Course Of Liver Transplantation Research Articles

THU-481 - HBV re-infection or de-novo infection in the course of liver transplantation in patients chronically infected with HBV, HBV/HDV, or HCV

THU-481 - HBV re-infection or de-novo infection in the course of liver transplantation in patients chronically infected with HBV, HBV/HDV, or HCV

Clinical Course and Outcome of Liver Transplantation in Patients with Hepatitis C in Iran

Background: Hepatitis C is one of the most common causes of end-stage liver disease and liver transplant worldwide. In recent years, with the rapid advances in the treatment of hepatitis C by direct-acting antiviral drugs (DAAs), the clinical course of the disease as well as liver transplantation have had significant improvement. Also, DAAs have completely replaced interferon-based regimens in the treatment and prevention of HCV recurrence after liver transplant. Objectives: This is the first study that aimed to investigate the clinical course of liver transplantation in patients with hepatitis C in Iran. Methods: This retrospective study was conducted on patients with HCV liver transplantation within five years (2012 - 2017) with the age range of 18 to 65 years at Shiraz Organ Transplant Center. All demographic and clinical data were recorded. Pre-transplant viral load, disease recurrence, graft rejection, and mortality rate were the most important indices in this study. Results: Among 55 transplant patients, 49% had received hepatitis C treatment before liver transplantation and interferon-based regimens were more prevalent. Besides, HCV genotype 3, followed by genotype 1, was the most prevalent one. A liver biopsy was performed in patients with elevated liver enzyme levels. The numbers of patients with HCV recurrence at 2, 6, 12, and 24-month intervals were three, two, zero, and two patients, respectively. At these time intervals, eight, eight, one, and three cases of acute graft rejection were found, respectively. Eight patients died with a one-year survival rate of 85%. Sepsis and infectious complications were the most leading causes of death. Conclusions: This study is the first study of liver transplant patients with hepatitis C in Iran. In the five-year study period, rapid development was made in the treatment of HCV patients. It led to the introduction of DAAs, which replaced interferon-based therapies. The results of this study indicated the high success rate of liver transplantation in patients with hepatitis C in Iran. The results of this study could be used to compare the efficacy of DAAs in future research.

Inhibition of miR-450b-5p ameliorates hepatic ischemia/reperfusion injury via targeting CRYAB

Hepatic ischemia/reperfusion injury (IRI) is an unavoidable course in liver transplantation, during which the immune response of inflammation plays a leading part. MicroRNA-450b-5p (miR-450b-5p), which has been reported to participate in several inflammatory diseases, was investigated in this study. The purpose of this study is to identify the potential function of miR-450b-5p toward remission of hepatic IRI and elucidate the specific mechanism. Herein we found that expression of miR-450b-5p, interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 was stimulated in hepatic IRI. Inhibition of miR-450b-5p could remarkably alleviate mouse hepatic IRI and improve liver function measured by hematoxylin–eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), and enzyme-linked immunosorbent assay (ELISA). We further assessed protein expression undergoing Western blot and immunofluorescence, and discovered that miR-450b-5p suppressed alpha B-crystallin (CRYAB), thus restraining the inhibitory κB kinase (IKK) β-mediated canonical nuclear factor-κB (NF-κB) signaling, instead of the noncanonical path guided by IKKα in hepatic IRI. In addition, we demonstrated CRYAB as an activator of M2 polarization through protein kinase B (Akt) 1/mammalian target of rapamycin (mTOR), thus resulting in relief of liver IRI. Combination treatment containing both paths revealed a better antidamage efficacy than adjusting either path alone, suggesting that the joint therapy might be a promising solution in hepatic IRI.

Impact of the venting via vena cava inferior on the outcome of liver transplantation.

