|
1
|
Borges A, Irie N. Maternal immune activation does not affect maternal microchimeric cells. Biol Open 2024; 13:bio061830. [PMID: 39714034 PMCID: PMC11695574 DOI: 10.1242/bio.061830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 12/24/2024] Open
Abstract
We are naturally chimeras. Apart from our own cells originating from the fertilized egg, placental mammals receive small numbers of maternal cells called maternal microchimerism (MMc) that persist throughout one's whole life. Not only are varying frequencies of MMc cells reported in seemingly contradicting phenomena, including immune tolerance and possible contribution to autoimmune-like disease, but frequencies are observable even among healthy littermates showing varying MMc frequencies and cell type repertoire. These varying differences in MMc frequencies or cell types could be contributing to the diverse phenomena related to MMc. However, factors biasing these MMc differences remain largely unknown. Here, we tested whether immunological activation leads to differing MMc frequencies, based on our recent study that suggests that most maternal cells are immune-related. Unexpectedly, fluorescence-activated cell sorting analysis on the murine spleen, thymus, and liver following maternal immune activation by mid-gestational lipopolysaccharide intraperitoneal injections detected no significant difference in the number, or ratio of, immune-related maternal cells in the tested embryonic organs of healthy offspring. These findings suggest that MMc frequencies remain stable even under immune-activated conditions, implying a possible control system of MMc migration against changes in the immunological conditions.
Collapse
Affiliation(s)
- Alexandria Borges
- Graduate School of Science, Department of Biological Sciences, The University of Tokyo, 113-0033 7-3-1 Bunkyo-ku, Hongo, Tokyo, Japan
| | - Naoki Irie
- Research Center for Integrative Evolutionary Science, SOKENDAI 240-0193 Shonan Village, Hayama, Kanagawa, Japan
| |
Collapse
|
|
2
|
Feng S, Cheng Y, Sheng C, Yang C, Li Y. Biliary atresia: the role of gut microbiome, and microbial metabolites. Front Cell Infect Microbiol 2024; 14:1411843. [PMID: 39104854 PMCID: PMC11298464 DOI: 10.3389/fcimb.2024.1411843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 07/05/2024] [Indexed: 08/07/2024] Open
Abstract
Biliary atresia (BA) is a progressive fibroinflammatory disease affecting both the extrahepatic and intrahepatic bile ducts, potentially leading to chronic cholestasis and biliary cirrhosis. Despite its prevalence, the exact mechanisms behind BA development remain incompletely understood. Recent research suggests that the gut microbiota and its metabolites may play significant roles in BA development. This paper offers a comprehensive review of the changing characteristics of gut microbiota and their metabolites at different stages of BA in children. It discusses their influence on the host's inflammatory response, immune system, and bile acid metabolism. The review also explores the potential of gut microbiota and metabolites as a therapeutic target for BA, with interventions like butyrate and gut microbiota preparations showing promise in alleviating BA symptoms. While progress has been made, further research is necessary to untangle the complex interactions between gut microbiota and BA, paving the way for more effective prevention and treatment strategies for this challenging condition.
Collapse
Affiliation(s)
| | | | | | | | - Yumei Li
- Department of pediatric intensive care unit, Children’s Medical Center, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
3
|
Tam PKH, Wells RG, Tang CSM, Lui VCH, Hukkinen M, Luque CD, De Coppi P, Mack CL, Pakarinen M, Davenport M. Biliary atresia. Nat Rev Dis Primers 2024; 10:47. [PMID: 38992031 PMCID: PMC11956545 DOI: 10.1038/s41572-024-00533-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/10/2024] [Indexed: 07/13/2024]
Abstract
Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.
Collapse
Affiliation(s)
- Paul K H Tam
- Medical Sciences Division, Macau University of Science and Technology, Macau, China.
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Rebecca G Wells
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Clara S M Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Vincent C H Lui
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Maria Hukkinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Carlos D Luque
- Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Paolo De Coppi
- NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children NHS Foundation Trust and Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Cara L Mack
- Department of Paediatrics, Division of Paediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI, USA
| | - Mikko Pakarinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, London, UK
| |
Collapse
|
|
4
|
Borges A, Castellan F, Irie N. Emergent roles of maternal microchimerism in postnatal development. Dev Growth Differ 2023; 65:75-81. [PMID: 36519824 DOI: 10.1111/dgd.12830] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/24/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
Maternal microchimerism (MMc) is the phenomenon that a low number of cells from the mother persists within her progeny. Despite their regular presence in mammalian pregnancies, the overall cell type repertoire and roles of maternal cells, especially after birth, remain unclear. By using transgenic mouse strains and human umbilical blood samples, recent studies have for the first time characterized and quantified MMc cell type repertoires in offspring, identified the cross-generational influence on fetal immunity, and determined possible factors that affect their presence in offspring. This review summarizes new findings, especially on the maternal cell type repertoires and their potential role in utero, in postnatal life, and long after birth.
Collapse
Affiliation(s)
- Alexandria Borges
- Graduate School of Science, Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
| | - Flore Castellan
- Graduate School of Science, Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
| | - Naoki Irie
- Graduate School of Science, Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
5
|
Selective enlargement of left lateral segment liver volume as a potential diagnostic predictor for biliary atresia. Pediatr Surg Int 2022; 38:1815-1820. [PMID: 36109363 DOI: 10.1007/s00383-022-05227-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2022] [Indexed: 10/14/2022]
Abstract
PURPOSE To determine an early diagnostic indicator of biliary atresia (BA), we focused on morphological left-right differences of BA livers. METHODS Of 74 infants with suspected BA at our hospital in the last 12 years, 25 met the conditions for investigation: 15 infants with BA (BA group) and 10 with other pathologies (non-BA group). CT volumetry of the liver in each patient was performed using a 3D image analysis system. Patient characteristics, blood data, and proportion of the left lateral segment to the total liver volume (LLS ratio) were compared between the two groups. RESULTS Among the patient characteristics and liver function tests, only γ-glutamyl transpeptidase (GGT) were significantly higher in the BA group (p < 0.001). The LLS ratio was 0.321 (0.227-0.382) in the BA group and 0.243 (0.193-0.289) in the non-BA group (p = 0.01). The summary cut-off, area under the curve, sensitivity, and specificity were 0.322, 0.813, 53.3, and 100% for the LLS ratio and 94.26, 0.95, 86.7, and 100% for the GGT × LLS ratio, respectively. CONCLUSIONS The LLS ratio is highly specific and may be an early diagnostic predictor of BA. Moreover, this segmental LLS enlargement may be associated with the etiology of BA.
Collapse
|
|
6
|
Fujimoto K, Nakajima A, Hori S, Tanaka Y, Shirasaki Y, Uemura S, Irie N. Whole-embryonic identification of maternal microchimeric cell types in mouse using single-cell RNA sequencing. Sci Rep 2022; 12:18313. [PMID: 36333354 PMCID: PMC9636240 DOI: 10.1038/s41598-022-20781-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 09/19/2022] [Indexed: 11/06/2022] Open
Abstract
Even though the mother and the fetus of placental mammals are immunologically non-self with respect to one other, mutual exchange of small numbers of cells between them is known to occur. Maternal cells entering the fetus, called maternal microchimeric cells (MMc cells), are thought to be involved in different physiological phenomena, such as establishing immune tolerance, tissue repair, and the pathogenesis or deterioration of some inflammatory diseases and congenital malformations. While specific MMc cell types have been reported as associated with these phenomena, the contribution of MMc cells to these different outcomes remains unknown. As one possibility, we hypothesized that different embryos have differing repertoires of MMc cell types, leading to or biasing embryos toward different fates. To date, no studies have succeeded in identifying the MMc cell type repertoire of a single embryo. Accordingly, here, we isolated MMc cells from whole mouse embryos, determined their types, and analyzed their MMc cell type variability. By combining our previously established, whole-embryonic MMc isolation method with single-cell RNA sequencing, we successfully estimated the cell type repertoires of MMc cells isolated from 26 mouse embryos. The majority of MMc cells were immune-related cells, such as myeloid cells and granulocytes. We also detected stem cell-like MMc cells expressing proliferation marker genes and terminally differentiated cells. As hypothesized, we noted statistically significant inter-individual variation in the proportion of immune-related cells in the different embryos. We here successfully estimated MMc cell types in individual whole mouse embryos. The proportion of immune-related cells significantly differed among the individual embryos, suggesting that the variations are one of the potential mechanisms underlying the differing MMc-related physiological phenomena in offspring. These findings provide insight into cell-level epigenetics by maternal cells.
