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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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2
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Luo Y, Fraser L, Jezykowski J, Gupta NA, Miethke AG, Taylor SA, Alonso EM, Horslen S, Kohli R, Molleston JP, Kamath BM, Guthery SL, Loomes KM, Magee JC, Rosenthal P, Valentino P, Sokol RJ, Mack CL. Interleukin 8-CXCR2-mediated neutrophil extracellular trap formation in biliary atresia associated with neutrophil extracellular trap-induced stellate cell activation. Hepatology 2024:01515467-990000000-01113. [PMID: 39693274 DOI: 10.1097/hep.0000000000001195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 11/23/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed that neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and the risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and whether NETs induce stellate cell activation. APPROACH AND RESULTS BA and other liver disease control plasma and tissue were obtained at diagnosis and transplant. Elastase, NETs, and IL-8 were quantified by ELISA for plasma and by immunohistochemistry for liver tissue. FACS analysis of neutrophils co-cultured with BA or control plasma measured BA-specific NETosis. Stellate cell activation from co-culture studies of stellate cells with NETs was measured by real-time quantitative PCR, ELISA, and FACS. Liver neutrophils and NETs, and plasma elastase, NETs, and IL-8, were significantly increased in BA at diagnosis and transplant. Normal neutrophils co-cultured with BA plasma had increased NETosis and activation of CXCR2, an IL-8 receptor; CXCR2 inhibition decreased NET production. Immunohistochemistry identified increased NET expression of profibrogenic tissue factor and IL-17. NETs co-cultured with stellate cells resulted in stellate cell activation based on increased ACTA2 and COL1A1 mRNA, collagen protein, and cell surface expression of actin, collagen1A, and platelet-derived growth factor receptor-beta. CONCLUSIONS Patients with BA have persistent IL-8-CXCR2-mediated NETosis that correlates with biomarkers of injury and fibrosis, and NETs induce stellate cell activation, suggesting a role for NETs in the immunopathogenesis of disease. Future investigations should focus on therapeutic agents that inhibit NETs in BA.
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Affiliation(s)
- Yuhuan Luo
- Department of Pediatrics, University of Colorado Anschutz, Aurora, Colorado, USA
| | - Lisa Fraser
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Julia Jezykowski
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Nitika A Gupta
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Alexander G Miethke
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Sarah A Taylor
- Department of Pediatrics, University of Colorado Anschutz, Aurora, Colorado, USA
| | - Estella M Alonso
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Simon Horslen
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rohit Kohli
- Department of Pediatrics, University of Southern California, Los Angeles, California, USA
| | - Jean P Molleston
- Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana, USA
| | - Binita M Kamath
- Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Stephen L Guthery
- Department of Pediatrics, University of Utah College of Medicine, Salt Lake City, Utah, USA
| | - Kathleen M Loomes
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - John C Magee
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Phillip Rosenthal
- Department of Pediatrics, University of California, San Francisco, California, USA
| | - Pamela Valentino
- Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
| | - Ronald J Sokol
- Department of Pediatrics, University of Colorado Anschutz, Aurora, Colorado, USA
| | - Cara L Mack
- Department of Pediatrics, University of Colorado Anschutz, Aurora, Colorado, USA
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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3
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Tidwell J, Wu GY. Heritable Chronic Cholestatic Liver Diseases: A Review. J Clin Transl Hepatol 2024; 12:726-738. [PMID: 39130622 PMCID: PMC11310751 DOI: 10.14218/jcth.2024.00119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/14/2024] [Accepted: 05/28/2024] [Indexed: 08/13/2024] Open
Abstract
Chronic cholestasis due to heritable causes is usually diagnosed in childhood. However, many cases can present and survive into adulthood. The time course varies considerably depending on the underlying etiology. Laboratory data usually reveal elevated conjugated hyperbilirubinemia, alkaline phosphatase, and gamma-glutamyl transpeptidase. Patients may be asymptomatic; however, when present, the typical symptoms are pruritus, jaundice, fatigue, and alcoholic stools. The diagnostic methods and management required depend on the underlying etiology. The development of genome-wide associated studies has allowed the identification of specific genetic mutations related to the pathophysiology of cholestatic liver diseases. The aim of this review was to highlight the genetics, clinical pathophysiology, presentation, diagnosis, and treatment of heritable etiologies of chronic cholestatic liver disease.