The liver transplantation is a standard treatment method for the indicated group of patients with a final hepatic failure. The aim of this paper was to compare two reperfusion methods of implanted liver, non-venting and venting vena cava, and to evaluate the impact of both techniques on the post reperfusion syndrome. We compared two groups of patients: non-venting (n = 42) andventing (n = 41). We monitored bilirubin, liver enzymes and hemodynamic changes after reperfusion. We recorded monitored parameters immediately prior to the transplantation, during and after the reperfusion and on the 1st postoperative day. All liver grafts were used from the donors after a brain death. We did not find a statistically significant difference in input monitored parameters. We detected significant changes of pH after reperfusion in both monitored groups. We determined a significantly better saturation in the non-venting group, bigger consumption of fresh frozen plasma and thrombo-concentrate in the non-venting group, a significantly higher value of total bilirubin and a lower value of Quick's time in the non-venting group. Venting via vena cava inferior did not impact the perioperative and early postoperative course of liver transplantation in our group of patients. However, further analyses are required (Tab. 2, Fig. 3, Ref. 20).

Graft Regeneration and Functional Recovery in Patients with Early Allograft Dysfunction After Living-Donor Liver Transplantation.

BackgroundSuccessful graft regeneration is important in living-donor liver transplantation (LDLT) because partial liver grafts are used. Early allograft dysfunction (EAD) is an intermediate outcome that affects the long-term postoperative course in liver transplantation. The aim of the present study was to investigate liver graft regeneration under EAD development in LDLT.Material/MethodsThe data of 226 patients who underwent LDLT from September 2010 to July 2014 were retrospectively analyzed. The patients were classified into 2 groups: one with and one without EAD. Graft regeneration, functional recovery, and long-term patient survival were compared between the 2 groups.ResultsThe grafts grew more vigorously in the EAD group than in the non-EAD group, as evidenced by the larger absolute (ALV) and relative liver volumes (RLV) of the former on postoperative days (POD) 7 and 21. The median (interquartile range) RLVs of the non-EAD group versus the EAD group were as follows: 55.2 (47.9–65.8) vs. 53.7 (46.6–64.5)% preoperatively, p>0.05; 76.1 (66.9–85.7) vs. 86.7 (73.9–96.8)% on POD 7, p<0.01; 79.6 (69.3–91.2) vs. 93.7 (79.6–101.6)%, p<0.01 on POD 21. In the early postoperative period, hepatic function, measured as total bilirubin and international normalized ratio, was higher in the EAD group; however, after EAD development, graft function recovered in these patients. In the follow-up period, overall patient survival was comparable between the 2 groups.ConclusionsThe liver grafts of EAD patients steadily regenerated, such that the development of EAD did not affect long-term patient survival after LDLT.

Methicillin-resistant Staphylococcus aureus bacteremia among liver transplant recipients: epidemiology and associated risk factors for morbidity and mortality.

Bacteremia due to Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), complicates the clinical course of liver transplantation and is associated with high morbidity and mortality. Intravascular catheters had been reported to be the most frequent source of MRSA bacteremia. Among bacteremic liver recipients, 26.3%–100% of S. aureus were MRSA. Previous studies identified pre-transplant and post-transplant acquired S. aureus carriage, greater severity of liver disease, hepatocellular carcinoma and infection with immuno-modulatory viruses as predictors of S. aureus bacteremia in liver recipients. MRSA bacteremia accompanied by pneumonia and abdominal infections was related to mortality. Vancomycin, as well as daptomycin, is a first-line antibiotic for MRSA bacteremia. The purpose of this review is to better understand the characteristics of MRSA bacteremia by summarizing the epidemiology and antimicrobial resistance of S. aureus, the primary source, and related risk factors for morbidity and mortality of MRSA bacteremia. We have also explored the diagnostic, therapeutic and preventive measures for MRSA bacteremia to improve the outcomes of liver recipients.

Phenotype of fibrinolytic activity and prophylaxis of hyperfibrinolysis in the course of liver transplantation

Phenotype of fibrinolytic activity and prophylaxis of hyperfibrinolysis in the course of liver transplantation

Does Preoperative Beta-blocker Use Influence Intraoperative Hemodynamic Profile and Post-operative Course of Liver Transplantation?

