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Ou LL, Jiang JL, Guo ML, Wu JH, Zhong WW, He YH. Research progress on the roles of complement in liver injury. World J Hepatol 2025; 17:103839. [PMID: 40177195 PMCID: PMC11959660 DOI: 10.4254/wjh.v17.i3.103839] [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] [Received: 12/04/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
The complement system is crucial for maintaining immunological homeostasis in the liver, playing a significant role in both innate and adaptive immune responses. Dysregulation of this system is closely linked to the pathogenesis of various liver diseases. Modulating the complement system can affect the progression of these conditions. To provide insights into treating liver injury by targeting the regulation of the complement system, we conducted a comprehensive search of major biomedical databases, including MEDLINE, PubMed, EMBASE, and Web of Science, to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.
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Affiliation(s)
- Li-Li Ou
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Lian Jiang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Man-Lu Guo
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Hua Wu
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Wei-Wei Zhong
- Department of Infectious Diseases, Jingmen Central Hospital, Jingmen Central Hospital Affiliated to Jingchu University of Technology, Jingmen 448000, Hubei Province, China
| | - Yi-Huai He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China.
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Tang Y, Xu M, Wang C, Wu M, Hu L, Li J, Lu W, Zheng Y, Zhang M, Jiang X, Zhu C, Audsley J, Tangkijvanich P, Avihingsanon A, Song S, Liu S, Lewin SR, George J, Douglas MW, Ling Y, Yuan Z, Zhu L, Zhang Z, Zhang X. Circulating capsid-antibody-complexes (CACs) drive intrahepatic complement deposition and inform subclinical liver inflammation in chronic hepatitis B. Antiviral Res 2024; 231:106017. [PMID: 39396554 DOI: 10.1016/j.antiviral.2024.106017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/20/2024] [Accepted: 10/04/2024] [Indexed: 10/15/2024]
Abstract
Chronic infection with Hepatitis B Virus (HBV) often results in a dysfunctional virus-specific T cell response hampering viral clearance. Paradoxically, intrahepatic inflammatory responses that contribute more to liver histopathology than to viral suppression are commonly observed, which are widely believed to be cell mediated. The involvement of humoral immunity in this process however is not well documented. To investigate the possible roles of HBV Capsid-Antibody Complexes (CACs) in eliciting chronic liver inflammation, we developed a novel microplate-based assay for the quantification of CACs in serum. The CACs assay showed high sensitivity and specificity with its readout closely correlating with the molecular features of CACs. A cross-sectional study on untreated chronic hepatitis B (CHB) patients showed a 77% positive rate for CACs with significant association with alanine transaminase (ALT), intrahepatic inflammation, and complement deposition, suggestive of its functional role in hepatic injury. Multiple staining of complement activation fragment C4d with major leukocyte and myofibroblast markers revealed an intertwined picture in periportal area with a morphology reminiscent of "piecemeal necrosis". In a pooled cohort with ALT levels lower than 40 IU/ml, CACs alone revealed subclinical liver inflammation. We provide definitive evidence for a causative role for CACs in complement-mediated intrahepatic immunopathology, an additional mechanism contributing to liver damage in CHB. Assessment of CACs in serum complements current clinical markers for assessing CHB associated inflammation.
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Affiliation(s)
- Yijie Tang
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China; Department of Clinical Laboratory Medicine, Shanghai Skin Disease Hospital, School of Medicine, Tonji University, Shanghai, China
| | - Mingzhu Xu
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cong Wang
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China
| | - Min Wu
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China
| | - Lyuyin Hu
- Faculty of Science and Technology, University of Canberra, Australia
| | - Jin Li
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Wei Lu
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China
| | - Ye Zheng
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China
| | - Min Zhang
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China
| | - Xizi Jiang
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Jennifer Audsley
- Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Thailand
| | - Anchalee Avihingsanon
- HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand
| | - Shu Song
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China
| | - Shuangzhe Liu
- Faculty of Science and Technology, University of Canberra, Australia
| | - Sharon R Lewin
- Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
| | - Jacob George
- The Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Sydney, Australia
| | - Mark W Douglas
- The Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Sydney, Australia; Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, The University of Sydney at Westmead Hospital, Sydney, Australia
| | - Yun Ling
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu Province, China.
| | - Zhanqing Zhang
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China.
| | - Xiaonan Zhang
- Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China; Faculty of Science and Technology, University of Canberra, Australia.
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González IA, Lu HC, Alipour Z, Kulkarni SS, Stoll JM, Liss KH, Dehner LP, He M. Clinicopathologic Characteristics of Centrilobular Injury in Pediatric Liver Transplantation. Liver Transpl 2021; 27:416-424. [PMID: 33253466 PMCID: PMC10619582 DOI: 10.1002/lt.25958] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/18/2020] [Accepted: 11/13/2020] [Indexed: 12/15/2022]
Abstract
Centrilobular injury (CLI) is defined as the presence of perivenular mononuclear inflammation, hepatocyte dropout, and extravasated erythrocytes. In pediatric liver allografts, CLI has been associated with advanced fibrosis and chronic rejection (CR). We sought to better characterize the clinicopathologic features of CLI in the setting of T cell-mediated rejection (TCMR) and its association with complement component 4d (C4d) deposition. A total of 206 posttransplant pediatric patients (491 allograft liver biopsies) were available from 2000 to 2018, of which 63 patients (102 biopsies) showed evidence of TCMR and were included in the study. Of the patients, 35 (55.6%) had CLI on their initial episode of TCMR; those patients with CLI were significantly associated with the type of immunosuppression treatment (P = 0.03), severity of TCMR (P < 0.001), higher gamma-glutamyltransferase (P = 0.01), and advanced fibrosis (P = 0.03). There was a trend to shorter time interval from transplantation to presentation of CLI compared with those without CLI (P = 0.06). No difference was observed in graft or overall survival in the patients with CLI. In 20 patients with CLI, additional biopsies were available; in 45% of these patients, CLI was a persistent/recurrent finding. C4d deposition was noted in 12% of all biopsies (6 patients) with CLI. No significant correlation was noted in C4d deposition and CLI, CR, or graft/overall survival. In conclusion, CLI, although not significantly associated with worse graft survival, was significantly associated with severe TCMR and degree of fibrosis, which highlights the importance of active clinical management and follow-up for these patients.
