|
1
|
Ram AK, Vats A, Bhatia A, Kumar Y. Evolving Concepts in Etiology of Biliary Atresia: Insights and Perspectives from India. Fetal Pediatr Pathol 2025; 44:236-258. [PMID: 40181637 DOI: 10.1080/15513815.2025.2477704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 03/01/2025] [Accepted: 03/04/2025] [Indexed: 04/05/2025]
Abstract
Introduction: Biliary atresia (BA) is a potentially fatal newborn cholestatic disease. It is a rapidly advancing fibro-obliterative cholangiopathy that leads to liver failure and death if not treated early. The well-known multihit hypothesis proposes that viral or chemical disruption to the biliary epithelium triggers an immune-mediated inflammatory response, resulting in fibrosis and blockage of the intra and extrahepatic biliary systems. Methods: In recent years, several papers have noticed an upsurge in many aspects of BA, particularly its etiopathogenesis, which has opened a vista of various probable mechanisms currently being examined. This review brings them together with an emphasis on reflecting current scientific views for those interested in this illness. Conclusions: Among the different etiological factors proposed for BA, viruses and immune-mediated injury are the strongest contenders as contributors to the disease onset and pathogenesis.
Collapse
Affiliation(s)
- Anil Kumar Ram
- Department of Pathology, University of Kansas Medical Center, Kansas City, USA
| | - Akshit Vats
- Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Yashwant Kumar
- Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| |
Collapse
|
|
2
|
Vutukuru S, Solanki S, Kanojia RP. Delphi Method Analysis and Consensus of Prevalent Distinctive Practices for Biliary Atresia Management after Kasai Portoenterostomy. J Indian Assoc Pediatr Surg 2024; 29:271-276. [PMID: 38912031 PMCID: PMC11192269 DOI: 10.4103/jiaps.jiaps_250_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/29/2024] [Accepted: 02/05/2024] [Indexed: 06/25/2024] Open
Abstract
Background Extrahepatic biliary atresia (BA) is seen in infants, with an incidence of 1 in 15,000 live births. The presentation is progressive jaundice, dark-colored urine, and clay-colored stools. Kasai portoenterostomy (KPE) is the commonly performed surgical procedure in these patients. Postoperatively, phenobarbitone, ursodeoxycholic acid (UDCA), steroids, and other drugs are given to improve bile drainage and prevent inflammation and fibrosis. However, a definitive protocol regarding the need for different drugs, dosage, and duration varies across individual surgeons and centers. No universally accepted protocol exists for postoperative management after KPE. Aim The aim of this study was to know the prevailing postoperative management of BA by subject experts and use the Delphi process to know if the experts want to change their practice based on the results from the survey. Material and Methods A questionnaire was made after discussing with two experts in the field of BA. The questionnaire was mailed to 25 subject experts. The first survey data were analyzed and shared with all responders. In the second survey, change in the management based on the results from the first survey was assessed. Results The Delphi questionnaire was answered by 17 experts. Postoperatively, prophylactic antibiotics are prescribed for 6-12 weeks by around 40% and >12 weeks by 30% of respondents. Phenobarbitone is prescribed for <3 months by nearly 50%. UDCA is prescribed for <3 months, ≤6 months, and 6 months-1 year by 47.1%, 23.5%, and 23.5% responders, respectively. Nearly 50% prescribe steroids (mostly prednisolone), and among them, two-thirds prescribe it for 6-12 weeks. Approximately 60% give antiviral drugs to children who are cytomegalovirus immunoglobulin M positive. In our survey, 50% of experts perform 5-10 KPE per year, and 25% each perform 10-15 and >15 KPE per year. The second survey noted that a significant percentage of responders want to change their practice according to consensus. Conclusion From our Delphi survey, an overview of the postoperative management of BA could be made. However, multicentric studies are required for uniform protocol on the postoperative management of BA.
Collapse
Affiliation(s)
- Sravanthi Vutukuru
- Department of Pediatric Surgery, Siddhartha Medical College, Vijayawada, Andhra Pradesh, India
| | - Shailesh Solanki
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ravi Prakash Kanojia
- Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
3
|
Kemme S, Canniff JD, Feldman AG, Garth KM, Li S, Pan Z, Sokol RJ, Weinberg A, Mack CL. Cytomegalovirus in biliary atresia is associated with increased pretransplant death, but not decreased native liver survival. Hepatol Commun 2023; 7:e0175. [PMID: 37471052 PMCID: PMC10351947 DOI: 10.1097/hc9.0000000000000175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 04/09/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Biliary atresia (BA) is likely caused by a common phenotypic response to various triggers; one proposed trigger, cytomegalovirus (CMV), may lead to worse outcomes. The aim of this study was to determine the severity of disease and pretransplant outcomes of infants with BA, who have evidence of CMV (CMV+) at diagnosis compared with CMV-negative (CMV-) infants. METHODS The study used data and biospecimens from the Childhood Liver Disease Research Network PROBE study of cholestatic infants. Plasma obtained at the time of hepatic portoenterostomy (HPE) of 249 infants with BA was tested for CMV by DNA-PCR and CMV-IgM. Comparisons between CMV+ and CMV- infants were made using Wilcoxon rank sum, Student t test, chi-square, or Fisher exact test. Native liver survival (NLS) outcomes were analyzed using Kaplan-Meier and Cox regression adjusting for age at HPE; pretransplant patient survival outcomes were analyzed using a competing risk model and adjusting for age at HPE. RESULTS CMV+ infants (n = 29, 12%) underwent HPE later (67.8±13.6 d vs. 55.1±18.5 d, p = 0.0005) and had higher baseline alkaline phosphatase and aminotransferases. There was no difference between groups in jaundice clearance or NLS. The subdistribution HR of pretransplant death for CMV+ infants adjusted for age at HPE was 3.8 (p = 0.034). CONCLUSIONS CMV infection at the time of HPE in infants with BA is not associated with worse NLS despite the association with worse liver injury, older age at HPE, and increased risk of pretransplant death adjusted for age at HPE. Continued evaluation of the consequences of CMV infection and the effects of antiviral treatment should be explored.
Collapse
Affiliation(s)
- Sarah Kemme
- D.Brent Polk Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Monroe Carrell Jr. Children’s Hospital at Vanderbilt, Nashville, Tennessee, USA
| | - Jennifer D. Canniff
- Department of Pediatrics, Medicine, and Pathology, University of Colorado, Aurora, Colorado, USA
| | - Amy G. Feldman
- Digestive Health Institute, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Krystle M. Garth
- Department of Pediatrics, Medicine, and Pathology, University of Colorado, Aurora, Colorado, USA
| | - Shaobing Li
- Pediatric Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Zhaoxing Pan
- Department of Pediatrics, Research Institute, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Ronald J. Sokol
- Digestive Health Institute, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Adriana Weinberg
- Department of Pediatrics, Medicine, and Pathology, University of Colorado, Aurora, Colorado, USA
| | - Cara L. Mack
- Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology & Nutrition, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, Wisconsin, USA
| |
Collapse
|
|
4
|
Akter S, Karim ASMB, Mazumder MW, Rukunuzzaman M, Nahid KL, Dey BP, Sayeed M, Rahman AZMR, Fathema K, Khadga M. A Comparative Study Between Cytomegalovirus Immunoglobulin M-Positive and CMV Immunoglobulin M-Negative Biliary Atresia in Infants Attending a Tertiary Care Hospital in Bangladesh. Pediatr Gastroenterol Hepatol Nutr 2022; 25:413-421. [PMID: 36148290 PMCID: PMC9482831 DOI: 10.5223/pghn.2022.25.5.413] [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: 01/21/2022] [Revised: 04/04/2022] [Accepted: 07/07/2022] [Indexed: 11/19/2022] Open
Abstract
PURPOSE Perinatal cytomegalovirus (CMV) infection can lead to biliary atresia (BA) in different entities. This study aimed to compare the clinical, hematological, biochemical, and histological features of infants with BA based on their CMV immunoglobulin M (IgM) status at presentation. METHODS This cross-sectional descriptive study was carried out between January 2019 and June 2020 at the Department of Pediatric Gastroenterology and Nutrition at the Bangabandhu Sheikh Mujib Medical University (BSMMU) in Dhaka. Forty-three patients with BA were selected purposively and categorized into either the CMV IgM-positive or CMV IgM-negative BA group. Categorical variables were compared using Fisher's exact test and chi-square tests, while the Student's t-test and Mann-Whitney U-test were used to compare continuous variables. For all statistical tests, a p-value <0.05 was considered statistically significant. RESULTS Thirty-three (76.7%) of the cases were between 2 and 3 months of age on admission. The clinical, hematological, and biochemical parameters did not differ significantly between the CMV IgM-positive and CMV IgM-negative BA groups. Most (50.0%) of the CMV IgM-positive cases had fibrosis stage F2, while 43.5% of the CMV IgM-negative cases had fibrosis stage F3, with no significant difference between the groups (p=0.391). CONCLUSION Our data shows no significant distinction between CMV IgM-positive and CMV IgM-negative BA, suggesting that CMV does not contribute to BA pathogenesis.
