The short and long-term prognostic influences of liver grafts with high bilirubin levels at the time of organ recovery.

BACKGROUND: Donors with hyperbilirubinemia are often not utilized for liver transplantation (LT) due to concerns about potential liver dysfunction and graft survival. The potential to mitigate organ shortages using such donors remains unclear. METHODS: This study analyzed adult deceased donor data from the United Network for Organ Sharing database (2002-2022). Hyperbilirubinemia was categorized as high total bilirubin (3.0-5.0 mg/dL) and very high bilirubin (≥5.0 mg/dL) in brain-dead donors. We assessed the impact of donor hyperbilirubinemia on 3-month and 3-year graft survival, comparing these outcomes to donors after circulatory death (DCD). RESULTS: Of 138 622 donors, 3452 (2.5%) had high bilirubin and 1999 (1.4%) had very high bilirubin levels. Utilization rates for normal, high, and very high bilirubin groups were 73.5%, 56.4%, and 29.2%, respectively. No significant differences were found in 3-month and 3-year graft survival between groups. Donors with high bilirubin had superior 3-year graft survival compared to DCD (hazard ratio .83, p = .02). Factors associated with inferior short-term graft survival included recipient medical condition in intensive care unit (ICU) and longer cold ischemic time; factors associated with inferior long-term graft survival included older donor age, recipient medical condition in ICU, older recipient age, and longer cold ischemic time. Donors with ≥10% macrosteatosis in the very high bilirubin group were also associated with worse 3-year graft survival (p = .04). DISCUSSION: The study suggests that despite many grafts with hyperbilirubinemia being non-utilized, acceptable post-LT outcomes can be achieved using donors with hyperbilirubinemia. Careful selection may increase utilization and expand the donor pool without negatively affecting graft outcome.

Asystolic donor warm ischemia time is associated with development of postreperfusion syndrome in donation after circulatory death liver transplant.

BACKGROUND: Individual events during donation after circulatory death (DCD) procurement, such as hypotensive or hypoxic warm ischemia, or circulatory arrest are all a part of donor warm ischemia time (dWIT), and may have differing effects on the outcome of the liver graft. This study aimed to identify risk factors for postreperfusion syndrome (PRS), a state of severe hemodynamic derangement following graft reperfusion, and its impact on DCD liver transplantation (LT) outcomes. METHODS: This was a retrospective analysis using 106 DCD LT. Detailed information for events during procurement (withdrawal of life support; systolic blood pressure < 80 mmHg; oxygen saturation < 80%; circulatory arrest; aortic cold perfusion) and their association with the development of PRS were examined using logistic regression. RESULTS: The overall incidence of PRS was 26.4%, occurring in 28 patients. Independent risk factors for PRS were asystolic dWIT (odds ratio (OR) 3.65, 95% confidence interval (CI) 1.38-9.66) and MELD score (OR 1.06, 95% CI 1.01-1.10). Total bilirubin was significantly higher in the PRS group at postoperative day (POD) 1 (p = .02; 5.2 mg/dL vs. 3.4 mg/dL), POD 3 (p = .049; 4.5 mg/dL vs. 2.8 mg/dL), and POD 7 (p = .04; 3.1 mg/dL vs. 1.9 mg/dL). Renal replacement therapy after LT was more likely to be required in the PRS group (p = .01; 48.2% vs. 23.1%). CONCLUSION: Asystolic dWIT is a risk factor for the development of PRS in DCD LT. Our results suggest that asystolic dWIT should be considered when selecting DCD liver donors.

Validation of Japanese indication criteria for deceased donor liver transplantation for hepatocellular carcinoma: Analysis of US national registry data.

