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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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Pal N, Joy PS, Sergi CM. Biliary Atresia Animal Models: Is the Needle in a Haystack? Int J Mol Sci 2022; 23:7838. [PMID: 35887185 PMCID: PMC9324346 DOI: 10.3390/ijms23147838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000-20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a "needle in a haystack". This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway.
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Affiliation(s)
- Nutan Pal
- Jefferson Graduate School of Biomedical Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Parijat S. Joy
- Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA;
| | - Consolato M. Sergi
- Anatomic Pathology Division, Department of Laboratory Medicine and Pathology, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Department of Lab. Medicine and Pathology, Stollery Children’s Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada
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Islek A, Tumgor G. Biliary atresia and congenital disorders of the extrahepatic bile ducts. World J Gastrointest Pharmacol Ther 2022; 13:33-46. [PMID: 36051179 PMCID: PMC9297290 DOI: 10.4292/wjgpt.v13.i4.33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/10/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia (BA) and choledochal cysts are diseases of the intrahepatic and extrahepatic biliary tree. While their exact etiopathogeneses are not known, they should be treated promptly due to the potential for irreversible parenchymal liver disease. A diagnosis of BA may be easy or complicated, but should not be delayed. BA is always treated surgically, and performing the surgery before the age of 2 mo greatly increases its effectiveness and extends the time until the need for liver transplantation arises. While the more common types of choledochal cysts require surgical treatment, some can be treated with endoscopic retrograde cholangiopancreatography. Choledochal cysts may cause recurrent cholangitis and the potential for malignancy should not be ignored.
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Affiliation(s)
- Ali Islek
- Department of Pediatric Gastroenterology, Cukurova University School of Medicine, Adana 01320, Turkey
| | - Gokhan Tumgor
- Department of Pediatric Gastroenterology, Cukurova University School of Medicine, Adana 01320, Turkey
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Abstract
Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the Hippo signaling pathway, to regulate biological processes like proliferation, survival, and differentiation. YAP1 is most prominently expressed in biliary epithelial cells (BECs) in normal adult livers and during development. In the current review, we will discuss the multiple roles of YAP1 in the development and morphogenesis of bile ducts inside and outside the liver, as well as in orchestrating the cholangiocyte repair response to biliary injury. We will review how biliary repair can occur through the process of hepatocyte-to-BEC transdifferentiation and how YAP1 is pertinent to this process. We will also discuss the liver's capacity for metabolic reprogramming as an adaptive mechanism in extreme cholestasis, such as when intrahepatic bile ducts are absent due to YAP1 loss from hepatic progenitors. Finally, we will discuss the roles of YAP1 in the context of pediatric pathologies afflicting bile ducts, such as Alagille syndrome and biliary atresia. In conclusion, we will comprehensively discuss the spatiotemporal roles of YAP1 in biliary development and repair after biliary injury while describing key interactions with other well-known developmental pathways.
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Affiliation(s)
- Laura Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine
| | - Kari Nejak-Bowen
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine,Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Satdarshan P. Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine,Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania,Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania
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Sergi CM, Gilmour S. Biliary Atresia: A Complex Hepatobiliary Disease with Variable Gene Involvement, Diagnostic Procedures, and Prognosis. Diagnostics (Basel) 2022; 12:330. [PMID: 35204421 PMCID: PMC8870870 DOI: 10.3390/diagnostics12020330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
The diagnosis of biliary atresia is still terrifying at the 3rd decade of the 21st century. In a department of neonatal intensive care unit, parents and physicians face a challenge with a jaundiced baby, who may or may not have a surgically correctable hepatopathy. The approach has been systematically evaluated, but the etiology remains ambiguous. The study of families with recurrent biliary atresia has been undertaken at a molecular level. The primary interest with this disease is to identify the etiology and change the treatment from symptomatic to curative. The occurrence of this obstructive cholangio-hepatopathy in well-known genetic syndromes has suggested just coincidental finding, but the reality can be more intriguing because some of these diseases may have some interaction with the development of the intrahepatic biliary system. Several genes have been investigated thoroughly, including ADD3 and GPC1 shifting the interest from viruses to genetics. In this review, the intriguing complexities of this hepatobiliary disease are highlighted.
