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1
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Shi D. Application of extended criteria donor liver grafts in liver transplantation. Hepatobiliary Pancreat Dis Int 2025:S1499-3872(25)00025-6. [PMID: 39855994 DOI: 10.1016/j.hbpd.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/29/2024] [Indexed: 01/27/2025]
Affiliation(s)
- Dan Shi
- Department of Child Health Care, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
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2
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Abbas SH, Ceresa CDL, Pollok JM. Steatotic Donor Transplant Livers: Preservation Strategies to Mitigate against Ischaemia-Reperfusion Injury. Int J Mol Sci 2024; 25:4648. [PMID: 38731866 PMCID: PMC11083584 DOI: 10.3390/ijms25094648] [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: 03/12/2024] [Revised: 04/21/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Liver transplantation (LT) is the only definitive treatment for end-stage liver disease, yet the UK has seen a 400% increase in liver disease-related deaths since 1970, constrained further by a critical shortage of donor organs. This shortfall has necessitated the use of extended criteria donor organs, including those with evidence of steatosis. The impact of hepatic steatosis (HS) on graft viability remains a concern, particularly for donor livers with moderate to severe steatosis which are highly sensitive to the process of ischaemia-reperfusion injury (IRI) and static cold storage (SCS) leading to poor post-transplantation outcomes. This review explores the pathophysiological predisposition of steatotic livers to IRI, the limitations of SCS, and alternative preservation strategies, including novel organ preservation solutions (OPS) and normothermic machine perfusion (NMP), to mitigate IRI and improve outcomes for steatotic donor livers. By addressing these challenges, the liver transplant community can enhance the utilisation of steatotic donor livers which is crucial in the context of the global obesity crisis and the growing need to expand the donor pool.
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Affiliation(s)
- Syed Hussain Abbas
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX1 2JD, UK;
| | - Carlo Domenico Lorenzo Ceresa
- Department of Hepatopancreatobiliary and Liver Transplant Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK;
| | - Joerg-Matthias Pollok
- Department of Hepatopancreatobiliary and Liver Transplant Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK;
- Division of Surgery & Interventional Science, University College London, Gower Street, London WC1E 6BT, UK
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3
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Kim DS, Yoon YI, Kim BK, Choudhury A, Kulkarni A, Park JY, Kim J, Sinn DH, Joo DJ, Choi Y, Lee JH, Choi HJ, Yoon KT, Yim SY, Park CS, Kim DG, Lee HW, Choi WM, Chon YE, Kang WH, Rhu J, Lee JG, Cho Y, Sung PS, Lee HA, Kim JH, Bae SH, Yang JM, Suh KS, Al Mahtab M, Tan SS, Abbas Z, Shresta A, Alam S, Arora A, Kumar A, Rathi P, Bhavani R, Panackel C, Lee KC, Li J, Yu ML, George J, Tanwandee T, Hsieh SY, Yong CC, Rela M, Lin HC, Omata M, Sarin SK. Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation. Hepatol Int 2024; 18:299-383. [PMID: 38416312 DOI: 10.1007/s12072-023-10629-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/18/2023] [Indexed: 02/29/2024]
Abstract
Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.
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Affiliation(s)
- Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jongman Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, Republic of Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Cheon-Soo Park
- Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Deok-Gie Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Woo-Hyoung Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsan, Republic of Korea
| | - Pil Soo Sung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Soek Siam Tan
- Department of Medicine, Hospital Selayang, Batu Caves, Selangor, Malaysia
| | - Zaigham Abbas
- Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ananta Shresta
- Department of Hepatology, Alka Hospital, Lalitpur, Nepal
| | - Shahinul Alam
- Crescent Gastroliver and General Hospital, Dhaka, Bangladesh
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Pravin Rathi
- TN Medical College and BYL Nair Hospital, Mumbai, India
| | - Ruveena Bhavani
- University of Malaya Medical Centre, Petaling Jaya, Selangor, Malaysia
| | | | - Kuei Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jun Li
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Ming-Lung Yu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | | | | | | | | | - H C Lin
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Bunkyo City, Japan
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4
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Pagano G, Fundora Y, Crespo G. Outcomes using steatotic liver grafts: Will machines score the final goal? Liver Transpl 2024; 30:341-342. [PMID: 38009946 DOI: 10.1097/lvt.0000000000000309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023]
Affiliation(s)
- Giulia Pagano
- Department of Hepatology, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Spain
- Liver Transplant Unit,Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Spain
| | - Yilliam Fundora
- Liver Transplant Unit,Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Spain
- Department of Hepatobiliary Surgery, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Spain
| | - Gonzalo Crespo
- Department of Hepatology, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Spain
- Liver Transplant Unit,Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Spain
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Akabane M, Imaoka Y, Esquivel CO, Melcher ML, Kwong A, Sasaki K. Overcoming the hurdles of steatotic grafts in liver transplantation: Insights into survival and prognostic factors. Liver Transpl 2024; 30:376-385. [PMID: 37616509 DOI: 10.1097/lvt.0000000000000245] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 08/08/2023] [Indexed: 08/26/2023]
Abstract
With increasing metabolic dysfunction-associated steatotic liver disease, the use of steatotic grafts in liver transplantation (LT) and their impact on postoperative graft survival (GS) needs further exploration. Analyzing adult LT recipient data (2002-2022) from the United Network for Organ Sharing database, outcomes of LT using steatotic (≥30% macrosteatosis) and nonsteatotic donor livers, donors after circulatory death, and standard-risk older donors (age 45-50) were compared. GS predictors were evaluated using Kaplan-Meier and Cox regression analyses. Of the 35,345 LT donors, 8.9% (3,155) were fatty livers. The initial 30-day postoperative period revealed significant challenges with fatty livers, demonstrating inferior GS. However, the GS discrepancy between fatty and nonfatty livers subsided over time ( p = 0.10 at 5 y). Long-term GS outcomes showed comparable or even superior results in fatty livers relative to nonsteatotic livers, conditional on surviving the initial 90 postoperative days ( p = 0.90 at 1 y) or 1 year ( p = 0.03 at 5 y). In the multivariable Cox regression analysis, the high body surface area (BSA) ratio (≥1.1) (HR 1.42, p = 0.02), calculated as donor BSA divided by recipient BSA, long cold ischemic time (≥6.5 h) (HR 1.72, p < 0.01), and recipient medical condition (intensive care unit hospitalization) (HR 2.53, p < 0.01) emerged as significant adverse prognostic factors. Young (<40 y) fatty donors showed a high BSA ratio, diabetes, and intensive care unit hospitalization as significant indicators of a worse prognosis ( p < 0.01). Our study emphasizes the initial postoperative 30-day survival challenge in LT using fatty livers. However, with careful donor-recipient matching, for example, avoiding the use of steatotic donors with long cold ischemic time and high BSA ratios for recipients in the intensive care unit, it is possible to enhance immediate GS, and in a longer time, outcomes comparable to those using nonfatty livers, donors after circulatory death livers, or standard-risk older donors can be anticipated. These novel insights into decision-making criteria for steatotic liver use provide invaluable guidance for clinicians.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, Division of Abdominal Transplant, Stanford University Medical Center, Stanford, California, USA
| | - Yuki Imaoka
- Department of Surgery, Division of Abdominal Transplant, Stanford University Medical Center, Stanford, California, USA
| | - Carlos O Esquivel
- Department of Surgery, Division of Abdominal Transplant, Stanford University Medical Center, Stanford, California, USA
| | - Marc L Melcher
- Department of Surgery, Division of Abdominal Transplant, Stanford University Medical Center, Stanford, California, USA
| | - Allison Kwong
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California, USA
| | - Kazunari Sasaki
- Department of Surgery, Division of Abdominal Transplant, Stanford University Medical Center, Stanford, California, USA
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6
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Kikuchi AT, Akanuma N, Choi WT, Gill RM, Kakar S. Assessment of large droplet fat in frozen sections of donor liver biopsies: utility and interobserver variability of the newly described Banff method compared to a simplified Average of Fields method. J Clin Pathol 2024; 77:151-156. [PMID: 38053274 DOI: 10.1136/jcp-2023-209237] [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: 10/13/2023] [Accepted: 11/09/2023] [Indexed: 12/07/2023]
Abstract
AIMS There is great variability in the assessment and reporting of fat in frozen sections of donor liver biopsies. The Banff Working Group has proposed a novel method and definition for scoring large droplet fat (LDF) in donor liver biopsies. This study compares the Banff method with a simpler Average of Fields (AF) method and evaluates the impact of different LDF definitions. METHODS Three pathologists assessed percentage of LDF (LDF%) in 10 donor liver biopsies using Banff and AF methods, applying the Banff LDF definition (cell distention with a single droplet larger than adjacent hepatocytes). Additionally, LDF% by the AF method was compared using two LDF definitions: Banff definition versus LDF definition 2 (single fat droplet occupying greater than half of a hepatocyte with nuclear displacement). RESULTS Intraobserver concordance between the Banff and AF methods was similar for all three pathologists (kappa 0.76-1). Both methods exhibited 70% interobserver concordance, and there was substantial agreement (kappa 0.68) in the LDF% among the three pathologists for both methods. Comparing the two LDF definitions, results were significantly lower with the Banff definition; LDF >50% was observed in four cases with LDF definition 2 but none of the cases with the Banff definition. CONCLUSIONS There is high interobserver and intraobserver concordance of LDF% between the Banff and AF methods. LDF% determined by the Banff definition was lower than with LDF definition 2, and needs to be validated based on graft outcome before it can be recommended for clinical use.
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Affiliation(s)
- Alexander T Kikuchi
- Pathology, University of California San Francisco, San Francisco, California, USA
- Pathology, University of Utah Health, Salt Lake City, Utah, USA
| | - Naoki Akanuma
- Pathology, University of California San Francisco, San Francisco, California, USA
| | - Won-Tak Choi
- Pathology, University of California San Francisco, San Francisco, California, USA
| | - Ryan M Gill
- Pathology, University of California San Francisco, San Francisco, California, USA
| | - Sanjay Kakar
- Pathology, University of California San Francisco, San Francisco, California, USA
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7
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Zhang X, Dutton M, Liu R, Ali AA, Sherbeny F. Deep Learning-Based Survival Analysis for Receiving a Steatotic Donor Liver Versus Waiting for a Standard Liver. Transplant Proc 2023; 55:2436-2443. [PMID: 37872066 DOI: 10.1016/j.transproceed.2023.09.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 08/12/2023] [Accepted: 09/22/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND An emerging strategy to expand the donor pool is the use of a steatotic donor liver (SDLs; ≥ 30% macrosteatosis on biopsy). With the obesity epidemic and prevalence of nonalcoholic fatty liver disease, SDLs have been reported in 59% of all deceased donors. Many potential candidates need to decide whether to accept an SDL offer or remain on the waitlist for a nonsteatotic donor liver (non-SDL). The objective of this study was to compare the survival of accepting an SDL vs using a non-SDL after waiting various times. METHODS Using data from the United States' organ procurement and transplantation network, deep survival learning predictive models were built to compare post-decision survival after accepting an SDL vs waiting for a non-SDL. The comparison subjects contain simulated 20,000 different scenarios of a candidate either accepting an SDL immediately or receiving a non-SDL after waiting various times. The research variables were selected using the LASSO-Cox and Random Survival Forest (RSF) models. The Cox proportional hazards and RSF models were also comparatively included for survival prediction. In addition, personalized survival curves for randomly selected candidates were generated. RESULT Deep survival learning outperformed Cox proportional hazards and RSF in predicting the survival of liver transplants. Among the simulations, 25% to 30% of scenarios demonstrated a higher 3-year survival post-decision for candidates accepting an SDL than waiting and receiving a non-SDL. The difference was only 1.43% in 3-year survival post-decision between accepting an SDL and waiting 260 days (mean waitlist time) for a non-SDL. As the number of days on the waitlist increases, the difference in survival between accepting SDLs and waiting for non-SDLs decreases. CONCLUSIONS Appropriately used SDLs could expand the donor pool and relieve the candidates' unmet need for donor livers, which presents long-term survival benefits for recipients.
