The Addition of C-Reactive Protein and von Willebrand Factor to Model for End-Stage Liver Disease-Sodium Improves Prediction of Waitlist Mortality.

BACKGROUND AND AIMS: Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF-Ag) and C-reactive protein (CRP) are simple, broadly available markers of these processes. APPROACH AND RESULTS: We determined whether addition of vWF-Ag and CRP to the Model for End-Stage Liver Disease-Sodium (MELD-Na) score improves risk stratification of patients awaiting LT. CRP and vWF-Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD-Na, and mortality on the waiting list were recorded. Prediction of 3-month waiting list mortality was assessed by receiver operating characteristics curve (ROC-AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF-Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF-Ag and CRP both improved the predictive value of MELD-Na for 3-month waitlist mortality and showed the highest predictive value when combined (AUC: MELD-Na, 0.764; MELD-Na + CRP, 0.790; MELD-Na + vWF, 0.803; MELD-Na + CRP + vWF-Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD-Na, 0.677; MELD-Na + CRP + vWF-Ag, 0.882). vWF-Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation. CONCLUSIONS: The addition of vWF-Ag and CRP-reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT-to the MELD-Na score improves prediction of waitlist mortality. Using the vWFAg-CRP-MELD-Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.

Admission Urinary and Serum Metabolites Predict Renal Outcomes in Hospitalized Patients With Cirrhosis.

BACKGROUND AND AIMS: Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort. APPROACH AND RESULTS: Inpatients with cirrhosis from 11 North American Consortium of End-stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis-free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor-adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3-dihydroxy-5-methylthio-4-pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8-methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor-adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched-chain amino-acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes. CONCLUSIONS: Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

LncRNA-Airn alleviates acute liver injury by inhibiting hepatocyte apoptosis via the NF-κB signaling pathway.

Acute liver injury is a common and serious syndrome caused by multiple factors and unclear pathogenesis. If the injury persists, liver injury can lead to cirrhosis and liver failure and ultimately results in the development of liver cancer. Emerging evidence has indicated that long noncoding RNAs (lncRNAs) play an important role in the development of liver injury. However, the role of antisense Igf2r RNA (Airn) in acute liver injury and its underlying mechanism remain largely unclear. In this study, we show that Airn is upregulated in liver tissue and primary hepatocytes from an acute liver injury mouse model. Consistently, Airn is also overexpressed in serum samples of patients with acute-on-chronic liver failure and is negatively correlated with the Model for End-Stage Liver Disease (MELD) score. Moreover, gene knockout and rescue assays reveal that Airn alleviates CCl 4-induced liver injury by inhibiting hepatocyte apoptosis and oxidative stress in vivo. Further investigation reveals that Airn decreases H 2O 2-induced hepatocyte apoptosis in vitro. Mechanistically, we reveal that Airn represses CCl 4- and H 2O 2-induced enhancement of phosphorylation of p65 and IκBα, suggesting that Airn inhibits hepatocyte apoptosis by inactivating the NF-κB pathway. In conclusion, our results demonstrate that Airn can alleviate acute liver injury by inhibiting hepatocyte apoptosis via inactivating the NF-κB signaling pathway, and Airn could be a potential biomarker for acute liver injury.

Exercise physiology in cirrhosis and the potential benefits of exercise interventions: A review.

Reduction in muscle mass is a highly prevalent phenomenon in cirrhosis and is now well-documented to be associated with significant morbidity and mortality. Research into muscle loss in cirrhosis remains limited by an ongoing poor understanding of its relationship with muscle function, physical activity, and aerobic capacity. Alterations in exercise physiology have been documented in studies of individuals with cirrhosis that provide important information on physical function that is not captured by simple quantification of muscle mass. Despite expert consensus recommending regular exercise in end-stage liver disease to maintain muscle mass and function, there is little evidence guiding clinicians as to which form of exercise or delivery mechanism is most effective. It also remains unproven whether any specific intervention can alter clinically relevant outcomes. This review article summarizes the available literature regarding the changes in exercise physiology observed in cirrhosis, the associated impact on physical capacity, and the results of existing trials that examine the potential benefits of exercise delivery in patients with cirrhosis, particularly pertaining to their impact on exercise physiology.