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Affiliation(s)
- Jasmine Tidwell
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - George Y. Wu
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
- Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Tam PKH, Wells RG, Tang CSM, Lui VCH, Hukkinen M, Luque CD, De Coppi P, Mack CL, Pakarinen M, Davenport M. Biliary atresia. Nat Rev Dis Primers 2024; 10:47. [PMID: 38992031 PMCID: PMC11956545 DOI: 10.1038/s41572-024-00533-x] [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] [Accepted: 06/10/2024] [Indexed: 07/13/2024]
Abstract
Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.
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Affiliation(s)
- Paul K H Tam
- Medical Sciences Division, Macau University of Science and Technology, Macau, China.
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Rebecca G Wells
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Clara S M Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Vincent C H Lui
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Maria Hukkinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Carlos D Luque
- Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Paolo De Coppi
- NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children NHS Foundation Trust and Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Cara L Mack
- Department of Paediatrics, Division of Paediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI, USA
| | - Mikko Pakarinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, London, UK
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Yoeli D, Mack CL, Luo Y, Chaidez A, De La Rosa NL, Wang Z, Cervantes-Alvarez E, Huang CA, Navarro-Alvarez N. Galectin-3 in biliary atresia and other pediatric cholestatic liver diseases. Hepatol Res 2024; 54:392-402. [PMID: 37950561 DOI: 10.1111/hepr.13987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 10/28/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023]
Abstract
AIMS Biliary atresia (BA) is characterized by intrahepatic inflammation and rapid progression of liver fibrosis. Galectin-3, a beta-galactoside binding protein, is a key regulator of inflammation and fibrosis. The aim of this study was to characterize circulating and hepatic Galectin-3 levels in children with BA. METHODS Plasma and liver samples were obtained from children with early BA at time of Kasai hepatoportoenterostomy, late BA at time of transplant, early and late other cholestatic liver diseases (CLD), and controls. Plasma Galectin-3 was measured using standard enzyme-linked immunoassay. Liver tissue was analyzed with multiplex immunohistochemistry and quantified using whole slide analysis. Statistical comparisons were made using nonparametric testing. RESULTS Plasma Galectin-3 in late BA was significantly higher than in early BA (20.82 [12.45-30.46] vs. 11.30 [8.74-16.83] ng/mL, p = 0.0096). Galectin-3 levels correlated with markers of disease severity and interleukin-6. There were significantly more Galectin-3+ M2 macrophages in late BA in comparison to late other CLD (162 [157-233] vs. 49 [33-59] cells/mm2, p = 0.03). The number of Galectin-3+ M2 macrophages correlated with the number of activated hepatic stellate cells and bile duct proliferation. CONCLUSIONS Plasma Galectin-3 is higher in late BA at time of transplant in comparison to early BA at time of Kasai. The number of Galectin-3 expressing M2 macrophages in late BA is elevated relative to late other CLD and was associated with other prognostic histological findings. Galectin-3 targeted therapy may be beneficial in slowing disease progression to cirrhosis in children with BA.
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Affiliation(s)
- Dor Yoeli
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Cara L Mack
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Yuhuan Luo
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Alexander Chaidez
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nathaly Limon De La Rosa
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Zhaohui Wang
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Eduardo Cervantes-Alvarez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Christene A Huang
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nalu Navarro-Alvarez
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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6
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Eiamkulbutr S, Tubjareon C, Sanpavat A, Phewplung T, Srisan N, Sintusek P. Diseases of bile duct in children. World J Gastroenterol 2024; 30:1043-1072. [PMID: 38577180 PMCID: PMC10989494 DOI: 10.3748/wjg.v30.i9.1043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/26/2023] [Accepted: 02/04/2024] [Indexed: 03/06/2024] Open
Abstract
Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common disease of the bile duct in newborns is biliary atresia, whose prognosis varies according to the age of surgical correction. Other diseases such as Alagille syndrome, inspissated bile duct syndrome, and choledochal cysts are also time-sensitive because they can cause severe liver damage due to obstruction. The majority of these diseases present with cholestatic jaundice in the newborn or infant period, which is quite difficult to differentiate regarding clinical acumen and initial investigations. Intraoperative cholangiography is potentially necessary to make an accurate diagnosis, and further treatment will be performed synchronously or planned as findings suggest. This article provides a concise review of bile duct diseases, with interesting cases.
