condition. Initially, all patients got external diversion, either cholecystojejunostomy (25 patients) or button placed in the gallbladder or a jejunal conduit. Early complications occurred in 14 (42%) patients, of which 3 were Clavien-Dindo grade 3. Long-term stoma-related complications were common (55%). Twenty secondary surgeries were performed due to stoma problems such as prolapse, stricture, and bleeding, or conversion to another form of PBD. Thirteen children have undergone liver transplantation, and two are listed for transplantation due to inefficient effect of PBD on pruritus. Serum levels of bile acids in the first week after PBD construction were significantly lower in patients with good relief of pruritus than in those with poor effect (13 [2-192] vs. 148 [5-383] μmol/L; p = 0.02). CONCLUSION PBD may ensure long-term satisfactory effect on intolerable pruritus and native liver survival in children with cholestatic liver disease. However, stoma-related problems and reoperations are common.
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Affiliation(s)
- Kristin Bjørnland
- Section of Pediatric Surgery, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway
| | - Maria Hukkinen
- Department of Pediatric Surgery, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
| | - Vladimir Gatzinsky
- Department of Pediatric Surgery, The Queen Silvia Children's Hospital, Gothenburg, Sweden
| | - Henrik Arnell
- Department of Pediatrics, Astrid Lindgren Children's Hospital, Stockholm, Sweden
| | - Mikko P Pakarinen
- Department of Pediatric Surgery, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
| | - Runar Almaas
- Department of Pediatrics, Oslo universitetssykehus, Rikshospitalet, University of Oslo, Oslo, Norway
| | - Jan F Svensson
- Department of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden
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29
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Hertel PM, Bull LN, Thompson RJ, Goodrich NP, Ye W, Magee JC, Squires RH, Bass LM, Heubi JE, Kim GE, Ranganathan S, Schwarz KB, Bozic MA, Horslen SP, Clifton MS, Turmelle YP, Suchy FJ, Superina RA, Wang KS, Loomes KM, Kamath BM, Sokol RJ, Shneider BL, Childhood Liver Disease Research Network (ChiLDReN). Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis. J Pediatr Gastroenterol Nutr 2021; 73:169-177. [PMID: 34016879 PMCID: PMC8373673 DOI: 10.1097/mpg.0000000000003153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVES To advance our understanding of monogenic forms of intrahepatic cholestasis. METHODS Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. RESULTS Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. CONCLUSIONS In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.
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Affiliation(s)
- Paula M. Hertel
- Texas Children’s Hospital, Baylor College of Medicine, Houston TX
| | - Laura N. Bull
- University of California, San Francisco, San Francisco CA
| | | | | | - Wen Ye
- University of Michigan Hospitals and Health Centers, Ann Arbor MI
| | - John C. Magee
- University of Michigan Hospitals and Health Centers, Ann Arbor MI
| | | | - Lee M. Bass
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago IL
| | - James E. Heubi
- Cincinnati Children’s Hospital Medical Center, Cincinnati OH
| | - Grace E. Kim
- University of California, San Francisco, San Francisco CA
| | | | | | - Molly A. Bozic
- Indiana University-Riley Hospital for Children, Indianapolis IN
| | | | | | | | - Frederick J. Suchy
- University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora CO
| | | | - Kasper S. Wang
- Children’s Hospital Los Angeles, University of Southern California, Los Angeles CA
| | | | | | - Ronald J. Sokol
- University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora CO
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30
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van Wessel DB, Thompson RJ, Gonzales E, Jankowska I, Shneider BL, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipiński P, Czubkowski P, Rock N, Shagrani M, Broering D, Algoufi T, Mazhar N, Nicastro E, Kelly D, Nebbia G, Arnell H, Fischler B, Hulscher JB, Serranti D, Arikan C, Debray D, Lacaille F, Goncalves C, Hierro L, Muñoz Bartolo G, Mozer‐Glassberg Y, Azaz A, Brecelj J, Dezsőfi A, Luigi Calvo P, Krebs‐Schmitt D, Hartleif S, van der Woerd WL, Wang J, Li L, Durmaz Ö, Kerkar N, Hørby Jørgensen M, Fischer R, Jimenez‐Rivera C, Alam S, Cananzi M, Laverdure N, Targa Ferreira C, Ordonez F, Wang H, Sency V, Mo Kim K, Chen H, Carvalho E, Fabre A, Quintero Bernabeu J, Alonso EM, Sokol RJ, Suchy FJ, Loomes KM, McKiernan PJ, Rosenthal P, Turmelle Y, Rao GS, Horslen S, Kamath BM, Rogalidou M, Karnsakul WW, Hansen B, Verkade HJ, Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium. Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency. Hepatology 2021; 74:892-906. [PMID: 33666275 PMCID: PMC8456904 DOI: 10.1002/hep.31787] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 01/17/2021] [Accepted: 01/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 μmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.
