Neutrophil extracellular traps (NETs), transfusion requirements and clinical outcomes in orthotopic liver transplantation.

Inflammatory phenomena have a direct impact on the prognosis of orthotopic liver transplantation (OLT). Neutrophil extracellular traps (NETs) contribute to OLT inflammation and hemostasis imbalance in OLT. The association between NETosis, clinical outcomes and transfusion requirements is not determined. To evaluate NETs release during OLT and the effect of NETosis ontransfusion requirements and adverse outcomes in a prospective cohort of patients submitted to OLT. We quantified citrullinated histones (cit-H3) and circulating-free-DNA (cf-DNA) in ninety-three patients submitted to OLT in three periods: pre-transplant, after graft reperfusion and before discharge. NETs markers were compared between these periods using ANOVA test. The association of NETosis and adverse outcomes was evaluated using regression models adjusted for age, sex and corrected MELD. We observed a peak of circulating NETs following reperfusion, evidenced by a 2.4-fold increase in cit-H3 levels in the post-graft reperfusion period (median levels of cit-H3 pre transplant: 0.5 ng/mL, after reperfusion: 1.2 ng/mL and at discharge 0.5 ng/mL, p < 0.0001). We observed an association between increased levels of cit-H3 and in-hospital death (OR = 1.168, 95% CI 1.021-1.336, p = 0.024). No association was found between NETs markers and transfusion requirements. There is a prompt release of NETs after reperfusion that is associated with poorer outcomes and death. Intraoperative NETs release seems to be independent of transfusion requirements. These findings highlight the relevance of inflammation promoted by NETS and its impact on OLT adverse clinical outcomes.

Modelling kidney outcomes based on MELD eras - impact of MELD score in renal endpoints after liver transplantation.

BACKGROUND: Acute kidney injury is a common complication in solid organ transplants, notably liver transplantation. The MELD is a score validated to predict mortality of cirrhotic patients, which is also used for organ allocation, however the influence of this allocation criteria on AKI incidence and mortality after liver transplantation is still uncertain. METHODS: This is a retrospective single center study of a cohort of patients submitted to liver transplant in a tertiary Brazilian hospital: Jan/2002 to Dec/2013, divided in two groups, before and after MELD implementation (pre-MELD and post MELD). We evaluate the differences in AKI based on KDIGO stages and mortality rates between the two groups. RESULTS: Eight hundred seventy-four patients were included, 408 in pre-MELD and 466 in the post MELD era. The proportion of patients that developed AKI was lower in the post MELD era (p 0.04), although renal replacement therapy requirement was more frequent in this group (p < 0.01). Overall mortality rate at 28, 90 and 365 days was respectively 7%, 11% and 15%. The 1-year mortality rate was lower in the post MELD era (20% vs. 11%, p < 0.01). AKI incidence was 50% lower in the post MELD era even when adjusted for clinically relevant covariates (p < 0.01). CONCLUSION: Liver transplants performed in the post MELD era had a lower incidence of AKI, although there were more cases requiring dialysis. 1-year mortality was lower in the post MELD era, suggesting that patient care was improved during this period.

Evaluation of drug-induced liver injury as etiology for acute liver failure in Brazil.

INTRODUCTION AND OBJECTIVES: Little is known about the etiology of acute liver failure (ALF) in Latin America. The objective of this paper is to investigate the main etiologies of ALF in Brazil, including Drug Induced Liver Injury (DILI) using stringent causality criteria. PATIENTS OR MATERIAL AND METHODS: All the cases of individuals who underwent liver transplantation (LT) in 12 centers in Brazil for ALF were reviewed. When DILI was stated as the cause of ALF, causality criteria were applied on site by the main investigator in order to rule out other etiologies. RESULTS: 325 individuals had ALF mainly for unknown reasons (34%), DILI (27%) and AIH (18%). Reassessment of the 89 cases of DILI, using stringent causality criteria, revealed that in only 42 subjects could DILI be confirmed as the cause of ALF. Acetaminophen (APAP) toxicity (n = 3) or DILI due to herbal and dietary supplements (HDS) (n = 2) were not commonly observed. CONCLUSIONS: Undetermined etiology and DILI are the main causes of ALF in Brazil. However, APAP toxicity and DILI due to HDS are mostly uncommon.