Metabolomic Signature as a Predictor of Liver Disease Events in Patients With HIV/HCV Coinfection.

BACKGROUND: Advanced liver disease due to hepatitis C virus (HCV) is a leading cause of human immunodeficiency virus (HIV)-related morbidity and mortality. There remains a need to develop noninvasive predictors of clinical outcomes in persons with HIV/HCV coinfection. METHODS: We conducted a nested case-control study in 126 patients with HIV/HCV and utilized multiple quantitative metabolomic assays to identify a prognostic profile that predicts end-stage liver disease (ESLD) events including ascites, hepatic encephalopathy, hepatocellular carcinoma, esophageal variceal bleed, and spontaneous bacterial peritonitis. Each analyte class was included in predictive modeling, and area under the receiver operator characteristic curves (AUC) and accuracy were determined. RESULTS: The baseline model including demographic and clinical data had an AUC of 0.79. Three models (baseline plus amino acids, lipid metabolites, or all combined metabolites) had very good accuracy (AUC, 0.84-0.89) in differentiating patients at risk of developing an ESLD complication up to 2 years in advance. The all combined metabolites model had sensitivity 0.70, specificity 0.85, positive likelihood ratio 4.78, and negative likelihood ratio 0.35. CONCLUSIONS: We report that quantification of a novel set of metabolites may allow earlier identification of patients with HIV/HCV who have the greatest risk of developing ESLD clinical events.

Screening for abnormal glycosylation in a cohort of adult liver disease patients.

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of vacuolar-ATPase (V-ATPase) assembly defects, various degrees of hepatic injury have been described, including end-stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be associated with abnormal glycosylation. Therefore, we collected serum samples of patients with a wide range of liver pathology to study the performance and yield of two CDG screening methods. Our aim was to identify glycosylation patterns that could help to differentiate between primary and secondary glycosylation defects in liver disease. To this end, we analyzed serum samples of 1042 adult liver disease patients. This cohort consisted of 567 liver transplant candidates and 475 chronic liver disease patients. Our workflow consisted of screening for abnormal glycosylation by transferrin isoelectric focusing (tIEF), followed by in-depth analysis of the abnormal samples with quadruple time-of-flight mass spectrometry (QTOF-MS). Screening with tIEF resulted in identification of 247 (26%) abnormal samples. QTOF-MS analysis of 110 of those did not reveal glycosylation abnormalities comparable with those seen in V-ATPase assembly factor defects. However, two patients presented with isolated sialylation deficiency. Fucosylation was significantly increased in liver transplant candidates compared to healthy controls and patients with chronic liver disease. In conclusion, a significant percentage of patients with liver disease presented with abnormal CDG screening results. However, the glycosylation pattern was not indicative for a V-ATPase assembly factor defect. Advanced glycoanalytical techniques assist in the dissection of secondary and primary glycosylation defects.

Exploring the Link Between Platelet Numbers and Vascular Homeostasis Across Early and Late Stages of Fibrosis in Hepatitis C.

BACKGROUND: Thrombocytopenia is a hallmark of advanced liver disease. Platelets, growth factors (GFs), and vascular integrity are closely linked factors in disease pathogenesis, and their relationship, particularly in early disease stages, is not entirely understood. The aim was to compare circulating platelets, growth factors, and vascular injury markers (VIMs) in hepatitis C-infected (HCV) patients with early fibrosis and cirrhosis. METHODS: Retrospective evaluation of serum GFs and VIMs by ELISA were evaluated from twenty-six HCV patients. Analytes from an earlier time-point were correlated with MELD at a later time-point. RESULTS: Platelets and GFs decreased, and VIMs increased with fibrosis. Platelets correlated positively with PDGF-AA, PDGF-BB, TGFB1, EGF, and P-selectin, and negatively with ICAM-3 and VCAM-1. P-selectin showed no correlations with VIMs but positively correlated with PDGF-AA, PDGF-BB, TGFB1, and EGF. Soluble VCAM-1 and ICAM-3 were linked to increasing fibrosis, liver enzymes, and synthetic dysfunction. Higher VCAM-1 and ICAM-3 and lower P-selectin at an earlier time-point were linked to higher MELD score at a later time-point. CONCLUSION: In chronic HCV, progressive decline in platelets and growth factors with fibrosis and their associations suggest that platelets are an important source of circulating GFs and influence GF decline with fibrosis. Enhanced markers of vascular injury in patients with early fibrosis suggest an earlier onset of endothelial dysfunction preceding cirrhosis. Associations of VIMs with platelets suggest a critical link between platelets and vascular homeostasis. Circulating markers of vascular injury may not only have prognostic importance but emphasize the role of vascular dysfunction in liver disease pathogenesis (NCT00001971).

