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Objective: Portal vein thrombosis (PVT) does not preclude liver transplantation (LT), but poor portal vein (PV) flow after LT remains a predictor of poor outcomes. Given the physiologic tendency of the hepatic artery (HA) to compensate for low PV flow via vasodilation, we investigated whether adequate HA flow would have a favorable prognostic impact among patients with low PV flow following LT., Methods: This study included 163 patients with PVT who underwent LT between 2004 and 2015. PV and HA flow were categorized into quartiles, and their association with 1-year graft survival (GS) and biliary complication rates was assessed. For both the HA and the PV, patients at the lowest two quartiles were categorized as having low flow and the remainder as having high flow., Results: The median MELD score was 22 and 1-year GS was 87.3%. As expected, GS paralleled PV flow with patients at the lowest flow quartile faring the worst. In combination of PV and HA flows, high HA flow was associated with improved 1-year GS among patients with low PV flow (P = .03). Similar findings were observed with respect to biliary complication rates., Conclusions: Sufficient HA flow may compensate for poor PV flow. Consequently, meticulous HA reconstruction may be central to achieving optimal outcomes in PVT cases., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Donation after circulatory death (DCD) donors show heterogeneous hemodynamic trajectories following withdrawal of life support. Impact of hemodynamics in DCD liver transplant is unclear, and objective measures of graft viability would ease transplant surgeon decision making and inform safe expansion of the donor organ pool. This retrospective study tested whether hemodynamic trajectories were associated with transplant outcomes in DCD liver transplantation (n = 87). Using longitudinal clustering statistical techniques, we phenotyped DCD donors based on hemodynamic trajectory for both mean arterial pressure (MAP) and peripheral oxygen saturation (SpO 2 ) following withdrawal of life support. Donors were categorized into 3 clusters: those who gradually decline after withdrawal of life support (cluster 1), those who maintain stable hemodynamics followed by rapid decline (cluster 2), and those who decline rapidly (cluster 3). Clustering outputs were used to compare characteristics and transplant outcomes. Cox proportional hazards modeling revealed hepatocellular carcinoma (hazard ratio [HR] = 2.53; P = 0.047), cold ischemia time (HR = 1.50 per hour; P = 0.027), and MAP cluster 1 were associated with increased risk of graft loss (HR = 3.13; P = 0.021), but not SpO 2 cluster (P = 0.172) or donor warm ischemia time (DWIT; P = 0.154). Despite longer DWIT, MAP and SpO 2 clusters 2 showed similar graft survival to MAP and SpO 2 clusters 3, respectively. In conclusion, despite heterogeneity in hemodynamic trajectories, DCD donors can be categorized into 3 clinically meaningful subgroups that help predict graft prognosis. Further studies should confirm the utility of liver grafts from cluster 2. Liver Transplantation 22 1469-1481 2016 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Split liver transplantation (SLT), while widely accepted in pediatrics, remains underutilized in adults. Advancements in surgical techniques and donor-recipient matching, however, have allowed expansion of SLT from utilization of the right trisegment graft to now include use of the hemiliver graft as well. Despite less favorable outcomes in the early experience, better outcomes have been reported by experienced centers and have further validated the feasibility of SLT. Importantly, more than two decades of experience have identified key requirements for successful SLT in adults. When these requirements are met, SLT can achieve outcomes equivalent to those achieved with other types of liver transplantation for adults. However, substantial challenges, such as surgical techniques, logistics, and ethics, persist as ongoing barriers to further expansion of this highly complex procedure. This review outlines the current state of SLT in adults, focusing on donor and recipient selection based on physiology, surgical techniques, surgical outcomes, and ethical issues., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest or potential conflicts of interest for this article.

Introduction: Normothermic machine perfusion (NMP) is an emerging preservation modality that holds the potential to prevent the injury associated with low temperature and to promote organ repair that follows ischemic cell damage. While several animal studies have showed its superiority over cold storage (CS), minimal studies in the literature have focused on safety, feasibility, and reliability of this technology, which represent key factors in its implementation into clinical practice. The aim of the present study is to report safety and performance data on NMP of DCD porcine livers., Materials and Methods: After 60 minutes of warm ischemia time, 20 pig livers were preserved using either NMP (n = 15; physiologic perfusion temperature) or CS group (n = 5) for a preservation time of 10 hours. Livers were then tested on a transplant simulation model for 24 hours. Machine safety was assessed by measuring system failure events, the ability to monitor perfusion parameters, sterility, and vessel integrity. The ability of the machine to preserve injured organs was assessed by liver function tests, hemodynamic parameters, and histology., Results: No system failures were recorded. Target hemodynamic parameters were easily achieved and vascular complications were not encountered. Liver function parameters as well as histology showed significant differences between the 2 groups, with NMP livers showing preserved liver function and histological architecture, while CS livers presenting postreperfusion parameters consistent with unrecoverable cell injury., Conclusion: Our study shows that NMP is safe, reliable, and provides superior graft preservation compared to CS in our DCD porcine model., (© The Author(s) 2014.)

