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1
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Condon S, Levy C, Martin EF. Recurrent and De Novo Liver Disease After Liver Transplantation. Clin Liver Dis 2025; 29:313-335. [PMID: 40287274 DOI: 10.1016/j.cld.2024.12.008] [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] [Indexed: 04/29/2025]
Abstract
Disease recurrence after liver transplantation (LT) is common. Certain liver diseases such as autoimmune hepatitis and steatotic liver disease may appear de novo after LT. This review discusses post LT alcohol-associated liver disease, metabolic dysfunction-associated liver disease, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Both recurrent and de novo diseases are important causes of allograft failure.
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Affiliation(s)
- Sally Condon
- Transplant Hepatology/Gastroenterology, Swedish Organ Transplant Center, 1124 Columbia Street #600, Seattle, WA 98104, USA.
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USA
| | - Eric F Martin
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, 1801 NW 9th Avenue, 7th Floor, Miami, FL 33136, USA
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2
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Lytvyak E, Wang D, Shreekumar D, Ebadi M, Alrifae Y, Mason A, Montano-Loza AJ. PSC-specific prognostic scores associated with graft loss and overall mortality in recurrent PSC after liver transplantation. Dig Liver Dis 2025:S1590-8658(25)00223-3. [PMID: 40011121 DOI: 10.1016/j.dld.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 02/28/2025]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a progressive liver disease with no treatment apart from liver transplantation (LT). After LT, patients can develop recurrent PSC (rPSC). The United-Kingdom (UK-PSC) and Amsterdam-Oxford (AOPSC) scores are used as prognostic models for PSC outcomes. AIM We aimed to assess these scores as predictive tools for graft loss and overall mortality in rPSC. METHODS We evaluated 67 people who developed rPSC. Using Cox regression models, we quantified associations between UK-PSC and AOPSC scores and graft loss and overall mortality. Cut-offs were established using receiver operator characteristic analysis and the highest Youden index. RESULTS Fifty-one individuals (76.1%) were males, with a mean age of 40±15 years. Both UK-PSC and AOPSC scores were independently associated with graft loss (hazard ratio [HR] 2.43 (p < 0.001) and HR 3.45 (p < 0.001), respectively), but only the UK-PSC score was independently associated with overall mortality (HR 2.63 (p = 0.009)). Individuals with UK-PSC ≥-4.2 (6.1 ± 0.8 vs. 14.7 ± 1.0 years; p = 0.001) and AOPSC ≥2.4 (5.4 ± 1.3 vs. 12.0 ± 1.1 years; p < 0.001) had shorter graft survival. CONCLUSION UK-PSC score at rPSC predicts both graft loss and overall mortality, while AOPSC scores using either age at rPSC or at diagnosis along with severe cholestasis predict graft loss in people with rPSC. These easy-to-administer tools can be utilized in clinical practice to identify high-risk rPSC patients and guide decisions about monitoring/interventions.
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Affiliation(s)
- Ellina Lytvyak
- Division of Preventive Medicine, Department of Medicine, University of Alberta, 5-30 University Terrace, 8303 112 Street, Edmonton, Alberta T6G 2T4, Canada.
| | - Dennis Wang
- Division of Gastroenterology & Liver Unit, Department of Medicine, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta T6G 2×8, Canada.
| | - Devika Shreekumar
- Division of Gastroenterology & Liver Unit, Department of Medicine, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta T6G 2×8, Canada.
| | - Maryam Ebadi
- Division of Gastroenterology & Liver Unit, Department of Medicine, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta T6G 2×8, Canada.
| | - Yousef Alrifae
- Division of Gastroenterology & Liver Unit, Department of Medicine, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta T6G 2×8, Canada.
| | - Andrew Mason
- Division of Gastroenterology & Liver Unit, Department of Medicine, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta T6G 2×8, Canada.
| | - Aldo J Montano-Loza
- Division of Gastroenterology & Liver Unit, Department of Medicine, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta T6G 2×8, Canada.
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3
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Pierrard J, Foguenne M, Baldin P, Bonaccorsi-Riani E, Coubeau L, Ciccarelli O, Dahlqvist G, Delire B, Van Ooteghem G. Does prior radiotherapy impact the acute cellular liver graft rejection? Cancer Radiother 2025; 29:104590. [PMID: 40043526 DOI: 10.1016/j.canrad.2025.104590] [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: 04/11/2024] [Revised: 08/19/2024] [Accepted: 08/26/2024] [Indexed: 04/01/2025]
Abstract
PURPOSE Radiotherapy can be used as a bridge therapy prior to liver transplantation. Radiotherapy generates immune reactions involving T cells, which are the main effectors of acute cellular rejection after transplantation. Here, we investigated the impact of radiotherapy on acute cellular rejection. MATERIALS AND METHODS We retrospectively reviewed the data of oncological patients who benefited from liver transplantation. Patients who received radiotherapy prior to liver transplantation ("RT cohort", n=17) were compared to a matched cohort ("NoRTmatched cohort", n=17) obtained through propensity score-matching analysis of the total non-irradiated cohort ("NoRTall" cohort, n=136). The acute cellular rejection was evaluated using the Banff score for rejection (mild:<5, moderate: 5-6, and severe: 7-9) obtained on an early post-transplantation biopsy. Overall and disease-free survival were reported for patients with hepatocellular carcinoma. RESULTS Median Banff scores was significantly lower for the RT cohort compared to the NoRTall cohort (2.5 versus 5, respectively, P=0.043) but this statistical difference was eliminated after comparison with the NoRTmatched cohort (median: 4, P=0.62). The 5-year overall and disease-free survival rates were 62 % and 69 %, respectively, for hepatocellular carcinoma patients of the RT cohort (n=14) and did not differ from the 5-year overall (83 %, P=0.15) and disease-free survival rates (90 %, P=0.05) of those of the NoRTmatched cohort (n=16). CONCLUSION Radiotherapy given prior to liver transplantation did not impact the rate or severity of acute cellular rejection. Furthermore, overall and disease-free survival rates were not impacted by radiotherapy.
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Affiliation(s)
- Julien Pierrard
- UCLouvain, Institut de recherche expérimentale et clinique (Irec), Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Brussels, Belgium; Department of Radiation Oncology, cliniques universitaires Saint-Luc, Brussels, Belgium.
| | - Maxime Foguenne
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Pamela Baldin
- UCLouvain, Institut de recherche expérimentale et clinique (Irec), Morphology Lab (MORF), Brussels, Belgium; Department of Pathology, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Eliano Bonaccorsi-Riani
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Laurent Coubeau
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Olga Ciccarelli
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Géraldine Dahlqvist
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium; Department of Hepato-gastroenterology, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Bénédicte Delire
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium; Department of Hepato-gastroenterology, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Geneviève Van Ooteghem
- UCLouvain, Institut de recherche expérimentale et clinique (Irec), Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Brussels, Belgium; Department of Radiation Oncology, cliniques universitaires Saint-Luc, Brussels, Belgium
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4
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Kang M, Park HK, Kim KS, Choi D. Animal models for transplant immunology: bridging bench to bedside. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:354-376. [PMID: 39233453 PMCID: PMC11732767 DOI: 10.4285/ctr.24.0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/05/2024] [Accepted: 07/07/2024] [Indexed: 09/06/2024]
Abstract
The progress of transplantation has been propelled forward by animal experiments. Animal models have not only provided opportunities to understand complex immune mechanisms in transplantation but also served as a platform to assess therapeutic interventions. While small animals have been instrumental in uncovering new therapeutic concepts related to immunosuppression and immune tolerance, the progression to human trials has largely been driven by studies in large animals. Recent research has begun to explore the potential of porcine organs to address the shortage of available organs. The consistent progress in transplant immunology research can be attributed to a thorough understanding of animal models. This review provides a comprehensive overview of the available animal models, detailing their modifications, strengths, and weaknesses, as well as their historical applications, to aid researchers in selecting the most suitable model for their specific research needs.
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Affiliation(s)
- Minseok Kang
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Hwon Kyum Park
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Kyeong Sik Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Department of HY-KIST Bio-convergence, Hanyang University, Seoul, Korea
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5
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Guo Z, Liu Y, Ling Q, Xu L, Wang T, Zhu J, Lin Y, Lu X, Qu W, Zhang F, Zhu Z, Zhang J, Jia Z, Zeng P, Wang W, Sun Q, Luo Q, Hu Z, Zheng Z, Jia Y, Li J, Zheng Y, Wang M, Wang S, Han Z, Yu S, Li C, Zhang S, Xiong J, Deng F, Liu Y, Chen H, Wang Y, Li L, Liang W, Schlegel A, Nashan B, Liu C, Zheng S, He X. Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: A multicenter, retrospective cohort study. Am J Transplant 2024; 24:1837-1856. [PMID: 38642712 DOI: 10.1016/j.ajt.2024.04.007] [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: 12/19/2023] [Revised: 03/24/2024] [Accepted: 04/15/2024] [Indexed: 04/22/2024]
Abstract
Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.
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Affiliation(s)
- Zhiyong Guo
- Organ Transplant Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China; NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Yao Liu
- Organ Transplant Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Qi Ling
- Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Leibo Xu
- Department of Biliary Pancreatic Surgery and Liver Transplantation Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tielong Wang
- Organ Transplant Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jiaxing Zhu
- Organ Transplant Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yimou Lin
- Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Xinjun Lu
- Department of Biliary Pancreatic Surgery and Liver Transplantation Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Qu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Fan Zhang
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Zhijun Zhu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Jian Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, China
| | - Zehua Jia
- Organ Transplant Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Ping Zeng
- Organ Transplant Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Wenjing Wang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qiang Sun
- Department of General Surgery, Zhongshan People's Hospital, Zhongshan, China
| | - Qijie Luo
- Department of General Surgery, Zhongshan People's Hospital, Zhongshan, China
| | - Zemin Hu
- Department of General Surgery, Zhongshan People's Hospital, Zhongshan, China
| | - Zhouying Zheng
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Yingbin Jia
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Jian Li
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Yujian Zheng
- Department of Hepatobiliary Surgery & Liver Transplantation Center, General Hospital of Southern Theater Command, Guangzhou, China
| | - Mengchao Wang
- Department of Hepatobiliary Surgery & Liver Transplantation Center, General Hospital of Southern Theater Command, Guangzhou, China
| | - Shaoping Wang
- Department of Hepatobiliary Surgery & Liver Transplantation Center, General Hospital of Southern Theater Command, Guangzhou, China
| | - Zemin Han
- Division of Hepato-Bilio-Pancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Sheng Yu
- Division of Hepato-Bilio-Pancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chuanjiang Li
- Division of Hepato-Bilio-Pancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shuhua Zhang
- Department of Hepatobiliary Surgery of General Surgery, Liver transplant center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Xiong
- Department of Hepatobiliary Surgery of General Surgery, Liver transplant center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feiwen Deng
- Organ Transplant Centre, Liver Surgery Department, The First People's Hospital of Foshan, Foshan, China
| | - Ying Liu
- Organ Transplant Centre, Liver Surgery Department, The First People's Hospital of Foshan, Foshan, China
| | - Huanwei Chen
- Organ Transplant Centre, Liver Surgery Department, The First People's Hospital of Foshan, Foshan, China
| | - Yanfeng Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Ling Li
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Wenjin Liang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Andrea Schlegel
- Transplantation Center, Digestive Disease and Surgery Institute, Department of Immunity and Inflammation, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Björn Nashan
- Organ Transplantation Center, The First Affiliated Hospital of the University of Science and Technology of China, Hefei, China
| | - Chao Liu
- Department of Biliary Pancreatic Surgery and Liver Transplantation Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Shusen Zheng
- Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.
| | - Xiaoshun He
- Organ Transplant Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China.
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6
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Wang H, Vannilam A, Hafberg ET, Gillis LA, Kassardjian A, Naini BV, Prasad V, Kelly DR, Mroczek-Musulman EC, Knox K, Correa H, Liang J. Clinical and Histopathologic Characteristics of Acute Severe Hepatitis Associated With Human Herpesvirus 6 Infection. Am J Surg Pathol 2024; 48:1117-1130. [PMID: 38907627 DOI: 10.1097/pas.0000000000002266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/24/2024]
Abstract
Acute severe hepatitis associated with active human herpesvirus 6 (HHV-6) infection is a rare life-threatening condition with unclear clinical course and histopathology. In this study, we retrospectively analyzed 5 patients with indeterminate acute severe hepatitis found to have active hepatic HHV-6 infection during care. All patients were previously healthy children presenting with a nonspecific prodrome. Four developed acute liver failure (ALF) and 3 received liver transplantation. The explanted livers and biopsies demonstrated a centrilobular pattern of necroinflammation characterized by moderate to marked central perivenulitis and confluent centrilobular to panlobular necrosis in 4 cases, accompanied by marked hepatocellular swelling and milder portal inflammation in 3. Central perivenulitis was more prominent in comparison to a control of group of ALF without HHV-6 ( P =0.01). When compared with the children with acute severe hepatitis associated with adenovirus encountered in the recent outbreak, both central perivenulitis and centrilobular necrosis were significant predictors for association with HHV-6 ( P <0.01). Liver immunohistochemistry detected HHV-6 structural protein in biliary epithelium in all cases and a predominance of CD8 + T cells in the perivenular inflammatory infiltrate. Among the 4 patients with ALF, one received early anti-HHV-6 therapy and had transplant-free survival, while the other 3 received either general prophylactic antiviral treatment only (n=2) or late anti-HHV-6 therapy (n=1) and needed liver transplantation. Our findings were similar to those in previously reported cases. In summary, acute severe hepatitis associated with HHV-6 tends to affect children, progress to ALF, and exhibit characteristic centrilobular necroinflammation which likely represents an immune-mediated process.