The imperative for an updated cirrhosis surgical risk score.

The burden of cirrhosis is increasing, as is the need for surgeries in patients with cirrhosis. These patients have increased surgical risk relative to non-cirrhotic patients. Unfortunately, currently available cirrhosis surgical risk prediction tools are non-specific, poorly calibrated, limited in scope, and/or outdated. The Mayo score is the only dedicated tool to provide discrete post-operative mortality predictions for patients with cirrhosis, however it has several limitations. First, its single-center nature does not reflect institution-specific practices that may impact surgical risk. Second, it pre-dates major surgical changes that have changed the landscape of patient selection and surgical risk. Third, it has been shown to overestimate risk in external validation. Finally, and perhaps most importantly, the score does not account for differences in risk based on surgery type. The clinical consequences of inaccurate prediction and risk overestimation are significant, as patients with otherwise acceptable risk may be denied elective surgical procedures, thereby increasing their future need for higher-risk emergent procedures. Confident evaluation of the risks and benefits of surgery in this growing population requires an updated, generalizable, and accurate cirrhosis surgical risk calculator that incorporates the type of surgery under consideration.

Protein S Exacerbates Chronic Liver Injury and Fibrosis.

Protein S is a vitamin K-dependent glycoprotein produced mainly in the liver with anticoagulant, anti-inflammatory, immune-modulatory, and antiapoptotic properties. Protein S exacerbates acute liver injury by prolonging the survival of liver immune cells. However, the effect of protein S on chronic liver injury and fibrosis is unknown. Here, we investigated whether human protein S can affect chronic liver injury and fibrosis. Liver injury/fibrosis was induced by carbon tetrachloride injection in mice overexpressing human protein S and in wild-type mice. Human protein S transgenic mice receiving carbon tetrachloride showed significantly higher circulating levels of liver transaminases, increased liver expression of inflammatory cytokines, significantly more extended liver fibrosis, and areas with DNA breakage after chronic injury compared with wild-type mice. Wild-type mice infused with exogenous human protein S exhibited exacerbated liver injury and increased number of hepatic stellate cells compared with untreated mice. Human protein S inhibited apoptosis and increased Akt pathway activation in hepatic stellate cells. The antiapoptotic activity of protein S may play a role in chronic liver injury and subsequent liver fibrosis.

Prospective Assessment of Liver Function by an Enzymatic Liver Function Test to Estimate Short-Term Survival in Patients with Liver Cirrhosis.

BACKGROUND: MELD attempts to objectively predict the risk of mortality of patients with liver cirrhosis and is commonly used to prioritize organ allocation. Despite the usefulness of the MELD, updated metrics could further improve the accuracy of estimates of survival. AIMS: To assess and compare the prognostic ability of an enzymatic 13C-based liver function test (LiMAx) and distinct markers of liver function to predict 3-month mortality of patients with chronic liver failure. METHODS: We prospectively investigated liver function of 268 chronic liver failure patients without hepatocellular carcinoma. Primary study endpoint was liver-related death within 3 months of follow-up. Prognostic values were calculated using Cox proportional hazards and logistic regression analysis. RESULTS: The Cox proportional hazard model indicated that LiMAx (p < 0.001) and serum creatinine values (p < 0.001) were the significant parameters independently associated with the risk of liver failure-related death. Logistic regression analysis revealed LiMAx and serum creatinine to be independent predictors of mortality. Areas under the receiver-operating characteristic curves for MELD (0.86 [0.80-0.92]) and for a combined score of LiMAx and serum creatinine (0.83 [0.76-0.90]) were comparable. CONCLUSIONS: Apart from serum creatinine levels, enzymatic liver function measured by LiMAx was found to be an independent predictor of short-term mortality risk in patients with liver cirrhosis. A risk score combining both determinants allows reliable prediction of short-term prognosis considering actual organ function. Trial Registration Number (German Clinical Trials Register) # DRKS00000614.