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Affiliation(s)
- Consolato M. Sergi
- Stollery Children’s Hospital, Laboratory Medicine and Pathology, University Alberta Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada
- Division of Anatomic Pathology, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
| | - Susan Gilmour
- Department of Pediatric Gastroenterology and Nutrition, University of Alberta, Edmonton, AB T6G 2B7, Canada;
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The usefulness of immunohistochemical staining of bile tracts in biliary atresia. Clin Exp Hepatol 2021; 7:41-46. [PMID: 34027114 PMCID: PMC8122094 DOI: 10.5114/ceh.2021.104676] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 11/02/2020] [Indexed: 12/30/2022] Open
Abstract
Aim of the study To assess ductular proliferation (DP) and ductal plate malformation (DPM) in biliary atresia (BA) by means of immunohistochemical staining using cytokeratins CK7 and CK19 and neural cell adhesion molecule (NCAM) antibody CD56. Material and methods In 10 cases of BA, liver surgical biopsies obtained at the time of hepatoportoenterostomy were stained with H&E, PAS, Gomori and Azan methods. Immunohistochemical technique was used to outline bile ducts, ductular reaction, reactive bile duct/ductules and DPM by CK7, CK19 and NCAM antibody CD56. Results We found fibrosis, bile stasis and mild inflammation in all cases. In the routine staining DP was not seen in 3 cases. The immunohistochemical staining by means of CK19 was helpful in the detection of DP, and allowed it to be demonstrated in all cases. The biliary epithelial cell markers for CD56, CK7, CK19 were used for demonstration of bile duct cell but not hepatocyte alterations in the structure of intrahepatic biliary ducts and different stages of maturation. CD56 as a marker of immature bile ducts was expressed on biliary epithelium of bile ducts and bizarre forms of DPM in 6 cases. The positive expression of CD56 corresponded to the co-localization of CK19 of DPM, but not CK7, to the ductular reaction at the limiting plate of portal tracts. CD7, considered as a marker of DP, also stained ductal hepatocytes and multipotential oval cells, and was a marker of DPM in 3 cases. Conclusions Use of CK7, CK19 and CD56 is helpful in BA diagnosis and allows differentiation of the stage of developing bile duct cells according to the expression pattern.
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Vij M, Rela M. Biliary atresia: pathology, etiology and pathogenesis. Future Sci OA 2020; 6:FSO466. [PMID: 32518681 PMCID: PMC7273417 DOI: 10.2144/fsoa-2019-0153] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the intrahepatic and extrahepatic biliary system, resulting in obstruction of bile flow and neonatal jaundice. Histopathological findings in liver biopsies include the expansion of the portal tracts, with edematous fibroplasia and bile ductular proliferation, with bile plugs in duct lumen. Lobular morphological features may include variable multinucleate giant cells, bilirubinostasis and hemopoiesis. The etiopathogenesis of biliary atresia is multifactorial and multiple pathomechanisms have been proposed. Experimental and clinical studies have suggested that viral infection initiates biliary epithelium destruction and release of antigens that trigger a Th1 immune response, which leads to further injury of the bile duct, resulting in inflammation and obstructive scarring of the biliary tree. It has also been postulated that biliary atresia is caused by a defect in the normal remodelling process. Genetic predisposition has also been proposed as a factor for the development of biliary atresia.
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Affiliation(s)
- Mukul Vij
- Senior Consultant Histopathologist, Department of Pathology, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India, 600044
| | - Mohamed Rela
- Institute of Liver Disease & Transplantation, Chairmen, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India, 600044
- Liver Transplant Unit, Kings College Hospital, London SE5 9RS, UK
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8
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Abstract
OBJECTIVES The present study aimed to estimate the value of serum interleukin-33 (IL-33) levels in infants with cholestasis, correlate serum IL-33 levels with the clinicopathological profile of infants with cholestasis, and compare its level with that of healthy infants who served as control. METHODS Sixty infants with cholestasis were enrolled in the present study and divided into biliary atresia (BA) group and non-BA group, in addition to 30 healthy infants as a control group. All infants were analyzed for their clinical and biochemical features, histopathological profile, and serum level of IL-33 by enzyme-linked immune sorbent assay. RESULTS Serum level of IL-33 in BA group (median 48.0, interquartile range: 28.9-106.2) was significantly higher than that of the non-BA group (median 17.3, interquartile range: 13.7-18.8 pg/mL) and both were higher than that of the control group. There was a positive correlation between serum IL-33 and aspartate aminotransferase, alanine aminotransferase, bilirubin (total and direct) levels, and fibrosis stage among the BA group. Serum IL-33 at a cut-off value of 20.8 pg/mL can detect BA with a specificity of 95% and a sensitivity of 96.7%. CONCLUSION The significantly higher production of IL-33 in patients with BA compared to non-BA suggests a potential role of IL-33 for initiation and progression of the disease process, also, IL-33 may have a diagnostic role in infants with BA.