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Affiliation(s)
- Daan B.E. van Wessel
- Pediatric Gastroenterology and HepatologyUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | | | - Emmanuel Gonzales
- Pediatric Hepatology & Pediatric Liver Transplant DepartmentCentre de Référence de l’Atrésie des Voies Biliaires et des Cholestases GénétiquesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAssistance Publique‐Hôpitaux de ParisFaculté de Médecine Paris‐SaclayCHU BicêtreParisFrance
- European Reference Network on Hepatological Diseases
| | - Irena Jankowska
- European Reference Network on Hepatological Diseases
- Gastroenterology, Hepatology, Nutritional Disorders and Pediatricsthe Children’s Memorial Health InstituteWarsawPoland
| | - Benjamin L. Shneider
- Division of Pediatric Gastroenterology, Hepatology, and NutritionDepartment of PediatricsBaylor College of MedicineHoustonTXUSA
- Childhood Liver Disease Research Network (ChiLDReN)
| | - Etienne Sokal
- European Reference Network on Hepatological Diseases
- Cliniques St. LucUniversité Catholique de LouvainBrusselsBelgium
| | | | | | - Emmanuel Jacquemin
- Pediatric Hepatology & Pediatric Liver Transplant DepartmentCentre de Référence de l’Atrésie des Voies Biliaires et des Cholestases GénétiquesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAssistance Publique‐Hôpitaux de ParisFaculté de Médecine Paris‐SaclayCHU BicêtreParisFrance
- INSERMUMR‐S 1193Université Paris‐SaclayOrsayFrance
| | - Anne Spraul
- INSERMUMR‐S 1193Université Paris‐SaclayOrsayFrance
- Biochemistry UnitCentre de Référence de l’Atrésie des Voies Biliaires et des Cholestases GénétiquesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAssistance Publique‐Hôpitaux de ParisFaculté de Médecine Paris‐SaclayCHU BicêtreParisFrance
| | - Patryk Lipiński
- European Reference Network on Hepatological Diseases
- Gastroenterology, Hepatology, Nutritional Disorders and Pediatricsthe Children’s Memorial Health InstituteWarsawPoland
| | - Piotr Czubkowski
- European Reference Network on Hepatological Diseases
- Gastroenterology, Hepatology, Nutritional Disorders and Pediatricsthe Children’s Memorial Health InstituteWarsawPoland
| | - Nathalie Rock
- Cliniques St. LucUniversité Catholique de LouvainBrusselsBelgium
| | - Mohammad Shagrani
- Department of Liver & SB Transplant & Hepatobiliary‐Pancreatic SurgeryKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
- College of MedicineAlfaisal UniversityRiyadhSaudi Arabia
| | - Dieter Broering
- Department of Liver & SB Transplant & Hepatobiliary‐Pancreatic SurgeryKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
| | - Talal Algoufi
- Department of Liver & SB Transplant & Hepatobiliary‐Pancreatic SurgeryKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
| | - Nejat Mazhar
- Department of Liver & SB Transplant & Hepatobiliary‐Pancreatic SurgeryKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
| | - Emanuele Nicastro
- Pediatric Hepatology, Gastroenterology and TransplantationOspedale Papa Giovanni XXIIIBergamoItaly
| | - Deirdre Kelly
- European Reference Network on Hepatological Diseases
- Liver UnitBirmingham Women’s and Children’s HospitalUniversity of BirminghamBirminghamUnited Kingdom
| | - Gabriella Nebbia
- Servizio Di Epatologia e Nutrizione PediatricaFondazione Irccs Ca’ Granda Ospedale Maggiore PoliclinicoMilanoItaly
| | - Henrik Arnell
- European Reference Network on Hepatological Diseases
- Pediatric Digestive DiseasesAstrid Lindgren Children’s HospitalCLINTECKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | - Björn Fischler
- European Reference Network on Hepatological Diseases