Metallothionein Expression in Horses With Chronic Liver Disease and Its Correlation With Ki-67 Immunoreactivity.

Chronic liver disease is an important cause of illness in horses, and treatment is mainly supportive. Research into new treatment modalities for humans has shown promising data regarding metallothionein (MT), which has been shown to possess regenerative, antifibrotic, and anti-inflammatory properties. This study aimed to examine the relationship between hepatic MT expression and the histopathologic markers of hepatic inflammation, fibrosis and bile duct proliferation, as well as cellular regeneration in 77 selected cases of chronic liver disease in horses. We hypothesized that higher MT expression would be associated with increased heptocellular proliferation and decreased fibrosis, inflammation, and bile duct proliferation. Hepatocellular MT expression was evaluated with immunohistochemistry. Additionally, cellular regeneration was evaluated with immunohistochemistry for Ki-67, a protein expressed during all active stages of the cell cycle. The severity of inflammation and fibrosis was scored, and bile duct proliferation was assessed by counting bile duct profiles. MT expression was observed in 73 of 77 (94.8%) cases of chronically diseased livers. Ki-67 expression was seen in resident Kupffer cells ( n = 42, 54.6%), lymphocytes ( n = 39, 50.7%), bile duct epithelium ( n = 10, 13.0%), and hepatocytes ( n = 8, 10.4%). MT expression was significantly associated with Ki-67 staining in bile duct epithelium and Kupffer cells. Additionally, median MT expression was higher in cases containing lymphocytic infiltrates as compared with cases with no lymphocytic infiltrate ( P < .05). These findings are the first known report of MT expression within chronic equine hepatic disease.

High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease.

BACKGROUND & AIMS: The high replication and mutation rate of hepatitis C virus (HCV) results in a heterogeneous population of viral sequences in vivo. HCV replicates in the liver and infected hepatocytes occur as foci surrounded by uninfected cells that may promote compartmentalization of viral variants. Given recent reports showing interferon stimulated gene (ISG) expression in chronic hepatitis C, we hypothesized that local interferon responses may limit HCV replication and evolution. METHODS: To investigate the spatial influence of liver architecture on viral replication we measured HCV RNA and ISG mRNA from each of the 8 Couinaud segments of the liver from 21 patients undergoing liver transplant. RESULTS: HCV RNA and ISG mRNA levels were comparable across all sites from an individual liver but showed up to 500-fold difference between patients. Importantly, there was no association between ISG and HCV RNA expression across all sites in the liver or plasma. Deep sequencing of HCV RNA isolated from the 8 hepatic sites from two subjects showed a similar distribution of viral quasispecies across the liver and uniform sequence diversity. Single genome amplification of HCV E1E2-envelope clones from 6 selected patients at 2 hepatic sites supported these data and showed no evidence for HCV compartmentalization. CONCLUSIONS: We found no differences between the hepatic and plasma viral quasispecies in all patients sampled. We conclude that in end-stage liver disease HCV RNA levels and the genetic pool of HCV envelope sequences are indistinguishable between distant sites in the liver and plasma, arguing against viral compartmentalization. LAY SUMMARY: HCV is an RNA virus that exists as a quasispecies of closely related genomes that are under continuous selection by host innate and adaptive immune responses and antiviral drug therapy. The primary site of HCV replication is the liver and yet our understanding of the spatial distribution of viral variants within the liver is limited. High resolution sequencing of HCV and monitoring of innate immune responses at multiple sites across the liver identified a uniform pattern of diversity and argues against viral compartmentalization.

CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma.

CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention.NEW & NOTEWORTHY Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated in chronic liver disease and hepatocellular carcinoma (HCC) and is regulated on endothelium by tissue remodeling and procarcinogenic factors. These regulatory and functional studies identify CD151 as a potential therapeutic target to treat liver fibrosis and HCC.

Patients Undergoing Orthotopic Liver Transplantation Require Lower Concentrations of the Volatile Anesthetic Sevoflurane.

