Development of a portable abdominal normothermic regional perfusion (A-NRP) program in the United States.

In situ abdominal normothermic regional perfusion (A-NRP) has been used for liver transplantation (LT) with donation after circulatory death (DCD) liver grafts in Europe with excellent results; however, adoption of A-NRP in the United States has been lacking. The current report describes the implementation and results of a portable, self-reliant A-NRP program in the United States. Isolated abdominal in situ perfusion with an extracorporeal circuit was achieved through cannulation in the abdomen or femoral vessels and inflation of a supraceliac aortic balloon and cross-clamp. The Quantum Transport System by Spectrum was used. The decision to use livers for LT was made through an assessment of perfusate lactate (q15min). From May to November 2022, 14 A-NRP donation after circulatory death procurements were performed by our abdominal transplant team (N = 11 LT, N = 20 kidney transplants, and 1 kidney-pancreas transplant). The median A-NRP run time was 68 minutes. None of the LT recipients had post-reperfusion syndrome, nor were there any cases of primary nonfunction. All livers were functioning well at the time of maximal follow-up with zero cases of ischemic cholangiopathy. The current report describes the feasibility of a portable A-NRP program that can be used in the United States. Excellent short-term post-transplant results were achieved with both livers and kidneys procured from A-NRP.

Radiation Segmentectomy for the Treatment of Solitary Hepatocellular Carcinoma: Outcomes Compared with Those of Surgical Resection.

PURPOSE: To investigate the outcomes of radiation segmentectomy (RS) versus standard-of-care surgical resection (SR). MATERIALS AND METHODS: A multisite, retrospective analysis of treatment-naïve patients who underwent either RS or SR was performed. The inclusion criteria were solitary hepatocellular carcinoma ≤8 cm in size, Eastern Cooperative Oncology Cohort performance status of 0-1, and absence of macrovascular invasion or extrahepatic disease. Target tumor and overall progression, time to progression (TTP), and overall survival rates were assessed. Outcomes were censored for liver transplantation. RESULTS: A total of 123 patients were included (RS, 57; SR, 66). Tumor size, Child-Pugh class, albumin-bilirubin score, platelet count, and fibrosis stage were significantly different between cohorts (P ≤ .01). Major adverse events (AEs), defined as grade ≥3 per the Clavien-Dindo classification, occurred in 0 patients in the RS cohort vs 13 (20%) patients in the SR cohort (P < .001). Target tumor progression occurred in 3 (5%) patients who underwent RS and 5 (8%) patients who underwent SR. Overall progression occurred in 19 (33%) patients who underwent RS and 21 (32%) patients who underwent SR. The median overall TTP was 21.9 and 29.4 months after RS and SR, respectively (95% confidence interval [CI], 15.5-28.2 and 18.5-40.3, respectively; P = .03). Overall TTP subgroup analyses showed no difference between treatment cohorts with fibrosis stages 3-4 (P = .26) and a platelet count of <150 × 109/L (P = .29). The overall progression hazard ratio for RS versus SR was not significant per the multivariate Cox regression analysis (1.16; 95% CI, 0.51-2.63; P = .71). The median overall survival was not reached for either of the cohorts. Propensity scores were calculated but were too dissimilar for analysis. CONCLUSIONS: RS and SR were performed in different patient populations, which limits comparison. RS approached SR outcomes, with a lower incidence of major AEs, in patients who were not eligible for hepatectomy.

Using the electronic medical record to increase testing for HIV and hepatitis C virus in an Appalachian emergency department.

BACKGROUND: The ongoing Appalachian opioid epidemic has led to increasing hepatitis C virus (HCV) infections among people who inject drugs (PWID), and Human Immunodeficiency Virus (HIV) outbreaks have been observed. The primary aim of this study was to assess the potential increase in screening for HIV and HCV in an academic central Appalachian emergency department (ED) through the use of Best Practice Alerts (BPAs) in the electronic medical record (EMR). A secondary aim was to assess for an increase in linkage to care using patient navigators. METHODS: EMR algorithms based on current Centers for Disease Control and Prevention HIV and HCV testing recommendations were created that triggered Best Practice Alerts (BPAs), giving providers a one-click acceptance option to order HIV and/or HCV testing. Placards were placed in care areas, informing patients of the availability of routine screening. Patient navigators facilitated linkage to care for seropositive patients. RESULTS: The BPA appeared 58,936 times on 21,098 patients eligible for HIV screening and 24,319 times on 11,989 patients eligible for HCV screening over a one-year period. Of those, 7106 (33.7%) patients were screened for HIV and 3496 (29.2%) patients were screened for HCV, for an overall testing increase of 2269% and 1065% for HIV and HCV, respectively. Linkage to care increased by 15% for HIV to 100, and 14% for HCV to 64%. CONCLUSION: HIV and HCV screening and linkage to care were increased in an academic ED setting in central Appalachia using EMR alerts. This approach could be utilized in multiple ambulatory settings. Increased testing and earlier linkage to care may help combat the current injection drug use-related HCV epidemic and avoid additional HIV outbreaks.

