IMPACT OF MELD SODIUM ON LIVER TRANSPLANTATION WAITING LIST.

BACKGROUND: Serum sodium was incorporated to MELD score for the allocation of liver transplantation In the USA in 2016. Hyponatremia significantly increased the efficacy of the score to predict mortality on the waiting list. Such modification was not adopted in Brazil. AIM: To carry out a simulation using MELD-Na as waiting list ordering criteria in the state of Paraná and to compare to the list ordered according to MELD score. METHODS: The study used data of 122 patients waiting for hepatic transplantation and listed at Parana´s Transplantation Central. Two classificatory lists were set up, one with MELD, the current qualifying criteria, and another with MELD-Na. We analyzed the changes on classification comparing these two lists. RESULTS: Among all patients, 95.1% of the participants changed position, 30.3% showed improvement, 64.8% presented worsening and 4.9% maintained their position. There were 19 patients with hyponatremia, of whom 94.7% presented a change of position, and in all of them there was an improvement of position. One hundred and one patients presented sodium within the normal range and 95% of them presented a change of position: Improved placement was observed in 18.8%, and worsened placement in 76.2%. Two patients presented hypernatremia and changed their position, both worsening the placement. There was a significant different behavior on waiting list according to sodium serum level when MELD-Na was applied. CONCLUSION: The inclusion of serum sodium caused a great impact in the classification, bringing benefit to patients with hyponatremia.

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.

Low PCSK9 levels are correlated with mortality in patients with end-stage liver disease.

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in the cholesterol metabolism and is synthesized by the liver. It interacts with the LDL-receptor to promote its degradation. The model of end-stage liver disease (MELD) score is a well-established tool to estimate the risk of mortality in patients with end-stage chronic liver disease. The study aims to assess the associations between PCSK9, hypocholesterinemia, liver synthesis, cholestasis, MELD score and mortality in patients with end-stage liver disease. METHODS: Serum samples were obtained from 74 patients with severe liver disease. The study participants were aged between 23 and 70 y (mean: 55.8 y; 47 males [63.5%], 27 females [36.5%]). Samples were selected from those with a wide range of MELD scores (7 to 40). Patients that underwent liver transplantation (17 / 74) were censored at the time of transplantation for mortality analysis. RESULTS: PCSK9 values ranged from 31.47 ng/mL to 261.64 ng/mL. The median value was 106.39 ng/ml. PCSK9 was negatively correlated with markers of liver function and cholestasis (INR, bilirubin). Over a 90-d follow-up, 15 of 57 (26,3%) patients died within the 90-d follow-up without receiving liver transplantation. Thirteen of 31 (42%) patients with PCSK9 levels below the median died compared to 2/26 (8%) patients with higher PCSK9 levels (p = 0.006). In this cohort, there were no significant correlations between PCSK9, cholesterol, its precursors and several phytosterols. CONCLUSIONS: Low PCSK9 serum concentrations were associated with higher mortality in patients with end-stage liver disease. The mean PCSK9 levels in the study population were much lower than those found in normal or healthy populations. Further studies are required to acquire a more detailed understanding of the role of PCSK9 in liver-related mortality.

Butrylcholinesterase activity in chronic liver disease patients and correlation with Child-Pugh classification and MELD scoring system.

BACKGROUND: After 40 years since establishment of Child-Pugh staging, 14 years since establishment of MELD scoring system, and 25 years since establishment of King's College Criteria, there is still a search for more accurate systems for determination of prognosis in patients with acute liver failure--cirrhosis and prioritization for receipt of a liver transplant--prediction of post transplant mortality. Butrylcholinesterase is an enzyme which is synthesized in the liver. The aim of the study was to evaluate the clinical utility of butrylcholinesterase as a discriminatory and prognostic factor in chronic liver disease patients. METHODS: Intergroup diversity for butrylcholinesterase activity was investigated in sixty cirrhotic, 20 chronic hepatitis patients, and 20 healthy subjects. Correlations between butrylcholinesterase activity and Child-Pugh classification and MELD scoring systems were examined. RESULTS: In addition to the statistically significant decrease in butrylcholinesterase activity among Child-Pugh A/B/C stages, the decrease in butrylcholinesterase activity was also statistically significant in control vs. Child-Pugh stage A and chronic hepatitis vs. Child Pugh stage A groups. A statistically significant correlation was determined between butrylcholinesterase activity and Child Pugh/MELD scores. CONCLUSIONS: Serum butrylcholinesterase activity might be helpful for discrimination of chronic hepatitis from cirrhosis after determination of reliable cut-off levels and dependent on the reductions of serum levels in acute liver failure and cirrhosis. It might be a useful tool for prioritization of liver transplantation.