ObjectiveWe compared the intraoperative hemodynamic profiles and outcomes of liver transplant (LT) patients receiving preoperative beta-blockers for portal hypertension with those of patients not receiving beta-blockers. MethodsBeat-to-beat hemodynamic data were recorded with the use of a lithium dilution cardiac output monitor, including heart rate (HR), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), SVR index, mean arterial pressure, stroke volume (SV), and SV index. Perioperative data included age, sex, etiology of cirrhosis, Model of End-Stage Liver Disease score, warm and cold ischemia times, and intraoperative blood and blood products replacement. Postoperative data included Acute Physiology and Chronic Health Evaluation II score, Intensive Care National Audit and Research Centre (ICNARC) score, length of intensive care unit stay, renal replacement treatment, and mortality. ResultsAfter exclusion, 215 patients not receiving and 93 patients receiving beta-blockers for portal hypertension were included. There was no significant difference between groups in demographic data. HR, CO, and CI were significantly lower in the beta-blocker group (P = .0001). Regarding outcomes, the ICNARC score was significantly higher in the beta-blocker group (P < .05). ConclusionsPreoperative administration of beta-blockers attenuates the hyperdynamic circulation in LT patients; this is clearly seen through a reduction in intraoperative CO, CI, and HR. This decreased hyperdynamic state was not shown to relate to outcomes in any of the variables except for a higher ICNARC score reported in the group treated with beta-blockers.

Mitochondrial Damage-Associated Molecular Patterns (MTDs) Are Released during Hepatic Ischemia Reperfusion and Induce Inflammatory Responses.

Ischemia / reperfusion injury (IRI) during the course of liver transplantation enhances the immunogenicity of allografts and thus impacts overall graft outcome. This sterile inflammatory insult is known to activate innate immunity and propagate organ damage through the recognition of damage-associate molecular pattern (DAMP) molecules. The purpose of the present study was to investigate the role of mitochondrial DAMPs (MTDs) in the pathogenesis of hepatic IRI. Using in vitro models we observed that levels of MTDs were significantly higher in both transplantation-associated and warm IR, and that co-culture of MTDs with human and rat hepatocytes significantly increased cell death. MTDs were also released in an in vivo rat model of hepatic IRI and associated with increased secretion of inflammatory cytokines (TNF-α, IL-6, and IL-10) and increased liver injury compared to the sham group. Our results suggest that hepatic IR results in a significant increase of MTDs both in vitro and in vivo suggesting that MTDs may serve as a novel marker in hepatic IRI. Co-culture of MTDs with hepatocytes showed a decrease in cell viability in a concentration dependent manner, which indicates that MTDs is a toxic mediator participating in the pathogenesis of liver IR injury.

Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry

A vaccine against hepatitis C virus (HCV) is unavailable and cost-effective antivirals that prevent HCV infection and re-infection, such as in the transplant setting, do not exist. In a search for novel and economical prophylactic agents, we examined the antiviral activity of saikosaponins (SSa, SSb2, SSc, and SSd) from Bupleurum kaoi root (BK) as entry inhibitors against HCV infection. Infectious HCV culture systems were used to examine the effect of saikosaponins on the complete virus life cycle (entry, RNA replication/translation, and particle production). Antiviral activity against various HCV genotypes, clinical isolates, and infection of primary human hepatocytes were also evaluated. BK and the saikosaponins potently inhibited HCV infection at non-cytotoxic concentrations. These natural agents targeted early steps of the viral life cycle, while leaving replication/translation, egress, and spread relatively unaffected. In particular, we identified SSb2 as an efficient inhibitor of early HCV entry, including neutralization of virus particles, preventing viral attachment, and inhibiting viral entry/fusion. Binding analysis, using soluble viral glycoproteins, demonstrated that SSb2 acted on HCV E2. Moreover, SSb2 inhibited infection by several genotypic strains and prevented binding of serum-derived HCV onto hepatoma cells. Finally, treatment with the compound blocked HCV infection of primary human hepatocytes. Due to its potency, SSb2 may be of value for development as an antagonist of HCV entry and could be explored as prophylactic treatment during the course of liver transplantation.