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Affiliation(s)
- Sutha Eiamkulbutr
- Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Chomchanat Tubjareon
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Teerasak Phewplung
- Department of Radiology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nimmita Srisan
- Department of Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Palittiya Sintusek
- Center of Excellence in Thai Pediatric Gastroenterology, Hepatology and Immunology, Division of Gastroenterology, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand
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7
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Schmidt HC, Hagens J, Schuppert P, Appl B, Raluy LP, Trochimiuk M, Philippi C, Li Z, Reinshagen K, Tomuschat C. Biliatresone induces cholangiopathy in C57BL/6J neonates. Sci Rep 2023; 13:10574. [PMID: 37386088 PMCID: PMC10310722 DOI: 10.1038/s41598-023-37354-z] [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: 12/31/2022] [Accepted: 06/20/2023] [Indexed: 07/01/2023] Open
Abstract
Exposure to plant toxins or microbiota that are able to digest common food ingredients to toxic structures might be responsible for biliary atresia (BA). An isoflavonoid, biliatresone is known to effectively alter the extrahepatic bile duct (EHBD) development in BALB/c mice. Biliatresone causes a reduction of Glutathione (GSH) levels, SOX17 downregulation and is effectively countered with N-Acetyl-L-cysteine treatment in vitro. Therefore, reversing GSH-loss appears to be a promising treatment target for a translational approach. Since BALB/c mice have been described as sensitive in various models, we evaluated the toxic effect of biliatresone in robust C57BL/6J mice and confirmed its toxicity. Comparison between BALB/c and C57BL/6J mice revealed similarity in the toxic model. Affected neonates exhibited clinical symptoms of BA, such as jaundice, ascites, clay-colored stools, yellow urine and impaired weight gain. The gallbladders of jaundiced neonates were hydropic and EHBD were twisted and enlarged. Serum and histological analysis proved cholestasis. No anomalies were seen in the liver and EHBD of control animals. With our study we join a chain of evidence confirming that biliatresone is an effective agent for cross-lineage targeted alteration of the EHBD system.
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Affiliation(s)
- Hans Christian Schmidt
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
| | - Johanna Hagens
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Pauline Schuppert
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Birgit Appl
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Laia Pagerols Raluy
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Magdalena Trochimiuk
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Clara Philippi
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Zhongwen Li
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Konrad Reinshagen
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Christian Tomuschat
- Research Laboratory W23, Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
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Kotb MA, Ieiri S, Shehata SM. Editorial: Elimination of biliary atresia. Front Pediatr 2023; 11:1202727. [PMID: 37284287 PMCID: PMC10241068 DOI: 10.3389/fped.2023.1202727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 04/24/2023] [Indexed: 06/08/2023] Open
Affiliation(s)
- Magd Ahmed Kotb
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
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Abstract
This article discusses current standard of care in neonatal biliary disease, particularly management of biliary atresia and choledochal cysts. It highlights surgical considerations, guidelines for adjuvant therapies, and promising therapeutic options that are under investigation.
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Affiliation(s)
- Sarah Mohamedaly
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, HSW 1652, Campus Box 0570, San Francisco, CA 94143-0570, USA
| | - Amar Nijagal
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, HSW 1652, Campus Box 0570, San Francisco, CA 94143-0570, USA; The Liver Center, University of California, San Francisco, CA, USA; The Pediatric Liver Center at UCSF Benioff Childrens' Hospitals, San Francisco, CA, USA.
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10
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Cellular Therapies in Pediatric Liver Diseases. Cells 2022; 11:cells11162483. [PMID: 36010561 PMCID: PMC9406752 DOI: 10.3390/cells11162483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/30/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022] Open
Abstract
Liver transplantation is the gold standard for the treatment of pediatric end-stage liver disease and liver based metabolic disorders. Although liver transplant is successful, its wider application is limited by shortage of donor organs, surgical complications, need for life long immunosuppressive medication and its associated complications. Cellular therapies such as hepatocytes and mesenchymal stromal cells (MSCs) are currently emerging as an attractive alternative to liver transplantation. The aim of this review is to present the existing world experience in hepatocyte and MSC transplantation and the potential for future effective applications of these modalities of treatment.
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11
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Antala S, Taylor SA. Biliary Atresia in Children: Update on Disease Mechanism, Therapies, and Patient Outcomes. Clin Liver Dis 2022; 26:341-354. [PMID: 35868678 PMCID: PMC9309872 DOI: 10.1016/j.cld.2022.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Biliary atresia is a rare disease but remains the most common indication for pediatric liver transplantation as there are no effective medical therapies to slow progression after diagnosis. Variable contribution of genetic, immune, and environmental factors contributes to disease heterogeneity among patients with biliary atresia. Developing a deeper understanding of the disease mechanism will help to develop targeted medical therapies and improve patient outcomes.