Collapse
Affiliation(s)
- Kana Fujimoto
- grid.26999.3d0000 0001 2151 536XDepartment of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Akira Nakajima
- grid.26999.3d0000 0001 2151 536XGraduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Shohei Hori
- grid.26999.3d0000 0001 2151 536XGraduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yumiko Tanaka
- grid.26999.3d0000 0001 2151 536XDepartment of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Yoshitaka Shirasaki
- grid.26999.3d0000 0001 2151 536XGraduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Sotaro Uemura
- grid.26999.3d0000 0001 2151 536XDepartment of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Naoki Irie
- grid.26999.3d0000 0001 2151 536XDepartment of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan ,grid.26999.3d0000 0001 2151 536XUniversal Biology Institute, University of Tokyo, Bunkyo-ku, Tokyo, Japan
| |
Collapse
|
|
7
|
Rosa JA, Pinto AMR, Del Bigio JZ, Lima LB, Silva MMD, Mano RBC, Falcão MC. Omphalocele and biliary atresia: chance or causality. A case report. EINSTEIN-SAO PAULO 2022; 20:eRC0072. [PMID: 36169552 PMCID: PMC9491385 DOI: 10.31744/einstein_journal/2022rc0072] [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] [Received: 02/21/2022] [Accepted: 07/20/2022] [Indexed: 11/12/2022] Open
Abstract
To relate omphalocele and biliary atresia and investigate possible embryological correlations that justify the simultaneous occurrence. A female preterm newborn diagnosed as omphalocele; cesarean delivery, weight 2,500g, 46 XX karyotype. Initially, the newborn remained fasting and on parenteral nutrition, and enteral diet was introduced later, with good acceptance. On the 12th day of life, the newborn presented direct hyperbilirubinemia, increased levels of liver enzymes and fecal acholia, with a presumptive diagnosis of biliary atresia. However, the ultrasound was inconclusive, due to anatomical changes resulting from omphalocele. A surgical approach was chosen on the 37th day of life aiming to confirm diagnosis of biliary atresia and to repair omphalocele. During the surgical procedure, structural alterations compatible with biliary atresia were observed, later confirmed by pathological examination; a hepatoportoenterostomy was performed and the omphalocele was corrected. She evolved well in the postoperative period, with a decrease in direct bilirubin and liver enzymes, as well as resolution of fecal acholia, and was discharged in good clinical condition. This is a bizarre and extremely rare association, but the prognosis may be good when an early diagnosis is made and surgery performed, besides support and clinical management to prevent complications in the perioperative period. Although the pathogenesis of the diseases has not been fully defined yet, there is, to date, no direct relation between them. The association between omphalocele and biliary atresia is extremely uncommon, with only two published cases.
Collapse
|
|
8
|
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: 2] [Impact Index Per Article: 0.7] [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: 06/17/2022] [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
|
|
9
|
Cavallo L, Kovar EM, Aqul A, McLoughlin L, Mittal NK, Rodriguez-Baez N, Shneider BL, Zwiener RJ, Chambers TM, Langlois PH, Canfield MA, Agopian AJ, Lupo PJ, Harpavat S. The Epidemiology of Biliary Atresia: Exploring the Role of Developmental Factors on Birth Prevalence. J Pediatr 2022; 246:89-94.e2. [PMID: 35364097 PMCID: PMC9332904 DOI: 10.1016/j.jpeds.2022.03.038] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/04/2022] [Accepted: 03/24/2022] [Indexed: 01/05/2023]
Abstract
OBJECTIVE To identify key epidemiologic factors relevant to fetal development that are associated with biliary atresia. STUDY DESIGN This population-based registry study examined infants born in Texas between 1999 and 2014. Epidemiologic data relevant to fetal development were compared between cases of biliary atresia identified in the Texas Birth Defects Registry (n = 305) vs all live births (n = 4 689 920), and Poisson regression was used to calculate prevalence ratios (PRs) and 95% CIs. RESULTS The prevalence of biliary atresia over the study period was 0.65 per 10 000 live births. Biliary atresia was positively associated with female sex (adjusted PR, 1.68; 95% CI, 1.33-2.12), delivery before 32-37 weeks of gestation (adjusted PR, 1.64; 95% CI, 1.18-2.29), delivery before 32 weeks of gestation (adjusted PR, 3.85; 95% CI, 2.38-6.22), and non-Hispanic Black vs non-Hispanic White maternal race/ethnicity (adjusted PR, 1.54, 95% CI, 1.06-2.24), while biliary atresia was inversely associated with season of conception in the fall relative to spring (adjusted PR, 0.62; 95% CI, 0.45-0.86). In addition, biliary atresia was associated with maternal diabetes (adjusted PR, 2.34; 95% CI, 1.57-3.48), with a stronger association with pregestational diabetes compared with gestational diabetes. In subgroup analyses, these associations were present in isolated biliary atresia cases that do not have any additional birth defects. CONCLUSIONS Biliary atresia is associated with multiple factors related to fetal development, including pregestational maternal diabetes, female sex, and preterm birth. These associations also were observed in isolated cases of biliary atresia without other malformations or laterality defects. Our results are consistent with early life events influencing the pathogenesis of biliary atresia, and support further studies investigating in utero events to better understand etiology and time of onset.
Collapse
Affiliation(s)
- Laurel Cavallo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX
| | - Erin M. Kovar
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - Amal Aqul
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | | | - Naveen K. Mittal
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Norberto Rodriguez-Baez
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | - Benjamin L. Shneider
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX
| | | | - Tiffany M. Chambers
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | | | - Mark A. Canfield
- Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, TX
| | - A. J. Agopian
- Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas School of Public Health, Houston, TX
| | - Philip J. Lupo
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - Sanjiv Harpavat
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, TX.
| |
Collapse
|
|
10
|
Shpoliansky M, Tobar A, Mozer-Glassberg Y, Rosenfeld Bar-Lev M, Shamir R, Shafir M, Gurevich M, Waisbourd-Zinman O. Portal plate bile duct diameter in biliary atresia is associated with long-term outcome. Pediatr Surg Int 2022; 38:825-831. [PMID: 35322291 DOI: 10.1007/s00383-022-05113-2] [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] [Accepted: 03/06/2022] [Indexed: 11/26/2022]
Abstract
PURPOSE Kasai portoenterostomy (KPE) is the only treatment currently available for biliary atresia (BA). Age at KPE and surgical experience are prognostic factors for a successful KPE. Here, we aimed to assess whether the size of bile ductules at the porta hepatis during KPE correlates with KPE success and transplant-free survival (TFS). METHODS A retrospective analysis of patients diagnosed with BA during 2000-2019. Porta hepatis biopsies were reviewed for diameters of five representative ducts, and a mean ductal diameter (MDD) was calculated. Laboratory values including pre- and postoperative bilirubin levels were analyzed. RESULTS The cohort included 77 patients; for 33, ductal plate biopsy was available. KPE was successful in six of eight patients with MDD ≥ 50 µm, and in five of 25 with MDD < 50 µm, p = 0.008, OR = 12.0 (95% CI 1.83-78.3). Ten-year survival with native liver was higher in patients with MDD ≥ 50 µm than in patients with MDD < 50 µm, p < 0.001, HR 0.038 (95% CI 0.007-0.207). Direct bilirubin < 1 mg/dl 3 months post-KPE was associated with improved 2-year post-KPE TFS (27.7% vs. 13.9%, p < 0.0001). CONCLUSIONS MDD ≥ 50 µm correlates with KPE success and a higher rate of TFS. Direct bilirubin < 1 mg/dl 3 months post-operation may serve as a marker of successful biliary excretion, and a predictor of 2-year TFS.
Collapse
Affiliation(s)
- Michael Shpoliansky
- Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Ana Tobar
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Pathology, Rabin Medical Center, Petach Tikva, Israel
| | - Yael Mozer-Glassberg
- Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michal Rosenfeld Bar-Lev
- Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Raanan Shamir
- Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michal Shafir
- Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Michael Gurevich
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Transplant Surgery, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Orith Waisbourd-Zinman
- Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
11
|
Tamaoka S, Fukuda A, Katoh-Fukui Y, Hattori A, Uchida H, Shimizu S, Yanagi Y, Kanaan SB, Sakamoto S, Kasahara M, Yoshioka T, Fukami M. Quantification of Maternal Microchimeric Cells in the Liver of Children With Biliary Atresia. J Pediatr Gastroenterol Nutr 2022; 74:e83-e86. [PMID: 35082246 DOI: 10.1097/mpg.0000000000003388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
ABSTRACT Biliary atresia (BA) is a rare disorder of unknown etiology. There is a debate as to whether maternal microchimerism plays a significant role in the development of BA or in graft tolerance after liver transplantation. Here, we performed quantitative-PCR-based assays for liver tissues of children with BA and other diseases. Maternal cells were detected in 4/13 and 1/3 of the BA and control groups, respectively. The estimated number of maternal cells ranged between 0 and 34.7 per 106 total cells. The frequency and severity of maternal microchimerism were similar between the BA and control groups, and between patients with and without acute rejection of maternal grafts. These results highlight the high frequency of maternal microchimerism in the liver. This study provides no evidence for roles of microchimerism in the etiology of BA or in graft tolerance. Thus, the biological consequences of maternal microchimerism need to be clarified in future studies.