AIM: The Japanese indication criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC) have been updated based on living donor LT data to include either the Milan criteria (MC) or the 5-5-500 rule, which requires a nodule size of ≤5 cm, ≤5 nodules, and an alpha-fetoprotein (AFP) level ≤500 ng/mL. We aimed to validate the 5-5-500 rule and the MC for deceased donor LT (DDLT). METHODS: Using national registry data from the United States from 2010 to 2014, we separated DDLT patients into four groups based on the MC and the 5-5-500 rule. The AFP values were stratified into categories: ≤100, 101-300, 301-500, and >500 ng/mL. RESULTS: The 5-year survival rate was significantly lower for patients in the groups within MC/beyond 5-5-500 (56.3%) or beyond MC/5-5-500 (60.7%) than for patients in the groups within MC/5-5-500 (76.2%) and beyond MC/within 5-5-500 (72.3%) (p < 0.01). Hepatocellular carcinoma recurrence at 5 years was highest for the within MC/beyond 5-5-500 (25.4%) group, followed by the beyond MC/within 5-5-500 (13.1%), beyond MC/5-5-500 (9.6%), and within MC/5-5-500 (7.4%) groups. The stratified 5-year survival rates after DDLT were 76.5%, 72.4%, 58.4%, and 55.6% in the AFP ≤100, 101-300, 301-500, and >500 categories, respectively (p < 0.01). CONCLUSION: The 5-5-500 rule guides the appropriate selection of patients with HCC for DDLT. Patients with AFP levels from 300 to 500 ng/mL had inferior outcomes even when they met the 5-5-500 rule, so further investigation is needed to guide their treatment.

Impact of albumin-lymphocyte-platelet-C-reactive protein index as a prognostic indicator of hepatocellular carcinoma after resection: Associated with nuclear factor erythroid 2-related factor 2.

AIM: To investigate the prognostic value of the preoperative albumin-lymphocyte-platelet-C-reactive protein (ALPC) index in patients with hepatocellular carcinoma (HCC) undergoing curative hepatectomy. We also evaluated the relationship between the ALPC index and the phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) levels. METHODS: Data were analyzed retrospectively from 256 patients who underwent resection for HCC. For cross-validation, patients were divided into the training and testing cohort. We assessed eight combinations of inflammatory markers for predictive value for recurrence. We examined the associations of the ALPC index with recurrence-free survival and overall survival in univariate and multivariate analyses (Cox proportional hazards model). Immunohistochemical staining of p-Nrf2 was performed on tumor samples of 317 patients who underwent hepatic resection for HCC. RESULTS: A high preoperative ALPC index correlated with a high serum albumin concentration, small tumor size, low rate of poor differentiation, solitary tumor, early Barcelona Clinic Liver Cancer stage, and low rate of microscopic intrahepatic metastasis in the training dataset. A high preoperative ALPC index correlated with a high serum albumin concentration, high serum alpha-fetoprotein concentration, small tumor size, a low rate of poor differentiation and a low rate of microscopic intrahepatic metastasis in the testing dataset. A higher preoperative ALPC index was an independent predictor of longer recurrence-free survival and overall survival in the training and testing datasets. A high ALPC index was associated with negative p-Nrf2 expression in HCC tumor cells. CONCLUSIONS: We showed that a high ALPC index was an independent prognostic factor for patients with HCC undergoing curative hepatic resection.

The learning curve of liver procurement from donation after circulatory death donor.

PURPOSE: This study aimed to evaluate the learning curve for donation after circulatory death (DCD) liver procurement. METHODS: DCD liver procurements performed by a single surgeon (n = 36) were separated into two phases: the learning and established phases. RESULTS: A cumulative sum analysis using the operative donor warm ischemia time (oWIT) and donor hepatectomy time (dHT) showed that ten and seven cases, respectively, were needed for stable surgical procedures. The established phase (n = 26, since Case 11) was likely to have a shorter oWIT (p = 0.06; 7.5 min vs. 9 min) and dHT (p = 0.09; 32 min vs. 37 min) than the learning phase. While the hospital stay was significantly shorter and donor age was older in the established phase (p = 0.04 and p < 0.01; 12 days vs. 41 days and 38 years vs. 24 years, respectively), the incidence rates of post-transplant complications such as early allograft dysfunction (p = 0.74) and vascular complications (p = 0.53) were similar. CONCLUSIONS: The learning curve for DCD liver procurement demonstrated that 10 cases were required to establish these techniques. The oWIT and dHT for DCD liver procurement can represent markers of operative efficiency.

