ABSTRACT
Liver transplantation is a vital treatment for end-stage liver disease. However, the shortage of donor livers has limited the development of liver transplantation. How to expand the source of donor livers has become a challenge in the academic community. In recent years, the proportion of donors with non-alcoholic fatty liver disease (NAFLD) has been increased. Rational use of steatotic donor livers is a feasible approach to expand the donor pool. Cold ischemia injury during donor liver preservation before liver transplantation increases the risk of postoperative organ dysfunction. Therefore, it is of significance to unravel the mechanism and intervention measures of cold ischemia injury of steatotic donor livers. Cold ischemia injury of steatotic donor livers is characterized as the damage of mitochondria, lysosomes and endoplasmic reticulum at the organelle level, and up-regulated expression of adenosine monphosphate activated protein kinase (AMPK), aldehyde dehydrogenase 2 (ALDH2) and heme oxygenase (HO)-1 at the protein level. In this article, the research progresses on cold ischemia injury of steatotic donor livers and relevant intervention measures were reviewed.
ABSTRACT
Objective:To investigate the prognosis and influencing factors of liver transplantation (LT) for hepatocellular carcinoma (HCC) using steatotic donor liver.Methods:The retrospective cohort study was conducted. The clinicopathological data of 152 pairs of donors and the corresponding recipients undergoing LT for HCC in the two medical centers [89 pairs in Shulan (Hangzhou) Hospital and 63 pairs in the First Affiliated Hospital of Zhejiang University School of Medicine] from January 2015 to December 2019 were collected. Of 152 donors, there were 131 males and 21 females, aged (48±12)years, and there were 130 cases with liver mild steatosis and 22 cases with liver moderate steatosis. Of 152 recipients, there were 138 males and 14 females, aged (52±9)years. Observation indicators: (1) follow-up, overall survival and tumor recurrence free survival of recipients; (2) influencing factors for overall survival and tumor recurrence free survival of recipients; (3) construction and validation of nomogram prediction model for overall survival and tumor recurrence free survival of recipients. Follow-up was conducted using outpatient examination and telephone interview to detect survival and tumor recurrence of recipients up to December 2020. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M( IQR). Count data were described as absolute numbers. The Kaplan-Meier method was used to calculate the survival time and draw survival curve, and the Log-Rank test was used for survival analysis. The COX regression model was used for univariate and multivariate analysis. The independent risk factors were brought into the R 3.6.2 software to construct nomogram prediction model and draw the receiver operating characteristic (ROC) curve. The accuracy and discrimination of the nomogram prediction model were evaluated using the area under curve (AUC) and the calibration curve. Results:(1) Follow-up, overall survival and tumor recurrence free survival of recipients. All the 152 recipients undergoing LT for HCC using steatotic donor liver were followed up for 45.8(27.6)months, with the overall survival time and tumor recurrence free survival time of 36.5(32.3)months and 30.4(34.6)months. The 1-year, 3-year overall survival rates and tumor recurrence free rates of the 152 recipients were 73.4%, 55.8% and 62.2%, 43.4%, respectively. (2) Influencing factors for overall survival and tumor recurrence free survival of recipients. Results of univariate analysis showed that the donor liver cold ischemia time (CIT), the donor liver warm ischemia time (WIT), graft-to-recipient weight ratio (GRWR), ABO compatibility, recipient body mass index (BMI), recipient tumor diameter, recipient tumor number, recipient tumor differentiation degree, recipient preoperative alpha fetoprotein (AFP) were related factors influencing the overall survival of recipients ( hazard ratio=6.26, 1.90, 2.47, 4.08, 0.55, 5.16, 3.62, 5.28, 2.65, 95% confidence interval as 3.01?13.03, 1.07?3.38, 1.36?4.49, 2.07?8.03, 0.31?0.98, 2.56?10.42, 1.95?6.72, 1.60?17.42, 1.48?5.01, P<0.05) and the donor liver CIT, GRWR, ABO compatibility, recipient tumor diameter, recipient tumor number, recipient tumor differentiation degree, recipient preoperative AFP were related factors influencing the tumor recurrence free survival of recipients ( hazard ratio=4.24, 2.53, 4.05, 3.39, 3.10, 5.19, 2.63, 95% confidence interval as 2.50?7.21, 1.54?4.17, 2.12?7.72, 2.04?5.62, 1.91?5.03, 2.04?13.18, 1.61?4.30, P<0.05). Results of multivariate analysis showed that donor liver CIT ≥8 