Collapse
Affiliation(s)
- Satoshi Tamaoka
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development
| | - Akinari Fukuda
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Yuko Katoh-Fukui
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development
| | - Atsushi Hattori
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development
| | - Hajime Uchida
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Seiichi Shimizu
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Yusuke Yanagi
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Sami B Kanaan
- Research and Development, Chimerocyte, Inc
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Seisuke Sakamoto
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Takako Yoshioka
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Maki Fukami
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development
| |
Collapse
|
|
12
|
Masuya R, Muraji T, Kanaan SB, Harumatsu T, Muto M, Toma M, Yanai T, Stevens AM, Nelson JL, Nakame K, Nanashima A, Ieiri S. Circulating maternal chimeric cells have an impact on the outcome of biliary atresia. Front Pediatr 2022; 10:1007927. [PMID: 36204668 PMCID: PMC9530628 DOI: 10.3389/fped.2022.1007927] [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: 07/31/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION We aimed to quantify the DNA of maternal chimeric (MC) cells in the peripheral blood of the BA patients and investigated the impact on the outcome. METHODS Patients with progressive jaundice because of no bile flow, which necessitated liver transplantation, or who showed inadequate bile flow with or without episodes of cholangitis and progressive hepatic fibrosis and portal hypertension were classified into the poor group. Those with adequate bile flow with completely normal liver function tests beyond 2 years were classified into the good group. The qPCR were separately carried out in buffy coat samples and plasma samples, targeting the non-inherited maternal HLA alleles in the DNA samples. RESULTS MC-DNA was present in the buffy coat (10-328 gEq per 106 host cells) in seven patients. There was no MC-DNA in the remaining five patients. MC-DNA (214-15,331 gEq per 106 host cells) was observed in the plasma of five patients. The quantity of MC-DNA in the buffy coat showed a significant difference between the two prognostic groups (p = 0.018), whereas there was no significant difference in the quantity of MC-DNA in plasma (p = 0.205). MC-DNA in the buffy coat was significantly associated with the outcome (p = 0.028), whereas MC-DNA in the plasma did not influence the outcome (p = 0.56). CONCLUSIONS Poor outcomes in BA were correlated with circulating maternal chimeric lymphocytes.
Collapse
Affiliation(s)
- Ryuta Masuya
- Division of the Gastrointestinal, Endocrine and Pediatric Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Toshihiro Muraji
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Sami B Kanaan
- Research and Development, Chimerocyte, Inc., Seattle, WA, United States.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Toshio Harumatsu
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Mitsuru Muto
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Miki Toma
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Japan
| | - Toshihiro Yanai
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Japan
| | - Anne M Stevens
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
| | - J Lee Nelson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Kazuhiko Nakame
- Division of the Gastrointestinal, Endocrine and Pediatric Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Atsushi Nanashima
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| |
Collapse
|
|
13
|
Kosaka S, Muraji T, Ohtani H, Toma M, Miura K. Placental chronic villitis in biliary atresia in dizygotic twins: A case report. Pediatr Int 2022; 64:e15101. [PMID: 35313054 DOI: 10.1111/ped.15101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 11/13/2021] [Accepted: 12/03/2021] [Indexed: 11/27/2022]
Affiliation(s)
- Seitaro Kosaka
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Japan
| | - Toshihiro Muraji
- Department of Pediatric Surgery, Kagoshima University Hospital, Kagoshima, Japan
| | - Haruo Ohtani
- Department of Pathology, Ibaraki Children's Hospital, Mito, Japan
| | - Miki Toma
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Japan
| | - Kiyonori Miura
- Department of Obstetrics and Gynecology, Nagasaki University School of Medicine, Nagasaki, Japan
| |
Collapse
|
|
14
|
Muraji T, Masuya R, Harumatsu T, Kawano T, Muto M, Ieiri S. New insights in understanding biliary atresia from the perspectives on maternal microchimerism. Front Pediatr 2022; 10:1007987. [PMID: 36210938 PMCID: PMC9539747 DOI: 10.3389/fped.2022.1007987] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Biliary atresia (BA) is a fibroinflammatory cholangiopathy and portal venopathy. It is of unknown etiology and is associated with systemic immune dysregulation, in which the first insult begins before birth. Maternal microchimerism is a naturally occurring phenomenon during fetal life in which maternal alloantigens promote the development of tolerogenic fetal regulatory T-cells in utero. However, maternal cells may alter the fetus's response to self-antigens and trigger an autoimmune response under certain histocompatibility combinations between the mother and the fetus. A recent report on a set of dizygotic discordant twins with BA, one of whose placentae showed villitis of unknown etiology, implies a certain immune-mediated conflict between the fetus with BA and the mother. Maternal chimeric cells persist postnatally for various time spans and can cause cholangitis, which ultimately leads to liver failure. In contrast, patients who eliminate maternal chimeric cells may retain their liver function.
Collapse
Affiliation(s)
- Toshihiro Muraji
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Ryuta Masuya
- Division of the Gastrointestinal, Endocrine and Pediatric Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Toshio Harumatsu
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Takafumi Kawano
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Mitsuru Muto
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| |
Collapse
|
|
15
|
Fujimoto K, Nakajima A, Hori S, Irie N. Whole embryonic detection of maternal microchimeric cells highlights significant differences in their numbers among individuals. PLoS One 2021; 16:e0261357. [PMID: 34941916 PMCID: PMC8699925 DOI: 10.1371/journal.pone.0261357] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 11/29/2021] [Indexed: 11/23/2022] Open
Abstract
During pregnancy in placental mammals, small numbers of maternal cells (maternal microchimeric cells, or MMc cells) migrate into the fetus and persist decades, or perhaps for the rest of their lives, and higher frequencies of MMc cells are reported to correlate with variety of phenomena, such as immune tolerance, tissue repair, and autoimmune diseases. While detection of these MMc cells is considered in all pregnancies, their frequency differs largely according to tissue type and disease cases, and it remains unclear whether the number of MMc cells differs significantly among embryos in normal pregnancies. Here, for the first time, we developed a whole embryonic detection method for MMc cells using transgenic mice and counted live MMc cells in each individual embryo. Using this technique, we found that the number of MMc cells was comparable in most of the analyzed embryos; however, around 500 times higher number of MMc cells was detected in one embryo at the latest stage. This result suggests that the number of MMc cells could largely differ in rare cases with unknown underlying mechanisms. Our methodology provides a basis for testing differences in the numbers of MMc cells among individual embryos and for analyzing differences in MMc cell type repertoires in future studies. These data could provide a hint toward understanding the mechanisms underlying the variety of apparently inconsistent MMc-related phenomena.
Collapse
Affiliation(s)
- Kana Fujimoto
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan
- * E-mail: (NI); (KF)
| | - Akira Nakajima
- Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Shohei Hori
- Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Naoki Irie
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo, Japan
- * E-mail: (NI); (KF)
| |
Collapse
|
|
16
|
Tran KT, Le VS, Dao LTM, Nguyen HK, Mai AK, Nguyen HT, Ngo MD, Tran QA, Nguyen LT. Novel findings from family-based exome sequencing for children with biliary atresia. Sci Rep 2021; 11:21815. [PMID: 34750413 PMCID: PMC8575792 DOI: 10.1038/s41598-021-01148-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/21/2021] [Indexed: 12/13/2022] Open
Abstract
Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. This study aimed to explore the elusive aetiology of BA by conducting whole exome sequencing for 41 children with BA and their parents (35 trios, including 1 family with 2 BA-diagnosed children and 5 child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, 6 de novo and 5 homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and had a low minor allele frequency against the employed databases: Kinh Vietnamese (KHV), GnomAD and 1000 Genome Project. Interestingly, AMER1, INVS and OCRL variants were found in unrelated probands and were first reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic variants were unlikely to occur during morphogenesis. Consistent with earlier attempts, this study implicated genetic heterogeneity and non-Mendelian inheritance of BA.