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Affiliation(s)
- Huiying Wang
- Department of Pathology, Microbiology and Immunology
| | - Annette Vannilam
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN
| | - Einar T Hafberg
- Landspitali University Hospital, Reykjavík, Capital Region, Iceland
| | - Lynette A Gillis
- Division of Gastroenterology, Department of Pediatrics, University of Louisville, Louisville, KY
| | | | - Bita V Naini
- Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Vinay Prasad
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH
| | - David R Kelly
- Department of Pathology and Laboratory Medicine, Children's of Alabama, Birmingham, AL
| | | | | | - Hernan Correa
- Department of Pathology, Microbiology and Immunology
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7
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Bellamy COC, O'Leary JG, Adeyi O, Baddour N, Batal I, Bucuvalas J, Del Bello A, El Hag M, El-Monayeri M, Farris AB, Feng S, Fiel MI, Fischer SE, Fung J, Grzyb K, Guimei M, Haga H, Hart J, Jackson AM, Jaeckel E, Khurram NA, Knechtle SJ, Lesniak D, Levitsky J, McCaughan G, McKenzie C, Mescoli C, Miquel R, Minervini MI, Nasser IA, Neil D, O'Neil MF, Pappo O, Randhawa P, Ruiz P, Fueyo AS, Schady D, Schiano T, Sebagh M, Smith M, Stevenson HL, Taner T, Taubert R, Thung S, Trunecka P, Wang HL, Wood-Trageser M, Yilmaz F, Zen Y, Zeevi A, Demetris AJ. Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health. Am J Transplant 2024; 24:905-917. [PMID: 38461883 DOI: 10.1016/j.ajt.2024.03.008] [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: 09/12/2023] [Revised: 02/27/2024] [Accepted: 03/06/2024] [Indexed: 03/12/2024]
Abstract
The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.
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Affiliation(s)
- Christopher O C Bellamy
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland and Department of Pathology, Edinburgh Royal Infirmary, Edinburgh, Scotland.
| | - Jacqueline G O'Leary
- Dallas VA Medical Center & University of Texas, Southwestern, Department of Medicine, Dallas Texas, USA
| | - Oyedele Adeyi
- University of Minnesota Medical School, Department of Pathology, Minneapolis, Minnesota, USA
| | - Nahed Baddour
- Faculty of Medicine, University of Alexandria, Egypt
| | - Ibrahim Batal
- Pathology, Columbia University Irving Medical Center, New York, New York, USA
| | | | | | | | | | - Alton B Farris
- Pathology, Emory University Hospital, Atlanta, Georgia, USA
| | - Sandy Feng
- UCSF Health, Department of Surgery, San Francisco, California, USA
| | - Maria Isabel Fiel
- Pathology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | | | - John Fung
- Uchicago Medicine, Department of Surgery, Chicago, Illinois, USA
| | | | - Maha Guimei
- Armed Forces College of Medicine, Cairo, Egypt
| | | | - John Hart
- Uchicago Medicine, Department of Pathology, Chicago, Illinois, USA
| | | | | | - Nigar A Khurram
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | | | - Drew Lesniak
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | | | | | | | | | - Rosa Miquel
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Marta I Minervini
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Imad Ahmad Nasser
- Beth Israel Deaconess Medical Center, Harvard, Boston, Massachusetts, USA
| | - Desley Neil
- University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Maura F O'Neil
- University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Orit Pappo
- Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Parmjeet Randhawa
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Phillip Ruiz
- University of Miami Hospital, Miami, Florida, USA
| | | | | | - Thomas Schiano
- Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, New York, USA
| | | | - Maxwell Smith
- Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | | | - Timucin Taner
- Division of Transplantation Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Richard Taubert
- Dept. of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Swan Thung
- Pathology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Pavel Trunecka
- Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia
| | - Hanlin L Wang
- Pathology, UCLA Health, Los Angeles, California, USA
| | - Michelle Wood-Trageser
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Funda Yilmaz
- Pathology, University of Ege, Imir, Bornova, Turkey
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Adriana Zeevi
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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8
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Elalouf A, Elalouf H, Rosenfeld A. Modulatory immune responses in fungal infection associated with organ transplant - advancements, management, and challenges. Front Immunol 2023; 14:1292625. [PMID: 38143753 PMCID: PMC10748506 DOI: 10.3389/fimmu.2023.1292625] [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: 09/11/2023] [Accepted: 11/20/2023] [Indexed: 12/26/2023] Open
Abstract
Organ transplantation stands as a pivotal achievement in modern medicine, offering hope to individuals with end-stage organ diseases. Advancements in immunology led to improved organ transplant survival through the development of immunosuppressants, but this heightened susceptibility to fungal infections with nonspecific symptoms in recipients. This review aims to establish an intricate balance between immune responses and fungal infections in organ transplant recipients. It explores the fundamental immune mechanisms, recent advances in immune response dynamics, and strategies for immune modulation, encompassing responses to fungal infections, immunomodulatory approaches, diagnostics, treatment challenges, and management. Early diagnosis of fungal infections in transplant patients is emphasized with the understanding that innate immune responses could potentially reduce immunosuppression and promise efficient and safe immuno-modulating treatments. Advances in fungal research and genetic influences on immune-fungal interactions are underscored, as well as the potential of single-cell technologies integrated with machine learning for biomarker discovery. This review provides a snapshot of the complex interplay between immune responses and fungal infections in organ transplantation and underscores key research directions.
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Affiliation(s)
- Amir Elalouf
- Department of Management, Bar-Ilan University, Ramat Gan, Israel
| | - Hadas Elalouf
- Information Science Department, Bar-Ilan University, Ramat Gan, Israel
| | - Ariel Rosenfeld
- Information Science Department, Bar-Ilan University, Ramat Gan, Israel
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9
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Rabindranath M, Zaya R, Prayitno K, Orchanian-Cheff A, Patel K, Jaeckel E, Bhat M. A Comprehensive Review of Liver Allograft Fibrosis and Steatosis: From Cause to Diagnosis. Transplant Direct 2023; 9:e1547. [PMID: 37854023 PMCID: PMC10581596 DOI: 10.1097/txd.0000000000001547] [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: 08/01/2023] [Revised: 09/11/2023] [Accepted: 09/14/2023] [Indexed: 10/20/2023] Open
Abstract
Despite advances in posttransplant care, long-term outcomes for liver transplant recipients remain unchanged. Approximately 25% of recipients will advance to graft cirrhosis and require retransplantation. Graft fibrosis progresses in the context of de novo or recurrent disease. Recurrent hepatitis C virus infection was previously the most important cause of graft failure but is now curable in the majority of patients. However, with an increasing prevalence of obesity and diabetes and nonalcoholic fatty liver disease as the most rapidly increasing indication for liver transplantation, metabolic dysfunction-associated liver injury is anticipated to become an important cause of graft fibrosis alongside alloimmune hepatitis and alcoholic liver disease. To better understand the landscape of the graft fibrosis literature, we summarize the associated epidemiology, cause, potential mechanisms, diagnosis, and complications. We additionally highlight the need for better noninvasive methods to ameliorate the management of graft fibrosis. Some examples include leveraging the microbiome, genetic, and machine learning methods to address these limitations. Overall, graft fibrosis is routinely seen by transplant clinicians, but it requires a better understanding of its underlying biology and contributors that can help inform diagnostic and therapeutic practices.
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Affiliation(s)
- Madhumitha Rabindranath
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Rita Zaya
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Khairunnadiya Prayitno
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Ani Orchanian-Cheff
- Library and Information Services, University Health Network, Toronto, ON, Canada
| | - Keyur Patel
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Elmar Jaeckel
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
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10
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Khalil A, Quaglia A, Gélat P, Saffari N, Rashidi H, Davidson B. New Developments and Challenges in Liver Transplantation. J Clin Med 2023; 12:5586. [PMID: 37685652 PMCID: PMC10488676 DOI: 10.3390/jcm12175586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/15/2023] [Accepted: 08/26/2023] [Indexed: 09/10/2023] Open
Abstract
Liver disease is increasing in incidence and is the third most common cause of premature death in the United Kingdom and fourth in the United States. Liver disease accounts for 2 million deaths globally each year. Three-quarters of patients with liver disease are diagnosed at a late stage, with liver transplantation as the only definitive treatment. Thomas E. Starzl performed the first human liver transplant 60 years ago. It has since become an established treatment for end-stage liver disease, both acute and chronic, including metabolic diseases and primary and, at present piloting, secondary liver cancer. Advances in surgical and anaesthetic techniques, refined indications and contra-indications to transplantation, improved donor selection, immunosuppression and prognostic scoring have allowed the outcomes of liver transplantation to improve year on year. However, there are many limitations to liver transplantation. This review describes the milestones that have occurred in the development of liver transplantation, the current limitations and the ongoing research aimed at overcoming these challenges.
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Affiliation(s)
- Amjad Khalil
- Liver Unit, Wellington Hospital, London NW8 9TA, UK
- Centre for Surgical Innovation, Organ Regeneration and Transplantation, University College London, London NW3 2PS, UK
- Clinical Service of HPB Surgery and Liver Transplantation, Royal Free Hospital, London NW3 2QG, UK
| | - Alberto Quaglia
- Cancer Institute, University College London, London WC1E 6DD, UK
| | - Pierre Gélat
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
| | - Nader Saffari
- Department of Mechanical Engineering, University College London, London WC1E 7JE, UK
| | - Hassan Rashidi
- Institute of Child Health, University College London, London WC1N 1EH, UK;
| | - Brian Davidson
- Liver Unit, Wellington Hospital, London NW8 9TA, UK
- Centre for Surgical Innovation, Organ Regeneration and Transplantation, University College London, London NW3 2PS, UK
- Clinical Service of HPB Surgery and Liver Transplantation, Royal Free Hospital, London NW3 2QG, UK
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11
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El Hag MI, Kaneku H, Jorgensen D, Zeevi A, Stevenson HL, Yadak N, Hassan M, Du X, Demetris AJ. Morphologic and immunophenotypic evaluation of liver allograft biopsies with contemporaneous serum DSA measurements. Clin Transplant 2023; 37:e14997. [PMID: 37096730 DOI: 10.1111/ctr.14997] [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: 02/02/2022] [Revised: 02/27/2023] [Accepted: 04/09/2023] [Indexed: 04/26/2023]
Abstract
BACKGROUND Acute antibody mediated rejection is increasingly identified in liver allografts as a unique form of alloimmune injury associated with donor specific antibodies (DSA). This manifests pathologically as microvascular injury and C4d uptake. Despite the liver allograft's relative resistance to alloimmune injury, liver allografts are not impervious to cellular and antibody-mediated rejection. METHODS In this blinded control study, we evaluated CD163 immunohistochemistry and applied the Banff 2016 criteria for diagnosis of acute AMR on a group of indication allograft liver biopsies from DSA positive patients and compared them to indication biopsies from DSA negative controls. RESULTS Most DSA positive patients were females (75%, p = .027), and underwent transplantation for HCV infection. Significant histopathological predictors of serum DSA positivity were Banff H-score (p = .01), moderate to severe cholestasis (p = .03), and CD163 score > 2 (p = .029). Other morphologic features that showed a trend with DSA positivity include Banff portal C4d-score (p = .06), bile ductular reaction (p = .07), and central perivenulitis (p = .07). The odds of DSA sMFI ≥5000 was 12.5 times higher in those with a C4d score >1 than those with a C4d score ≤ 1 (p = .04). Incidence of definite for aAMR in the DSA positive cohort was 25% (n = 5), and 0% in the DSA negative cohort. A group of 5 DSA positive cases were not classifiable by the current scheme. CONCLUSION Sinusoidal CD163, Banff H-score, and diffuse C4d are predictors of serum DSA, and facilitate recognition of histopathological features associated with serum DSA and tissue-antibody interaction.