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Abstract
Navigating the complexities of interpreting a liver biopsy performed on a neonate with conjugated/direct hyperbilirubinemia can be an arduous task given these biopsies are infrequently encountered. The list of entities is long and yet there are only a few histologic patterns of liver injury. The first step for the pathologist is to determine the histologic pattern, which will guide further inquiry into the useful clinical information to have while evaluating the biopsy. Ultimately, the goal is to identify those conditions that will benefit from early intervention. We begin with a review of biliary development to help understand what findings may be physiologic versus pathologic, particularly in premature infants. Then we review eight cases that cover the three most common histologic patterns of injury in patients with neonatal cholestasis: biliary obstructive, neonatal hepatitis, and paucity of intrahepatic bile ducts. The entities that serve as prototypes for these histologic patterns are covered, including biliary atresia, idiopathic neonatal hepatitis, and Alagille syndrome, along with rarer entities that have histologic overlap. The cases with accompanying tables and algorithms are intended to help place the histologic findings in the context of the overall clinical work-up, including genetic testing.
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Affiliation(s)
- Soo-Jin Cho
- Department of Pathology, University of California San Francisco, San Francisco, CA United States
| | - Grace E Kim
- Department of Pathology, University of California San Francisco, San Francisco, CA United States.
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Russo P, Magee JC, Anders RA, Bove KE, Chung C, Cummings OW, Finegold MJ, Finn LS, Kim GE, Lovell MA, Magid MS, Melin-Aldana H, Ranganathan S, Shehata BM, Wang L, White FV, Chen Z, Spino C. Key Histopathologic Features of Liver Biopsies That Distinguish Biliary Atresia From Other Causes of Infantile Cholestasis and Their Correlation With Outcome: A Multicenter Study. Am J Surg Pathol 2016; 40:1601-1615. [PMID: 27776008 PMCID: PMC5123664 DOI: 10.1097/pas.0000000000000755] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The liver biopsy guides diagnostic investigation and therapy in infants with undiagnosed cholestasis. Histologic features in the liver may also have prognostic value in the patient with biliary atresia (BA). We assessed the relative value of histologic features in 227 liver needle biopsies in discriminating between BA and other cholestatic disorders in infants enrolled in a prospective Childhood Liver Disease Research Network (ChiLDReN) cohort study by correlating histology with clinical findings in infants with and without BA. In addition, we reviewed 316 liver biopsies from clinically proven BA cases and correlated histologic features with total serum bilirubin 6 months after hepatoportoenterostomy (the Kasai procedure, HPE) and transplant-free survival up to 6 years. Review pathologists were blinded to clinical information except age. Semiquantitative scoring of 26 discrete histologic features was based on consensus. Bile plugs in portal bile ducts/ductules, moderate to marked ductular reaction, and portal stromal edema had the largest odds ratio for predicting BA versus non-BA by logistic regression analysis. The diagnostic accuracy of the needle biopsy was estimated to be 90.1% (95% confidence interval [CI]: 85.2%, 94.9%), whereas sensitivity and specificity for a diagnosis of BA are 88.4% (95% CI: 81.4, 93.5) and 92.7% (95% CI: 84.8, 97.3), respectively. No histologic features were associated with an elevated serum bilirubin 6 months after HPE, although it (an elevated serum bilirubin) was associated with an older age at HPE. Higher stages of fibrosis, a ductal plate configuration, moderate to marked bile duct injury, an older age at HPE, and an elevated international normalized ratio were independently associated with a higher risk of transplantation.
