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World J Gastroenterol. Dec 7, 2021; 27(45): 7771-7783
Published online Dec 7, 2021. doi: 10.3748/wjg.v27.i45.7771
Chronic rejection after liver transplantation: Opening the Pandora’s box
Roberta Angelico, Bruno Sensi, Tommaso M Manzia, Giuseppe Tisone, Giuseppe Grassi, Alessandro Signorello, Martina Milana, Ilaria Lenci, Leonardo Baiocchi
Roberta Angelico, Bruno Sensi, Tommaso M Manzia, Giuseppe Tisone, Department of Surgery Sciences, HPB and Transplant Unit, University of Tor Vergata, Rome 00100, Italy
Giuseppe Grassi, Alessandro Signorello, Martina Milana, Ilaria Lenci, Leonardo Baiocchi, Hepatology Unit, University of Tor Vergata, Rome 00100, Italy
Author contributions: Angelico R, Sensi B, Manzia TM, Tisone G, Grassi G, Signorello A, Milana M, Lenci I acquisition of data; Angelico R did the analysis and interpretation, drafting of manuscript, critical revision; Sensi B, Manzia TM, Tisone G, Grassi G, Signorello A, Milana M, Lenci I critical revision; Baiocchi L proposal of study, study conception, correction of manuscript, critical revision.
Conflict-of-interest statement: None to disclose by all authors.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Leonardo Baiocchi, MD, PhD, Associate Professor, Hepatology Unit, University of Tor Vergata, Viale Oxford 81, Rome 00100, Italy. baiocchi@uniroma2.it
Received: April 27, 2021
Peer-review started: April 27, 2021
First decision: June 13, 2021
Revised: June 25, 2021
Accepted: November 20, 2021
Article in press: November 20, 2021
Published online: December 7, 2021
Abstract

Chronic rejection (CR) of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation. Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy, CR still represents an important cause of graft injury, which might be irreversible, leading to graft loss requiring re-transplantation. To date, we still do not fully appreciate the mechanisms underlying this process. In addition to T cell-mediated CR, which was initially the only recognized type of CR, recently a new form of liver allograft CR, antibody-mediated CR, has been identified. This has indeed opened an era of thriving research and renewed interest in the field. Liver biopsy is needed for a definitive diagnosis of CR, but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation. Moreover, the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury, which should not be disregarded. Therapies for CR may only be effective in the “early” phases, and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage. Herein, we provide an overview of the current knowledge and research on CR, focusing on early detection, identification of non-invasive biomarkers, immunosuppressive management, re-transplantation and future perspectives of CR.

Keywords: Liver transplantation, Chronic rejection, Immunosuppression, T cell-mediated rejection, Antibody-mediated rejection, Donor-specific antibody, Re-transplantation, Graft loss, Complications, Outcomes

Core Tip: Chronic rejection (CR) still represents a cause of graft loss after liver transplantation. Recent advances in understanding the pathways leading to CR, through a T cell-mediated or antibody mediated injury, are opening new strategies for its management. Early detection of CR, tailored immunosuppressive regimen and strict monitoring are essential to prevent graft loss rejection-related requiring re-transplantation. The current perspectives aim to identify non-invasive biomarkers predicting patients at risk for CR in order to prevent irreversible liver damage by adequate immunosuppressive regimen and improving long-term outcomes after liver transplantation.