Cardiac considerations in liver transplantation.

Cardiovascular events have a major impact on overall outcomes after liver transplantation. Today's transplant patients are older than those in the past and therefore are more likely to have coexisting cardiac comorbidities. In addition, pathophysiologic effects of advanced liver disease on the circulatory system pose challenges in perioperative management. This review discusses important preoperative, intraoperative, and postoperative cardiac considerations in patients undergoing liver transplant.

Neuroendocrine liver metastases: The role of liver transplantation.

PURPOSE OF REVIEW: Neuroendocrine tumor (NET) metastasis localized to the liver is an accepted indication for liver transplantation as such tumors have a low biological aggressiveness in terms of malignancy and are slow growing. RECENT FINDINGS: The long-term results are comparable with and in some cases even better than those of transplantations performed for primary liver cancer. However, compared with nonmalignant conditions, neuroendocrine liver metastasis (NELM) may result in an inferior outcome of transplantation. In the face of the scarcity of donated organs and recent improved results of non-surgical treatment for NELM, controversy over patient selection and timing for liver transplantation continues. SUMMARY: In this review, we provide an overview of the diagnostic work-up and selection criteria of patients with NELM being considered for liver transplantation. Thereafter, we provide a critical analysis of the reported outcomes of OLT.

Intravascular ultrasound in the diagnosis and treatment of central venous diseases.

Intravascular ultrasound (IVUS) has been used extensively in coronary applications. Its use in venous applications has increased as endovascular therapy has increasingly become the mainstay therapy for central venous diseases. IVUS has been used for both diagnostic and therapeutic purposes in managing venous stenotic disease, venous occlusive disease, and IVC filter placement and removal. IVUS has been proven to be effective in providing detailed measurement of the venous anatomy, which aid in determining the appropriate size and the approach for venous stent placement. In IVC filter placement, IVUS can provide detailed measurement and guide IVC filter placement in emergent and critical care settings. It also has certain utility in filter removal. At any rate, to date there are only a few studies examining its impact on patient outcomes. Prospective randomized controlled trials are warranted in the future.

Does graft hemodynamics affect the risk of hepatocellular carcinoma recurrence after liver transplantation?

Although experimental studies have reported that hepatic ischemia-reperfusion injury promotes tumor growth and metastases, the impact of graft hemodynamics on the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is unclear. To investigate the association between graft hemodynamics and HCC recurrence after LT, we conducted a retrospective analysis of 279 patients who underwent LT for HCC. Graft hemodynamics including portal vein flow (PVF), hepatic artery flow (HAF), and total hepatic flow (THF) was analyzed as a predictor of HCC recurrence, using competing risk regression analyses. The cutoff values of PVF, HAF, and THF were set at the lower quartile of distribution. A cumulative recurrence curve demonstrated that low THF (<1511 mL/min, P = .005) was significantly associated with increased recurrence, whereas neither low PVF (<1230 mL/min, P = .150) nor low HAF (<164 mL/min, P = .110) was significant. On multivariate analysis, outside Milan criteria (sub-hazard ratio [SHR] = 3.742; P < .001), microvascular invasion (SHR = 3.698; P < .001), and low THF (SHR = 2.359; P = .010) were independently associated with increased HCC recurrence. In conclusion, our findings suggest that graft hemodynamics may play an important role in HCC recurrence after LT.

Can pretransplant TIPS be harmful in liver transplantation? A propensity score matching analysis.