Kidney transplantation on extracorporeal life support for primary cardiac allograft dysfunction.

Patients undergoing heart-kidney transplants who have primary graft dysfunction (PGD) of the heart are at risk of losing both organs, which may cause reluctance on the part of the transplant team to proceed with transplanting the kidney while the transplanted heart is being supported by mechanical device. We describe a case series in which 2 patients received kidney transplants while on veno-arterial ECMO support for PGD after heart transplant. Both patients are alive more than 1 year following transplant, with good cardiac and renal function and no signs of cardiac rejection. Kidney transplant surgery is safe for patients on veno-arterial ECMO support for cardiac PGD. It allows the heart recipient to receive a kidney from the same donor with both immunologic and survival advantages.

Intraoperative Events in Liver Transplantation Using Donation After Circulatory Death Donors.

Liver grafts from donation after circulatory death (DCD) are a source of organs to decrease wait-list mortality. While there have been lower rates of graft loss, there are concerns of an increased incidence of intraoperative events in recipients of DCD grafts. We aim to look at the incidence of intraoperative events between recipients of livers from DCD and donation after brain death (DBD) donors. We collected data for 235 DCD liver recipients between 2006 and 2017. We performed a 1:1 propensity match between these patients and patients with DBD donors. Variables included recipient age, liver disease etiology, biological Model for End-Stage Liver Disease (MELD) score, allocation MELD score, diagnosis of hepatocellular carcinoma, and year of transplantation. DCD and DBD groups had no significant differences in incidence of postreperfusion syndrome (P = 0.75), arrhythmia requiring cardiopulmonary resuscitation (P = 0.66), and treatments for hyperkalemia (P = 0.84). In the DCD group, there was a significant increase in amount of total intraoperative and postreperfusion blood products (with exception of postreperfusion packed red blood cells) utilized (P < 0.05 for all products), significant differences in postreperfusion thromboelastography parameters, as well as inotropes and vasopressors used (P < 0.05 for all infusions). There was no difference in patient (P = 0.49) and graft survival (P = 0.10) at 1, 3, and 5 years. In conclusion, DCD grafts compared with a cohort of DBD grafts have a similar low incidence of major intraoperative events, but increased incidence of transient vasopressor/inotropic usage and increased blood transfusion requirements. This does not result in differences in longterm outcomes. While centers should continue to look at DCD liver donors, they should be cognizant regarding intraoperative care to prevent adverse outcomes.

Intraregional model for end-stage liver disease score variation in liver transplantation: Disparity in our own backyard.

Variation in average Model for End-Stage Liver Disease (MELD) score at liver transplantation (LT) by United Network for Organ Sharing (UNOS) regions is well documented. The present study aimed to investigate MELD variation at the interregional, intraregional, and intra-donation service area (DSA) levels. Patients undergoing LT between 2015 and 2016 were obtained from the UNOS standard analysis and research file. The distribution of allocation MELD score including median, skew, and kurtosis was examined for all transplant programs. Intraregional median allocation MELD varied significantly within all 11 UNOS regions. The largest variation between programs was seen in region 5 (MELD 24.0 versus 38.5) and region 3 (MELD 20.5 versus 32.0). Regions 1, 5, and 9 had the largest proportion of programs with a highly negative skewed MELD score (50%, 57%, and 57%, respectively), whereas regions 3, 6, 10, and 11 did not have any programs with a highly negative skew. MELD score distribution was also examined in programs located in the same DSA, where no barriers exist and theoretically no significant difference in allocation should be observed. The largest DSA variation in median allocation MELD score was seen in NYRT-OP1 LiveOnNY (MELD score variation 11), AZOB-OP1 Donor Network of Arizona (MELD score variation 11), MAOB-OP1 New England Organ Bank (MELD score variation 9), and TXGC-OP1 LifeGift Organ Donation Ctr (MELD score variation 9). In conclusion, the present study demonstrates that this MELD disparity is not only present at the interregional level but can be seen within regions and even within DSAs between programs located as close as several city blocks away. Although organ availability likely accounts for a component of this disparity, the present study suggests that transplant center behavior may also play a significant role. Liver Transplantation 24 488-496 2018 AASLD.