- Pediatric Digestive DiseasesAstrid Lindgren Children’s HospitalCLINTECKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | - Jan B.F. Hulscher
- European Reference Network on Hepatological Diseases
- Pediatric SurgeryUniversity Medical Center GroningenGroningenthe Netherlands
| | - Daniele Serranti
- Pediatric and Liver UnitMeyer Children’s University Hospital of FlorenceFlorenceItaly
| | - Cigdem Arikan
- Pediatric GI and Hepatology Liver Transplantation CenterKuttam System in Liver MedicineKoc University School of MedicineIstanbulTurkey
| | - Dominique Debray
- Pediatric Hepatology unit, Reference Center for Biliary Atresia and Genetic Cholestatic DiseasesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAPHP‐Neckler Enfants Malades University HospitalFaculté de Médecine Paris‐CentreParisFrance
| | - Florence Lacaille
- Pediatric Hepatology unit, Reference Center for Biliary Atresia and Genetic Cholestatic DiseasesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAPHP‐Neckler Enfants Malades University HospitalFaculté de Médecine Paris‐CentreParisFrance
| | - Cristina Goncalves
- European Reference Network on Hepatological Diseases
- Coimbra University Hospital CenterCoimbraPortugal
| | - Loreto Hierro
- European Reference Network on Hepatological Diseases
- Pediatric Liver ServiceLa Paz University HospitalMadridSpain
| | - Gema Muñoz Bartolo
- European Reference Network on Hepatological Diseases
- Pediatric Liver ServiceLa Paz University HospitalMadridSpain
| | - Yael Mozer‐Glassberg
- Institute of Gastroenterology, Nutrition and Liver DiseasesSchneider Children’s Medical Center of IsraelPetach TikvahIsrael
| | - Amer Azaz
- Sheikh Khalifa Medical CityAbu DhabiUnited Arab Emirates
| | - Jernej Brecelj
- Department of Gastroenterology, Hepatology and NutritionUniversity Children’s Hospital LjubljanaLjubljanaSlovenia
- Department of PediatricsFaculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
| | - Antal Dezsőfi
- First Department of PediatricsSemmelweis UniversityBudapestHungary
| | - Pier Luigi Calvo
- Pediatic Gastroenterology UnitRegina Margherita Children’s HospitalAzienda Ospedaliera Città Della Salute e Della Scienza University HospitalTorinoItaly
| | | | - Steffen Hartleif
- European Reference Network on Hepatological Diseases
- University Children’s Hospital TϋbingenTϋbingenGermany
| | - Wendy L. van der Woerd
- Pediatric Gastroenterology, Hepatology and NutritionWilhelmina Children’s HospitalUniversity Medical Center UtrechtUtrechtthe Netherlands
| | - Jian‐She Wang
- Children’s Hospital of Fudan UniversityShanghaiChina
| | - Li‐ting Li
- Children’s Hospital of Fudan UniversityShanghaiChina
| | - Özlem Durmaz
- Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey
| | - Nanda Kerkar
- Pediatric Gastroenterology, Hepatology and NutritionUniversity of Rochester Medical CenterRochesterNYUSA
| | - Marianne Hørby Jørgensen
- European Reference Network on Hepatological Diseases
- Pediatric and Adolescent DepartmentDepartment of Pediatrics and Adolescent MedicineRigshospitalet Copenhagen University HospitalCopenhagenDenmark
| | - Ryan Fischer
- Section of Hepatology and Transplant MedicineChildren’s Mercy HospitalKansas CityMOUSA
| | - Carolina Jimenez‐Rivera
- Department of PediatricsChildren’s Hospital of Eastern OntarioUniversity of OttawaOttawaCanada
| | - Seema Alam
- Pediatric HepatologyInstitute of Liver and Biliary SciencesNew DelhiIndia
| | - Mara Cananzi
- European Reference Network on Hepatological Diseases
- Pediatric Gastroenterology and HepatologyUniversity Hospital of PadovaPadovaItaly
| | - Noémie Laverdure
- European Reference Network on Hepatological Diseases
- Service de Gastroentérologie, Hépatologie et Nutrition PédiatriquesHospices Civils de LyonHôpital Femme Mère EnfantLyonFrance