BACKGROUND: Transjugular intrahepatic portosystemic shunt has been established as an effective treatment for complicated portal hypertension. This retrospective study investigated the effect of pretransplant transjugular intrahepatic portosystemic shunt placement on intraoperative graft hemodynamics and surgical outcomes after liver transplantation. METHODS: Of 1,081 patients who underwent liver transplantation between January 2007 and June 2017 at Cleveland Clinic (OH, USA), 130 patients had transjugular intrahepatic portosystemic shunt placement before liver transplant. We performed a 1:2 propensity score matching to compare intraoperative graft hemodynamics and surgical outcomes between the transjugular intrahepatic portosystemic shunt group (n = 130) and the no-transjugular intrahepatic portosystemic shunt group (n = 260). RESULTS: The transjugular intrahepatic portosystemic shunt did not increase operative time, the volume of blood transfusion, duration of hospital stay, or complication rates. Graft and patient survivals were similar between the groups. Mean intraoperative cardiac output and graft portal flow in the transjugular intrahepatic portosystemic shunt group were greater than in the no-transjugular intrahepatic portosystemic shunt group (P = .03 and P = .003, respectively). In multivariate analysis, male sex, younger age, low platelet count, absence of portal vein thrombosis, and pretransplant transjugular intrahepatic portosystemic shunt placement were independently associated with increased portal flow volume (P < or = 0.03 each). Transjugular intrahepatic portosystemic shunt malposition was observed in 17 patients (13.1%). The 1-year patient survival was 70.6% with transjugular intrahepatic portosystemic shunt malposition and 92.0% without transjugular intrahepatic portosystemic shunt malposition (P = .01). CONCLUSION: Our findings suggest that pretransplant transjugular intrahepatic portosystemic shunt placement increases graft portal flow but does not compromise surgical outcomes after liver transplantation. Transjugular intrahepatic portosystemic shunt malposition, however, is not uncommon and may increase the complexity of transplantation.

Too Much, Too Little, or Just Right? The Importance of Allograft Portal Flow in Deceased Donor Liver Transplantation.

BACKGROUND: While portal flow (PF) plays an important role in determining graft outcomes in living donor liver transplantation, its impact in deceased donor liver transplantation (DDLT) is unclear. The aim of this study was to investigate the correlations between graft PF and graft outcomes in DDLT. METHODS: We retrospectively investigated 1001 patients who underwent DDLT between January 2007 and June 2017 at our institution. The patients were divided into 3 groups according to hazard ratio for 1-year graft loss at each PF value, which was standardized with graft weight. Graft and recipient outcomes were compared between the groups. RESULTS: The low-PF group (PF < 65 mL/min/100 g, n = 210, P = 0.011) and the high-PF group (PF ≥ 155 mL/min/100 g, n = 159, P = 0.018) showed significantly poorer 1-year graft survival compared with the intermediate-PF group (PF ≥ 65 mL/min/100 g and < 155 mL/min/100 g, n = 632). The patients in the low-PF group had severe reperfusion injury and were more frequently complicated with primary nonfunction (P = 0.013) and early allograft dysfunction (P < 0.001) compared with the other groups. In contrast, the patients in the high-PF group had milder reperfusion injury, but had lower intraoperative hepatic artery flow with higher incidence of hepatic artery thrombosis (P = 0.043) and biliary complication (P = 0.041) compared with the other groups. CONCLUSIONS: These results suggest that intraoperative PF plays an important role in determining early graft outcomes after DDLT.

Lipid metabolism and functional assessment of discarded human livers with steatosis undergoing 24 hours of normothermic machine perfusion.

Normothermic machine perfusion (NMP) is an emerging technology to preserve liver allografts more effectively than cold storage (CS). However, little is known about the effect of NMP on steatosis and the markers indicative of hepatic quality during NMP. To address these points, we perfused 10 discarded human livers with oxygenated NMP for 24 hours after 4-6 hours of CS. All livers had a variable degree of steatosis at baseline. The perfusate consisted of packed red blood cells and fresh frozen plasma. Perfusate analysis showed an increase in triglyceride levels from the 1st hour (median, 127 mg/dL; interquartile range [IQR], 95-149 mg/dL) to 24th hour of perfusion (median, 203 mg/dL; IQR, 171-304 mg/dL; P = 0.004), but tissue steatosis did not decrease. Five livers produced a significant amount of bile (≥5 mL/hour) consistently throughout 24 hours of NMP. Lactate in the perfusate cleared to <3 mmol/L in most livers within 4-8 hours of NMP, which was independent of bile production rate. This is the first study to characterize the lipid profile and functional assessment of discarded human livers at 24 hours of NMP. Liver Transplantation 24 233-245 2018 AASLD.