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Affiliation(s)
- Mohamed I El Hag
- Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Hugo Kaneku
- Department of Surgery - Immunology and Histocompatibility Laboratory, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Dana Jorgensen
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Adriana Zeevi
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Division of Hepatic and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Nour Yadak
- Department of Pathology, Methodist University Hospital, University of Tennessee, Memphis, Tennessee, USA
| | - Mohamed Hassan
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Xiaotang Du
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Anthony J Demetris
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Division of Hepatic and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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12
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Lundberg Båve A, Olén O, Söderling J, Ludvigsson JF, Bergquist A, Nordenvall C. Colectomy in patients with ulcerative colitis is not associated to future diagnosis of primary sclerosing cholangitis. United European Gastroenterol J 2023; 11:471-481. [PMID: 37169725 PMCID: PMC10256996 DOI: 10.1002/ueg2.12388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/08/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Primary Sclerosing Cholangitis (PSC) is a hepatobiliary disease closely related to ulcerative colitis (UC). In PSC patients, colectomy has been linked to improved prognosis, especially following liver transplantation. This suggests an involvement of the gut-liver axis in PSC etiology. OBJECTIVE We aimed to investigate the association between colectomy and the risk of future PSC in an epidemiological setting. METHOD Through nationwide registers, we identified all adults diagnosed with UC in Sweden 1990-2018 and retrieved information on PSC diagnosis and colectomy. Within the UC cohort (n = 61,993 patients), we matched 5577 patients with colectomy to 15,078 without colectomy. Matching criteria were sex, age at UC onset (±5 years), year of UC onset (±3 years), and proctitis at the time of colectomy. Incidence rates of PSC per 1000-person year were calculated, and the Cox proportional hazard regression model estimated hazard ratios (HRs) for PSC until 31 December 2019. RESULTS During the follow-up, 190 (3.4%) colectomized UC patients and 450 (3.0%) UC comparators developed PSC, yielding incidence rates of 2.6 and 2.4 per 1000 person-years (HR 1.07 [95% CI 0.90-1.28]). The cumulative incidence of colectomy decreased remarkably over calendar periods, but the cumulative incidence of PSC remained unchanged. The risk of developing PSC in colectomized versus comparators changed over time (HR 0.68 [95% CI; 0.48-0.96] in 1990-97 and HR 2.10 [95% CI; 1.37-3.24] in 2011-18). CONCLUSIONS In UC patients, colectomy was not associated with a decreased risk of subsequent PSC. The observed differences in the risk of PSC development over calendar periods are likely due to changes in PSC-diagnosis and UC-treatment.
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Affiliation(s)
- Aiva Lundberg Båve
- Department of Medicine HuddingeKarolinska InstitutetStockholmSweden
- Department of Upper GI DiseaseDivision of HepatologyKarolinska University HospitalStockholmSweden
| | - Ola Olén
- Department of Medicine SolnaClinical Epidemiology DivisionKarolinska InstitutetStockholmSweden
- Department of Clinical Science and Education SödersjukhusetKarolinska InstitutetSachs' Children and Youth HospitalStockholmSweden
| | - Jonas Söderling
- Department of Medicine SolnaClinical Epidemiology DivisionKarolinska InstitutetStockholmSweden
| | - Jonas F. Ludvigsson
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
- Department of PediatricsÖrebro University HospitalStockholmSweden
| | - Annika Bergquist
- Department of Medicine HuddingeKarolinska InstitutetStockholmSweden
- Department of Upper GI DiseaseDivision of HepatologyKarolinska University HospitalStockholmSweden
| | - Caroline Nordenvall
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
- Department of Pelvic CancerKarolinska University HospitalStockholmSweden
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13
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Montano-Loza AJ, Rodríguez-Perálvarez ML, Pageaux GP, Sanchez-Fueyo A, Feng S. Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation. J Hepatol 2023; 78:1199-1215. [PMID: 37208106 DOI: 10.1016/j.jhep.2023.01.030] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/30/2022] [Accepted: 01/30/2023] [Indexed: 05/21/2023]
Abstract
Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.
| | - Manuel L Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, Córdoba, Spain; CIBER de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - George-Philippe Pageaux
- Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom
| | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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14
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Bateman J, Anugwom C, Zhou Y, Lim N, Adeyi O. Late-Onset Rejection in Liver Allograft Biopsies: An Analysis of Process, Pattern, and Clinical Implications. Am J Clin Pathol 2023; 159:283-292. [PMID: 36807634 DOI: 10.1093/ajcp/aqac162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 11/28/2022] [Indexed: 02/22/2023] Open
Abstract
OBJECTIVES Both alloimmune and nonalloimmune factors affect the long-term survival of liver allograft recipients. Various patterns of late-onset rejection are recognized, including typical acute cellular rejection (tACR), ductopenic rejection (DuR), nonspecific hepatitis (NSH), isolated central perivenulitis (ICP), and plasma cell-rich rejection (PCRR). This study compares the clinicopathologic features of late-onset rejection (LOR) in a large-cohort context. METHODS For-cause liver biopsies more than 6 months after transplant were included from the University of Minnesota between 2014 and 2019. Histopathologic, clinical, laboratory, treatment, and other data were analyzed in nonalloimmune and LOR cases. RESULTS The study consisted of 160 patients (122 adults, 38 pediatric patients), with 233 (53%) biopsies showing LOR: 51 (22%) tACR; 24 (10%) DuR; 23 (10%) NSH; 19 (8%) PCRR; and 3 (1%) ICP. Mean onset of 80 vs 61 months was longer for nonalloimmune injury (P = .04), a difference lost without tACR (mean, 26 months). Graft failure was highest with DuR. Response to treatment, as measured by changes in liver function tests, was similar between tACR and other LORs, and NSH occurred more often in pediatric patients (P = .001); tACR and other LOR incidence was similar. CONCLUSIONS LORs occur in pediatric and adult patients. Except for tACR, patterns overlap in many ways, with DuR having the greatest risk of graft loss, but other LORs respond well to antirejection treatments.
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Affiliation(s)
- Justin Bateman
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Chimaobi Anugwom
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Yan Zhou
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Nicholas Lim
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, Minneapolis, MN, USA.,University of Minnesota Medical Center, Minneapolis, MN, USA
| | - Oyedele Adeyi
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.,University of Minnesota Medical Center, Minneapolis, MN, USA
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15
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Narita S, Miuma S, Okudaira S, Koga Y, Fukushima M, Sasaki R, Haraguchi M, Soyama A, Hidaka M, Miyaaki H, Futakuchi M, Nagai K, Ichikawa T, Eguchi S, Nakao K. Regular protocol liver biopsy is useful to adjust immunosuppressant dose after adult liver transplantation. Clin Transplant 2023; 37:e14873. [PMID: 36443801 DOI: 10.1111/ctr.14873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 11/08/2022] [Accepted: 11/25/2022] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Adjusting immunosuppression to minimal levels post-adult liver transplantation (LT) is critical; however, graft rejection has been reported in LT recipients with normal liver function evaluated by liver biopsy (LBx). Continual protocol liver biopsy (PLB) is performed regularly in LT recipients with normal liver function in some centers; however, its usefulness remains inadequately evaluated. This study aimed to assess retrospectively the usefulness of late PLB after adult LT. METHODS LBx evaluations of LT recipients with normal liver function and hepatitis B and C virus seronegativity were defined as PLB. The cases requiring immunosuppressive therapy for rejection findings based on Banff criteria were extracted from the PLBs, and pathological data collected before and after immunosuppressive dosage adjustment (based on modified histological activity index [HAI] score) were compared. RESULTS Among 548 LBx cases, 213 LBx in 110 recipients fulfilled the inclusion criteria for PLB. Immunosuppressive therapy after PLB was intensified in 14 LBx (6.6%) recipients (12.7%); of these, nine had late-onset acute rejection, three had isolated perivenular inflammation, one had plasma cell-rich rejection, and one had early chronic rejection. Follow-up LBx after immunosuppressive dose adjustment showed improvement in the modified HAI score grading in 10 of 14 cases (71.4%). No clinical background and blood examination data, including those from the post-LT period, immunosuppressant trough level, or examination for de novo DSA, predicted rejection in PLB. Complications of PLB were found in only three cases. CONCLUSION PLB is useful in the management of seemingly stable LT recipients, to discover subclinical rejection and allow for appropriate immunosuppressant dose adjustment.
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Affiliation(s)
- Shohei Narita
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Sadayuki Okudaira
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yoshito Koga
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Masanori Fukushima
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mitsuru Futakuchi
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuhiro Nagai
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Tatsuki Ichikawa
- Nagasaki Harbor Medical Center, Department of Gastroenterology, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
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16
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Cheung A, Levitsky J. CAQ Corner: Basic concepts of transplant immunology. Liver Transpl 2023; 29:331-339. [PMID: 37160065 PMCID: PMC9935643 DOI: 10.1002/lt.26501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/15/2022] [Accepted: 05/04/2022] [Indexed: 01/12/2023]
Affiliation(s)
- Amanda Cheung
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center , Northwestern University Feinberg School of Medicine , Chicago , Illinois , USA
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17
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Haller W, Hodson J, Brown R, Lloyd C, Hubscher S, McKiernan P, Kelly D. The role of immunosuppression in long-term graft hepatitis and fibrosis after paediatric liver transplant - comparison of two treatment protocols. FRONTIERS IN TRANSPLANTATION 2023; 1:1042676. [PMID: 38994383 PMCID: PMC11235287 DOI: 10.3389/frtra.2022.1042676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 12/22/2022] [Indexed: 07/13/2024]
Abstract
Background and aims We have previously demonstrated high rates of chronic allograft hepatitis and fibrosis in liver transplant patients on long-term cyclosporine monotherapy. We subsequently changed practice to add low-dose prednisolone to maintenance treatment with tacrolimus post-transplant. The aim of the study was to assess the impact of the immunosuppression change on graft histopathology. Methods Patients treated in this era (Tac + Pred, 2000-2009, N = 128) were compared to a historical cohort, who had been maintained on a steroid-free, cyclosporine-based regime (CSA-Only, 1985-1996, N = 129). Protocol liver biopsies and laboratory tests were performed five- and ten-years post-transplant in both groups. Results Compared to CSA-Only, the Tac + Pred cohort had significantly lower rates of chronic hepatitis (CH) at five (20% vs. 44%, p < 0.001) and ten (15% vs. 67%, p < 0.001) years post-transplant, with similar trends observed in inflammation and fibrosis at five years. The Tac + Pred cohort also had significantly lower hepatic transaminases and IgG levels and was less likely to be autoantibody positive at both time points. However, the degree of graft fibrosis at ten years did not differ significantly between eras (p = 0.356). Conclusion Increased immunosuppression effectively reduced chronic allograft hepatitis and fibrosis at five years, suggesting it is an immunologically driven variant of rejection. However, there was no significant reduction in the degree of fibrosis at ten years, indicating a multifactorial origin for long term graft fibrosis.
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Affiliation(s)
- Wolfram Haller
- Department of Gastroenterology & Nutrition, Birmingham Woman's and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom
- Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom
| | - James Hodson
- Research Development and Innovation, Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Rachel Brown
- Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Carla Lloyd
- Liver Unit, Birmingham Woman's and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom
| | - Stefan Hubscher
- Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom
- Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Patrick McKiernan
- Liver Unit, Birmingham Woman's and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom
| | - Deirdre Kelly
- Liver Unit, Birmingham Woman's and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom
- Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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18
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Vargas PA, Cullen JM, Dalzell C, DiPaola F, Pelletier S, Soltys KA, Mazariegos GV, Oberholzer J, Goldaracena N. Increased use of split liver grafts in adult recipients following implementation of a pediatric liver transplant program. Pediatr Transplant 2022; 26:e14159. [PMID: 34687473 DOI: 10.1111/petr.14159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/23/2021] [Accepted: 09/26/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Split liver transplantation (SLT) is a strategy to address organ shortage, but is a technically more demanding procedure than whole graft liver transplantation (LT). We aimed to determine the outcomes following SLT in adult recipients as well as to highlight the impact that having a pediatric LT program has on SLT implementation. METHODS All SLTs conducted at a single-center from 2010 to 2019 were identified. Patient data was obtained through retrospective review of the electronic medical record. Kaplan-Meier analysis assessed primary outcomes of 1-,3-, and 5-year graft and patient survival. RESULTS We identified 37 SLTs performed at our institution from 2010 to 2019. Twenty-four donated livers resulted in 21 extended right lobes and 16 left lateral segments for adults and pediatrics recipients, respectively. Eighty-one percent (30/37) of the SLTs were performed after introduction of the combined pediatric program in 2016. 13/24 donor livers were split with both grafts allocated and used at our institution and 92% occurred after introduction of the pediatric program. Graft survival rates at 1-, 3-, and 5-years were 94% in adult recipients and 100% for all time periods in pediatric recipients. Actuarial post-transplant patient survival was 100% at 1-, 3-, and 5-years in both. CONCLUSIONS The introduction of a pediatric liver transplantation program resulted in more than a fourfold increase in the number of SLTs performed at our center. Increase in allocation and use of both grafts at our institution was also seen.