Improved outcomes of liver resection for hepatitis C-related hepatocellular carcinoma after the introduction of direct-acting antiviral therapy.

BACKGROUND: Assess impact of direct-acting antivirals introduction on outcomes after liver resection for hepatocellular carcinoma. METHODS: 391 patients (1991-2021) treated with resection for hepatocellular carcinoma on Hepatitis C background were divided according to receiving Hepatitis C treatment, treatment type, achievement of sustained virological response (SVR), time of resection pre- (Era 1, 1991-2011) and post-direct acting antivirals introduction (Era 2, 2012-2021). Survival was estimated with Kaplan-Meier curves, Cox regression analysis performed to identify survival predictors. RESULTS: Majority of patients had single lesion (67.8%), diameter >2 cm in 60.6%, no evidence of macroscopic vascular invasion on imaging. Pathology showed vascular invasion in 69.6% of patients, 76.5% microvascular. Recurrence developed in 247 patients (63.2%). 194 patients (49.6%) achieved SVR. Overall survival at 1-, 3-, 5-years was 94.6%, 85.7%, 78.8% for patients who achieved SVR, 80.1%, 48.1%, 29.9% in those who did not (p < 0.001). 220 patients (56.3%) were in Era 1, 171 (43.7%) in Era 2. Survival at 1-, 3-, 5-years was 76.1%, 49%, 36% in Era 1, 94.5%, 82.5%, 70.3% in Era 2 (p < 0.001). SVR was an independent predictor of survival on multiple Cox Regression analysis. CONCLUSION: While many aspects of HCC management have evolved, SVR following direct-acting antivirals independently improves HCC resection outcomes.

The Importance of Segment 4 Anatomy on Outcomes Following Living Donor Left Lateral Segmentectomy.

BACKGROUND: During left lateral section (LLS) resection for live liver donation, the vascular inflow and the bile drainage of segment 4 (S4) are compromised. We investigated the long-term changes of S4 after donation and their potential prognostic impact on living liver donors. MATERIALS AND METHODS: This was a retrospective analysis of 42 consecutive left lateral (LLS, S2/3) liver resections for living donation. RESULTS: There were 25 female and 17 male donors. Median age was 33 y and median body mass index was 26. Median LLS, S2/3, volume was 262 cc, and median sS4 volume was 160 cc. Complications were encountered in three donors (7%). An independent extrahepatic S4 artery (S4A) (with a proximal left heptic artery or a right hepatic artery origin) was identified in 41% of the donors. Ligation of the independent S4A was not associated with the rate of post resection liver dysfunction, complications, or the degree of S4 atrophy. Having a dominant S4 portal triad pedicle feeding the right anterior sectors, segment 5/8, of the liver was associated with increased parenchymal damage as evidenced by a higher peak of alanine aminotransferase but was not associated with postoperative complications. The median degree of atrophy of S4 at 1 y post donation as noted on imaging was 66%. The presence of a dominant S4 portal triad pedicle and the peak alanine aminotransferase early postoperatively were both predictors of the degree of S4 atrophy post donation. CONCLUSIONS: The presence of an independent S4A or dominant S4 portal triad pedicle feeding the liver right anterior sectors, segment 5/8, should not be a contraindication for left lateral segment living donation.

The impact of geographic location versus center practice on center volume in liver transplantation after the acuity circle policy.