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Affiliation(s)
- Xiao Zhang
- Economic, Social and Administrative Pharmacy, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida.
| | - Matthew Dutton
- Economic, Social and Administrative Pharmacy, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida
| | - Rongjie Liu
- Department of Statistics, Florida State University, Tallahassee, Florida
| | - Askal A Ali
- Economic, Social and Administrative Pharmacy, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida
| | - Fatimah Sherbeny
- Economic, Social and Administrative Pharmacy, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida
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8
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Takemura Y, Shinoda M, Hasegawa Y, Yamada Y, Obara H, Kitago M, Kasahara M, Umeshita K, Eguchi S, Kitagawa Y, Ohdan H, Egawa H. Japanese national survey on declined liver allografts from brain-dead donors: High decline rate but promising outcomes in allografts with moderate steatosis. Ann Gastroenterol Surg 2023; 7:654-665. [PMID: 37416736 PMCID: PMC10319622 DOI: 10.1002/ags3.12661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 01/04/2023] [Accepted: 01/20/2023] [Indexed: 07/08/2023] Open
Abstract
Aim Liver allografts from brain-dead donors, which were declined and were eventually not transplanted due to accompanying marginal factors, have never been surveyed in Japan. We surveyed the declined allografts and discussed the graft potential focusing on various marginal factors. Methods We collected data on brain-dead donors between 1999 and 2019 from the Japan Organ Transplant Network. We divided their liver allografts into declined (nontransplanted) and transplanted ones, and then characterized declined ones focusing on their timepoints of decline and accompanying marginal factors. For each marginal factor, we calculated the decline rate from the number of declined and transplanted allografts, and assessed the 1-year graft survival rate from transplanted allografts. Results A total of 571 liver allografts were divided into 84 (14.7%) declined and 487 (85.3%) transplanted ones. In the declined allografts, a majority was declined after laparotomy (n = 55, 65.5%), most of which had steatosis and/or fibrosis (n = 52). Out of the moderate steatotic (without F ≥ 2 fibrosis) allografts (n = 33), 21 were declined and 12 were transplanted, leading to a 63.6% decline rate. The latter 12 achieved a 92.9% 1-year graft survival rate after transplantation. Comparison of donor background showed no significant difference between the declined and transplanted allografts. Conclusion Pathological abnormalities of steatosis/fibrosis seem to be the most common donor factor leading to graft decline in Japan. Allografts with moderate steatosis were highly declined; however, transplanted ones achieved promising outcomes. This national survey highlights the potential utility of liver allografts with moderate steatosis.
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Affiliation(s)
- Yusuke Takemura
- Department of SurgeryKeio University School of MedicineTokyoJapan
| | - Masahiro Shinoda
- Digestive Disease CenterMita Hospital, International University of Health and WelfareTokyoJapan
| | - Yasushi Hasegawa
- Department of SurgeryKeio University School of MedicineTokyoJapan
| | - Yohei Yamada
- Department of SurgeryKeio University School of MedicineTokyoJapan
| | - Hideaki Obara
- Department of SurgeryKeio University School of MedicineTokyoJapan
| | - Minoru Kitago
- Department of SurgeryKeio University School of MedicineTokyoJapan
| | - Mureo Kasahara
- Organ Transplantation CenterNational Center for Child Health and DevelopmentTokyoJapan
| | - Koji Umeshita
- Department of SurgeryOsaka International Cancer InstituteOsakaJapan
- Division of Health ScienceOsaka University Graduate School of MedicineOsakaJapan
| | - Susumu Eguchi
- Department of SurgeryNagasaki University Graduate School of Biomedical ScienceNagasakiJapan
| | - Yuko Kitagawa
- Department of SurgeryKeio University School of MedicineTokyoJapan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant SurgeryHiroshima University Graduate School of Biomedical and Health SciencesHiroshimaJapan
| | - Hiroto Egawa
- Department of Surgery, Institute of GastroenterologyTokyo Women's Medical UniversityTokyoJapan
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9
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Patrono D, De Stefano N, Vissio E, Apostu AL, Petronio N, Vitelli G, Catalano G, Rizza G, Catalano S, Colli F, Chiusa L, Romagnoli R. How to Preserve Steatotic Liver Grafts for Transplantation. J Clin Med 2023; 12:3982. [PMID: 37373676 DOI: 10.3390/jcm12123982] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 06/05/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Liver allograft steatosis is a significant risk factor for postoperative graft dysfunction and has been associated with inferior patient and graft survival, particularly in the case of moderate or severe macrovesicular steatosis. In recent years, the increasing incidence of obesity and fatty liver disease in the population has led to a higher proportion of steatotic liver grafts being used for transplantation, making the optimization of their preservation an urgent necessity. This review discusses the mechanisms behind the increased susceptibility of fatty livers to ischemia-reperfusion injury and provides an overview of the available strategies to improve their utilization for transplantation, with a focus on preclinical and clinical evidence supporting donor interventions, novel preservation solutions, and machine perfusion techniques.
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Affiliation(s)
- Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Nicola De Stefano
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Elena Vissio
- Department of Pathology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Ana Lavinia Apostu
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Nicoletta Petronio
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Giovanni Vitelli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Giorgia Catalano
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Giorgia Rizza
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Silvia Catalano
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Fabio Colli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Luigi Chiusa
- Department of Pathology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
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10
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Guo H, Tikhomirov AB, Mitchell A, Alwayn IPJ, Zeng H, Hewitt KC. Real-time assessment of liver fat content using a filter-based Raman system operating under ambient light through lock-in amplification. BIOMEDICAL OPTICS EXPRESS 2022; 13:5231-5245. [PMID: 36425639 PMCID: PMC9664892 DOI: 10.1364/boe.467849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 06/16/2023]
Abstract
During liver procurement, surgeons mostly rely on their subjective visual inspection of the liver to assess the degree of fatty infiltration, for which misclassification is common. We developed a Raman system, which consists of a 1064 nm laser, a handheld probe, optical filters, photodiodes, and a lock-in amplifier for real-time assessment of liver fat contents. The system performs consistently in normal and strong ambient light, and the excitation incident light penetrates at least 1 mm into duck fat phantoms and duck liver samples. The signal intensity is linearly correlated with MRI-calibrated fat contents of the phantoms and the liver samples.
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Affiliation(s)
- Hao Guo
- Department of Physics and Atmospheric Science, Dalhousie University, 6310 Coburg Road, Halifax, NS B3H 4R2, Canada
- Department of Medical Physics, Nova Scotia Health Authority, 5820 University Avenue Halifax, NS B3H 1V7, Canada
| | - Alexey B. Tikhomirov
- Department of Physics and Atmospheric Science, Dalhousie University, 6310 Coburg Road, Halifax, NS B3H 4R2, Canada
| | - Alexandria Mitchell
- Department of Physics and Atmospheric Science, Dalhousie University, 6310 Coburg Road, Halifax, NS B3H 4R2, Canada
- Department of Medical Physics, Nova Scotia Health Authority, 5820 University Avenue Halifax, NS B3H 1V7, Canada
| | - Ian Patrick Joseph Alwayn
- Department of Surgery, Leiden University Medical Center (LUMC) Transplant Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Haishan Zeng
- Imaging Unit, Integrative Oncology Department, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada
| | - Kevin C. Hewitt
- Department of Physics and Atmospheric Science, Dalhousie University, 6310 Coburg Road, Halifax, NS B3H 4R2, Canada
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11
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Philosophe B, Noel Wesson R. High time for common ground in the assessment of steatosis. Liver Transpl 2022; 28:1427-1428. [PMID: 35596619 DOI: 10.1002/lt.26506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 05/13/2022] [Indexed: 01/13/2023]
Affiliation(s)
- Benjamin Philosophe
- Division of Transplant Surgery, Department of Surgery, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Russell Noel Wesson
- Division of Transplant Surgery, Department of Surgery, The Johns Hopkins University, Baltimore, Maryland, USA.,Division of Transplant Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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12
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A Novel Digital Algorithm for Identifying Liver Steatosis Using Smartphone-Captured Images. Transplant Direct 2022; 8:e1361. [PMID: 35935028 PMCID: PMC9355111 DOI: 10.1097/txd.0000000000001361] [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: 05/13/2022] [Revised: 06/17/2022] [Accepted: 06/27/2022] [Indexed: 11/26/2022] Open
Abstract
Access to lifesaving liver transplantation is limited by a severe organ shortage. One factor contributing to the shortage is the high rate of discard in livers with histologic steatosis. Livers with <30% macrosteatosis are generally considered safe for transplant. However, histologic assessment of steatosis by a pathologist remains subjective and is often limited by image quality. Here, we address this bottleneck by creating an automated digital algorithm for calculating histologic steatosis using only images of liver biopsy histology obtained with a smartphone.
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13
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Ghazaly M, Tiwari N, Sethi P, Surendrakumar V, Duckworth A. Use of Steatotic Donor Livers for Transplantation: Do They Affect Outcome? SURGICAL PRACTICE 2022. [DOI: 10.1111/1744-1633.12563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Mohamed Ghazaly
- Department of Transplant Surgery Addenbrookes Hospital Cambridge United Kingdom
- Department of Surgery Tanta University Tanta Gharbia Egypt
| | - Navneet Tiwari
- Department of Transplant Surgery Addenbrookes Hospital Cambridge United Kingdom
| | - Pulkit Sethi
- Department of Transplant Surgery Addenbrookes Hospital Cambridge United Kingdom
| | - Veena Surendrakumar
- Department of Transplant Surgery Addenbrookes Hospital Cambridge United Kingdom
| | - Adam Duckworth
- Department of Pathology Addenbrookes Hospital Cambridge United Kingdom
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14
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Danis N, Weeks SR, Kim A, Baghdadi A, Ghadimi M, Kamel IR, Saberi B, Woreta T, Garonzik-Wang J, Philosophe B, Gurakar A, Loomba R. Noninvasive Risk Stratification for Nonalcoholic Fatty Liver Disease Among Living Liver Donor Candidates: A Proposed Algorithm. Liver Transpl 2022; 28:670-677. [PMID: 34753223 PMCID: PMC9683539 DOI: 10.1002/lt.26365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 10/27/2021] [Accepted: 11/03/2021] [Indexed: 12/16/2022]
Abstract
To reduce waitlist mortality, living donor liver transplantation (LDLT) has increased over the past decade in the United States, but not at a rate sufficient to completely mitigate organ shortage. As a result, there are ongoing efforts to expand the living liver donor pool. Simultaneously, the prevalence of nonalcoholic fatty liver disease (NAFLD) in the general population has increased, which has significant implications on the pool of potential living liver donors. As such, a clinical assessment algorithm that exhaustively evaluates for NAFLD and fibrosis is critical to the safe expansion of LDLT. An ideal algorithm would employ safe and noninvasive methods, relying on liver biopsy only when necessary. While exclusion of NAFLD and fibrosis by noninvasive means is widely studied within the general population, there are no well-accepted guidelines for evaluation of living donors using these modalities. Here we review the current literature regarding noninvasive NALFD and fibrosis evaluation and propose a potential algorithm to apply these modalities for the selection of living liver donors.