Short-term prognostic factors for primary sclerosing cholangitis.

BACKGROUND: It was recently reported that alkaline phosphatase (ALP) levels below 1.5 upper limit of normal (ULN) predicted better prognosis in primary sclerosing cholangitis (PSC). We evaluated whether ALP as well as other laboratory values were useful for the short-term prognosis of PSC in a Japanese cohort. METHODS: In 78 patients with PSC (41 males and 37 females, mean onset age 41.9 years), the relationship between nine parameters (albumin, bilirubin, international normalized ratio of prothrombin time [PT-INR], ALP, aspartate aminotransferase [AST], alanine aminotransferase [ALT], γ-glutamyl transpeptidase [γ-GTP], platelet, and calculated Model for End-Stage Liver Disease [MELD] score), and liver related clinical endpoints (death due to liver failure, variceal bleeding, liver transplantation, and biliary carcinoma) were retrospectively examined. Using receiver operating characteristic (ROC) analysis, we investigated which parameter was useful for predicting the short-term prognosis. RESULTS: Average follow-up period was 8.6 years. The endpoints were evaluated in 40 patients. Seven patients died of liver failure, three patients developed variceal bleeding, nine patients received liver transplantation from a living donor, 13 patients received certified brain-dead liver transplantation, and eight patients developed biliary carcinoma. The parameters with an area under the curve (AUC) of more than 0.8 were albumin, bilirubin, PT-INR, ALP, and MELD score. AUC for ALP was 0.85. The optimal cutoff value was 2.3 ULN. Despite the use or non-use of ursodeoxycholic acid, short-term prognosis of patients with an ALP level below 2.3 ULN was good. CONCLUSIONS: We confirmed that keeping ALP low is associated with better short-term prognosis in a Japanese cohort. In addition, Alb, Bil, PT-INR, and MELD score were good predictors.

Relationships between transient elastography values and liver fibrosis in chronic liver disease patients with normal or mildly abnormal aminotransferase levels.

This study aimed to evaluate relationships between transient elastography values and liver fibrosis in chronic liver disease patients with normal or mildly abnormal aminotransferase levels. Fifty-six patients were enrolled in the study. Transient elastography and liver biopsy were performed on the same day, and the fibrosis was staged based on the Scheuer scoring system. Liver stiffness was measured to assessed liver fibrosis using transient elastography. The transient elastography values of 12 patients with chronic hepatitis B were studied before and 6 months after antiviral treatment. The sensitivity and specificity for 10.88 kPa in S3 were 80 and 87.8%, and for 19.4 kPa in S4, were 100 and 90.7%, respectively. In univariate analysis, liver stiffness strongly correlated with the fibrosis stage (r = 0.70, P < 0.5), moderately correlated with the aminotransferases (r = 0.398, P < 0.05), and poorly correlated with the degree of necroinflammatory activity (r = 0.19, P < 0.5). In multivariate regression, liver stiffness correlated only with the fibrosis stage (P < 0.05). Pre- and post-treatment viral loads were not significantly different [(4.81 ± 0.15) x 10(6) vs (7.62 ± 0. 16) x 10(3), P > 0.05]. Pre- and post-treatment LS measurements were not correlated with viral load (P > 0.05). Pre- and post-treatment LS measurements were not significantly different (P > 0.02). In conclusion, transient elastography values correlated with the stage of cirrhosis, alanine aminotransferase levels, and antiviral treatment in patients with chronic hepatitis B and did not correlate with viral loads.

Expression of P450 and nuclear receptors in normal and end-stage Chinese livers.