BACKGROUND: The allocation system for livers used the acuity circles (AC) beginning in 2020. In this study, we sought to evaluate the effect of the AC policy on center transplant volumes, from geographic and center practice perspectives. METHODS: Using the US national registry data between 2018 and 2022, adult liver transplantations (LTs) were separated into two eras: before AC and after AC. RESULTS: The number of LT for Model for End-Stage Liver Disease (MELD) scores ≥29 have significantly increased by 10%, and waitlist times for those patients have been significantly shorter after AC. These benefits were not found in patients with MELD scores <29. The geographic distribution of transplant centers reveals that the majority of centers which increased their transplant volume (18 out of 25 centers) are located in high-population states while there are seven transplant centers in nonhigh-population states. The centers in the nonhigh-population states utilized more marginal donation after brain death (DBD) and donation after circulatory death (DCD) donors by 27% and 155%, respectively. MELD scores were significantly lower in the nonhigh-population states compared with those in the high-population states (p < .01). CONCLUSION: AC improved the LT access for patients with MELD scores ≥29, which benefited the high-population states. However, aggressive center practices to utilize marginal DBD and DCD donors were able to increase transplant volume and lower median allocation MELD scores.

Prediction, prevention, and treatment of post reperfusion syndrome in adult orthotopic liver transplant patients.

IMPORTANCE: This review explores proposed predictors, preventative measures, and treatment options for post-reperfusion syndrome (PRS) in liver transplantation and provides updated data for clinicians. OBJECTIVES: The review aims to understand the status and progress made regarding PRS during orthotopic liver transplantation. Moreover, the predictors of PRS will be analyzed to highlight risk factors. Mediators of PRS and the modes of action of the currently available preventative and management agents that target particular PRS factors will be investigated. DATA SOURCES: Data is drawn from secondary sources from databases of peer-reviewed journals. The bibliographies of select sources were also used to obtain additional data studies using the 'snowball' method. STUDY SELECTION: The initial data search provided 1394 studies analyzed using PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines. After applying the eligibility criteria, 18 studies were fit for inclusion. RESULTS: The study identified that in addition to the severity of underlying medical conditions, other significant PRS predictors included patient age, sex, duration of cold ischemia, and the surgical technique. While the use of epinephrine and norepinephrine is well-established, further preventative measures commonly involve specifically targeting known mediators of the syndrome, such as antioxidants, vasodilators, free radical scavengers, and anticoagulants. Current management strategies involve supportive therapy. Machine Perfusion may ultimately decrease the risk of PRS. CONCLUSION: PRS still holds unknowns, including the underlying pathophysiology, controllable factors, and ideal management practices. There is a need for further study, particularly prospective trials since liver transplantation is the gold standard for treating end-stage liver disease and the incidence of PRS remains high.

Has the risk of liver re-transplantation improved over the two decades?

BACKGROUND: Despite advancements in liver transplantation (LT) over the past two decades, liver re-transplantation (re-LT) presents challenges. This study aimed to assess improvements in re-LT outcomes and contributing factors. METHODS: Data from the United Network for Organ Sharing database (2002-2021) were analyzed, with recipients categorized into four-year intervals. Trends in re-LT characteristics and postoperative outcomes were evaluated. RESULTS: Of 128,462 LT patients, 7254 received re-LT. Graft survival (GS) for re-LT improved (91.3%, 82.1%, and 70.8% at 30 days, 1 year, and 3 years post-LT from 2018 to 2021). However, hazard ratios (HRs) for GS remained elevated compared to marginal donors including donors after circulatory death (DCD), although the difference in HRs decreased in long-term GS. Changes in re-LT causes included a reduction in hepatitis C recurrence and an increase in graft failure post-primary LT involving DCD. Trends identified included recent decreased cold ischemic time (CIT) and increased distance from donor hospital in re-LT group. Meanwhile, DCD cohort exhibited less significant increase in distance and more marked decrease in CIT. The shortest CIT was recorded in urgent re-LT group. The highest Model for End-Stage Liver Disease score was observed in urgent re-LT group, while the lowest was recorded in DCD group. Analysis revealed shorter time interval between previous LT and re-listing, leading to worse outcomes, and varying primary graft failure causes influencing overall survival post-re-LT. DISCUSSION: While short-term re-LT outcomes improved, challenges persist compared to DCD. Further enhancements are required, with ongoing research focusing on optimizing risk stratification models and allocation systems for better LT outcomes.