Probability, management, and long-term outcomes of biliary complications after hepatic artery thrombosis in liver transplant recipients.

BACKGROUND: Hepatic artery thrombosis after liver transplantation is a devastating complication associated with ischemic cholangiopathy that can occur even after successful revascularization. This study explores long-term outcomes after hepatic artery thrombosis in adult liver transplantation recipients, focusing on the probability, risk factors, and resolution of ischemic cholangiopathy. METHODS: A retrospective chart review of 1,783 consecutive adult liver transplantations performed between 1995 and 2014 identified 44 cases of hepatic artery thrombosis (2.6%); 10 patients underwent immediate retransplantation, and 34 patients received nontransplant treatments, involving revascularization (n = 19) or expectant nonrevascularization management (n = 15). RESULTS: The 1-year graft survival after nontransplant treatment was favorable (82%); however, 16 of the 34 patients who received a nontransplant treatment developed ischemic cholangiopathy and required long-term biliary intervention. A Cox regression model showed that increased serum transaminase and bilirubin levels at the time of hepatic artery thrombosis diagnosis, but not nonrevascularization treatment versus revascularization, were risk factors for the development of ischemic cholangiopathy. Ischemic cholangiopathy in revascularized grafts was less extensive with a greater likelihood of resolution within 5-years than that in nonrevascularized grafts (100% vs 17%). Most liver abscesses without signs of liver failure also were reversible. Salvage retransplantation after a nontransplant treatment was performed in 8 patients with a 1-year survival rate equivalent to immediate retransplantation (88% vs 80%). CONCLUSION: Selective nontransplant treatments for hepatic artery thrombosis resulted in favorable graft survival. Biliary intervention can resolve liver abscess and ischemic cholangiopathy that developed in revascularized grafts in the long-term; salvage retransplantation should be considered for ischemic cholangiopathy in nonrevascularized grafts because of a poor chance of resolution.

Split liver transplantation in adults.

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.

Risk stratification of allograft failure secondary to hepatitis C recurrence after liver transplantation.

AIM: Hepatitis C virus (HCV) recurrence after liver transplantation decreases survival rates. Improved understanding of the multiple factors influencing HCV recurrence could aid decision-making for donor-recipient pairing and maximize transplant outcomes. The aim of this study was to create a model based on pretransplant variables to stratify patients at risk of HCV-related allograft failure. METHODS: This retrospective study enrolled 154 liver transplant recipients with HCV at Cleveland Clinic. RESULTS: Among the study population, 54 recipients (35.1%) experienced HCV recurrence, histologically defined as moderate to severe hepatitis and/or bridging fibrosis to cirrhosis. The multivariate analysis found donor age (≥60 years, P < 0.002), donor body mass index (≥30 kg/m2 , P < 0.05), African American recipient (P < 0.01) and genotype 1 (P < 0.02) as risk factors for HCV-related allograft failure. When these four factors were scored as a combined index (no factor [n = 15], one factor [n = 76], two factors [n = 43] and three or more factors [n = 20]), the HCV recurrence-free survival showed good stratification according to the scores: 93.3% with no factor, 79.3% with one factor, 52.0% with two factors and 24.4% with three or more factors at 3 years after transplant (P < 0.0001). Moreover, this risk index also identified the patient group at high risk of HCV recurrence after acute rejection. CONCLUSION: While the introduction of direct-acting antiviral agents has been changing the paradigm of HCV treatment, the natural history of recipients with HCV as shown in this study would help estimate the risk of HCV-related allograft failure in those who do not tolerate such new treatment.

Liver transplantation for metastatic neuroendocrine tumors: Outcomes and prognostic variables.