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Affiliation(s)
- P Russo
- Department of Pathology and Laboratory Medicine, the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - JC Magee
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - RA Anders
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - KE Bove
- Division of Pediatric Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | - C Chung
- Division of Pathology, The Hospital of Sick Children, Toronto, Canada
| | - OW Cummings
- Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana
| | - MJ Finegold
- Department of Pathology, Texas Children’s Hospital, Houston, Texas
| | - LS Finn
- Department of Pathology, Seattle Children’s Hospital, Seattle, Washington
| | - GE Kim
- Department of Pathology, University of California San Francisco, San Francisco, California
| | - MA Lovell
- Department of Pathology, Children’s Hospital Colorado, Aurora, Colorado
| | - MS Magid
- Department of Pathology, Kravis Children’s Hospital, Mount Sinai Health System, New York, New York
| | - H Melin-Aldana
- Department of Pathology, Ann & Robert H. Lurie Children’s Hospital, Chicago, Illinois
| | - S Ranganathan
- Department of Pathology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
| | - BM Shehata
- Department of Pathology, Children’s Healthcare of Atlanta, Atlanta, Georgia
| | - L Wang
- Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, California
| | - FV White
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri
| | - Z Chen
- Quest Diagnostics, Health Informatics, Madison New Jersey
| | - C Spino
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
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Obayashi J, Tanaka K, Ohyama K, Manabe S, Nagae H, Shima H, Sato H, Furuta S, Wakisaka M, Koike J, Takagi M, Kitagawa H. Relation between amount of bile ducts in portal canal and outcomes in biliary atresia. Pediatr Surg Int 2016; 32:833-8. [PMID: 27457233 DOI: 10.1007/s00383-016-3941-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/21/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND There is no good prognostic indicator for biliary atresia (BA). We reviewed liver biopsies taken during the initial procedure to find a prognostic marker. METHODS Thirty-two BA cases underwent Kasai operation from 1976 to 2009. We compared two groups at 1, 3, and 9 years. Group A required liver transplantation or died. Group B survived with their native liver. Biopsies were analyzed for liver fibrosis, portal-central vein bridging (P-C bridging), ductal plate malformation (DPM) and the number of the bile ducts in portal canal/measured surface area of the portal canal (BDP ratio). Statistical comparisons of the multiple data were evaluated by Mann-Whitney U test, Student's t test and Pearson's Chi-square test. Regression analysis with P < 0.05 was considered significant. RESULTS BDP ratios (/mm(2)) were 2.4 ± 1.5 in Group A1 (n = 9) vs 4.6 ± 2.4 in Group B1 (n = 23) (P = 0.01); 2.6 ± 1.4 in Group A3 (n = 14) vs 5.1 ± 2.5 in Group B3 (n = 18) (P < 0.01), 3.0 ± 2.2 in Group A9 (n = 15) vs 4.9 ± 2.5 in Group B9 (n = 15) (P < 0.05). There was no significant difference in any other finding. CONCLUSION The BDP ratio is a sound prognostic indicator in BA.
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Affiliation(s)
- Juma Obayashi
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Kunihide Tanaka
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Kei Ohyama
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Shutaro Manabe
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Hideki Nagae
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Hideki Shima
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Hideaki Sato
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Shigeyuki Furuta
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Munechika Wakisaka
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan
| | - Junki Koike
- Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Masayuki Takagi
- Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Hiroaki Kitagawa
- Division of Pediatric Surgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan.
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Recent Trends in the Diagnosis and Management of Biliary Atresia in Developing Countries. Indian Pediatr 2016; 52:871-9. [PMID: 26499012 DOI: 10.1007/s13312-015-0735-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
NEED AND PURPOSE OF REVIEW Biliary atresia is a progressive obstructive cholangiopathy and is fatal if left untreated within 2 years of life. Delay in referral is because of difficulties in differentiating it from physiologic jaundice and identifying an abnormal stool color. This paper presents an overview on the diagnosis and discusses the current strategies in the management of this disease in developing countries. METHODS Articles were retrieved from the PubMed database using the terms biliary atresia, Kasai portoenterostomy and pediatric liver transplantation. Contents of the article are also based on personal experience of the authors. CONCLUSION A national screening program using stool color cards as part of standard care in the neonatal period will greatly improve early detection of biliary atresia. Outcomes will improve if it is diagnosed at the earliest after birth, the child is referred to an experienced pediatric hepatobiliary unit for evaluation, and undergoes an early Kasai procedure. If an early Kasai portoenterostomy is performed, nearly half of all children survive into adolescence, and about one-third are likely to have a long-term, symptom-free life with normal liver biochemistry. Sequential treatment combining Kasai as first line and liver transplantation as second line results in 90% survival for children with biliary atresia.