Surgical Treatments of Hepatobiliary Cancers.

Hepatobiliary cancers which include hepatocellular carcinoma (HCC) and biliary tract cancers (i.e., cholangiocarcinoma and gallbladder carcinoma) are associated with significant morbidity and mortality based on the stage of the disease at presentation. With improved screening for hepatobiliary malignancies in patients with risk factors and with widespread use of laparoscopic cholecystectomy, hepatobiliary malignancies, including incidental diagnosis of gallbladder carcinoma, are on the rise. Definitive treatment of hepatobiliary malignancies include surgical resection, ablation, and liver transplantation. However, management of these cancers is challenging due to the complex hepatobiliary anatomy and the need for meticulous perioperative management especially in patients with advanced liver disease. The management and prognosis of hepatobiliary malignancies vary widely based on the stage of presentation, with surgical options providing the possibility of definitive cure in patients presenting with early-stage disease. Surgical resection for HCC results in good outcomes if performed in ideal candidates. For patients with early HCC who are not candidates for surgical resection, ablation and liver transplantation should be considered. Similarly, surgical resection is also the definitive treatment for biliary tract cancers, and liver transplantation can be curative in selected patients with perihilar cholangiocarcinoma after neoadjuvant chemoradiotherapy. The role of routine adjuvant chemotherapy and radiotherapy is not clearly established, but adjuvant therapies can offer better outcomes in patients with advanced disease at presentation. Outcomes of surgical management of hepatobiliary cancers seem to be improving. Given the complex decision-making process involved, multidisciplinary evaluation is essential to provide and coordinate the best treatments for these patients.

Impact of the donor hepatectomy time on short-term outcomes in liver transplantation using donation after circulatory death: A review of the US national registry.

BACKGROUND: During the donor hepatectomy time (dHT), defined as the time from the start of cold perfusion to the end of the hepatectomy, liver grafts have a suboptimal temperature. The aim of this study was to analyze the impact of prolonged dHT on outcomes in donation after circulatory death (DCD) liver transplantation (LT). METHODS: Using the US national registry data between 2012 and 2020, DCD LT patients were separated into two groups based on their dHT: standard dHT (< 42 min) and prolonged dHT (≥42 min). RESULTS: There were 3810 DCD LTs during the study period. Median dHT was 32 min (interquartile range 25-41 min). Kaplan-Meier graft survival curves demonstrated inferior outcomes in the prolonged dHT group at 1-year after DCD LT compared to those in the standard dHT group (85.3% vs 89.9%; P < .01). Multivariate Cox proportional hazards models for 1-year graft survival identified that prolonged dHT [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.19 - 1.79], recipient age ≥ 64 years (HR 1.40, 95% CI 1.14 - 1.72), and MELD score ≥ 24 (HR 1.43, 95% CI 1.16 - 1.76) were significant predictors of 1-year graft loss. Spline analysis shows that the dHT effects on the risk for 1-year graft loss with an increase in the slope after median dHT of 32 min. CONCLUSION: Prolonged dHTs significantly reduced graft and patient survival after DCD LT. Because dHT is a modifiable factor, donor surgeons should take on cases with caution by setting the dHT target of < 32 min.

Postreperfusion syndrome in liver transplantation: Outcomes, predictors, and application for recipient selection.

BACKGROUND: This study aimed to identify risk factors for postreperfusion syndrome (PRS) and its impact on LT outcomes. METHODS: Data analysis was performed in 1021 adult patients undergoing donation after brain death (DBD) LT to identify PRS incidence, the risk factors for PRS development, and its impact on LT outcomes. RESULTS: The overall incidence of PRS was 16.1%. Independent risk factors for PRS included donor age (odds ratio (OR) 1.01, P = .02), donor body mass index (BMI) (OR 1.04, P = .003), moderate macrosteatosis (OR 2.48, P = .02), and cold ischemia time (CIT) (OR 1.06, P = .02). On multivariable analysis for 30-day graft failure, PRS (hazard ratio (HR) 3.49; P < .001) and Model for End-stage Liver Disease (MELD) score (HR 1.01; P = .05) were independent risk factors. Patients were categorized into four distinct groups based on PRS risk groups and MELD groups, which showed different 1-year graft survival (P < .001). There were comparable outcomes between low PRS risk - high MELD and high PRS risk - low MELD group (P = .33). CONCLUSIONS: Donor age, donor BMI, moderate macrosteatosis, and CIT were identified as risk factors for the development of PRS in LT using DBD grafts. PRS risk evaluation may improve donor-to-recipient matching based on their MELD scores.

