Liver Transplantation in Recipients With High Model for End-stage Liver Disease Score.

OBJECTIVES: The score in the Model of End-stage Liver Disease, or MELD, is a good indicator of the survival in patients on the liver transplant waiting list. In this study, an analysis is performed on the benefits of liver transplant on those patients with a very high MELD score and who thus start from a very severe baseline state that could affect the surgical outcome. MATERIALS AND METHODS: A prospective study was conducted on a cohort of 331 patients that received a liver transplant between 2002 and 2014. The patients were divided into 2 groups according to the MELD score (<28 vs ≥28), and differences in age, postoperative complications, stay in the intensive care unit (ICU), hospital stay, and survival were compared. RESULTS: Of the total of 331 patients, 21 (6.3%) had a MELD score ≥ 28. The mean age of the group with MELD score ≥ 28 was lower than the age in the group with MEDL score < 28 (42.5 vs 53.7 years; P < .0001). No significant increase was observed in postoperative complications. Although there were also no differences in survival, the group with MELD score ≥ 28 did have a longer stay in ICU and a longer hospital stay (with a mean of 6.7 days in ICU and 41.5 days admission vs 4.1 and 26.9, respectively). CONCLUSIONS: A very high MELD score is associated with a longer stay in ICU and more days of hospital admission, although no differences were observed in postoperative complications or survival. Therefore, there does not seem to be any contraindication in transplantation in this group of patients.

Analysis of Indications and Results in Liver Retransplantation: Is Late Retransplantation Worthwhile?

BACKGROUND: Liver retransplantation (LrT) is the only therapeutic option for irreversible hepatic graft failure. Despite various improvements, its technical complexity entails a greater morbidity in the short and long term. The main goal of the study was to analyze the activity of LrT at our center, as well as its indications, timing, postoperative evolution, and the long-term survival of patients. METHODS: We designed a descriptive study of a cohort of patients who underwent LrT in a Spanish Hepatic Transplant Unit, between April 1, 2002 and December 31, 2015. RESULTS: A total of 366 primary orthotopic liver transplantations were performed, 20 of which were LrTs, resulting in a 5.5% retransplantation rate. The most frequent indication for LrT was hepatic artery thrombosis (HAT) (35%). Twenty-five percent of the LrTs were early retransplantations and 75% were late retransplantations. After LrT, 35% of the grafts showed liver dysfunction. The overall mortality rate was 45%: in early LrT this was 25% and in late LrT it was 46.7%. Graft actuarial survival at 1 month post-LrT was 75% and at 5 years it was 63.6%. The overall actuarial survival after LrT at month 1, year 1, year 3, and year 5 was 80%, 69.6%, 58.9%, and 50.5%, respectively. In the late LrT group, the results proved less favorable, so it is necessary to define the minimum acceptable result before proceeding to a second graft. CONCLUSION: Our LrT rate was lower than that reported by other groups in our country. The actuarial survival rates for graft and patient are comparable to those obtained by other groups.

Analysis of the Predictive Ability for Graft Loss and Mortality of Two Criteria for Early Allograft Dysfunction After Liver Transplantation.

INTRODUCTION: The current imbalance between available donors and potential recipients for orthotopic liver transplantation (OLT) has led to a liberalization of organ acceptance criteria, increasing the risk of post-transplant complications such as early allograft dysfunction (EAD). Consequently, we need accurate criteria to detect patients with early poor graft function to guide the strategies of management. We evaluated the usefulness of two frequently used criteria: the definition from Olthoff et al and the Model for Early Allograft Function (MEAF) scoring. PATIENTS AND METHODS: Unicentric cohort study of patients undergoing OLT between January 1, 2010, and November 20, 2016. We performed a univariate study to detect donor, recipient, and transplant factors favoring EAD, defined both by Olthoff criteria and a MEAF score higher than 7. Finally, we developed a comparative survival analysis for cases having or not EAD. RESULTS: In all, 201 transplants met inclusion criteria. According to the stated cutoff for MEAF score, the frequency of EAD was 9.3%, with a significant association to low recipient body mass index and prolonged total graft ischemia time, resulting in lower patient 3-month postoperative survival. According to Olthoff criteria, EAD incidence was 22.1% and was associated with younger donor and recipient ages and higher Model for End-stage Liver Disease and Child-Pugh recipient scores. Its development resulted in lower graft and recipient survival at 3 months after OLT. CONCLUSION: MEAF score and Olthoff criteria are useful tools for detection of EAD. The latter could select more appropriately patients at risk, but its calculation cannot be done until the seventh day after OLT, unlike MEAF score, available on third day.