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Affiliation(s)
- Swati Antala
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
| | - Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
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12
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Fligor SC, Hirsch TI, Tsikis ST, Adeola A, Puder M. Current and emerging adjuvant therapies in biliary atresia. Front Pediatr 2022; 10:1007813. [PMID: 36313875 PMCID: PMC9614654 DOI: 10.3389/fped.2022.1007813] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2022] Open
Abstract
Following Kasai hepatic portoenterostomy (HPE), most patients with biliary atresia will eventually require liver transplantation due to progressive cirrhosis and liver failure. Preventing liver transplantation, or even delaying eventual liver transplantation, is the key to improving long-term outcomes. This review first examines the commonly used adjuvant therapies in post-HPE biliary atresia and the strength of the evidence supporting these therapies. Next, it examines the evolving frontiers of management through a comprehensive evaluation of both recently completed and ongoing clinical trials in biliary atresia. Promising therapies used in other cholestatic liver diseases with potential benefit in biliary atresia are discussed. Improving post-HPE management is critical to prevent complications, delay liver transplantation, and ultimately improve the long-term survival of patients with biliary atresia.
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Affiliation(s)
- Scott C Fligor
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Thomas I Hirsch
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Savas T Tsikis
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Andrew Adeola
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Mark Puder
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
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13
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Abstract
Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition-associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line-associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.
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Affiliation(s)
- Amy G Feldman
- Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
| | - Ronald J Sokol
- Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
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Abstract
"Biliary atresia (BA) is a common cause of jaundice in infancy. There is increasing evidence that newborn screening with direct or conjugated bilirubin leads to earlier diagnosis. Although the Kasai portoenterostomy is the primary treatment, there are scientific advances in adjuvant therapies. As pediatric patients transition to adult care, multidisciplinary care is essential, given the complexity of this patient population."
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Affiliation(s)
- Sara E Yerina
- Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, USA
| | - Udeme D Ekong
- Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, USA; Department of Pediatrics, Georgetown University School of Medicine, Washington, DC, USA.
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15
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Goh L, Phua KB, Low Y, Chiang LW, Yong C, Chiou FK. Analysis of Cholangitis Rates with Extended Perioperative Antibiotics and Adjuvant Corticosteroids in Biliary Atresia. Pediatr Gastroenterol Hepatol Nutr 2021; 24:366-376. [PMID: 34316471 PMCID: PMC8279824 DOI: 10.5223/pghn.2021.24.4.366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/24/2021] [Accepted: 05/15/2021] [Indexed: 12/14/2022] Open
Abstract
PURPOSE There is no consensus regarding adjuvant therapies following Kasai portoenterostomy (KP) for biliary atresia (BA). This study aimed to analyze the effect of extended perioperative intravenous antibiotics (PI-Abx) and adjuvant corticosteroid on cholangitis and jaundice clearance rates in the 3 years post-KP in children with BA. METHODS Data of patients who underwent KP between 1999-2018 at a single center were retrospectively analyzed. Group A (1999-2010) received PI-Abx for 5 days, Group B (2010-2012) received PI-Abx for 5 days plus low-dose prednisolone (2 mg/kg), and Group C (2012-2017) received PI-Abx for 14 days plus high-dose prednisolone (5 mg/kg). RESULTS Fifty-four patients were included with groups A, B, and C comprising 25, 9, and 20 patients, respectively. The number of episodes of cholangitis was 1.0, 1.6, and 1.3 per patient (p=NS) within the first year and 1.8, 2.3, and 1.7 (p=NS) over 3 years in Groups A, B, and C, respectively. The jaundice clearance rate at 6 months was 52%, 78%, and 50% (p=NS), and the 3-year native liver survival (NLS) rate was 76%, 100%, and 80% (p=NS) in Groups A, B, and C, respectively. A near-significant association was observed between the incidence of cholangitis within the first year and decompensated liver cirrhosis/death at 3 years post KP (p=0.09). Persistence of jaundice at 6 months was significantly associated with decompensated cirrhosis/death at 3 years (p<0.001). CONCLUSION The extended duration of PI-Abx and adjuvant corticosteroids was not associated with improved rates of cholangitis, jaundice clearance, or NLS in patients with BA.