Collapse
Affiliation(s)
- Sharmin Akter
- Department of Pediatric Gastroenterology & Nutrition, Faculty of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - A S M Bazlul Karim
- Department of Pediatric Gastroenterology & Nutrition, Faculty of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Md Wahiduzzaman Mazumder
- Department of Pediatric Gastroenterology & Nutrition, Faculty of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Md Rukunuzzaman
- Department of Pediatric Gastroenterology & Nutrition, Faculty of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Khan Lamia Nahid
- Department of Pediatric Gastroenterology & Nutrition, Faculty of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Bishnu Pada Dey
- Department of Pathology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Maimuna Sayeed
- Department of Gastroenterology, Evercare Hospital, Dhaka, Bangladesh
| | - A Z M Raihanur Rahman
- Department of Pediatric Gastroenterology & Nutrition, Faculty of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Kaniz Fathema
- Department of Paediatric Gastroenterology & Nutrition, Sir Salimullah Medical College, Dhaka, Bangladesh
| | - Mukesh Khadga
- Department of Pediatrics, Sumeru Hospital, Dhapakhel, Kathmundu, Nepal
| |
Collapse
|
|
5
|
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.
Collapse
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
| |
Collapse
|
|
6
|
Mohamed SOO, Elhassan ABE, Elkhidir IHE, Ali AH, Elbathani MEH, Abdallah OOA, Ahmed AAM, Ibrahim AAH, Salman MST, Elnil M, Elhassan MA, Abuzied AIH. Detection of Cytomegalovirus Infection in Infants with Biliary Atresia: A Meta-analysis. Avicenna J Med 2021; 12:3-9. [PMID: 35620589 PMCID: PMC9130029 DOI: 10.1055/s-0041-1739236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives
Biliary atresia (BA) is the most common indication of liver transplantation in children. Several reports attributed BA to both prenatal and perinatal etiologies, including a viral infection-induced autoimmune response that targets the bile ducts.
Cytomegalovirus
(CMV) remains the most common virus being linked to BA. This meta-analysis aimed to estimate to what extent CMV infection is detected in patients with BA.
Methods
This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases of MEDLINE, Embase, Scopus, WHO-Virtual Health Library (VHL), ScienceDirect, and Google Scholar were used for the systematic search. The risk of bias was assessed using the Newcastle–Ottawa scale. Random effects model was used to estimate the pooled prevalence estimate with the corresponding 95% confidence interval (CI) using Comprehensive Meta-Analysis Software version 3.3.
Results
A total of 19 studies that fulfilled the eligibility criteria were included in the meta-analysis. The total number of infants with BA was 630 patients, and the pooled overall prevalence of CMV infection among them was 25.4% (95% CI: 15.9%–38.0%). There was high heterogeneity among studies (I
2
= 85.1%,
p
< .001), and subgroup analyses showed significant regional differences (X
2
= 48.9,
p
<.001). Data on the prognosis of CMV-associated BA were scarce and obtainable from few studies that suggested an association between detection of CMV infection and poor prognosis of BA.
Conclusions
The limited available data demonstrates that the rate of detection of CMV infection is high in infants with BA. There is still a need for large studies with appropriate controls for obtaining more reliable results about the various aspects of the association between CMV infection and BA.
Collapse
Affiliation(s)
| | | | | | - Almigdad H.M. Ali
- Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | | | | | | | - Abazr A. H. Ibrahim
- Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | | | - Mahmoud Elnil
- Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | - Mazin A.M. Elhassan
- Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | | |
Collapse
|
|
7
|
Cho SJ, Perito ER, Shafizadeh N, Kim GE. Dialogs in the assessment of neonatal cholestatic liver disease. Hum Pathol 2021; 112:102-115. [PMID: 33359238 DOI: 10.1016/j.humpath.2020.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/13/2020] [Accepted: 12/15/2020] [Indexed: 11/15/2022]
Abstract
Neonatal cholestatic liver disease is rarely encountered by pathologists outside of specialized pediatric centers and navigating the long list of potential diseases can be daunting. However, the differential diagnosis can be rapidly narrowed through open conversations between the pathologist and pediatric gastroenterologist. The dialog should ideally begin before obtaining the liver biopsy and continue through the rendering of the final pathologic diagnosis. Such dialogs are necessary to first ensure the proper handling of the precious sample and then to allow for synthesis of the clinical, laboratory, imaging, and genetic data in the context of the histologic features seen in the liver biopsy. In this review, we aim to provide a broad template on which such dialogs may be based and pitfalls that may be encountered on both the clinical and pathologic sides. This review will focus on non-biliary atresia etiologies of neonatal cholestasis, including select infectious, genetic, and metabolic entities.
Collapse
Affiliation(s)
- Soo-Jin Cho
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Emily R Perito
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA
| | | | - Grace E Kim
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.
| |
Collapse
|
|
8
|
Hilscher MB, Kamath PS, Eaton JE. Cholestatic Liver Diseases: A Primer for Generalists and Subspecialists. Mayo Clin Proc 2020; 95:2263-2279. [PMID: 33012354 DOI: 10.1016/j.mayocp.2020.01.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 01/03/2020] [Accepted: 01/16/2020] [Indexed: 02/08/2023]
Abstract
Cholestasis describes impairment in bile formation or flow which can manifest clinically with fatigue, pruritus, and jaundice. The differential diagnosis of cholestatic liver diseases is broad, and the etiologies of cholestasis vary in the anatomical location of the defect and acuity of presentation. Cholestasis may occur in a variety of clinical scenarios. Therefore, it is important for a diverse audience with varied clinical practices to have a basic understanding of manifestations of cholestatic liver diseases.
Collapse
Affiliation(s)
- Moira B Hilscher
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - John E Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
| |
Collapse
|
|
9
|
Redkar R, Raj V, Chigicherla S, Tewari S, Tampi C, Joshi S. Risk Prediction Scoring System to Predict the Postsurgical Outcomes of Biliary Atresia. J Indian Assoc Pediatr Surg 2020; 25:280-285. [PMID: 33343108 PMCID: PMC7732010 DOI: 10.4103/jiaps.jiaps_118_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/21/2019] [Accepted: 12/21/2019] [Indexed: 11/04/2022] Open
Abstract
AIM To find out association between liver function, liver histopathology and outcomes of biliary atresia (BA) following Kasai Portoenterostomy (KPE). MATERIALS AND METHODS This is a retrospective study of children who underwent KPE at a single institute by single surgeon. The patient records analyzed and data of complete blood counts, liver function tests, coagulation profile and histopathology reports collected. The outcomes recorded as alive and jaundice free, alive but jaundiced, and deceased. Statistical analysis done using SPSS 23. OBSERVATIONS Total of 148 children operated during January 2000 to December 2018. Of these, 26 matched inclusion criteria. The parameters assessed were percentage of direct bilirubin, ratios of Aspartate transaminase (AST) to Alanine transaminase (ALT); Gamma glutamyl transferase (GGT) to AST; GGT to ALT and Aspartate transaminase to platelet ratio index (APRi). Among histopathology reports, fibrosis grade and bile ductular size noted. Among 26, 16 alive and ten are deceased. Among 16 alive, all are jaundice free. Of the parameters, ratio of AST to ALT, APRi and grade of fibrosis found statistically significant and further analysis showed if AST to ALT ratio < 2.1, APRi < 1.8 and grade of fibrosis < four, irrespective of age at surgery, had 96.2 % probability of successful KPE. Based on these observations, a scoring system and risk prediction model constructed based on Receiver operating characteristic (ROC) curves which are first in BA management. RESULTS AND CONCLUSION Although numbers are sufficient for statistical analysis, we further intend to validate the scoring system in a prospective trial. BA children can be subjected to risk prediction model and KPE performed in those who have a score less than seven and offered to those with score between eight and 16 out of 20. KEY MESSAGE The scoring system and risk prediction model can guide in the management and post-operative follow up of children with biliary atresia.
Collapse
Affiliation(s)
- Rajeev Redkar
- Department of Paediatric Surgery, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India
| | - Vinod Raj
- Department of Paediatric Surgery, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India
| | - Swathi Chigicherla
- Department of Paediatric Surgery, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India
| | - Shruti Tewari
- Department of Paediatric Surgery, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India
| | - Chandralekha Tampi
- Department of Histopathology, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India
| | - Shirin Joshi
- Department of Paediatric Surgery, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India
| |
Collapse
|
|
10
|
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.
Collapse
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.
| |
Collapse
|
|
11
|
Averbukh LD, Wu GY. Evidence for Viral Induction of Biliary Atresia: A Review. J Clin Transl Hepatol 2018; 6:410-419. [PMID: 30637219 PMCID: PMC6328731 DOI: 10.14218/jcth.2018.00046] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 09/05/2018] [Accepted: 09/07/2018] [Indexed: 12/14/2022] Open
Abstract
Biliary atresia (BA) is a childhood disease which manifests with abnormal narrowing, blockage or complete absence of bile ducts within the liver. Many possible etiologies have been reported for the development of BA, including congenital, perinatal and acquired conditions. Since the 1970's, there has been increasing evidence linking BA development to viral perinatal infections. The viral vectors most commonly implicated include members of the herpesviridae family (cytomegalovirus and Epstein-Barr virus) as well as those of the reoviridae family (reovirus and rotavirus). While extensive work has been done on a murine model of disease, the current review focuses primarily on evidence from human studies of viral vectors in children afflicted with BA.