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Affiliation(s)
- Nilay Danis
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sharon R. Weeks
- Division of Transplant Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ahyoung Kim
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Azarakhsh Baghdadi
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Maryam Ghadimi
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ihab R. Kamel
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Behnam Saberi
- Division of Gastroenterology and Hepatology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA
| | - Tinsay Woreta
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | - Benjamin Philosophe
- Division of Transplant Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA,Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA
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15
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A Clinical Tool to Guide Selection and Utilization of Marginal Donor Livers With Graft Steatosis in Liver Transplantation. Transplant Direct 2022; 8:e1280. [PMID: 35047662 PMCID: PMC8759620 DOI: 10.1097/txd.0000000000001280] [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: 06/16/2021] [Revised: 11/03/2021] [Accepted: 11/19/2021] [Indexed: 11/26/2022] Open
Abstract
Supplemental Digital Content is available in the text. Background. Donor liver biopsy (DLBx) in liver transplantation provides information on allograft quality; however, predicting outcomes from these allografts remains difficult. Methods. Between 2006 and 2015, 16 691 transplants with DLBx were identified from the Standard Transplant Analysis and Research database. Cox proportional hazard regression analyses identified donor and recipient characteristics associated with 30-d, 90-d, 1-y, and 3-y graft survival. A composite model, the Liver Transplant After Biopsy (LTAB) score, was created. The Mini-LTAB was then derived consisting of only donor age, macrosteatosis on DLBx, recipient model for end-stage liver disease score, and cold ischemic time. Risk groups were identified for each score and graft survival was evaluated. P values <0.05 were considered significant. Results. The LTAB model used 14 variables and 5 risk groups and identified low-, mild-, moderate-, high-, and severe-risk groups. Compared with moderate-risk recipients, severe-risk recipients had increased risk of graft loss at 30 d (hazard ratio, 3.270; 95% confidence interval, 2.568-4.120) and at 1 y (2.258; 1.928-2.544). The Mini-LTAB model identified low-, moderate-, and high-risk groups. Graft survival in Mini-LTAB high-risk transplants was significantly lower than moderate- or low-risk transplants at all time points. Conclusions. The LTAB and Mini-LTAB scores represent guiding principles and provide clinically useful tools for the successful selection and utilization of marginal allografts in liver transplantation.
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16
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An Update on Usage of High-Risk Donors in Liver Transplantation. J Clin Med 2021; 11:jcm11010215. [PMID: 35011956 PMCID: PMC8746244 DOI: 10.3390/jcm11010215] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/01/2021] [Accepted: 12/28/2021] [Indexed: 12/13/2022] Open
Abstract
The ideal management for end stage liver disease, acute liver failure, and hepatocellular carcinoma (HCC), within specific criteria, is liver transplantation (LT). Over the years, there has been a steady increase in the candidates listed for LT, without a corresponding increase in the donor pool. Therefore, due to organ shortage, it has been substantially difficult to reduce waitlist mortality among patients awaiting LT. Thus, marginal donors such as elderly donors, steatotic donors, split liver, and donors after cardiac death (DCD), which were once not commonly used, are now considered. Furthermore, it is encouraging to see the passing of Acts, such as the HIV Organ Policy Equity (HOPE) Act, enabling further research and development in utilizing HIV grafts. Subsequently, the newer antivirals have aided in successful post-transplant period, especially for hepatitis C positive grafts. However, currently, there is no standardization, and protocols are center specific in the usage of marginal donors. Therefore, studies with longer follow ups are required to standardize its use.
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17
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A proof of concept study on real-time LiMAx CYP1A2 liver function assessment of donor grafts during normothermic machine perfusion. Sci Rep 2021; 11:23444. [PMID: 34873187 PMCID: PMC8648778 DOI: 10.1038/s41598-021-02641-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 11/08/2021] [Indexed: 12/12/2022] Open
Abstract
No single reliable parameter exists to assess liver graft function of extended criteria donors during ex-vivo normothermic machine perfusion (NMP). The liver maximum capacity (LiMAx) test is a clinically validated cytochromal breath test, measuring liver function based on 13CO2 production. As an innovative concept, we aimed to integrate the LiMAx breath test with NMP to assess organ function. Eleven human livers were perfused using NMP. After one hour of stabilization, LiMAx testing was performed. Injury markers (ALT, AST, miR-122, FMN, and Suzuki-score) and lactate clearance were measured and related to LiMAx values. LiMAx values ranged between 111 and 1838 µg/kg/h, and performing consecutive LiMAx tests during longer NMP was feasible. No correlation was found between LiMAx value and miR-122 and FMN levels in the perfusate. However, a significant inverse correlation was found between LiMAx value and histological injury (Suzuki-score, R = − 0.874, P < 0.001), AST (R = − 0.812, P = 0.004) and ALT (R = − 0.687, P = 0.028). Furthermore, a significant correlation was found with lactate clearance (R = 0.683, P = 0.043). We demonstrate, as proof of principle, that liver function during NMP can be quantified using the LiMAx test, illustrating a positive correlation with traditional injury markers. This new breath-test application separates livers with adequate cytochromal liver function from inadequate ones and may support decision-making in the safe utilization of extended criteria donor grafts.
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18
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Li B, Chen PY, Tan YF, Huang H, Jiang M, Wu ZR, Jiang CH, Zheng DF, He D, Shi YJ, Luo Y, Yang JY. Standard liver weight model in adult deceased donors with fatty liver: A prospective cohort study. World J Gastroenterol 2021; 27:6701-6714. [PMID: 34754162 PMCID: PMC8554397 DOI: 10.3748/wjg.v27.i39.6701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/22/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Standard liver weight (SLW) is frequently used in deceased donor liver transplantation to avoid size mismatches with the recipient. However, some deceased donors (DDs) have fatty liver (FL). A few studies have reported that FL could impact liver size. To the best of our knowledge, there are no relevant SLW models for predicting liver size. AIM To demonstrate the relationship between FL and total liver weight (TLW) in detail and present a related SLW formula. METHODS We prospectively enrolled 212 adult DDs from West China Hospital of Sichuan University from June 2019 to February 2021, recorded their basic information, such as sex, age, body height (BH) and body weight (BW), and performed abdominal ultrasound (US) and pathological biopsy (PB). The chi-square test and kappa consistency score were used to assess the consistency in terms of FL diagnosed by US relative to PB. Simple linear regression analysis was used to explore the variables related to TLW. Multiple linear regression analysis was used to formulate SLW models, and the root mean standard error and interclass correlation coefficient were used to test the fitting efficiency and accuracy of the model, respectively. Furthermore, the optimal formula was compared with previous formulas. RESULTS Approximately 28.8% of DDs had FL. US had a high diagnostic ability (sensitivity and specificity were 86.2% and 92.9%, respectively; kappa value was 0.70, P < 0.001) for livers with more than a 5% fatty change. Simple linear regression analysis showed that sex (R2, 0.226; P < 0.001), BH (R2, 0.241; P < 0.001), BW (R2, 0.441; P < 0.001), BMI (R2, 0.224; P < 0.001), BSA (R2, 0.454; P < 0.001) and FL (R2, 0.130; P < 0.001) significantly impacted TLW. In addition, multiple linear regression analysis showed that there was no significant difference in liver weight between the DDs with no steatosis and those with steatosis within 5%. Furthermore, in the context of hepatic steatosis, TLW increased positively (non-linear); compared with the TLW of the non-FL group, the TLW of the groups with hepatic steatosis within 5%, between 5% and 20% and more than 20% increased by 0 g, 90 g, and 340 g, respectively. A novel formula, namely, -348.6 + (110.7 x Sex [0 = Female, 1 = Male]) + 958.0 x BSA + (179.8 x FLUS [0 = No, 1 = Yes]), where FL was diagnosed by US, was more convenient and accurate than any other formula for predicting SLW. CONCLUSION FL is positively correlated with TLW. The novel formula deduced using sex, BSA and FLUS is the optimal formula for predicting SLW in adult DDs.
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Affiliation(s)
- Bo Li
- Department of Liver Surgery, Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Pan-Yu Chen
- Operating Room, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi-Fei Tan
- Department of Liver Surgery, Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - He Huang
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Min Jiang
- Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zhen-Ru Wu
- Laboratory of Pathology, Key Laboratory of Transplant Immunology and Engineering, National Health Commission, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Chen-Hao Jiang
- Department of Liver Surgery, Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dao-Feng Zheng
- Department of Liver Surgery, Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Diao He
- Department of Liver Surgery, Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Jun Shi
- Laboratory of Pathology, Key Laboratory of Transplant Immunology and Engineering, National Health Commission, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Luo
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yin Yang
- Department of Liver Surgery, Liver Transplantation Centre, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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19
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Chen M, Chen Z, Lin X, Hong X, Ma Y, Huang C, He X, Ju W. Application of ischaemia-free liver transplantation improves prognosis of patients with steatotic donor livers - a retrospective study. Transpl Int 2021; 34:1261-1270. [PMID: 33484201 PMCID: PMC8361689 DOI: 10.1111/tri.13828] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/21/2020] [Accepted: 01/19/2021] [Indexed: 12/20/2022]
Abstract
The use of steatotic livers in liver transplantation (LT) is controversial. Ischaemia‐free liver transplantation (IFLT) has obvious advantages for the recovery of allograft function. The aim of this study was to examine the effect of liver grafts with steatosis on outcome and the effect of IFLT with steatotic livers. 360 patients with LT were enrolled in this study. Perioperative characteristics and differences in outcome among different grades of steatotic groups, and between the IFLT and conventional LT (CLT) groups were analysed. Occurrence of early allograft dysfunction (EAD; 50%) and primary nonfunction (PNF; 20%) was significantly higher in the severe steatosis group (P < 0.001 and <0.001, respectively). Survival rate is significantly low in severe steatosis group (3‐year: 60%, P = 0.0039). The IFLT group had a significantly lower occurrence of EAD than the CLT group (0% vs. 60%, P = 0.01). The level of postoperative peak AST, GGT and creatine were significantly lower in IFLT group (P = 0.009, 0.032 and 0.024, respectively). In multivariable analysis, IFLT and EAD were independent factors affecting postoperative survival. Severe steatotic livers lead to severe complications and poor outcomes in LT. IFLT has obvious advantages for reducing the rate of EAD in LT with steatotic livers.
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Affiliation(s)
- Maogen Chen
- Organ Transplant Center, First Affiliated Hospital of 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
| | - Zhitao Chen
- Organ Transplant Center, First Affiliated Hospital of 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
| | - Xiaohong Lin
- Division of General Surgery, The Eastern Hospital of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xitao Hong
- Organ Transplant Center, First Affiliated Hospital of 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
| | - Yihao Ma
- Organ Transplant Center, First Affiliated Hospital of 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
| | - Changjun Huang
- Organ Transplant Center, First Affiliated Hospital of 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
| | - Xiaoshun He
- Organ Transplant Center, First Affiliated Hospital of 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
| | - Weiqiang Ju
- Organ Transplant Center, First Affiliated Hospital of 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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20
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Pre-transplant Psoas Muscle Density as a Ready-to-Use and Low-cost Predictor of Patient Survival After Liver Transplant. HEPATITIS MONTHLY 2021. [DOI: 10.5812/hepatmon.99690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Sarcopenia, defined as low muscle mass with reduced function, is frequently encountered in cirrhotic patients and is a major predictor of adverse events, including post-liver transplant (LT) outcome. Objectives: This study assessed the impact of sarcopenia using computed tomography (CT)-based measurements on post-LT mortality and complications. Methods: From January 2008 to June 2016, 646 adult patients underwent 613 LTs at our institution. We analyzed the postoperative outcome of 287 patients who had pathologically proven cirrhosis on the explanted liver and who had performed a CT examination three months before LT. Psoas muscle density (PMD) was detected for every patient using standard instruments present in the radiological workstation and was related to postoperative survival rates and complications. Statistical analysis was carried out using the appropriate tests. Results: Postoperative mortality was 6.3%. At least one grade III-IV postoperative complication was experienced by 121 patients. Respiratory and infective complications occurred in 30 and 32 patients, respectively. Also, PMD was an independent predictor of postoperative mortality (P = 0.021), respiratory complications (P = 0.015), and infections (P = 0.010). The ROC analysis identified a PMD ≤ 43.72 HU as the best cutoff value for predicting 90-day mortality after LT. Conclusions: Psoas muscle density accurately predicted post-LT mortality and complications. Its ease and low-cost determination can allow widespread use of this parameter to improve clinical care and help with the decision to give these patients some priority on the transplant waiting list.