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Affiliation(s)
- Lynette Goh
- Gastroenterology, Hepatology & Nutrition Service, Pediatric Medicine, KK Women's and Children's Hospital, Singapore
| | - Kong Boo Phua
- Gastroenterology, Hepatology & Nutrition Service, Pediatric Medicine, KK Women's and Children's Hospital, Singapore
| | - Yee Low
- Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore
| | - Li Wei Chiang
- Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore
| | - Chen Yong
- Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore
| | - Fang Kuan Chiou
- Gastroenterology, Hepatology & Nutrition Service, Pediatric Medicine, KK Women's and Children's Hospital, Singapore
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16
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Alsaleem M. Intravenous Immune Globulin Uses in the Fetus and Neonate: A Review. Antibodies (Basel) 2020; 9:E60. [PMID: 33158209 PMCID: PMC7709108 DOI: 10.3390/antib9040060] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/07/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
Intravenous immune globulin (IVIG) is made after processing plasma from healthy donors. It is composed mainly of pooled immunoglobulin and has clinical evidence-based applications in adult and pediatric populations. Recently, several clinical applications have been proposed for managing conditions in the neonatal population, such as hemolytic disease of the newborn, treatment, and prophylaxis for sepsis in high-risk neonates, enterovirus parvovirus and COVID-19 related neonatal infections, fetal and neonatal immune-induced thrombocytopenia, neonatal hemochromatosis, neonatal Kawasaki disease, and some types of immunodeficiency. The dosing, mechanism of action, effectiveness, side effects, and adverse reactions of IVIG have been relatively well studied in adults but are not well described in the neonatal population. This review aims to provide the most recent evidence and consensus guidelines about the use of IVIG in the fetus and neonate.
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Affiliation(s)
- Mahdi Alsaleem
- Pediatrics Department, Neonatology, Children’s Mercy Hospital, Kansas City, MO 64108, USA;
- Pediatrics Department, University of Kansas, Wichita, KS 67208, USA
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17
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Venkat V, Ng VL, Magee JC, Ye W, Hawthorne K, Harpavat S, Molleston JP, Murray KF, Wang KS, Soufi N, Bass LM, Alonso EM, Bezerra JA, Jensen MK, Kamath BM, Loomes KM, Mack CL, Rosenthal P, Shneider BL, Squires RH, Sokol RJ, Karpen SJ. Modeling Outcomes in Children With Biliary Atresia With Native Liver After 2 Years of Age. Hepatol Commun 2020; 4:1824-1834. [PMID: 33305153 PMCID: PMC7706301 DOI: 10.1002/hep4.1602] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/21/2020] [Accepted: 07/31/2020] [Indexed: 12/15/2022] Open
Abstract
Approximately 50% of infants with biliary atresia (BA) undergoing Kasai portoenterostomy show survival with native liver (SNL) at age 2 years. Predictors of disease progression after age 2 years are unknown, despite estimates of 20%-30% undergoing liver transplant (LT) between age 2 and 18 years. We sought to address this knowledge gap by developing prognostic models in participants of the multicenter prospective National Institutes of Health-supported Childhood Liver Disease Research Network. We extracted 14 clinical and biochemical variables at age 2 years to develop two models for future outcomes: 1) LT or death (LTD) and 2) first sentinel event (SE), either new onset ascites, hepatopulmonary syndrome (HPS), or gastrointestinal (GI) bleed. A total of 240 participants, enrolled between 2004 and 2017, were followed until a median age of 5.1 years (range, 2.0-13.3 years). Of these participants, 38 underwent LT (n = 37) or death (n = 1); cumulative incidence, 23.7% (95% confidence interval [CI], 16.2%-32.0%). Twenty-seven experienced either new-onset ascites (n = 13), HPS (n = 1), or GI bleed (n = 14). One participant had ascites and GI bleed concurrently; cumulative incidence, 21.5% (95% CI, 14.2%-29.8%) by age 10 years. The Cox proportional hazard model predicted risk of LTD, using total bilirubin, albumin, platelet count, and history of either ascites or cholangitis (BA LTD model), with a C-index of 0.88 (range, 0.86-0.89). A cause-specific hazard competing risk model predicted SE using platelet count and gamma glutamyltransferase levels (BA SE model) with a C-index of 0.81 (range, 0.80-0.84). Internal model validity was assessed using Harrell's C-index with cross-validation. Conclusion: Stratification using these models identified risk of poor outcomes in patients with BA SNL after age 2 years. The models may identify those who would benefit from enhanced clinical surveillance and prioritization in clinical trials.