Collapse
Affiliation(s)
- Kien Trung Tran
- Vinmec Research Institute of Stem Cell and Gene Technology, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam.
| | - Vinh Sy Le
- Vinmec Research Institute of Stem Cell and Gene Technology, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
- University of Engineering and Technology, Vietnam National University Hanoi, 144 Xuan Thuy, Cau Giay District, Hanoi, Vietnam
| | - Lan Thi Mai Dao
- Vinmec Research Institute of Stem Cell and Gene Technology, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| | - Huyen Khanh Nguyen
- Bioequivalence Center, National Institute of Drug Quality Control, 11/157 Bang B, Hoang Mai District, Hanoi, Vietnam
| | - Anh Kieu Mai
- Vinmec International Hospital, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| | - Ha Thi Nguyen
- Vinmec International Hospital, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| | - Minh Duy Ngo
- Vinmec International Hospital, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| | - Quynh Anh Tran
- Vietnam National Children's Hospital, 18/879 La Thanh, Dong Da District, Hanoi, Vietnam
| | - Liem Thanh Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| |
Collapse
|
|
17
|
Segmental Atrophy of Explanted Livers in Biliary Atresia: Pathological Data From 63 Cases of Failed Portoenterostomy. J Pediatr Gastroenterol Nutr 2021; 72:88-94. [PMID: 32868669 DOI: 10.1097/mpg.0000000000002929] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Atrophy of the left lateral segment (LLS) is often encountered in liver transplantation (LT) for biliary atresia (BA). To clarify the meaning of the heterogeneous atrophy, we compared the pathological characteristics of the LLS with the right posterior segment (RPS) of BA livers obtained during LT. METHODS Among the 116 patients with BA who underwent LT at our hospital between 2014 and 2018, 63 patients with persistent cholestasis after the Kasai portoenterostomy (KP) were selected. Three pathologists evaluated tissues from the LLS and RPS for 5 pathological parameters. Positive areas in whole-slide image observed as portal inflammation, fibrosis, cholestasis, and ductular reaction, were analyzed with automated image quantitation. Moreover, we examined the relationship between the pathological score and the Pediatric End-stage Liver Disease (PELD) score. RESULTS The median age at LT was 7 months (range 4-26 months). Inflammation and fibrosis were significantly greater in the LLS than in the RPS (P < 0.001, for both); however, there were no differences in cholestasis, ductular reaction, and hepatocellular damage (P = 0.3, 0.3, and 0.82). The same results were obtained in automated image quantitation. Moreover, the sums of the 5 pathological scores in the LLS showed a significant positive correlation with the PELD score (P = 0.016, rs = 0.3). CONCLUSIONS More severe inflammation and fibrosis without cholestasis were observed in the LLS. The segmental atrophy may not be associated with poor bile drainage, but with etiopathogenesis of BA. Moreover, the proper site for biopsy during KP could be the LLS.
Collapse
|
|
18
|
Abstract
Biliary atresia is characterised as an obliterative cholangiopathy of both extra-and intra-hepatic bile ducts. There is marked aetiological heterogeneity with a number of different variants, some syndromic and others perhaps virally-mediated. Current research aims to try and define possible mechanisms and pathogenesis though an actual breakthrough remains elusive. There has been little in the way of surgical advances beyond subtle variations in the Kasai portoenterostomy and laparoscopic equivalents have no declared advantage and have yet to prove equivalence in measures of outcome. The next target has been to maximise potential with better adjuvant therapy, though the evidence base for most currently available therapies such as steroids and ursodeoxycholic acid remains limited. Still high-dose steroid use is widespread, certainly in Europe and the Far East. Clearance of jaundice can be achieved in 50-60% of those subjected to portoenterostomy at <70 days and should be an achievable benchmark. Transplantation is a widely available "rescue" therapy though whether it should be an alternative as a primary procedure is arguable but becoming increasingly heard. The aim of clinical practice remains to get these infants for surgery as early as is possible though this can be difficult to accomplish in practice, and "low-cost" screening projects using stool colour charts have been limited outside of Taiwan and Japan. Centralisation of resources (medical and surgical) is associated with a diminution of time to portoenterostomy but application has been limited by entrenched health delivery models or geographical constraints.
Collapse
Affiliation(s)
- Federico Scottoni
- Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS, United Kingdom
| | - Mark Davenport
- Department of Paediatric Surgery, Kings College Hospital, London SE5 9RS, United Kingdom.
| |
Collapse
|
|
19
|
Johnson BN, Ehli EA, Davies GE, Boomsma DI. Chimerism in health and potential implications on behavior: A systematic review. Am J Med Genet A 2020; 182:1513-1529. [PMID: 32212323 DOI: 10.1002/ajmg.a.61565] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 02/03/2020] [Accepted: 03/02/2020] [Indexed: 12/12/2022]
Abstract
In this review, we focus on the phenomenon of chimerism and especially microchimerism as one of the currently underexplored explanations for differences in health and behavior. Chimerism is an amalgamation of cells from two or more unique zygotes within a single organism, with microchimerism defined by a minor cell population of <1%. This article first presents an overview of the primary techniques employed to detect and quantify the presence of microchimerism and then reviews empirical studies of chimerism in mammals including primates and humans. In women, male microchimerism, a condition suggested to be the result of fetomaternal exchange in utero, is relatively easily detected by polymerase chain reaction molecular techniques targeting Y-chromosomal markers. Consequently, studies of chimerism in human diseases have largely focused on diseases with a predilection for females including autoimmune diseases, and female cancers. We detail studies of chimerism in human diseases and also discuss some potential implications in behavior. Understanding the prevalence of chimerism and the associated health outcomes will provide invaluable knowledge of human biology and guide novel approaches for treating diseases.
Collapse
Affiliation(s)
- Brandon N Johnson
- Avera Institute for Human Genetics, Avera McKennan Hospital and University Health Center, Sioux Falls, South Dakota, USA
| | - Erik A Ehli
- Avera Institute for Human Genetics, Avera McKennan Hospital and University Health Center, Sioux Falls, South Dakota, USA
| | - Gareth E Davies
- Avera Institute for Human Genetics, Avera McKennan Hospital and University Health Center, Sioux Falls, South Dakota, USA
| | - Dorret I Boomsma
- Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
| |
Collapse
|
|
20
|
Abstract
Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the intrahepatic and extrahepatic biliary system, resulting in obstruction of bile flow and neonatal jaundice. Histopathological findings in liver biopsies include the expansion of the portal tracts, with edematous fibroplasia and bile ductular proliferation, with bile plugs in duct lumen. Lobular morphological features may include variable multinucleate giant cells, bilirubinostasis and hemopoiesis. The etiopathogenesis of biliary atresia is multifactorial and multiple pathomechanisms have been proposed. Experimental and clinical studies have suggested that viral infection initiates biliary epithelium destruction and release of antigens that trigger a Th1 immune response, which leads to further injury of the bile duct, resulting in inflammation and obstructive scarring of the biliary tree. It has also been postulated that biliary atresia is caused by a defect in the normal remodelling process. Genetic predisposition has also been proposed as a factor for the development of biliary atresia.
Collapse
|
|
21
|
Kim MH, Akbari O, Genyk Y, Kohli R, Emamaullee J. Immunologic benefit of maternal donors in pediatric living donor liver transplantation. Pediatr Transplant 2019; 23:e13560. [PMID: 31402535 DOI: 10.1111/petr.13560] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/18/2019] [Accepted: 07/08/2019] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Long-term follow-up has suggested that pediatric LDLT may have superior outcomes compared to deceased donor recipients. In this review, we describe the subset of LDLT recipients with maternal donors that have lower reported rates of rejection and improved allograft survival. RECENT FINDINGS Pediatric LDLT recipients, particularly those with a primary diagnosis of biliary atresia who receive grafts from their mothers, have been reported to have lower rates of acute cellular rejection post-transplant and graft failure. Maternal-fetal microchimerism and the persistence of regulatory T cells may be related to improved outcomes observed in recipients with maternal donors. Further, recent studies have shown that up to 60% of pediatric LDLT recipients can undergo intentional withdrawal of immunosuppression and achieve long-term operational tolerance. The impact of graft type on operational tolerance has not been thoroughly investigated; however, investigation of tolerant pediatric LDLT patients with maternal donors may provide key insights into the mechanisms of immune tolerance. SUMMARY While excellent outcomes can be achieved in pediatric LDLT, there is still a measurable decrease in graft and patient survival over time post-transplant. Recipients of maternal donor liver transplants are a subset of patients who may be advantaged toward improved outcomes by means of immune tolerance.
Collapse
Affiliation(s)
- Michelle H Kim
- Division of Hepatobiliary and Transplant Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yuri Genyk
- Division of Hepatobiliary and Transplant Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Pediatric Liver Care Center, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Rohit Kohli
- Pediatric Liver Care Center, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Juliet Emamaullee
- Division of Hepatobiliary and Transplant Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Pediatric Liver Care Center, Children's Hospital Los Angeles, Los Angeles, CA, USA
| |
Collapse
|
|
22
|
Biliary Atresia as a Disease Starting In Utero: Implications for Treatment, Diagnosis, and Pathogenesis. J Pediatr Gastroenterol Nutr 2019; 69:396-403. [PMID: 31335837 PMCID: PMC6942669 DOI: 10.1097/mpg.0000000000002450] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Biliary atresia (BA) is the most common reason for pediatric liver transplant. BA's varied presentation, natural history, and treatment with the Kasai portoenterostomy have been well described; however, when BA starts relative to birth has not been clearly defined. In this review, we discuss laboratory, imaging, and clinical data which suggest that most if not all forms of BA may start before birth. This early onset has implications in terms of delivering treatments earlier and identifying possible factors underlying BA's etiology.