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21
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Ivanics T, Abreu P, De Martin E, Sapisochin G. Changing Trends in Liver Transplantation: Challenges and Solutions. Transplantation 2021; 105:743-756. [PMID: 32910093 DOI: 10.1097/tp.0000000000003454] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Despite improvements in postliver transplant outcomes through refinements in perioperative management and surgical techniques, several changing trends in liver transplantation have presented challenges. Mortality on the waitlist remains high. In the United States, Europe, and the United Kingdom, there is an increasing need for liver transplantation, primarily as a result of increased incidence of nonalcoholic steatohepatitis-related cirrhosis and cancer indications. Meanwhile, donor suitability has decreased, as donors are often older and have more comorbidities. Despite a mismatch between organ need and availability, many organs are discarded. Notwithstanding this, many solutions have been developed to overcome these challenges. Innovative techniques in allograft preservation, viability assessment, and reconditioning have allowed the use of suboptimal organs with adequate results. Refinements in surgical procedures, including live donor liver transplantations, have increased the organ pool and are decreasing the time and mortality on the waitlist. Despite many challenges, a similar number of solutions and prospects are on the horizon. This review seeks to explore the changing trends and challenges in liver transplantation and highlight possible solutions and future directions.
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Affiliation(s)
- Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Phillipe Abreu
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Eleonora De Martin
- APHP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM 1193, Université Paris-Sud, DHU Hepatinov, Villejuif, France
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
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22
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Chu KKW, Wong KHC, Chok KSH. Expanding Indications for Liver Transplant: Tumor and Patient Factors. Gut Liver 2021; 15:19-30. [PMID: 32102130 PMCID: PMC7817931 DOI: 10.5009/gnl19265] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 11/29/2019] [Accepted: 11/29/2019] [Indexed: 12/16/2022] Open
Abstract
During the past few decades, liver transplant has developed from a high-mortality procedure to an almost routine procedure with good survival outcomes. The development of living donor liver transplant has increased the availability of liver grafts, and the scope of indications for liver transplant has been expanding ever since. The aim of this review is to provide an overview of such an expansion of scope. Various criteria have been proposed to expand the eligibility of patients with hepatocellular carcinoma exceeding the Milan criteria for liver transplant. Furthermore, liver transplant is increasingly performed as a treatment modality for cholangiocarcinoma, neuroendocrine liver metastasis and colorectal liver metastasis. The number of elderly patients receiving liver transplant is on the rise. Combined organ transplantation has also been adopted to treat patients with multiple organ failure. Going forward, further development of preoperative noninvasive predictors in tumor, patient and even donor factors is needed to identify patients at risk of poor outcomes and hence optimize patient management.
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Affiliation(s)
- Kevin Ka-Wan Chu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | | | - Kenneth Siu-Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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23
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Liu Z, Wang W, Zhuang L, Liu J, Que S, Zhu D, Dong L, Yu J, Zhou L, Zheng S. Clear mortality gap caused by graft macrosteatosis in Chinese patients after cadaveric liver transplantation. Hepatobiliary Surg Nutr 2020; 9:739-758. [PMID: 33299829 PMCID: PMC7720047 DOI: 10.21037/hbsn.2019.12.02] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/21/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Liver transplantation (LT) is one of the most effective surgical treatment for patients with end-stage liver disease. Steatosis is a contributor for inferior graft quality. But its impact and safety on transplantation was less assessed in Chinese patients. METHODS Graft steatosis and related information involved in recipients, donors and surgical procedures were retrospectively collected from 239 patients. RESULTS Donor macrosteatosis (MaS) caused about 2.14 and 2.80 folds of increment on patient and graft mortality. Dose-response analysis revealed prominent risk of grafts on overall patient/organ mortality when MaS content exceeded 10% (P<0.05). Noteworthy, deaths were only observed in MaS group when concurrent with extremely higher post-transplant alanine aminotransferase (ALT, 64%). However, microsteatosis (MiS) grafts didn't affect outcomes after LT. In a cohort of Chinese patients, MaS had comprehensive effects on post-transplant outcomes with relatively lower safety threshold at 10%. Mortality gap caused by MaS grafts was observed in patients with severer ischemia reperfusion injury. CONCLUSIONS Our study revealled the graft MaS affected the post-transplant outcomes in lower risk cutoff in Chinese patients. Further study is worthy to validate these results and investigate inner mechanism under the phenomenon.
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Affiliation(s)
- Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenchao Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Zhuang
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Jingfeng Liu
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Shuping Que
- Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21, Stockholm, Sweden
- Dingxiang Clinics, Hangzhou, China
| | - Dan Zhu
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Linfang Dong
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Jian Yu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
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Miyachi Y, Yagi S, Hirata M, Iwamura S, Yao S, Shirai H, Okumura S, Iida T, Ito T, Uozumi R, Kaido T, Uemoto S. Etiology of Liver Steatosis Influences the Severity of Ischemia/Reperfusion Injury and Survival After Liver Transplantation in Rats. Liver Transpl 2020; 26:1504-1515. [PMID: 32511857 DOI: 10.1002/lt.25814] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/27/2020] [Accepted: 05/21/2020] [Indexed: 01/13/2023]
Abstract
Liver steatosis is a leading cause of graft disposal in liver transplantation, though the degree of steatosis is often the single factor determining acceptability of the graft. We investigated how the cause of liver steatosis affects graft function in rat orthotopic liver transplantation (OLT). OLT was performed using 2 types of steatotic liver grafts: the fasting and hyperalimentation (FHA) model and the methionine- and choline-deficient diet models. The FHA and 4-week feeding of a methionine- and choline-deficient diet (MCDD4wk) groups showed similar liver triglyceride levels without signs of steatohepatitis. Therefore, the 2 groups were compared in the following experiment. With 6-hour cold storage, the 7-day survival rate after OLT was far worse in the FHA than in the MCDD4wk group (0% versus 100%, P = 0.002). With 1-hour cold storage, the FHA group showed higher aspartate aminotransferase and alanine aminotransferase levels and histological injury scores in zones 1 and 2 at 24 hours after reperfusion than the normal liver and MCDD4wk groups. Intrahepatic microcirculation and tissue adenosine triphosphate levels were significantly lower in the FHA group after reperfusion. Hepatocyte necrosis, sinusoidal endothelial cell injury, and abnormal swelling of the mitochondria were also found in the FHA group after reperfusion. Tissue malondialdehyde levels were higher in the MCDD4wk group before and after reperfusion. However, the grafts up-regulated several antioxidant enzymes soon after reperfusion. Even though the degree of steatosis was equivalent, the 2 liver steatosis models possessed quite unique basal characteristics and showed completely different responses against ischemia/reperfusion injury and survival after transplantation. Our results demonstrate that the degree of fat accumulation is not a single determinant for the usability of steatotic liver grafts.
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Affiliation(s)
- Yosuke Miyachi
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shintaro Yagi
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Masaaki Hirata
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Sena Iwamura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Siyuan Yao
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Hisaya Shirai
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shinya Okumura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Taku Iida
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Takashi Ito
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Ryuji Uozumi
- Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
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Duan X, Yan L, Shen Y, Zhang M, Bai X, Liang T. Outcomes of liver transplantation using moderately steatotic liver from donation after cardiac death (DCD). ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1188. [PMID: 33241037 PMCID: PMC7576094 DOI: 10.21037/atm-20-5888] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Background Liver grafts from donation after cardiac death (DCD) with moderate steatosis (MS) are generally considered unsui for liver transplantation (LT) because DCD and MS are independent risk factors of poor prognosis of LT. Many centers have begun to accept this type of liver graft. However, the clinical outcomes are indeed controversial. This study aimed to examine the outcomes after LT of using such liver grafts. Methods This study retrospectively reviewed our experiences in 80 allografts from May 2015 to September 2019. A total of 16 allografts using MS liver grafts from DCD (MS-DCD group) were compared with a matched control group of 64 allografts using a nonsteatotic liver graft (NS group) (1:4 ratio). Postoperative outcomes, including primary nonfunction (PNF), initial poor function (IPF), postoperative complications, and graft/patient survival rates, were extracted for pooled analysis. Results Recipient and surgical characteristics of patients and clinical data of donors between MS-DCD group and NS group were balanced. No significant differences were observed in hepatitis B virus (HBV) infection, model for end-stage liver disease (MELD) score, cold ischemia time (CIT), donor risk index, warm ischemia time (WIT). A significant difference was detected in the incidence of initial poor function (IPF) (11/16 vs. 26/64; P=0.02), and the average peak value of aspartate transaminase (AST) (3,469 vs. 1,295; P<0.01) was significantly higher in the steatosis group. Meanwhile, alanine transaminase (ALT) was only higher on day 1, and international normalized ratio (INR) level was only higher on days 1 and 3 and disappeared on day 7. The serum total bilirubin (TB) was the same between the two groups. Postoperative complications were similar between the two groups. The 90-day, 1-year, and 3-year survival rates in patients and grafts between the two groups were similar (patient survival(MS-DCD group vs. NS group): 75% vs. 85.9%, 75% vs. 78.1%, 68.8% vs. 71.9%, log-rank test, P=0.77; graft survival(MS-DCD group vs. NS group): 75% vs. 84.4%, 75% vs. 75%, 68.8% vs. 68.8%, log-rank test, P=0.79). Conclusions After rigorous evaluation, it was found that moderately steatotic liver from DCD is an effective means to expand the source of liver supply.
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Affiliation(s)
- Xin Duan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liting Yan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yan Shen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xueli Bai
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tingbo Liang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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26
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Liu Z, Zhu H, Wang W, Xu J, Que S, Zhuang L, Qian J, Wang S, Yu J, Zhang F, Yin S, Xie H, Zhou L, Geng L, Zheng S. Metabonomic Profile of Macrosteatotic Allografts for Orthotopic Liver Transplantation in Patients With Initial Poor Function: Mechanistic Investigation and Prognostic Prediction. Front Cell Dev Biol 2020; 8:826. [PMID: 32984324 PMCID: PMC7484052 DOI: 10.3389/fcell.2020.00826] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/03/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Our previous study revealled amplified hazardous effects of macrosteatosis (MaS) on graft failure (GF) in recipients with severe liver damage in short post-operative days, with vague mechanism inside. AIM We aimed to uncover the molecular mechanism of donor MaS on GF, and construct the predictive model to monitor post-transplant prognosis based on "omics" perspective. METHODS Ultra-performance liquid chromatography coupled to mass spectrometry metabolomic analysis was performed in allograft tissues from 82 patients with initial poor function (IPF) from multi-liver transplant (LT) centers. Pathway analysis was performed by on-line toolkit Metaboanalyst (v 3.0). Predictive model was constructed based on combinative metabonomic and clinical data extracted by stepwised cox proportional analysis. RESULTS Principle component analysis (PCA) analysis revealled stratification on metabolic feature in organs classified by MaS status. Differential metabolits both associated with MaS and GF were significantly enriched on pathway of glycerophospholipid metabolism (P < 0.05). Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) involved in glycerophospholipid metabolism was significantly decreased in cases with MaS donors and GF (P < 0.05). Better prediction was observed on graft survival by combinative model (area under the curve = 0.91) and confirmed by internal validation. CONCLUSION Metabonomic features of allografts can be clearly distinguished by MaS status in patients with IPF. Dysfunction on glycerophospholipid metabolism was culprit to link donor MaS and final GF. Decrement on PC and PE exerted the fatal effects of MaS on organ failure. Metabonomic data might help for monitoring long-term graft survival after LT.