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Affiliation(s)
- Iván A. González
- Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology and Immunology
| | - Hsiang-Chih Lu
- Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology and Immunology
| | - Zahra Alipour
- Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology and Immunology
| | - Sakil S. Kulkarni
- Department of Pediatrics, St. Louis Children’s Hospital, Washington University Medical Center, St. Louis, MO
| | - Janis M. Stoll
- Department of Pediatrics, St. Louis Children’s Hospital, Washington University Medical Center, St. Louis, MO
| | - Kim H. Liss
- Department of Pediatrics, St. Louis Children’s Hospital, Washington University Medical Center, St. Louis, MO
| | - Louis P. Dehner
- Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology and Immunology
| | - Mai He
- Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology and Immunology
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The role of complement activation in autoimmune liver disease. Autoimmun Rev 2020; 19:102534. [PMID: 32234403 DOI: 10.1016/j.autrev.2020.102534] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The complement system, an essential part of the innate immune system, is involved in various autoimmune diseases. Activation of the complement system by autoantibodies results in immune activation and tissue damage. At the moment little is known about the role of the complement system in autoimmune liver disease, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Since inhibition of the complement system is currently being tested in several autoimmune diseases as a therapeutic option, its role in autoimmune liver disease requires further clarification. METHODS A review of the literature was performed on studies investigating complement activation in PBC, PSC and AIH. Since data on AIH were lacking immunohistochemical staining for IgG, C1q, C3d, C4d and C5b9 was performed on liver tissue of nine AIH patients, two healthy controls and one positive control (acute liver failure caused by paracetamol intoxication). RESULTS Immunohistochemical analysis in AIH revealed increased production of C3 and C4 by hepatocytes. Despite a strong staining for IgG in the immune infiltrate in AIH, C3d, C4d and C5b9 deposition was only present in one AIH patient and the deposition was restricted to the interface between portal tracts and liver parenchyma. No deposition was found in all other AIH patients or healthy controls. Literature review showed raised plasma C3 and C4 levels in AIH, PBC and PSC patients compared to healthy controls. For PBC and PSC no complement depositions at the bile ducts were reported. CONCLUSION AND DISCUSSION Although complement is involved in various autoimmune diseases, the role of complement in autoimmune liver disease seems limited. Therefore it is unlikely that complement inhibition will become a novel treatment option for these diseases.
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Chen L, Himmelfarb EA, Sun M, Choi EK, Fan L, Lai J, Kim CJ, Xu H, Wang HL. Immunostaining Patterns of Posttransplant Liver Biopsies Using 2 Anti-C4d Antibodies. Appl Immunohistochem Mol Morphol 2020; 28:146-153. [PMID: 32044883 DOI: 10.1097/pai.0000000000000723] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Histopathologic diagnosis of antibody-mediated rejection in posttransplant liver biopsies is challenging. The recently proposed diagnostic criteria by the Banff Working Group on Liver Allograft Pathology require positive C4d immunohistochemical staining to establish the diagnosis. However, the reported C4d staining patterns vary widely in different studies. One potential explanation may be due to different antibody preparations used by different investigators. In this study, posttransplant liver biopsies from 69 patients histopathologically diagnosed with acute cellular rejection, chronic rejection, or recurrent hepatitis C were immunohistochemically stained using 2 polyclonal anti-C4d antibodies. On the basis of the distribution of C4d immunoreactivity, 5 different staining patterns were observed: portal vein and capillary, hepatic artery, portal stroma, central vein, and sinusoids. The frequency, extent, and intensity of positive C4d staining with the 2 antibody preparations differed significantly for portal veins/capillaries and central veins, but not for hepatic arteries and portal stroma. Positive sinusoidal staining was seen in only 1 case. There were no significant differences in the frequency, extent, and intensity of positive C4d staining among the acute cellular rejection, chronic rejection, and recurrent hepatitis C groups with the 2 anti-C4d antibodies. These data show that different anti-C4d antibodies can show different staining patterns, which may lead to different interpretation. Caution is thus needed when selecting C4d antibodies for clinical use to aid in the diagnosis of antibody-mediated rejection.
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Affiliation(s)
- Lihong Chen
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles
- Department of Pathology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou, Fujian, China
| | - Eric A Himmelfarb
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Melissa Sun
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles
| | - Eunice K Choi
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles
| | - Lifang Fan
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Pathology, Wuhan University School of Medicine, Wuhan, Hubei, China
| | - Jinping Lai
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Christopher J Kim
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles
| | - Haodong Xu
- Department of Pathology, University of Washington Medical Center, Seattle, WA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
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Torbenson M, Washington K. Pathology of liver disease: advances in the last 50 years. Hum Pathol 2019; 95:78-98. [PMID: 31493428 DOI: 10.1016/j.humpath.2019.08.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 08/28/2019] [Indexed: 02/07/2023]
Abstract
Liver disease has been recognized in various forms for centuries. Incredible advances, however, have been made especially in the last 50 years, driven by improvements in histology, the development of immunostains, the development of high resolution imaging methods, improved biopsy and resection methods, and the emergence of the molecular era. With these tools, pathologists and their clinical and basic science colleagues moved from classifying liver disease using an observational, pattern-based approach to a refined classification of disease, one based on etiology for medical disease and tumor classification for neoplastic disease. Examples of liver specific diseases are used to illustrate these exciting advances. These impressive advances of the past provide the foundation for hope in the future, as liver pathology continues to play an important role in improving patient care through disease identification and classification and emerging roles in guiding therapy for cures.
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Affiliation(s)
- Michael Torbenson
- Department of Pathology and Laboratory Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905.
| | - Kay Washington
- C-3321 MCN, Department of Pathology, Vanderbilt University Medical Center, 1161 21(st) Avenue S, Nashville, TN 37232.
