Coagulation Factors Accumulate During Normothermic Liver Machine Perfusion Regardless of Donor Type and Severity of Ischemic Injury.

BACKGROUND: Coagulation factors may inform on liver function during normothermic machine perfusion (NMP). We investigated whether graft ischemic injury impairs the accumulation of anticoagulation factors during NMP of porcine and human livers. METHODS: Dynamics of FV, FVII, FVIII, FIX, and FX during NMP and their correlation with graft injury was investigated in porcine livers with minimal (no warm ischemia, n = 5) or severe injury (60 min warm ischemia, n = 5). Next, FV, FVIII, FIX, fibrinogen, and antithrombin were measured in 35 matched human liver NMPs from the COPE trial. Correlation of these factors with outcomes was explored. Livers were categorized in to 4 groups depending on donor type and posttransplant peak aspartate aminotransferase (AST) as surrogate of minimal (peak < 500 IU/L) or moderate injury (peak > 1000 IU/L). RESULTS: Factor concentrations increased significantly during NMP regardless of severity of injury. In porcine livers, factor concentrations were 2- to 6-fold lower in severely injured grafts (all P < 0.05). All factors negatively correlated with AST (coefficient range: from -0.50 to -0.93; all P < 0.05) and lactate (range: from -0.51 to -0.67; all P < 0.05). In human livers, no difference in factor accumulation rates and no correlation with other markers were observed. One graft with primary nonfunction had low rate of factor accumulation. CONCLUSIONS: Anticoagulation factors accumulate during NMP regardless of donor type and severity of injury. In pigs, severe ischemic injury resulted in significantly lower factor concentrations. In human livers with life-sustaining function, they do not correlate with hepatic injury. Whether low concentrations predict nonfunction in high-risk livers with severe injury requires further investigation.

Porcine Isolated Liver Perfusion for the Study of Ischemia Reperfusion Injury: A Systematic Review.

BACKGROUND: Understanding ischemia reperfusion injury (IRI) is essential to further improve outcomes after liver transplantation (LT). Porcine isolated liver perfusion (ILP) is increasingly used to reproduce LT-associated IRI in a strictly controlled environment. However, whether ILP is a reliable substitute of LT was never validated. METHODS: We systematically reviewed the current experimental setups for ILP and parameters of interest reflecting IRI. RESULTS: Isolated liver perfusion was never compared with transplantation in animals. Considerable variability exists between setups, and comparative data are unavailable. Experience so far suggests that centrifugal pump(s) with continuous flow are preferred to reduce the risk of embolism. Hepatic outflow can be established by cannulation of the inferior vena cava or freely drained in an open bath. Whole blood at approximately 38°C, hematocrit of 20% or greater, and the presence of leukocytes to trigger inflammation is considered the optimal perfusate. A number of parameters related to the 4 liver compartments (hepatocyte, cholangiocyte, endothelium, immune cells) are available; however, their significance and relation to clinical outcomes is not well described. CONCLUSIONS: Porcine ILP provides a reproducible model to study early IRI events. As all models, it has its limitations. A standardization of the setup would allow comparison of data and progress in the field.

Short-term outcomes of paediatric liver transplant recipients after transition to Adult Healthcare Service.

BACKGROUND & AIMS: Survival rates after liver transplantation (LT) in paediatric recipients have significantly improved over time. However, data regarding outcomes after transition from Paediatric to Adult Healthcare Service (AHS) are still lacking. Therefore, we aimed to prospectively evaluate the outcome of LT recipients after transition, to access patients' non-adherence and identify potential risk factors for non-adherence. METHODS: All consecutive adolescent LT recipients moving to the AHS at Padua University Hospital were evaluated between 2010 and 2015. Demographic data, liver function tests, incidence of acute or chronic rejection episodes and adherence to medical prescription, were prospectively evaluated. An educational pilot study was implemented since 2015 to foster adherence during transition. RESULTS: In all, 32 patients (M/F 16/16, median age: 23 years) were evaluated. Median interval time between LT and transition was 15 years (range: 1-26 years). The main indication for LT was biliary atresia (31%), whereas immunosuppression regimen was tacrolimus-based in 75%. After a median follow-up of 29 months (range: 12-83), no significant modifications of liver function tests were observed. Biopsy-proven chronic rejection was diagnosed in 6/32 (18%) of patients, who had higher standard deviation of tacrolimus trough level than patients without (1.5 vs 1, P = .03). Non-adherence was reported in 8/32 (25%) of patients and was significantly associated with alcohol consumption (P = .003). Patient and graft survival were 96% and 93%, respectively. CONCLUSIONS: Adolescent LT patients who undergo transition to the AHS have good long-term outcomes. However, a multidisciplinary approach aiming at fostering adherence should be used.

Female gender in the setting of liver transplantation.

The evolution of liver diseases to end-stage liver disease or to acute hepatic failure, the evaluation process for liver transplantation, the organ allocation decision-making, as well as the post-transplant outcomes are different between female and male genders. Women's access to liver transplantation is hampered by the use of model for end-stage liver disease (MELD) score, in which creatinine values exert a systematic bias against women due to their lower values even in the presence of variable degrees of renal dysfunction. Furthermore, even when correcting MELD score for gender-appropriate creatinine determination, a quantifiable uneven access to transplant prevails, demonstrating that other factors are also involved. While some of the differences can be explained from the epidemiological point of view, hormonal status plays an important role. Moreover, the pre-menopausal and post-menopausal stages imply profound differences in a woman's physiology, including not only the passage from the fertile age to the non-fertile stage, but also the loss of estrogens and their potentially protective role in delaying liver fibrosis progression, amongst others. With menopause, the tendency to gain weight may contribute to the development of or worsening of pre-existing metabolic syndrome. As an increasing number of patients are transplanted for non-alcoholic steatohepatitis, and as the average age at transplant increases, clinicians must be prepared for the management of this particular condition, especially in post-menopausal women, who are at particular risk of developing metabolic complications after menopause.

Adherence in liver transplant recipients.

Adherence to a medical regimen has been defined as the extent to which a patient's behavior coincides with clinical prescriptions. In liver transplant patients, adherence to immunosuppressive therapy and to medical indications in general is crucial for short- and long-term outcomes. Nonadherence to immunosuppression carries a risk of graft rejection and potential graft loss, whereas nonadherence to general medical indications (eg, avoiding alcohol intake and smoking after transplantation) may be associated with other complications such as de novo tumors and increasing health care costs. Among adult liver transplant patients, the rate of nonadherence to immunosuppressive drugs ranges from 15% to 40%, whereas the rate of nonadherence to clinical appointments ranges from 3% to 47%. The wide range of reported rates is due to different definitions of the term nonadherence and the variety of methods used to measure adherence in the medical literature. Nonadherence seems to be nearly 4 times higher in pediatric and adolescent patients versus adult transplant recipients. Several nonadherence risk factors, such as high medication costs, psychiatric disorders, the conviction that the medication is harmful, and side effects of immunosuppressive therapy, have been described among adult liver transplant patients. The risk factors for nonadherence in pediatric and adolescent liver transplant patients are psychological distress, the functional status of their families, and the impact of immunosuppressive side effects on their physical appearance. A single approach to promoting adherence to general medical prescriptions has been proved to be ineffectual, so a multidisciplinary strategy should be adopted to achieve significant improvements in this field. The aim of this review is to analyze the published literature on adherence in liver transplant patients with a particular focus on the reported prevalence and the identified risk factors. Patients have been split into 2 age groups (adults and children/adolescents) because the scale of the problem and the potential risk factors differ in the 2 groups.