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Affiliation(s)
- Veena Venkat
- UPMC Children's Hospital of Pittsburgh Pittsburgh PA
| | - Vicky L Ng
- Hospital for Sick Children University of Toronto Toronto Canada
| | - John C Magee
- University of Michigan Hospitals and Health Centers Ann Arbor MI
| | - Wen Ye
- University of Michigan Hospitals and Health Centers Ann Arbor MI
| | | | - Sanjiv Harpavat
- Texas Children's Hospital Liver Center, Baylor College of Medicine Houston TX
| | | | | | | | | | - Lee M Bass
- Ann & Robert H. Lurie Children's Hospital of Chicago Chicago IL
| | | | | | - M Kyle Jensen
- University of Utah School of Medicine Primary Children's Hospital Salt Lake City UT
| | - Binita M Kamath
- Hospital for Sick Children University of Toronto Toronto Canada
| | | | - Cara L Mack
- University of Colorado School of Medicine Children's Hospital Colorado Aurora CO
| | | | - Benjamin L Shneider
- Texas Children's Hospital Liver Center, Baylor College of Medicine Houston TX
| | | | - Ronald J Sokol
- University of Colorado School of Medicine Children's Hospital Colorado Aurora CO
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18
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Mohamedaly S, Alkhani A, Nijagal A. The relative abundance of monocyte subsets determines susceptibility to perinatal hepatic inflammation. JOURNAL OF CLINICAL & CELLULAR IMMUNOLOGY 2020; 11:602. [PMID: 36304699 PMCID: PMC9603689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The devastating consequences of perinatal liver inflammation contribute to a pressing need to develop therapeutics for the diseases that underly this condition. Biliary atresia (BA) is a perinatal inflammatory disease of the liver that results in obliterative cholangiopathy and rapidly progresses to liver failure, requiring transplantation. The ability to develop targeted therapies requires an understanding of the immune mechanisms that mitigate perinatal liver inflammation. This article reviews our recent findings demonstrating that in a murine model of perinatal hepatic inflammation, Ly6cLo non-classical monocytes express a pro-reparative transcriptomic profile and that the relative abundance of Ly6cLo monocytes promotes resolution of perinatal liver inflammation, rendering neonatal pups resistant to disease. We also examine the lineage relationship between monocyte subsets, reviewing data that suggests classical monocytes are a precursor for non-classical monocytes, and the alternative possibility that separate progenitors exist for each subset. Although a precursor-product relationship between classical and non-classical monocytes might exist in certain environments, we argue that they may also arise from separate progenitors, which is evident by sustained Ly6cLo non-classical monocyte expansion when Ly6cHi monocytes are absent. An improved understanding of monocyte subsets and their developmental trajectories during perinatal hepatic inflammation will provide insight into how therapies directed at controlling monocyte function may help alleviate the devastating consequences of diseases like BA.
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Affiliation(s)
| | | | - Amar Nijagal
- ‡ Corresponding Author: Amar Nijagal, MD, Assistant Professor of Surgery, Division of Pediatric Surgery, 513 Parnassus Avenue, HSW 1652, Campus Box 0570, University of CA, San Francisco, San Francisco, CA 94143-0570, Office: 415-476-4086; Fax: 415-476-2314,
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19
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Abstract
Biliary atresia is characterised as an obliterative cholangiopathy of both extra-and intra-hepatic bile ducts. There is marked aetiological heterogeneity with a number of different variants, some syndromic and others perhaps virally-mediated. Current research aims to try and define possible mechanisms and pathogenesis though an actual breakthrough remains elusive. There has been little in the way of surgical advances beyond subtle variations in the Kasai portoenterostomy and laparoscopic equivalents have no declared advantage and have yet to prove equivalence in measures of outcome. The next target has been to maximise potential with better adjuvant therapy, though the evidence base for most currently available therapies such as steroids and ursodeoxycholic acid remains limited. Still high-dose steroid use is widespread, certainly in Europe and the Far East. Clearance of jaundice can be achieved in 50-60% of those subjected to portoenterostomy at <70 days and should be an achievable benchmark. Transplantation is a widely available "rescue" therapy though whether it should be an alternative as a primary procedure is arguable but becoming increasingly heard. The aim of clinical practice remains to get these infants for surgery as early as is possible though this can be difficult to accomplish in practice, and "low-cost" screening projects using stool colour charts have been limited outside of Taiwan and Japan. Centralisation of resources (medical and surgical) is associated with a diminution of time to portoenterostomy but application has been limited by entrenched health delivery models or geographical constraints.
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Affiliation(s)
- Federico Scottoni
- Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS, United Kingdom
| | - Mark Davenport
- Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS, United Kingdom.