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Arafa RS, Abdel Haie OM, El-Azab DS, Abdel-Rahman AM, Sira MM. Significant hepatic expression of IL-2 and IL-8 in biliary atresia compared with other neonatal cholestatic disorders. Cytokine 2016; 79:59-65. [PMID: 26765485 DOI: 10.1016/j.cyto.2015.12.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 12/14/2015] [Accepted: 12/29/2015] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Although the exact etiology of biliary atresia (BA) is still elusive, inflammation plays a key role. Release of proinflammatory cytokines from activated immune cells perpetuates the injury and causes biliary destruction. We aimed to study interleukin (IL)-2 and IL-8 expression in liver tissue of BA patients compared with other neonatal cholestatic disorders. METHODS The study included 59 infants with neonatal cholestasis in two groups; BA group (n=31) and non-BA group (n=28) with cholestatic disorders other than BA as controls. Demographic, clinical, laboratory, and histopathological parameters were collected. IL-2 and IL-8 immunostaining was performed. Immunostaining in portal cellular infiltrate was scored as positive or negative and expressed as the mean cell count in three portal tracts. RESULTS The mean value of IL-2 and IL-8 positive inflammatory cells was significantly higher in BA than in non-BA group (P-values of 0.004 and 0.002 respectively). IL-2 correlated significantly with IL-8 immunostaining in both BA and non-BA group (P<0.0001 for both). Furthermore, both cytokines in both groups correlated significantly with inflammatory activity in liver biopsy while there was no significant correlation with the other studied parameters. Yet, there was a trend of increased expression of IL-2 and IL-8 with increasing stage of fibrosis in BA group. This trend was not observed in non-BA group. CONCLUSION The significantly higher expression of IL-2 and IL-8 in patients with BA compared to non-BA suggests a potential role for these cytokines in the pathogenesis in therapy of this devastating neonatal hepatic disorder.
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Affiliation(s)
- Reda Sanad Arafa
- Department of Pediatrics, Faculty of Medicine, Benha University, Egypt
| | | | - Dina Shehata El-Azab
- Department of Pathology, National Liver Institute, Menofiya University, 32511 Shebin El-koom, Menofiya, Egypt
| | | | - Mostafa M Sira
- Department of Pediatric Hepatology, National Liver Institute, Menofiya University, 32511 Shebin El-koom, Menofiya, Egypt.
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Safwan M, Ramachandran P, Vij M, Shanmugam N, Rela M. Impact of ductal plate malformation on survival with native liver in children with biliary atresia. Pediatr Surg Int 2015; 31:837-843. [PMID: 26140838 DOI: 10.1007/s00383-015-3728-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/23/2015] [Indexed: 11/29/2022]
Abstract
PURPOSE Ductal plate malformation (DPM) like arrays in the liver which resemble the characteristic persistent embryonal ductular structures have been shown to adversely affect the outcome of Kasai portoenterostomy (KPE) in biliary atresia (BA). We studied the impact of DPM on survival with native liver (SNL) in children with BA who underwent liver transplantation (LT) after KPE as well as those who underwent primary LT without KPE. METHODS Records of children with BA who underwent LT in our institute were reviewed and divided into three groups-Group 1 had primary LT because of delayed diagnosis of BA and synthetic liver failure, Group 2 had LT for synthetic liver failure after a failed KPE, and Group 3 had LT despite clearing jaundice after KPE for other indications. The impact of DPM on SNL was analyzed using standard statistical means. RESULTS In Group 1 (n = 26) and Group 2 (n = 26), the incidence of DPM was high and was associated with a significantly shorter SNL compared to children with no DPM. The incidence of DPM was significantly lower in Group 3 (n = 13). CONCLUSION DPM shortens SNL and influences the pathogenesis of disease progression in children with BA who had synthetic liver failure requiring transplantation either because of a failed KPE or due to a delay in diagnosis. Its incidence is low in children who cleared jaundice after KPE and needed transplantation for other indications at a later age. The presence of DPM signifies an adverse outcome for the disease.
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Affiliation(s)
- Mohamed Safwan
- Institute of Liver Disease and Transplantation, Global Health City, #439, Cheran Nagar, Perumbakkam, Chennai, 600 100, India
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Abstract
Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease.