Comparison between Milan and UCSF criteria for liver transplantation in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Liver transplantation is the main treatment for hepatocellular carcinoma (HCC). However, because of the limited supply of transplant organs, it is necessary to adopt a criterion that selects patients who will achieve adequate survival after transplantation. The aim of this review is to compare the two main staging criteria of HCC for the indication of liver transplantation (Milan and UCSF) and to analyze the post-transplantation survival rate at 1, 3 and 5 years. METHODS: This is a systematic review and meta-analysis in which scientific articles from 5 databases (PubMed, Lilacs, Embase, Central, and Cinahl) were analyzed. The studies included in the review consisted of liver transplantation in patients with HCC in different subgroups according to donor type (deceased × living), population (eastern × western) and tumor evaluation (radiological × pathological) and adopted the Milan or UCSF criteria for the indication of the procedure. RESULTS: There was no significant difference between the Milan and UCSF criteria in the overall survival rate at 1, 3 or 5 years, and the overall estimated value found was 1.03 [0.90, 1.17] at 1 year, 1.06 [0.96, 1.16] at 3 years and 1.04 [0.96, 1.12] at 5 years. Regarding the analysis of the subgroups, no significant difference was observed in any of the subgroups with a follow-up of 1, 3 or 5 years. CONCLUSIONS: Both the Milan and UCSF criteria have equivalent survival rate. Thus, less restrictive method would not result in a great loss in the final overall survival rate and would benefit a greater number of patients.

Diagnosis and management of hepatic artery in-stent restenosis after liver transplantation by optical coherence tomography: A case report.

BACKGROUND: Percutaneous transluminal angioplasty and stenting represent an effective treatment for hepatic artery stenosis after liver transplantation. In the first year after stenting, approximately 22% of patients experience in-stent restenosis, increasing the risk of artery thrombosis and related complications, and 50% experience liver failure. Although angiography is an important tool for diagnosis and the planning of therapeutic interventions, it may raise doubts, especially in small-diameter arteries, and it provides low resolution rates compared with newer intravascular imaging methods, such as optical coherence tomography (OCT). CASE SUMMARY: A 64-year-old male developed hepatic artery stenosis one year after orthotropic liver transplantation and was successfully treated with percutaneous transluminal angioplasty with stenting. Five months later, the Doppler ultrasound results indicated restenosis. Visceral arteriography confirmed hepatic artery tortuosity but was doubtful for significant in-stent restenosis (ISR) and intrahepatic flow reduction. To confirm ISR, identify the etiology and guide treatment, OCT was performed. OCT showed severe stenosis due to four mechanisms: Focal and partial stent fracture, late stent malapposition, in-stent neointimal hyperplasia, and neoatherosclerosis. CONCLUSION: Intravascular diagnostic methods can be useful in evaluating cases in which initial angiography results are not sufficient to provide a proper diagnosis of significant stenosis, especially with regard to ISR. A wide range of diagnoses are provided by OCT, resulting in different treatment options. Interventional radiologists should consider intravascular diagnostic methods as additional tools for evaluating patients when visceral angiography results are unclear.

Imaging response predictors following drug eluting beads chemoembolization in the neoadjuvant liver transplant treatment of hepatocellular carcinoma.

BACKGROUND: Drug-eluting bead transarterial chemoembolization (DEB-TACE) is an endovascular treatment to release chemotherapeutic agents within a target lesion, minimizing systemic exposure and adverse effects to chemotherapeutics. Therefore, identifying which patient characteristics may predict imaging response to DEB-TACE can improve treatment results while selecting the best candidates. Predictors of the response after DEB-TACE still have not been fully elucidated. This is the first prospective study performed with standardized DEB-TACE technique that aim to identify predictors of radiological response, assessing patients clinical and laboratory characteristics, diagnostic imaging and intraprocedure data of the hepatocellular carcinoma treated in the neoadjuvant context for liver transplantation. AIM: To identify pre- and intraoperative clinical and imaging predictors of the radiological response of drug-eluting bead transarterial chemoembolization (DEB-TACE) for the neoadjuvant treatment of hepatocellular carcinoma (HCC). METHODS: This is prospective, cohort study, performed in a single transplant center, from 2011 to 2014. Consecutive patients with HCC considered for liver transplant who underwent DEB-TACE in the first session for downstaging or bridging purposes were recruited. Pre and post-chemoembolization imaging studies were performed by computed tomography or magnetic resonance. The radiological response of each individual HCC was evaluated by objective response using mRECIST and the percentage of necrosis. RESULTS: Two hundred patients with 380 HCCs were examined. Analysis of the objective response (nodule-based analysis) demonstrated that HCC with pseudocapsules had a 2.01 times greater chance of being responders than those without pseudocapsules (P = 0.01), and the addition of every 1mg of chemoembolic agent increased the chance of therapeutic response in 4% (P < 0.001). Analysis of the percentage of necrosis through multiple linear regression revealed that the addition of each 1mg of the chemoembolic agent caused an average increase of 0.65% (P < 0.001) in necrosis in the treated lesion, whereas the hepatocellular carcinoma with pseudocapsules presented 18.27% (P < 0.001) increased necrosis compared to those without pseudocapsules. CONCLUSION: The presence of a pseudocapsule and the addition of the amount of chemoembolic agent increases the chance of an objective response in hepatocellular carcinoma and increases the percentage of tumor necrosis following drug-eluting bead chemoembolization in the neoadjuvant treatment, prior to liver transplantation.