Results of 15-Year Experience in Liver Transplant for Hepatocellular Carcinoma.

BACKGROUND: Liver transplant (LT) supposes a curative option for those patients with hepatocellular carcinoma (HCC) meeting the Milan criteria. Adjuvant therapies, such as transarterial chemoembolization (TACE), can prevent tumor progression. Our aim was to analyze the outcomes of patients who have been transplanted at our center and to assess the effectiveness of TACE in patients on the waiting list for LT. METHODS: Eighty-nine patients who underwent LT for HCC at our hospital from 2002 to 2017 were included. Data on the number and size of nodules on image testing and explant, frequency of TACE and tumor response, mortality, and tumor recurrence were collected. TACE was indicated when waiting time was estimated to exceed 6 months in patients with well-preserved liver function (Child-Pugh score A-B7). Magnetic resonance imaging (MRI) was performed after TACE. RESULTS: We found a single nodule in 64% of patients and multiple nodules in 36% of patients. Mean size of nodule on image testing was 38.29 mm, similar to the mean size at explant (32.65 mm). TACE was performed in 66 patients (74.2%). Ten patients did not meet the Milan criteria at explant, 6 of whom died, and 10 patients had tumor recurrence at mean of 22.6 months. Overall mortality was 44.9%, but only 10 patients died because of tumor recurrence. CONCLUSIONS: TACE responses were achieved in one third of patients and there was an 11.2% recurrence rate for HCC. Mortality in our experience has been related to exceeding the Milan criteria at explant.

Influence of Obesity on Liver Transplantation Outcomes.

OBJECTIVE: The aim of this work was to determine the impact of obesity on the morbidity and mortality of liver transplantation (LT) recipients. METHODS: A single-center, observational-cohort, retrospective study was conducted in patients undergoing LT from January 2008 to December 2014 to compare complications and survival between those with body mass index (BMI) <35 kg/m2 and those with BMI ≥35 kg/m2. RESULTS: The study included 170 patients: 162 (95.3%) with BMI <35 kg/m2 and 8 (4.7%) with BMI ≥35 kg/m2. The groups significantly differed in overall mortality and graft survival: The risk of death was 3.54-fold higher (95% confidence interval, 1.39-9.03) and the mean graft survival was shorter (61 vs 21 mo; P = .001) in the group with BMI ≥35 kg/m2. The groups did not significantly differ in rates of biliary complications, arterial and portal vein thrombosis, retransplantation or reintervention, intraoperative requirement for blood products, length of intensive care unit stay, or post-reperfusion syndrome or rejection rates. CONCLUSIONS: Although no significant differences were found between these groups in post-transplantation complications, BMI ≥35 kg/m2 emerged as a mortality risk factor in these patients.

Influence of Waiting List in Recurrence Disease of Hepatocellular Carcinoma.

BACKGROUND: We describe the results of our liver transplantation (LT) patients for hepatocellular carcinoma (HCC) in 2004 to 2012 to determine the differences on the basis of time on the waiting list to establish the risk of recurrence of liver disease. METHODS: Clinical variables were recorded for both donors and recipients as well as variables of diagnosis, the use of transarterial chemoembolization during the waiting list time (WLT), complications, re-transplantation, and exitus. Fifty-eight patients were analyzed. Mean age was 57 ± 8 years (men, 83%; 48 patients). Viral etiology of HCC was 50% (n = 29); alcoholic, 26% (n = 15); and others, 24% (n = 14). RESULTS: Exitus was established in 24 patients (41%); only 5 patients (7%) were attributable to HCC. In the cohort of patients with less than 6 months of WLT, we registered both higher rates of downstaging protocols (10.7% vs 7.5%) and tumor size (3 cm vs 2 cm) compared with the other group. Bivariate studies were conducted according to the WLT (WLT <6 months, WLT ≥6 months), finding differences in recurrence of liver disease (P < .05). This fact was confirmed after a binary logistic regression. CONCLUSIONS: Our results in a subgroup of less than 6 months of WLT included patients with increased tumor size or presentation of multiple nodes, with a worse prognosis and therefore to be prioritized in the treatment of LT. Therefore, in our population there is a significant risk of tumor recurrence in patients with less WLT for LT, but it cannot be overestimated to all type of patients with HCC.

Perioperative values of glutathione peroxidase activity and malondialdehyde levels in enolic cirrhotic recipients of a liver transplant.