Radiological and pathological assessment with EOB-MRI after Y90 radiation lobectomy prior to liver resection for hepatocellular carcinoma.

BACKGROUND: Radiation lobectomy (RL) utilizes Yttrium-90 (Y90) radioembolization for achieving tumor control and inducing contralateral lobe hypertrophy. Our objective was to evaluate the chronological changes occurring radiologically and histopathologically after Y90 RL. METHODS: We retrospectively reviewed 22 patients with chronic liver disease who underwent Y90 RL prior to planned liver resection for hepatocellular carcinoma. Gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (EOB-MRI) was performed every 3 months. RESULTS: Future liver remnant volume (FLRV) significantly increased up to 9 months after Y90 RL. Gd-EOB-DTPA uptake in the treated lobe experienced a 40% reduction in enhancement ratio (ER) during ensuing first 3 months, and never recovered. The reduced ER in the non-tumoral parenchyma was significantly correlated with increased FLRV and FLR (r = 0.41 and r = 0.35, respectively; both p < 0.01). Histopathological evaluation of non-tumor liver tissue found features of sinusoidal obstruction syndrome as an early change after Y90 RL (median 5.7 months) and parenchymal collapse as a late change (mean 11 months). DISCUSSION: The reduced uptake of Gd-EOB-DTPA at 3 months post Y90 RL correlates with a significant increase in FLRV prior to liver resection. EOB-MRI evaluation at 3 months can guide future plan of action after Y90 RL.

p62 Promotes Amino Acid Sensitivity of mTOR Pathway and Hepatic Differentiation in Adult Liver Stem/Progenitor Cells.

Autophagy is a homeostatic process regulating turnover of impaired proteins and organelles, and p62 (sequestosome-1, SQSTM1) functions as the autophagic receptor in this process. p62 also functions as a hub for intracellular signaling such as that in the mammalian target of rapamycin (mTOR) pathway. Liver stem/progenitor cells have the potential to differentiate to form hepatocytes or cholangiocytes. In this study, we examined effects of autophagy, p62, and associated signaling on hepatic differentiation. Adult stem/progenitor cells were isolated from the liver of mice with chemically induced liver injury. Effects of autophagy, p62, and related signaling pathways on hepatic differentiation were investigated by silencing the genes for autophagy protein 5 (ATG5) and/or SQSTM1/p62 using small interfering RNAs. Hepatic differentiation was assessed based on increased albumin and hepatocyte nuclear factor 4α, as hepatocyte markers, and decreased cytokeratin 19 and SOX9, as stem/progenitor cell markers. These markers were measured using quantitative RT-PCR, immunofluorescence, and Western blotting. ATG5 silencing decreased active LC3 and increased p62, indicating inhibition of autophagy. Inhibition of autophagy promoted hepatic differentiation in the stem/progenitor cells. Conversely, SQSTM1/p62 silencing impaired hepatic differentiation. A suggested mechanism for p62-dependent hepatic differentiation in our study was activation of the mTOR pathway by amino acids. Amino acid activation of mTOR signaling was enhanced by ATG5 silencing and suppressed by SQSTM1/p62 silencing. Our findings indicated that promoting amino acid sensitivity of the mTOR pathway is dependent on p62 accumulated by inhibition of autophagy and that this process plays an important role in the hepatic differentiation of stem/progenitor cells. J. Cell. Physiol. 232: 2112-2124, 2017. © 2016 Wiley Periodicals, Inc.