Long-term outcomes of hepatocellular carcinoma that underwent chemoembolization for bridging or downstaging.

BACKGROUND: Prospective study of 200 patients with hepatocellular carcinoma (HCC) that underwent liver transplant (LT) after drug-eluting beads transarterial chemoembolization (DEB-TACE) for downstaging versus bridging. Overall survival and tumor recurrence rates were calculated, eligibility for LT, time on the waiting list and radiological response were compared. After TACE, only patients within Milan Criteria (MC) were transplanted. More patients underwent LT in bridging group. Five-year post-transplant overall survival, recurrence-free survival has no difference between the groups. Complete response was observed more frequently in bridging group. Patients in DS group can achieve post-transplant survival and HCC recurrence-free probability, at five years, just like patients within MC in patients undergoing DEB-TACE. AIM: To determine long-term outcomes of patients with HCC that underwent LT after DEB-TACE for downstaging vs bridging. METHODS: Prospective cohort study of 200 patients included from April 2011 through June 2014. Bridging group included patients within MC. Downstaging group (out of MC) was divided in 5 subgroups (G1 to G5). Total tumor diameter was ≤ 8 cm for G1, 2, 3, 4 (n = 42) and was > 8 cm for G5 (n = 22). Downstaging (n = 64) and bridging (n = 136) populations were not significantly different. Overall survival and tumor recurrence rates were calculated by the Kaplan-Meier method. Additionally, eligibility for LT, time on the waiting list until LT and radiological response were compared. RESULTS: After TACE, only patients within MC were transplanted. More patients underwent LT in bridging group 65.9% (P = 0.001). Downstaging population presented: higher number of nodules 2.81 (P = 0.001); larger total tumor diameter 8.09 (P = 0.001); multifocal HCC 78% (P = 0.001); more post-transplantation recurrence 25% (P = 0.02). Patients with maximal tumor diameter up to 7.05 cm were more likely to receive LT (P = 0.005). Median time on the waiting list was significantly longer in downstaging group 10.6 mo (P = 0.028). Five-year post-transplant overall survival was 73.5% in downstaging and 72.3% bridging groups (P = 0.31), and recurrence-free survival was 62.1% in downstaging and 74.8% bridging groups (P = 0.93). Radiological response: complete response was observed more frequently in bridging group (P = 0.004). CONCLUSION: Tumors initially exceeding the MC down-staged after DEB-TACE, can achieve post-transplant survival and HCC recurrence-free probability, at five years, just like patients within MC in patients undergoing DEB-TACE.

Risk Factors for Transfusion after Orthotopic Liver Transplantation.

BACKGROUND: Transfusion of blood products during orthotopic liver transplantation (OLT) is associated with increased morbidity and mortality. Although risk factors associated with intraoperative transfusion requirements have been widely assessed, published data on the prediction of postoperative transfusion requirements are sparse. OBJECTIVES: The aim of this study was to evaluate risk factors for postoperative allogeneic transfusion requirements in OLT. METHODS: Clinical characteristics and intraoperative parameters of 645 consecutive adult patients undergoing OLT were retrospectively reviewed. Multivariate logistic regression was used to determine the main determinants for postoperative transfusion requirements. RESULTS: Determinants of postoperative transfusion requirements of any blood product in the postoperative period were the number of blood products transfused in the intraoperative period (OR 1.17, 95% CI 1.08-1.28), warm ischemia time (OR 1.05, 95% CI 1.02-1.08), MELD score (OR 1.05, 95% CI 1.01-1.08) and hepatocellular carcinoma (OR 0.45, 95% CI 0.28-0.72). A dose-dependent effect between the number of units transfused in the intraoperative period and transfusion requirements in the postoperative period was also observed. The relative risk of postoperative allogeneic transfusion of any blood component was 5.9 (95% CI 3.4-10.4) for patients who received 1-2 units in the intraoperative period, 7.3 (95% CI 3.6-14.7) for those who received 3-5 units in the intraoperative period, and 11.1 (95% CI 4.7-26.4) for those who received 6 or more units, when compared to no intraoperative blood transfusion. CONCLUSION: Our study demonstrated an association between intraoperative transfusion and warm ischemia time with postoperative transfusion requirements. The identification of risk factors for transfusion in the postoperative period may improve management of these patients by increasing awareness to bleeding complications in this high-risk population and by expanding hemostasis monitoring to the postoperative period.

