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Miller PN, Baskaran S, Nijagal A. Immunology of Biliary Atresia. Semin Pediatr Surg 2024; 33:151474. [PMID: 39862687 DOI: 10.1016/j.sempedsurg.2025.151474] [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: 10/01/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Abstract
Biliary atresia is a progressive neonatal cholangiopathy that leads to liver failure. Characterized by inflammation-mediated liver injury, the immune system plays a critical role in the pathogenesis of this disease. Though several types of immune cells and mediators have been implicated in animal models of biliary atresia, emerging literature reflects the complex interplay of components of the immune response that contributes to disease progression in humans. Novel therapies targeting the immune system are needed to mitigate the devastating effects of biliary atresia. This review highlights the current literature on the components of the immune system that have been in implicated in biliary atresia and the rich interplay between the major arms of the immune system- innate and adaptive immunity- to cause the highly morbid consequences of this disease.
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Affiliation(s)
- Phoebe N Miller
- Department of Surgery, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Suruthi Baskaran
- Department of Surgery, University of Texas Health Science Center, 7703 Floyd Curl Drive San Antonio, TX 78229, USA
| | - Amar Nijagal
- Department of Surgery, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA; The Liver Center, University of California San Francisco, San Francisco, CA 94143; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
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2
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Jeropoulos RM, Arroyo J, Davenport M. Predicting and optimising outcome for biliary atresia. Semin Pediatr Surg 2024; 33:151479. [PMID: 39884180 DOI: 10.1016/j.sempedsurg.2025.151479] [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: 10/16/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025]
Abstract
Biliary atresia (BA) remains a disease of significant morbidity and mortality world-wide. Early and accurate diagnosis facilitates early intervention and improves outcomes. The gold standard in diagnosing BA is a liver biopsy followed by cholangiography, usually performed intra-operatively. Serum markers, like the aspartate aminotransferase-to-platelet ratio, matrix metalloproteinase-7 and several inflammatory cytokines have been recently investigated as non-invasive alternatives with varying degrees of success. Newer immunohistochemical analysis of liver biopsies, such as the expression of secretin receptors and Ki-67, from infants with BA have improved our understanding of the disease process and has shed a little light in predicting post-operative outcomes. There is little standardisation in the care of BA post operatively, though administration of steroids, prevention and treatment of cholangitis with antibiotics and anti-viral therapy for CMV+ve infants are becoming universally accepted as treatment. Experimental stem cell treatments show promise although remain in the out-of-reach future for now in routine clinical practice. This chapter aims to comprehensively describe recent knowledge on predicting the clinical outcomes of infants with BA, as well as optimising their care post operatively.
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Affiliation(s)
- Renos M Jeropoulos
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Jorge Arroyo
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Mark Davenport
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom.
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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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Alkhani A, Baskaran S, Murti A, Rapp B, Levy CS, Wang B, Nijagal A. Perinatal liver inflammation is associated with persistent elevation of CXCL10 and its canonical receptor CXCR3 on common myeloid progenitors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.15.607661. [PMID: 39229070 PMCID: PMC11370417 DOI: 10.1101/2024.08.15.607661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Biliary atresia (BA) is a leading cause of liver failure in infants. Despite effective surgical drainage, patients with BA exhibit attenuated immune responses to childhood vaccines, suggesting there are long-lasting alterations to immune function. The perinatal liver is home to hematopoietic stem and progenitor cells (HSPCs) and serves as the epicenter for rapidly progressive and significantly morbid inflammatory diseases like BA. We have previously established the role of neonatal myeloid progenitors in the pathogenesis of perinatal liver inflammation (PLI) and hypothesize that PLI leads to long-term changes to HSPCs in mice that recovered from PLI. To test this hypothesis, we compared the changes that occur to HSPCs and mature myeloid populations in the bone marrow of adult mice during homeostasis and during PLI. Our results demonstrate that HSPCs from animals that recover from PLI ("PLI-recovered") undergo long-term expansion with a reduced proliferative capacity. Notably, PLI leads to persistent activation of common myeloid progenitors through the involvement of CXCL10 and its canonical receptor, CXCR3. Our data suggests that the CXCR3-CXCL10 axis may mediate the changes in HSPCs that lead to altered immune function observed in BA, providing support for a targetable pathway to mitigate the detrimental long-term immune effects observed in patients with BA.