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Abstract
PURPOSE OF REVIEW The review outlines the diagnosis, clinical implications, and treatment strategies for acute and chronic antibody-mediated rejection (AMR) after orthotopic liver transplantation (OLT). RECENT FINDINGS A combination of clinical work-up, histopathology, C4d staining, and donor-specific antibody (DSA) should be used to diagnose AMR. The differential diagnosis for idiopathic fibrosis now includes chronic AMR. Characterization of pathogenic DSA continues to progress. De-novo and persistent DSA, particularly of the IgG3 subtype, are associated with inferior long-term outcomes.The liver allograft may confer long-term immunologic benefits to the kidney allograft after simultaneous liver-kidney transplant.The more widespread use of rituximab has improved outcomes in ABO-incompatible OLT.Although larger long-term studies of treatment options are needed, compliance with tacrolimus-based immunosuppression and transfusion minimization are agreed upon preventive strategies. SUMMARY AMR has evolved into an established pathology in OLT recipients. Acute AMR may lead to early graft loss whereas chronic AMR results in progressive fibrosis if unrecognized. DSAs, likely in the setting of predisposing environmental factors, appear to play a role in T cell-mediated rejection and long-term graft outcomes.
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Abstract
Antibody-mediated rejection (AMR) in liver transplants is a field in its infancy compared with its allograft cohorts of the kidney and lung. Acute AMR is diagnosed based on specific clinical and histopathologic criteria: serum donor specific antibodies, C4d staining, histopathologic findings on liver biopsy, and exclusion of other entities. In contrast, the histologic features of chronic AMR are not as specific and it is a more challenging diagnosis to make. Treatments of acute and chronic AMR include some combination of steroids, immune-modulating agents, intravenous immunoglobulin, plasmapheresis, and proteasome inhibitors.
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Affiliation(s)
- Michael Lee
- Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, VC14-238, New York, NY 10032, USA.
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Lee KB. What Is Antibody-Mediated Rejection in Histologic Diagnosis in Liver Recipients? KOREAN JOURNAL OF TRANSPLANTATION 2017. [DOI: 10.4285/jkstn.2017.31.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Kyoung-Bun Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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Demetris AJ, Bellamy C, Hübscher SG, O'Leary J, Randhawa PS, Feng S, Neil D, Colvin RB, McCaughan G, Fung JJ, Del Bello A, Reinholt FP, Haga H, Adeyi O, Czaja AJ, Schiano T, Fiel MI, Smith ML, Sebagh M, Tanigawa RY, Yilmaz F, Alexander G, Baiocchi L, Balasubramanian M, Batal I, Bhan AK, Bucuvalas J, Cerski CTS, Charlotte F, de Vera ME, ElMonayeri M, Fontes P, Furth EE, Gouw ASH, Hafezi-Bakhtiari S, Hart J, Honsova E, Ismail W, Itoh T, Jhala NC, Khettry U, Klintmalm GB, Knechtle S, Koshiba T, Kozlowski T, Lassman CR, Lerut J, Levitsky J, Licini L, Liotta R, Mazariegos G, Minervini MI, Misdraji J, Mohanakumar T, Mölne J, Nasser I, Neuberger J, O'Neil M, Pappo O, Petrovic L, Ruiz P, Sağol Ö, Sanchez Fueyo A, Sasatomi E, Shaked A, Shiller M, Shimizu T, Sis B, Sonzogni A, Stevenson HL, Thung SN, Tisone G, Tsamandas AC, Wernerson A, Wu T, Zeevi A, Zen Y. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transplant 2016; 16:2816-2835. [PMID: 27273869 DOI: 10.1111/ajt.13909] [Citation(s) in RCA: 423] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/01/2016] [Accepted: 05/25/2016] [Indexed: 02/06/2023]
Abstract
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
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Affiliation(s)
- A J Demetris
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C Bellamy
- The University of Edinburgh, Edinburgh, Scotland
| | | | - J O'Leary
- Baylor University Medical Center, Dallas, TX
| | - P S Randhawa
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - S Feng
- University of California San Francisco Medical Center, San Francisco, CA
| | - D Neil
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - R B Colvin
- Massachusetts General Hospital, Boston, MA
| | - G McCaughan
- Royal Prince Alfred Hospital, Sydney, Australia
| | | | | | - F P Reinholt
- Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - H Haga
- Kyoto University Hospital, Kyoto, Japan
| | - O Adeyi
- University Health Network and University of Toronto, Toronto, Canada
| | - A J Czaja
- Mayo Clinic College of Medicine, Rochester, MN
| | - T Schiano
- Mount Sinai Medical Center, New York, NY
| | - M I Fiel
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - M L Smith
- Mayo Clinic Health System, Scottsdale, AZ
| | - M Sebagh
- AP-HP Hôpital Paul-Brousse, Paris, France
| | - R Y Tanigawa
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - F Yilmaz
- University of Ege, Faculty of Medicine, Izmir, Turkey
| | | | - L Baiocchi
- Policlinico Universitario Tor Vergata, Rome, Italy
| | | | - I Batal
- Columbia University College of Physicians and Surgeons, New York, NY
| | - A K Bhan
- Massachusetts General Hospital, Boston, MA
| | - J Bucuvalas
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - C T S Cerski
- Universidade Federal do Rio Grande do Sul, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - M ElMonayeri
- Ain Shams University, Wady El-Neel Hospital, Cairo, Egypt
| | - P Fontes
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - E E Furth
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - A S H Gouw
- University Medical Center Groningen, Groningen, the Netherlands
| | | | - J Hart
- University of Chicago Hospitals, Chicago, IL
| | - E Honsova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - W Ismail
- Beni-Suef University, Beni-Suef, Egypt
| | - T Itoh
- Kobe University Hospital, Kobe, Japan
| | | | - U Khettry
- Lahey Hospital and Medical Center, Burlington, MA
| | | | - S Knechtle
- Duke University Health System, Durham, NC
| | - T Koshiba
- Soma Central Hospital, Soma, Fukushima, Japan
| | - T Kozlowski
- University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - C R Lassman
- David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - J Lerut
- Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - J Levitsky
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - L Licini
- Pope John XXIII Hospital, Bergamo, Italy
| | - R Liotta
- Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center, Palermo, Italy
| | - G Mazariegos
- Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA
| | - M I Minervini
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - J Misdraji
- Massachusetts General Hospital, Boston, MA
| | - T Mohanakumar
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, AZ
| | - J Mölne
- University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - I Nasser
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA
| | - J Neuberger
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - M O'Neil
- University of Kansas Medical Center, Kansas City, KS