BACKGROUND: Patient selection for liver transplantation for metastatic neuroendocrine tumors remains a topic of debate. There is no established MELD exception, making it difficult to obtain donor organs. METHODS: A multicenter database was created assessing outcomes for liver and multivisceral transplantation for metastatic neuroendocrine tumors and identifying prognostic factors for survival. Demographic, transplant, primary tumor site and management, pathology, recurrent disease and survival data were collected and analyzed. Survival probabilities were calculated using the Kaplan-Meier method. RESULTS: Analysis included 85 patients who underwent liver transplantation November 1988-January 2012 at 28 centers. One, three, and five-year patient survival rates were 83%, 60%, and 52%, respectively; 40 of 85 patients died, with 20 of 40 deaths due to recurrent disease. In univariate analyses, the following were predictors of poor prognosis: large vessel invasion (P < 0.001), extent of extrahepatic resection at liver transplant (P = 0.007), and tumor differentiation (P = 0.003). In multivariable analysis, predictors of poor overall survival included large vessel invasion (P = 0.001), and extent of extrahepatic resection at liver transplant (P = 0.015). CONCLUSION: In the absence of poor prognostic factors, metastatic neuroendocrine tumor is an acceptable indication for liver transplantation. Identification of favorable prognostic factors should allow assignment of a MELD exception similar to hepatocellular carcinoma.

Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers.

The effects of normothermic machine perfusion (NMP) on the postreperfusion hemodynamics and extrahepatic biliary duct histology of donation after cardiac death (DCD) livers after transplantation have not been addressed thoroughly and represent the objective of this study. Ten livers (5 per group) with 60 minutes of warm ischemia were preserved via cold storage (CS) or sanguineous NMP for 10 hours, and then they were reperfused for 24 hours with whole blood in an isolated perfusion system to simulate transplantation. In our experiment, the arterial and portal vein flows were stable in the NMP group during the entire reperfusion simulation, whereas they decreased dramatically in the CS group after 16 hours of reperfusion (P < 0.05); these findings were consistent with severe parenchymal injury. Similarly, significant differences existed between the CS and NMP groups with respect to the release of hepatocellular enzymes, the volume of bile produced, and the levels of enzymes released into bile (P < 0.05). According to histology, CS livers presented with diffuse hepatocyte congestion, necrosis, intraparenchymal hemorrhaging, denudated biliary epithelium, and submucosal bile duct necrosis, whereas NMP livers showed very mild injury to the liver parenchyma and biliary architecture. Most importantly, Ki-67 staining in extrahepatic bile ducts showed biliary epithelial regeneration. In conclusion, our findings advance the knowledge of the postreperfusion events that characterize DCD livers and suggest NMP as a beneficial preservation modality that is able to improve biliary regeneration after a major ischemic event and may prevent the development of ischemic cholangiopathy in the setting of clinical transplantation.

Role of vasodilation during normothermic machine perfusion of DCD porcine livers.

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.

Preparing for the inevitable: the death of a living liver donor.

Living donor liver transplantation (LDLT) is associated with a low but finite and well-documented risk of donor morbidity and mortality, so organizations and individuals involved in this activity must accept the fact that a donor death is a question of when and not if. Studies in the field of crisis management show that preparing for the inevitable not only is critical in preparing institutions to better respond to catastrophic events but more importantly plays a crucial role in preventing them. This article describes the background of crisis management with specific reference to the death of a living liver donor and proposes a general framework that can be adopted by LDLT programs around the world.

Is there an advantage of living over deceased donation in liver transplantation?

Living donor liver transplantation (LDLT) is a well-established strategy to decrease the mortality in the waiting list and recent studies have demonstrated its value even in patients with low MELD score. However, LDLT is still under a high level of scrutiny because of its technical complexity and ethical challenges as demonstrated by a decline in the number of procedures performed in the last decade in Western Countries. Many aspects make LDLT different from deceased donor liver transplantation, including timing of transplantation, procedure-related complications as well as immunological factors that may affect graft outcomes. Our review suggests that in selected cases, LDLT offers significant advantages over deceased donor liver transplantation and should be used more liberally.