T-51 Study of HBV (re)infection in the course of liver transplantation in HBV, HBV/HDV and occult HBV infected patients

T-51 Study of HBV (re)infection in the course of liver transplantation in HBV, HBV/HDV and occult HBV infected patients

Metabolic preconditioning with fructose prior to organ recovery attenuates ischemia-reperfusion injury in the isolated perfused rat liver

Objective. Ischemia-reperfusion injury is associated with a high rate of primary organ dysfunction and thereby contributes substantially to morbidity and mortality in the course of liver transplantation. In the present study, the impact of metabolic preconditioning with fructose on ischemia-reperfusion injury in the isolated perfused rat liver model is evaluated. Methods. Fasted rats received a single intravenous fructose injection to induce metabolic preconditioning (fructose group) or a volume equivalent of normal saline (control group) 10 min before liver explantation. After 26 h of cold storage, livers were reperfused for 90 min at 37°C with Krebs-Henseleit buffer. The parameters used to quantify ischemia-reperfusion injury included hepatic oxygen consumption, enzyme release, and cell viability. Results. During reperfusion, livers in the fructose group consumed more oxygen than livers in the control group (p < 0.005), indicating ATP synthesis as a result of glycolytic fructose degradation. Moreover, cell injury was reduced by fructose administration, as reflected by a lower enzyme release during both cold ischemia and reperfusion (p < 0.05). Finally, hepatocyte viability at the end of reperfusion was significantly higher in the fructose group (p < 0.01). However, there was no significant difference between the two experimental groups in reference to the viability of endothelial cells. Conclusion. In clinical use, metabolic preconditioning with fructose prior to organ recovery might contribute to a reduction in the incidence of primary organ dysfunction after liver transplantation.

Fatal Escherichia coli skin and soft tissue infections in liver transplant recipients: report of three cases

Gram-negative bacilli are unusual agents of skin and soft tissue infections. Most previous cases have been reported in cirrhotic or immunocompromised patients, including a single case in a liver transplant recipient. The present report describes 3 cases of fatal skin or soft tissue infections caused by Escherichia coli that occurred in the postoperative course of liver transplantation. The 3 patients were profoundly immunosuppressed as a result of pre-transplant cirrhosis and the postoperative administration of a potent immunosuppressive therapy. Skin and soft tissue infections developed within the first week after liver transplantation, while graft liver function was satisfactory. The 3 patients presented with fever and skin lesions with or without bullae. Despite prompt appropriate antibiotic therapy and surgical debridement, the outcome was rapidly fatal (24h on average). E.coli was isolated from subcutaneous tissues in 2 cases and from several blood cultures in the third one. The 3 isolates belonged to distinct phylogenetic groups, and did not harbor most of the virulence factors usually reported in extraintestinal pathogenic E.coli isolates. Our report suggests that E.coli can cause severe skin or soft tissue infection in the postoperative course of liver transplantation. The onset of infection is very early and the outcome is extremely poor, despite prompt adapted medical and surgical treatment. Host factors, rather than E.coli bacterial virulence potential, appear to be the major determinants of severity in these patients.

Hepatic and Abdominal Carbon Dioxide Measurements Detect and Distinguish Hepatic Artery Occlusion and Portal Vein Occlusion in Pigs

Hepatic artery (HA) occlusion and portal vein (PV) occlusion are the most common vascular complications after liver transplantation with an impact on mortality and retransplantation rates. The detection of severe hypoperfusion may be delayed with currently available diagnostic tools. Hypoperfusion and anaerobically produced lactic acid lead to increases in tissue carbon dioxide. We investigated whether the continuous assessment of the intrahepatic and intra-abdominal partial pressure of carbon dioxide (PCO(2) ) could be used to detect and distinguish HA and PV occlusions in real time. In 13 pigs, the HA and the PV were fully occluded (n = 7) or gradually occluded (n = 6). PCO(2) was monitored intrahepatically and between loops of small intestine. The hepatic and intestinal metabolism was assessed with microdialysis and PV as well as hepatic vein blood samples, and the results were compared to clinical parameters for the systemic circulation and blood gas analysis. Total HA occlusion led to significant increases in hepatic PCO(2) and lactate, and this was accompanied by significant decreases in the partial pressure of oxygen and glucose. PV occlusion induced a significant increase in intestinal PCO(2) (but not hepatic PCO(2) ) along with significant increases in intestinal lactate and glycerol. Gradual HA occlusion and PV occlusion caused steady hepatic and intestinal PCO(2) increases, respectively. Systemic clinical parameters such as the blood pressure, heart rate, and cardiac output were affected only by PV occlusion. In conclusion, even gradual HA occlusion affects liver metabolism and can be reliably identified with hepatic PCO(2) measurements. Intestinal PCO(2) increases only during PV occlusion. A combination of hepatic and intestinal PCO(2) measurements can reliably diagnose the affected vessel and depict the severity of the occlusion, and this may emerge as a potential real-time clinical monitoring tool for the postoperative course of liver transplantation and enable early interventions.