| | - O Pappo
- Hadassah Medical Center, Jerusalem, Israel
| | - L Petrovic
- University of Southern California, Los Angeles, CA
| | - P Ruiz
- University of Miami, Miami, FL
| | - Ö Sağol
- School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | | | - E Sasatomi
- University of North Carolina School of Medicine, Chapel Hill, NC
| | - A Shaked
- University of Pennsylvania Health System, Philadelphia, PA
| | - M Shiller
- Baylor University Medical Center, Dallas, TX
| | - T Shimizu
- Toda Chuo General Hospital, Saitama, Japan
| | - B Sis
- University of Alberta Hospital, Edmonton, Canada
| | - A Sonzogni
- Pope John XXIII Hospital, Bergamo, Italy
| | | | - S N Thung
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - G Tisone
- University of Rome-Tor Vergata, Rome, Italy
| | | | - A Wernerson
- Karolinska University Hospital, Stockholm, Sweden
| | - T Wu
- Tulane University School of Medicine, New Orleans, LA
| | - A Zeevi
- University of Pittsburgh, Pittsburgh, PA
| | - Y Zen
- Kobe University Hospital, Kobe, Japan
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11
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Prevention and treatment of liver allograft antibody-mediated rejection and the role of the 'two-hit hypothesis'. Curr Opin Organ Transplant 2016; 21:209-18. [PMID: 26918881 DOI: 10.1097/mot.0000000000000275] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The review outlines the diagnosis, prevention strategies, and possible treatment options for acute and chronic antibody-mediated rejection (AMR). RECENT FINDINGS Although rare, severe acute AMR (aAMR) usually occurs in patients with high mean fluorescence intensity despite serial dilutions or high-titer preformed class I donor-specific alloantibodies (DSA). The diagnosis is suspected when allograft dysfunction occurs with DSA, diffuse C4d staining, and a microvascular injury, and may be aided by the aAMR score. However, the incidence of and treatment approach to combined T-cell-mediated rejection (TCMR) with DSA present and some but not all features of AMR is yet to be determined. Chronic liver allograft AMR is characterized by low-grade chronic inflammation and progressive fibrosis with DSA, the chronic AMR (cAMR) score may facilitate diagnosis. The 'two-hit' hypothesis, whereby a coexistent insult upregulates human leukocyte antigen class II target antigens on the microvascular endothelium, may explain why suboptimal donors with lower sensitization levels might suffer from acute AMR and those with chronic complications (e.g., recurrent original disease) might be more susceptible to chronic AMR. Although treatment algorithms are needed, prevention is preferable and at a minimum includes transfusion minimization, and medication adherence. SUMMARY Severe acute AMR is rare but diagnosable, and there is need to determine the incidence of and optimal therapy for less severe combined AMR and TCMR. Chronic AMR is likely more common and of significant relevance to long-term allograft survival improvement. The two-hit hypothesis may help to explain the rarity of both findings and shed insight onto future prevention and treatment strategies.
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Troxell ML, Lanciault C. Practical Applications in Immunohistochemistry: Evaluation of Rejection and Infection in Organ Transplantation. Arch Pathol Lab Med 2016; 140:910-25. [PMID: 26759930 DOI: 10.5858/arpa.2015-0275-cp] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT -Immunohistochemical analysis of tissue biopsy specimens is a crucial tool in diagnosis of both rejection and infection in patients with solid organ transplants. In the past 15 years, the concept of antibody-mediated rejection has been refined, and diagnostic criteria have been codified in renal, heart, pancreas, and lung allografts (with studies ongoing in liver, small intestine, and composite grafts), all of which include immunoanalysis for the complement split product C4d. OBJECTIVES -To review the general concepts of C4d biology and immunoanalysis, followed by organ-allograft-specific data, and interpretative nuances for kidney, pancreas, and heart, with discussion of early literature for lung and liver biopsies. Additionally, practical applications and limitations of immunostains for infectious organisms (Polyomavirus, Adenoviridae [adenovirus], and the herpes virus family, including Herpes simplex virus, Cytomegalovirus, Human herpes virus 8, and Epstein-Barr virus) are reviewed in the context of transplant recipients. DATA SOURCES -Our experience and published primary and review literature. CONCLUSIONS -Immunohistochemistry continues to have an important role in transplant pathology, most notably C4d staining in assessment of antibody-mediated rejection and assessment of viral pathogens in tissue. In all facets of transplant pathology, correlation of morphology with special studies and clinical data is critical, as is close communication with the transplant team.
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Affiliation(s)
| | - Christian Lanciault
- From the Department of Pathology, Oregon Health & Science University, Portland
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Donor-Specific Anti-HLA Antibodies and Endothelial C4d Deposition-Association With Chronic Liver Allograft Failure. Transplantation 2015; 99:1869-75. [PMID: 25706274 DOI: 10.1097/tp.0000000000000613] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The significance of humoral immune response for allograft survival after liver transplantation (LT) is still a matter of debate. The aim of this cross-sectional study was to assess immunological and clinical factors associated with advanced fibrosis (F3-F4) and chronic graft failure in LT recipients. METHODS Serum samples from 174 patients prospectively enrolled and followed up for 12 months were tested for anti-HLA antibodies and compared against donor HLA types. Immunohistochemical C4d staining was performed on formalin-fixed, paraffin-embedded liver tissue. RESULTS Mean time period from LT to enrollment was 66.9 ± 51.9 months. Independent predictive factors for graft failure included donor-positive cytomegalovirus serostatus (P = 0.02), donor-specific antibodies (DSA) against HLA class II (P = 0.03), donor age (P = 0.01), hepatitis C virus allograft reinfection (P = 0.0008), and biliary complications (P = 0.003). HLA class II DSA and HLA class I antibody positivity, hepatitis C virus reinfection, and mycophenolate mofetil-free regimens were significant risk factors for advanced fibrosis after LT. There was a significant association between C4d deposition on allograft endothelial cells and presence of class II DSA (P < 0.0001). Patients with C4d deposits had a 4.3 times higher risk of graft failure than those with negative staining and a significantly lower median time to graft failure (94.6 months [range, 3.6-158.9 months] vs 176.4 months [range, 9.4-217.8 months], P < 0.0001). CONCLUSIONS Screening for HLA DSA might be useful for early identification of LT recipients at increased risk of graft failure who could benefit from closer surveillance and tailored immunosuppressive regimens.