Is impaired hepatic arterial buffer response a risk factor for biliary anastomotic stricture in liver transplant recipients?

BACKGROUND: Blood flow to the liver is partly maintained by the hepatic arterial buffer response (HABR), which is an intrinsic autoregulatory mechanism. Temporary clamping of the portal vein (PV) results in augmentation in hepatic artery flow (augHAF). Portal hyperperfusion impairs HAF due to the HABR in liver transplantation (LT). The aim of this study is to examine the effect of the HABR on biliary anastomotic stricture (BAS). METHODS: In 234 cadaveric whole LTs, PV flow (PVF), basal HAF, and augHAF were measured intra-operatively after allograft implantation. All recipients with a vascular complication were excluded. Buffer capacity (BC) was calculated as (augHAF - basal HAF)/PVF to quantify the HABR. Recipients were divided into 2 groups based on their BC: low BC (<0.074; n = 117) or high BC (> or =0.074; n = 117). RESULTS: Of the 234 recipients, 23 (9.8%) had early BAS (< or =60 days after LT) and 18 (7.7%) had late BAS (>60 days after LT). The incidence of late BAS and bile leakage was similar between the groups; however, the incidence of early BAS in the low BC group was greater than that in the high BC group (15% vs 5.1%; P = .0168). In the multivariate analysis, low BC (P = .0325) and bile leakage (P = .0002) were found to be independent risk factors affecting early BAS. CONCLUSION: Recipients with low BC who may have impaired HABR are at greater risk of early BAS after LT. Intraoperative measurements of blood flow help predict the risk of BAS.

Vascular endothelial growth factor receptor 2 expression in non-tumorous cirrhotic liver is higher when hepatoma is beyond Milan criteria.

Hepatocellular carcinoma (HCC) is a highly vascular tumor. Angiogenesis in HCC is mediated at least in part by vascular endothelial growth factor (VEGF), which is expressed in HCC and surrounding cirrhotic tissue. VEGF mediates its angiogenic effects through multiple receptors including VEGF receptor 2 (VEGFr2, KDR/FLK-1), The distribution and clinical significance of VEGFr2 expression in HCC and cirrhotic liver in the setting of liver transplantation have not been tissue site specific evaluated. Immunohistochemical staining for VEGFr2 was performed in 78 liver explants from patients with HCC undergoing liver transplantation. VEGFr2 levels in HCC were significantly increased compared to adjacent, nontumorous cirrhotic liver areas (P < 0.05). VEGFr2 levels were significantly higher in the veins and sinusoids of poorly differentiated tumors (P < 0.05). VEGFr2 levels in the tumors were not significantly different between patients within and beyond Milan criteria. However, VEGFr2 levels were significantly higher in the arteries of non-tumorous liver in patients beyond Milan criteria (P < 0.05). No significant association was observed between VEGFr2 levels and the presence of tumor vascular invasion or recurrence post transplantation. These findings suggest that VEGFr2 up-regulation is a feature of poor differentiation and tumor progression. Further investigation is needed to assess the value of angiogenesis modulation in preventing tumor formation and/or progression in cirrhotic patients.

Side-to-side cavocavostomy with an endovascular stapler: Rescue technique for severe hepatic vein and/or inferior vena cava outflow obstruction after liver transplantation using the piggyback technique.

Venous outflow obstruction is a rare but potentially lethal complication after orthotopic liver transplantation (OLT) with the "piggyback" technique. Therapeutic options include angioplasty with or without stent placement, surgical reconstruction of the venous anastomosis, and retransplantation. Surgical options are technically very challenging and the outcomes discouraging. We describe here two cases of venous outflow obstruction in recipients of piggyback liver grafts, one involving both the vena cava and hepatic veins and the other affecting only hepatic vein outflow. Both patients were treated successfully with side-to-side cavo-cavostomy using an endovascular (endo-GIA) stapler. This novel technique is fast and effective in resolving the outflow obstruction.