Introduction: Normothermic machine perfusion (NMP) of the liver is a promising preservation modality that holds the potential to better preserve and even repair marginal grafts. In spite of several literature studies showing the benefits of NMP over cold storage, there is paucity of data regarding the mechanisms involved in the optimization of the microcirculation during preservation of these organs. We present our data on the impact of different vasodilators on DCD porcine livers preserved with NMP., Materials and Methods: Livers from 15 female Yorkshire pigs (30-40 kg) were subjected to 60 min of WIT followed by 10 h of NMP. Group PC (n = 5) received a prostacyclin analog (epoprostenol sodium) and the AD group (n = 5) received adenosine, whereas group WV (n = 5) was perfused without using any vasodilator. Liver function was assessed by measuring, liver enzyme levels, bile production rate, and histological analysis., Results: At the end of perfusion, the PC group showed significantly lower AST (583 ± 62 vs. 2471 ± 745 and 2547 ± 690 IU/dl), ALT (41 ± 3 vs. 143 ± 28 and 111 ± 25 IU/dl) and LDH (840 ± 85 vs. 2756 ± 408 and 4153 ± 1569 IU/dl) levels compared to the AD and WV groups respectively (p<0.05). Bile production was significantly higher in the PC group compared to the AD group and WV, respectively (95 ± 9 vs. 37 ± 10 and 45 ± 18ml) (p<0.05). Histological samples of the PC group showed preserved hepatic architecture while those of the AD group and WV showed sinusoidal dilatation, architectural distortion, and profuse intraparenchymal hemorrhage., Conclusions: Maintenance of optimal microcirculatory homeostasis using proper vasodilators is a key factor in NMP of DCD livers.

Complement 4d (C4d) is a marker of complement activation that has been used to evaluate humoral rejection in renal and heart allografts. Studies suggested a role for C4d detection in liver allografts in diagnosing acute cellular and humoral rejection but none correlated this with the pre-transplant liver disease. Our study analyzed the association of C4d deposition in liver allografts with the pre-transplant liver disease. C4d deposition was evaluated by indirect immunofluorescence and correlated with lymphocytotoxic crossmatch results, post-transplant clinicopathological diagnosis and type of pre-transplant liver disease. Allograft biopsies were classified by the native liver disease. After excluding 20 patients with rare liver diseases; C4d deposition was evaluated in 506 biopsies from 310 patients including 25 with PSC, 198 with viral hepatitis and 87 with other diseases. C4d immunereactivity distribution was not different among biopsies from patients with different lymphocytotoxic crossmatch results. Sinusoidal C4d deposition was noted in 11.9% of biopsies and 15.2% of patients (in one or more biopsies). 26% (9/35) of biopsies from patients with PSC had sinusoidal C4d deposition; more frequently than from patients with viral hepatitis 12% (43/348) (p=0.04) and other liver diseases 7% (8/123) (p=0.005). In conclusion, C4d deposition in liver allografts is independent of the crossmatch results. It occurs with a variety of pathologic abnormalities and underlying liver diseases; but is more frequent in patients with PSC. This suggests that mechanisms other than allo-immunity activate complement. The mechanisms and clinical significance of C4d deposition in liver allografts in patients with PSC remain to be determined.

The growing demand for liver transplantation and the concomitant scarcity of cadaveric livers have increased the need for living donor liver transplantation (LDLT). Ensuring the safety of donors and recipients is critical. The preoperative identification of the vascular and biliary tract anatomy with 3-dimensional (3D) printing may allow better preoperative surgical planning, avert unnecessary surgery in patients with potentially unsuitable anatomy, and thereby decrease the complications of liver transplant surgery. We developed a protocol and successfully 3D-printed synthetic livers (along with their complex networks of vascular and biliary structures) replicating the native livers of 6 patients: 3 living donors and 3 respective recipients who underwent LDLT. To our knowledge, these are the first complete 3D-printed livers. Using standardized preoperative, intraoperative, and postoperative assessments, we demonstrated identical anatomical and geometrical landmarks in the 3D-printed models and native livers., (© 2013 American Association for the Study of Liver Diseases.)