Reactive oxygen species play a central role in ischemia-reperfusion injury after organ transplantation. They are degraded by endogenous radical scavengers such as antioxidant enzymes. The purpose of this study was to evaluate the temporal variation in glutathione peroxidase (GPX) activity and malondialdehyde (MDA) levels among alcoholic cirrhotic recipients of liver transplantations. The study included 30 recipients: 26 males and 4 females in the provided blood samples before and after transplantation. The results showed significant enhancement of MDA levels at 1 and 6 hours after transplantation: 4.458 ± 2.273 µmol/L and 4.4628 ± 2.405 µmol/L respectively (P < .001). In contrast, GPX activity showed a maximum at 3 days there after 3.541 ± 2,315 nmol/mg protein. In conclusion, although MDA levels show an enormous increase at 1 hour after transplantation suggesting lipid peroxidation, they were compensated by GPX activity thereafter, indicating control of the oxidative stress generated by liver transplantation.

Echocardiographic study in cirrhotic patient candidates for liver transplantation.

We studied 81 cirrhotic patients who were candidates for liver transplantation to evaluate frequently detected cardiac alterations by echocardiographic study. Patients were distributed into three groups: group 1 comprised alcoholic cirrhotic patients (n = 40); group 2, viral cirrhotic patients (hepatitis C or B virus) (n = 35); and group 3, patients with primary biliary cirrhosis (n = 6). Cardiac chambers and diastolic functions were estimated by two-dimensional transthoracic echocardiography in M mode and Doppler. The most frequently detected cardiac structural alterations were left atrial diameter enlargement in 100% of the women and 40% of the men in group 1; 87.5% of the women and 15.4% of the men in group 2; and 33.3% of the women in group 3. Interventricular wall thickness enlargement in 50% of the women and 27.8% of the men in group 1, 25% of the women and 30.8% of the men in group 2, and 16.4% of the women in group 3. The prevalence of diastolic dysfunction was 45% in group 1, 32.3% in group 2, and 16.4% in group 3 (P > .05). There were no significant differences between the groups in cardiac chamber dimensions, left ventricular wall thickness, or prevalence of diastolic dysfunction.

Early detection of biliary complications and graft rejection in a non-RH Identitical liver transplant recipient from a non-heart-beating donor: a case report.

Because of a shortage of organs, non-heart-beating donors have been proposed to be a possible source of grafts for orthotopic liver transplantation. Herein, we have presented a blood group A+ patient with primary biliary cirrhosis, who underwent orthotopic liver transplantation from a non-heart-beating blood group A- donor. On day 5 after transplantation the patient displayed a low hemoglobin levels as well as an increased total bilirubin with progressive encephalopathy, hypotension, and oligoanuria on day 11. The patient responded to steroid treatment. We assume the main cause of organ dysfunction was a passenger lymphocyte syndrome (ABO-Rh incompatibility). Biliary complications were detected at a 6-month follow-up visit by increased hepatic enzymes. We thus concluded that it is useful to take Rh group into account.

Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients.

The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation. Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis. Selected up-regulated genes were further validated by quantitative real-time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis (n=5). Selected genes up-regulated before transplantation were: TNFRSF9 (tumor necrosis factor [TNF] receptor superfamily, member 9); IL2RB (interleukin-2 receptor beta); BCL2L2 (BCL2-like 2); NOX5 (NADPH) oxidase, EF-hand calcium binding domain 5); PEX5 (peroxisomal biogenesis factor 5); PPARG (peroxisome proliferator-activated receptor gamma); NIBP (IKK2 binding protein); NKIRAS2 (NFKappaBeta inhibitor interacting Ras-like 2); IL4 (interleukin-4); IL-4R (interleukin 4 receptor); ADH1A (alcohol dehydrogenase 1A, class 1); ALDH1L1 (aldehyde dehydrogenase 1 family, member L1); MPO (myeloperoxidase); NPPA (natriuretic peptide precursor A); BCL2A1 (BCL2-related protein A1); GADD45A (growth arrest and DNA-damage-inducible alpha); TEGT (Bax inhibitor 1); PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide); IFNGR2 (interferon gamma receptor 2); JAK2 (Janus Kinase 2); FAS (Fas, TNF receptor superfamily, member 6); TANK (TRAF family member-associated NFKB activator); TTRAP (TRAF and TNF receptor-associated protein); and ANXA5 (annexin A5).

Hepatopulmonary syndrome among cirrhotic candidates for liver transplantation.