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Affiliation(s)
- Paola Andrea Vargas
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Jonathan Michael Cullen
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Christina Dalzell
- School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Frank DiPaola
- Division of Pediatric Gastroenterology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA
| | - Shawn Pelletier
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Kyle A Soltys
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.,Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - George Vincent Mazariegos
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.,Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jose Oberholzer
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Nicolas Goldaracena
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
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19
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Vargas PA, Dalzell C, Robinson T, Cunningham M, Henry Z, Stotts MJ, Su F, Argo C, Pelletier S, Oberholzer J, Goldaracena N. Split liver transplantation with extended right grafts on adult recipients: A propensity score matching analysis. Clin Transplant 2022; 36:e14801. [PMID: 35997030 DOI: 10.1111/ctr.14801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/24/2022] [Accepted: 08/14/2022] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Split liver transplantation (SLT) emerged due to its potential to contribute to the organ pool and reduce organ shortage. However, SLT is technically challenging and has been associated with higher rates of postoperative complications leading to concerns about graft and patient survival. Moreover, there are few studies on matched-pair adult recipients of SLT and whole-liver transplant (WLT), with conflicting results. METHODS This retrospective study analyze outcomes among adults who underwent SLT at our institution from 2010 to 2019. A 1:1 propensity score matching analysis was performed based on important donor and recipient variables. Baseline characteristics and postoperative outcomes were analyzed and compared between groups. Actuarial graft and patient survival were analyzed by KM curves. RESULTS Out of 592 adults receiving a LT in our institution, 21 SLT adult recipients were identified and matched with 21 adults undergoing WLT. As expected donor age was significantly lower in SLT recipients (16 (15-22) vs. 32 (17-47), P = .012). Additional donor characteristics, including anthropometrics, and ischemic times were similar between groups. Baseline recipient characteristics and postoperative outcomes, including length of stay, vascular complications, biliary complications, and re-transplantation were comparable between SLT and WLT recipients. Graft (95/95/95 vs. 100/94/94, P = .98) and patient (100/100/100 vs. 100/94/94, P = .30) survival at 1-, 3-, 5-years, were similar between the SLT- and WLT group, respectively. CONCLUSION Split liver transplantation has the potential to increase the availability of organs for adult recipients without compromising individual outcomes.
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Affiliation(s)
- Paola A Vargas
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Christina Dalzell
- School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Todd Robinson
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Michaela Cunningham
- Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Zachary Henry
- Department of Medicine, Division of Gastroenterology, University of Virginia, Charlottesville, Virginia, USA
| | - Matthew J Stotts
- Department of Medicine, Division of Gastroenterology, University of Virginia, Charlottesville, Virginia, USA
| | - Feng Su
- Department of Medicine, Division of Gastroenterology, University of Virginia, Charlottesville, Virginia, USA
| | - Curtis Argo
- Department of Medicine, Division of Gastroenterology, University of Virginia, Charlottesville, Virginia, USA
| | - Shawn Pelletier
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Jose Oberholzer
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Nicolas Goldaracena
- Division of Transplant Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
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20
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Ebada HE, Montasser MF, Abdelghaffar MF, Bahaa MM, Elbaset HSA, Sakr MA, Dabbous HM, Montasser IF, Hassan MS, Aboelmaaty ME, Elmeteini MS. Ascites post-living donor liver transplantation: Risk factors and outcome. JOURNAL OF LIVER TRANSPLANTATION 2022; 8:100112. [DOI: 10.1016/j.liver.2022.100112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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21
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Hübscher SG, Feng S, Gouw ASH, Haga H, Kang HJ, Kelly DA, Komuta M, Lesniak A, Popp BA, Verkade HJ, Yu E, Demetris AJ. Standardizing the histological assessment of late posttransplantation biopsies from pediatric liver allograft recipients. Liver Transpl 2022; 28:1475-1489. [PMID: 35429359 DOI: 10.1002/lt.26482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 03/30/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023]
Abstract
Excellent short-term survival after pediatric liver transplantation (LT) has shifted attention toward the optimization of long-term outcomes. Despite considerable progress in imaging and other noninvasive modalities, liver biopsies continue to be required to monitor allograft health and to titrate immunosuppression. However, a standardized approach to the detailed assessment of long-term graft histology is currently lacking. The aim of this study was to formulate a list of histopathological features relevant for the assessment of long-surviving liver allograft health and to develop an approach for assessing the presence and severity of these features in a standardized manner. Whole-slide digital images from 31 biopsies obtained ≥4 years after transplantation to determine eligibility for an immunosuppression withdrawal trial were selected to illustrate a range of typical histopathological findings seen in children with clinically stable grafts, including those associated with alloantibodies. Fifty histological features were independently assessed and, where appropriate, scored semiquantitatively by six pathologists to determine inter- and intraobserver reproducibility of the histopathological features using unweighted and weighted kappa statistics; the latter metric enabled distinction between minor and major disagreements in parameter severity scoring. Weighted interobserver kappa statistics showed a high level of agreement for various parameters of inflammation, interface activity, fibrosis, and microvascular injury. Intraobserver agreement for these features was even more substantial. The results of this study will help to standardize the assessment of biopsies from long-surviving liver allografts, aid the recognition of important histological features, and facilitate international comparisons and clinical trials aiming to improve outcomes for children undergoing LT.
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Affiliation(s)
- Stefan G Hübscher
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Sandy Feng
- Division of Transplantation, Department of Surgery, University of California, San Francisco, California, USA
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
| | - Hironori Haga
- Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hyo Jeong Kang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Deirdre A Kelly
- Liver Unit, Birmingham Women's & Children's NHS Trust and University of Birmingham, Birmingham, UK
| | - Mina Komuta
- Department of Pathology, Keio University, Tokyo, Japan
| | - Andrew Lesniak
- Division of Liver and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Benjamin A Popp
- Division of Liver and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Henkjan J Verkade
- Pediatric Gastroenterology/Hepatology, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Eunsil Yu
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Anthony J Demetris
- Division of Liver and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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22
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Garcia-Saenz-de-Sicilia M, Al-Obaid L, Hughes DL, Duarte-Rojo A. Mastering Core Recommendations during HEPAtology ROUNDS in Patients with Advanced Chronic Liver Disease. Semin Liver Dis 2022; 42:341-361. [PMID: 35764316 DOI: 10.1055/a-1886-5909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Efficient and thorough care of hospitalized patients with advanced chronic liver disease is of utter importance to improve outcomes and optimize quality of life. This requires understanding current evidence and best practices. To facilitate focus on up-to-date knowledge and a practical approach, we have created the HEPA-ROUNDS mnemonic while outlining a practical review of the literature with critical appraisal for the busy clinician. The HEPA-ROUNDS mnemonic provides a structured approach that incorporates critical concepts in terms of prevention, management, and prognostication of the most common complications frequently encountered in patients with advanced chronic liver disease. In addition, implementing the HEPA-ROUNDS mnemonic can facilitate education for trainees and staff caring for patients with advanced chronic liver disease.
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Affiliation(s)
| | - Lolwa Al-Obaid
- Division of Gastroenterology, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Dempsey L Hughes
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Andrés Duarte-Rojo
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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23
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Montano-Loza AJ, Ronca V, Ebadi M, Hansen BE, Hirschfield G, Elwir S, Alsaed M, Milkiewicz P, Janik MK, Marschall HU, Burza MA, Efe C, Calışkan AR, Harputluoglu M, Kabaçam G, Terrabuio D, de Quadros Onofrio F, Selzner N, Bonder A, Parés A, Llovet L, Akyıldız M, Arikan C, Manns MP, Taubert R, Weber AL, Schiano TD, Haydel B, Czubkowski P, Socha P, Ołdak N, Akamatsu N, Tanaka A, Levy C, Martin EF, Goel A, Sedki M, Jankowska I, Ikegami T, Rodriguez M, Sterneck M, Weiler-Normann C, Schramm C, Donato MF, Lohse A, Andrade RJ, Patwardhan VR, van Hoek B, Biewenga M, Kremer AE, Ueda Y, Deneau M, Pedersen M, Mayo MJ, Floreani A, Burra P, Secchi MF, Beretta-Piccoli BT, Sciveres M, Maggiore G, Jafri SM, Debray D, Girard M, Lacaille F, Lytvyak E, Mason AL, Heneghan M, Oo YH. Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation. J Hepatol 2022; 77:84-97. [PMID: 35143897 DOI: 10.1016/j.jhep.2022.01.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival. METHODS We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis. RESULTS AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001). CONCLUSION Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH. LAY SUMMARY Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.
| | - Vincenzo Ronca
- Center for Liver Research & NIHR Birmingham BRC, University of Birmingham & University Hospital Birmingham NHS Foundation Trust, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Maryam Ebadi
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada
| | - Bettina E Hansen
- Toronto Center for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Gideon Hirschfield
- Toronto Center for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Saleh Elwir
- Baylor University Medical Center, Dallas, USA
| | | | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, Poland
| | - Maciej K Janik
- Liver and Internal Medicine Unit, Medical University of Warsaw, Poland
| | | | | | - Cumali Efe
- Department of Gastroenterology, Harran University Hospital, Şanlıurfa, Turkey
| | - Ali Rıza Calışkan
- Department of Gastroenterology, Inönü University School of Medicine, Malatya, Turkey
| | - Murat Harputluoglu
- Department of Gastroenterology, Inönü University School of Medicine, Malatya, Turkey
| | - Gökhan Kabaçam
- Clinic of Gastroenterology and Liver Transplantation, Guven Hospital Ankara, Turkey
| | - Débora Terrabuio
- Department of Gastroenterology - University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Nazia Selzner
- Toronto Center for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Alan Bonder
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Albert Parés
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Laura Llovet
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Murat Akyıldız
- Koç University School of Medicine, Department of Gastroenterology and Liver Transplantation Center, Istanbul, Turkey
| | - Cigdem Arikan
- Koc University School of Medicine, Pediatric Gastroenterology and Hepatology, Organ Transplantation Center, Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Michael P Manns
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Department Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Department Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anna-Lena Weber
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Department Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas D Schiano
- Recanati/Miller Transplantation Institute/Division of Liver Diseases, Mount Sinai Medical Center, New York, USA
| | - Brandy Haydel
- Recanati/Miller Transplantation Institute/Division of Liver Diseases, Mount Sinai Medical Center, New York, USA
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Natalia Ołdak
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | | | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Cynthia Levy
- University of Miami Miller School of Medicine, Miami, USA
| | - Eric F Martin
- University of Miami Miller School of Medicine, Miami, USA
| | | | | | | | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | | | | | | | - Maria Francesca Donato
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Liver Tranplant Hepatology Unit, Division of Gastroenterology and Hepatology, Milan, Italy
| | | | - Raul J Andrade
- Gastroenterology Service -IBIMA. University Hospital and CIBERehd. University of Málaga, Spain
| | - Vilas R Patwardhan
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Bart van Hoek
- Leiden University Medical Center, Leiden, Netherlands
| | | | - Andreas E Kremer
- Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Mark Pedersen
- University of Texas Southwestern Medical Center, Dallas, USA
| | - Marlyn J Mayo
- University of Texas Southwestern Medical Center, Dallas, USA
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | | | | | | | - Giuseppe Maggiore
- Hepatogastroenterology, Nutrition and Liver Transplant IRCCS Bambino Gesù Pediatric Hospital, Rome, Italy
| | | | - Dominique Debray
- Pediatric Liver Unit, French National Reference Center for Rare Diseases BA and Genetic Cholestasis, Hôpital Necker, Université de Paris, Paris, France
| | - Muriel Girard
- Pediatric Liver Unit, French National Reference Center for Rare Diseases BA and Genetic Cholestasis, Hôpital Necker, Université de Paris, Paris, France
| | - Florence Lacaille
- Gastroenterology-Hepatology-Nutrition Unit, Hôpital Necker-Enfants Malades, Paris, France
| | - Ellina Lytvyak
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada
| | - Andrew L Mason
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada
| | | | - Ye Htun Oo
- Center for Liver and Gastro Research & National Institute of Health Research Birmingham Biomedical Research Centre, University of Birmingham; Centre for Rare Disease and ERN Rare Liver Centre, Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, UK.