Severe ischemia/reperfusion (IR) injury is associated with poor hepatic microperfusion. The aim of this study was to investigate the role of hepatic artery flow (HAF) and portal vein flow (PVF) in IR injury. From January 2004 to June 2008, 566 patients underwent orthotopic liver transplantation (OLT). The data were retrospectively reviewed via the transplant database. Patients with hepatic artery (HA) or portal vein (PV) thrombosis and retransplant patients were excluded. Intraoperative PVF and HAF values and graft weights were measured routinely, and the central venous pressure, mean arterial pressure, cardiac output, and cardiac index were recorded with hepatic blood flow measurements. Complete data were available for 312 primary OLT recipients (215 males and 97 females; mean age = 54 ± 10 years). The patients' follow-up ranged from 215 to 1746 days (705 ± 408 days). IR injury was defined by the aspartate aminotransferase (AST) level on postoperative day (POD) 2, and the patients were divided into 3 groups: (1) mild IR injury [AST < 500 U/L; n = 160 (51%)], (2) moderate IR injury [AST = 500-1000 U/L; n = 85 (27%)], and (3) severe IR injury [AST > 1000 U/L; n = 67 (21%)]. The demographics and pre-OLT variables (the Model for End-Stage Liver Disease score (MELD), platelet counts, PV thrombosis, transjugular intrahepatic portosystemic shunts, and shunts on computed tomography scans) were similar in all groups. The graft survival rate was 99% in group 1, 95.2% in group 2 (P = 0.02), and 92.3% in group 3 (P = 0.016). The patient survival rates were similar in the 3 groups. The cold ischemia time (CIT) was significantly higher in group 3 versus group 1 (P < 0.007). In the statistical analysis, low HAF, PVF, total liver blood flow (TLBF), and augmented HAF values were associated with a greater likelihood of elevated AST levels on POD 2. The strongest univariate predictors of AST were reduced augmented HAF (mL/minute/100 g) values (P < 0.001) and reduced TLBF (mL/minute/100 g) values (P < 0.001). In a covariate analysis with adjustments for CIT and donor variables, the blood flow parameters remained important predictors of graft function. In conclusion, this report demonstrates for the first time that reduced hepatic blood flow is a significant finding in patients with severe hepatic IR injury., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Splenic artery embolization (SAE) improves hepatic artery (HA) flow in liver transplant (OLT) recipients with so-called splenic artery steal syndrome. We propose that SAE actually improves HA flow by reducing the HA buffer response (HABR). Patient 1: On postoperative day (POD) 1, Doppler ultrasonography (US) showed patent vasculature with HA resistive index (RI) of 0.8. On POD 4, aminotransferases rose dramatically; his RI was 1.0 with no diastolic flow. Octreotide was begun, but on POD 5 US showed reverse diastolic HA flow with no signal in distal HA branches. After SAE, US showed markedly improved flow, RI was 0.6, diastolic flow in the main artery, and complete visualization of all distal branches. By POD 6, liver function had normalized. RI in the main HA is 0.76 at 2 months postsurgery. Patient 2: On POD 1, RI was 1.0. US showed worsening intrahepatic signal, with no signal in the intrahepatic branches and reversed diastolic flow despite good graft function. On POD 7, SAE improved the intrahepatic waveform and RI (from 1.0 to 0.72). Patient 3: Intraoperative reverse diastolic arterial flow persisted on PODs 1, 2, and 3, with progressive loss of US signal in peripheral HA branches. SAE on POD 4 improved the RI (0.86) and peripheral arterial branch signals. Patient 4: US on POD 1 showed good HA flow with a normal RI (0.7). A sudden waveform change on POD 2 with increasing RI (0.83) prompted SAE, after which the wave form normalized, with reconstitution of a normal diastolic flow (RI 0.68). In conclusion, these reports confirm the usefulness of SAE for poor HA flow but suggest that inflow steal was not the problem. Rather than producing an increase in arterial inflow, SAE worked by reducing portal flow and HABR, thereby reducing end-organ outflow resistance. Evidence of this effect is the marked reduction of the RI after the SAE to 0.6, 0.72, 0.86, and 0.68, in patients 1-4, respectively. SAE reduces excessive portal vein flow and thereby ameliorates an overactive HABR that can cause graft dysfunction and ultimately HA thrombosis.

The cytosolic beta-glucosidase of mammalian liver has been implicated in the metabolic transformation of plant glycosides, such as vicine and amygdalin, which are associated with the development of toxic syndromes. We investigated which cell types express cytosolic beta-glucosidase in guinea pig liver, and characterized the contribution of this enzyme to the hydrolysis of aromatic glucosides in cultured cells and in tissue slices. Cytosolic beta-glucosidase was expressed in hepatocytes and not in Kupffer or endothelial cells as determined by enzyme-specific activity and Western blots of liver cell extracts. Intracellular beta-glucosidase activity was visualized using the fluorescent beta-glucosidase substrate, resorufin beta-D-glucoside, and shown to be caused by the cytosolic beta-glucosidase using the inhibitors, conduritol beta-epoxide and dinitrophenol-2-deoxy-2-fluoro-beta-D-glucopyranoside (DNP2FGlc). Staining of fresh liver slices with resorufin beta-glucoside revealed that cytosolic beta-glucosidase is expressed in all hepatocytes, with no significant portal-central gradient. These data indicate that cytosolic beta-glucosidase is a hepatocyte-specific enzyme, and support the hypothesis that cytosolic beta-glucosidase in the liver functions to hydrolyze small glucosides absorbed by the intestine. Furthermore, toxic injury to cultured hepatocytes by CCl4 resulted in release of cytosolic beta-glucosidase in parallel with the hepatocyte marker enzymes alanine transaminase and lactate dehydrogenase. This suggests that acute increases in serum levels of cytosolic beta-glucosidase in animal models of liver injury may reflect direct injury of hepatocytes.