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Ductal plate malformation in patients with biliary atresia. Eur J Pediatr 2012; 171:1799-804. [PMID: 22983023 DOI: 10.1007/s00431-012-1820-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Accepted: 08/30/2012] [Indexed: 10/27/2022]
Abstract
UNLABELLED The presence of ductal plate malformation (DPM+) on liver histology in children with biliary atresia (BA) is a marker of early intrauterine disease onset and an indication of an unfavorable prognosis. We studied the prognostic value of DPM in infants with BA after hepatoportoenterostomy (HPE). We reviewed 28 BA patients who underwent HPE in a single medical center. We examined the time of jaundice onset after delivery (conjugated hyperbilirubinemia): early onset (fetal phenotype with no jaundice-free interval) vs. late onset (perinatal phenotype with jaundice-free interval) and the presence or absence of DPM (DPM+ or DPM-) histopathology. Primary outcome was jaundice clearance at 3 months after HPE and survival with native liver (SNL). Eight children had fetal and 20 had perinatal BA (8 DPM+, 12 DPM-). At 3 months after HPE, no patients with fetal BA had achieved jaundice clearance, while jaundice clearance was achieved in five patients with DPM+ perinatal disease and four patients with DPM- perinatal BA (P = 0.03, comparing all three groups; P = 0.36, comparing DPM+ vs. DPM- perinatal patients). Median SNL was 8.6 months for fetal BA patients, 148.2 months for DPM+ perinatal BA patients, and 93.2 months for DPM- perinatal BA patients (log-rank test, P < 0.001, comparing all three groups; P = 0.59, comparing DPM+ vs. DPM- perinatal patients). After adjusting for BA type, age older than 2 months at HPE was associated with worse SNL [P = 0.03; hazard ratio = 4.0 (95 % CI, 1.1-14.2)]. CONCLUSIONS Early onset of jaundice, regardless of DPM histology, was the most ominous sign of poor outcome in infants with BA after HPE.
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Wang ZM, Chen YJ. Recent progress in understanding pathogenesis and liver pathology in biliary atresia. Shijie Huaren Xiaohua Zazhi 2012; 20:2576-2582. [DOI: 10.11569/wcjd.v20.i27.2576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia is an infantile destructive inflammatory cholangiopathy that causes obliteration of both intrahepatic and extrahepatic bile ducts and eventually liver cirrhosis. So far, the exact etiology and pathogenesis of biliary atresia remain unclear, and possible etiologies include congenital and genetic factors, infection, inflammation, immune reaction, maternal factors, and vascular factors. Immunoinflammatory theory has been accepted by most researchers, which is supported by liver pathological changes. This review focuses on the recent progress in understanding pathogenesis and liver pathology in biliary atresia.
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Moreira RK, Cabral R, Cowles RA, Lobritto SJ. Biliary atresia: a multidisciplinary approach to diagnosis and management. Arch Pathol Lab Med 2012; 136:746-60. [PMID: 22742548 DOI: 10.5858/arpa.2011-0623-ra] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Biliary atresia is an inflammatory cholangiopathy of infancy that results in progressive fibrosis and obliteration of bile ducts and represents the main indication for liver transplant in young children. In spite of extensive investigation, its etiology has remained poorly understood. Timely surgical intervention (Kasai procedure) may result in significant benefit to these patients and represents the final goal of an accurate diagnostic evaluation. OBJECTIVE To present an overview of biliary atresia, including clinical and surgical approaches to this disease, with emphasis on the histopathologic evaluation. DATA SOURCES Review of relevant literature indexed in PubMed (US National Library of Medicine). CONCLUSION A well-coordinated multidisciplinary approach is required in the assessment of suspected cases of biliary atresia. Pathologic examination of biopsy specimens is an integral part of the diagnostic algorithm and, therefore, plays a pivotal role in the diagnostic evaluation of this disease.
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Affiliation(s)
- Roger Klein Moreira
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
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Abstract
Biliary atresia is the most common cholangiopathy of childhood. With complete obstruction of segments or the entire length of extrahepatic bile ducts, the timely pursuit of hepatoportoenterostomy is the best strategy to restore bile drainage. However, even with prompt surgical intervention, ongoing injury of intrahepatic bile ducts and progressive cholangiopathy lead to end-stage cirrhosis. The pace of disease progression is not uniform; it may relate to clinical forms of disease and/or staging of liver pathology at diagnosis. Although the etiology of disease is not yet defined, several biological processes have been linked to pathogenic mechanisms of bile duct injury. Among them, there is increasing evidence that the immune system targets the duct epithelium and disrupts bile flow. We discuss how careful clinical phenotyping, staging of disease, and basic mechanistic research are providing insights into clinical trial designs and directions for development of new therapies to block progression of disease.