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24
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Neil DAH, Minervini M, Smith ML, Hubscher SG, Brunt EM, Demetris AJ. Banff consensus recommendations for steatosis assessment in donor livers. Hepatology 2022; 75:1014-1025. [PMID: 34676901 PMCID: PMC9299655 DOI: 10.1002/hep.32208] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/09/2021] [Accepted: 10/12/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIMS No consensus criteria or approaches exist regarding assessment of steatosis in the setting of human donor liver suitability for transplantation. The Banff Working Group on Liver Allograft Pathology undertook a study to determine the consistency with which steatosis is assessed and reported in frozen sections of potential donor livers. APPROACH AND RESULTS A panel of 59 pathologists from 16 countries completed a questionnaire covering criteria used to assess steatosis in donor liver biopsies, including droplet size and magnification used; subsequently, steatosis severity was assessed in 18 whole slide images of donor liver frozen sections (n = 59). Survey results (from 56/59) indicated a wide variation in definitions and approaches used to assess and report steatosis. Whole slide image assessment led to a broad range in the scores. Findings were discussed at a workshop held at the 15th Banff Conference on Allograft Pathology, September 2019. The aims of discussions were to (i) establish consensus criteria for defining "large droplet fat" (LDF) that predisposes to increased risk of initial poor graft function and (ii) develop an algorithmic approach to determine fat droplet size and the percentage of hepatocytes involved. LDF was defined as typically a single fat droplet that expands the involved hepatocyte and is larger than adjacent nonsteatotic hepatocytes. Estimating severity of steatosis involves (i) low magnification estimate of the approximate surface area of the biopsy occupied by fat, (ii) higher magnification determination of the percentage of hepatocytes within the fatty area with LDF, and (iii) final score calculation. CONCLUSIONS The proposed guidelines herein are intended to improve standardization in steatosis assessment of donor liver biopsies. The calculated percent LDF should be provided to the surgeon.
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Affiliation(s)
- Desley A. H. Neil
- Department of Cellular PathologyQueen Elizabeth Hospital BirminghamBirminghamUK
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | - Marta Minervini
- Division of Transplant PathologyUniversity of Pittsburgh Medical CentrePittsburghPennsylvaniaUSA
| | - Maxwell L. Smith
- Department of Pathology and Laboratory MedicineMayo Clinic ArizonaScottsdaleArizonaUSA
| | - Stefan G. Hubscher
- Department of Cellular PathologyQueen Elizabeth Hospital BirminghamBirminghamUK
- Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | - Elizabeth M. Brunt
- Department of Pathology and ImmunologyWashington University School of MedicineSt LouisMissouriUSA
| | - A. Jake Demetris
- Division of Transplant PathologyUniversity of Pittsburgh Medical CentrePittsburghPennsylvaniaUSA
- Division of Liver and Transplantation PathologyUniversity of PittsburghPittsburghPennsylvaniaUSA
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25
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Lee SK, Park MJ, Choi JW, Baek JA, Kim SY, Choi HJ, You YK, Jang JW, Sung PS, Bae SH, Yoon SK, Choi JY, Cho ML. Patient-Derived Avatar Mouse Model to Predict the Liver Immune Homeostasis of Long-Term Stable Liver Transplant Patients. Front Immunol 2022; 13:817006. [PMID: 35418987 PMCID: PMC8995467 DOI: 10.3389/fimmu.2022.817006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
Although rejection or tolerance can occur in liver transplantation (LT) patients, there are no reliable non-invasive methods for predicting immune homeostasis. In this study, we developed a humanized mouse model to predict liver immune homeostasis in patients who underwent LT. The patient-derived avatar model was developed by injecting peripheral blood mononuclear cells from healthy controls (HCs) or LT patients with stable, rejection, or tolerance into NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJ (NSG) mice, followed by injection of human hepatic stellate cells and Carbone tetrachloride (CCl4). After 7 weeks, the patient's T-cell engraftment and liver inflammation in the avatar model were evaluated and compared with the liver histology of LT patients. Changes in liver inflammation following treatment with tacrolimus and/or biguanide derivatives were also examined. The C-X-C Motif Chemokine Receptor 3 (CXCR3)-dependently engrafted patient T cells led to differences in liver inflammation in our model according to the status of LT patients. The livers of avatar models from rejection patients had severe inflammation with more T helper 17 cells and fewer regulatory T cells compared to those of models from tolerance and HCs showing only mild inflammation. Moreover, our model classified stable post-LT patients into severe and mild inflammation groups, which correlated well with liver immunity in these patients. Our models revealed alleviation of inflammation after combination treatment with tacrolimus and biguanide derivatives or monotherapy. Consequently, using our new patient-derived avatar model, we predicted liver immune homeostasis in patients with stable LT without biopsy. Moreover, our avatar model may be useful for preclinical analysis to evaluate treatment responses while reducing risks to patients.
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Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Min-Jung Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jeong Won Choi
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jin-Ah Baek
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Se-Young Kim
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Young Kyoung You
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Pil Soo Sung
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, Eunpyeong Se. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Mi-La Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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26
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Harputluoglu M, Caliskan AR, Akbulut S. Autoimmune hepatitis and liver transplantation: Indications, and recurrent and de novo autoimmune hepatitis. World J Transplant 2022; 12:59-64. [PMID: 35433333 PMCID: PMC8968478 DOI: 10.5500/wjt.v12.i3.59] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/15/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels. Liver transplantation may be required for patients with acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Recurrence is defined as development of the same disease in the allograft following liver transplantation. Autoimmune hepatitis recurs in 36%-68% of the recipients 5 years after liver transplantation. De novo autoimmune hepatitis is the development of autoimmune hepatitis like clinical and laboratory characteristics in patients who had undergone liver transplantation for causes other than autoimmune hepatitis. Diagnostic work up for recurrent and de novo autoimmune hepatitis is similar to the diagnosis of the original disease, and it is usually difficult. Predniso(lo)ne with or without azathioprine is the main treatment for recurrent and de novo autoimmune hepatitis. Early diagnosis and treatment are vital for patient prognosis because de novo autoimmune hepatitis and recurrent autoimmune hepatitis cause graft loss and result in subsequent retransplantation if medical treatment fails.
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Affiliation(s)
- Murat Harputluoglu
- Department of Gastroenterology and Transplant Hepatology, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Ali Riza Caliskan
- Department of Gastroenterology, Adiyaman Education and Research Hospital, Adıyaman 04120, Turkey
| | - Sami Akbulut
- Liver Transplant Institute, Inonu University, Malatya 44280, Turkey
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Vannas M, Arola J, Nordin A, Isoniemi H. Value of posttransplant protocol biopsies in 2 biliary autoimmune liver diseases: A step toward personalized immunosuppressive treatment. Medicine (Baltimore) 2022; 101:e28509. [PMID: 35029206 PMCID: PMC8758011 DOI: 10.1097/md.0000000000028509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 12/17/2021] [Indexed: 01/05/2023] Open
Abstract
The value of protocol liver graft biopsies with good liver function was evaluated in patients with primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC).A total of 250 protocol liver biopsy reports from 182 PSC and PBC patients were compared. Overall histopathological findings and those leading to changes in immunosuppression therapy were retrospectively analyzed.The mean time to first protocol biopsy after transplantation was 5.5 (±4.5) years for PSC patients and 9.3 (±6.6) years for PBC patients. More than 1 abnormal histopathological parameter was found in 43% and 62% of PSC and PBC patients, respectively. However, the histology was interpreted as normal by the pathologist in 78% of PSC and 60% of PBC patients. Immunosuppression therapy was reduced in 10% and increased in 6% patients due to protocol biopsy findings. Biopsies leading to increased immunosuppression therapy had more portal (P = .004), endothelial (P = .008), interphase (P = .021), and lobular (P = .000) inflammation.Mild histopathological findings were frequently found in the protocol biopsies despite the normal biochemistry. PBC patients had more histological abnormalities than those transplanted due to PSC; however, PBC patients had longer follow-up times. Immunosuppression therapy could be safely increased or decreased according to protocol biopsy findings after multidisciplinary meeting discussions.
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Affiliation(s)
- Marko Vannas
- Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, HUH Diagnostic Centre, Helsinki University Hospital and University of Helsinki, Finland
| | - Arno Nordin
- Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Helena Isoniemi
- Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Razafindrazoto CI, Trystram N, Martins GM, Stern C, Charlotte F, Lebray P. Late acute cellular rejection after switch to everolimus monotherapy at 11 months following liver transplantation. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00170-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Acute cellular rejection beyond the 6th month posttransplant is an uncommon complication after liver transplantation. The inadequate immunosuppression (IS) remains the main risk factor. We report a case of acute cellular rejection after a switch to everolimus monotherapy at 11 months following liver transplantation.
Case presentation
This was a 69-year-old man who underwent liver transplantation after hepatocellular carcinoma. The initial immunosuppression was a combination of three immunosuppressive drugs (corticosteroids + tacrolimus + mycophenolate mofetil). The corticosteroid therapy was stopped at the 4th month posttransplant. Serious side effects of the immunosuppressive drugs (agranulocytosis and renal dysfunction), which occurred 4 months after transplantation, required a reduction and then a discontinuation of tacrolimus and mycophenolate mofetil. Everolimus was introduced as a replacement. The patient was consulted at 11 months after liver transplantation, 1 month after stopping the two immunosuppressive drugs, for liver function test abnormalities such as cytolysis and anicteric cholestasis. A moderate late acute cellular rejection was confirmed by a liver biopsy. A satisfactory biological evolution was observed following corticosteroid boluses and optimization of basic immunosuppressive drugs.
Conclusion
Late acute cellular rejection remains an uncommon complication, observed mostly in the first year after liver transplantation. The main risk factor is usually the decrease of immunosuppression.
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Wei Q, Wang K, Yang M, Chen J, Shen T, Song P, Xie H, Zhou L, Zheng S, Xu X. Recipient gender and body mass index are associated with early acute rejection in donation after cardiac death liver transplantation. Clin Res Hepatol Gastroenterol 2021; 44S:100004. [PMID: 33602482 DOI: 10.1016/j.clirex.2020.100004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 02/21/2020] [Accepted: 02/24/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Early acute rejection (EAR) is a common complication after liver transplantation (LT). AIM The aim of this study was to evaluate the incidence and risk factors of EAR in donation after cardiac death (DCD) liver transplantation recipients. METHOD We retrospectively analysed the data of 461 DCD liver transplants performed during the period from January 2010 to June 2016 to study the relationship between EAR and various clinical factors. EAR was defined as histologically proven acute cellular rejection occurring less than 90 days after transplantation. RESULT The median follow-up time for this study was 33.1 months (range: 0.03-92.8 months). Thirty-two (6.9%) patients developed EAR with a median period of 20.5 days (5-88 days) after transplantation. A multivariate analysis revealed that female recipient (hazard ratio: 2.801; P=0.024) and high recipient body mass index (BMI) (hazard ratio: 1.005; P=0.049) were two independent risk factors for early acute rejection. CONCLUSIONS In DCD liver transplantation, recipient female gender and high BMI were associated with a higher incidence of EAR, while the use of CD25-Ab and/or MMF had a protective effect.
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Affiliation(s)
- Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou,China
| | - Kun Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China
| | - Modan Yang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou,China
| | - Junli Chen
- China Liver Transplant Registry, 310003 Hangzhou, China
| | - Tian Shen
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China
| | - Penghong Song
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China
| | - Haiyang Xie
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China
| | - Lin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China; China Liver Transplant Registry, 310003 Hangzhou, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou,China.; China Liver Transplant Registry, 310003 Hangzhou, China.
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Immunosuppression in liver and intestinal transplantation. Best Pract Res Clin Gastroenterol 2021; 54-55:101767. [PMID: 34874848 DOI: 10.1016/j.bpg.2021.101767] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 02/07/2023]
Abstract
Immunosuppression handling plays a key role in the early and long-term results of transplantation. The development of multiple immunosuppressive drugs led to numerous clincial trials searching to reach the ideal regimen. Due to heterogeneity of the studied patient cohorts and flaws in many, even randomized controlled, study designs, the answer still stands out. Nowadays triple-drug immunosuppression containing a calcineurin inhibitor (preferentially tacrolimus), an antimetabolite (using mycophenolate moffettil or Azathioprine) and short-term steroids with or without induction therapy (using anti-IL2 receptor blocker or anti-lymphocytic serum) is the preferred option in both liver and intestinal transplantation. This chapter aims, based on a critical review of the definitions of rejection, corticoresistant rejection and standard immunosuppression to give some reflections on how to reach an optimal immunosuppressive status and to conduct trials allowing to draw solid conclusions. Endpoints of future trials should not anymore focus on biopsy proven, acute and chronic, rejection but also on graft and patient survival. Correlation between early- and long-term biologic, immunologic and histopathologic findings will be fundamental to reach in much more patients the status of operational tolerance.