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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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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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Alkhani A, Korsholm C, Levy CS, Mohamedaly S, Duwaerts CC, Pietras EM, Nijagal A. Neonatal Hepatic Myeloid Progenitors Expand and Propagate Liver Injury in Mice. J Clin Med 2023; 12:jcm12010337. [PMID: 36615137 PMCID: PMC9821039 DOI: 10.3390/jcm12010337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/24/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Biliary atresia (BA) is a progressive pediatric inflammatory disease of the liver that leads to cirrhosis and necessitates liver transplantation. The rapid progression from liver injury to liver failure in children with BA suggests that factors specific to the perinatal hepatic environment are important for disease propagation. Hematopoietic stem and progenitor cells (HSPCs) reside in the fetal liver and are known to serve as central hubs of inflammation. We hypothesized that HSPCs are critical for the propagation of perinatal liver injury (PLI). METHODS Newborn BALB/c mice were injected with rhesus rotavirus (RRV) to induce PLI or with PBS as control. Livers were compared using histology and flow cytometry. To determine the effects of HSPCs on PLI, RRV-infected neonatal mice were administered anti-CD47 and anti-CD117 to deplete HSPCs. RESULTS PLI significantly increased the number of common myeloid progenitors and the number of CD34+ hematopoietic progenitors. Elimination of HSPCs through antibody-mediated myeloablation rescued animals from PLI and significantly increased survival (RRV+isotype control 36.4% vs. RRV+myeloablation 77.8%, Chi-test = 0.003). CONCLUSIONS HSPCs expand as a result of RRV infection and propagate PLI. Targeting of HSPCs may be useful in preventing and treating neonatal inflammatory diseases of the liver such as BA.
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Affiliation(s)
- Anas Alkhani
- Department of Surgery, University of California, San Francisco, CA 94143, USA
- The Liver Center, University of California, San Francisco, CA 94143, USA
| | - Cathrine Korsholm
- Department of Surgery, University of California, San Francisco, CA 94143, USA
- The Liver Center, University of California, San Francisco, CA 94143, USA
- Department of Comparative Pediatrics and Nutrition, University of Copenhagen, 1870 Frederiksberg C, Denmark
| | - Claire S. Levy
- Department of Surgery, University of California, San Francisco, CA 94143, USA
- The Liver Center, University of California, San Francisco, CA 94143, USA
| | - Sarah Mohamedaly
- Department of Surgery, University of California, San Francisco, CA 94143, USA
- The Liver Center, University of California, San Francisco, CA 94143, USA
| | - Caroline C. Duwaerts
- The Liver Center, University of California, San Francisco, CA 94143, USA
- Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Eric M. Pietras
- Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Amar Nijagal
- Department of Surgery, University of California, San Francisco, CA 94143, USA
- The Liver Center, University of California, San Francisco, CA 94143, USA
- The Pediatric Liver Center, UCSF Benioff Childrens’ Hospital, San Francisco, CA 94143, USA
- Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, CA 94143, USA
- Correspondence: ; Tel.: +1-415-476-4086
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8
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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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9
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Lyu H, Ye Y, Chi Hang Lui V, Wang B. Reducing fibrosis progression of biliary atresia by continuous administration of aducanumab at low dose: A potential treatment. Med Hypotheses 2022. [DOI: 10.1016/j.mehy.2022.110901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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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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Chang D, Geng X, Zhou L, Hou G. Serum TGF- β1 and VEGF Levels Reflect the Liver Hardness and Function in Children with Biliary Atresia. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:5802548. [PMID: 35912145 PMCID: PMC9334070 DOI: 10.1155/2022/5802548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 11/17/2022]
Abstract
Objective This study further explored the wind direction correlation analysis between serum levels of TGF-β1 and VEGF and liver function assessment in children with biliary atresia. Methods A total of 62 children with biliary atresia (BA) who received surgical treatment in our hospital from October 2020 to October 2021 were selected as the research objects (BA group), and 50 normal healthy children who received routine physical examination in our hospital during the same period were selected as blank control group. Outcome measures included postoperative total bilirubin levels and conjugality of enrolled patients. Bilirubin level, unbound bilirubin level, serum transforming growth factor-beta-1 (TGF-β1), vascular endothelial growth factor (VEGF), liver function indicators albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and other observation indicators were included. All data in this study were collected and analyzed by SPSS 23.0 software, and t-test was performed. Results The serum levels of TGF-β1, VEGF, ALT, AST, GGT, and liver hardness were significantly higher in children with jaundice than those without jaundice, and the serum ALB level was significantly lower than that in children without jaundice (P < 0.05). The levels of TGF-β1 and VEGF in BA group were positively correlated with the levels of ALT, AST, GGT, and liver hardness (P < 0.05) but negatively correlated with the level of ALB (P < 0.05). Conclusion The levels of serum TGF-β1 and VEGF in children with biliary atresia have a certain risk correlation with liver function damage, which will become a research focus on the mechanism of liver fibrosis in the diagnosis and treatment of biliary atresia in children.