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Affiliation(s)
- Kazuhiko Bessho
- Pediatric Liver Care Center and Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229-3031, USA
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Ductal plates in hepatic ductular reactions. Hypothesis and implications. III. Implications for liver pathology. Virchows Arch 2011; 458:271-9. [PMID: 21301864 DOI: 10.1007/s00428-011-1050-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Revised: 01/18/2011] [Accepted: 01/20/2011] [Indexed: 02/08/2023]
Abstract
This article discusses on the basis of the ductal plate hypothesis the implication of the concept for several liver abnormalities. The occurrence of ductal plates (DP) during liver growth in childhood would explain the paraportal and parenchymal localizations of von Meyenburg complexes in postnatally developed parts of the liver, and their higher incidence in adulthood versus childhood. It partly clarifies the lack of postnatal intrahepatic bile duct development in Alagille syndrome and the reduced number of portal tracts in this disease. Ductular reactions (DRs) in DP configuration are the predominant type of progenitor cell reaction in fulminant necro-inflammatory liver disease, when lack of sufficient parenchymal regeneration results in liver failure. The concept of dissecting DRs explains the micronodular pattern of advanced biliary and alcoholic cirrhosis. The concept explains the DP patterns of bile ducts in several cases of biliary atresia, with implications for diagnosis and prognosis. The hypothesis also has an impact on concepts about stem/progenitor cells and their niche.
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Desmet VJ. Ductal plates in hepatic ductular reactions. Hypothesis and implications. III. Implications for liver pathology. Virchows Arch 2011; 458:251-9. [PMID: 21301864 DOI: 10.1007/s00428-011-1048-3] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2010] [Revised: 01/18/2011] [Accepted: 01/20/2011] [Indexed: 01/09/2023]
Abstract
This article discusses on the basis of the ductal plate hypothesis the implication of the concept for several liver abnormalities. The occurrence of ductal plates (DP) during liver growth in childhood would explain the paraportal and parenchymal localizations of von Meyenburg complexes in postnatally developed parts of the liver, and their higher incidence in adulthood versus childhood. It partly clarifies the lack of postnatal intrahepatic bile duct development in Alagille syndrome and the reduced number of portal tracts in this disease. Ductular reactions (DRs) in DP configuration are the predominant type of progenitor cell reaction in fulminant necro-inflammatory liver disease, when lack of sufficient parenchymal regeneration results in liver failure. The concept of dissecting DRs explains the micronodular pattern of advanced biliary and alcoholic cirrhosis. The concept explains the DP patterns of bile ducts in several cases of biliary atresia, with implications for diagnosis and prognosis. The hypothesis also has an impact on concepts about stem/progenitor cells and their niche.
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Affiliation(s)
- Valeer J Desmet
- Department of Pathology, University Hospital K.U.Leuven, Leuven, Belgium,
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Advances in biliary atresia: from patient care to research. Braz J Med Biol Res 2010; 43:522-7. [PMID: 20464347 DOI: 10.1590/s0100-879x2010007500035] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Accepted: 04/19/2010] [Indexed: 01/01/2023] Open
Abstract
Biliary atresia, the most common cause of liver transplantation in children, remains a challenge for clinicians and investigators. The development of new therapeutic options, besides the typical hepatoportoenterostomy, depends on a greater understanding of its pathogenesis and how it relates to the clinical phenotypes at diagnosis and the rate of disease progression. In this review, we present a perspective of how recent research has advanced the understanding of the disease and has improved clinical care protocols. Molecular and morphological analyses at diagnosis point to the potential contributions of polymorphism in the CFC1 and VEGF genes to the pathogenesis of the disease, and to an association between the degree of bile duct proliferation and long-term outcome. In experimental models, cholangiocytes do not appear to have antigen-presenting properties despite a substantial innate and adaptive immune response that targets the biliary epithelium and produces duct obstruction. Initial clinical trials assessing the efficacy of corticosteroids in decreasing the inflammation and improving outcome do not show a superior effect of corticosteroids as an adjuvant treatment following hepatoportoenterostomy. The best outcome still remains linked to an early diagnosis and surgical treatment. In this regard, the Yellow Alert campaign by the Sociedade Brasileira de Pediatria and the inclusion of the Stool Color Card in the health booklet given to every neonate in Brazil have the potential to decrease the age of diagnosis, shorten the time between diagnosis and surgical treatment, and improve the long-term outcome of children with this devastating disease.
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