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Féray C, Taupin JL, Sebagh M, Allain V, Demir Z, Allard MA, Desterke C, Coilly A, Saliba F, Vibert E, Azoulay D, Guettier C, Chatton A, Debray D, Caillat-Zucman S, Samuel D. Donor HLA Class 1 Evolutionary Divergence Is a Major Predictor of Liver Allograft Rejection : A Retrospective Cohort Study. Ann Intern Med 2021; 174:1385-1394. [PMID: 34424731 DOI: 10.7326/m20-7957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The HLA evolutionary divergence (HED), a continuous metric quantifying the peptidic differences between 2 homologous HLA alleles, reflects the breadth of the immunopeptidome presented to T lymphocytes. OBJECTIVE To assess the potential effect of donor or recipient HED on liver transplant rejection. DESIGN Retrospective cohort study. SETTING Liver transplant units. PATIENTS 1154 adults and 113 children who had a liver transplant between 2004 and 2018. MEASUREMENTS Liver biopsies were done 1, 2, 5, and 10 years after the transplant and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSAs) were measured in children at the time of biopsy. The HED was calculated using the physicochemical Grantham distance for class I (HLA-A or HLA-B) and class II (HLA-DRB1 or HLA-DQB1) alleles. The influence of HED on the incidence of liver lesions was analyzed through the inverse probability weighting approach based on covariate balancing, generalized propensity scores. RESULTS In adults, class I HED of the donor was associated with acute rejection (hazard ratio [HR], 1.09 [95% CI, 1.03 to 1.16]), chronic rejection (HR, 1.20 [CI, 1.10 to 1.31]), and ductopenia of 50% or more (HR, 1.33 [CI, 1.09 to 1.62]) but not with other histologic lesions. In children, class I HED of the donor was also associated with acute rejection (HR, 1.16 [CI, 1.03 to 1.30]) independent of the presence of DSAs. There was no effect of either donor class II HED or recipient class I or class II HED on the incidence of liver lesions in adults and children. LIMITATION The DSAs were measured only in children. CONCLUSION Class I HED of the donor predicts acute or chronic rejection of liver transplant. This novel and accessible prognostic marker could orientate donor selection and guide immunosuppression. PRIMARY FUNDING SOURCE Institut National de la Santé et de la Recherche Médicale.
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Affiliation(s)
- Cyrille Féray
- Centre Hépato-Biliaire, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale 1193, Villejuif, France (C.F., M.A., C.D., A.C., F.S., E.V., D.A., D.S.)
| | - Jean-Luc Taupin
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, and unité Institut National de la Santé et de la Recherche Médicale 976, Université de Paris, Paris, France (J.T., S.C.)
| | - Mylène Sebagh
- Laboratoire d'Anatomopathologie, Assistance Publique-Hôpitaux de Paris, Hôpital Paul-Brousse, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale, Physiopathogénèse et traitement des maladies du Foie, and FHU Hepatinov, Villejuif, France (M.S., C.G.)
| | - Vincent Allain
- Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Laboratoire d'Immunologie et Histocompatibilité, and Institut National de la Santé et de la Recherche Médicale, Paris, France (V.A.)
| | - Zeynep Demir
- Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, and Unité d'Hépatologie pédiatrique, Paris, France (Z.D., D.D.)
| | - Marc-Antoine Allard
- Centre Hépato-Biliaire, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale 1193, Villejuif, France (C.F., M.A., C.D., A.C., F.S., E.V., D.A., D.S.)
| | - Christophe Desterke
- Centre Hépato-Biliaire, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale 1193, Villejuif, France (C.F., M.A., C.D., A.C., F.S., E.V., D.A., D.S.)
| | - Audrey Coilly
- Centre Hépato-Biliaire, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale 1193, Villejuif, France (C.F., M.A., C.D., A.C., F.S., E.V., D.A., D.S.)
| | - Faouzi Saliba
- Centre Hépato-Biliaire, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale 1193, Villejuif, France (C.F., M.A., C.D., A.C., F.S., E.V., D.A., D.S.)
| | - Eric Vibert
- Centre Hépato-Biliaire, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale 1193, Villejuif, France (C.F., M.A., C.D., A.C., F.S., E.V., D.A., D.S.)
| | - Daniel Azoulay
- Centre Hépato-Biliaire, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale 1193, Villejuif, France (C.F., M.A., C.D., A.C., F.S., E.V., D.A., D.S.)
| | - Catherine Guettier
- Laboratoire d'Anatomopathologie, Assistance Publique-Hôpitaux de Paris, Hôpital Paul-Brousse, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale, Physiopathogénèse et traitement des maladies du Foie, and FHU Hepatinov, Villejuif, France (M.S., C.G.)
| | - Arthur Chatton
- Institut National de la Santé et de la Recherche Médicale UMR 1246-SPHERE, Nantes University, Tours University, Nantes, and IDBC, Pacé, France (A.C.)
| | - Dominique Debray
- Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, and Unité d'Hépatologie pédiatrique, Paris, France (Z.D., D.D.)
| | - Sophie Caillat-Zucman
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, and unité Institut National de la Santé et de la Recherche Médicale 976, Université de Paris, Paris, France (J.T., S.C.)
| | - Didier Samuel
- Centre Hépato-Biliaire, Hôpital Paul-Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, unité Institut National de la Santé et de la Recherche Médicale 1193, Villejuif, France (C.F., M.A., C.D., A.C., F.S., E.V., D.A., D.S.)
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Colucci G, Invernizzi F, Uceda Renteria S, Perbellini R, Degasperi E, D'Ambrosio R, Galmozzi E, Lunghi G, Sguazzini E, Lampertico P, Donato MF. The CCR5 and CXCR3 Pathways in Hepatitis C Virus Liver Transplanted Recipients Treated by a Direct Antiviral Agent Regimen: Informative Kinetics Profiles. Viral Immunol 2021; 34:542-551. [PMID: 34252334 DOI: 10.1089/vim.2021.0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The CC5 and CXC3 chemokines (CK) pathways are involved in the pathogenesis and outcome of several disease states, including chronic hepatitis C (CHC). The kinetics of Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) (CCL5) and IP-10 (CXCL10) during direct-acting antivirals (DAA) treatment was retrospectively analyzed in 18 liver transplant recipients (LT-R) compared with 20 patients with CHC and 49 healthy controls (HC). CK levels were determined at baseline, week 4, end of treatment, 24 weeks post-treatment (sustained virological response [SVR]), and later-on during follow-up (FU), 12 and 24 months post-DAA. At baseline, median RANTES levels were higher in HC than in both LT-R (p > 0.01) and CHC (p > 0.01), whereas IP-10 levels were higher in LT-R and CHC than in HC (p > 0.05 and p = 0.01), respectively. Mean RANTES values increased during DAA therapy to peak at SVR and FU with significantly higher levels than at baseline in LT-R (p < 0.01) and in CHC, but only at FU (p < 0.003). A subsequent return to baseline or lower levels was observed at extended FU. On the contrary, IP-10 values showed a significant decrease from baseline to SVR and FU in both LT-R (p < 0.03) and CHC (p < 0.01). RANTES profiles during the first 4 weeks of DAA treatment showed an increase or decrease from baseline according to baseline RANTES levels. CCR5 genotyping in LT-R showed the presence of 1 homozygous Δ32/Δ32 and 2 heterozygous WT/Δ32 haplotypes with a prevalence of 5.5% and 11.1%, respectively. In conclusion, although IP-10 showed the expected kinetics, the CC5 pathway appears extensively altered during CHC infection: monitoring these patients may be indicated as they may be at risk of other infections or immune-mediated disorders.
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Affiliation(s)
- Giuseppe Colucci
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Federica Invernizzi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Sara Uceda Renteria
- Virology Unit, Division of Clinical Laboratory, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Riccardo Perbellini
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Elisabetta Degasperi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Roberta D'Ambrosio
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Enrico Galmozzi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Giovanna Lunghi
- Virology Unit, Division of Clinical Laboratory, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Enrico Sguazzini
- Department of Medical Biotechnology, Università Degli Studi di Milano, Milan, Italy
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy.,Department of Medical Surgical Physiopatology and Transplantation, University of Milan, Milan, Italy
| | - Maria Francesca Donato
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
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Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients: 5-year Prospective Follow-up of Patients in the DIAMOND Study. Transplant Direct 2021; 7:e722. [PMID: 34263020 PMCID: PMC8274734 DOI: 10.1097/txd.0000000000001166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 01/27/2023] Open
Abstract
Background Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basiliximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). Methods DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). Results Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74.7%. Overall graft survival in patients remaining on PR-T for ≥30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mL/min/1.73 m2, respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had ≥1 adverse drug reaction, considered possibly related to PR-T in 6 patients. Conclusions In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.
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Schotters FL, Beime J, Briem-Richter A, Binder T, Herden U, Grabhorn EF. Impact of donor-specific antibodies on long-term graft survival with pediatric liver transplantation. World J Hepatol 2021; 13:673-685. [PMID: 34239702 PMCID: PMC8239487 DOI: 10.4254/wjh.v13.i6.673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/12/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In a previous paper, we reported a high prevalence of donor-specific antibody (DSA) in pediatric patients with chronic rejection and expressed the need for confirmation of these findings in a larger cohort.
AIM To clarify the importance of DSAs on long-term graft survival in a larger cohort of pediatric patients.
METHODS We performed a retrospective analysis of 123 pediatric liver transplantation (LT) recipients who participated in yearly follow-ups including Luminex testing for DSA at our center. The cohort was split into two groups according to the DSA status (DSA-positive n = 54, DSA-negative n = 69). Groups were compared with regard to liver function, biopsy findings, graft survival, need for re-LT and immunosuppressive medication.
RESULTS DSA-positive pediatric patients showed a higher prevalence of chronic rejection (P = 0.01), fibrosis (P < 0.001) and re-transplantation (P = 0.018) than DSA-negative patients. Class II DSAs particularly influenced graft survival. Alleles DQ2, DQ7, DQ8 and DQ9 might serve as indicators for the risk of chronic rejection and/or allograft fibrosis. Mean fluorescence intensity levels and DSA number did not impact graft survival. Previous episodes of chronic rejection might lead to DSA development.
CONCLUSION DSA prevalence significantly affected long-term liver allograft performance and liver allograft survival in our cohort of pediatric LT. Screening for class II DSAs in combination with assessment of protocol liver biopsies for chronic antibody-mediated rejection improved early identification of patients at risk of graft loss.
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Affiliation(s)
- Felicitas Leonie Schotters
- Department of Pediatric Hepatology and Liver Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Jan Beime
- Department of Pediatric Hepatology and Liver Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Andrea Briem-Richter
- Department of Pediatric Hepatology and Liver Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Thomas Binder
- Department of Transfusion Medicine, Human Leucocyte Antigen Laboratory, University Medicine Rostock, Rostock 18057, Germany
| | - Uta Herden
- Department of Hepatobiliary & Transplant Surgery, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Enke Freya Grabhorn
- Department of Pediatric Hepatology and Liver Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
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Lee S, Kim JM, Kim S, Rhu J, Choi GS, Joh JW. Early use of everolimus improved renal function after adult deceased donor liver transplantation. KOREAN JOURNAL OF TRANSPLANTATION 2021; 35:8-14. [PMID: 35769619 PMCID: PMC9235327 DOI: 10.4285/kjt.20.0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/29/2020] [Accepted: 10/29/2020] [Indexed: 11/04/2022] Open
Abstract
Background Tacrolimus (TAC) is a main therapy for liver transplantation (LT) patients, but it has side effects such as chronic nephrotoxicity that progressively aggravate renal function. The purpose of this study was to retrospectively compare the renal function between a TAC group and a combination of everolimus and reduced TAC (EVR-TAC) group after deceased donor liver transplantation (DDLT). Methods The study comprised 131 patients who underwent DDLT between January 2013 and April 2018 at our institution. They received TAC or EVR-TAC after DDLT. Everolimus (EVR) was introduced between 1 and 6 months after DDLT. Results Thirty-six of 131 patients (27.5%) received EVR-TAC. The incidence of chronic kidney disease (CKD; estimated glomerular filtration rate, <60 mL/1.73 m2) in the EVR-TAC group was higher than in the TAC group (25% vs. 8.4%; P=0.019). Increasing serum creatinine (n=23, 63.9%) was the most common cause for adding EVR to treatment of the posttransplant patients. There were no statistical differences in acute rejection and CKD between the two groups. The TAC trough level was significantly lower in the EVR-TAC group than in the TAC group, and the renal function of the EVR-TAC group was worse than that of the TAC group until 1 year after DDLT. However, the renal function of the EVR-TAC group improved and became similar to that of TAC group at 3 years posttransplant. Conclusions The present study suggests that EVR should be introduced as soon as possible after DDLT to reduce exposure to high doses of TAC to improve the renal function.