Aktuelle Aspekte zur Histopathologie im Rahmen der Lebertransplantation

Liver allograft pathology continues to play an important role in the diagnosis and management of complications in the course of liver transplantation. This article summarizes important patterns of liver damage and also considers new aspects of transplant pathology from the literature. In the context of transplant rejection, late cellular rejection has aroused new interest. Histopathological changes in late rejection differ from acute cellular rejection and there seem to be similarities to de novo autoimmune hepatitis and idiopathic post-transplant hepatitis. Central perivenulitis is a typical change in late cellular rejection and should be differentiated from central toxic necrosis. Other important areas of transplant pathology include vascular and biliary changes resulting from surgical complications or as sequelae of immunosuppressive therapy. Furthermore, disease recurrence plays an important role and combined patterns of disease poses a challenge for the pathologist.

Development of a Severe von Willebrand Factor/ADAMTS13 Dysbalance During Orthotopic Liver Transplantation

Patients with liver disease show profound changes in their hemostatic system, which may further change during liver transplantation. We previously demonstrated that highly elevated levels of the platelet adhesive protein von Willebrand factor (VWF) in patients with cirrhosis lead to an increased VWF-dependent platelet deposition under flow as compared to healthy controls. In this study we examined VWF parameters during the course of liver transplantation. We collected serial plasma samples from 20 patients undergoing liver transplantation in which we determined plasma levels of VWF and the VWF-cleaving protease ADAMTS13. Furthermore, we performed functional tests of VWF-dependent platelet adhesion. We found persistently elevated levels of VWF during and after liver transplantation. The capacity of VWF to interact with platelets normalized during the course of transplantation, and flow-mediated VWF-dependent platelet adhesion remained at levels far exceeding those observed in healthy individuals during and after transplantation. Plasma levels of ADAMTS13 dropped during transplantation, and in four patients levels below 10% of normal were observed after reperfusion. We observed the development of a hyperreactive primary hemostatic system, as evidenced by high levels of fully functional VWF and a temporary ADAMTS13 deficiency, during liver transplantation, and speculate that these changes contribute to postoperative thrombotic complications.

Distribution of the MHC antigens after liver transplantation: relationship with biochemical and histological parameters

The aim of this study was to analyse the change in tissue distribution of HLA class I and class II molecules in patients during the course of liver transplantation. Sixty-one liver biopsies were analysed in 24 patients with or without rejection (acute or chronic) episode. In 93% of cases with chronic rejection and in 48% of cases with acute rejection episodes, HLA class I antigens are expressed in the membrane and/or the cytoplasm of hepatocytes. The expression of these molecules was significantly correlated with the ASP (aspartate amino transferase), AP (alkaline phosphatase), the bile duct damage and the centrolobular lesions. In contrast, the expression of HLA class II molecules is not correlated with either the type of rejection, the biological or histological findings. A strong expression of HLA class I antigen on hepatocytes after day 60 may be one of the best signs of chronic rejection.