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Cuadrado A, San Segundo D, López-Hoyos M, Crespo J, Fábrega E. Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation. World J Gastroenterol 2015; 21:11016-11026. [PMID: 26494958 PMCID: PMC4607901 DOI: 10.3748/wjg.v21.i39.11016] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 06/29/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Antibody-mediated rejection (AMR) caused by donor-specific anti-human leukocyte antigen antibodies (DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This “immune-tolerance” liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant (LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class II human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional anti-rejection therapy, can allow a rational approach to this threat.
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Abstract
PURPOSE OF REVIEW Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: first, solid phase antibody testing enabled more precise antibody characterization; second, increased expectations for long-term, morbidity-free survival; and third, immunosuppression minimization trials. RECENT FINDINGS Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by donor-specific antibodies (DSA) persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophag-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling, and hepatocanalicular cholestasis often combined with T-cell-mediated rejection (TCMR). Chronic AMR is less well defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection, and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis can be more difficult to identify than in acute AMR. SUMMARY More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all solid organ AMR.
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Song ATW, Mello ESD, Alves VAF, Cavalheiro NDP, Melo CE, Bonazzi PR, Tengan FM, Freire MP, Barone AA, D'Albuquerque LAC, Abdala E. Quantification of C4d deposition and hepatitis C virus RNA in tissue in cases of graft rejection and hepatitis C recurrence after liver transplantation. Mem Inst Oswaldo Cruz 2015; 110:56-64. [PMID: 25742264 PMCID: PMC4371218 DOI: 10.1590/0074-02760140192] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 12/01/2014] [Indexed: 01/20/2023] Open
Abstract
Histology is the gold standard for diagnosing acute rejection and hepatitis C
recurrence after liver transplantation. However, differential diagnosis between the
two can be difficult. We evaluated the role of C4d staining and quantification of
hepatitis C virus (HCV) RNA levels in liver tissue. This was a retrospective study of
98 liver biopsy samples divided into four groups by histological diagnosis: acute
rejection in patients undergoing liver transplant for hepatitis C (RejHCV+), HCV
recurrence in patients undergoing liver transplant for hepatitis C (HCVTx+), acute
rejection in patients undergoing liver transplant for reasons other than hepatitis C
and chronic hepatitis C not transplanted (HCVTx-). All samples were submitted for
immunohistochemical staining for C4d and HCV RNA quantification. Immunoexpression of
C4d was observed in the portal vessels and was highest in the HCVTx- group. There was
no difference in C4d expression between the RejHCV+ and HCVTx+ groups. However,
tissue HCV RNA levels were higher in the HCVTx+ group samples than in the RejHCV+
group samples. Additionally, there was a significant correlation between tissue and
serum levels of HCV RNA. The quantification of HCV RNA in liver tissue might prove to
be an efficient diagnostic test for the recurrence of HCV infection.
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Affiliation(s)
- Alice Tung Wan Song
- Divisão de Transplante de Fígado e Órgãos do Aparelho Digestivo, Universidade de São Paulo
| | | | | | | | | | | | | | | | | | | | - Edson Abdala
- Divisão de Transplante de Fígado e Órgãos do Aparelho Digestivo, Universidade de São Paulo
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17
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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.
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Affiliation(s)
- Sorahiko Fujisawa
- Department of Pediatric Surgery, Ibaraki Children's Hospital, 3-3-1 Futabadai, Mito, Ibaraki, 311-4145, Japan
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18
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Naini BV, Lassman CR. Liver Transplant Pathology: Review of Challenging Diagnostic Situations. Surg Pathol Clin 2013; 6:277-93. [PMID: 26838975 DOI: 10.1016/j.path.2013.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Histopathologic assessment of allograft liver biopsies has an important role in managing patients who have undergone liver transplantation. In this review, several topics are discussed that create diagnostic problems in transplant pathology, with emphasis on pathologic features and differential diagnosis. The topics discussed are acute cellular rejection, late acute rejection (centrizonal/parenchymal rejection), chronic rejection, plasma cell hepatitis, idiopathic posttransplant chronic hepatitis, fibrosing cholestatic hepatitis, selected viral infections (cytomegalovirus, Epstein-Barr virus, and hepatitis E), and acute antibody-mediated rejection.
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Affiliation(s)
- Bita V Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 1P-172 CHS, Los Angeles, CA 90095-1732, USA.
| | - Charles R Lassman
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 13-145 CHS, Los Angeles, CA 90095-1732, USA
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19
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Abstract
PURPOSE OF REVIEW There is increasing evidence to suggest that antibody-mediated mechanisms play a role in the pathogenesis of liver allograft rejection. This article will review the pathology of antibody-mediated rejection (AMR) focusing on recent studies which have improved our understanding of the clinicopathological features and diagnostic approaches. RECENT FINDINGS Recent studies have investigated the patterns of immunohistochemical staining for C4d as a tissue marker of AMR in posttransplant biopsies, and have correlated these findings with other histopathological changes and with the presence of donor-specific antibodies (DSAs). These studies have highlighted the diagnostic applications and limitations of C4d immunostaining. They have also emphasized the importance of using strict criteria for defining 'pure' AMR in the liver allograft - that is, graft dysfunction associated with compatible histological findings (typically resembling biliary obstruction), the presence of DSAs and diffusely positive staining for C4d. SUMMARY Pure AMR is relatively uncommon in ABO-compatible grafts - it should be diagnosed on the basis of strict criteria and requires treatment with antibody-depleting immunosuppression. C4d immunostaining in isolation has limited diagnostic value. However, the presence of diffuse C4d immunostaining (involving endothelium or stroma in >50% of portal tracts or sinusoids) suggests a significant component of antibody-mediated graft damage. In a person with suggestive histological features, this finding should prompt testing for DSAs. Even in the absence of typical histological features of AMR, the combined presence of DSAs and diffuse C4d positivity is associated with more frequent or severe acute and chronic rejection, which may also warrant treatment with antibody-depleting immunosuppression.