Thromboelastometry versus standard coagulation tests versus restrictive protocol to guide blood transfusion prior to central venous catheterization in cirrhosis: study protocol for a randomized controlled trial.

BACKGROUND: Liver failure patients have traditionally been empirically transfused prior to invasive procedures. Blood transfusion is associated with immunologic and nonimmunologic reactions, increased risk of adverse outcomes and high costs. Scientific evidence supporting empirical transfusion is lacking, and the best approach for blood transfusion prior to invasive procedures in cirrhotic patients has not been established so far. The aim of this study is to compare three transfusion strategies (routine coagulation test-guided - ordinary or restrictive, or thromboelastometry-guided) prior to central venous catheterization in critically ill patients with cirrhosis. METHODS/DESIGN: Design and setting: a double-blinded, parallel-group, single-center, randomized controlled clinical trial in a tertiary private hospital in São Paulo, Brazil. INCLUSION CRITERIA: adults (aged 18 years or older) admitted to the intensive care unit with cirrhosis and an indication for central venous line insertion. Patients will be randomly assigned to three groups for blood transfusion strategy prior to central venous catheterization: standard coagulation tests-based, thromboelastometry-based, or restrictive. The primary efficacy endpoint will be the proportion of patients transfused with any blood product prior to central venous catheterization. The primary safety endpoint will be the incidence of major bleeding. Secondary endpoints will be the proportion of transfusion of fresh frozen plasma, platelets and cryoprecipitate; infused volume of blood products; hemoglobin and hematocrit before and after the procedure; intensive care unit and hospital length of stay; 28-day and hospital mortality; incidence of minor bleeding; transfusion-related adverse reactions; and cost analysis. DISCUSSION: This study will evaluate three strategies to guide blood transfusion prior to central venous line placement in severely ill patients with cirrhosis. We hypothesized that thromboelastometry-based and/or restrictive protocols are safe and would significantly reduce transfusion of blood products in this population, leading to a reduction in costs and transfusion-related adverse reactions. In this manner, this trial will add evidence in favor of reducing empirical transfusion in severely ill patients with coagulopathy. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02311985 . Retrospectively registered on 3 December 2014.

Minor salivary gland biopsy for the diagnosis of familial amyloid polyneuropathy.

The diagnosis of Val30Met familial amyloidotic polyneuropathy (FAP) is based on genetic tests, clinical manifestations, familial history and biopsy of peripheral tissues (e.g. rectum, abdominal fat pad, sural nerve, and minor salivary gland) to confirm the presence of amyloid deposits. The aim of this study was to determine the frequency of amyloid deposits in minor salivary glands biopsied from FAP patients and to investigate whether an association exists between the presence of these deposits and clinical features. Seventeen patients with FAP were submitted to minor salivary gland biopsy to confirm the presence of amyloid deposits. The histopathology of the salivary glands confirmed glandular amyloid deposits in nine symptomatic patients (sensitivity of 75.0%). In general, FAP patients who tested positive for glandular amyloid deposits exhibited significantly higher frequencies of sensorimotor and dysautonomic dysfunctions (p = 0.001) compared with those who tested negative. None of the patients reported xerostomia. Minor salivary gland biopsy may help confirm the diagnosis of FAP in symptomatic cases, as it is noninvasive, easy to execute, and causes minimal discomfort to patients.

Liver transplant outcome: a comparison between high and low MELD score recipients.

OBJECTIVE: To compare low and high MELD scores and investigate whether existing renal dysfunction has an effect on transplant outcome. METHODS: Data was prospectively collected among 237 liver transplants (216 patients) between March 2003 and March 2009. Patients with cirrhotic disease submitted to transplantation were divided into three groups: MELD > or = 30, MELD < 30, and hepatocellular carcinoma. Renal failure was defined as a +/- 25% decline in estimated glomerular filtration rate as observed 1 week after the transplant. Median MELD scores were 35, 21, and 13 for groups MELD > or = 30, MELD < 30, and hepatocellular carcinoma, respectively. RESULTS: Recipients with MELD > or = 30 had more days in Intensive Care Unit, longer hospital stay, and received more blood product transfusions. Moreover, their renal function improved after liver transplant. All other groups presented with impairment of renal function. Mortality was similar in all groups, but renal function was the most important variable associated with morbidity and length of hospital stay. CONCLUSION: High MELD score recipients had an improvement in the glomerular filtration rate after 1 week of liver transplantation.