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Affiliation(s)
- Dongzhe Chang
- General Surgery Department, Henan Provincial Children's Hospital, Affiliated Hospital of Zhengzhou University, China
| | - Xianjie Geng
- General Surgery Department, Henan Provincial Children's Hospital, Affiliated Hospital of Zhengzhou University, China
| | - Liang Zhou
- General Surgery Department, Henan Provincial Children's Hospital, Affiliated Hospital of Zhengzhou University, China
| | - Guangjun Hou
- General Surgery Department, Henan Provincial Children's Hospital, Affiliated Hospital of Zhengzhou University, China
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Study protocol of Phase 2 open-label multicenter randomized controlled trial for granulocyte-colony stimulating factor (GCSF) in post-Kasai Type 3 biliary atresia. Pediatr Surg Int 2022; 38:1019-1030. [PMID: 35391541 DOI: 10.1007/s00383-022-05115-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2022] [Indexed: 12/07/2022]
Abstract
Animal studies support RCT findings of improved liver function and short-term benefits using repurposed Granulocyte Colonic Stimulating Factor GCSF in adults with decompensated cirrhosis. We describe the protocol for phase 2 RCT of sequential Kasai-GCSF under an FDA-approved IND to test that GCSF improves early bile flow and post-Kasai biliary atresia BA clinical outcome. Immediate post-Kasai neonates, age 15-180 days, with biopsy-confirmed type 3 BA, without access to early liver transplantation, will be randomized 1:1 to standard of care SOC + GCSF at 10 ug/kg in 3 daily doses within 4 days of Kasai vs SOC + NO-GCSF (ClinicalTrials.gov NCT0437391). They will be recruited from children's hospitals in Vietnam, Pakistan and one US center. The primary objective is to demonstrate that GCSF decreases the proportion of subjects with a 3-month post-Kasai serum Total Bilirubin ≥ 34 umol/L by 20%, (for a = 0.05, b = 0.80, i.e., calculated sample size of 218 subjects). The secondary objectives are to demonstrate that the frequency of post-Kasai cholangitis at 6-month and 24-month transplant-free survival are improved. The benefits are that GCSF is an affordable BA adjunct therapy, especially in developing countries, to improve biliary complications, enhance quality of liver and survival while diminishing costly liver transplantation.Clinical trial registration: A phase 1 for GCSF dose and safety determination under ClinicalTrials.gov identifier NCT03395028 was completed in 2019. The current Phase 2 trial was registered under NCT04373941.
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Udomsinprasert W, Ungsudechachai T, Vejchapipat P, Poovorawan Y, Honsawek S. Systemic cytokine profiles in biliary atresia. PLoS One 2022; 17:e0267363. [PMID: 35452452 PMCID: PMC9032369 DOI: 10.1371/journal.pone.0267363] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 04/06/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Inflammation and immune dysregulation persuade biliary duct injury in biliary atresia (BA), a leading cause of pediatric liver transplantation given lack of specific biomarkers. We aimed to determine associations between systemic cytokine profiles and clinical parameters in BA patients and to identify potential BA biomarkers. METHODS Systemic levels of 27 cytokines were measured in 82 BA patients and 25 healthy controls using a multiplex immunoassay. Relative mRNA expressions of candidate cytokines in 20 BA livers and 5 non-BA livers were assessed using quantitative real-time PCR. RESULTS Higher levels of 17 cytokines including IL-1β, IL-6, IL-7, IL-8, IL-9, IL-2, IL-15, eotaxin, IP-10, MCP-1, MIP-1α, MIP-1β, G-CSF, IL-1ra, IL-4, IL-5, and IL-10 and lower levels of IFN-α and PDGF were significantly associated with BA. In BA patients, increased levels of IL-7, eotaxin, IP-10, and IL-13 were significantly associated with unfavorable outcomes including jaundice, fibrosis, and portal hypertension. Indeed, systemic levels of those cytokines were significantly correlated with clinical parameters indicating jaundice, fibrosis, and hepatic dysfunction in BA patients. Out of 27 cytokines, 4 (IL-8, IP-10, MCP-1, and PDGF) had potential as sensitive and specific biomarkers of BA. Of these, higher IL-8 levels were significantly associated with reduced survival of BA. In BA livers, relative mRNA expressions of IL-8, IP-10, and MCP-1 were significantly up-regulated. CONCLUSIONS Higher levels of several cytokines including inflammatory cytokines, immunomodulatory cytokines, chemokines, and anti-inflammatory cytokines and lower levels of growth factors would reflect inflammatory and immune responses related to BA development. Among 27 cytokines, plasma IL-8 might have great potential as a diagnostic and prognostic biomarker for BA.