Collapse
Affiliation(s)
- Leon D. Averbukh
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- *Correspondence to: Leon D. Averbukh, Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, 236 Farmington Ave., Farmington, CT 06030, USA. Tel: +1-347-306-4752, E-mail:
| | | |
Collapse
|
|
12
|
Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2017; 64:154-168. [PMID: 27429428 DOI: 10.1097/mpg.0000000000001334] [Citation(s) in RCA: 311] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholestatic jaundice in infancy affects approximately 1 in every 2500 term infants and is infrequently recognized by primary providers in the setting of physiologic jaundice. Cholestatic jaundice is always pathologic and indicates hepatobiliary dysfunction. Early detection by the primary care physician and timely referrals to the pediatric gastroenterologist/hepatologist are important contributors to optimal treatment and prognosis. The most common causes of cholestatic jaundice in the first months of life are biliary atresia (25%-40%) followed by an expanding list of monogenic disorders (25%), along with many unknown or multifactorial (eg, parenteral nutrition-related) causes, each of which may have time-sensitive and distinct treatment plans. Thus, these guidelines can have an essential role for the evaluation of neonatal cholestasis to optimize care. The recommendations from this clinical practice guideline are based upon review and analysis of published literature and the combined experience of the authors. The committee recommends that any infant noted to be jaundiced after 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin, and that an elevated serum direct bilirubin level (direct bilirubin levels >1.0 mg/dL or >17 μmol/L) warrants timely consideration for evaluation and referral to a pediatric gastroenterologist or hepatologist. Of note, current differential diagnostic plans now incorporate consideration of modern broad-based next-generation DNA sequencing technologies in the proper clinical context. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all infants with cholestasis. Broad implementation of these recommendations is expected to reduce the time to the diagnosis of pediatric liver diseases, including biliary atresia, leading to improved outcomes.
Collapse
|
|
13
|
Cytomegalovirus-associated biliary atresia: An aetiological and prognostic subgroup. J Pediatr Surg 2015; 50:1739-45. [PMID: 25824438 DOI: 10.1016/j.jpedsurg.2015.03.001] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 02/12/2015] [Accepted: 03/02/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Perinatal cytomegalovirus (CMV) infection is a possible cause or trigger of biliary atresia though clinical evidence is scant. We hypothesised that CMV IgM+ve biliary atresia is a separate clinical entity compared to CMV IgM-ve biliary atresia. METHODS Prospective single-centre study. 210 infants with histologically confirmed biliary atresia were treated in our institution (Jan. 2004 to Dec. 2011); of these 20 (9.5%) were CMV IgM+ve at presentation. We compared these with 111 infants who were CMV IgM-ve (controls) for clinical features, biochemistry at presentation and outcome following Kasai portoenterostomy (KPE). A blinded comparison of age-matched liver histology was also performed. Data are quoted as median (interquartile range). A P value ≤ 0.05 was regarded as significant. RESULTS Infants with CMV IgM+ve biliary atresia were older at Kasai portoenterostomy (or laparotomy) [70 (60-80) days vs. 56 (44-75)days; P = 0.003] and were more jaundiced [175 (147-224) vs. 140 (121-181) μmol/L; P = 0.002+ with higher AST*287 (157-403) vs. 180 (133-254) IU/L; P = 0.005] and aspartate aminotransferase-to-platelet ratio index [1.1 (0.79-3.0) vs. 0.63 (0.43-0.95)] levels. Liver histology: CMV IgM+ve biliary atresia was characterised by a greater degree of inflammation (P < 0.0001) and fibrosis (P = 0.02), whereas CMV IgM-ve isolated biliary atresia had a higher degree of lobular cholestasis (P = 0.001). This effect was independent of the effects of age at KPE. OUTCOME CMV IgM+ve biliary atresia had a poorer outcome with a reduced clearance of jaundice (15% vs. 52.2%; P = 0.002), native liver survival (P < 0.0001) and increased mortality (P = 0.002). CONCLUSIONS CMV IgM+ve biliary atresia is a distinct clinical and pathological entity with a diminished response to Kasai portoenterostomy.
Collapse
|
|
14
|
Saito T, Terui K, Mitsunaga T, Nakata M, Ono S, Mise N, Yoshida H. Evidence for viral infection as a causative factor of human biliary atresia. J Pediatr Surg 2015; 50:1398-404. [PMID: 25979202 DOI: 10.1016/j.jpedsurg.2015.04.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 04/07/2015] [Accepted: 04/20/2015] [Indexed: 01/01/2023]
Abstract
OBJECTIVES To explore the evidence for viral infections triggering human biliary atresia (BA) by reviewing archival original articles that analyzed human samples via polymerase chain reaction (PCR) experiments, considering the recent experimental trend of extensive use of rotaviral BA animal models. METHODS A PubMed search retrieved original articles that reported the results of PCR experiments for detecting viral DNA or RNA in patient samples as proof of past infection. Search terms included the often-debated DNA or RNA viruses and BA. Special focus was directed toward PCR analyses that targeted reovirus and rotavirus, where PCR accuracy, specimen characteristics and their interpretations were compared. RESULTS Nineteen studies were conducted on 16 different kinds of viruses using PCR, with 5 studies on reovirus, 3 on rotavirus, 10 on cytomegalovirus, 5 on Epstein-Barr virus, 4 on parvovirus B19, and so on. Among the papers suggesting a possible viral link to only BA, there was no study on reovirus, 1 on rotavirus, 3 on cytomegalovirus, 1 on EB virus, and 1 on papillomavirus. Of the 6 PCR studies on Reoviridae, 3 on reovirus and 2 on rotavirus were evaluated rigorously for experimental accuracy, including their sensitivity. Two research groups analyzed preoperative stool samples in addition to generic hepatobiliary tissue obtained at surgery. Sample collection timing varied widely, with storage period prior to PCR experimentation not revealed in most reports on Reoviridae. CONCLUSION Although a considerable number of PCR studies have sought to clarify a viral role in the pathogenesis of BA using human samples, the findings have been contradictory and have not succeeded in achieving an obvious differentiation between causative and accidental infection of the focused virus. Reproducible and convincing evidence for a causative Reoviridae infection has been lacking based on objective data from highly sensitive PCR experiments. Even though the possibility remains of viral disappearance at the timing of collection, to avoid further ambiguous interpretations of PCR results, rigorous and meticulous collection of large numbers of specimens at carefully planned timing, along with a strictly adjusted and finely tuned PCR system, is strongly recommended for obtaining more reliable and consistent results.
Collapse
Affiliation(s)
- Takeshi Saito
- Department of Pediatric Surgery (E6), Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Keita Terui
- Department of Pediatric Surgery (E6), Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuya Mitsunaga
- Department of Pediatric Surgery (E6), Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Mitsuyuki Nakata
- Department of Pediatric Surgery (E6), Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sachie Ono
- Department of Pediatric Surgery (E6), Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoko Mise
- Department of Pediatric Surgery (E6), Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hideo Yoshida
- Department of Pediatric Surgery (E6), Graduate School of Medicine, Chiba University, Chiba, Japan
| |
Collapse
|
|
15
|
Affiliation(s)
- Dong Zhao
- Shanghai Jiao Tong University, Shanghai, China
| | - Xi-Dai Long
- Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
16
|
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.
Collapse
|
|
17
|
Arva NC, Russo PA, Erlichman J, Hancock WW, Haber BA, Bhatti TR. The inflammatory phenotype of the fibrous plate is distinct from the liver and correlates with clinical outcome in biliary atresia. Pathol Res Pract 2015; 211:252-60. [PMID: 25624184 DOI: 10.1016/j.prp.2014.12.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 11/18/2014] [Accepted: 12/05/2014] [Indexed: 01/24/2023]
Abstract
Biliary atresia is an inflammatory cholangiopathy of still undetermined etiology. Correlations between histologic findings and clinical outcome in this disease have largely been based on evaluation of liver parenchyma. This study aimed to characterize the pattern of inflammation within the biliary remnant and identify associations between the type and degree of inflammation and clinical outcome as reflected by the transplant-free interval. The inflammation within the fibrous plates and livers of 41 patients with biliary atresia was characterized using immunohistochemical markers and the cell populations were digitally quantified. The type and quantity of cells within the infiltrate were then correlated with length of time from Kasai portoenterostomy until transplant. Histologic and immunohistochemical features of the biliary remnant allowed stratification of patients into "inflammatory plate" and "fibrotic plate" groups. Overall there was no significant difference in transplant-free interval between the two cohorts; however, there was a trend towards a longer time to transplant among patients in the "fibrotic plate" group. In addition, the composition of the inflammatory infiltrate in the fibrous plate was distinctly different from that present in the liver and only the characteristics of the inflammation in the fibrous plate, in particular the number of Foxp3+ T regulatory lymphocytes correlated with clinical outcome. The results of this study support the view of the extra-hepatic biliary tree as the primary site of injury in BA with the changes seen in the liver as secondary manifestations of outflow obstruction. The association between specific inflammatory cell subtypes within the fibrous plate and the length of transplant-free interval also supports the role of the immune system in the initial process of bile duct damage in biliary atresia.