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Affiliation(s)
- Seohee Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sangjin Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Gül-Klein S, Kästner A, Haber PK, Krenzien F, Wabitsch S, Krannich A, Andreou A, Eurich D, Tacke F, Horst D, Pratschke J, Schmelzle M. Recurrence of Hepatocellular Carcinoma After Liver Transplantation is Associated with Episodes of Acute Rejections. J Hepatocell Carcinoma 2021; 8:133-143. [PMID: 33777855 PMCID: PMC7987264 DOI: 10.2147/jhc.s292010] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/21/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose The impact of acute rejection (AR) after liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient outcome is uncertain. This aim of this study is to investigate whether AR is associated with HCC relapse and overall survival. Patients and Methods Patients undergoing LT for HCC between 2001 and 2015 were retrospectively analyzed with regard to histopathological proven AR within the median time until recurrence. Cox’s regression analysis was conducted revealing risk factors for HCC recurrence. Results HCC recurred in 47 of 252 analyzed patients with a median time to recurrence of 20 months. Patients with AR (28.6%) had a significantly higher frequency of recurrence compared to patients without AR (13.0%, p=0.002). Multiple Cox regression analyses identified AR within 20 months to be an independent risk factor for HCC recurrence both as dichotomized (HR=2.91, 95%CI: 1.30–6.53; p=0.009) and as a continuous variable (HR=1.81, 95%CI: 1.28–2.54; p=0.001). HCC recurrence and AR were associated with higher grades of liver fibrosis one year after LT, when compared to patients without AR (p=0.019). Conclusion Our results demonstrate an association of AR with HCC recurrence after LT with implications for intervals of monitoring in tumor surveillance. Graft fibrosis and immune mechanisms are potentially related and causal interactions are worth further investigation.
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Affiliation(s)
- Safak Gül-Klein
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Anika Kästner
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Philipp Konstantin Haber
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Wabitsch
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Alexander Krannich
- Clinical Study Center, Clinical Trial Office, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Andreou
- Division of Acute Care Surgery, Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Dennis Eurich
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology/Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - David Horst
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Ma L, Li M, Zhang T, Xu JQ, Cao XB, Wu SS, Sun LY. Incidence of de novo autoimmune hepatitis in children and adolescents with increased autoantibodies after liver transplantation: a meta-analysis. Transpl Int 2021; 34:412-422. [PMID: 33316839 DOI: 10.1111/tri.13801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/21/2020] [Accepted: 12/09/2020] [Indexed: 11/29/2022]
Abstract
The objective of this meta-analysis was to assess the incidence of de novo autoimmune hepatitis (AIH) in children and adolescents with increased autoantibodies after liver transplantation. We systematically retrieved studies from PubMed, Embase, Central, CNKI, VIP and Wanfang published before February 1, 2020. All analyses were conducted using R-4.0.1 statistical package (Meta). Seven studies with high quality were pooled in our final analysis (N = 251 participants). The incidence of de novo AIH was 9% [95% confidence interval (CI) 1-23%, I2 = 86%]. Subgroup analysis suggested that publications not using the International Autoimmune Hepatitis Group (IAIHG) criteria have marginally significantly higher incidence of de novo AIH than those using IAIHG criteria (P for interaction = 0.08). The incidence of chronic rejection was 8% (95% CI 2-17%, I2 = 72%). Meta-regression indicated significant correlation (P = 0.04; estimate: 1.51) between the incidence of de novo AIH and the rate of increase of antibodies to liver/kidney microsome (anti-LKM). It is still challenging to distinguish de novo AIH and chronic rejection in children and adolescents with increased autoantibodies after liver transplantation. The diagnostic criteria for de novo AIH in children and adolescents and the role of anti-LKM in the development of de novo AIH deserve future investigation.
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Affiliation(s)
- Lin Ma
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China.,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ming Li
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China.,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ting Zhang
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China.,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jia-Qi Xu
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China.,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xue-Bin Cao
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China.,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shan-Shan Wu
- National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Li-Ying Sun
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China.,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Navez J, Iesari S, Kourta D, Baami-Mariza K, Nadiri M, Goffette P, Baldin P, Ackenine K, Bonaccorsi-Riani E, Ciccarelli O, Coubeau L, Moreels T, Lerut J. The real incidence of biliary tract complications after adult liver transplantation: the role of the prospective routine use of cholangiography during post-transplant follow-up. Transpl Int 2021; 34:245-258. [PMID: 33188645 DOI: 10.1111/tri.13786] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/13/2020] [Accepted: 11/10/2020] [Indexed: 12/20/2022]
Abstract
Biliary tract complications (BTCs) still burden liver transplantation (LT). The wide reporting variability highlights the absence of systematic screening. From 2000 to 2009, simultaneous liver biopsy and direct biliary visualization were prospectively performed in 242 recipients at 3 and 6 months (n = 212, 87.6%) or earlier when indicated (n = 30, 12.4%). Median follow-up was 148 (107-182) months. Seven patients (2.9%) experienced postprocedural morbidity. BTCs were initially diagnosed in 76 (31.4%) patients; 32 (42.1%) had neither clinical nor biological abnormalities. Acute cellular rejection (ACR) was present in 27 (11.2%) patients and in 6 (22.2%) BTC patients. Nine (3.7%) patients with normal initial cholangiography developed BTCs after 60 (30-135) months post-LT. BTCs directly lead to 7 (2.9%) re-transplantations and 14 (5.8%) deaths resulting in 18 (7.4%) allograft losses. Bile duct proliferation at 12-month biopsy proved an independent risk factor for graft loss (P = 0.005). Systematic biliary tract and allograft evaluation allows the incidence and extent of biliary lesions to be documented more precisely and to avoid erroneous treatment of ACR. The combination 'abnormal biliary tract-canalicular proliferation' is an indicator of worse graft outcome. BTCs are responsible for important delayed allograft and patient losses. These results underline the importance of life-long follow-up and appropriate timing for re-transplantation.
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Affiliation(s)
- Julie Navez
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
- Medico-Surgical Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Samuele Iesari
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
- Pôle de Chirurgie Expérimentale et Transplantation, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Dhoha Kourta
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Kente Baami-Mariza
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Marwan Nadiri
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Pierre Goffette
- Interventional Radiology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Pamela Baldin
- Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Kevin Ackenine
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Eliano Bonaccorsi-Riani
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
- Pôle de Chirurgie Expérimentale et Transplantation, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Olga Ciccarelli
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Laurent Coubeau
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Tom Moreels
- Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Jan Lerut
- Pôle de Chirurgie Expérimentale et Transplantation, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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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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40
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Harrington CR, Yang GY, Levitsky J. Advances in Rejection Management: Prevention and Treatment. Clin Liver Dis 2021; 25:53-72. [PMID: 33978583 DOI: 10.1016/j.cld.2020.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Extended survival of liver transplant recipients has brought rejection management to the forefront of liver transplant research. This article discusses T-cell-mediated rejection, antibody-mediated rejection, and chronic rejection. We focus on the prevention and then discuss treatment options. Future directions of rejection management include biomarkers of rejection, which may allow for monitoring of patients who are considered high risk for rejection and detection of rejection before there is any clinical evidence to improve graft and patient survival. With improved graft life and survival of liver transplant recipients, the new frontier of rejection management focuses on immunosuppression minimization, withdrawal, and personalization.
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Affiliation(s)
- Claire R Harrington
- Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 2330, Chicago, IL 60611, USA
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, 251 E Huron St. Chicago, IL 60611, USA
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1400, Chicago, IL 60611, USA; Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1900, Chicago, IL 60611, USA.
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41
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Abdelsameea E, Alsebaey A, Ehsan N, Elrefaey A, Aboelela K, Ibrahim ES, Elsabaawy M. Liver biopsy is still needed in liver transplantation recipients: a single center experience. EGYPTIAN LIVER JOURNAL 2020; 10:18. [DOI: 10.1186/s43066-020-00031-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 03/19/2020] [Indexed: 02/08/2023] Open
Abstract
Abstract
Background
Liver transplantation is a final treatment for decompensated liver disease.
Aim
Description of post-liver transplant histopathology. We enrolled 89 patients divided into two groups according to if they underwent on demand liver biopsy (n = 34; 38.2%) or not (n = 55; 61.8%). Albumin-bilirubin (ALBI) score and model for end-stage liver disease (MELD) assessed the degree of liver dysfunction.
Results
Patient underwent liver biopsy (LB) was 44.65 ± 8.46 years old, mainly males (88.2%) with average MELD of 8.74 ± 4.71. Most patients were positive pre-transplant for HCV (91.2%) and 29.4% had hepatocellular carcinoma on top of hepatitis C. Patients underwent LB had worse liver dysfunction by ALBI score (− 2.62 ± 0.6 vs. − 2.96 ± 0.5; p = 0.014) but comparable MELD. The time till first biopsy was 19.88 ± 11.22 (4-44) months. It was not different statistically with various histopathology (p > 0.05). Histopathology of first biopsy was viral chronic hepatitis (50%), acute rejection (20.6%), steatohepatitis (11.8%), chronic rejection (5.9%), chronic hepatitis (5.9%), biliary obstruction (2.9%), and cytomegalovirus hepatitis (2.9%). Most patients were F1 (38.2%) and A1 (35.3%). The immunosuppressive drug regimen had no impact on the histopathology (p > 0.05). Patients with hepatitis C pre-transplant had in a descending manner the following histological diagnosis (p = 0.001): viral chronic hepatitis 16 (51.6%), acute rejection 7 (22.6%), steatohepatitis 4 (12.9%), chronic rejection 2 (6.5%), biliary obstruction 1 (3.2%), and CMV hepatitis 1(3.2%). Some patients required on demand second (n = 9) and third biopsied (n = 5) that were the same as the first biopsy or completely different.
Conclusion
Liver biopsy is a useful tool for diagnosis of liver transplantation complications.
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Abstract
INTRODUCTION Liver transplantation is a life-changing event for patients and survival following transplantation has improved significantly since the first transplantation in 1967. Following liver transplantation, patients face a unique set of healthcare management decisions including transplantation-specific complications, recurrence of primary liver disease, as well as metabolic and malignancy concerns related to immunosuppression. As more patients with liver disease receive transplantation and live longer, understanding and managing these patients will require not only transplant specialist but also local subspecialist and primary care physicians. AREAS COVERED This review covers common issues related to the management of patients following liver transplantation including immunosuppression, liver allograft dysfunction, metabolic complications, as well as routine health maintenance such as immunizations and cancer screening. EXPERT OPINION Optimizing medical care for patients following liver transplant will benefit from ensuring all providers, not just transplant specialist, have a basic understanding of the common issues encountered in the post-transplant patient. This review provides an overview of common healthcare concerns and management options for patients following liver transplantation.
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Affiliation(s)
- Nicholas Hoppmann
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham , Birmingham, Alabama, USA
| | - Omar Massoud
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham , Birmingham, Alabama, USA
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Ronca V, Wootton G, Milani C, Cain O. The Immunological Basis of Liver Allograft Rejection. Front Immunol 2020; 11:2155. [PMID: 32983177 PMCID: PMC7492390 DOI: 10.3389/fimmu.2020.02155] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/07/2020] [Indexed: 12/15/2022] Open
Abstract
Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy.,National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Grace Wootton
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | - Owen Cain
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 543] [Impact Index Per Article: 108.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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Nakanuma S, Tajima H, Takamura H, Sakai S, Gabata R, Okazaki M, Shinbashi H, Ohbatake Y, Makino I, Hayashi H, Miyashita T, Fushida S, Ohta T. Pretreatment with a Phosphodiesterase-3 Inhibitor, Milrinone, Reduces Hepatic Ischemia-Reperfusion Injury, Minimizing Pericentral Zone-Based Liver and Small Intestinal Injury in Rats. Ann Transplant 2020; 25:e922306. [PMID: 32661218 PMCID: PMC7380127 DOI: 10.12659/aot.922306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Severe pericentral zone (zone 3)-based liver injury (LI) may become intractable, with allograft dysfunction after liver transplantation. The phosphodiesterase-3 inhibitor, milrinone, has been reported to attenuate hepatic ischemia-reperfusion injury (IRI). This study clarified how hepatic IRI involved zone 3-based LI, in which zone milrinone was effective, and whether milrinone could improve small intestinal injury (SII) with hepatic IRI. MATERIAL AND METHODS Rats were divided into sham, ischemia-reperfusion (IR), or IR+milrinone groups (n=13 per group). Milrinone was administered intraportally via intrasplenic injection, and whole hepatic ischemia was induced for 30 min. Five hours after reperfusion, serum chemistry and histopathological findings were compared. Expression of CD34 for the detection of altered sinusoidal endothelium as sinusoidal capillarization and cleaved caspase-3 as an apoptosis marker were analyzed via immunohistochemistry. Survival rates were examined after 45 min of whole hepatic ischemia. RESULTS Serum aspartate aminotransferase and direct bilirubin levels were significantly decreased in the IR+milrinone group compared with those of the IR group. The degree of LI, sinusoidal capillarization and apoptosis at zone 3 in the IR group was significantly increased compared with those at the periportal zone (zone 1). These findings at zone 3 in the IR group were improved in the IR+milrinone group. SII with villus congestion and apoptosis in the IR group was significantly attenuated in the IR+milrinone group. The 7-day survival rate was significantly elevated in the IR+milrinone group as compared with that of the IR group. CONCLUSIONS A hepatic IRI model caused zone 3-based LI and SII, which were attenuated by intraportal administration of milrinone.