Comparison of longterm outcomes and quality of life in recipients of donation after cardiac death liver grafts with a propensity-matched cohort.

The use of liver grafts from donation after cardiac death (DCD) has been limited due to the increased rate of graft failure, mostly related to ischemic cholangiopathy (IC). It is our hypothesis that longterm outcomes and quality of life (QOL) similar to patients undergoing liver transplantation (LT) with donation after brain death (DBD) can be achieved. Clinical outcomes of all patients undergoing DCD LT (n = 300) between 1998 and 2015 were compared with a propensity score-matched cohort of patients undergoing DBD LT (n = 300). Patients were contacted for a follow-up questionnaire and short-form (SF)-12 QOL Survey administration. Median follow-up was >5 years. Graft survival at 1-, 3-, and 5-years was 83.8%, 75.5%, and 70.1% in the DCD LT group and 88.4%, 80.3%, and 73.9% in the DBD LT group (P = 0.27). Patient survival at 1-, 3-, and 5-years was 92.3%, 86.1%, and 80.3% in the DCD LT group and 92.3%, 85.1%, and 79.5% in the DBD LT group (P = 0.81). IC developed in 11.7% and 2% of patients in the DCD LT group and DBD LT group, respectively (P < 0.001). DCD LT recipients who developed IC had inferior graft survival compared with both the DCD non-IC group (P < 0.001) and the DBD LT group (P < 0.001); no difference in graft survival was observed between the DCD non-IC group and the DBD LT group (P = 0.50). Physical and Mental Composite Scores on the SF-12 QOL questionnaire were similar between the DCD LT and DBD LT groups (44.0 versus 45.4; P = 0.34 and 51.9 versus 52.2; P = 0.83), respectively. Similar longterm survival and QOL scores can be achieved between DCD LT and DBD LT. Prevention of IC in DCD LT yields excellent graft and patient survival with virtually no difference compared with DBD LT. Liver Transplantation 23 342-351 2017 AASLD.

Liver Transplantation for Hepatocellular Carcinoma: Impact of Wait Time at a Single Center.

INTRODUCTION AND AIM: Liver transplantation (LT) provides durable survival for hepatocellular carcinoma (HCC). However, there is continuing debate concerning the impact of wait time and acceptable tumor burden on outcomes after LT. We sought to review outcomes of LT for HCC at a single, large U.S. center, examining the influence of wait time on post-LT outcomes. MATERIAL AND METHODS: We reviewed LT for HCC at Mayo Clinic in Florida from 1/1/2003 until 6/30/2014. Follow up was updated through 8/1/ 2015. RESULTS: From 2003-2014, 978 patients were referred for management of HCC. 376 patients were transplanted for presumed HCC within Milan criteria, and the results of these 376 cases were analyzed. The median diagnosis to LT time was 183 days (8 - 4,337), and median transplant list wait time was 62 days (0 - 1815). There was no statistical difference in recurrence-free or overall survival for those with wait time of less than or greater than 180 days from diagnosis of HCC to LT. The most important predictor of long term survival after LT was HCC recurrence (HR: 18.61, p < 0.001). Recurrences of HCC as well as survival were predicted by factors related to tumor biology, including histopathological grade, vascular invasion, and pre-LT serum alpha-fetoprotein levels. Disease recurrence occurred in 13%. The overall 5-year patient survival was 65.8%, while the probability of 5-year recurrence-free survival was 62.2%. CONCLUSIONS: In this large, single-center experience with long-term data, factors of tumor biology, but not a longer wait time, were associated with recurrence-free and overall survival.

Oxygen and Bis(3',5')-cyclic Dimeric Guanosine Monophosphate Binding Control Oligomerization State Equilibria of Diguanylate Cyclase-Containing Globin Coupled Sensors.