Collapse
Affiliation(s)
- Nicoleta C Arva
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Pierre A Russo
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | - Jessi Erlichman
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Wayne W Hancock
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | | | - Tricia R Bhatti
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
| |
Collapse
|
|
18
|
Feldman AG, Tucker RM, Fenner EK, Pelanda R, Mack CL. B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia. PLoS One 2013; 8:e73644. [PMID: 23991203 PMCID: PMC3749125 DOI: 10.1371/journal.pone.0073644] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 07/19/2013] [Indexed: 02/04/2023] Open
Abstract
A leading theory regarding the pathogenesis of biliary atresia (BA) is that bile duct injury is initiated by a virus infection, followed by an autoimmune response targeting bile ducts. In experimental models of autoimmune diseases, B cells have been shown to play an important role. The aim of this study was to determine the role of B cells in the development of biliary obstruction in the Rhesus rotavirus (RRV)-induced mouse model of BA. Wild-type (WT) and B cell-deficient (Ig-α(-/-)) mice received RRV shortly after birth. Ig-α(-/-) RRV-infected mice had significantly increased disease-free survival rate compared to WT RRV-infected BA mice (76.8% vs. 17.5%). In stark contrast to the RRV-infected BA mice, the RRV-infected Ig-α(-/-) mice did not have hyperbilirubinemia or bile duct obstruction. The RRV-infected Ig-α(-/-) mice had significantly less liver inflammation and Th1 cytokine production compared to RRV-infected WT mice. In addition, Ig-α(-/-) mice had significantly increased numbers of regulatory T cells (Tregs) at baseline and after RRV infection compared to WT mice. However, depletion of Tregs in Ig-α(-/-) mice did not induce biliary obstruction, indicating that the expanded Tregs in the Ig-α(-/-) mice were not the sole reason for protection from disease. Conclusion : B cell deficient Ig-α(-/-) mice are protected from biliary obstruction in the RRV-induced mouse model of BA, indicating a primary role of B cells in mediating disease pathology. The mechanism of protection may involve lack of B cell antigen presentation, which impairs T-cell activation and Th1 inflammation. Immune modulators that inhibit B cell function may be a new strategy for treatment of BA.
Collapse
Affiliation(s)
- Amy G Feldman
- Department of Pediatrics, Section of Pediatric Gastroenterology, Children's Hospital, Colorado, Aurora, Colorado, USA.
| | | | | | | | | |
Collapse
|
|
19
|
Abstract
Biliary atresia (BA) is an infantile obstructive cholangiopathy of unknown etiology with suboptimal therapy, which is responsible for 40 to 50% of all pediatric liver transplants. Although the etiology of bile duct injury in BA in unknown, it is postulated that a pre- or perinatal viral infection initiates cholangiocyte apoptosis and release of antigens that trigger a Th1 immune response that leads to further bile duct injury, inflammation, and obstructive fibrosis. Humoral immunity and activation of the innate immune system may also play key roles in this process. Moreover, recent investigations from the murine BA model and human data suggest that regulatory T cells and genetic susceptibility factors may orchestrate autoimmune mechanisms. What controls the coordination of these events, why the disease only occurs in the first few months of life, and why a minority of infants with perinatal viral infections develop BA are remaining questions to be answered.
Collapse
Affiliation(s)
- Cara L. Mack
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
| | - Amy G. Feldman
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
| | - Ronald J. Sokol
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
| |
Collapse
|
|
20
|
Detection of hepatotropic viruses has no impact on the prognosis after Kasai procedure. J Pediatr Surg 2012; 47:1828-32. [PMID: 23084192 DOI: 10.1016/j.jpedsurg.2012.04.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2011] [Revised: 04/02/2012] [Accepted: 04/21/2012] [Indexed: 11/20/2022]
Abstract
BACKGROUND/PURPOSE A viral origin of biliary atresia (BA) is discussed, and several studies have demonstrated different viral strains in liver biopsies of patients undergoing Kasai portoenterostomy. We hypothesized that the presence of hepatotropic viruses in patients undergoing portoenterostomy contributes to the progression of the disease and negatively affect the outcome. METHODS Liver biopsies were prospectively taken from 70 patients undergoing portoenterostomy in our department from April 1996 to April 2004. Samples were screened by polymerase chain reaction for all common hepatic viruses. Primary outcome parameter was survival with the native liver. Secondary parameters were postoperative serum activity of liver enzymes and serum bilirubin levels at different time points. Patients underwent regular follow-up until October 2008. RESULTS Twenty-eight patients (40%) were positive for 1 or more hepatotropic viruses. Four patients were lost to follow-up. In the remaining 66 patients, there was no significant difference in survival with their native liver between virus-positive and virus-negative patients. After a mean follow-up of 7.7 years (range, 4.6-16.1 years), 15 (23%) of 66 patients still lived with their native liver. There was no difference in liver enzymes, C-reactive protein, or bilirubin at any time point between both groups. CONCLUSION A significant number of our patients tested positive for hepatotropic viruses in liver biopsies at the time of the Kasai procedure, but the presence of virus had no influence on the course of BA. This suggests that the ongoing inflammatory process of BA leading to liver cirrhosis in most Kasai-treated patients is not affected by hepatotropic viruses. Our data question the necessity to aggressively screen for and treat viral infections in patients with BA.
Collapse
|
|
21
|
Brindley SM, Lanham AM, Karrer FM, Tucker RM, Fontenot AP, Mack CL. Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells. Hepatology 2012; 55:1130-8. [PMID: 22105891 PMCID: PMC3319336 DOI: 10.1002/hep.24807] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED Biliary atresia (BA) is a progressive, inflammatory cholangiopathy that culminates in fibrosis of extrahepatic and intrahepatic bile ducts. A leading theory on the pathogenesis of BA is that the bile duct damage is initiated by a virus infection, followed by a bile duct-targeted autoimmune response. One mechanism of autoimmunity entails a diminished number or function of regulatory T cells (Tregs). The aim of this study was to identify potential virus-specific liver T cells from infants with BA at the time of diagnosis, implicating the virus involved in early bile duct damage. A subaim was to determine if the presence of virus infection was associated with quantitative changes in Tregs. Liver T cells from BA and control patients were cultured with antigen-presenting cells in the presence of a variety of viral or control proteins. 56% of BA patients had significant increases in interferon-gamma-producing liver T cells in response to cytomegalovirus (CMV), compared with minimal BA responses to other viruses or the control group CMV response. In addition, a positive correlation between BA plasma CMV immunoglobulin M (IgM) and liver T-cell CMV reactivity was identified. Investigation of peripheral blood Tregs revealed significant deficits in Treg frequencies in BA compared with controls, with marked deficits in those BA patients who were positive for CMV. CONCLUSION Liver T-cell responses to CMV were identified in the majority of BA patients at diagnosis, suggesting perinatal CMV infection as a plausible initiator of bile duct damage. Deficiency of Tregs in BA implies decreased inhibition of inflammation and autoreactivity, potentially allowing for exaggerated bile duct injury.
Collapse
Affiliation(s)
- Stephen M. Brindley
- Division of Allergy & Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
| | - Allison M. Lanham
- Division of Allergy & Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
| | - Frederick M. Karrer
- Division of Pediatric Gastroenterology, Hepatology & Nutrition, Digestive Health Institute, Children’s Hospital Colorado, Aurora, Colorado
| | - Rebecca M. Tucker
- Division of Allergy & Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
| | - Andrew P. Fontenot
- Division of Allergy & Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
| | - Cara L. Mack
- Division of Allergy & Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado,Division of Pediatric Gastroenterology, Hepatology & Nutrition, Digestive Health Institute, Children’s Hospital Colorado, Aurora, Colorado
| |
Collapse
|
|
22
|
Lee HC, Chang TY, Yeung CY, Chan WT, Jiang CB, Chen WF, Chan HW, Yang HW, Lin M, Lee YJ. Genetic variability of interleukin4 gene in Taiwanese children with biliary atresia. Cytokine 2012; 57:402-405. [PMID: 22227092 DOI: 10.1016/j.cyto.2011.12.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Revised: 12/05/2011] [Accepted: 12/14/2011] [Indexed: 01/28/2023]
Abstract
Biliary atresia (BA) is a neonatal cholangiopathy of unknown etiology that leads to biliary cirrhosis and is the most common cause of liver transplantation in children. A still undetermined hepatobiliary viral infection may elicit an uncontrollable autoimmune response against the biliary epithelial cells in genetically predisposed children and culminates in atresia of the biliary trees. Interleukin 4 (IL4) is crucial for the differentiation of naive T helper cells into the T helper 2 effector cells that promote humoral immunity. This study aims to investigate whether polymorphisms of the IL4 gene are associated with susceptibility to BA. Genomic DNA was extracted from whole blood samples of 53 Taiwanese children with BA and 904 ethnically-matched healthy controls. The IL4 -590 C/T, -33 C/T, and 8375 A/G polymorphisms were genotyped using the Pre-Developed TaqMan Allelic Discrimination Assay in a real-time polymerase chain reaction system. No significant difference between children with BA and healthy controls were found when comparing genotype, allele, carrier, and haplotype frequencies of these IL4 gene variants. These results suggest that the tested polymorphisms of IL4 gene are unlikely to contribute significantly to BA susceptibility in Taiwanese children.
Collapse
Affiliation(s)
- Hung-Chang Lee
- Department of Pediatrics, Mackay Memorial Hospital, New Taipei City, Taiwan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
|
|
24
|
Abstract
AIM To study the impact of ongoing cytomegalovirus (CMV) infection at presentation of biliary atresia (BA) on the long-term outcome after Kasai procedure. METHODS Twenty-eight patients with BA born 1988-1997 were included and followed-up until 2007. Eleven patients (group A) had ongoing CMV infection at presentation and were compared to the remaining 17 patients (group B). Median age at Kasai procedure was 75 days in group A and 70 days in group B (p = 0.12). RESULTS Including all patients, survival with native liver was 50% and 36% at 4 and 10 years of follow-up respectively. At the end of follow-up, it was 25% and overall survival was 68%. When comparing groups A and B, neither difference in survival with native liver (p = 0.67, log-rank test) nor in survival after liver transplantation was detected. CONCLUSION Survival with native liver after Kasai procedure is comparable to that of other centres. CMV positive patients may present with a later onset, alternatively the detection of CMV infection could delay the referral of BA patients. No significant differences in long-term outcome were detected with regard to early CMV infection.