This study assess of hepatopulmonary syndrome (HPS) prevalence and the influence of etiology among cirrhotic patients due to an alcoholic or viral etiology. We examined the records of patients were distributed as Group 1, alcoholic (n = 40) and Group 2, hepatic cirrhosis of viral etiology (n = 35). Hepatic cirrhosis status was estimated by CHILD and MELD scores. Presence of clinical ascites spell out was noted as well as size and diastolic functions of the cardiac chambers using two-dimensional transthoracic echocardiography in M mode and by Doppler. HPS was studied with agitated saline serum and intravenous contrast administration. HPS was considered to be present when serum or contrast passed to the left chamber before the 5th cardiac cycle. There was no significant differences among related to sex, age, cirrhosis status or ascites. HPS frequency was 35% in Group 1 versus 64.7% among Group 2-Patients (P = .01). Taking into account the results, we concluded that HPS frequency was related to cirrhotic etiology. Upon multivariate analysis a patients with cirrhosis from viral etiology showed significantly increased HPS frequency compared with those displaying cirrhosis of an alcoholic etiology.

Perioperative levels of glutathione reductase in liver transplant recipients with hepatitis C virus cirrhosis.

Surgical intervention causes oxidative stress leading to an adaptive responses by the body. To evaluate changes in the defense capacity of antioxidant enzymes, we determined the activity of glutathione reductase (GR) levels among liver transplant recipients with due to hepatitis C virus cirrhosis. The study was performed in 22 patients (16 males and 6 females) of average ages 52.63 ± 5.49 years for males and 59.67 ± 5.65 years for females. Blood samples for glutathione reductase activity were drawn on admission before as well as at 1, 6, and 12 h and 1, 2, 3, 5 and 7 days after the liver transplantation. Perioperative glutathione reductase levels were significant (P = .014) over the period using Bonferroni tests. GR activity reached a maximum (15.6112 ± 6.56035 nmol/mg protein) at 3 days after liver transplantation (T3d) (P = .001). The increased GR activity values detected perioperatively indicated scavenging of reactive oxygen species generated after liver transplantation of hepatitis C virus cirrhosis patients.

Preoperative natriuretic peptide-B values and ascites in male liver transplant recipients.

Plasma preoperative values of natriuretic B peptide (pro-BNP) were correlated with ascites in men experiencing hepatic cirrhosis due to different etiologies on the active waiting list for liver transplantation. The study was performed in 54 male recipients of a liver transplant. Written informed consent was obtained from the patients or their relatives, and the study protocol was approved by our local Clinical Research (Ethics) Committee. Male patients were classified into two groups: group 1 included patients with alcoholic hepatic cirrhosis (n = 30) distributed as 19 men with no ascites, four with nonrefractory ascites, and seven with refractory ascites; group 2 included cases of viral hepatitis cirrhosis (n = 24) distributed as 13 men with no ascites, nine with non-refractory ascites, and two with refractory ascites. A group of six healthy male volunteers was used to establish normal (basal) values of pro-BNP and left auricular diameter (LAD). Pro-BNP values were determined in plasma samples by an electrochemiluminiscence immunoassay. Pro-BNP plasma levels in patients with alcoholic cirrhosis were threefold greater among patients with no ascites or no refractory ascites compared with healthy men, whereas pro-BNP values were fivefold enhanced among alcoholic patients with refractory ascites. The viral hepatitis cirrhosis group showed pro-BNP plasma values 1.5-fold enhanced in men with no ascites, whereas pro-BNP reached fivefold with either nonrefractory or refractory ascites. The enhanced pro-BNP plasma levels indicated advanced hepatic degradation, seemingly related to the presence of refractory ascites associated with cirrhosis.

Intraoperative pH values after N-acetylcysteine administration during liver transplantation.

We investigated whether intraoperative administration of N-acetylcysteine (NAC) to liver transplant recipients affected pH values. This prospective, randomized, double-blind clinical trial included liver transplant recipients who were randomly assigned to NAC-treated (n=25) or placebo (n=25) groups. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose during the next 24 hours. The placebo group received equal amounts of 5% dextrose solution during the same times. Peripheral blood samples were drawn in Ca2+-80 IU-containing syringes after induction of anesthesia (I-1), at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo, at 5 minutes before reperfusion (I-3), at 5 minutes after reperfusion (I-4), at 20 minutes after reperfusion (I-5), at 60 minutes after reperfusion (I-6), and at 1 hour after completion of the procedure (I-7). pH levels, which were determined using a radiometer ABL77 (Copenhagen, Denmark), were significantly lower among the NAC than the placebo group at I-4 (P=.027) and I-5 (P=.031). An early decrease in pH values was detected in the NAC-treated group at 5 minutes before reperfusion (I-3; P=.051). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly decreased recipient pH values at 5 and 20 minutes after reperfusion, a decrease that was detected at 5 minutes before reperfusion (I-3). The decrease seemed to be associated with NAC metabolism.