| | | | - Felipe Ordonez
- Fundación Cardioinfantil Instituto de CardiologiaPediatric Gastroenterology and HepatologyBogotáColombia
| | - Heng Wang
- DDC Clinic Center for Special Needs ChildrenMiddlefieldOHUSA
| | - Valerie Sency
- DDC Clinic Center for Special Needs ChildrenMiddlefieldOHUSA
| | - Kyung Mo Kim
- Department of PediatricsAsan Medical Center Children’s HospitalSeoulSouth Korea
| | - Huey‐Ling Chen
- Division of Pediatric Gastroenterology, Hepatology and NutritionNational Taiwan University Children’s HospitalTaipeiTaiwan
| | - Elisa Carvalho
- Pediatric Gastroenterology and HepatologyBrasília Children’s HospitalBrasiliaBrazil
| | - Alexandre Fabre
- INSERMMMGAix Marseille UniversityMarseilleFrance
- Serveice de Pédiatrie MultidisciplinaireTimone EnfantMarseilleFrance
| | - Jesus Quintero Bernabeu
- European Reference Network on Hepatological Diseases
- Pediatric Hepatology and Liver Transplant UnitBarcelonaSpain
| | - Estella M. Alonso
- Childhood Liver Disease Research Network (ChiLDReN)
- Division of Pediatric Gastroenterology, Hepatology and NutritionAnn & Robert H. Lurie Children’s HospitalChicagoILUSA
| | - Ronald J. Sokol
- Childhood Liver Disease Research Network (ChiLDReN)
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsChildren’s Hospital ColoradoUniversity of Colorado School of MedicineAuroraCOUSA
| | - Frederick J. Suchy
- Childhood Liver Disease Research Network (ChiLDReN)
- Icahn School of Medicine at Mount SinaiMount Sinai Kravis Children’s HospitalNew YorkNYUSA
| | - Kathleen M. Loomes
- Childhood Liver Disease Research Network (ChiLDReN)
- Division of Gastroenterology, Hepatology and NutritionChildren’s Hospital of PhiladelphiaPhiladelphiaPAUSA
| | - Patrick J. McKiernan
- Childhood Liver Disease Research Network (ChiLDReN)
- Department of Pediatric Gastroenterology and HepatologyUniversity of Pittsburgh Medical Center Children’s Hospital of PittsburghPittsburghPAUSA
| | - Philip Rosenthal
- Childhood Liver Disease Research Network (ChiLDReN)
- Department of Pediatrics and SurgeryUCSF Benioff Children’s HospitalUniversity of California San Francisco School of MedicineSan FranciscoCAUSA
| | - Yumirle Turmelle
- Childhood Liver Disease Research Network (ChiLDReN)
- Section of HepatologyDepartment of PediatricsSt. Louis Children’s HospitalWashington University School of MedicineSt. LouisMOUSA
| | - Girish S. Rao
- Childhood Liver Disease Research Network (ChiLDReN)
- Riley Hospital for ChildrenIndiana University School of MedicineIndianapolisINUSA
| | - Simon Horslen
- Childhood Liver Disease Research Network (ChiLDReN)
- Department of PediatricsSeattle Children’s HospitalUniversity of WashingtonSeattleWAUSA
| | - Binita M. Kamath
- Childhood Liver Disease Research Network (ChiLDReN)
- The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
| | - Maria Rogalidou
- Division of Pediatric Gastroenterology & HepatologyFirst Pediatrics DepartmentUniversity of AthensAgia Sofia Children’s HospitalAthensGreece
| | - Wikrom W. Karnsakul
- Division of Pediatric Gastroenterology, Nutrition, and HepatologyDepartment of PediatricsJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Bettina Hansen
- Toronto Center for Liver DiseaseUniversity Health NetworkTorontoCanada
- IHPMEUniversity of TorontoTorontoCanada
| | - Henkjan J. Verkade
- Pediatric Gastroenterology and HepatologyUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
- European Reference Network on Hepatological Diseases