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20
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Karpen SJ, Kelly D, Mack C, Stein P. Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int 2020; 14:677-689. [PMID: 32653991 DOI: 10.1007/s12072-020-10070-w] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/22/2020] [Indexed: 12/20/2022]
Abstract
Biliary atresia is a rare cholestatic liver disease that presents in infants and rapidly advances to death in the absence of intervention. As a result of blockage or destruction of the biliary tract, bile acids accumulate and drive inflammation, fibrosis, and disease progression. The standard of care, Kasai portoenterostomy (KPE), is typically performed shortly after diagnosis (currently at ~ 2 months of age) and aims to restore bile flow and relieve cholestasis. Nevertheless, most patients continue to experience liver injury from accumulation of bile acids after KPE, since there are no known effective therapeutics that may enhance survival after KPE. Improving cholestasis via interruption of the enterohepatic circulation of bile acids may directly attenuate hepatic bile acid retention and reduce the risk of early organ failure. Directly addressing intrahepatic accretion of bile acids to avoid inherent bile acid toxicities provides an attractive and plausible therapeutic target for biliary atresia. This review explores the novel therapeutic concept of inhibiting the sole ileal bile acid transporter (IBAT), also known as ASBT (apical sodium-bile acid transporter, encoded by SLC10A2), as a means to reduce hepatic bile acid concentration after KPE. By reducing return of bile acids to the cholestatic liver, IBAT inhibitors may potentially lessen or delay liver damage associated with the hepatotoxicity and cholangiopathy of bile acid accumulation. The clinical programs of 2 IBAT inhibitors in development for the treatment of pediatric cholestatic liver diseases, maralixibat and odevixibat, are highlighted.
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Affiliation(s)
- Saul J Karpen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine and Children's Healthcare of Atlanta, 1760 Haygood Dr., HSRB E204, Atlanta, GA, 30322, USA.
| | - Deirdre Kelly
- Liver Unit, Birmingham Women's and Children's NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, UK
| | - Cara Mack
- Section of Pediatric Gastroenterology, Hepatology and Nutrition and the Digestive Health Institute, University of Colorado School of Medicine and Children's Hospital Colorado, 13123 E 16th Ave B290, Aurora, CO, 80045, USA
| | - Philip Stein
- Medical Affairs, Albireo Pharma, Inc, 10 Post Office Square, Suite 1000, Boston, MA, 02109, USA
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21
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Abstract
The treatment of biliary atresia (BA) is predominantly surgical with firstly an attempt at restoration of bile flow from the native liver by wide excision of the obstructed, obliterated extrahepatic biliary tree to the level of the porta hepatis and a portoenterostomy using a long Roux loop-Kasai portoenterostomy (KPE). Liver transplantation is reserved for those that fail this and for those where surgery is considered futile for reasons of age or stage of disease. As the aetiology of BA remains ill-defined, so adjuvant treatment has been largely based on pragmatism, trial and error. Systematic analysis of the few randomized placebo-controlled trial data and less well-controlled cohort studies have suggested benefit from post-operative high-dose steroids and ursodeoxycholic acid (UDCA) while the benefit of long-term prophylactic antibiotics, bile acid sequestrants (e.g., colestyramine) or probiotics remains unproven. Newer modalities such as antiviral therapy (AVT), immunoglobulin, FXR agonists (e.g., obeticholic acid), ileal bile acid transporter (IBAT) antagonists (e.g., maralixibat) remain unproven. This article reviews the current evidence for the efficacy of adjuvant medical therapy in BA.
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Affiliation(s)
- Jessica Burns
- Department of Paediatric Surgery, King's College Hospital, London, UK
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, London, UK
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22
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Kriegermeier A, Green R. Pediatric Cholestatic Liver Disease: Review of Bile Acid Metabolism and Discussion of Current and Emerging Therapies. Front Med (Lausanne) 2020; 7:149. [PMID: 32432119 PMCID: PMC7214672 DOI: 10.3389/fmed.2020.00149] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 04/06/2020] [Indexed: 02/06/2023] Open
Abstract
Cholestatic liver diseases are a significant cause of morbidity and mortality and the leading indication for pediatric liver transplant. These include diseases such as biliary atresia, Alagille syndrome, progressive intrahepatic cholestasis entities, ductal plate abnormalities including Caroli syndrome and congenital hepatic fibrosis, primary sclerosing cholangitis, bile acid synthesis defects, and certain metabolic disease. Medical management of these patients typically includes supportive care for complications of chronic cholestasis including malnutrition, pruritus, and portal hypertension. However, there are limited effective interventions to prevent progressive liver damage in these diseases, leaving clinicians to ultimately rely on liver transplantation in many cases. Agents such as ursodeoxycholic acid, bile acid sequestrants, and rifampicin have been mainstays of treatment for years with the understanding that they may decrease or alter the composition of the bile acid pool, though clinical response to these medications is frequently insufficient and their effects on disease progression remain limited. Recently, animal and human studies have identified potential new therapeutic targets which may disrupt the enterohepatic circulation of bile acids, alter the expression of bile acid transporters or decrease the production of bile acids. In this article, we will review bile formation, bile acid signaling, and the relevance for current and newer therapies for pediatric cholestasis. We will also highlight further areas of potential targets for medical intervention for pediatric cholestatic liver diseases.