hours, GRWR ≥2.5%, recipient tumor diameter ≥8 cm and recipient preoperative AFP ≥400 μg/L were independent risk factors influencing the overall survival of recipients ( hazard ratio=4.21, 2.58, 4.10, 2.27, 95% confidence interval as 1.98?8.96, 1.24?5.35, 1.35?12.43, 1.13?4.56, P<0.05) and donor liver CIT ≥8 hours, GRWR ≥2.5%, recipient tumor diameter ≥8 cm, recipient tumor number ≥3 and recipient preoperative AFP ≥400 μg/L were independent risk factors influencing the tumor recurrence free survival of recipients ( hazard ratio=3.37, 2.63, 2.42, 2.12, 2.22, 95% confidence interval as 1.70?6.67, 1.40?4.96, 1.04?5.66, 1.08?4.18, 1.26?3.90, P<0.05). (3) Construction and validation of nomogram prediction model for overall survival and tumor recurrence free survival of recipients. The donor live CIT, GRWR, recipient tumor diameter, recipient preoperative AFP were used to construct nomogram prediction model for overall survival of recipients and the donor liver CIT, GRWR, recipient tumor diameter, recipient tumor number, recipient preoperative AFP were used to construct nomogram prediction model for tumor recurrence free survival of recipients. The ROC curve showed that the AUC of the nomogram prediction model for overall survival of recipients was 0.84 (95% confidence interval as 0.76?0.92, P<0.05), with the optimal diagnostic value as 7.3 and the specificity and sensitivity as 87.6% and 70.0%. The AUC of the nomogram prediction model for tumor recurrence free survival of recipients was 0.79 (95% confidence interval as 0.71?0.87, P<0.05), with the optimal diagnostic value as 5.8 and the specificity and sensitivity as 97.4% and 52.5%. The calibration curve showed that the nomogram prediction model had good distinction for high risk recipients in overall survival and tumor recurrence free survival. Conclusion:Donor liver CIT ≥8 hours, GRWR ≥2.5%, recipient tumor diameter ≥8 cm and recipient preoperative AFP ≥400 μg/L are independent risk factors influencing the overall survival of recipients who underwent LT for HCC using steatotic donor liver and donor liver CIT ≥8 hours, GRWR ≥2.5%, recipient tumor diameter ≥8 cm, recipient tumor number ≥ 3 and recipient preoperative AFP ≥400 μg/L are independent risk factors influencing the tumor recurrence free survival of recipients.
ABSTRACT
Objective:To investigate the role of ferroptosis in bone marrow mesenchymal stem cells (BMMSCs) combine with normothermic machine perfusion (NMP) in repairing steatotic liver donor after cardiac death (DCD) in SD rats.Methods:BMMSCs were derived from SD rats to establish the DCD model of rats steatotic liver. A total of 24 rats were randomly divided into four groups: simple steatotic liver model group (Sham), static cold storage group (SCS), NMP, BMMSCs combine with NMP preservation group (BNMP), and the preservation time was 4 hours. The donor liver function was evaluated by liver structure, liver enzymes and lactic acid content of perfusion fluid, bile secretion and inflammatory cytokines; furthermore, in order to evaluate the occurrence of liver ferroptosis, the content of Fe 2+, malondialdehyde and glutathione (GSH) in liver tissue, as well as the mRNA or protein expression changes of cyclooxygenase-2 (COX-2), prostaglandin-endoperoxide synthase 2 (Ptgs2), glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) were detected. Results:After DCD steatotic donor liver was preserved for 4 hours, the liver injury, pro-inflammatory and anti-inflammatory cytokines expression in the BNMP and NMP groups were better than those in the SCS group. During the machine perfusion preservation period, alanine aminotransferase [(189.0±12.5)U/L vs. (227.7±16.2)U/L], aspartate aminotransferase [(207.3±18.6)U/L vs. (247.0±11.8)U/L] and lactic acid [(2.3±0.3)mmol/L vs. (2.9±0.2)mmol/L] in the BNMP group is lower than those in NMP group, moreover, the amount of hepatic bile secretion in the BNMP group [(1 245.7±46.8) μl vs. (1 014.3±67.9) μl] was more than that in NMP group, the difference was statistically significant (all P<0.05). The content of Fe 2+ and malondialdehyde in the liver tissue of BNMP group was significantly lower than those of SCS and NMP groups, on the contrary, the content of GSH was significantly higher than those of SCS and NMP groups. In addition, in the BNMP group, the mRNA level of Ptgs2 and protein level of COX-2 in the liver were significantly reduced, and expression of GPX4 and FTH1 were significantly higher than those of NMP and SCS groups, the differences were statistically significant (all P<0.05). Conclusion:BMMSCs combine with normothermic machine perfusion can better repair SD rats DCD steatotic donor liver and its mechanism of action may be related to its regulation on liver ferroptosis.