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Jankowska I, Pawłowska J, Szymczak M, Ismail H, Broniszczak D, Cielecka-Kuszyk J, Socha P, Jarzębicka D, Czubkowski P. A Report of 2 Infant Siblings with Progressive Intrahepatic Familial Cholestasis Type 1 and a Novel Homozygous Mutation in the ATP8B1 Gene Treated with Partial External Biliary Diversion and Liver Transplant. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e932374. [PMID: 34283821 PMCID: PMC8311386 DOI: 10.12659/ajcr.932374] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Case series Patients: Male • Male / (siblings) Final Diagnosis: Progressive intrahepatic familial cholestasis type 1 (PFIC-1) Symptoms: Jaundice Medication: — Clinical Procedure: — Specialty: Transplantology
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Affiliation(s)
- Irena Jankowska
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Joanna Pawłowska
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Marek Szymczak
- Department of Pediatric Surgery and Organ Transplantation, The Children's Memorial Health Institute, Warsaw, Poland
| | - Hor Ismail
- Department of Pediatric Surgery and Organ Transplantation, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dorota Broniszczak
- Department of Pediatric Surgery and Organ Transplantation, The Children's Memorial Health Institute, Warsaw, Poland
| | | | - Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dorota Jarzębicka
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
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Epidemiology and burden of progressive familial intrahepatic cholestasis: a systematic review. Orphanet J Rare Dis 2021; 16:255. [PMID: 34082807 PMCID: PMC8173883 DOI: 10.1186/s13023-021-01884-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 05/21/2021] [Indexed: 02/08/2023] Open
Abstract
Background Progressive familial intrahepatic cholestasis is a rare, heterogeneous group of liver disorders of autosomal recessive inheritance, characterised by an early onset of cholestasis with pruritus and malabsorption, which rapidly progresses, eventually culminating in liver failure. For children and their parents, PFIC is an extremely distressing disease. Significant pruritus can lead to severe cutaneous mutilation and may affect many activities of daily living through loss of sleep, irritability, poor attention, and impaired school performance. Methods Databases including MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Results Three systematic reviews and twenty-two studies were eligible for inclusion for the epidemiology of PFIC including a total of 2603 patients. Study periods ranged from 3 to 33 years. Local population prevalence of PFIC was reported in three studies, ranging from 9.0 to 12.0% of children admitted with cholestasis, acute liver failure, or splenomegaly. The most detailed data come from the NAPPED study where native liver survival of >15 years is predicted in PFIC2 patients with a serum bile acid concentration below 102 µmol/L following bile diversion surgery. Burden of disease was mainly reported through health-related quality of life (HRQL), rates of surgery and survival. Rates of biliary diversion and liver transplant varied widely depending on study period, sample size and PFIC type, with many patients have multiple surgeries and progressing to liver transplant. This renders data unsuitable for comparison. Conclusion Using robust and transparent methods, this systematic review summarises our current knowledge of PFIC. The epidemiological overview is highly mixed and dependent on presentation and PFIC subtype. Only two studies reported HRQL and mortality results were variable across different subtypes. Lack of data and extensive heterogeneity severely limit understanding across this disease area, particularly variation around and within subtypes. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-01884-4.