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Affiliation(s)
| | | | - Paisarn Vejchapipat
- Department of Surgery, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Sittisak Honsawek
- Department of Biochemistry, Osteoarthritis and Musculoskeleton Research Unit, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
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Nguyen BU, Holterman A, Holterman M, Dinh LT. Academic Pediatric Surgery Capacity Building in Vietnam Through PASS, a Pediatric Acute Surgical Support Course. Front Surg 2022; 9:868483. [PMID: 35529908 PMCID: PMC9069233 DOI: 10.3389/fsurg.2022.868483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/04/2022] [Indexed: 01/06/2023] Open
Abstract
Neonatal and pediatric surgical emergencies in Low and Low Middle Income countries remain a significant challenge in combatting the burden and inequities of global health. IPSAC-Vietnam is a small Non-Governmental Organization that has been engaged in a 12-year multi-pronged partnership with several children’s hospitals in Vietnam VN to enhance pediatric surgery capacity. We describe the health care, medical training and emergency system in VN as the background for IPSAC activities and development of Pediatric Acute Surgical Support (PASS) course. The course goal is to prepare health care personnel in the immediate management of neonatal/pediatric life-threatening surgical conditions and road injuries at their first point of entry into Vietnam hospitals. PASS is a horizontal outreach initiative that adopts an interprofessional, multidisciplinary, team-training, train-the-trainers, and outcome-based training approach. PASS can be used as a tool for sustainable horizontal capacity-building by champion leaders at the teaching children’s hospitals and medical universities in developing countries, to strengthen training for pediatric surgical emergencies, to integrate pediatric and pediatric surgical care and to advocate for a comprehensive approach to emergency care of the critically ill child.
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Affiliation(s)
- Bich-Uyen Nguyen
- Department of Pediatric Surgery, Ho Chi Minh University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
| | - Aixuan Holterman
- Department of Surgery at Peoria and Chicago; Department of Pediatrics at Chicago, University of Illinois College of Medicine at Peoria and Chicago, Chicago, IL, United States
| | - Mark Holterman
- Department of Surgery at Peoria and Chicago; Department of Pediatrics at Chicago, University of Illinois College of Medicine at Peoria and Chicago, Chicago, IL, United States
| | - Le-Thanh Dinh
- Department of Pediatric Surgery, Children’s Hospital 1, Ho Chi Minh City, Vietnam
- Correspondence: L-T Dinh
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Wu LN, Zhu ZJ, Sun LY. Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia. Front Pediatr 2022; 10:912154. [PMID: 35844731 PMCID: PMC9277099 DOI: 10.3389/fped.2022.912154] [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: 04/04/2022] [Accepted: 06/08/2022] [Indexed: 12/12/2022] Open
Abstract
Biliary Atresia, a common basis for neonatal cholestasis and primary indication for Liver Transplantation, accounts for 60% of pediatric Liver Transplantations. While the pathogenesis of Biliary Atresia remains obscure, abnormalities within bile ducts and the liver, inflammation, fibrosis and cilia defects are thought to comprise the pathological basis for this condition. The findings of genetic variants in Biliary Atresia, such as Copy Number Variations and Single Nucleotide Polymorphism, are considered as essential factors in the development of this condition. In this review, we summarize and analyze these Biliary Atresia variants from a perspective of their pathological characteristics. In conclusion, such analyses may offer novel insights into the pathogenesis of Biliary Atresia and provide a foundation for future studies directed toward a better understanding and treatment of Biliary Atresia.
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Affiliation(s)
- Li-Na Wu
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Zhi-Jun Zhu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Li-Ying Sun
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
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