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Affiliation(s)
- Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hai Zhu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenchao Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jun Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | | | - Li Zhuang
- Shulan Hospital (Hangzhou), Hangzhou, China
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shuai Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Yu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Feng Zhang
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shengyong Yin
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haiyang Xie
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lei Geng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Shulan Hospital (Hangzhou), Hangzhou, China
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27
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Irie R, Nakazawa A, Sakamoto S, Takeda M, Yanagi Y, Shimizu S, Uchida H, Fukuda A, Kasahara M. Outcome for Pediatric Recipients of Macrosteatotic Liver Grafts From Living Donors. Liver Transpl 2020; 26:899-905. [PMID: 32314485 DOI: 10.1002/lt.25784] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/09/2020] [Accepted: 04/04/2020] [Indexed: 01/13/2023]
Abstract
In deceased donor liver transplantation, a donor liver with moderate (>30%) macrosteatosis used to be considered inappropriate for grafting. We examined the outcomes of children who underwent living donor liver transplantation (LDLT) at the National Center for Child Health and Development whose donor livers had moderate-to-severe macrosteatosis. Twelve children were enrolled who had received a moderate-to-severe macrosteatotic liver graft and underwent liver biopsy soon after LDLT. The primary diseases were biliary atresia in 7 patients, acute liver failure in 3 patients, glycogen storage disease type 1 in 1 patient, and primary sclerosing cholangitis in 1 patient. Median age was 11 months. There were 4 recipients who received grafts from their fathers, and 8 received grafts from their mothers. Median donor age was 35.5 years. We compared the degree of donor liver steatosis with the results of graft liver biopsies that were collected 4-105 days after LDLT. The levels of donor liver macrovesicular steatosis were moderate (34%-66%) in 9 patients and severe (>66%) in 3 patients. The nonalcoholic fatty liver disease activity score was 3 in 7 patients and 4 in 5 patients. Shortly after LDLT, 11 of 12 patients showed improvement in steatosis compared with the donor livers. One biopsy specimen taken 22 days after LDLT showed 60% macrosteatosis, which was the same as that in the donor liver. However, this patient was alive and well 6 years after LDLT. One patient died after LDLT because of infection and respiratory failure. The levels of steatosis of the donor liver grafts improved soon after LDLT in children, and the outcomes of children receiving a moderate-to-severe macrosteatotic liver from their parents were excellent.
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Affiliation(s)
- Rie Irie
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Atsuko Nakazawa
- Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Masahiro Takeda
- 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
| | - Seiichi Shimizu
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Hajime Uchida
- 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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Macrosteatotic Allografts and Obese Recipients Have Nearly Equal Negative Impact on Liver Transplant Survival. Transplantation 2020; 104:1193-1200. [DOI: 10.1097/tp.0000000000002990] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Núñez K, Hamed M, Fort D, Bruce D, Thevenot P, Cohen A. Links between donor macrosteatosis, interleukin-33 and complement after liver transplantation. World J Transplant 2020; 10:117-128. [PMID: 32864357 PMCID: PMC7428792 DOI: 10.5500/wjt.v10.i5.117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/07/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND As prevalence of nonalcoholic fatty liver disease increases in the population, livers with steatosis will continue to infiltrate the donor pool. Safe utilization of these extended criteria grafts is paramount given the increased risk associated with their use in transplantation. Prognostic factors that can predict liver dysfunction immediately after transplantation with macrosteatotic grafts are lacking. AIM To understand the relationship between interleukin-33 (IL-33) and complement in recipients immediately following liver reperfusion as a marker of liver dysfunction. METHODS Cohort consisted of patients who received a liver transplant from September 2016-September 2019 at our institution. Clinical variables were retrospectively extracted from the electronic medical record. Back-table donor biopsies were obtained with donor steatosis percentage retrospectively determined by a board-certified pathologist. Blood samples were available immediately following liver transplantation. Quantification of plasma IL-33 and complement proteins, C3a and C5a, were determined by enzyme-linked immunosorbent assay. For mRNA expression, RNA was extracted from donor biopsies and used against a 780 gene panel. RESULTS Cohort consisted of 99 donor and recipients. Donor median age was 45 years and 55% male. Recipients had a median age of 59 years with 62% male. The main etiologies were alcoholic hepatitis, nonalcoholic steatohepatitis, and hepatocellular carcinoma. Median MELD-Na at transplant was 21. Donors were grouped based on moderate macrosteatosis (≥ 30%). Recipients implanted with moderate macrosteatotic grafts had significantly higher peak alanine aminotransferase/aspartate aminotransferase (P < 0.001 and P < 0.004), and increased incidence of early allograft dysfunction (60% compared to 18%). Circulating IL-33 levels were significantly elevated in recipients of ≥ 30% macrosteatotic grafts (P < 0.05). Recipients with detectable levels of circulating IL-33 immediately following reperfusion had significantly higher alanine aminotransferase/aspartate aminotransferase (P < 0.05 and P < 0.01). Activated complement (C3a and C5a) were elevated in recipients implanted with moderate macrosteatotic grafts. RNA expression analysis of donor biopsies revealed moderate steatotic grafts upregulated genes inflammatory processes while downregulated hepatocyte-produced complement factors. CONCLUSION Circulating IL-33 and activated complement levels immediately following liver reperfusion in recipients of moderate macrosteatotic grafts may identify which patients are at risk of early allograft dysfunction.
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Affiliation(s)
- Kelley Núñez
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Mohammad Hamed
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Daniel Fort
- Center for Outcomes and Health Services Research, Research Administration, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - David Bruce
- Multi-Organ Transplant Program, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Ari Cohen
- Multi-Organ Transplant Program, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
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30
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Salvi M, Molinaro L, Metovic J, Patrono D, Romagnoli R, Papotti M, Molinari F. Fully automated quantitative assessment of hepatic steatosis in liver transplants. Comput Biol Med 2020; 123:103836. [PMID: 32658781 DOI: 10.1016/j.compbiomed.2020.103836] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/25/2020] [Accepted: 05/25/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The presence of macro- and microvesicular steatosis is one of the major risk factors for liver transplantation. An accurate assessment of the steatosis percentage is crucial for determining liver graft transplantability, which is currently based on the pathologists' visual evaluations on liver histology specimens. METHOD The aim of this study was to develop and validate a fully automated algorithm, called HEPASS (HEPatic Adaptive Steatosis Segmentation), for both micro- and macro-steatosis detection in digital liver histological images. The proposed method employs a hybrid deep learning framework, combining the accuracy of an adaptive threshold with the semantic segmentation of a deep convolutional neural network. Starting from all white regions, the HEPASS algorithm was able to detect lipid droplets and classify them into micro- or macrosteatosis. RESULTS The proposed method was developed and tested on 385 hematoxylin and eosin (H&E) stained images coming from 77 liver donors. Automated results were compared with manual annotations and nine state-of-the-art techniques designed for steatosis segmentation. In the TEST set, the algorithm was characterized by 97.27% accuracy in steatosis quantification (average error 1.07%, maximum average error 5.62%) and outperformed all the compared methods. CONCLUSIONS To the best of our knowledge, the proposed algorithm is the first fully automated algorithm for the assessment of both micro- and macrosteatosis in H&E stained liver tissue images. Being very fast (average computational time 0.72 s), this algorithm paves the way for automated, quantitative and real-time liver graft assessments.
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Affiliation(s)
- Massimo Salvi
- Politobiomed Lab, Biolab, Department of Electronics and Telecommunications, Politecnico di Torino, Turin, Italy.
| | - Luca Molinaro
- Division of Pathology, AOU Città Della Salute e Della Scienza di Torino, Turin, Italy
| | - Jasna Metovic
- Division of Pathology, Department of Oncology, University of Turin, Turin, Italy
| | - Damiano Patrono
- General Surgery 2U, Liver Transplant Center, AOU Città Della Salute e Della Scienza di Torino, University of Turin, Turin, Italy
| | - Renato Romagnoli
- General Surgery 2U, Liver Transplant Center, AOU Città Della Salute e Della Scienza di Torino, University of Turin, Turin, Italy
| | - Mauro Papotti
- Division of Pathology, Department of Oncology, University of Turin, Turin, Italy
| | - Filippo Molinari
- Politobiomed Lab, Biolab, Department of Electronics and Telecommunications, Politecnico di Torino, Turin, Italy
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Jadhav PV, Kothakota SR, Sasidharan M, Kareem H, Nair AK. Effect of Donor Hepatic Steatosis on Ischemia Reperfusion Injury in Liver Transplant Recipient. J Clin Exp Hepatol 2020; 10:236-244. [PMID: 32405180 PMCID: PMC7212288 DOI: 10.1016/j.jceh.2019.07.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 07/05/2019] [Indexed: 01/02/2023] Open
Abstract
INTRODUCTION Ischemia reperfusion injury (IRI) is an important complication of liver transplant (LT). The donor risk index, which does not incorporate steatosis, includes several variables known to impact on allograft survival. The purpose of this study was to report on donor liver allograft steatosis and its association with severity of IRI. AIM The aim of this study was to determine the effect of type and grade of donor liver steatosis on the occurrence and severity of IRI in LT recipients. METHODS This was an observational study conducted at a single center over a period of 37 months from July 2013 to August 2016. Liver biopsy was performed twice, initially at the time of procurement before graft perfusion for steatosis assessment. Steatosis was classified as microsteatosis (MiS) or macrosteatosis (MaS) with mild, moderate, or severe grade. Second biopsy for IRI assessment was taken before skin closure in death donor LT (DDLT) and at the time of transaminitis in postoperative period (<72 hrs) in living donor LT (LDLT). IRI was graded as per neutrophil infiltrate, apoptosis, and hepatocyte cell dropout. Prevalence of IRI and association steatosis was studied along with other factors. RESULTS Among 53 subjects, 35 were DDLTs and 18 were LDLTs. All live donor grafts were restricted to <15% MaS and the deceased liver grafts had different type and degree of steatosis. In DDLTs, the association between occurrence of IRI and MaS was not statistically significant (P = 0.201). In DDLTs, the mild steatosis was not significantly associated with IRI. Death donor and ischemic time were significantly associated with IRI. Child's stage and MELD scores, gender, and age were not associated with risk of IRI. Severity of IRI is significantly associated with 3-month mortality (P = 0.001). CONCLUSION In patients with mild steatosis, IRI does not correlate with steatosis. However, more patients with moderate and severe steatosis are needed to define the relationship of the two in this group of patients.