Collapse
|
|
23
|
Noguchi Y, Ueno T, Kodama T, Saka R, Takama Y, Tazuke Y, Bessho K, Okuyama H. The effect of maternal grafts in early acute cellular rejection after pediatric living-donor liver transplantation. Pediatr Surg Int 2019; 35:765-771. [PMID: 31111216 DOI: 10.1007/s00383-019-04487-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2019] [Indexed: 10/26/2022]
Abstract
PURPOSE Living-donor liver transplantations (LDLTs) with maternal grafts can be more successful than those with paternal grafts because of their tolerance to non-inherited maternal antigens. We reviewed LDLT patients to investigate the relationship between acute rejection and donor sex. METHODS LDLT patients between January 2010 and November 2015 were enrolled. ACR was defined by a rejection activity index of > 3. RESULTS Forty-six patients (22 males and 24 females), of whom 28 had biliary atresia, were enrolled. The median age of the patients was 2.8 years and the donor types were maternal (n = 25) and paternal (n = 21). Acute cellular rejection (ACR) was observed in 22 patients. Twelve (48%) of the 25 patients in the maternal group had at least one episode of rejection compared with 10 (48%) of the 21 in the paternal group. Among the patients with ACR, the first rejection in the maternal group occurred significantly earlier than that in the paternal group (p < 0.01). In the multivariable analysis, the only variable significantly related to the first rejection day after LDLT was donor sex (male) (p < 0.005). CONCLUSION Our results showed that maternal grafts had an effect on causing earlier ACR in LDLT.
Collapse
Affiliation(s)
- Yuki Noguchi
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takehisa Ueno
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Tasuku Kodama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryuta Saka
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuichi Takama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuko Tazuke
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroomi Okuyama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| |
Collapse
|
|
24
|
Masuya R, Muraji T, Ohtani H, Mukai M, Onishi S, Harumatsu T, Yamada K, Yamada W, Kawano T, Machigashira S, Nakame K, Kaji T, Ieiri S. Morphometric demonstration of portal vein stenosis and hepatic arterial medial hypertrophy in patients with biliary atresia. Pediatr Surg Int 2019; 35:529-537. [PMID: 30762106 DOI: 10.1007/s00383-019-04459-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/08/2019] [Indexed: 11/28/2022]
Abstract
PURPOSE Portal hypertension in patients with biliary atresia (BA) is generally thought to result from portal vein (PV) narrowing secondary to hepatic fibrosis. To test the hypothesis, we morphometrically analyzed the PVs and hepatic arteries (HAs). METHODS Morphometrical analyses of 25 BA and 26 non-BA liver biopsy specimens from patients treated from 2000 to 2014. The total specimen area, the fibrotic portal area, vessel diameter and medial thickness of the HAs were measured. RESULTS The PV diameter in BA patients was significantly smaller than that in non-BA patients. In BA, the numbers of normal-sized PVs and capillaries were decreased and increased, respectively. The PV diameter was not significantly correlated with the degree of fibrosis. We newly found that medial hypertrophy and the HA diameter increased with the number of endothelial cells in BA. The PV diameter was not significantly correlated with the medial thickness and was positively correlated with the HA diameter in BA. CONCLUSIONS The narrowing of the PV is unlikely to occur secondarily to liver fibrosis. The medial hypertrophy of the HA is not correlated with the decrease in the PV blood flow. These findings seem to be unique to the primary vascular lesions of BA.
Collapse
Affiliation(s)
- Ryuta Masuya
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Toshihiro Muraji
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.,Department of Pediatric Surgery, Kirishima Medical Center, Kagoshima, Japan
| | - Haruo Ohtani
- Department of Pathology, Ibaraki Children's Hospital, Mito, Japan
| | - Motoi Mukai
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Shun Onishi
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Toshio Harumatsu
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Koji Yamada
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Waka Yamada
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Takafumi Kawano
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Seiro Machigashira
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Kazuhiko Nakame
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Tatsuru Kaji
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.
| |
Collapse
|
|
25
|
Suda K, Muraji T, Ohtani H, Aiyoshi T, Sasaki T, Toma M, Yanai T. Histological significance of hepatitis-like findings in biliary atresia: An analysis of 34 Japanese cases. Pediatr Int 2019; 61:364-368. [PMID: 30811786 DOI: 10.1111/ped.13816] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 12/21/2018] [Accepted: 02/23/2019] [Indexed: 11/27/2022]
Abstract
BACKGROUND Hepatocellular injury including multinuclear changes are common histological features in biliary atresia (BA), as well as in neonatal hepatitis. To date, however, no reports have examined how those findings correlate with the prognosis of BA. We clarified the clinical implications of hepatitis-related changes in BA on histological analysis. METHODS We retrospectively reviewed 34 cases of BA treated over the past 30 years at Ibaraki Children's Hospital. Liver biopsy specimens during Kasai procedures were evaluated for hepatocyte multinuclear change, ballooning, and acidophilic body, hereby defined as hepatitis-like findings (HLF). Each finding was semi-quantitatively scored as 0-2, and their sum was defined as the HLF score, ranging from 0 to 6. We examined the correlation between HLF score and total bilirubin (T-Bil), direct bilirubin (D-Bil), and other liver function test results at the Kasai procedure, as well as 1 week, and 1, 3, and 6 months after the Kasai procedure. Subsequently, HLF score was compared between native liver survivors (NLS; n = 16) and non-NLS (n = 18) for long-term analyses. RESULTS Hepatitis-like findings score except for aspartate aminotransferase (AST), had no correlation with the preoperative data. HLF score was positively correlated, however, with T-Bil, D-Bil, and AST at 1 week and 1 month after the Kasai procedure (1 week: P = 0.009, 0.023, and 0.019; 1 month: 0.022, 0.019, and 0.013, respectively). HLF score was not significantly different between the NLS and non-NLS groups. CONCLUSION Higher HLF score at Kasai procedure is an indicator of poor liver function at short-term follow up.
Collapse
Affiliation(s)
- Kazuto Suda
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Ibaraki, Japan
| | - Toshihiro Muraji
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Ibaraki, Japan.,Department of Pediatric Surgery, Kirishima Medical Center affiliated with Research Field in Medical and Health Sciences, Kagoshima University, Kirishima, Kagoshima, Japan
| | - Haruo Ohtani
- Department of Pathology, Ibaraki Children's Hospital, Mito, Ibaraki, Japan
| | - Tsubasa Aiyoshi
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Ibaraki, Japan
| | - Takato Sasaki
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Ibaraki, Japan
| | - Miki Toma
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Ibaraki, Japan
| | - Toshihiro Yanai
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, Ibaraki, Japan
| |
Collapse
|
|
26
|
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
|
|
27
|
Muraji T, Tanaka H, Ieiri S. Ethnic variation in the incidence of biliary atresia correlates with the frequency of the most prevalent haplotype in its population. Hum Immunol 2018; 79:668-671. [PMID: 30006139 DOI: 10.1016/j.humimm.2018.07.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/12/2018] [Accepted: 07/04/2018] [Indexed: 12/18/2022]
Abstract
The cause of biliary atresia (BA) remains an enigma. However, an ethnic diversity in the incidence of BA is so unique that anthropological approach may provide some etiopathogenetic implications in the disease mechanism. We previously reported that an association of maternal microchimerism (MMc) in BA and a significant compatibility of HLA-A between the patient with BA and their mother. Across the 10 countries (Japan, South Korea, Taiwan, Philippines, New Zealand (Maori population), UK, France, Germany, Norway, and Sweden), we determined the frequency of the most prevalent HLA haplotypes of each country from Allele Frequency Database and found that it was significantly correlated with the incidence of BA of the respective country (p = 0.0126). This observation better fits the MMc theory as an etiopathogenesis, that is, maternal effector cells are likely to migrate into the fetus in a relatively homogenous population and may damage the developing bile duct structure and portal vein endothelium, depending on materno-fetal tolerance and immunity.