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Yamada H, Kondou H, Kimura T, Ikeda K, Tachibana M, Hasegawa Y, Kiyohara Y, Ueno T, Miyoshi Y, Mushiake S, Ozono K. Humoral immunity is involved in the development of pericentral fibrosis after pediatric live donor liver transplantation. Pediatr Transplant 2012; 16:858-65. [PMID: 22931465 DOI: 10.1111/j.1399-3046.2012.01781.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although LT can be successful for treating end-stage liver disease in children, some patients develop fibrosis around the central vein area (PCF). This raises the possibility that PCF could lead to later cirrhosis and graft failure. Here, we report a retrospective immunohistochemical study of 28 patients who received a live donor liver transplant. We assessed the incidence and etiology of PCF using CD3, CD20, HLA-DR, and C4d-specific antibodies. Histological evidence of PCF was found in 13 cases (46.4%), of which 11 (84.6%) had experienced ACR and/or CP events post-transplant. Immunohistochemical evaluation revealed significantly stronger staining with these antibodies in the central vein area in PCF, especially for CD20 and C4d. This implies humoral immunopathology and suggests involvement of humoral immunity in the development of PCF. These results further imply that suppression of cellular immunity alone is insufficient to prevent PCF. We therefore suggest that suppression of both humoral and cellular immunity in combination would be required for prevention of PCF.
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Affiliation(s)
- Hiroyuki Yamada
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
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Okroj M, Holmquist E, King BC, Blom AM. Functional analyses of complement convertases using C3 and C5-depleted sera. PLoS One 2012; 7:e47245. [PMID: 23071769 PMCID: PMC3468486 DOI: 10.1371/journal.pone.0047245] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 09/11/2012] [Indexed: 01/30/2023] Open
Abstract
C3 and C5 convertases are central stages of the complement cascade since they converge the different initiation pathways, augment complement activation by an amplification loop and lead to a common terminal pathway resulting in the formation of the membrane attack complex. Several complement inhibitors attenuate convertase formation and/or accelerate dissociation of convertase complexes. Functional assays used to study these processes are often performed using purified complement components, from which enzymatic complexes are reconstituted on the surface of erythrocytes or artificial matrices. This strategy enables identification of individual interactions between convertase components and putative regulators but carries an inherent risk of detecting non-physiological interactions that would not occur in a milieu of whole serum. Here we describe a novel, alternative method based on C3 or C5-depleted sera, which support activation of the complement cascade up to the desired stages of convertases. This approach allows fast and simple assessment of the influence of putative regulators on convertase formation and stability. As an example of practical utility of the assay, we performed studies on thioredoxin-1 in order to clarify the mechanism of its influence on complement convertases.
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Affiliation(s)
- Marcin Okroj
- Department of Laboratory Medicine, Lund University, The Wallenberg Laboratory, Malmö, Sweden
| | - Emelie Holmquist
- Department of Laboratory Medicine, Lund University, The Wallenberg Laboratory, Malmö, Sweden
| | - Ben C. King
- Department of Laboratory Medicine, Lund University, The Wallenberg Laboratory, Malmö, Sweden
| | - Anna M. Blom
- Department of Laboratory Medicine, Lund University, The Wallenberg Laboratory, Malmö, Sweden
- * E-mail:
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22
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Fayek SA. The value of C4d deposit in post liver transplant liver biopsies. Transpl Immunol 2012; 27:166-70. [PMID: 22975227 DOI: 10.1016/j.trim.2012.08.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Revised: 08/20/2012] [Accepted: 08/20/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND Presence of C4d in renal and cardiac allografts is a sign of antibody-mediated rejection and is associated with worse outcomes. The value of C4d in liver specimens is controversial. We aimed to determine the association of C4d deposition with acute cellular rejection (ACR), hepatitis C (HCV) recurrence, and clinical outcome after ABO compatible liver transplants (OLT). METHODS Using immunohistochemical stain, 70 liver biopsies (44 study and 26 control groups) were evaluated for C4d deposition. Study group included for-cause post OLT biopsies. Staining of endothelial cells was considered positive. RESULTS In the study group C4d was positive in 22.7% versus 3.8% in controls (P=0.03), all had portal vein deposits. In 17 biopsies with ACR, 3 had positive C4d (17.6%) versus 7/27 with HCV recurrence (25.9%) (P=0.4). In HCV recurrence, 3/7 biopsies with fibrosing cholestatic hepatitis had positive C4d (42.9%) versus 4/20 without these features (20%) (P=0.24). Out of 10 recipients with positive C4d 4 had poor outcomes versus 3/22 with negative C4d (P=0.12). CONCLUSIONS C4d staining was significantly more frequent in post OLT biopsies compared with controls. C4d is not specifically associated with ACR and does not differentiate it from HCV recurrence but is associated with a trend toward poorer outcome.
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Kozlowski T, Andreoni K, Schmitz J, Hayashi PH, Nickeleit V. Sinusoidal C4d deposits in liver allografts indicate an antibody-mediated response: diagnostic considerations in the evaluation of liver allografts. Liver Transpl 2012; 18:641-58. [PMID: 22298469 DOI: 10.1002/lt.23403] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
There is a paucity of data concerning the correlation of complement component 4d (C4d) staining in liver allografts and antibody-mediated rejection. Data about the location and character of C4d deposits in native and allograft liver tissues are inconsistent. We performed C4d immunofluorescence (IF) on 141 fresh-frozen liver allograft biopsy samples and native livers, documented the pattern of C4d IF staining, and correlated the findings with the presence of donor-specific alloantibodies (DSAs). A linear/granular sinusoidal pattern of C4d IF was noted in 18 of 28 biopsy samples obtained after transplantation from patients with positive crossmatch and detectable donor-specific alloantibody (pos-XM/DSA) findings. None of the 59 tested biopsy samples from patients with negative crossmatch and detectable donor-specific alloantibody (neg-XM/DSA) findings were C4d-positive (P < 0.001). No significant association was found between pos-XM/DSA and C4d IF staining in other nonsinusoidal liver compartments. To compare the results of sinusoidal C4d staining with IF and 2 immunohistochemistry (IHC) techniques, C4d IHC was performed on 19 liver allograft biopsy samples in which a sinusoidal pattern of C4d IF had been noted. Sinusoidal C4d IHC findings were negative for 17 of the 19 biopsy samples; 2 showed weak and focal staining, and both patients had pos-XM/DSA findings. Portal vein endothelium staining was present in only 1 IF-stained biopsy sample (pos-XM/DSA) but in 11 IHC-stained biopsy samples (2 of the 11 samples had neg-XM/DSA findings). We conclude that sinusoidal C4d deposits detected by IF in frozen tissue samples from liver allograft recipients correlate with the presence of DSAs and an antibody-mediated alloresponse. These observations are similar to findings reported for other solid organ transplants and can provide relevant information for patient management. Further validation of IHC techniques for C4d detection in liver allograft tissue is required.