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Key Words
- ALT, alanine transferase
- AST, aspartate transferase
- CIT, cold ischemia time
- DDLT, death donor liver transplant
- DRI, donor risk index
- ECD, extended criteria donor
- EHBA, extrahepatic biliary atresia
- H&E, haematoxilin & eosin
- HBV, hepatitis B virus
- HCV, hepatitis C virus
- HPE, histopathological examination
- IRI, ischemia reperfusion injury
- LAI, liver attenuation index
- LDLT, living donor liver transplant
- LT, liver transplant
- MELD, model for end-stage liver disease
- MaS, macrosteatosis
- MiS, microsteatosis
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- PNF, primary nonfunction (graft)
- WIT, warm ischemia time
- cold ischemic time
- ischemia reperfusion injury
- macrosteatosis
- microsteatosis
- warm ischemic time
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Affiliation(s)
- Prafulla V. Jadhav
- Department of Gastroenterology, KIMS Hospital, Trivandrum, Kerala, India
| | | | - Madhu Sasidharan
- Department of Gastroenterology, KIMS Hospital, Trivandrum, Kerala, India
| | - Harish Kareem
- Department of Gastroenterology, KIMS Hospital, Trivandrum, Kerala, India
| | - Ajith K. Nair
- Department of Gastroenterology, KIMS Hospital, Trivandrum, Kerala, India
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Higher thresholds for the utilization of steatotic allografts in liver transplantation: Analysis from a U.S. national database. PLoS One 2020; 15:e0230995. [PMID: 32240235 PMCID: PMC7117730 DOI: 10.1371/journal.pone.0230995] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 03/02/2020] [Indexed: 12/29/2022] Open
Abstract
Background Historically, liver allografts with >30% macrosteatosis (MaS) on donor biopsy have been associated with early allograft dysfunction and worse graft survival; however, successful outcomes have been reported in small cohorts. This study proposes an elevated MaS threshold for organ utilization without detriment to graft survival. Methods The UNOS Standard Transplant Analysis and Research database was evaluated for transplants between 2006–2015. Graft survival up to 1-year was evaluated by Kaplan-Meier (KM) survival analyses, and by univariate and multivariable logistic regression analyses, including donor and recipient characteristics. Odds ratios (OR) with 95% confidence intervals (CI) for risk of graft loss are reported. Results Thirty-day risk of graft loss was increased with MaS as low as 10–19% (OR [95% CI] 1.301 [1.055–1.605], p<0.0001) and peaked with MaS 50–59% (2.921 [1.672–5.103]). At 1-year, risk of graft loss remained elevated with MaS 40–49% (1.465 [1.002–2.142]) and MaS 50–59% (1.978 [1.281–3.056], p = 0.0224). Multivariable models were created for Lower and Higher MELD recipients and MaS cutoffs were established. In Lower MELD recipients, organs with ≥50% MaS had increased risk of graft loss at 30 days (2.451 [1.541–3.897], p = 0.0008) and 1-year post-transplant (1.720 [1.224–2.418], p = 0.0125). Higher MELD recipients had increased risk of graft loss at 30 days with allografts showing MaS ≥40% (4.204 [1.440–5.076], p = 0.0016). At 1-year the risk remained increased, but MaS was not significant predictor of graft loss.048 [1.131–3.710], p = 0.0616). In both MELD cohorts, organs with MaS levels below threshold had similar survival to those transplanted without a donor biopsy. Conclusions In conjunction with recipient selection, organs with MaS up to 50% may be safely used without detriment to outcomes.
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Patel MS, Mohebali J, Coe TM, Sally M, Groat T, Niemann CU, Malinoski DJ, Vagefi PA. The role of deceased donor liver biopsy: An analysis of 5449 liver transplant recipients. Clin Transplant 2020; 34:e13835. [PMID: 32068301 DOI: 10.1111/ctr.13835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/02/2020] [Accepted: 02/16/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND No standard exists for the use of deceased donor liver biopsy during procurement. We sought to evaluate liver biopsy and the impact of findings on outcomes and graft utilization. METHODS A prospective observational study of donors after neurologic determination of death was conducted from 02/2012-08/2017 (16 OPOs). Donor data were collected through the UNOS Donor Management Goals Registry Web Portal and linked to the Scientific Registry of Transplant Recipients (SRTR) for recipient outcomes. Recipients of biopsied donor livers (BxDL) were studied and a Cox proportional hazard analysis was used to identify independent predictors of 1-year graft survival. RESULTS Data from 5449 liver transplant recipients were analyzed, of which 1791(33%) received a BxDL. There was no difference in graft or patient survival between the non-BxDL and BxDL recipient groups. On adjusted analysis of BxDL recipients, macrosteatosis (21%-30%[n = 148] and >30%[n = 92]) was not found to predict 1-year graft survival, whereas increasing donor age (HR1.02), donor Hispanic ethnicity (HR1.62), donor INR (HR1.18), and recipient life support (HR2.29) were. CONCLUSIONS Excellent graft and patient survival can be achieved in recipients of BxDL grafts. Notably, as demonstrated by the lack of effect of macrosteatosis on survival, donor to recipient matching may contribute to these outcomes.
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Affiliation(s)
- Madhukar S Patel
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Jahan Mohebali
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Taylor M Coe
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Mitchell Sally
- Section of Surgical Critical Care, VA Portland Health Care System (VAPORHCS), Portland, Oregon, USA.,Division of Trauma, Critical Care, and Acute Care Surgery, Oregon Health & Science University, Portland, Oregon, USA
| | - Tahnee Groat
- Section of Surgical Critical Care, VA Portland Health Care System (VAPORHCS), Portland, Oregon, USA
| | - Claus U Niemann
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA.,Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, California, USA
| | - Darren J Malinoski
- Section of Surgical Critical Care, VA Portland Health Care System (VAPORHCS), Portland, Oregon, USA.,Division of Trauma, Critical Care, and Acute Care Surgery, Oregon Health & Science University, Portland, Oregon, USA
| | - Parsia A Vagefi
- Division of Transplantation, Department of Surgery, Southwestern Medical Center, University of Texas, Dallas, Texas, USA
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Samji NS, Heda R, Satapathy SK. Peri-transplant management of nonalcoholic fatty liver disease in liver transplant candidates . Transl Gastroenterol Hepatol 2020; 5:10. [PMID: 32190778 PMCID: PMC7061181 DOI: 10.21037/tgh.2019.09.09] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 09/23/2019] [Indexed: 12/12/2022] Open
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly growing, affecting 25% of the world population. Non-alcoholic steatohepatitis (NASH) is the most severe form of NAFLD and affects 1.5% to 6.5% of the world population. Its rising incidence will make end-stage liver disease (ESLD) due to NASH the number one indication for liver transplantation (LT) in the next 10 to 20 years, overtaking Hepatitis C. Patients with NASH also have a high prevalence of associated comorbidities such as type 2 diabetes, obesity, metabolic syndrome, cardiovascular disease, and chronic kidney disease (CKD), which must be adequately managed during the peritransplant period for optimal post-transplant outcomes. The focus of this review article is to provide a comprehensive overview of the unique challenges these patients present in the peritransplant period, which comprises the pre-transplant, intraoperative, and immediate postoperative periods.
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Affiliation(s)
- Naga Swetha Samji
- Tennova Cleveland Hospital, 2305 Chambliss Ave NW, Cleveland, TN, USA
| | - Rajiv Heda
- University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA
| | - Sanjaya K. Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY, USA
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35
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Pisano G, Donato MF, Consonni D, Oberti G, Borroni V, Lombardi R, Invernizzi F, Bertelli C, Caccamo L, Porzio M, Dondossola D, Rossi G, Fargion S, Fracanzani AL. High prevalence of early atherosclerotic and cardiac damage in patients undergoing liver transplantation: Preliminary results. Dig Liver Dis 2020; 52:84-90. [PMID: 31521545 DOI: 10.1016/j.dld.2019.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 07/15/2019] [Accepted: 07/15/2019] [Indexed: 12/11/2022]
Abstract
Liver transplanted patients are at high risk of metabolic syndrome and its complications. We aimed to prospectively evaluate the early onset of cardiovascular alterations in patients submitted to the transplant waiting list. From January 2014 to January 2016, 54 out of 79 patients on the waiting list with decompensated cirrhosis or hepatocellular-carcinoma received the transplant, 50 were followed for 24 months, 2 died post-surgery and 2 were lost to follow-up. A significantly increased prevalence of visceral adiposity (epicardial adipose tissue thickness (p = 0.001) and worsening of carotid damage (p = 0.003) and diastolic dysfunction (E/A p = 0.001) was observed at 6 months after transplant and remained stable at 24 months, corresponding to an increased prevalence of diabetes, metabolic syndrome, hypertension and dyslipidemia. The duration of steroid therapy, withdrawn in the majority of patients at 3 months, did not influence cardiovascular damage. No significant difference in early progression of cardiovascular damage was observed between patients who did or did not receive a graft with steatosis. CONCLUSION: The occurrence of early cardiovascular alterations in the first 6 months after OLT accounts for the reported cardiovascular events in the first years after transplant. In light of these results, new strategies aimed at preventing or delaying cardiovascular alterations should be provided, starting from the first weeks after transplant.
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Affiliation(s)
- Giuseppina Pisano
- Department of Pathophysiology and Transplantation, Unit of Medicine and Metabolic Disorders, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Maria Francesca Donato
- Division of Gastroenterology and Hepatology, Unit of Transplant Hepatology Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, RC AM and A Migliavacca Center for the Study of Liver disease University of Milan, Milan, Italy
| | - Dario Consonni
- Epidemiological Unit, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanna Oberti
- Department of Pathophysiology and Transplantation, Unit of Medicine and Metabolic Disorders, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Vittorio Borroni
- Unit of Medicine, ASST Valle Olona, Ospedale di Gallarate, Varese, Italy
| | - Rosa Lombardi
- Department of Pathophysiology and Transplantation, Unit of Medicine and Metabolic Disorders, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Federica Invernizzi
- Division of Gastroenterology and Hepatology, Unit of Transplant Hepatology Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, RC AM and A Migliavacca Center for the Study of Liver disease University of Milan, Milan, Italy
| | - Cristina Bertelli
- Department of Pathophysiology and Transplantation, Unit of Medicine and Metabolic Disorders, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Lucio Caccamo
- Unit of Hepatic Surgery, Department of Pathophysiology and Transplantation, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Marianna Porzio
- Unit of Emergency Medicine, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniele Dondossola
- Unit of Hepatic Surgery, Department of Pathophysiology and Transplantation, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Giorgio Rossi
- Unit of Hepatic Surgery, Department of Pathophysiology and Transplantation, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Unit of Medicine and Metabolic Disorders, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Unit of Medicine and Metabolic Disorders, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
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36
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Patrono D, Martini S, Romagnoli R. Liver Transplantation and NAFLD/NASH. NON-ALCOHOLIC FATTY LIVER DISEASE 2020:343-362. [DOI: 10.1007/978-3-319-95828-6_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Zhang N, Sheng M, Wu M, Zhang X, Ding Y, Lin Y, Yu W, Wang S, Du H. Berberine protects steatotic donor undergoing liver transplantation via inhibiting endoplasmic reticulum stress-mediated reticulophagy. Exp Biol Med (Maywood) 2019; 244:1695-1704. [PMID: 31554427 DOI: 10.1177/1535370219878651] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Steatotic livers are more susceptible to ischemia/reperfusion injury, and increase the risk of primary graft non-function after liver transplantation. The protective effects of berberine have been described in various liver pathological models. However, it is unknown if berberine exerts its beneficial action in steatotic donors undergoing liver transplantation. In the present study, male Wistar rats were fed with high-fat diet (HFD) for 12 weeks to induce moderate steatotic liver. Then orthotropic liver transplantation was constructed. Berberine (200 mg/kg/d) was given intragastrically one week before liver transplantation. Thapsigargin (TG) (0.2 mg/kg) was administrated intravenously 24 h before liver transplantation. Liver function, oxidative stress, and inflammatory cytokine were detected by biochemical or histopathological analysis. The morphology of autophagosomes and endoplasmic reticulum (ER) was observed by transmission electron microscopy. The expression of CHOP, BIP, the phosphorylation of PERK, LC3-II/I, Beclin-1, and p62 were determined by Western blot assay. The co-localization of endoplasmic reticulum marker (KDEL) and autophagic protein (LC3B) was analyzed by immunofluorescence microscopy. The level of reticulophagy hallmark (FAM134B) was determined by immunohistochemistry. Compared with HFD + LT group, berberine ameliorated hepatocellular damage, decreased the oxidative stress level and inflammatory cytokine release. Simultaneously, berberine inhibited the expression of both endoplasmic reticulum stress parameters and autophagy-related proteins. Additionally, the co-localization of endoplasmic reticulum marker and LC3B was also reduced in HFD + BBR + LT group. berberine down-regulated the level of FAM134B. TG reversed the beneficial effects of berberine. Our study revealed that berberine exerts protective effects on steatotic livers undergoing transplantation by inhibiting endoplasmic reticulum stress-mediated reticulophagy. Impact statement Berberine is isolated from traditional Chinese medicine plants and has dramatically therapeutic potential against inflammation, diarrhea, and diabetes. But the benefits of BBR on steatotic grafts after liver transplantation remain poorly understood. Our findings might help explain the mechanism of berberine in protecting steatotic livers undergoing transplantation and give advantageous insights that berberine has potential as a suitable candidate for preventing hepatic injury after steatotic liver transplantation by inhibiting ER stress-mediated reticulophagy.
