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International Journal of Molecular... Nov 2020The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed.... (Review)
Review
The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.
Topics: Animals; Fatty Liver; Hepatectomy; Humans; Liver; Liver Regeneration; Liver Transplantation
PubMed: 33182515
DOI: 10.3390/ijms21218414 -
Journal of Hepatology Jun 2023With the increasing number of accepted candidates on waiting lists worldwide, there is an urgent need to expand the number and the quality of donor livers. Dynamic... (Review)
Review
With the increasing number of accepted candidates on waiting lists worldwide, there is an urgent need to expand the number and the quality of donor livers. Dynamic preservation approaches have demonstrated various benefits, including improving liver function and graft survival, and reducing liver injury and post-transplant complications. Consequently, organ perfusion techniques are being used in clinical practice in many countries. Despite this success, a proportion of livers do not meet current viability tests required for transplantation, even with the use of modern perfusion techniques. Therefore, devices are needed to further optimise machine liver perfusion - one promising option is to prolong machine liver perfusion for several days, with ex situ treatment of perfused livers. For example, stem cells, senolytics, or molecules targeting mitochondria or downstream signalling can be administered during long-term liver perfusion to modulate repair mechanisms and regeneration. Besides, today's perfusion equipment is also designed to enable the use of various liver bioengineering techniques, to develop scaffolds or for their re-cellularisation. Cells or entire livers can also undergo gene modulation to modify animal livers for xenotransplantation, to directly treat injured organs or to repopulate such scaffolds with "repaired" autologous cells. This review first discusses current strategies to improve the quality of donor livers, and secondly reports on bioengineering techniques to design optimised organs during machine perfusion. Current practice, as well as the benefits and challenges associated with these different perfusion strategies are discussed.
Topics: Animals; Liver Transplantation; Organ Preservation; Liver; Perfusion; Bioengineering
PubMed: 37208105
DOI: 10.1016/j.jhep.2023.02.009 -
Liver Transplantation : Official... May 2020Robust physical activity after liver transplantation is an important determinant of longterm health, similar in its importance to the value of pretransplant activity for... (Review)
Review
Robust physical activity after liver transplantation is an important determinant of longterm health, similar in its importance to the value of pretransplant activity for withstanding the immediate stress of transplantation. Although transplantation normally enables rapid recovery of liver synthetic and metabolic functions, the recovery of physical capacity and performance to normal levels is delayed and often incomplete. Anatomic measurements of sarcopenia and the physical performance indicators of frailty both tend to improve slowly, and they may, in fact, decrease further in the posttransplant period, especially when the common extrahepatic drivers of muscle loss, such as the elements of the metabolic syndrome, persist or intensify after transplantation. Posttransplant exercise improves fitness, which is a conclusion based on 2 observational studies and 3 randomized trials that assessed endpoints of strength testing, energy expenditure in metabolic equivalents, and peak or maximal oxygen uptake. Importantly, 1 controlled trial found that exercise also improved quality of life (QOL) measured by the Short Form 36 survey, consistent with multiple reports of the value of social support and engagement in sports activity for improving posttransplant QOL. Developing evidence-based standards for post-liver transplant physical activity baseline testing and sustainment of intensity and quality is a key unmet need in transplant hepatology. At present, it is reasonable for transplant teams to assess fitness and design a tailored exercise program when a recipient is first discharged, to record and reinforce progress at all posttransplant visits, and to set realistic longterm performance goals that will often achieve recommended standards for the healthy general population.
Topics: Exercise; Exercise Therapy; Humans; Liver Transplantation; Quality of Life; Sarcopenia
PubMed: 32128971
DOI: 10.1002/lt.25742 -
Journal of Hepatology Aug 2023Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes.
METHODS
In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI.
RESULTS
Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025).
CONCLUSIONS
Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach.
CLINICAL TRIAL REGISTRATION
chictr.org. ChiCTR1900021158.