Collapse
Affiliation(s)
- Toshihiro Muraji
- Department of Pediatric Surgery, Kirishima Medical Center, 3320, Matsunaga, Kirishima City, Kagoshima 899-5112, Japan; Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima City, Japan.
| | - Hidenori Tanaka
- HLA Foundation Laboratory, 2F #1 Kyoto Research Park, Shimogyo-ku, Kyoto 600-8813, Japan
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima City, Japan
| |
Collapse
|
|
28
|
Durable Clinical and Immunologic Advantage of Living Donor Liver Transplantation in Children. Transplantation 2018; 102:953-960. [DOI: 10.1097/tp.0000000000002110] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
|
|
29
|
|
|
30
|
Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
31
|
Muraji T, Ohtani H, Ieiri S. Unique manifestations of biliary atresia provide new immunological insight into its etiopathogenesis. Pediatr Surg Int 2017; 33:1249-1253. [PMID: 29022092 DOI: 10.1007/s00383-017-4155-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2017] [Indexed: 01/27/2023]
Abstract
Biliary atresia (BA) is a unique cholestatic disease of newborns with a background of exaggerated immune response in the liver of unknown mechanism. Three hypotheses have been proposed; autoimmune type of cholangiopathy triggered by virus infection, graft-versus-host disease type of immune-mediated disease associated with maternal microchimerism and ductal plate malformation theory. Researchers on virus infection theory have experimentally explored immune process causing cholangiopathy on murine models of this disease, while in maternal microchimerism hypothesis were detected maternal cells in the BA patients' liver, of which roles are yet to be determined. Ductal plate malformation theory is an intriguing hypothesis in the sense that it suggests the onset of this disease is in the first trimester. This theory can be secondary to either one of these two immune-related insults. In this review, four unique points are focused; (1) the timing of onset, (2) hepatitis-like pathological picture, (3) heterogenous atrophy of the liver segments when advanced, and (4) swollen lymph nodes at the porta hepatis. These unique clinicopahtological aspects of this disease should be well explained by these hypotheses.
Collapse
Affiliation(s)
- Toshihiro Muraji
- Department of Pediatric Surgery, Kirishima Medical Center, Kirishima, Japan. .,Department of Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kogoshima, Japan.
| | - Haruo Ohtani
- Department of Pathology, Ibaraki Children's Hospital, Mito, Japan
| | - Satoshi Ieiri
- Department of Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kogoshima, Japan
| |
Collapse
|
|
32
|
Schady DA, Finegold MJ. Contemporary Evaluation of the Pediatric Liver Biopsy. Gastroenterol Clin North Am 2017; 46:233-252. [PMID: 28506363 DOI: 10.1016/j.gtc.2017.01.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver disease in the neonate, infant, child, and adolescent may manifest differently depending on the type of disorder. These disorders show marked overlap clinically and on light microscopy. Histology and ultrastructural examination are used in tandem for the diagnosis of most disorders. A final diagnosis or interpretation of the pediatric liver biopsy depends on appropriate and adequate clinical history, laboratory test results, biochemical assays, and molecular analyses, as indicated by the light microscopic and ultrastructural examination.
Collapse
Affiliation(s)
- Deborah A Schady
- Department of Pathology and Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
| | - Milton J Finegold
- Department of Pathology and Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| |
Collapse
|
|
33
|
Harada K. Immunopathology of Biliary Atresia. PATHOLOGY OF THE BILE DUCT 2017:121-137. [DOI: 10.1007/978-981-10-3500-5_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
34
|
Guthrie KA, Gammill HS, Kamper-Jørgensen M, Tjønneland A, Gadi VK, Nelson JL, Leisenring W. Statistical Methods for Unusual Count Data: Examples From Studies of Microchimerism. Am J Epidemiol 2016; 184:779-786. [PMID: 27769989 DOI: 10.1093/aje/kww093] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 08/04/2016] [Indexed: 02/04/2023] Open
Abstract
Natural acquisition of small amounts of foreign cells or DNA, referred to as microchimerism, occurs primarily through maternal-fetal exchange during pregnancy. Microchimerism can persist long-term and has been associated with both beneficial and adverse human health outcomes. Quantitative microchimerism data present challenges for statistical analysis, including a skewed distribution, excess zero values, and occasional large values. Methods for comparing microchimerism levels across groups while controlling for covariates are not well established. We compared statistical models for quantitative microchimerism values, applied to simulated data sets and 2 observed data sets, to make recommendations for analytic practice. Modeling the level of quantitative microchimerism as a rate via Poisson or negative binomial model with the rate of detection defined as a count of microchimerism genome equivalents per total cell equivalents tested utilizes all available data and facilitates a comparison of rates between groups. We found that both the marginalized zero-inflated Poisson model and the negative binomial model can provide unbiased and consistent estimates of the overall association of exposure or study group with microchimerism detection rates. The negative binomial model remains the more accessible of these 2 approaches; thus, we conclude that the negative binomial model may be most appropriate for analyzing quantitative microchimerism data.
Collapse
|
|
35
|
Absence of Maternal Microchimerism in Regional Lymph Nodes of Children With Biliary Atresia. J Pediatr Gastroenterol Nutr 2016; 62:804-7. [PMID: 26756872 DOI: 10.1097/mpg.0000000000001093] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Maternal lymphocytes have been cited as a potential cause of infantile biliary atresia (BA). When hepatoportoenterostomy is performed, locoregional lymphadenopathy is frequently encountered. METHODS We screened enlarged nodes from 6 consecutive nonsyndromatic BA patients (age: 68 days ± 18.9 days) for maternal elements using DNA fingerprinting with short tandem repeat analysis and quantitative real-time polymerase chain reaction for allelic (single nucleotide) sequence polymorphisms. RESULTS Although being partly positive in infants' peripheral blood, no maternal microchimerism could be demonstrated in any of the lymph nodes. CONCLUSION This result challenges the hypothesis that maternal cells play a role in hilar lymphadenopathy of children with BA.
Collapse
|
|
36
|
Living Donor Liver Transplantation in Children: Surgical and Immunological Results in 250 Recipients at Université Catholique de Louvain. Ann Surg 2016; 262:1141-9. [PMID: 25563870 DOI: 10.1097/sla.0000000000001094] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVES To evaluate the outcome of pediatric living donor liver transplantation (LDLT) regarding portal vein (PV) reconstruction, ABO compatibility, and impact of maternal donation on graft acceptance. BACKGROUND LDLT and ABO-mismatched transplantation constitute feasible options to alleviate organ shortage in children. Vascular complications of portal hypoplasia in biliary atresia (BA) and acute rejection (AR) are still major concerns in this field. METHODS Data from 250 pediatric LDLT recipients, performed at Cliniques Universitaires Saint-Luc between July 1993 and June 2012, were collected retrospectively. Results were analyzed according to ABO matching and PV complications. Uni- and multivariate analyses were performed to study the impact of immunosuppression, sex matching, and maternal donation on AR rate. RESULTS Overall, the 10-year patient survival rate was 93.2%. Neither patient or graft loss nor vascular rejection, nor hemolysis, was encountered in the ABO nonidentical patients (n = 58), provided pretransplant levels of relevant isoagglutinins were below 1/16. In BA recipients, the rate of PV complications was lower after portoplasty (4.6%) than after truncal PV anastomosis (9.8%) and to jump graft interposition (26.9%; P = 0.027). In parental donation, maternal grafts were associated with higher 1-year AR-free survival (55.2%) than paternal grafts (39.8%; P = 0.041), but only in BA patients. CONCLUSIONS LDLT, including ABO-mismatched transplantation, constitutes a safe and efficient therapy for liver failure in children. In BA patients with PV hypoplasia, portoplasty seems to constitute the best technique for PV reconstruction. Maternal donation might be a protective factor for AR.
Collapse
|
|
37
|
Abstract
PURPOSE OF REVIEW The purpose of this study is to review advances in both the pathogenesis and clinical management of biliary atresia. RECENT FINDINGS Immunologic studies have further characterized roles of helper T-cells, B-cells, and natural killer cells in the immune dysregulation following viral replication within and damage of biliary epithelium. Prominin-1-expressing portal fibroblasts may play an integral role in the biliary fibrosis associated with biliary atresia. A number of genetic polymorphisms have been characterized as leading to susceptibility for biliary atresia. Postoperative corticosteroid therapy is not associated with greater transplant-free survival. Newborn screening may improve outcomes of infants with biliary atresia and may also provide a long-term cost benefit. SUMMARY Although recent advances have enhanced our understanding of pathogenesis and clinical management, biliary atresia remains a significant challenge requiring further investigation.
Collapse
|
|
38
|
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
|
|
39
|
Götze T, Blessing H, Grillhösl C, Gerner P, Hoerning A. Neonatal Cholestasis - Differential Diagnoses, Current Diagnostic Procedures, and Treatment. Front Pediatr 2015; 3:43. [PMID: 26137452 PMCID: PMC4470262 DOI: 10.3389/fped.2015.00043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 04/29/2015] [Indexed: 12/18/2022] Open
Abstract
Cholestatic jaundice in early infancy is a complex diagnostic problem. Misdiagnosis of cholestasis as physiologic jaundice delays the identification of severe liver diseases. In the majority of infants, prolonged physiologic jaundice represent benign cases of breast milk jaundice, but few among them are masked and caused by neonatal cholestasis (NC) that requires a prompt diagnosis and treatment. Therefore, a prolonged neonatal jaundice, longer than 2 weeks after birth, must always be investigated because an early diagnosis is essential for appropriate management. To rapidly identify the cases with cholestatic jaundice, the conjugated bilirubin needs to be determined in any infant presenting with prolonged jaundice at 14 days of age with or without depigmented stool. Once NC is confirmed, a systematic approach is the key to reliably achieve the diagnosis in order to promptly initiate the specific, and in many cases, life-saving therapy. This strategy is most important to promptly identify and treat infants with biliary atresia, the most common cause of NC, as this requires a hepatoportoenterostomy as soon as possible. Here, we provide a detailed work-up approach including initial treatment recommendations and a clinically oriented overview of possible differential diagnoses in order to facilitate the early recognition and a timely diagnosis of cholestasis. This approach warrants a broad spectrum of diagnostic procedures and investigations including new methods that are described in this review.