BACKGROUND: Sevoflurane is a volatile anesthetic commonly used to maintain anesthesia in patients with end-stage liver disease (ESLD) undergoing orthotopic liver transplantation (OLT). Growing evidence suggests that patients with ESLD have decreased anesthetic requirements compared to patients with preserved liver function. The potency of volatile anesthetics is expressed as the minimum alveolar concentration (MAC). In this prospective, blinded study, we compared the MAC of sevoflurane among patients with ESLD undergoing OLT and patients with normal liver function undergoing major abdominal surgery. METHODS: After propofol-induced anesthesia, the MAC of sevoflurane was assessed by evaluating motor response to initial skin incision in patients undergoing OLT and in patients with normal liver function undergoing major abdominal surgery. The MAC was determined using Dixon "up-and-down" method and compared between groups. In addition, the bispectral index was documented immediately before and after skin incision. RESULTS: Twenty patients undergoing OLT and 20 control patients were included in the study. The MAC of sevoflurane in patients undergoing OLT was 1.3% (95% confidence interval [CI], 1.1-1.4). In comparison, the MAC of sevoflurane in patients with normal liver function was 1.7% (95% CI, 1.6-1.9), equal to a relative reduction of the MAC in patients with ESLD of 26% (95% CI, 14-39). The bispectral index was higher in patients with ESLD than in control patients at 3 minutes before (47 [95% CI, 40-53] vs 35 [95% CI, 31-40], P = .011), 1 minute before (48 [95% CI, 42-54] vs 37 [95% CI, 33-43], P = .03), and 1 minute after skin incision (57 [95% CI, 50-64] vs 41 [95% CI, 36-47], P < .001). CONCLUSIONS: Our results suggest that the MAC of sevoflurane is lower in patients with ESLD than in patients with normal liver function after propofol-induced anesthesia. However, as we did not measure propofol concentrations at the time of skin incision, the difference in MAC should be interpreted with caution given that residual propofol may have been present at the time of skin incision.

Gallic Acid and Dodecyl Gallate Prevents Carbon Tetrachloride-Induced Acute and Chronic Hepatotoxicity by Enhancing Hepatic Antioxidant Status and Increasing p53 Expression.

Gallic acid (3,4,5-trihydroxybenzoic acid, GA), a natural phenolic acid has been reported as a strong antioxidant. Therefore the present study was designed to evaluate the effects of GA and dodecyl gallate (DGA) against acute and chronic carbon tetrachloride (CCl4)-induced hepatotoxicity. For acute model, rats were orally treated with GA and DGA for 7 d prior to CCl4 by intraperitoneally (i.p.) injection. For the chronic model, rats were orally treated with GA or DGA and CCl4 i.p. twice a week for four weeks. In both acute and chronic models, the CCl4-treated groups showed significantly increase in serum hepatic enzyme activities and histopathologic alterations, as well as a disruption in antioxidative status. In contrast, the treatment with GA and DGA restored serum hepatic enzymes activities, improved histopathologic alterations, increased glutathione (GSH) and decreased lipid peroxidation levels. The activities of liver antioxidant enzymes were increased by GA and DGA only in acute model. The expression of p53 gene increased about 3.5 times after GA and DGA treatments, which could result in cell death of damaged hepatocytes preventing of a lifelong liver failure. Thus, these results suggest that GA and DGA has the potential to prevent liver damages as the case of fibrosis condition.

Anaesthesia in patients with liver disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize the most recent up to date research data and recommendations regarding anaesthetic management of patients with liver disease undergoing surgery. The incidence of chronic liver disease (CLD) continues to rise and perioperative mortality and morbidity remains unacceptably high in this group. Meticulous preoperative assessment and carefully planned anaesthetic management are vital in improving outcomes in patients with liver disease undergoing surgery. RECENT FINDINGS: The presence of cirrhosis is associated with a significantly increased risk of postoperative morbidity and mortality in patients undergoing elective surgery. The Child--Pugh--Turcotte scale and model for end-stage liver disease (MELD) score remain the most commonly applied scoring systems in preoperative risk assessment, but new MELD-based indices and novel scoring systems might offer better prognostic value. Propofol and new inhalational agents (sevoflurane, desflurane) are recommended hypnotic agents. The titration of opiates in the perioperative period is recommended because of their altered metabolism in patients with liver disease. Perioperative management should include close haemodynamic monitoring and admission to a critical care area should be considered. SUMMARY: Patients with liver disease undergoing anaesthesia pose significant challenges and advanced planning and preparation are required in order to improve perioperative outcomes in this group. VIDEO ABSTRACT: http://links.lww.com/COAN/A43.

Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK.

BACKGROUND & AIMS: Characteristics of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) include susceptibility to infection, immuneparesis, and monocyte dysfunction. MER receptor tyrosine kinase (MERTK) is expressed by monocytes and macrophages and contributes to down-regulation of innate immune responses. We investigated whether MERTK expression is altered on monocytes from patients with liver failure. METHODS: We analyzed blood and liver samples collected from patients admitted to the liver intensive therapy unit at King's College Hospital in London from December 2012 through July 2014. Patients had either ACLF (n = 41), acute decompensation of cirrhosis without ACLF (n = 9), cirrhosis without decompensation (n = 17), or acute liver failure (n = 23). We also analyzed samples from healthy individuals (controls, n = 29). We used flow cytometry to determine the level of innate immune function, and associated the findings with disease severity. We developed an assay to measure recruitment and migration of immune cells from the tissue parenchyma. Immunohistochemistry and confocal microscopy were used to determine levels of MERTK in bone marrow, liver, and lymph node tissues. We performed immunophenotype analyses and measured the production of tumor necrosis factor and interleukin 6 and intracellular killing of Escherichia coli by monocytes and peritoneal macrophages incubated with lipopolysaccharide, with or without an inhibitor of MERTK (UNC569). RESULTS: The number of monocytes and macrophages that expressed MERTK was greatly increased in the circulation, livers, and lymph nodes of patients with ACLF, compared with patients with stable cirrhosis and controls. MERTK expression (mean fluorescence intensity) correlated with the severity of hepatic and extrahepatic disease and systemic inflammatory responses. Based on immunophenotype, migration, and functional analyses, MERTK-expressing monocytes migrate across the endothelia to localize into tissue sites and regional lymph nodes. Expression of MERTK reduced the response of cultured monocytes to lipopolysaccharide; the addition of UNC569 restored production of inflammatory cytokines in response to lipopolysaccharide. CONCLUSIONS: Patients with ACLF have increased numbers of immunoregulatory monocytes and macrophages that express MERTK and suppress the innate immune response to microbes. The number of these cells correlates with disease severity and the inflammatory response. MERTK inhibitors restore production of inflammatory cytokines by immune cells from patients with ACLF, and might be developed to increase the innate immune response in these patients.

Immunomodulatory and antioxidant function of albumin stabilises the endothelium and improves survival in a rodent model of chronic liver failure.

BACKGROUND & AIMS: Liver failure is characterized by endothelial dysfunction, which results in hemodynamic disturbances leading to renal failure. Albumin infusion improves hemodynamics and prevents renal dysfunction in advance liver failure. These effects are only partly explained by the oncotic properties of albumin. This study was designed to test the hypothesis that albumin exerts its beneficial effects by stabilising endothelial function. METHODS: In vivo: systemic hemodynamics, renal function, markers of endothelial dysfunction (ADMA) and inflammation were studied in analbuminaemic and Sprague-Dawley rats, 6-weeks after sham/bile duct ligation surgery. In vitro: human umbilical vein endothelial cells were stimulated with LPS with or without albumin. We studied protein expression and gene expression of adhesion molecules, intracellular reactive oxygen species, and cell stress markers. RESULTS: Compared to controls, analbuminaemic rats had significantly greater hemodynamic deterioration after bile duct ligation, resulting in worse renal function and shorter survival. This was associated with significantly greater plasma renin activity, worse endothelial function, and disturbed inflammatory response. In vitro studies showed that albumin was actively taken up by endothelial cells. Incubation of albumin pre-treated endothelial cells with LPS was associated with significantly less activation compared with untreated cells, decreased intracellular reactive oxygen species, and markers of cell stress. CONCLUSIONS: These results show, for the first time, that absence of albumin is characterised by worse systemic hemodynamics, renal function and higher mortality in a rodent model of chronic liver failure and illustrates the important non-oncotic properties of albumin in protecting against endothelial dysfunction.