IMPACT AND IMPLICATIONS
Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.
Topics: Humans; Liver Transplantation; End Stage Liver Disease; Ischemia; Liver; Reperfusion Injury; Perfusion; Organ Preservation
PubMed: 37086919
DOI: 10.1016/j.jhep.2023.04.010 -
Journal of Hepatology Jun 2023Liver transplantation (LT) is a life-saving treatment for individuals with end-stage liver disease. The management of LT recipients is complex, predominantly because of... (Review)
Review
Liver transplantation (LT) is a life-saving treatment for individuals with end-stage liver disease. The management of LT recipients is complex, predominantly because of the need to consider demographic, clinical, laboratory, pathology, imaging, and omics data in the development of an appropriate treatment plan. Current methods to collate clinical information are susceptible to some degree of subjectivity; thus, clinical decision-making in LT could benefit from the data-driven approach offered by artificial intelligence (AI). Machine learning and deep learning could be applied in both the pre- and post-LT settings. Some examples of AI applications pre-transplant include optimising transplant candidacy decision-making and donor-recipient matching to reduce waitlist mortality and improve post-transplant outcomes. In the post-LT setting, AI could help guide the management of LT recipients, particularly by predicting patient and graft survival, along with identifying risk factors for disease recurrence and other associated complications. Although AI shows promise in medicine, there are limitations to its clinical deployment which include dataset imbalances for model training, data privacy issues, and a lack of available research practices to benchmark model performance in the real world. Overall, AI tools have the potential to enhance personalised clinical decision-making, especially in the context of liver transplant medicine.
Topics: Humans; Liver Transplantation; Artificial Intelligence; Deep Learning; End Stage Liver Disease; Machine Learning
PubMed: 37208107
DOI: 10.1016/j.jhep.2023.01.006 -
Annals of Hepatology 2022The Child-Turcotte-Pugh (CTP) and the MELD (Model for End-Stage Liver Disease) scores were designed to predict the outcome of decompressive therapy for portal... (Review)
Review
The Child-Turcotte-Pugh (CTP) and the MELD (Model for End-Stage Liver Disease) scores were designed to predict the outcome of decompressive therapy for portal hypertension. They were prospectively validated to predict mortality risk in patients with a wide spectrum of liver disease etiology and severity. Unlike the CTP score, the MELD score was derived from prospectively gathered data. Its calculation was based on serum bilirubin, serum creatinine, international normalized ratio (INR) and etiology of liver disease. Instituting a continuous disease severity score that de-emphasizes waiting time resulted in better categorization of waiting patients and enhanced transparency. The US instituted the MELD system in 2002 and soon thereafter, MELD-based liver allocation was adopted throughout the world including Latin America. The most significant impact of MELD-based policies has been the reduction of waiting-list mortality. In the years after implementation of the MELD system, several options have been proposed to improve the MELD score's accuracy. Adding serum sodium (MELD-Na) increased the accuracy of the score in predicting waiting list mortality, thus completing the original MELD score as a prognostic model in liver allocation. On the 20th anniversary of the creation of MELD score we present a brief account of its development, its use to stratify patients on the waiting list for liver transplantation as well as its adoption as liver allocation system .
Topics: End Stage Liver Disease; Humans; Liver Transplantation; Prognosis; ROC Curve; Severity of Illness Index; Waiting Lists
PubMed: 34560316
DOI: 10.1016/j.aohep.2021.100535 -
Frontiers in Immunology 2022Rejection is still a critical barrier to the long-term survival of graft after liver transplantation, requiring clinicians to unveil the underlying mechanism of liver...