Transoesophageal echo-Doppler vs. thermodilution cardiac output measurement during hepatic vascular exclusion in liver transplantation

Continuous monitoring of cardiac output during liver transplantation is essential to evaluate the patient's haemodynamic tolerance to acute volume variations. The aim of this study was to compare the cardiac output values obtained with a transoesophageal echo-Doppler and those obtained with a continuous thermodilution cardiac output pulmonary artery catheter. Twenty adult patients were prospectively studied during a 5 min hepatic vascular exclusion test performed at the end of the dissection phase. Echo-Doppler and continuous thermodilution cardiac output, mean arterial pressure and end-tidal CO2 were measured before and at the end of the test. Before the test, echo-Doppler cardiac output was 7.0 +/- 2.7 L min(-1) and thermodilution was 9.4 +/- 3.1 L min(-1), (R = 0.85, P < 0.001). The end test values were, respectively, 3.5 +/- 2.7 and 7.8 +/- 3.5 L min(-1) (R = 0.23, P = 0.34). Bland and Altman analysis showed a bias of -2.2 before the test, which increased to -4.4 at the end of the test. Mean arterial pressure decreased from 85.5 +/- 15 to 66.8 +/- 16 mmHg, end-tidal CO2 from 31.4 +/- 2.3 to 23.8 +/- 2.7 mmHg. Echo-Doppler cardiac output values are different from those measured by thermodilution cardiac output in these patients. Echo-Doppler cardiac output monitoring seems to detect the output changes, which can occur during acute haemodynamic changes more rapidly than thermodilution cardiac output in the course of liver transplantation.

Hemodynamics During Liver Transplantation

Assessing the optimal volemia in the perioperative course of liver transplantation is a challenge for the anesthesiologist. Traditional estimates of intravascular volume status, such as pulmonary artery occlusion pressure (PAOP), have been widely shown to poorly correlate with changes in cardiac output among critically ill patients. Hence, there has been recent interest in alternative, catheter-related, bedside device volume estimates using thermodilution. Continuous end diastolic volume (CEDVI) showed better correlations with cardiac performance than cardiac filling pressures in studies performed in critically ill patients. When compared with conventional pressure-derived data, preload monitoring estimated as intrathoracic blood volume index (ITBVI) with the PiCCO system based on an integrated transpulmonary thermodilution technique better reflected left ventricular filling both in critically ill patients and those who underwent liver transplantation. Moreover, in liver transplantation, the use of transoesophageal echocardiography (TEE) has been increasing for it provides rapid visualization of the dimension and function of heart chambers as well as the left ventricular end diastolic area index (EDAI) that seem to correlate with graded acute hypovolemia, although its validity as on preload index is still under discussion.

Role of replicative senescence in the progression of fibrosis in hepatitis C virus (HCV) recurrence after liver transplantation.

Although hepatitis C virus (HCV) recurrence is almost universal after orthotopic liver transplantation (OLT), the impact of viral infection on liver graft is highly variable and difficult to predict. Because of the possible relationship between replicative senescence (RS) and the accelerated development of liver fibrosis, we aimed to assess the potential role of RS in the severity of HCV-related chronic hepatitis recurrence after OLT. One hundred three liver biopsies from 56 patients receiving transplants for HCV-related cirrhosis were studied, including 30 revascularization biopsies and 52 and 21 biopsies performed during and beyond the first year of OLT, respectively. The presence of senescent cells in liver grafts was assessed by the senescence-associated beta-galactosidase (SA-beta-Gal) staining method. Chronic hepatitis was defined by fibrosis stage and necrotico-inflammatory activity grade using the METAVIR score. A total of 34 of the 103 (33%) frozen liver biopsies displayed SA-beta-Gal-positive cells, including 6 (20%) of the revascularization biopsies, 14 (34%) of the biopsies performed within the first year, and 10 (46%) of the biopsies performed beyond 1 year of follow-up. The presence of senescent cells in revascularization biopsies was significantly associated with the degree of ischemic necrosis at time of OLT (P = 0.01) and hepatitis C recurrence in the first year after OLT (P = 0.05). Furthermore, the presence of RS in the biopsy performed within the first year was associated with further development of fibrosis (P = 0.05). These data show that RS has a significant impact upon the course of liver transplantation, especially in the long-term progression of fibrosis observed in HCV-infected patients.