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Affiliation(s)
- Tomasz Kozlowski
- Departments of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Lunz J, Ruppert KM, Cajaiba MM, Isse K, Bentlejewski CA, Minervini M, Nalesnik MA, Randhawa P, Rubin E, Sasatomi E, de Vera ME, Fontes P, Humar A, Zeevi A, Demetris AJ. Re-examination of the lymphocytotoxic crossmatch in liver transplantation: can C4d stains help in monitoring? Am J Transplant 2012; 12:171-82. [PMID: 21992553 DOI: 10.1111/j.1600-6143.2011.03786.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
C4d-assisted recognition of antibody-mediated rejection (AMR) in formalin-fixed paraffin-embedded tissues (FFPE) from donor-specific antibody-positive (DSA+) renal allograft recipients prompted study of DSA+ liver allograft recipients as measured by lymphocytotoxic crossmatch (XM) and/or Luminex. XM results did not influence patient or allograft survival, or cellular rejection rates, but XM+ recipients received significantly more prophylactic steroids. Endothelial C4d staining strongly correlates with XM+ (<3 weeks posttransplantation) and DSA+ status and cellular rejection, but not with worse Banff grading or treatment response. Diffuse C4d staining, XM+, DSA+ and ABO- incompatibility status, histopathology and clinical-serologic profile helped establish an isolated AMR diagnosis in 5 of 100 (5%) XM+ and one ABO-incompatible, recipients. C4d staining later after transplantation was associated with rejection and nonrejection-related causes of allograft dysfunction in DSA- and DSA+ recipients, some of whom had good outcomes without additional therapy. Liver allograft FFPE C4d staining: (a) can help classify liver allograft dysfunction; (b) substantiates antibody contribution to rejection; (c) probably represents nonalloantibody insults and/or complete absorption in DSA- recipients and (d) alone, is an imperfect AMR marker needing correlation with routine histopathology, clinical and serologic profiles. Further study in late biopsies and other tissue markers of liver AMR with simultaneous DSA measurements are needed.
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Affiliation(s)
- J Lunz
- Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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25
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Ali S, Ormsby A, Shah V, Segovia MC, Kantz KL, Skorupski S, Eisenbrey AB, Mahan M, Huang MAY. Significance of complement split product C4d in ABO-compatible liver allograft: diagnosing utility in acute antibody mediated rejection. Transpl Immunol 2011; 26:62-9. [PMID: 21907804 DOI: 10.1016/j.trim.2011.08.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 08/10/2011] [Accepted: 08/21/2011] [Indexed: 12/11/2022]
Abstract
Diagnosis of liver allograft antibody-mediated rejection (AMR) is difficult and requires a constellation of clinical, laboratory and histologic features that support the disease and exclude other causes. Histologic features of AMR may intermix with those of biliary obstruction, preservation/reperfusion injury, and graft ischemia. Tissue examination for complement degradation product 4d (C4d) has been proved to support this diagnosis in other allografts. For this reason, we conducted a retrospective review of all ABO compatible/identical re-transplanted liver patients with primary focus on identifying AMR as a possible cause of graft failure and to investigate the utility of C4d in liver allograft specimens. We reviewed 193 liver samples obtained from 53 consecutive ABO-compatible re-transplant patients. 142 specimens were stained with C4d. Anti-donor antibody screening and identification was determined by Luminex100 flow cytometry. For the study analysis, patients were stratified into 3 groups according to time to graft failure: group A, patients with graft failure within 0-7 days (n=7), group B within 8-90 days (n=13) and C >90 days (n=33). Two patients (3.7%) met the diagnostic criteria of acute AMR. Both patients experienced rapid decline of graft function with presence of donor specific antibodies (DSA), morphologic evidence of humoral rejection and C4d deposition in liver specimens. C4d-positive staining was identified in different medical liver conditions i.e., acute cellular rejection (52%), chronic ductopenic rejection (50%), recurrent liver disease (48%), preservation injury (18%), and hepatic necrosis (54%). Univariate analysis showed no significant difference of C4d-positive staining among the 3 patients groups, or patients with DSA (P>.05). In conclusion, AMR after ABO-compatible liver transplantation is an uncommon cause of graft failure. Unlike other solid organ allografts, C4d-positive staining is not a rugged indicator of humoral rejection, thus, interpretation should be done with caution to avoid diagnostic dilemmas.
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26
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Bellamy COC. Complement C4d immunohistochemistry in the assessment of liver allograft biopsy samples: applications and pitfalls. Liver Transpl 2011; 17:747-50. [PMID: 21542127 DOI: 10.1002/lt.22323] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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27
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Kozlowski T, Rubinas T, Nickeleit V, Woosley J, Schmitz J, Collins D, Hayashi P, Passannante A, Andreoni K. Liver allograft antibody-mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies. Liver Transpl 2011; 17:357-68. [PMID: 21445918 DOI: 10.1002/lt.22233] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The importance of antibody-mediated rejection (AMR) in ABO-compatible liver transplantation is controversial. Here we report a prospective series of liver recipients with a preoperative positive crossmatch. To establish the diagnosis of AMR in liver recipients, the criteria described for kidney allografts were adopted. In approximately 10% of 197 liver transplants, we observed a positive T and B cell flow crossmatch before transplantation. Fifteen of 19 patients converted to negative crossmatches early after transplantation and displayed normal liver function while they were on routine immunosuppression. Four patients maintained positive crossmatches. Three of the 4 met the criteria for AMR and showed evidence of graft dysfunction, the presence of donor-specific antibodies (DSAs), morphological tissue destruction with positive C4d linear staining on the graft sinusoidal endothelium, and improved function with attempts to eliminate DSAs. A persistently positive crossmatch after liver transplantation may lead to early, severe AMR and liver failure. C4d staining in the liver sinusoidal endothelium should alert one to the possibility of AMR. In our experience, patients with a positive crossmatch should have it repeated at 2 weeks and, if it is positive, again at 3 to 5 weeks. Recipients with an unknown preoperative crossmatch who develop early cholestasis of unclear etiology should be crossmatched or tested for the presence of DSAs to evaluate for AMR.
