Citation: Avramidou, E.; Vasileiadou, S.; Antoniadis, N.; Katsanos, G.; Kofinas, A.; Karakasi, K.-E.; Tsoulfas, G. Liver Transplantation and dd-cfDNA: A Small Solution for a Big Problem. Livers 2023, 3, 76–81. https://doi.org/10.3390/ livers3010007 Academic Editor: Ralf Weiskirchen Received: 29 November 2022 Revised: 14 February 2023 Accepted: 15 February 2023 Published: 20 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Opinion Liver Transplantation and dd-cfDNA: A Small Solution for a Big Problem Eleni Avramidou * , Stella Vasileiadou , Nikolaos Antoniadis, Georgios Katsanos , Athanasios Kofinas , Konstantina-Eleni Karakasi and Georgios Tsoulfas Departmentof Transplant Surgery, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece * Correspondence: avramidoue@auth.gr Abstract: Dd-cfDNA is a novel biomarker with many diagnostic applications in various areas of medicine. In this review of the literature, we investigate its role in the diagnosis of many complications that occur in liver transplantations. In our review, we retrieved data from the medical databases PubMed and Scopus. In our bibliography, many areas concerning the contributions of dd-cfDNA to the field of liver transplantation, such as in the diagnosis of complications that include signsof rejection or graft injury, are mentioned. Dd-cfDNA, which are correlated with other biomarkers such as liver enzymes, can have a high diagnostic value. Measurements of Dd-cfDNA also depend on the graft’s size and origin; therefore, these data should be taken into account for the estimation and explanation of dd-cfDNA values. Despite the utility of this novel diagnostic technique, it comes with some limitations and applicational exclusions, such as cases where there is a blood relation between the donor and recipient. Keywords: dd-cfDNA; liver transplantation; graft injury; rejection; biomarker 1. Introduction Long-term survival beyond the first year after liver transplantation (LT) has not significantly improved in the past decades due to many factors, including the long-term effects of immunosuppression and graft dysfunction. An important obstacle to LT is the lack of a reliable and non-invasive biomarker with which to determine graft function and the general success of transplantation. In clinical practice, liver enzymes are usually used for the determination of graft function post LT [1]. Serum measurement of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may be a non-invasive procedure, but it comes with certain limitations. Firstly, these enzymes are not liver- specific, and even when they are targeted towards the liver, they only reflect damage to specific cell types (hepatocytes or cholangiocytes). Moreover, they have long half- lives, which limits their ability to detect rapid damage [1,2]. Another and more accurate alternative procedure is surveillance liver graft biopsy (svLBxs). Although this method is more specific and accurate than the measurement of liver enzymes, when considering the complexity and large size of the liver, its sensitivity is far from 100%, which often leads to an inaccurate diagnosis. This, in combination with its high cost and the fact that it is an invasive procedure, have led to svLBxs’ exclusion from the routine examination of liver transplant recipients [3]. Donor-derived cell-free DNA (dd-cfDNA) has been heralded as a non-invasive, accu- rate biomarker with which to monitor liver transplant recipients. dd-cfDNA is a biomarker whose use has increased in the last several years, with potential applications including the early detection of cancer and graft dysfunction in various types of transplantation [4]. This biomarker is measured in serum and its assessment includes an evaluation of its quantity, but also an investigation of some quality characteristics, such as the size of the fragments and methylation patterns [5]. Particularly, for its detection in serum, various types of Livers 2023, 3, 76–81. https://doi.org/10.3390/livers3010007 https://www.mdpi.com/journal/livers