Collapse
Affiliation(s)
- Björn Fischler
- Department of Pediatrics, Karolinska University Hospital, CLINTEC, Karolinska Intitutet, Stockholm, Sweden.
| | | | | |
Collapse
|
|
25
|
Bellomo-Brandao MA, Andrade PD, Costa SCB, Escanhoela CAF, Vassallo J, Porta G, De Tommaso AMA, Hessel G. Cytomegalovirus frequency in neonatal intrahepatic cholestasis determined by serology, histology, immunohistochemistry and PCR. World J Gastroenterol 2009; 15:3411-6. [PMID: 19610143 PMCID: PMC2712903 DOI: 10.3748/wjg.15.3411] [Citation(s) in RCA: 4] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine cytomegalovirus (CMV) frequency in neonatal intrahepatic cholestasis by serology, histological revision (searching for cytomegalic cells), immunohistochemistry, and polymerase chain reaction (PCR), and to verify the relationships among these methods.
METHODS: The study comprised 101 non-consecutive infants submitted for hepatic biopsy between March 1982 and December 2005. Serological results were obtained from the patient’s files and the other methods were performed on paraffin-embedded liver samples from hepatic biopsies. The following statistical measures were calculated: frequency, sensibility, specific positive predictive value, negative predictive value, and accuracy.
RESULTS: The frequencies of positive results were as follows: serology, 7/64 (11%); histological revision, 0/84; immunohistochemistry, 1/44 (2%), and PCR, 6/77 (8%). Only one patient had positive immunohistochemical findings and a positive PCR. The following statistical measures were calculated between PCR and serology: sensitivity, 33.3%; specificity, 88.89%; positive predictive value, 28.57%; negative predictive value, 90.91%; and accuracy, 82.35%.
CONCLUSION: The frequency of positive CMV varied among the tests. Serology presented the highest positive frequency. When compared to PCR, the sensitivity and positive predictive value of serology were low.
Collapse
|
|
26
|
Mieli-Vergani G, Vergani D. Biliary atresia. Semin Immunopathol 2009; 31:371-81. [PMID: 19533128 DOI: 10.1007/s00281-009-0171-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2009] [Accepted: 06/01/2009] [Indexed: 12/17/2022]
Abstract
Biliary atresia (BA) is a condition unique to infancy. It results from inflammatory destruction of the intrahepatic and extrahepatic bile ducts. It is the most frequent surgically correctable liver disorder in infancy and the most frequent indication for liver transplantation in paediatric age. Clinical presentation is in the first few weeks of life with conjugated hyperbilirubinaemia (dark urine and pale stools); other manifestations of liver disease, such as failure to thrive, splenomegaly and ascites, appear only later, when surgery is unlikely to be successful. Hence, all infants with conjugated hyperbilirubinaemia must be urgently referred to specialised centres for appropriate treatment. Success of surgery depends on the age at which it is performed. With corrective surgery, followed, when necessary, by liver transplantation, the overall survival rate is approximately 90%. The cause of BA is unknown, but there is evidence for the involvement of infectious, genetic and immunologic mechanisms, which will be discussed in this review.
Collapse
Affiliation(s)
- Giorgina Mieli-Vergani
- Paediatric Liver Centre, Institute of Liver Studies, King's College London School of Medicine, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
| | | |
Collapse
|
|
27
|
Rauschenfels S, Krassmann M, Al-Masri AN, Verhagen W, Leonhardt J, Kuebler JF, Petersen C. Incidence of hepatotropic viruses in biliary atresia. Eur J Pediatr 2009; 168:469-76. [PMID: 18560888 DOI: 10.1007/s00431-008-0774-2] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Accepted: 05/21/2008] [Indexed: 12/29/2022]
Abstract
Biliary atresia (BA) is the most frequent indication for paediatric liver transplantation. We tested the hypothesis of a viral aetiology of this disease by screening liver samples of a large number of BA patients for the common human hepatotropic viruses. Moreover, we correlated our findings to the expression of Mx protein, which has been shown to be significantly up-regulated during viral infections. Seventy-four liver biopsies (taken during Kasai portoenterostomy) were tested by polymerase chain reaction (PCR) for DNA viruses (herpes simplex virus [HSV], Epstein-Barr virus [EBV], varicella zoster virus [VZV], cytomegalovirus [CMV], adenovirus, parvovirus B19 and polyoma BK) and RNA viruses (enteroviruses, rotavirus and reovirus 3). Mx protein expression was assessed by immunohistochemistry. Virus DNA/RNA was found in less than half of the biopsies (8/74 CMV, 1/74 adenovirus; 21/64 reovirus, 1/64 enterovirus). A limited number presented with double infection. Patients that had detectable viral RNA/DNA in their liver biopsies were significantly older than virus-free patients (P = 0.037). The majority (54/59) of the liver biopsies showed expression of Mx proteins in hepatocytes, bile ducts and epithelium. Our data suggest that the known hepatotropic viruses do not play a major role in the aetiology and progression of BA. Their incidence appears to be, rather, a secondary phenomenon. Nonetheless, the inflammatory response in the livers of BA patients mimics that observed during viral infections.
Collapse
Affiliation(s)
- Stefan Rauschenfels
- Department of Pediatric Kidney and Liver Diseases and Metabolic Disorders, Hannover Medical School, Hannover, Germany
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Jafri M, Donnelly B, Allen S, Bondoc A, McNeal M, Rennert PD, Weinreb PH, Ward R, Tiao G. Cholangiocyte expression of alpha2beta1-integrin confers susceptibility to rotavirus-induced experimental biliary atresia. Am J Physiol Gastrointest Liver Physiol 2008; 295:G16-G26. [PMID: 18436621 PMCID: PMC2494723 DOI: 10.1152/ajpgi.00442.2007] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inoculation of BALB/c mice with rhesus rotavirus (RRV) in the newborn period results in biliary epithelial cell (cholangiocyte) infection and the murine model of biliary atresia. Rotavirus infection of a cell requires attachment, which is governed in part by cell-surface expression of integrins such as alpha2beta1. We hypothesized that cholangiocytes were susceptible to RRV infection because they express alpha2beta1. RRV attachment and replication was measured in cell lines derived from cholangiocytes and hepatocytes. Flow cytometry was performed on these cell lines to determine whether alpha2beta1 was present. Cholangiocytes were blocked with natural ligands, a monoclonal antibody, or small interfering RNA against the alpha2-subunit and were infected with RRV. The extrahepatic biliary tract of newborn mice was screened for the expression of the alpha2beta1-integrin. Newborn mice were pretreated with a monoclonal antibody against the alpha2-subunit and were inoculated with RRV. RRV attached and replicated significantly better in cholangiocytes than in hepatocytes. Cholangiocytes, but not hepatocytes, expressed alpha2beta1 in vitro and in vivo. Blocking assays led to a significant reduction in attachment and yield of virus in RRV-infected cholangiocytes. Pretreatment of newborn pups with an anti-alpha2 monoclonal antibody reduced the ability of RRV to cause biliary atresia in mice. Cell-surface expression of the alpha2beta1-integrin plays a role in the mechanism that confers cholangiocyte susceptibility to RRV infection.
Collapse
Affiliation(s)
- Mubeen Jafri
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| | - Bryan Donnelly
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| | - Steven Allen
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| | - Alex Bondoc
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| | - Monica McNeal
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| | - Paul D. Rennert
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| | - Paul H. Weinreb
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| | - Richard Ward
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| | - Greg Tiao
- Department of Pediatric and Thoracic Surgery and the Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and Biogen Idec, Cambridge, Massachusetts
| |
Collapse
|
|
29
|
Abstract
Biliary atresia (BA) is the most frequent indication for paediatric liver transplantation. We tested the hypothesis of a viral aetiology of this disease by screening liver samples of a large number of BA patients for the common human hepatotropic viruses. Moreover, we correlated our findings to the expression of Mx protein, which has been shown to be significantly up-regulated during viral infections. Seventy-four liver biopsies (taken during Kasai portoenterostomy) were tested by polymerase chain reaction (PCR) for DNA viruses (herpes simplex virus [HSV], Epstein-Barr virus [EBV], varicella zoster virus [VZV], cytomegalovirus [CMV], adenovirus, parvovirus B19 and polyoma BK) and RNA viruses (enteroviruses, rotavirus and reovirus 3). Mx protein expression was assessed by immunohistochemistry. Virus DNA/RNA was found in less than half of the biopsies (8/74 CMV, 1/74 adenovirus; 21/64 reovirus, 1/64 enterovirus). A limited number presented with double infection. Patients that had detectable viral RNA/DNA in their liver biopsies were significantly older than virus-free patients (P = 0.037). The majority (54/59) of the liver biopsies showed expression of Mx proteins in hepatocytes, bile ducts and epithelium. Our data suggest that the known hepatotropic viruses do not play a major role in the aetiology and progression of BA. Their incidence appears to be, rather, a secondary phenomenon. Nonetheless, the inflammatory response in the livers of BA patients mimics that observed during viral infections.