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Affiliation(s)
- Tomasz Kozlowski
- Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7211, USA.
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Tu Z, Li Q, Chou HS, Hsieh CC, Meyerson H, Peters MG, Bu H, Fung JJ, Qian S, Lu L, Lin F. Complement mediated hepatocytes injury in a model of autoantibody induced hepatitis. Immunobiology 2011; 216:528-34. [PMID: 20851495 PMCID: PMC3557916 DOI: 10.1016/j.imbio.2010.08.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2010] [Revised: 07/26/2010] [Accepted: 08/03/2010] [Indexed: 02/08/2023]
Abstract
Despite multiple reports on autoantibody-initiated complement activation in autoimmune hepatitis (AIH), how does the humoral immunity contribute to the pathogenesis of AIH remained unclear. In this report, by adoptively transferring a polyclonal rabbit anti-OVA antibody into Hep-OVA Tg mice in which OVA is selectively expressed on the surface of hepatocytes, we found that excessive complement activation initiated by the autoantibody overwhelmed the protection of intrinsic cell surface complement regulators, and induced hepatocytes injury both in vitro and in vivo. The anti-OVA antibody induced hepatic injury in Hep-OVA Tg but not WT C57BL/6 mice as assessed by serum ALT levels and liver histopathology. Immunohistochemical analyses showed that after the antibody administration, there was massive complement activation on anti-OVA IgG coated hepatocytes in Hep-OVA Tg mice, but not in WT mice. Consistent with these results, depleting complement by cobra venom factor (CVF) prior to antibody injections protected Hep-OVA Tg mice from anti-OVA IgG induced hepatic injury. In addition, treating Hep-OVA Tg mice with recombinant mouse decay accelerating factor, a native complement inhibitor, protected them from autoantibody induced hepatitis. These results suggest that complement could play a pivotal role in liver specific autoantibody mediated hepatocyte injury in AIH, and that complement inhibitors could be, in principle, developed as novel therapeutics against AIH.
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Affiliation(s)
- Zhidan Tu
- Department of Pathology, Case Western Reserve University, Cleveland, USA
- Department of General Surgery, Cleveland Clinic, Cleveland, USA
| | - Qing Li
- Department of Pathology, Case Western Reserve University, Cleveland, USA
| | - Hong-Shiue Chou
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, USA
| | - Ching-Chuang Hsieh
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, USA
| | - Howard Meyerson
- Department of Pathology, Case Western Reserve University, Cleveland, USA
| | - Marion G. Peters
- Division of Gastroenterology, University of California, San Francisco, USA
| | - Hong Bu
- Department of Pathology, Sichuan University, Chengdu, China
| | - John J Fung
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, USA
| | - Shiguang Qian
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, USA
- Department of General Surgery, Cleveland Clinic, Cleveland, USA
| | - Lina Lu
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, USA
- Department of General Surgery, Cleveland Clinic, Cleveland, USA
| | - Feng Lin
- Department of Pathology, Case Western Reserve University, Cleveland, USA
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Musat AI, Agni RM, Wai PY, Pirsch JD, Lorentzen DF, Powell A, Leverson GE, Bellingham JM, Fernandez LA, Foley DP, Mezrich JD, D'Alessandro AM, Lucey MR. The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation. Am J Transplant 2011; 11:500-10. [PMID: 21342448 PMCID: PMC3357120 DOI: 10.1111/j.1600-6143.2010.03414.x] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.
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Affiliation(s)
- A I Musat
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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Huang HJ, Zheng ZY, Yu YH. Advances in research on antibody-mediated rejection after liver transplantation. Shijie Huaren Xiaohua Zazhi 2009; 17:3420-3425. [DOI: 10.11569/wcjd.v17.i33.3420] [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
T cell- and antibody-mediated immunity are also called cellular and humoral immunity, respectively. Both cellular and humoral immunity are known to mediate the rejection after allogeneic/xenogeneic organ transplantation. Liver transplantation is the most common type of organ transplantation. At present, many studies have shown that antibody-mediated immunity plays an important role in the development of rejection after liver transplantation. In this article, we will review the recent advances in understanding the basic theory, mechanism, pathological diagnosis and treatment of antibody-mediated rejection after liver transplantation.
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Abstract
Liver biopsy plays a central role in treatment algorithms in patients with hepatitis B and remains the gold standard for evaluating hepatic pathology. The pathology of hepatitis B is diverse and reflects the natural history of infection. An acute hepatitic pattern with lobular disarray is seen in acute infection, during acute flares of disease, and with acute hepatitis D superinfection. In chronic hepatitis B, inflammation is less pronounced in the immune-tolerant phase and is prominent during immune-mediated viral clearance. Active inflammation appears to be the driving force for development of fibrosis. Inflammatory grades and fibrosis stage are assigned as is done for hepatitis C. Although current management guidelines recommend liver biopsies only in select patients based on age, viral levels, and hepatitis B e antigen status, these clinical and biochemical parameters do not show consistent correlations with liver histology. Liver biopsy also helps identify preneoplastic lesions including large cell and small cell change. Unlike in other causes of chronic hepatitis, immunostains are widely used and can help determine the phase of infection. Liver biopsies can also identify additional pathology that may contribute to liver disease such as steatohepatitis, iron overload, autoimmune hepatitis, and drug-induced injury. Thus, liver biopsy can play an important role in staging and grading chronic hepatitis B and should be more widely used in assessing the need for therapy.
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Affiliation(s)
- Haresh Mani
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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