Collapse
Affiliation(s)
- Thomas Götze
- Department for Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany
| | - Holger Blessing
- Department for Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany
| | - Christian Grillhösl
- Department for Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany
| | - Patrick Gerner
- Department for Pediatric and Adolescent Medicine, Albert-Ludwigs-University Freiburg , Freiburg , Germany
| | - André Hoerning
- Department for Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany
| |
Collapse
|
|
40
|
Fujisawa S, Muraji T, Sakamoto N, Hosaka N, Matsuda S, Kawakami H, Hirai M, Yanai T. Positive C4d staining of the portal vein endothelium in the liver of patients with biliary atresia: a role of humoral immunity in ongoing liver fibrosis. Pediatr Surg Int 2014; 30:877-81. [PMID: 25064226 DOI: 10.1007/s00383-014-3553-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/15/2014] [Indexed: 12/20/2022]
Abstract
PURPOSE This study aimed to clarify the role of complement activation in fibrogenesis in BA. METHODS In total, 27 paraffin-embedded liver biopsy samples were immunohistochemically analyzed using C4d polyclonal antibody, vascular cell adhesion molecule-1 (VCAM-1), and CD45. The liver samples were obtained from 25 patients during Kasai operation, and two additional specimens were obtained from 2 patients by needle biopsy later at the time of liver function deterioration. The degree of liver fibrosis was histologically graded 1-3. RESULTS Among the 25 samples, 9 showed C4d-positive immunostaining localized on the endothelia of a few portal veins in the portal tract. The degree of fibrosis was correlated with C4d staining (p = 0.025). The age at Kasai operation correlated with the degree of fibrosis and the C4d positivity. Two needle biopsy samples were positive for C4d. Among 13 samples submitted for VCAM-1 staining, 2 negative samples were C4d negative and all positive C4d samples were VCAM-1 positive with CD45 mononuclear cell infiltration. CONCLUSION These findings suggest that ongoing cirrhosis could be a result of progressive "vasculopathy" of the portal vein caused by humoral and cell-mediated immune interaction.
Collapse
Affiliation(s)
- Sorahiko Fujisawa
- Department of Pediatric Surgery, Ibaraki Children's Hospital, 3-3-1 Futabadai, Mito, Ibaraki, 311-4145, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Muraji T. Maternal microchimerism in biliary atresia: are maternal cells effector cells, targets, or just bystanders? CHIMERISM 2014; 5:1-5. [PMID: 24670921 DOI: 10.4161/chim.28576] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The etiology of biliary atresia (BA) is unknown; however, the liver histology is similar to that observed in immune-mediated hepatic disorders. Liver fibrosis in BA progresses even after bile drainage has been achieved by the Kasai operation. Maternal microchimerism has been purported to play a part in the pathogenesis of BA as well as certain autoimmune diseases. However, the role of maternal cells has not yet been determined in BA. Specifically, it is unknown whether these maternal cells function as maternal effector T lymphocytes, or targets or bystanders. We currently hypothesize that the first hit is due to GvHD interaction by engrafted maternal effector T lymphocytes. Furthermore, we suggest that the secondary effects that are manifested by progressive cirrhosis are caused either by maternal chimeric effector T lymphocytes (e.g., GvHD interaction) or targets (e.g., HvGD interaction). Based on our hypothesis, mixed lymphocyte reactions between patients and their mothers might shed light on the etiopathogenesis and prognostic indicators.
Collapse
Affiliation(s)
- Toshihiro Muraji
- Department of Pediatric Surgery; Child Health and Cancer Research Center; Ibaraki Children's Hospital; Ibaraki, Japan
| |
Collapse
|
|
42
|
Bendon R, Coventry S, Bendon J, Nordmann A, Schikler K. Follow-up study of lympho-histiocytic villitis and incidental retroplacental hematoma. Pediatr Dev Pathol 2014; 17:94-101. [PMID: 24450427 DOI: 10.2350/13-10-1395-oa.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Placentas are usually submitted for pathologic examination based on obstetrical indications. We hypothesized that the placenta may have diagnostic value to the infant independent of obstetrical events. We specifically tested whether lymphohistiocytic villitis (noninfectious) would predict autoimmune or alloimmune disease based on transfer of activated maternal T-cells to the fetus and whether clinically silent placental separations (retroplacental hematomas, RPH) would predict neurologic injury in the infant. All placentas from consecutive deliveries had a routine pathologic examination of the placenta. The infants with placentas demonstrating inflammation of >1% of villi or RPH >2 cm and matched controls had their hospital charts reviewed and parental interviews by telephone at 5 to 7 years of age. The children of consented patients were also searched for in the office visits of the University of Louisville Pediatric Neurology and Rheumatology divisions. One thousand six hundred eighty-four patients consented to the follow-up study. We found no cases of autoimmune disease among 17 children with villitis >1%. Of 16 infants with RPH, 1 had cerebral palsy but with other placental findings, 1 had lethal hydranenecephaly, and the remainder had no adverse outcome. Of 15 children seen by a pediatric neurologist, none had the same placental lesion. The specific lesions of lymphohistiocytic villitis or asymptomatic RPH do not predict significant pediatric disease by 7 years of age. At least for these 2 lesions, the placenta does not have diagnostic value to the infant.
Collapse
Affiliation(s)
- Robert Bendon
- 1 Departments of Pathology and Pediatrics, University of Louisville, and Department of Pathology, Kosair Children's Hospital, Louisville, KY, USA
| | | | | | | | | |
Collapse
|
|
43
|
Sanada Y, Kawano Y, Miki A, Aida J, Nakamura KI, Shimomura N, Ishikawa N, Arai T, Hirata Y, Yamada N, Okada N, Wakiya T, Ihara Y, Urahashi T, Yasuda Y, Takubo K, Mizuta K. Maternal grafts protect daughter recipients from acute cellular rejection after pediatric living donor liver transplantation for biliary atresia. Transpl Int 2014; 27:383-90. [PMID: 24472036 DOI: 10.1111/tri.12273] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/23/2013] [Accepted: 01/22/2014] [Indexed: 01/09/2023]
Abstract
Some studies have found that gender mismatch between donors and recipients are related to poor graft prognosis after liver transplantation. However, few studies have investigated the impact of gender mismatch on acute cellular rejection (ACR) in pediatric living donor liver transplantation (LDLT). This retrospective study investigated the clinical significance of these factors in ACR after pediatric LDLT. Between November 2001 and February 2012, 114 LDLTs were performed for recipients with biliary atresia (BA) using parental grafts. We performed univariate and multivariate analyses to identify the factors associated with ACR. The donor-recipient classifications included mother donor to daughter recipient (MD; n = 43), mother to son (n = 18), father to daughter (FD; n = 33), and father to son (n = 20) groups. The overall incidence rate of ACR in the recipients was 36.8%. Multivariate analysis showed that gender mismatch alone was an independent risk factor for ACR (P = 0.012). The FD group had a higher incidence of ACR than the MD group (P = 0.002). In LDLT, paternal grafts with gender mismatch were associated with a higher increased incidence of ACR than maternal grafts with gender match. Our findings support the possibility that maternal antigens may have an important clinical impact on graft tolerance in LDLT for patients with BA.
Collapse
Affiliation(s)
- Yukihiro Sanada
- Department of Transplant Surgery, Jichi Medical University, Shimotsuke City, Japan; Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Petersen C, Davenport M. Aetiology of biliary atresia: what is actually known? Orphanet J Rare Dis 2013; 8:128. [PMID: 23987231 PMCID: PMC3766137 DOI: 10.1186/1750-1172-8-128] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 08/23/2013] [Indexed: 01/27/2023] Open
Abstract
Biliary atresia (BA) is a rare disease of unknown etiology and unpredictable outcome, even when there has been timely diagnosis and exemplary surgery. It has been the commonest indication for liver transplantation during childhood for the past 20 years. Hence much clinical and basic research has been directed at elucidating the origin and pathology of BA. This review summarizes the current clinical variations of BA in humans, its occasional appearance in animals and its various manifestations in the laboratory as an experimental model.