Collapse
|
|
30
|
|
|
31
|
Tiao MM, Tsai SS, Kuo HW, Chen CL, Yang CY. Epidemiological features of biliary atresia in Taiwan, a national study 1996-2003. J Gastroenterol Hepatol 2008; 23:62-6. [PMID: 17725591 DOI: 10.1111/j.1440-1746.2007.05114.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM The incidence of biliary atresia (BA) varies among different countries. It is supposed to be higher in Asian countries than in Western countries; however, the incidence of BA in Taiwan has not been well investigated. The aim of this study was to analyze the epidemiological characteristics and the incidence of BA in Taiwan. METHODS National Health Insurance (NHI) was implemented in Taiwan in 1995, and covers most of the population (>99%). We use the NHI database to investigate the epidemiological features of BA and compare Taiwan's annual BA incidence with that of other countries. RESULTS We identified 327 new BA cases during the period from 1996 to 2003. The overall incidence of BA was 1.46 cases per 10 000 live births (0.89-1.90 per 10 000). The estimation was 1.32-1.65 per 10 000 after adjustment for the misdiagnosis rate. The peak incidence occurred in 2002 (1.90 per 10 000), accompanying Taiwan's dengue fever epidemic in 2002. The 5-year overall survival rate during 1999-2003 was higher than that during 1996-1998 (74.8% vs 61.1%, P = 0.014). CONCLUSION Taiwan has the second-highest incidence of BA reported in world literature. Viral infection outbreaks remain a potential candidate as a cause of BA. The management of BA has been improving, with a better 5-year overall survival rate.
Collapse
Affiliation(s)
- Mao-Meng Tiao
- Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | | | | | | | | |
Collapse
|
|
32
|
Abstract
Biliary atresia is a mystifying cause of neonatal cholestasis, manifested by progressive inflammation and fibrosis of both the extrahepatic and intrahepatic bile ducts. It is a devastating disease that leads to cirrhosis and the need for liver transplantation in the majority of children. The etiology is unknown, and one theory is that it may involve a primary perinatal hepatobiliary viral infection and a secondary generation of an autoimmune-mediated bile duct injury. This review will outline the evidence from both human and murine studies supporting a potential cholangiotropic viral infection as the initiator of bile duct injury in biliary atresia and the role of the adaptive immune response and autoimmunity in progression of disease. Delineating the pathways of immune and autoimmune-mediated bile duct injury within biliary atresia could stimulate development of new medical interventions aimed at suppressing the specific immune response, decreasing the inflammatory damage to bile ducts, and delaying or negating the need for liver transplantation.
Collapse
Affiliation(s)
- Cara L Mack
- Pediatric Liver Center and Liver Transplant Program, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital, University of Colorado at Denver-Health Sciences Center, Denver, Colorado 80218, USA
| |
Collapse
|
|
33
|
Sokol RJ, Shepherd RW, Superina R, Bezerra JA, Robuck P, Hoofnagle JH. Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop. Hepatology 2007; 46:566-81. [PMID: 17661405 PMCID: PMC3888317 DOI: 10.1002/hep.21790] [Citation(s) in RCA: 179] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Biliary atresia is the most common cause of end-stage liver disease in the infant and is the leading pediatric indication for liver transplantation in the United States. Earlier diagnosis (<30-45 days of life) is associated with improved outcomes following the Kasai portoenterostomy and longer survival with the native liver. However, establishing this diagnosis is problematic because of its rarity, the much more common indirect hyperbilirubinemia that occurs in the newborn period, and the schedule for routine infant health care visits in the United States. The pathogenesis of biliary atresia appears to involve immune-mediated fibro-obliteration of the extrahepatic and intrahepatic biliary tree in most patients and defective morphogenesis of the biliary system in the remainder. The determinants of the outcome of portoenterostomy include the age at surgery, the center's experience, the presence of associated congenital anomalies, and the postoperative occurrence of cholangitis. A number of screening strategies in infants have been studied. The most promising are early measurements of serum conjugated bilirubin and a stool color card given to new parents that alerts them and their primary care provider to alcholic stools. This report summarizes a National Institutes of Health workshop held on September 12 and 13, 2006, in Bethesda, MD, that addressed the issues of outcomes, screening, and pathogenesis of biliary atresia.
Collapse
Affiliation(s)
- Ronald J Sokol
- Department of Pediatrics, University of Colorado School of Medicine, The Children's Hospital, Denver, CO, USA.
| | | | | | | | | | | |
Collapse
|
|
34
|
The NS, Honein MA, Caton AR, Moore CA, Siega-Riz AM, Druschel CM. Risk factors for isolated biliary atresia, National Birth Defects Prevention Study, 1997–2002. Am J Med Genet A 2007; 143A:2274-84. [PMID: 17726689 DOI: 10.1002/ajmg.a.31926] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Biliary atresia is a rare birth defect that affects 1 in 12,000 to 1 in 19,500 live births. We used data from the National Birth Defects Prevention Study, a multistate case-control study, to identify potential risk factors for isolated biliary atresia (no additional unrelated major birth defects diagnosed). Infants were identified from eight states from 1997 to 2002, with clinical information abstracted from medical records. Potential risk factors assessed include: demographic factors, seasonality, preterm birth, maternal smoking, maternal alcohol use, maternal illicit drug use, maternal health, maternal medication use, maternal vitamin use, and maternal nutrition. Infants of non-Hispanic black mothers were more likely to have biliary atresia than infants of non-Hispanic white mothers (adjusted odds ratio (aOR) = 2.29, 95% confidence interval (CI) 1.07-4.93) and infants conceived during the spring season were more likely to have biliary atresia than infants conceived in winter (aOR = 2.33, 95%CI 1.05-5.16). Low intakes of vitamin E, copper, phosphorus, and beta tocopherol were associated with the occurrence of isolated biliary atresia (borderline significance). Low iron intake had a borderline inverse association with biliary atresia. While this analysis provides support for previous reports of a possible association between seasonal variation and the occurrence of biliary atresia, more data are needed to evaluate whether the seasonal variation is related to infectious agents. The role of nutrients in the development of biliary atresia remains unclear. Further studies of genetic, infectious, and nutrient exposures and the association of biliary atresia are warranted.
Collapse
Affiliation(s)
- Natalie S The
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA
| | | | | | | | | | | |
Collapse
|
|
35
|
Tucker RM, Hendrickson RJ, Mukaida N, Gill RG, Mack CL. Progressive biliary destruction is independent of a functional tumor necrosis factor-alpha pathway in a rhesus rotavirus-induced murine model of biliary atresia. Viral Immunol 2007; 20:34-43. [PMID: 17425419 PMCID: PMC1978183 DOI: 10.1089/vim.2006.0088] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Rhesus rotavirus (RRV)-inoculated neonatal BALB/c mice develop an immune-mediated inflammation of extra- and intrahepatic bile ducts that progresses to biliary obstruction and death by 3 wk of age. Livers of diseased animals demonstrate increased numbers of T lymphocytes with elevated expression of helper T cell type 1 (Th1) cytokines at 1 wk, which transitions to increased numbers of macrophages and high expression of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha by 2 wk. We employed both pharmacologic and genetic approaches for attenuation of TNF-alpha to determine whether it plays a causal role in injury. First, RRV-inoculated BALB/c mice were subjected to multiple treatments with either the TNF receptor I (TNF-RI)-Fc fusion protein etanercept or neutralizing antibodies to mouse TNF-alpha. Also, TNF-RI(-/-) mice were injected with RRV in the same manner as wild-type mice. In all cases, TNF inhibition did not reduce the severity or incidence of disease. Survival curves of mice given blocking agents were similar to those of control RRV-inoculated mice, and survival of challenged TNF-RI(-/-) mice was worse than that of wild-type mice, likely because of the prolonged presence of infectious RRV. In all experimental groups, markers of disease were unchanged from those of control mice. In summary, although RRV-inoculated BALB/c mice have highly elevated expression of TNF-alpha, this cytokine does not play an obligate role in disease progression.
Collapse
Affiliation(s)
- Rebecca M Tucker
- Division of Allergy and Clinical Immunology, Department of Medicine, University of Colorado School of Medicine, Denver, Colorado 80262, USA.
| | | | | | | | | |
Collapse
|
|
36
|
Abstract
Biliary atresia is the single most common cause of chronic cholestasis in children and is the leading indication for liver transplantation worldwide. It results from an inflammatory and fibrosing obstruction of the extrahepatic bile ducts in the first few months of life. Early diagnosis and timely surgical portoenterostomy are necessary for improved biliary drainage, but the liver disease progresses to end-stage biliary cirrhosis in most patients. Although the pathogenesis of disease is largely unknown, recent patient- and animal-based experiments indicate interactions between infectious agents and inflammatory circuits may be important pathogenic mechanisms of disease.