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Affiliation(s)
- Nan Zhang
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China.,Department of Anesthesiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Mingwei Sheng
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Man Wu
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Xinyue Zhang
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Yijie Ding
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Yuanbang Lin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Wenli Yu
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Shusen Wang
- Key Laboratory for Critical Care Medicine of the Ministry of Health, Tianjin First Central Hospital, Tianjin 300192, China
| | - Hongyin Du
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
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Jiménez-Castro MB, Cornide-Petronio ME, Gracia-Sancho J, Peralta C. Inflammasome-Mediated Inflammation in Liver Ischemia-Reperfusion Injury. Cells 2019; 8:1131. [PMID: 31547621 PMCID: PMC6829519 DOI: 10.3390/cells8101131] [Citation(s) in RCA: 166] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/19/2019] [Accepted: 09/21/2019] [Indexed: 12/16/2022] Open
Abstract
Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction and liver failure post-transplantation. To date, ischemia-reperfusion injury is an unsolved problem in clinical practice. In this context, inflammasome activation, recently described during ischemia-reperfusion injury, might be a potential therapeutic target to mitigate the clinical problems associated with liver transplantation and hepatic resections. The present review aims to summarize the current knowledge in inflammasome-mediated inflammation, describing the experimental models used to understand the molecular mechanisms of inflammasome in liver ischemia-reperfusion injury. In addition, a clear distinction between steatotic and non-steatotic livers and between warm and cold ischemia-reperfusion injury will be discussed. Finally, the most updated therapeutic strategies, as well as some of the scientific controversies in the field will be described. Such information may be useful to guide the design of better experimental models, as well as the effective therapeutic strategies in liver surgery and transplantation that can succeed in achieving its clinical application.
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Affiliation(s)
| | | | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory IDIBAPS, 08036 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain.
| | - Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain.
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Wong TCL, Fung JYY, Cui TYS, Lam AHK, Dai JWC, Chan ACY, Cheung TT, Chok KSH, Ng KKC, Lo CM. Liver transplantation using hepatitis B core positive grafts with antiviral monotherapy prophylaxis. J Hepatol 2019; 70:1114-1122. [PMID: 30871981 DOI: 10.1016/j.jhep.2019.03.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 02/20/2019] [Accepted: 03/04/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The impact of hepatitis B core antibody (anti-HBc) positive liver grafts on survival and the risk of de novo hepatitis B virus (HBV) infection after liver transplantation (LT) remain controversial. Therefore, we aimed to analyze this risk and the associated outcomes in a large cohort of patients. METHODS This was a retrospective study that included all adults who underwent LT at Queen Mary Hospital, Hong Kong, between 2000 and 2015. Data were retrieved from a prospectively collected database. Antiviral monotherapy prophylaxis was given for patients receiving grafts from anti-HBc positive donors. RESULTS A total of 964 LTs were performed during the study period, with 416 (43.2%) anti-HBc positive and 548 (56.8%) anti-HBc negative donors. The median follow-up time was 7.8 years. Perioperative outcomes (hospital mortality, complications, primary nonfunction and delayed graft function) were similar between the 2 groups. The 1-, 5- and 10-year graft survival rates were comparable in anti-HBc positive (93.3%, 85.3% and 76.8%) and anti-HBc negative groups (92.5%, 82.9% and 78.4%, p = 0.944). The 1-, 5- and 10-year patient survival rates in anti-HBc positive group were 94.2%, 87% and 79% and were similar to the anti-HBc negative group (93.5%, 84% and 79.7%, p = 0.712). One-hundred and eight HBsAg negative recipients received anti-HBc positive grafts, of whom 64 received lamivudine and 44 entecavir monotherapy prophylaxis. The risk of de novo HBV was 3/108 (2.8%) and all occurred in the lamivudine era. There were 659 HBsAg-positive patients and 308 (46.7%) received anti-HBc positive grafts. The risk of HBV recurrence was similar between the 2 groups. Donor anti-HBc status did not impact on long-term patient and graft survival, or the risk of hepatocellular carcinoma recurrence after LT. CONCLUSIONS De novo HBV was exceedingly rare especially with entecavir prophylaxis. Anti-HBc positive grafts did not impact on perioperative and long-term outcomes after transplant. LAY SUMMARY The risk of de novo hepatitis B infection after liver transplantation was rare when using hepatitis B core positive liver grafts with entecavir monotherapy prophylaxis. Hepatitis B core antibody status did not impact on perioperative and long-term outcomes after liver transplantation. This provides support for the clinical use of hepatitis B core positive liver grafts when required.
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Affiliation(s)
- Tiffany Cho-Lam Wong
- Department of Surgery, The University of Hong Kong, Hong Kong; Department of Surgery, Queen Mary Hospital, Hong Kong; Department of Surgery, The University of Hong Kong-Shenzhen Hospital, China
| | - James Yan-Yue Fung
- Department of Medicine, The University of Hong Kong, Hong Kong; Department of Medicine, Queen Mary Hospital, Hong Kong.
| | | | | | - Jeff Wing-Chiu Dai
- Department of Surgery, The University of Hong Kong, Hong Kong; Department of Surgery, Queen Mary Hospital, Hong Kong
| | - Albert Chi-Yan Chan
- Department of Surgery, The University of Hong Kong, Hong Kong; Department of Surgery, Queen Mary Hospital, Hong Kong; Department of Surgery, The University of Hong Kong-Shenzhen Hospital, China
| | - Tan-To Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong; Department of Surgery, Queen Mary Hospital, Hong Kong; Department of Surgery, The University of Hong Kong-Shenzhen Hospital, China
| | - Kenneth Siu-Ho Chok
- Department of Surgery, The University of Hong Kong, Hong Kong; Department of Surgery, Queen Mary Hospital, Hong Kong; Department of Surgery, The University of Hong Kong-Shenzhen Hospital, China
| | | | - Chung-Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong; Department of Surgery, Queen Mary Hospital, Hong Kong; Department of Surgery, The University of Hong Kong-Shenzhen Hospital, China
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40
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Regional Variation in Utilization and Outcomes of Liver Allografts From Donors With High Body Mass Index and Graft Macrosteatosis: A Role for Liver Biopsy. Transplantation 2019; 103:122-130. [PMID: 30048394 DOI: 10.1097/tp.0000000000002379] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Obesity, defined as a high body mass index (hBMI) of 30 kg/m or greater, is a growing epidemic worldwide and is associated with multiple comorbidities. High BMI individuals account for an increasing portion of potential liver donors. Here we evaluate trends in the utilization and outcomes of hBMI donors on a national and regional level and the potential role of liver biopsy in donor evaluation. METHODS United Network for Organ Sharing Standard Transplant Analysis and Research database was evaluated for deceased donor liver transplants between 2006 and 2016 across 11 Organ Procurement and Transplantation Network regions. High BMI donors were compared with lower BMI counterparts and evaluated for biopsy rates, utilization rates and allograft outcomes. Univariate and multivariable analyses were performed. RESULTS Seventy-seven thousand fifty potential donors were identified and 60 200 transplants were evaluated. Utilization rates for hBMI donors were 66.1% versus 78.1% for lower BMI donors (P < 0.001). Pretransplant biopsy was performed more frequently in hBMI donors (52.1% vs 33.1%, P < 0.001) and macrosteatosis of 30% or greater was identified more often (21.1% vs 12.2%, P < 0.001). Biopsy performance increased utilization rate of hBMI donors in 7 of 11 Organ Procurement and Transplantation Network regions. region 6 showed the highest rate of biopsy performance, high rate of hBMI donor utilization, and highest 5-year estimated graft survival rates of all regions. CONCLUSIONS High BMI donors have not previously been associated with worse graft survival in multivariable analyses; however, they are used much less frequently. Liver biopsy may increase the utilization rate of hBMI donors and improve donor selection. Further evaluation of regions with high rates of utilization and good outcomes is warranted.
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The Impact of Steatosis on the Outcome of Liver Transplantation: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3962785. [PMID: 31218224 PMCID: PMC6536983 DOI: 10.1155/2019/3962785] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 04/14/2019] [Accepted: 04/22/2019] [Indexed: 12/18/2022]
Abstract
Background and Aims Liver transplantation is one of the most effective treatments for end-stage liver disease as well as for cases of acute liver failure. Facing organ donor shortage, liver transplant teams had to use marginal organs. Thus, increasing availability is a key concern of donor liver grafts including steatotic livers. However, the use of steatotic liver is still controversial. The aim of this systematic review and meta-analysis was to analyze the impact of steatosis on the outcome of liver transplantation. Methods We searched PubMed, Cochrane Library, Embase, Web of knowledge, and so on for studies published through May 31, 2018, in which patients experienced liver transplantation using fatty liver. All studies extracted outcome indicators, and we draw conclusions by contrasting outcome indicators in different groups of steatosis. Odds ratios and 95% confidence intervals were calculated. P<0.05 was considered as statistically significant difference. Results 19 publications were included. There was no significant difference between the group of no steatosis and mild group in primary nonfunction rate (P=0.605) or early graft dysfunction rate (P=0.44). The PNF rate was significantly higher in moderate group (P=0.003) and severe group (P <0.001) compared with that in no steatosis group. The same results were seen in early graft dysfunction rate. However, graft survival rate and patient survival rate did not differ between groups. Conclusions Livers with mild steatosis, even with moderate or severe steatosis, could be suitable donor under strict control of transplant conditions.
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Álvarez-Mercado AI, Gulfo J, Romero Gómez M, Jiménez-Castro MB, Gracia-Sancho J, Peralta C. Use of Steatotic Grafts in Liver Transplantation: Current Status. Liver Transpl 2019; 25:771-786. [PMID: 30740859 DOI: 10.1002/lt.25430] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/02/2019] [Indexed: 12/12/2022]
Abstract
In the field of liver transplantation, the demand for adequate allografts greatly exceeds the supply. Therefore, expanding the donor pool to match the growing demand is mandatory. The present review summarizes current knowledge of the pathophysiology of ischemia/reperfusion injury in steatotic grafts, together with recent pharmacological approaches aimed at maximizing the utilization of these livers for transplantation. We also describe the preclinical models currently available to understand the molecular mechanisms controlling graft viability in this specific type of donor, critically discussing the heterogeneity in animal models, surgical methodology, and therapeutic interventions. This lack of common approaches and interventions makes it difficult to establish the pathways involved and the relevance of isolated discoveries, as well as their transferability to clinical practice. Finally, we discuss how new therapeutic strategies developed from experimental studies are promising but that further studies are warranted to translate them to the bedside.
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Affiliation(s)
- Ana I Álvarez-Mercado
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - José Gulfo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Manuel Romero Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Inter-Centre Unit of Digestive Diseases, Virgen del Rocio University Hospitals, Sevilla, Spain; Institute of Biomedicine of Seville, Seville, Spain
- Institute of Biomedicine of Seville, Seville, Spain
| | | | - Jordi Gracia-Sancho
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Universidad Internacional de Cataluña, Barcelona, Spain
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43
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Liu Z, Jia J, Ning H, Que S, Zhou L, Zheng S. Systematic Evaluation of the Safety Threshold for Allograft Macrovesicular Steatosis in Cadaveric Liver Transplantation. Front Physiol 2019; 10:429. [PMID: 31105577 PMCID: PMC6494939 DOI: 10.3389/fphys.2019.00429] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/28/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Currently, 30% macrovesicular steatosis (MaS) content is usually assigned empirically as the boundary between “use” and “refuse” a donor liver for liver transplantation (LT); however, this cut-off is questionable due to the lack of systemic evidence of the efficiency relative to prognosis prediction. Clinicians have tried to identify the threshold for optimized utilization of marginal steatotic allografts, but controversy exists among different studies. Aim: Our study aimed to systematically determine an acceptable donor MaS content cut-off without incurring extra risk in liver transplantation, using meta-analysis. Methods: The relevant literature reporting the relationship between MaS content and post-transplant mortality/morbidity was searched and retrieved in Pubmed, Embase, and ISI Web of Science. Results: Nine studies were enrolled into the final analysis. A categorical comparison revealed that patients who received allografts with moderate steatosis (MaS content >30%) had significantly higher risks of graft failure/dysfunction, but not of mortality. Dose-response analysis showed that donor MaS content affected the graft failure/dysfunction in a non-linear relationship. Risks associated with MaS content in terms of poorer outcomes were independent of other risk covariates for liver transplantation. A non-significant increase in risk of inferior post-transplant outcomes was observed in patients who received allografts with a MaS content <35%. The risks of post-transplant graft failure and dysfunction increased with severe donor MaS content infiltration, without a consistent relationship. Conclusions: The threshold of allograft MaS content can be safely extended to 35% without additional risk burden on post-transplant inferior outcomes. Clarification on “the effects of stratification” for MaS content can provide theoretical evidence for further optimal utilization of marginal steatotic allografts in liver transplantation.