Rejection is still a critical barrier to the long-term survival of graft after liver transplantation, requiring clinicians to unveil the underlying mechanism of liver transplant rejection. The cellular diversity and the interplay between immune cells in the liver graft microenvironment remain unclear. Herein, we performed single-cell RNA sequencing analysis to delineate the landscape of immune cells heterogeneity in liver transplantation. T cells, NK cells, B cells, and myeloid cell subsets in human liver and blood were enriched to characterize their tissue distribution, gene expression, and functional modules. The proportion of CCR6+CD4+ T cells increased within an allograft, suggesting that there are more memory CD4+ T cells after transplantation, in parallel with exhausted CTLA4+CD8+ T and actively proliferating MKI67+CD8+ T cells increased significantly, where they manifested heterogeneity, distinct function, and homeostatic proliferation. Remarkably, the changes of CD1c+ DC, CADM+ DC, MDSC, and FOLR3+ Kupffer cells increase significantly, but the proportion of CD163+ Kupffer, APOE+ Kupffer, and GZMA+ Kupffer decreased. Furthermore, we identified LDLR as a novel marker of activated MDSC to prevent liver transplant rejection. Intriguingly, a subset of CD4+CD8+FOXP3+ T cells included in CTLA4+CD8+ T cells was first detected in human liver transplantation. Furthermore, intercellular communication and gene regulatory analysis implicated the LDLR+ MDSC and CTLA4+CD8+ T cells interact through TIGIT-NECTIN2 signaling pathway. Taken together, these findings have gained novel mechanistic insights for understanding the immune landscape in liver transplantation, and it outlines the characteristics of immune cells and provides potential therapeutic targets in liver transplant rejection.
Topics: CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Humans; Liver Transplantation; Sequence Analysis, RNA; Transplantation, Homologous
PubMed: 35619708
DOI: 10.3389/fimmu.2022.890019 -
Best Practice & Research. Clinical... Mar 2020The combined transplantation of a thoracic organ and the liver is performed in patients with dual-organ failure in whom survival is not expected with single-organ... (Review)
Review
The combined transplantation of a thoracic organ and the liver is performed in patients with dual-organ failure in whom survival is not expected with single-organ transplantation alone. Although uncommonly performed, the number of combined liver-lung and liver-heart transplants is increasing. Anesthetic management of this complex procedure is challenging. Major blood loss, prolonged operation time, difficult weaning of cardiopulmonary bypass and coagulation disturbances are common. Despite the complexity of surgery, the outcome is comparable to single-organ transplant.
Topics: Anesthesia; Heart Transplantation; Humans; Liver Transplantation; Lung Transplantation; Organ Transplantation; Thoracic Surgical Procedures
PubMed: 32334780
DOI: 10.1016/j.bpa.2020.01.001 -
Journal of Hepatology Apr 2023Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear.
METHODS
In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints.
RESULTS
Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015).
CONCLUSIONS
HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events.
IMPACT AND IMPLICATIONS
This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies.
Topics: Humans; Organ Preservation; Perfusion; Liver; Liver Transplantation; Brain Death; Postoperative Complications; Graft Survival
PubMed: 36681160
DOI: 10.1016/j.jhep.2022.12.030 -
International Journal of Surgery... Oct 2020Orthotopic liver transplantation is an established treatment for end stage liver diseases as well as for some severe metabolic disorders. With increasing number of... (Review)
Review
Orthotopic liver transplantation is an established treatment for end stage liver diseases as well as for some severe metabolic disorders. With increasing number of patients on the waiting list and the ongoing shortage of livers available, domino liver transplantation (DLT) became an option to further expand the organ donor pool. DLT utilizes the explanted liver of one liver transplant recipient as a donor graft in another patient. Despite being a surgically, and logistically demanding procedure, excellent results could be achieved in experienced high-volume transplant centers. In this review we present the current world status of DLT.
Topics: Amyloid Neuropathies, Familial; End Stage Liver Disease; Humans; Liver; Liver Transplantation; Living Donors; Patient Selection; Registries; Transplant Recipients; Transplants; Waiting Lists
PubMed: 32244002
DOI: 10.1016/j.ijsu.2020.03.017