Bacteria sense their environment to alter phenotypes, including biofilm formation, to survive changing conditions. Heme proteins play important roles in sensing the bacterial gaseous environment and controlling the switch between motile and sessile (biofilm) states. Globin coupled sensors (GCS), a family of heme proteins consisting of a globin domain linked by a central domain to an output domain, are often found with diguanylate cyclase output domains that synthesize c-di-GMP, a major regulator of biofilm formation. Characterization of diguanylate cyclase-containing GCS proteins from Bordetella pertussis and Pectobacterium carotovorum demonstrated that cyclase activity is controlled by ligand binding to the heme within the globin domain. Both O2 binding to the heme within the globin domain and c-di-GMP binding to a product-binding inhibitory site (I-site) within the cyclase domain control oligomerization states of the enzymes. Changes in oligomerization state caused by c-di-GMP binding to the I-site also affect O2 kinetics within the globin domain, suggesting that shifting the oligomer equilibrium leads to broad rearrangements throughout the protein. In addition, mutations within the I-site that eliminate product inhibition result in changes to the accessible oligomerization states and decreased catalytic activity. These studies provide insight into the mechanism by which ligand binding to the heme and I-site controls activity of GCS proteins and suggests a role for oligomerization-dependent activity in vivo.

Outcomes of liver transplantation with liver grafts from pediatric donors used in adult recipients.

Although there is an agreement that liver grafts from pediatric donors (PDs) should ideally be used for pediatric patients, there remain situations when these grafts are turned down for pediatric recipients and are then offered to adult recipients. The present study aimed to investigate the outcomes of using these grafts for liver transplantation (LT) in adult patients. Data from all patients undergoing LT between 2002 and 2014 were obtained from the United Network for Organ Sharing Standard Analysis and Research file. Adult recipients undergoing LT were divided into 2 groups: those receiving a pediatric liver graft (pediatric-to-adult group) and those receiving a liver graft from adult donors (adult-to-adult group). A separate subgroup analysis comparing the PDs used for adult recipients and those used for pediatric recipients was also performed. Patient and graft survival were not significantly different between pediatric-to-adult and adult-to-adult groups (P = 0.08 and P = 0.21, respectively). Hepatic artery thrombosis as the cause for graft loss was higher in the pediatric-to-adult group (3.6%) than the adult-to-adult group (1.9%; P < 0.001). A subanalysis looking at the pediatric-to-adult group found that patients with a predicted graft-to-recipient weight ratio (GRWR) < 0.8 had a higher 90-day graft loss rate than those with a GRWR ≥ 0.8 (39% versus 9%; P < 0.001). PDs used for adult recipients had a higher proportion of donors with elevated aspartate aminotransferase/alanine aminotransferase (20% vs. 12%; P < 0.001), elevated creatinine (11% vs. 4%; P < 0.001), donation after cardiac death donors (12% vs. 0.9%; P < 0.001), and were hepatitis B virus core positive (1% vs. 0.3%; P = 0.002) than PDs used for pediatric recipients. In conclusion, acceptable patient and graft survival can be achieved with the use of pediatric liver grafts in adult recipients, when these grafts have been determined to be inappropriate for usage in the pediatric population. Liver Transplantation 22 1099-1106 2016 AASLD.

Hepatic Resection for Metastatic Neuroendocrine Cancer in Patients with Bone Metastases.

BACKGROUND: Hepatic resection (HR) of metastatic neuroendocrine cancer has been associated with prolonged survival and durable symptom control for selected patients with metastatic neuroendocrine tumor (NET). The present study investigates the outcomes of this operative approach in selected patients with known bone metastases. METHODS: All patients undergoing HR at Mayo Clinic Rochester and Mayo Clinic Florida for metastatic NET between January 1989 and August 2015 were identified, and were divided into two groups: those undergoing HR with a known diagnosis of bone metastases (HRmNET/LB) and those who had metastatic disease confined to the liver (HRmNET/L). RESULTS: A total of 25 patients in the HRmNET/LB group were propensity matched with 100 patients in the HRmNET/L group. Major liver resection was performed in 60 % of patients in the HRmNET/LB group and 55 % of patients in the HRmNET/L group (p = 0.42). Median survival for the HRmNET/LB group was 54.0 months, compared with 97.7 months for the HRmNET/L group (p = 0.03). In the HRmNET/LB group, median survival was 73.3 months for patients with gastrointestinal NET(GNET), compared with 42.7 months for patients with pancreatic NET (PNET). The median number of bone metastases was 2 (range 1-10), and the sites of bone metastases were the spine (68 %), pelvis (24 %), and ribs (12 %). Bone metastases were treated with radiotherapy in ten (40 %) patients, by radiofrequency ablation in two (8 %) patients, and by resection in one (4 %) patient. CONCLUSIONS: The present study is the first report to describe HR for patients with metastatic NET and known bone metastases. We demonstrated that in properly selected cases, excellent survival can be achieved with liver debulking in these patients.