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Liver Steatosis and Diarrhea After Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Type 1: Can Biliary Diversion Solve These Problems? J Pediatr Gastroenterol Nutr 2021; 72:341-342. [PMID: 33230072 DOI: 10.1097/mpg.0000000000002990] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Bosma PJ, Wits M, Oude-Elferink RPJ. Gene Therapy for Progressive Familial Intrahepatic Cholestasis: Current Progress and Future Prospects. Int J Mol Sci 2020; 22:E273. [PMID: 33383947 PMCID: PMC7796371 DOI: 10.3390/ijms22010273] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/24/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Progressive Familial Intrahepatic Cholestasis (PFIC) are inherited severe liver disorders presenting early in life, with high serum bile salt and bilirubin levels. Six types have been reported, two of these are caused by deficiency of an ABC transporter; ABCB11 (bile salt export pump) in type 2; ABCB4 (phosphatidylcholine floppase) in type 3. In addition, ABCB11 function is affected in 3 other types of PFIC. A lack of effective treatment makes a liver transplantation necessary in most patients. In view of long-term adverse effects, for instance due to life-long immune suppression needed to prevent organ rejection, gene therapy could be a preferable approach, as supported by proof of concept in animal models for PFIC3. This review discusses the feasibility of gene therapy as an alternative for liver transplantation for all forms of PFIC based on their pathological mechanism. Conclusion: Using presently available gene therapy vectors, major hurdles need to be overcome to make gene therapy for all types of PFIC a reality.
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Affiliation(s)
- Piter J. Bosma
- Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AGEM, Amsterdam UMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (M.W.); (R.P.J.O.-E.)
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Nasobiliary drainage prior to surgical biliary diversion in progressive familial intrahepatic cholestasis type II. Eur J Pediatr 2020; 179:1547-1552. [PMID: 32291498 DOI: 10.1007/s00431-020-03646-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 03/18/2020] [Accepted: 03/27/2020] [Indexed: 12/12/2022]
Abstract
Progressive familial intrahepatic cholestasis (PFIC) can cause intense pruritus that is refractory to medical therapy. Surgical biliary diversion techniques, including partial internal biliary diversion (PIBD), have been developed over the years to relieve pruritus without requiring liver transplantation. No clinical or genetic features can currently predict postoperative pruritus response. We present three PFIC type 2 (PIFC 2) patients who underwent transient endoscopic nasobiliary drainage (NBD) prior to PIBD surgery. Two patients repeatedly responded to NBD and presented with complete pruritus resolution after subsequent PIBD. NBD failed technically in the third patient, and PIBD was partially successful. Mild post-endoscopic biological pancreatitis occurred in 2/6 NBD procedures and resolved spontaneously. The only adverse effect observed within 7 years post-PIBD was very mild transient osmotic diarrhea.Conclusion: Our limited data suggest that NBD is a safe and effective way to predict pruritus response before performing permanent biliary diversion surgery in PFIC patients. What is Known: • Surgical biliary diversion techniques have been developed to relieve intractable pruritus in progressive familial intrahepatic cholestasis (PFIC). • No clinical or genetic features can currently predict pruritus response to surgery. What is New: • Our data suggest that nasobiliary drainage could be a safe and effective tool to predict pruritus response to biliary diversion and avoid unnecessary surgery in PFIC patients.