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Affiliation(s)
- Alyssa Kriegermeier
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, United States
| | - Richard Green
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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23
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Ly6c Lo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation. Sci Rep 2020; 10:7165. [PMID: 32346042 PMCID: PMC7188847 DOI: 10.1038/s41598-020-64158-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 04/11/2020] [Indexed: 12/02/2022] Open
Abstract
Perinatal hepatic inflammation can have devastating consequences. Monocytes play an important role in the initiation and resolution of inflammation, and their diverse functions can be attributed to specific cellular subsets: pro-inflammatory or classical monocytes (Ly6cHi) and pro-reparative or non-classical monocytes (Ly6cLo). We hypothesized that inherent differences in Ly6cHi classical monocytes and Ly6cLo non-classical monocytes determine susceptibility to perinatal hepatic inflammation in late gestation fetuses and neonates. We found an anti-inflammatory transcriptional profile expressed by Ly6cLo non-classical monocytes, and a physiologic abundance of these cells in the late gestation fetal liver. Unlike neonatal pups, late gestation fetuses proved to be resistant to rhesus rotavirus (RRV) mediated liver inflammation. Furthermore, neonatal pups were rendered resistant to RRV-mediated liver injury when Ly6cLo non-classical monocytes were expanded. Pharmacologic inhibition of Ly6cLo non-classical monocytes in this setting restored susceptibility to RRV-mediated disease. These data demonstrate that Ly6cLo monocytes promote resolution of perinatal liver inflammation in the late gestation fetus, where there is a physiologic expansion of non-classical monocytes, and in the neonatal liver upon experimental expansion of these cells. Therapeutic strategies directed towards enhancing Ly6cLo non-classical monocyte function may mitigate the detrimental effects of perinatal liver inflammation.
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24
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Kim HB, Elisofon SA. Biliary Atresia: Biliary-Enteric Drainage or Primary Liver Transplant? Hepatology 2020; 71:751-752. [PMID: 31517392 DOI: 10.1002/hep.30935] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Heung Bae Kim
- Department of Surgery, Boston Children's Hospital, Boston, MA
| | - Scott A Elisofon
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA
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25
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Gallengangsatresie. Monatsschr Kinderheilkd 2019. [DOI: 10.1007/s00112-019-00768-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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26
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Abstract
Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.
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Affiliation(s)
- Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - David N. Assis
- Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Digestive Health Institute, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
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27
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Biliary Atresia as a Disease Starting In Utero: Implications for Treatment, Diagnosis, and Pathogenesis. J Pediatr Gastroenterol Nutr 2019; 69:396-403. [PMID: 31335837 PMCID: PMC6942669 DOI: 10.1097/mpg.0000000000002450] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Biliary atresia (BA) is the most common reason for pediatric liver transplant. BA's varied presentation, natural history, and treatment with the Kasai portoenterostomy have been well described; however, when BA starts relative to birth has not been clearly defined. In this review, we discuss laboratory, imaging, and clinical data which suggest that most if not all forms of BA may start before birth. This early onset has implications in terms of delivering treatments earlier and identifying possible factors underlying BA's etiology.
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29
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Kim S, Moore J, Alonso E, Bednarek J, Bezerra JA, Goodhue C, Karpen SJ, Loomes KM, Magee JC, Ng VL, Sherker AH, Smith C, Spino C, Venkat V, Wang K, Sokol RJ, Mack CL. Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy. Hepatol Commun 2019; 3:685-696. [PMID: 31061956 PMCID: PMC6492477 DOI: 10.1002/hep4.1332] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/11/2019] [Indexed: 12/13/2022] Open
Abstract
Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T‐ and B‐cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen‐DR isotype [HLA‐DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA‐DR+CD38+ NK cells and expression of NK cell activation markers CD69 and HLA‐DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)‐8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA‐DR+CD38+ NK cells and plasma IL‐8 levels was associated with an increased risk of transplant or death by day 360. Conclusion: Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL‐8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.
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Affiliation(s)
| | | | - Estella Alonso
- Ann and Robert H. Lurie Children's Hospital of Chicago Chicago IL
| | | | | | | | | | | | | | - Vicky L Ng
- The Hospital for Sick Children, University of Toronto Toronto Canada
| | - Averell H Sherker
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Bethesda MD
| | | | | | | | - Kasper Wang
- Children's Hospital Los Angeles Los Angeles CA
| | - Ronald J Sokol
- Children's Hospital Colorado, University of Colorado School of Medicine Aurora CO
| | - Cara L Mack
- Children's Hospital Colorado, University of Colorado School of Medicine Aurora CO
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