Imaging Active Surface Processes in Barnacle Adhesive Interfaces.

Surface plasmon resonance imaging (SPRI) and voltammetry were used simultaneously to monitor Amphibalanus (=Balanus) amphitrite barnacles reattached and grown on gold-coated glass slides in artificial seawater. Upon reattachment, SPRI revealed rapid surface adsorption of material with a higher refractive index than seawater at the barnacle/gold interface. Over longer time periods, SPRI also revealed secretory activity around the perimeter of the barnacle along the seawater/gold interface extending many millimeters beyond the barnacle and varying in shape and region with time. Ex situ experiments using attenuated total reflectance infrared (ATR-IR) spectroscopy confirmed that reattachment of barnacles was accompanied by adsorption of protein to surfaces on similar time scales as those in the SPRI experiments. Barnacles were grown through multiple molting cycles. While the initial reattachment region remained largely unchanged, SPRI revealed the formation of sets of paired concentric rings having alternately darker/lighter appearance (corresponding to lower and higher refractive indices, respectively) at the barnacle/gold interface beneath the region of new growth. Ex situ experiments coupling the SPRI imaging with optical and FTIR microscopy revealed that the paired rings coincide with molt cycles, with the brighter rings associated with regions enriched in amide moieties. The brighter rings were located just beyond orifices of cement ducts, consistent with delivery of amide-rich chemistry from the ducts. The darker rings were associated with newly expanded cuticle. In situ voltammetry using the SPRI gold substrate as the working electrode revealed presence of redox active compounds (oxidation potential approx 0.2 V vs Ag/AgCl) after barnacles were reattached on surfaces. Redox activity persisted during the reattachment period. The results reveal surface adsorption processes coupled to the complex secretory and chemical activity under barnacles as they construct their adhesive interfaces.

Simultaneous liver and kidney transplantation in elderly patients: Outcomes and validation of a clinical risk score for patient selection.

 Introduction and aim. Many transplant programs have expanded eligibility to include patients previously ineligible because of advanced age. Outcomes of simultaneous liver-kidney transplantation (SLK) in recipients with advanced age are not known. MATERIAL AND METHODS: Data from patients undergoing transplantation between 2002 and 2015 were obtained from the UNOS Standard Analysis and Research file. RESULTS: SLK recipients aged ≥ 65 years (N = 677), SLK recipients aged < 65 years (N = 4517), and recipients of liver transplant alone(LTA) aged ≥ 65 years(N = 8495) were compared. Recipient characteristics were similar between the SLK groups. Similar patient and graft survival were observed in SLK recipients aged ≥ 65 years compared to SLK recipients aged < 65 years and LTA recipients aged ≥ 65 years. Importantly, in a subgroup analysis, superior survival was seen in the SLK group aged ≥ 65 years compared to LTA recipients aged ≥ 65 years who underwent dialysis in the week prior to transplantation (p < 0.001). A prediction model of patient survival was developed for the SLK group aged ≥ 65 years with predictors including: age ≥ 70 years (3 points), calculated MELD score (-1 to 2 points), and recipient ventilator status at the time of SLK (4 points). The risk score predicted patient survival, with a significantly inferior survival seen in patients with a score ≥ 4 (p < 0.001). CONCLUSIONS: Age should not be used as a contraindication for SLK transplantation. The validated scoring system provides a guide for patient selection and can be used when evaluating elderly patients for SLK transplantation listing.

A novel objective method for deceased donor and recipient size matching in liver transplantation.