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Kelly C, Nayagam JS, Vogli S, Samyn M, Joshi D. Paediatric cholestatic liver disorders for the adult gastroenterologist: a practical guide. Frontline Gastroenterol 2020; 12:404-413. [PMID: 35401959 PMCID: PMC8989003 DOI: 10.1136/flgastro-2020-101554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/16/2020] [Accepted: 06/20/2020] [Indexed: 02/04/2023] Open
Abstract
With improvements in the outcomes for cholestatic liver diseases that present in childhood, increasing numbers of patients will require ongoing care as adults. The recent advances in management options coupled with the fact that each adult physician will have a limited number of patients with these conditions means there is a need for those in adult services to develop expertise in these conditions that were historically the domain of paediatrics. This review provides an overview of the most common paediatric cholestatic liver diseases and outlines the clinical manifestations and potential complications, and identifies key management issues unique to each condition for effective ongoing care of these patients.
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Affiliation(s)
- Claire Kelly
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Stamatina Vogli
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Marianne Samyn
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK
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Verkade HJ, Thompson RJ, Arnell H, Fischler B, Gillberg PG, Mattsson JP, Torfgård K, Lindström E. Systematic Review and Meta-analysis: Partial External Biliary Diversion in Progressive Familial Intrahepatic Cholestasis. J Pediatr Gastroenterol Nutr 2020; 71:176-183. [PMID: 32433433 DOI: 10.1097/mpg.0000000000002789] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES We assessed available data on impact of partial external biliary diversion (PEBD) surgery on clinical outcomes in patients with progressive familial intrahepatic cholestasis (PFIC). METHODS We performed a systematic literature review (PubMed) and meta-analysis to evaluate relationships between liver biochemistry parameters (serum bile acids, bilirubin, and alanine aminotransferase [ALT]) and early response (pruritus improvement) or long-term outcomes (need for liver transplant) in patients with PFIC who underwent PEBD. RESULTS Searches identified 175 publications before September 2018; 16 met inclusion criteria. Receiver operating characteristic (ROC) analysis examined ability of liver biochemistry parameters to discriminate patients who demonstrated early and long-term response to PEBD from those who did not. Regarding pruritus improvement in 155 included patients in aggregate, 104 (67%) were responders, 14 (9%) had partial response, and 37 (24%) were nonresponders. In ROC analyses of individual patient data, post-PEBD serum concentration of bile acids, in particular, could discriminate responders from nonresponders for pruritus improvement (area under the curve, 0.99; P < 0.0001; n = 42); to a lesser extent, this was also true for bilirubin (0.87; P = 0.003; n = 31), whereas ALT could not discriminate responders from nonresponders for pruritus improvement (0.74; P = 0.06; n = 28). Reductions from pre-PEBD values in serum bile acid concentration (0.89; P = 0.0003; n = 32) and bilirubin (0.98; P = 0.002; n = 18) but not ALT (0.62; P = 0.46; n = 18) significantly discriminated decreased aggregate need for liver transplant. CONCLUSION Changes in bile acids seem particularly useful in discriminating early and long-term post-PEBD outcomes and may be potential biomarkers of response to interruption of enterohepatic circulation in patients with PFIC.