Collapse
Affiliation(s)
- Claus Petersen
- Department of Pediatric Surgery, Hannover Medical School, Carl-Neuberg-Str, 1, 30625 Hannover, Germany.
| | | |
Collapse
|
|
45
|
Wang ZM, Chen YJ. Recent progress in understanding pathogenesis and liver pathology in biliary atresia. Shijie Huaren Xiaohua Zazhi 2012; 20:2576-2582. [DOI: 10.11569/wcjd.v20.i27.2576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia is an infantile destructive inflammatory cholangiopathy that causes obliteration of both intrahepatic and extrahepatic bile ducts and eventually liver cirrhosis. So far, the exact etiology and pathogenesis of biliary atresia remain unclear, and possible etiologies include congenital and genetic factors, infection, inflammation, immune reaction, maternal factors, and vascular factors. Immunoinflammatory theory has been accepted by most researchers, which is supported by liver pathological changes. This review focuses on the recent progress in understanding pathogenesis and liver pathology in biliary atresia.
Collapse
|
|
46
|
Moreira RK, Cabral R, Cowles RA, Lobritto SJ. Biliary atresia: a multidisciplinary approach to diagnosis and management. Arch Pathol Lab Med 2012; 136:746-60. [PMID: 22742548 DOI: 10.5858/arpa.2011-0623-ra] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Biliary atresia is an inflammatory cholangiopathy of infancy that results in progressive fibrosis and obliteration of bile ducts and represents the main indication for liver transplant in young children. In spite of extensive investigation, its etiology has remained poorly understood. Timely surgical intervention (Kasai procedure) may result in significant benefit to these patients and represents the final goal of an accurate diagnostic evaluation. OBJECTIVE To present an overview of biliary atresia, including clinical and surgical approaches to this disease, with emphasis on the histopathologic evaluation. DATA SOURCES Review of relevant literature indexed in PubMed (US National Library of Medicine). CONCLUSION A well-coordinated multidisciplinary approach is required in the assessment of suspected cases of biliary atresia. Pathologic examination of biopsy specimens is an integral part of the diagnostic algorithm and, therefore, plays a pivotal role in the diagnostic evaluation of this disease.
Collapse
Affiliation(s)
- Roger Klein Moreira
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
| | | | | | | |
Collapse
|
|
47
|
Early-onset chronic inflammatory disease associated with maternal microchimerism. Case Rep Pediatr 2012; 2012:323681. [PMID: 22924145 PMCID: PMC3423865 DOI: 10.1155/2012/323681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 07/15/2012] [Indexed: 11/18/2022] Open
Abstract
Maternal microchimerism (mMc) refers to the presence of a small population of cells originating from the mother. Whether mMc leads to autoimmune responses in children remains controversial. We describe here an 11-year-old boy with persistent fever and elevated levels of C-reactive protein from infancy onward. During infancy, the patient presented with high fever, skin rashes, and hepatic dysfunction. Careful examination including a liver biopsy failed to reveal the cause. At 4 years old, petechiae developed associated with thrombocytopenia and positive anti-dsDNA autoantibodies. Steroid pulse therapy was effective, but the effect of low-dose prednisone was insufficient. At age 9, an extensive differential diagnosis was considered especially for infantile onset autoinflammatory disorders but failed to make a definitive diagnosis. On admission, the patient exhibited short stature, hepatosplenomegaly, generalized superficial lymphadenopathy, and rashes. Laboratory findings revealed anemia, elevated levels of inflammation markers, and hypergammaglobulinemia. Serum complement levels were normal. Serum levels of IL-6 and B-cell activating factor were elevated. Viral infections were not identified. Although HLA typing revealed no noninherited maternal antigens in lymphocytes, female cells were demonstrated in the patient's skin and lymph nodes, suggesting that maternal microchimerism might be involved in the pathogenesis of fever without source in infants.
Collapse
|
|
48
|
Saadai P, Lee TH, Bautista G, Gonzales KD, Nijagal A, Busch MP, Kim CJ, Romero R, Lee H, Hirose S, Rand L, Miniati D, Farmer DL, MacKenzie TC. Alterations in maternal-fetal cellular trafficking after fetal surgery. J Pediatr Surg 2012; 47:1089-94. [PMID: 22703775 PMCID: PMC3377979 DOI: 10.1016/j.jpedsurg.2012.03.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2012] [Accepted: 03/05/2012] [Indexed: 01/17/2023]
Abstract
BACKGROUND/PURPOSE Bidirectional trafficking of cells between the mother and the fetus is routine in pregnancy and a component of maternal-fetal tolerance. Changes in fetal-to-maternal cellular trafficking have been reported in prenatal complications, but maternal-to-fetal trafficking has never been studied in the context of fetal intervention. We hypothesized that patients undergoing open fetal surgery would have altered maternal-fetal cellular trafficking. METHODS Cellular trafficking was analyzed in patients with myelomeningocele (MMC) who underwent open fetal surgical repair (n = 5), patients with MMC who had routine postnatal repair (n = 6), and healthy control healthy patients (n = 9). As an additional control for the fetal operation, trafficking was also analyzed in patients who were delivered by an ex utero intrapartum treatment procedure (n = 6). Microchimerism in maternal and cord blood was determined using quantitative real-time polymerase chain reaction for nonshared alleles. RESULTS Maternal-to-fetal trafficking was significantly increased in patients who underwent open fetal surgery for MMC compared with healthy controls, patients who underwent postnatal MMC repair, and patients who underwent ex utero intrapartum treatment. There were no differences in fetal-to-maternal cell trafficking among groups. CONCLUSION Patients undergoing open fetal surgery for MMC have elevated levels of maternal microchimerism. These results suggest altered trafficking and/or increased proliferation of maternal cells in fetal blood and may have important implications for preterm labor.
Collapse
Affiliation(s)
- Payam Saadai
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA 94143-0570, USA.
| | - Tzong-Hae Lee
- Blood Systems Research Institute, San Francisco, CA, USA
| | - Geoanna Bautista
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| | - Kelly D. Gonzales
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| | - Amar Nijagal
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| | | | - CJ Kim
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
| | - Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
| | - Hanmin Lee
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| | - Shinjiro Hirose
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| | - Larry Rand
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| | - Douglas Miniati
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| | - Diana L. Farmer
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| | - Tippi C. MacKenzie
- Division of Pediatric Surgery and Fetal Treatment Center, Department of Surgery, University of California, San Francisco, CA, USA
| |
Collapse
|
|
49
|
Nijagal A, Fleck S, MacKenzie TC. Maternal microchimerism in patients with biliary atresia: Implications for allograft tolerance. CHIMERISM 2012; 3:37-9. [PMID: 22772071 DOI: 10.4161/chim.20152] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Maternal-fetal cellular trafficking during pregnancy results in bidirectional microchimerism with potentially long-term consequences for the mother and her fetus. Exposure of the fetus to maternal cells results in tolerance to non-inherited maternal antigens (NIMA) and may therefore impact transplant outcomes. We investigated the rates of graft failure and retransplantation after parental liver transplantation in pediatric recipients with biliary atresia (BA), a disease with high levels of maternal microchimerism. We observed significantly lower rates of graft failure and retransplantation in BA recipients of maternal livers compared with BA recipients of paternal livers. Importantly, recipients without BA had equivalent transplant outcomes with maternal and paternal organs, suggesting that increased maternal microchimerism in BA patients may be the underlying etiology for tolerance. These results support the concept that prenatal exposure to NIMA may have consequences for living-related organ transplantation.
Collapse
Affiliation(s)
- Amar Nijagal
- Eli and Edythe Broad Center of Regeneration Medicine, University of California at San Francisco, San Francisco, CA, USA
| | | | | |
Collapse
|
|
50
|
Taba R, Yamakawa M, Miyakoshi C, Imai Y. Refractory cholestasis presenting as cholangiolitis in an Rh (E)-incompatible neonate. J Paediatr Child Health 2012; 48:E126-31. [PMID: 21040076 DOI: 10.1111/j.1440-1754.2010.01874.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Cholestasis in neonates is infrequently associated with Rh isoimmunization, and usually resolves within a month. The suggested pathophysiology is inspissated bile and hepatocellular damage. We report a rare case of refractory cholestasis presenting with cholangiolitis in a newborn with anti-E isoimmunisation. The cholangiolitis was disclosed by immunohistochemical investigation of conjugated hyperbilirubinaemia and by liver biopsy, which showed a number of CD8(+) lymphocytes within the portal tract damaging the interlobular bile duct. Bilirubin levels dramatically decreased after 14-day corticosteroid therapy (prednisolone, 2 mg/kg/day) implying that the cause of cholestasis could be immune-mediated cholangiolitis.
Collapse
Affiliation(s)
- Ryusuke Taba
- Department of Pediatrics, Kobe City Medical Center General Hospital, Kobe, Japan.
| | | | | | | |
Collapse
|