Gene expression profiling in liver transplant recipients with alcoholic cirrhosis.

The main objective of this study was to identify differences in gene expression profile using microarray technology in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation. The study was performed in liver transplant recipients with alcoholic cirrhosis (n = 10) and in healthy volunteers (n = 10), as a reference group. Peripheral blood samples were obtained before (T0) and 7 days after liver transplantation (T7d) using tubes with an RNA stabilizer. RNA was purified and quality tested. From each participant in the study, microarrays were done in duplicate using 10 mug of cRNA. After reverse transcription, complementary RNAs were labeled with Cy5 Streptavidine and used for hybridization of 20,000 human genes CodeLink bioarrays (Applied Microarrays, United States) overnight at 37 degrees C. Arrays were read with a laser scanner and quantified and normalized with CodeLink Software 4.2. Liver transplant recipients showed a gene expression profile before transplantation (T0) of 4310 overexpressed genes compared with healthy volunteers, with 407 of these genes increased more than 2-fold (P < .05). After transplantation (T7d), the same group of patients showed a profile of 1011 overexpressed genes compared with T0, with 109 of these genes increased more than 2-fold (P < .05). We determined gene expression profiles in peripheral blood samples obtained before and after liver transplantation, giving a report of array gene expression profiles of peripheral blood samples from each of these patients. One implication of these results is that gene profiling of peripheral blood samples using microarray technology could be used to dynamically monitor the impact and adequacy of immunosuppression in individual patients.

Study of gene expression profile in liver transplant recipients with hepatitis C virus.

The main objective of this study was to identify differences in gene expression profiles by liver transplant recipients with hepatitis C virus (HCV) using microarray technology before versus after liver transplantation. The study was performed in liver transplant recipients with HCV (n = 6) versus a group of healthy volunteers (n = 6). Peripheral blood samples were obtained before (T0) and 7 days after liver transplantation (T7d) using tubes with an RNA stabilizer. The quality of purified RNA was tested (28S/18S ratio >1.5) in a bioanalyzer. Each participant in the study underwent microarrays in duplicate using 10 mug of complementary RNA. After reverse transcription, cRNAs were labeled with Cy5 Streptavidine. Hybridization of 20000 human genes CodeLink bioarrays (Applied Microarrays, United States) was performed overnight at 37 degrees C. Arrays read with a laser scanner were normalized with CodeLink Software 4.2. At T0, liver transplant recipients showed 116 over-expressed genes when compared with healthy volunteers, who had 33 genes increased >2-fold (P < .05). At T7d after transplantation, the same group of patients showed 613 over-expressed genes compared with T0, of which 97 genes were increased >2-fold (P < .05). We determined gene expression profiles in peripheral blood samples obtained before and after liver transplantation, reporting the array of gene expression profiles in peripheral blood samples from each of these patients classes. One implication of these results is that gene profiling of peripheral blood samples could be used to dynamically monitor the impact and adequacy of immunosuppression in individual patients using microarray technology.

Effect of N-acetylcysteine administration on intraoperative plasma levels of interleukin-4 and interleukin-10 in liver transplant recipients.

We investigated whether intraoperative administration of N-acetylcysteine (NAC) in liver transplant recipients ameliorated their inflammatory responses by increasing intraoperative plasma levels of interleukin (IL)-4 and IL-10. This prospective, randomized, double-blind clinical trial included liver transplant recipients randomly assigned to the NAC-treated (n = 25) or the placebo (n = 25) group. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose over the next 24 hours, whereas the placebo group received equal amounts of 5% dextrose solution during the same time. Peripheral blood samples were drawn in EDTA-containing tubes after induction of anesthesia (I-1); at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo; at 5 minutes before reperfusion (I-3); at 10 minutes after reperfusion (I-4); at 20 minutes after reperfusion (I-5); at 60 minutes after reperfusion (I-6); and at 1 hour after completion of the liver transplantation (I-7). Cytokine levels were determined using a technique which combined enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Plasma IL-4 levels were significantly higher among the NAC-treated group than the placebo group at I-3 (P = .046) and I-4 (P = .041). Plasma IL-10 levels showed significant enhancement in the NAC-treated group at 5 minutes before reperfusion (I-3; P = .007). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly increased recipient IL-4 plasma levels before and after reperfusion, and IL-10 plasma values before reperfusion (I-3). These enhancements seemed to be associated with a protective effect against reperfusion injury.