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Affiliation(s)
- Henkjan J Verkade
- Department of Pediatrics, University of Groningen, Beatrix Children's Hospital/University Medical Center Groningen, Groningen, The Netherlands
| | - Richard J Thompson
- Institute of Liver Studies, King's College London, London, United Kingdom
| | - Henrik Arnell
- Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm
| | - Björn Fischler
- Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm
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Van Vaisberg V, Tannuri ACA, Lima FR, Tannuri U. Ileal exclusion for pruritus treatment in children with progressive familial intrahepatic cholestasis and other cholestatic diseases. J Pediatr Surg 2020; 55:1385-1391. [PMID: 31708211 DOI: 10.1016/j.jpedsurg.2019.09.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 09/02/2019] [Accepted: 09/07/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pruritus is a major health-related quality-of-life burden in progressive familial intrahepatic cholestasis (PFIC) and other childhood cholestatic liver diseases. Several nontransplant surgical techniques were developed in an attempt to ameliorate symptoms and slow disease progression. Very few case-series have been published on a particular intervention, ileal exclusion (IE), which has been considered to be inferior to the other approaches. METHODS We conducted a single-center retrospective chart-review case-series of patients submitted to IE as the first-line surgical treatment at our institution from 1995 to 2018. The primary goal was pruritus relief, followed by survival with the native liver and improvement in biochemical parameters. RESULTS Eleven patients were submitted to IE, with a mean follow-up of 60 months. Complete resolution or significant reduction of pruritus was obtained in 72.7% (n = 8) of patients. One patient (9.1%) had a major postoperative complication that required surgery. No other morbidities were reported. Two cases progressed to end-stage liver disease (ESLD) within the short-term and one year after surgery. CONCLUSIONS This case series study shows that IE provided excellent results in pruritus control and permitted survival with the native liver. We believe IE is a safe procedure, with few associated morbidities, and should be considered more often as primary surgical treatment for PFIC and other cholestasis. LEVEL OF EVIDENCE IV.
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Affiliation(s)
- Victor Van Vaisberg
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Ana Cristina Aoun Tannuri
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Fabiana Roberto Lima
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Uenis Tannuri
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil.
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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: 70] [Impact Index Per Article: 14.0] [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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Goldberg A, Mack CL. Inherited Cholestatic Diseases in the Era of Personalized Medicine. Clin Liver Dis (Hoboken) 2020; 15:105-109. [PMID: 32257121 PMCID: PMC7128029 DOI: 10.1002/cld.872] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 07/21/2019] [Indexed: 02/04/2023] Open
Abstract
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-mack a video presentation of this article.
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Affiliation(s)
- Alyssa Goldberg
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology & NutritionChildren's Hospital Colorado, Digestive Health Institute–Pediatric Liver Center, University of Colorado School of MedicineAuroraCO
| | - Cara L. Mack
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology & NutritionChildren's Hospital Colorado, Digestive Health Institute–Pediatric Liver Center, University of Colorado School of MedicineAuroraCO,Hewit/Andrews Chair in Pediatric Liver DiseasesUniversity of Colorado School of MedicineAuroraCO
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Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019; 11:450-463. [PMID: 31183005 PMCID: PMC6547292 DOI: 10.4254/wjh.v11.i5.450] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/19/2019] [Accepted: 04/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.
AIM To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.
METHODS We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.
RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.
CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (ATP8B1), BSEP (ABCB11), and MDR3 (ABCB4) transporter deficiencies, as well as more recently described gene mutations -- TJP2 (TJP2), FXR (NR1H4), MYO5B (MYO5B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.
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Affiliation(s)
- Sarah AF Henkel
- Division of Gastroenterology, Hepatology, and Nutrition, Emory School of Medicine, Atlanta, GA 30322, United States
| | - Judy H Squires
- Department of Radiology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Mary Ayers
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Armando Ganoza
- Division of Pediatric Transplantation, Department of Surgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Patrick Mckiernan
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - James E Squires
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
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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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Abstract
Genetic cholestasis has been dissected through genetic investigation. The major PFIC genes are now described. ATP8B1 encodes FIC1, ABCB11 encodes BSEP, ABCB4 encodes MDR3, TJP2 encodes TJP2, NR1H4 encodes FXR, and MYO5B encodes MYO5B. The full spectra of phenotypes associated with mutations in each gene are discussed, along with our understanding of the disease mechanisms. Differences in treatment response and targets for future treatment are emerging.
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Affiliation(s)
- Laura N Bull
- Department of Medicine and Institute for Human Genetics, University of California San Francisco, UCSF Liver Center Laboratory, Zuckerberg San Francisco General, 1001 Potrero Avenue, Building 40, Room 4102, San Francisco, CA 94110, USA.
| | - Richard J Thompson
- Institute of Liver Studies, King's College London, King's College Hospital, Denmark Hill, London SE5 9RS, UK
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