Although the consequences of implantation of a large whole liver graft into a small recipient such as compression and compromise of graft perfusion are well known, no accepted measure to aid in donor-to-recipient size matching exists. Donor liver graft and recipient native liver weights as well as donor and recipient size and amount of ascites were investigated in 1953 patients who underwent liver transplantation using deceased donor grafts between January 2002 and July 2013. We used a previously described formula for liver resections (standardized total liver volume [sTLV] = -794.41 + 1267.28 × body surface area [m(2)]) for calculating sTLV, in the current cohort of deceased liver donors. Early allograft dysfunction (EAD) and graft survival were the primary outcome measures. The formula for calculating sTLV for liver resections was validated as an accurate predictor of liver volume in the current cohort of deceased liver donors (r(2) = 0.45; P < 0.001). A cutoff point of sTLV ratio ≥ 1.25 was determined through receiver operating characteristic curves, and patients were dichotomized into 2 groups. In the sTLV ratio ≥ 1.25 group, 50% of patients developed EAD compared to 25% of patients in the sTLV ratio < 1.25 group (P < 0.001). The proportion of patients developing graft failure within 90 days was 9.6% in the sTLV ratio ≥ 1.25 group and 5.4% in the sTLV ratio < 1.25 group (P = 0.045). This study validates the use of the sTLV for prediction of actual donor liver weight in the transplant setting. Using this formula, donors with a calculated sTLV size ratio ≥ 1.25 have an increased risk of EAD and therefore caution should be used when that value is exceeded. This adjusted size ratio can be used as a decision aid when considering donor and recipient matching with potential liver organ offers.

Early allograft dysfunction in liver transplantation with donation after cardiac death donors results in inferior survival.

Donation after cardiac death (DCD) liver allografts have been associated with increased morbidity from primary nonfunction, biliary complications, early allograft failure, cost, and mortality. Early allograft dysfunction (EAD) after liver transplantation has been found to be associated with inferior patient and graft survival. In a cohort of 205 consecutive liver-only transplant patients with allografts from DCD donors at a single center, the incidence of EAD was found to be 39.5%. The patient survival rates for those with no EAD and those with EAD at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and 61% and 54%, respectively (P = 0.009). Allograft survival rates for recipients with no EAD and those with EAD at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P = 0.003). A multivariate analysis demonstrated a significant association between the development of EAD and the cold ischemia time [odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.01-1.56, P = 0.037] and hepatocellular cancer as a secondary diagnosis in recipients (OR = 2.26, 95% CI = 1.11-4.58, P = 0.025). There was no correlation between EAD and the development of ischemic cholangiopathy. In conclusion, EAD results in inferior patient and graft survival in recipients of DCD liver allografts. Understanding the events that cause EAD and developing preventive or early therapeutic approaches should be the focus of future investigations.

Intraoperative vascular air embolism and intracardiac thrombosis complicating liver transplantation: a case report.

BACKGROUND: Intracardiac thrombus and vascular air embolism represent rare complications in the context of orthotopic liver transplantation. While isolated reports exist for intracardiac thrombus and vascular air embolism during orthotopic liver transplantation, this report presents the first documentation of their simultaneous occurrence in this surgical setting. CASE PRESENTATION: This case report outlines the clinical course of a 60-year-old white female patient with end-stage liver disease complicated by portal hypertension, ascites, and hepatocellular carcinoma. The patient underwent orthotopic liver transplantation and encountered concurrent intraoperative complications involving intracardiac thrombus and vascular air embolism. Transesophageal echocardiography revealed the presence of air in the left ventricle and a thrombus in the right atrium and ventricle. Successful management ensued, incorporating hemodynamic support, anticoagulation, and thrombolytic therapy, culminating in the patient's discharge after a week. CONCLUSIONS: This report highlights the potential for simultaneous intraoperative complications during orthotopic liver transplantation, manifesting at any phase of the surgery. It underscores the critical importance of vigilant monitoring throughout orthotopic liver transplantation to promptly identify and effectively address these rare yet potentially catastrophic complications.

Receptor activator of nuclear factor-κB ligand (RANKL) protects against hepatic ischemia/reperfusion injury in mice.