Collapse
Affiliation(s)
- Claus Petersen
- Department of Pediatric Surgery, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
| |
Collapse
|
|
37
|
De Tommaso AMA, Andrade PD, Costa SCB, Escanhoela CAF, Hessel G. High frequency of human cytomegalovirus DNA in the liver of infants with extrahepatic neonatal cholestasis. BMC Infect Dis 2005; 5:108. [PMID: 16321152 PMCID: PMC1315325 DOI: 10.1186/1471-2334-5-108] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2005] [Accepted: 12/01/2005] [Indexed: 11/19/2022] Open
Abstract
Background Biliary atresia (BA) is the most severe hepatic disorder in newborns and its etiopathogenesis remains unknown. Viral involvement has been proposed, including the human cytomegalovirus (HCMV). The aims of the study were to use the polymerase chain reaction (PCR) to screen the liver tissue of infants with extrahepatic cholestasis for HCMV and to correlate the results with serological antibodies against HCMV and histological findings. Methods A retrospective study in a tertiary care setting included 35 patients (31 BA, 1 BA associated with a choledochal cyst, 2 congenital stenosis of the distal common bile duct and 1 hepatic cyst). HCMV serology was determined by ELISA. Liver and porta hepatis were examined histologically. Liver samples from infants and a control group were screened for HCMV DNA. Results Twelve patients had HCMV negative serology, 9 were positive for IgG antibodies and 14 were positive for IgG and IgM. Nine liver and seven porta hepatis samples were positive for HCMV DNA but none of the control group were positive (general frequency of positivity was 34.3% – 12/35). There was no correlation between HCMV positivity by PCR and the histological findings. The accuracy of serology for detecting HCMV antibodies was low. Conclusion These results indicate an elevated frequency of HCMV in pediatric patients with extrahepatic neonatal cholestasis. They also show the low accuracy of serological tests for detecting active HCMV infection and the lack of correlation between HCMV positivity by PCR and the histopathological changes.
Collapse
Affiliation(s)
- Adriana MA De Tommaso
- Department of Pediatrics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas-SP, Brazil
| | - Paula D Andrade
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas-SP, Brazil
| | - Sandra CB Costa
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas-SP, Brazil
| | - Cecília AF Escanhoela
- Department of Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas-SP, Brazil
| | - Gabriel Hessel
- Department of Pediatrics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas-SP, Brazil
| |
Collapse
|
|
38
|
Abstract
Biliary atresia is the most common cause of neonatal cholestasis and the leading indication for pediatric liver transplantation worldwide. The disease is caused by a progressive inflammatory and fibrosing obliteration of the extrahepatic bile ducts. Although the cause of this obstruction is largely unknown, patient-based studies have identified environmental and genetic factors that may interact and orchestrate disease pathogenesis. Chief among these factors are infectious and immunologic processes. While infectious agents have varied in different patient populations, studies of liver specimens at different phases of disease point to a pro-inflammatory commitment of lymphocytes at the time of diagnosis, and to their potential role in regulating bile duct obstruction. A review of these studies is the focus of this article.
Collapse
Affiliation(s)
- Jorge A Bezerra
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, OH 45229, USA.
| |
Collapse
|
|
39
|
Shih HH, Lin TM, Chuang JH, Eng HL, Juo SHH, Huang FC, Chen CL, Chen HL. Promoter polymorphism of the CD14 endotoxin receptor gene is associated with biliary atresia and idiopathic neonatal cholestasis. Pediatrics 2005; 116:437-441. [PMID: 16061600 DOI: 10.1542/peds.2004-1900] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE To investigate whether single-nucleotide polymorphisms in the promoter regions of endotoxin-responsive genes CD14 and tumor necrosis factor-alpha (TNF-alpha) are associated with biliary atresia (BA) and idiopathic neonatal cholestasis (INC). METHODS We obtained genomic DNA from 90 patients with established diagnosis of BA and 28 patients with INC. Forty-two adult patients with hepatitis B-related cirrhosis and 143 healthy children served as control populations. The genotypes of CD14/C(-159)T and TNF-alpha/G(-308)A (G allele, TNF*1; A allele, TNF*2) were determined by using a restriction enzyme-based assay. Plasma soluble CD14 levels were determined in different disease stages and genotypes of BA. RESULTS The frequencies of T allele and T/T homozygosity of the CD14/-159 promoter polymorphism were significantly higher in patients with BA (T allele: 61.7%; T/T genotype: 42.2%) and in patients with INC (T allele: 67.9%; T/T genotype: 53.6%) but not in control populations. Decrease of plasma soluble CD14 from the early stage of BA when the patients received a Kasai operation to the late stage of liver cirrhosis was observed in carriers of the T/T and T/C genotypes but not in carriers of the C/C genotype. The TNF-alpha/-308 promoter polymorphisms (TNF*1 and TNF*2) were not associated with BA. CONCLUSION These findings show that the single-nucleotide polymorphism at CD14/-159 is associated with the development of BA and INC. Endotoxin susceptibility may play a role in the pathogenesis of infantile cholestasis.
Collapse
Affiliation(s)
- Hsiang-Hung Shih
- Department of Pediatrics, Chang-Gung Memorial Hospital at Chiayi, Pu-Tz City, Chiayi Hsien, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Abstract
Biliary atresia (BA) is the most common and important neonatal hepatobiliary disorder. Because current treatment is inadequate, there is an urgent need to better understand the etiology and pathogenesis of BA. Two major forms of BA are recognized: an embryonic form associated with other congenital anomalies and a perinatal form in which bile ducts were presumably formed normally but underwent fibro-obliteration in the perinatal period. There are currently several proposed pathogenic pathways leading to the phenotype of BA, including an immune or autoimmune response to a perinatal insult (e.g. cholangiotropic viral infection) and dysregulated embryonic development of the extra- or intrahepatic biliary system. Recent advances in developmental biology, genomics and genetics, and cell immunology and biology, coupled with the development of appropriate animal models, have provided support for these postulated mechanisms. Future investigations combining animal model work and evaluation of clinical specimens holds the promise of identifying the etiology of BA and providing a scientific basis for treatment and preventative interventions.
Collapse
Affiliation(s)
- Cara L Mack
- Pediatric Liver Center and Liver Transplantation Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, Denver 80218, USA
| | | |
Collapse
|
|
41
|
|
|
42
|
Fischler B, Woxenius S, Nemeth A, Papadogiannakis N. Immunoglobulin deposits in liver tissue from infants with biliary atresia and the correlation to cytomegalovirus infection. J Pediatr Surg 2005; 40:541-6. [PMID: 15793732 DOI: 10.1016/j.jpedsurg.2004.11.035] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
PURPOSE The aim of this report was to study the amount and distribution of immunoglobulin deposits in liver biopsies from infants with biliary atresia (BA) and correlate the results to the cytomegalovirus (CMV) infection status. METHODS Stored liver biopsies from 18 patients with BA and from 6 control patients without liver disease were immunohistochemically stained to detect IgG and IgM deposits. The intensity of the immunoglobulin staining was evaluated by a semiquantitative scoring scale. Ongoing CMV infection was defined as the detection of CMV-IgM in serum and/or the isolation of CMV in the urine and was noted in 9 of the patients with BA. RESULTS When analyzing the immunoglobulin deposits on the hepatocellular canalicular membrane the intensity score for IgM deposits was significantly higher in biopsies from patients with BA infected with CMV than in those without. No canalicular staining was detected in control biopsies. CONCLUSIONS The results support the possibility that immunologic mechanisms are of importance in the pathogenesis of BA and that a CMV infection may trigger such mechanisms.
Collapse
Affiliation(s)
- Björn Fischler
- Department of Pediatrics, Huddinge University Hospital, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
| | | | | | | |
Collapse
|
|
43
|
Abstract
Biliary atresia (BA) remains a devastating disease of infants. It is still a disease of largely unknown etiology although many hypotheses such as an aberrant early bile duct development, perinatal viral infection, aberrant immune response, and abnormalities of bile acids have all been suggested as possibly etiologically important. Although recent studies, using the techniques of molecular biology and immunohistochemistry, have improved the understanding of some of the inflammatory elements of BA, there is a lack of understanding of how many such disparate elements interact and relate. Clinically, the management in the majority of cases should consist of a primary portoenterostomy (Kasai procedure) to try and restore bile flow and alleviate jaundice. Transplantation should be reserved for those who develop chronic liver disease and its attendant complications. Recent series would suggest that over 50% of infants in large centers will be able to clear their jaundice and therefore have a reasonable expectation of long-term survival with a good quality-of-life.
Collapse
Affiliation(s)
- Mark Davenport
- Department of Paediatric Surgery, Kings College Hospital, London, UK.
| |
Collapse
|
|
44
|
Abstract
Several etiological factors have been suggested in the pathogenesis of extrahepatic biliary atresia (EHBA); congenital, metabolic, infectious, and multifactorial. Herein we present a study of 10 children with EHBA, the aim being to explore viral infection as a possible cause of their condition. During a period of 2 yr, all infants with EHBA were included in a study and examined on viral disease on admittance for Kasai operation. In eight of the 10 children and in one parental couple the laboratory results suggested recent or persistent viral infection. Four infections were caused by cytomegalovirus (CMV) and another five by Epstein-Barr virus (EBV). CMV-DNA was detected in two liver biopsies, EBV-DNA in one liver biopsy. In a control group of 10 patients matched by age and tested by PCR in serum and viral antibodies, no sign of viral infections were detected. CMV or EBV infection were present in an unexpectedly high proportion of infants with EHBA, justifying exhaustive examination on viral disease in these children.