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Affiliation(s)
- Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Junjun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Huaijun Ning
- Department of Pediatrics, Women and Children's Hospital of Guangxi, Nanning, China
| | - Shuping Que
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Lin Zhou
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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44
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Croome KP, Lee DD, Taner CB. The "Skinny" on Assessment and Utilization of Steatotic Liver Grafts: A Systematic Review. Liver Transpl 2019; 25:488-499. [PMID: 30817859 DOI: 10.1002/lt.25408] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 12/25/2018] [Indexed: 02/07/2023]
Abstract
The frequency at which steatotic deceased donor liver grafts are encountered will likely continue to increase. Utilization of liver grafts with moderate-to-severe steatosis for liver transplantation (LT) has been previously shown to be associated with increased rates of primary nonfunction and decreased recipient survival. In order to better inform clinical decision making and guide future research, critical evaluation of the literature on donor liver steatosis and posttransplantation outcome is needed. This literature review aims to provide the "skinny" on using deceased donor steatotic livers for LT.
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Affiliation(s)
| | - David D Lee
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL
| | - C Burcin Taner
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL
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45
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46
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Riva G, Villanova M, Cima L, Ghimenton C, Bronzoni C, Colombari R, Crestani M, Sina S, Brunelli M, D'Errico A, Montin U, Novelli L, Eccher A. Oil Red O Is a Useful Tool to Assess Donor Liver Steatosis on Frozen Sections During Transplantation. Transplant Proc 2018; 50:3539-3543. [PMID: 30577233 DOI: 10.1016/j.transproceed.2018.06.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/19/2018] [Indexed: 02/07/2023]
Abstract
UNLABELLED Oil Red O is a useful tool to assess donor liver steatosis on frozen sections during transplantation. Steatosis is a frequent finding in liver evaluation during transplantation, accounting for 9% to 26% of biopsied donor liver. The degree of macrovesicular steatosis is classified as mild, moderate, and severe; the latter is considered an absolute contraindication to liver transplantation because it is associated with poor allograft outcome. Because of the scarcity of organs, there is a debate whether livers with less severe macrovesicular steatosis are still suitable for transplant. Consequently, tools or methods that allow a more accurate intraoperative assessment of steatosis on frozen sections are mandatory. The aim of this study is to improve intraoperative evaluation of steatosis during transplantation using Oil Red O stain on liver biopsies. METHODS Twenty consecutive liver biopsies of donors were collected during transplantation procedures from September 2017 to February 2018 at the Institute of Pathology of the University and Hospital Trust of Verona, Italy. Each liver biopsy was cut at a different thickness (3, 5, and 8 μm) and stained with both Oil Red O and conventional hematoxylin and eosin for intraoperative consultation. The degree (percentage of hepatocytes involved) of fatty changes was recorded. The results obtained during the intraoperative consultation were finally compared with the formalin-fixed and paraffin-embedded permanent section. RESULTS Assessment of steatosis on hematoxylin and eosin frozen sections was reported as mild in 17 cases (85%), moderate in 2 cases (10%) and severe in 1 case (5%). Oil Red O frozen sections reported the following results: mild steatosis in 16 cases (80%), moderate in 2 cases (10%), and severe in 2 cases (10%). The percentage of liver steatosis obtained with Oil Red O was consistent in all cases with that of the permanent sections. The staining procedure for Oil Red O required approximately 18 minutes. CONCLUSIONS Oil Red O special stain is a fast and inexpensive tool to improve the assessment of steatosis on frozen biopsies during liver transplantation.
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Affiliation(s)
- G Riva
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - M Villanova
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - L Cima
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - C Ghimenton
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - C Bronzoni
- Liver Transplant Unit, Department of Surgical Science, University and Hospital Trust of Verona, Verona, Italy
| | - R Colombari
- Anatomic Pathology, Fracastoro Hospital of San Bonifacio, Verona, Italy
| | - M Crestani
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - S Sina
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - M Brunelli
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - A D'Errico
- Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Italy
| | - U Montin
- Liver Transplant Unit, Department of Surgical Science, University and Hospital Trust of Verona, Verona, Italy
| | - L Novelli
- Department of Pathology, Careggi University Hospital, Florence, Italy
| | - A Eccher
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.
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47
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Badawy A, Kaido T, Uemoto S. Current Status of Liver Transplantation Using Marginal Grafts. J INVEST SURG 2018; 33:553-564. [PMID: 30457408 DOI: 10.1080/08941939.2018.1517197] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Amr Badawy
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of General Surgery, Alexandria University, Alexandria, Egypt
| | - Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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48
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Boteon YL, Boteon APCS, Attard J, Mergental H, Mirza DF, Bhogal RH, Afford SC. Ex situ machine perfusion as a tool to recondition steatotic donor livers: Troublesome features of fatty livers and the role of defatting therapies. A systematic review. Am J Transplant 2018; 18:2384-2399. [PMID: 29947472 DOI: 10.1111/ajt.14992] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/13/2018] [Accepted: 06/18/2018] [Indexed: 02/06/2023]
Abstract
Long-standing research has shown that increased lipid content in donor livers is associated with inferior graft outcomes posttransplant. The global epidemic that is obesity has increased the prevalence of steatosis in organ donors, to the extent that it has become one of the main reasons for declining livers for transplantation. Consequently, it is one of the major culprits behind the discrepancy between the number of donor livers offered for transplantation and those that go on to be transplanted. Steatotic livers are characterized by poor microcirculation, depleted energy stores because of an impaired capacity for mitochondrial recovery, and a propensity for an exaggerated inflammatory response following reperfusion injury culminating in poorer graft function postoperatively. Ex situ machine perfusion, currently a novel method in graft preservation, is showing great promise in providing a tool for the recovery and reconditioning of marginal livers. Hence, reconditioning these steatotic livers using machine perfusion has the potential to increase the number of liver transplants performed. In this review, we consider the problematic issues associated with fatty livers in the realm of transplantation and discuss pharmacological and nonpharmacological options that are being developed to enhance recovery of these organs using machine perfusion and defatting strategies.
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Affiliation(s)
- Yuri L Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK
| | - Amanda P C S Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Joseph Attard
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Darius F Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ricky H Bhogal
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Simon C Afford
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK
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49
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Ahmed EA, El-Badry AM, Mocchegiani F, Montalti R, Hassan AEA, Redwan AA, Vivarelli M. Impact of Graft Steatosis on Postoperative Complications after Liver Transplantation. Surg J (N Y) 2018; 4:e188-e196. [PMID: 30474065 PMCID: PMC6193803 DOI: 10.1055/s-0038-1675236] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/30/2018] [Indexed: 02/07/2023] Open
Abstract
Background Steatotic grafts are more susceptible to ischemia-reperfusion injury than are normal grafts. Therefore, using steatotic grafts for liver transplantation (LT) is associated with high primary dysfunction and decreased survival rates. The aim of this study is to evaluate the impact of graft steatosis on post LT outcomes. Methods A retrospective cohort analysis of 271 LT recipients from 2005 to 2016 was performed and patients were classified based on two types of steatosis, macrosteatosis (MaS), and microsteatosis (MiS). Each category was subdivided into three groups according to the degree of steatosis: no (< 5%), mild (≥5 to < 30%), and moderate (≥30 to ≤60%). The primary hospital stays and 6-month postoperative complications were analyzed by the Clavien-Dindo classification system. Additionally, patient and graft survivals were studied. Results Significant differences were observed in grade III MaS ( p -value = 0.019) and grade V MiS ( p -value = 0.020). A high trend of early graft dysfunction was found in the moderate MaS and MiS groups; however, they were not statistically significant ( p -value = 0.199 and 0.282, respectively). Interestingly, the acute cellular rejection (ACR) rate was found to be inversely proportional to the degree of steatosis in both categories but it did not reach a significant level ( p -value = 0.161 and 0.111, respectively). Conclusion Excellent post LT long-term outcomes using grafts with mild and moderate steatosis were determined. Further studies are needed to evaluate the newly proposed relationship between ACR and steatosis.
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Affiliation(s)
- Emad Ali Ahmed
- Division of Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
- Division of Hepatobiliary and Pancreatic Surgery Unit, Department of General Surgery, University of Sohag, Sohag, Egypt
| | - Ashraf Mohammad El-Badry
- Division of Hepatobiliary and Pancreatic Surgery Unit, Department of General Surgery, University of Sohag, Sohag, Egypt
| | - Federico Mocchegiani
- Division of Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
| | - Roberto Montalti
- Division of Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
| | - Asem Elsani Ali Hassan
- Division of Hepatobiliary and Pancreatic Surgery Unit, Department of General Surgery, University of Sohag, Sohag, Egypt
| | - Alaa Ahmed Redwan
- Division of Hepatobiliary and Pancreatic Surgery Unit, Department of General Surgery, University of Sohag, Sohag, Egypt
| | - Marco Vivarelli
- Division of Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
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50
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Yang F, Wang S, Liu Y, Zhou Y, Shang L, Feng M, Yuan X, Zhu W, Shi X. IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells. Free Radic Biol Med 2018; 124:395-407. [PMID: 29969718 DOI: 10.1016/j.freeradbiomed.2018.06.043] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/29/2018] [Accepted: 06/30/2018] [Indexed: 12/18/2022]
Abstract
Fatty liver is one of the widely accepted marginal donor for liver transplantation, but is also more sensitive to ischemia and reperfusion injury (IRI) and produces more reactive oxygen species (ROS). Moreover, so far, no effective method has been developed to alleviate it. Endoplasmic reticulum stress (ER-stress) of hepatocyte is associated with the occurrence of fatty liver disease, but ER-stress of kupffer cells (KCs) in fatty liver is not clear at all. This study evaluates whether ER-stress of KCs is activated in fatty liver and accelerate IRI of fatty livers. ER-stress of KCs was activated in fatty liver, especially the IRE1α signal pathway. KCs with activated ER-stress secreted more proinflammatory cytokine to induce its M1-phenotypic shift in fatty liver, resulting in more severe IRI. Also, activated ER-stress of BMDMs in vitro by tunicamycin can induce its pro-inflammatory shift and can be reduced by 4-PBA, an ER-stress inhibitor. Knockdown of IRE1α could regulate the STAT1 and STAT6 pathway of macrophage to inhibit the M1-type polarization and promote M2-phenotypic shift. Furthermore, transfusion of IRE1α-knockdown KCs significantly reduced the liver IRI as well as the ROS of HFD feeding mice. Altogether, these data demonstrated that IRE1α of KCs may be a potential target to reduce the fatty liver associated IRI in liver transplantation.
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Affiliation(s)
- Faji Yang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Shuai Wang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Yuan Zhou
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Longcheng Shang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Min Feng
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Xianwen Yuan
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Wei Zhu
- Department of Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China.
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China.
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