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Affiliation(s)
- Shinichi Nakanuma
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hidehiro Tajima
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroyuki Takamura
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Seisho Sakai
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Ryosuke Gabata
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Mitsuyoshi Okazaki
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroyuki Shinbashi
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yoshinao Ohbatake
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Isamu Makino
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hironori Hayashi
- Department of Surgery, Toyama Prefectural Central Hospital, Toyama City, Toyama, Japan
| | - Tomoharu Miyashita
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Sachio Fushida
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tetsuo Ohta
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
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46
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Hann A, Osei-Bordom DC, Neil DAH, Ronca V, Warner S, Perera MTPR. The Human Immune Response to Cadaveric and Living Donor Liver Allografts. Front Immunol 2020; 11:1227. [PMID: 32655558 PMCID: PMC7323572 DOI: 10.3389/fimmu.2020.01227] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
The liver is an important contributor to the human immune system and it plays a pivotal role in the creation of both immunoreactive and tolerogenic conditions. Liver transplantation provides the best chance of survival for both children and adults with liver failure or cancer. With current demand exceeding the number of transplantable livers from donors following brain death, improved knowledge, technical advances and the desire to prevent avoidable deaths has led to the transplantation of organs from living, ABO incompatible (ABOi), cardiac death donors and machine based organ preservation with acceptable results. The liver graft is the most well-tolerated, from an immunological perspective, of all solid organ transplants. Evidence suggests successful cessation of immunosuppression is possible in ~20–40% of liver transplant recipients without immune mediated graft injury, a state known as “operational tolerance.” An immunosuppression free future following liver transplantation is an ambitious but perhaps not unachievable goal. The initial immune response following transplantation is a sterile inflammatory process mediated by the innate system and the mechanisms relate to the preservation-reperfusion process. The severity of this injury is influenced by graft factors and can have significant consequences. There are minimal experimental studies that delineate the differences in the adaptive immune response to the various forms of liver allograft. Apart from ABOi transplants, antibody mediated hyperacute rejection is rare following liver transplant. T-cell mediated rejection is common following liver transplantation and its incidence does not differ between living or deceased donor grafts. Transplantation in the first year of life results in a higher rate of operational tolerance, possibly due to a bias toward Th2 cytokines (IL4, IL10) during this period. This review further describes the current understanding of the immunological response toward liver allografts and highlight the areas of this topic yet to be fully understood.
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Affiliation(s)
- Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | | | - Desley A H Neil
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Suz Warner
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
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47
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Takeda M, Sakamoto S, Irie R, Uchida H, Shimizu S, Yanagi Y, Abdelwahed MS, Fukuda A, Kasahara M. Late T cell-mediated rejection may contribute to poor outcomes in adolescents and young adults with liver transplantation. Pediatr Transplant 2020; 24:e13708. [PMID: 32333637 DOI: 10.1111/petr.13708] [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] [Received: 07/04/2019] [Revised: 01/31/2020] [Accepted: 03/10/2020] [Indexed: 12/23/2022]
Abstract
Although poor long-term graft survival in LT in AYA is recognized, detailed epidemiological data are still lacking. L-TCMR may have poor outcomes. This study aimed to provide a detailed, epidemiological assessment of the association between AYA age and rejection. L-TCMR was defined in this study as TCMR with central vein or perivenular inflammation occurring later than 3 months after LT. A total of 342 patients who survived for at least 3 months after LT between 2005 and 2015 were enrolled. The AYA group (10-24 years) was compared with the C group (less than 10 years), and the incidence and outcomes of L-TCMR were analyzed. In total, 342 patients had LT; 38 of these were AYA with the mean follow-up period of 6.7 years. A total of 304 patients in C group had a mean follow-up period of 6.3 years (P = .28). The incidence of L-TCMR in AYA group was significantly higher than in C group (15.8% vs 4.6%, P = .006). The time to L-TCMR after LT was significantly shorter in AYA group (P = .01). Neither patient survival nor the incidence of non-adherence differed significantly between the groups (P = .18 and P = .89). The number of additional immunosuppressants after L-TCMR was significantly higher in the AYA group (P = .04). A high incidence of L-TCMR was observed in AYA group irrespective of non-adherence. AYA patients with L-TCMR should be followed carefully due to the poor results of post-treatment biopsy and the need for intensive immunosuppressive therapy.
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Affiliation(s)
- Masahiro Takeda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Rie Irie
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Hajime Uchida
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seiichi Shimizu
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Yusuke Yanagi
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mohamed Sami Abdelwahed
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Akinari Fukuda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
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48
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Fels Elliott DR, Tavakol M, Lucas CH, Sheahon K, Kakar S, Hameed B, Ferrell LD, Gill RM. Clinicopathological features and outcomes of parenchymal rejection in liver transplant biopsies. Histopathology 2020; 76:822-831. [PMID: 31894595 DOI: 10.1111/his.14058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 11/26/2019] [Accepted: 12/30/2019] [Indexed: 11/27/2022]
Abstract
AIMS The aim of this study was to perform a comprehensive retrospective analysis of liver transplant biopsies with parenchymal rejection (PR) at our institution, including histological features, laboratory values and follow-up biopsies, and to compare PR with portal-based acute cellular rejection (ACR). METHODS AND RESULTS Biopsies from 173 patients were evaluated (retrospective database search 1990-2017), including 49 isolated PR, 35 PR with portal ACR (PR/ACR), 34 mild ACR and 52 moderate ACR cases. The rise and fall of serum liver enzymes was calculated as a measure of acute liver injury and response to immunotherapy, respectively. Isolated PR was associated with delayed-onset acute rejection (P < 0.001), as well as younger age (P = 0.004), and showed a similar rise in liver enzymes to mild ACR. PR/ACR and moderate ACR showed the highest elevations in transaminases (P < 0.05). Isolated PR on an initial biopsy was associated with recurrent episodes of PR (P = 0.01), chronic ductopaenic rejection (P = 0.002) and chronic vascular rejection (P = 0.017). Immunohistochemistry for C4d was performed, and strong C4d staining of venules was only detected in one severe isolated PR case (one of three, 33%) and one moderate ACR case (one of 20, 5%). CONCLUSIONS Isolated PR represents a form of late acute rejection with distinct clinical and histological features. There is value in reporting PR in liver transplant biopsies to identify patients at higher risk of developing recurrent PR and chronic rejection. Standardisation of terminology and histological criteria of PR can help in uniform reporting and ensure appropriate management.
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Affiliation(s)
| | - Mehdi Tavakol
- Division of Transplant Surgery, University of California, San Francisco, CA, USA
| | - Calixto-Hope Lucas
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Kathleen Sheahon
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Sanjay Kakar
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Bilal Hameed
- Hepatology and Liver Transplantation, Department of Medicine, UCSF, San Francisco, CA, USA
| | - Linda D Ferrell
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Ryan M Gill
- Department of Pathology, University of California, San Francisco, CA, USA
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49
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Uchida H, Sakamoto S, Shimizu S, Takeda M, Yanagi Y, Fukuda A, Uchiyama T, Irie R, Kasahara M. Efficacy of Antithymocyte Globulin Treatment for Severe Centrilobular Injury Following Pediatric Liver Transplant: Clinical Significance of Monitoring Lymphocyte Subset. EXP CLIN TRANSPLANT 2020; 18:325-333. [PMID: 32281527 DOI: 10.6002/ect.2019.0387] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Central perivenulitis can occur in association with T-cell-mediated rejection and can sometimes require strong immunosuppressant therapy as refractory rejection. Furthermore, patients with central perivenulitis are more likely to have subsequent episodes of T-cell-mediated rejection and develop chronic rejection than those without central perivenulitis. We retrospectively analyzed clinical data of pediatric patients with episodes of T-cell-mediated rejection according to severity of central perivenulitis and monitored HLA-DR-positive CD8-positive T cells and recent thymic emigrants during treatment for T-cell-mediated rejection. MATERIALS AND METHODS We identified biopsy-proven T-cell-mediated rejection in 50 liver transplant recipients (45 with living-related donors, 5 with deceased donors) between September 2014 and August 2018. Lymphocyte subsets in peripheral blood samples were analyzed. RESULTS Of 50 pediatric patients, 30 were boys and 20 were girls (median age at transplant of 1.1 y; interquartile range, 0.6-6.2 y). Central perivenulitis was found in 46 patients (92%), which was mild in 13, moderate in 16, and severe in 17. Antithymocyte globulin was more frequently administered to patients with severe central perivenulitis than others (P < .05). Patients with antithymocyte globulin treatment were less likely to have subsequent episodes of T-cell-mediated rejection than those without this treatment (P < .05). The absolute number of CD8-positive HLA-DR-positive T cells in patients during treatment was significantly higher than in control patients (P < .05). The absolute number of recent thymic emigrants in patients with active infection was significantly lower than in patients without infection (P < .05). CONCLUSIONS Our results suggest the efficacy and safety of antithymocyte globulin for treating T-cell-mediated rejection with severe central perivenulitis in pediatric liver transplant recipients and suggest that antithymocyte globulin can prevent subsequent episodes of T-cell-mediated rejection. Analyzing lymphocyte subsets during treatment for rejection may help highlight viable therapeutic strategies for achieving a good outcome.
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Affiliation(s)
- Hajime Uchida
- From the Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
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50
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Yamashiki N, Haga H, Ueda Y, Ito T, Yagi S, Kamo N, Hata K, Mori A, Kaido T, Okajima H, Uemoto S. Use of Nakanuma staging and cytokeratin 7 staining for diagnosing recurrent primary biliary cholangitis after living-donor liver transplantation. Hepatol Res 2020; 50:478-487. [PMID: 31851426 DOI: 10.1111/hepr.13476] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/12/2019] [Accepted: 12/09/2019] [Indexed: 02/08/2023]
Abstract
AIM Diagnosis of primary biliary cholangitis (PBC), which recurs in approximately 30% of liver transplant recipients, is histology-based, but no staging system has been established for recurrent PBC (rPBC). We used the Nakanuma staging system and cytokeratin 7 (CK7) staining to examine post-transplant liver biopsy specimens retrospectively and to evaluate histological features of rPBC. METHODS From 107 patients who underwent living donor liver transplantation for PBC, 60 recipients with 214 liver biopsies after 1-year post transplant were enrolled. Fibrosis, bile duct loss (BL), cholangitis activity, hepatitis activity, and CK7-positive hepatocytes were scored. Nakanuma staging was based on fibrosis and BL scores. We examined the correlation of scores and clinicolaboratory data among rPBC patients. We also evaluated whether chronological change of stage was correlated with liver-related failure. RESULTS Of 214 biopsies, 52 were protocol biopsy; 162 were episodic. Higher BL, cholangitis activity, and hepatitis activity scores were associated with rPBC diagnosis. At median follow up of 10.0 years (range 1.4-18.7 years), 29 (48%) patients were diagnosed with rPBC at 4.6 years (range 1.3-14.5 years). Liver-related failure occurred in five rPBC cases; three from rPBC, and two from chronic rejection. At rPBC diagnosis, higher BL and CK7 scores were more frequent in patients who developed liver-related failure than in other patients (P = 0.04, P < 0.01, respectively). In failure patients, the Nakanuma stage increased over time, and reached up to stage 4, whereas the Scheuer stage did not reach above stage 3. CONCLUSIONS Nakanuma staging is associated with rPBC and disease progression. Scores for BL and CK7 might be early markers for progressive rPBC.
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Affiliation(s)
- Noriyo Yamashiki
- Organ Transplantation Unit, Kyoto University Hospital, Kyoto, Japan.,Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata City, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihide Ueda
- Organ Transplantation Unit, Kyoto University Hospital, Kyoto, Japan.,Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Ito
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shintaro Yagi
- Organ Transplantation Unit, Kyoto University Hospital, Kyoto, Japan.,Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naoko Kamo
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akira Mori
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimi Kaido
- Organ Transplantation Unit, Kyoto University Hospital, Kyoto, Japan.,Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideaki Okajima
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Organ Transplantation Unit, Kyoto University Hospital, Kyoto, Japan.,Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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