Collapse
|
|
45
|
Mack CL, Tucker RM, Sokol RJ, Karrer FM, Kotzin BL, Whitington PF, Miller SD. Biliary atresia is associated with CD4+ Th1 cell-mediated portal tract inflammation. Pediatr Res 2004; 56:79-87. [PMID: 15128911 PMCID: PMC1948976 DOI: 10.1203/01.pdr.0000130480.51066.fb] [Citation(s) in RCA: 142] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
A proposed mechanism in the pathogenesis of biliary atresia involves an initial virus-induced, progressive T cell-mediated inflammatory obliteration of bile ducts. The aim of this study was to characterize the inflammatory environment present within the liver of infants with biliary atresia to gain insight into the role of a primary immune-mediated process versus a nonspecific secondary response to biliary obstruction. Frozen liver tissue obtained from patients with biliary atresia, neonatal giant cell hepatitis, total parenteral nutrition (TPN)-related cholestasis, choledochal cysts, and normal control subjects was used for fluorescent immunohistochemistry studies of cellular infiltrates, cytokine mRNA expression, and in situ hybridization for localization of cytokine-producing cells. Immunohistochemistry revealed increases in CD8(+) and CD4(+) T cells and Kupffer cells (CD68(+)) in the portal tracts of biliary atresia. Reverse transcription-PCR analysis of biliary atresia tissue showed a Th1-type cytokine profile with expression of IL-2, interferon-gamma, tumor necrosis factor-alpha, and IL-12. This profile was not seen in normal, neonatal hepatitis or choledochal cyst livers but was present in TPN-related cholestasis. In situ hybridization revealed that the Th1 cytokine-producing cells were located in the portal tracts in biliary atresia and in the parenchyma of TPN-related cholestasis. A distinctive portal tract inflammatory environment is present in biliary atresia, involving CD4(+) Th1 cell-mediated immunity. The absence of similar inflammation in other pediatric cholestatic conditions suggests that the portal tract inflammation in biliary atresia is not a secondary response to cholestasis but rather indicates a specific immune response involved in the pathogenesis of biliary atresia.
Collapse
Affiliation(s)
- Cara L Mack
- Department of Pediatric, The Children's Hospital, University of Colorado Health Science Center, Denver, CO 80218, USA.
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Caton AR, Druschel CM, McNutt LA. The epidemiology of extrahepatic biliary atresia in New York State, 1983-98. Paediatr Perinat Epidemiol 2004; 18:97-105. [PMID: 14996248 DOI: 10.1111/j.1365-3016.2003.00536.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The aetiology of biliary atresia, the leading cause of neonatal extrahepatic jaundice and the main indication for liver transplantation in children, is unknown. Recent research has focused on an infectious aetiology and the development of viral models in animals. The few published epidemiological studies report conflicting results for seasonal, geographical, and racial variations in incidence. In this study, New York State (NYS) Congenital Malformations Registry data from 1983 to 1998 were compared with resident live birth certificate data. County of residence, birth date, gestational age, birthweight, gender, maternal race and maternal age were extracted from the birth certificate data. Isolated and sequence cases were combined for analysis. Observed and expected numbers of cases were calculated by NYS region. Overall, 369 biliary atresia cases were reported in the 16-year study period, a rate of 0.85 [95% CI 0.76, 0.93] per 10,000 live births. Of these, 249 isolated/sequence cases were ascertained, a rate of 0.57 [95% CI 0.50, 0.64] per 10,000 live births. The rate ratio of biliary atresia in New York City (NYC) compared with other NYS was 2.19 [95% CI 1.69, 2.84]. Seasonal patterns varied by region with spring births at highest risk in NYC and September to November births at highest risk in other NYS. The rate ratio in black vs. white mothers was 1.94 [95% CI 1.48, 2.54]. Birthweight and gestational age were associated with biliary atresia with preterm low-birthweight infants at highest risk [RR 3.24, 95% CI 2.20, 4.76]. The association of isolated/sequence biliary atresia with season, preterm birth, and low birthweight in our study supports an infectious disease hypothesis.
Collapse
Affiliation(s)
- Alissa R Caton
- Department of Epidemiology, School of Public Health, University at Albany, NY 12144, USA.
| | | | | |
Collapse
|
|
47
|
Abstract
Extrahepatic biliary atresia (EHBA) is an inflammatory fibrosing process affecting the extrahepatic and intrahepatic biliary tree resulting in fibrous obliteration of the extrahepatic biliary tract, ductopenia of intrahepatic bile ducts, and biliary cirrhosis. EHBA is divided into a correctable and a noncorrectable type with focal patency of the otherwise atretic biliary tree in the former and no patency of the biliary tree in the noncorrectable type. EHBA is divided in a fetal, prenatal or embryonic, and a more common, perinatal, acquired form. The symptoms of the former start shortly after birth and there is frequently an association with a variety of congenital anomalies. Children with the perinatal form become jaundiced several weeks after birth; no associated congenital anomalies are present. Morphologically, an inflammatory and fibrosing process of the extrahepatic biliary tree leads to complete lumenal obliteration. The liver is characterized by a nonspecific giant cell transformation, and portal expansion by fibrous connective tissue with marked ductular proliferation. With time, ductopenia and biliary cirrhosis develop. The diffential diagnosis with other conditions with similar microscopic patterns such as as alpha-1 antitrypsin deficiency, total parental nutrition, obstruction by a choledochal cyst, arteriohepatic dysplasia, familial progressive intrahepatic cholestasis, and alteration of the bile acid metabolism is discussed. In the fetal group, abnormalities in different genes seem to play a role; ductal plate malformation is another possibility. Different etiologies have been postulated in the perinatal form of EHBA: genetic susceptibility, vascular factors, toxins, and infections mainly by rotavirus and reovirus. The pathogenesis is complex. EHBA is a heterogenous disease, resulting from a combination of genetic factors, insults, and activation of different genetic and immunologic pathways. The treatment of EHBA is surgical, with anastomosis between the biliary tree and the intestine in the correctable type and a hepatic portoenterostomy (HPE) for the noncorrectable group. HPE is a temporizing treatment allowing the infant to develop and grow, followed in the majority of the patients by liver transplantation.
Collapse
Affiliation(s)
- Ellen Kahn
- Department of Pathology, North Shore University Hospital, NYU School of Medicine, 300 Community Drive, Manhasset, NY 11030, USA.
| |
Collapse
|
|
48
|
Abstract
BA is a rare disease of unclear etiology; nevertheless, its impact in the field of pediatric hepatology is significant. It is the most common surgically correctable cause of neonatal cholestasis and is the most common pediatric disease referred for liver transplantation. Little progress has been made with regard to improving outcome or understanding its pathogenesis in the past decade. Fortunately, however, a national, government-sponsored collaborative endeavor has begun that will hopefully make a significant impact upon the progress of designing new treatments for BA and develop a better understanding of its pathogenesis.
Collapse
Affiliation(s)
- Barbara Anne Haber
- Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
| | | |
Collapse
|
|
49
|
Affiliation(s)
- Ronald J Sokol
- Pediatric Liver Center and Liver Transplantation Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado, U.S.A.
| | | | | | | |
Collapse
|
|
50
|
Oliveira NLGD, Kanawaty FR, Costa SCB, Hessel G. Infection by cytomegalovirus in patients with neonatal cholestasis. ARQUIVOS DE GASTROENTEROLOGIA 2002; 39:132-6. [PMID: 12612719 DOI: 10.1590/s0004-28032002000200012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Neonatal cholestasis syndrome with an intra or extrahepatic origin has been associated to viral infections. The participation of the cytomegalovirus in the etiopathogenesis of neonatal hepatitis has been already known for some time, but only recently there have been indications that this virus may be one of the possible etiological factors for extrahepatic biliary atresia. AIMS To assess the prevalence of infection by cytomegalovirus in patients with intrahepatic cholestasis and extrahepatic cholestasis. To compare the clinical characteristics of the intrahepatic cholestasis and extrahepatic cholestasis groups with the cytomegalovirus serological results. Patients and Methods - This study consisted of 76 patients with neonatal cholestasis who were admitted between January 1980 and January 1999 when they underwent a cytomegalovirus serologic study using the ELISA method. A case note was kept on each patient with the following data: age of patient at admission, serologic result for cytomegalovirus, history of maternal infection, prematurity, fetal distress, birth weight, ponderal gain, choluria and fecal acholia. The final anatomic diagnosis of cholestasis was based on the results of an abdominal ultrasonography, a liver biopsy and its evolution. The patients were then divided into two groups: group I - intrahepatic cholestasis and group II - extrahepatic cholestasis. Each of these groups were then divided into two subgroups: subgroup A - positive serology (IgM) for cytomegalovirus and subgroup B - negative serology (IgM) for cytomegalovirus. RESULTS The frequency of positive serology (IgM) for cytomegalovirus was 29.4% in children with intrahepatic cholestasis and 28.5% in children with extrahepatic cholestasis. In comparison with group IIB, group IIA presented a higher rate of maternal infection history. The patients in group IIA demonstrated a delayed access to the service in comparison with group IA. The groups did not demonstrate any significant differences regarding the onset age of jaundice, choluria and fecal acholia, birth weight and ponderal gain. CONCLUSIONS The positive (IgM) seroprevalence for cytomegalovirus in children with intrahepatic cholestasis and extrahepatic cholestasis is high. The history of maternal infection was more common in extrahepatic cholestasis patients with positive serology for cytomegalovirus. There was a delay in the referral of these patients which resulted in a late diagnosis and surgical treatment.
Collapse
|