UNLABELLED: The transcription factor nuclear factor kappaB (NF-κB) plays diverse roles in the acute injury response to hepatic ischemia/reperfusion (I/R). Activation of NF-κB in Kupffer cells promotes inflammation through cytokine expression, whereas activation in hepatocytes may be cell protective. The interaction of receptor activator of NF-κB (RANK) and its ligand (RANKL) promotes NF-κB activation; however, this ligand-receptor system has not been studied in acute liver injury. In the current study, we sought to determine if RANK and RANKL were important in the hepatic response to I/R. Mice were subjected to partial hepatic ischemia followed by reperfusion. In some experiments, mice received recombinant RANKL or neutralizing antibodies to RANKL 1 hour prior to surgery or at reperfusion to assess the role of RANK/RANKL signaling during I/R injury. RANK was constitutively expressed in the liver and was not altered by I/R. RANK was strongly expressed in hepatocytes and very weakly expressed in Kupffer cells. Serum RANKL concentrations increased after I/R and peaked 4 hours after reperfusion. Serum levels of osteoprotegerin (OPG), a decoy receptor for RANKL, steadily increased over the 8-hour period of reperfusion. Treatment with RANKL, before ischemia or at reperfusion, increased hepatocyte NF-κB activation and significantly reduced liver injury. These beneficial effects occurred without any effect on cytokine expression or liver inflammation. Treatment with anti-RANKL antibodies had no effect on liver I/R injury. CONCLUSION: During the course of injury, endogenous OPG appears to suppress the effects of RANKL. However, exogenous administration of RANKL, given either prophylactically or postinjury, reduces liver injury in a manner associated with increased hepatocyte NF-κB activation. The data suggest that RANK/RANKL may be a viable therapeutic target in acute liver injury.

Interleukin-33 is hepatoprotective during liver ischemia/reperfusion in mice.

UNLABELLED: Interleukin (IL)-33 is a recently identified member of the IL-1 family that binds to the receptor, ST2L. In the current study, we sought to determine whether IL-33 is an important regulator in the hepatic response to ischemia/reperfusion (I/R). Male C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia, followed by up to 8 hours of reperfusion. Some mice received recombinant IL-33 (IL-33) intraperitoneally (IP) before surgery or anti-ST2 antibody IP at the time of reperfusion. Primary hepatocytes and Kupffer cells were isolated and treated with IL-33 to assess the effects of IL-33 on inflammatory cytokine production. Primary hepatocytes were treated with IL-33 to assess the effects of IL-33 on mediators of cell survival in hepatocytes. IL-33 protein expression increased within 4 hours after reperfusion and remained elevated for up to 8 hours. ST2L protein expression was detected in healthy liver and was up-regulated within 1 hour and peaked at 4 hours after I/R. ST2L was primarily expressed by hepatocytes, with little to no expression by Kupffer cells. IL-33 significantly reduced hepatocellular injury and liver neutrophil accumulation at 1 and 8 hours after reperfusion. In addition, IL-33 treatment increased liver activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), p38 mitogen-activated protein kinase (MAPK), cyclin D1, and B-cell lymphoma 2 (Bcl-2), but reduced serum levels of CXC chemokines. In vitro experiments demonstrated that IL-33 significantly reduced hepatocyte cell death as a result of increased NF-κB activation and Bcl-2 expression in hepatocytes. CONCLUSION: The data suggest that IL-33 is an important endogenous regulator of hepatic I/R injury. It appears that IL-33 has direct protective effects on hepatocytes, associated with the activation of NF-κB, p38 MAPK, cyclin D1, and Bcl-2 that limits liver injury and reduces the stimulus for inflammation.

Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.

BACKGROUND & AIMS: The relative frequency of nonalcoholic steatohepatitis (NASH) as an indication for liver transplantation and comparative outcomes following transplantation are poorly understood. METHODS: We analyzed the Scientific Registry of Transplant Recipients for primary adult liver transplant recipients from 2001 to 2009. RESULTS: From 2001 to 2009, 35,781 patients underwent a primary liver transplant, including 1959 for who NASH was the primary or secondary indication. The percentage of patients undergoing a liver transplant for NASH increased from 1.2% in 2001 to 9.7% in 2009. NASH is now the third most common indication for liver transplantation in the United States. No other indication for liver transplantation increased in frequency during the study period. Compared with other indications for liver transplantation, recipients with NASH are older (58.5±8.0 vs 53.0±8.9 years; P<.001), have a larger body mass index (>30 kg/m2) (63% vs 32%; P<.001), are more likely to be female (47% vs 29%; P<.001), and have a lower frequency of hepatocellular carcinoma (12% vs 19%; P<.001). Survival at 1 and 3 years after liver transplantation for NASH was 84% and 78%, respectively, compared with 87% and 78% for other indications (P=.67). Patient and graft survival for liver recipients with NASH were similar to values for other indications after adjusting for level of creatinine, sex, age, and body mass index. CONCLUSIONS: NASH is the third most common indication for liver transplantation in the United States and is on a trajectory to become the most common. Outcomes for patients undergoing a liver transplant for NASH are similar to those for other indications.