AIM: To investigate the expression of P450 enzyme genes by using end-stage liver disease samples and trimmed normal Chinese donor livers. METHODS: The end-stage liver disease samples [n = 93, including hepatocellular carcinoma (HCC), peri-HCC tissue, hepatitis B virus cirrhosis, alcoholic cirrhosis, and severe cirrhosis] and trimmed normal Chinese donor livers (n = 35) from The Institute of Organ Transplantation in Beijing, China. Total RNA was extracted, purified, and subjected to real-time RT-PCR analysis. RESULTS: For cytochrome P450 enzymes 1 (CYP1) family, the expression of CYP1A2 was decreased 90% in HCC, 80% in alcoholic cirrhosis, and 65% in severe cirrhosis. For CYP2 family, the expression of CAR was decreased 50% in HCC, but increased 50% in peri-HCC tissues. Similar decreases (about 50%) of CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 were observed in HCC, as compared to peri-HCC tissues and normal livers. CYP2C19 were decreased in all end-stage liver diseases and CYP2E1 also decreased in alcoholic cirrhosis and severe cirrhosis. For CYP3 family, the expression of PXR was decreased 60% in HCC, together with decreases in CYP3A4, CYP3A5, and CYP3A7. In contrast, the expression of CYP3A7 was slightly increased in HBV cirrhosis. The expression of CYP4A11 was decreased 85% in HCC, 7% in alcoholic cirrhosis and severe liver cirrhosis, along with decreases in PPARα. The 93 end-stage livers had much higher inter-individual variations in gene expression than 35 normal livers. CONCLUSION: The expression of CYP enzyme genes and corresponding nuclear receptors was generally decreased in end-stage liver diseases, and significant differences in gene expression were evident between peri-HCC and HCC.

Telomere and telomerase in chronic liver disease and hepatocarcinoma.

The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma (HCC) whereas others have a benign course. Therefore, a genetic predisposition may contribute to the development of cirrhosis and HCC. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years. In addition to the results from epidemiological studies, polymorphisms studies and data on twins, the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed. Here we review the literature on telomerase mutations, telomere shortening and liver disease including hepatocellular carcinoma.

Automation of o-dianisidine assay for ceruloplasmin activity analyses: usefulness of investigation in Wilson's disease and in hepatic encephalopathy.

Ceruloplasmin (Cp) is a serum ferroxidase that plays an essential role in iron metabolism. It is routinely tested by immunoturbidimetric assays that quantify the concentration of the protein both in its active and inactive forms. Cp activity is generally analyzed manually; the process is time-consuming, has a limited repeatability, and is not suitable for a clinical setting. To overcome these inconveniences, we have set the automation of the o-dianisidine Cp activity assay on a Cobas Mira Plus apparatus. The automation was rapid and repeatable, and the data were provided in terms of IU/L. The assay was adapted for human sera and showed a good precision [coefficient of variation (CV) 3.7 %] and low limit of detection (LoD 11.58 IU/L). The simultaneous analysis of Cp concentration and activity in the same run allowed us to calculate the Cp-specific activity that provides a better index of the overall Cp status. To test the usefulness of this automation, we tested this assay on 104 healthy volunteers and 36 patients with Wilson's disease, hepatic encephalopathy, and chronic liver disease. Cp activity and specific activity distinguished better patients between groups with respect to Cp concentration alone, and providing support for the clinical investigation of neurological diseases in which liver failure is one of the clinical hallmarks.

Nonselective inhibition of prostaglandin-endoperoxide synthases by naproxen ameliorates acute or chronic liver injury in animals.

The rising prevalence of hepatic injury due to toxins, metabolites, viruses, etc., necessitates development of further mechanisms for protecting the liver and for treating acute or chronic liver diseases. To examine whether inhibition of inflammation is directed by cyclo-oxygenase pathways, we performed animal studies with naproxen, which inhibits prostaglandin-endoperoxide synthases 1 and 2 and is in extensive clinical use. We administered carbon tetrachloride to induce acute liver injury and ligated the common bile duct to induce chronic liver injury in adult rats. These experimental manipulations produced abnormalities in liver tests, tissue necrosis, compensatory hepatocyte or biliary proliferation, and onset of fibrosis, particularly after bile duct ligation. After carbon tetrachloride-induced acute injury, naproxen decreased liver test abnormalities, tissue necrosis and compensatory hepatocellular proliferation. After bile duct ligation-induced chronic injury, naproxen decreased liver test abnormalities, tissue injury and compensatory biliary hyperplasia. Moreover, after bile duct ligation, naproxen-treated rats showed more periductular oval liver cells, which have been classified as hepatic progenitor cells. In naproxen-treated rats, we found greater expression in hepatic stellate cells and mononuclear cells of cytoprotective factors, such as vascular endothelial growth factor. The ability of naproxen to induce expression of vascular endothelial growth factor was verified in cell culture studies with CFSC-8B clone of rat hepatic stellate cells. Whereas assays for carbon tetrachloride toxicity using cultured primary hepatocytes established that naproxen was not directly cytoprotective, we found conditioned medium containing vascular endothelial growth factor from naproxen-treated CFSC-8B cells protected hepatocytes from carbon tetrachloride toxicity. Therefore, naproxen was capable of ameliorating toxic liver injury, which involved naproxen-induced release of physiological cytoprotective factors in nonparenchymal liver cells. Such drug-induced release of endogenous cytoprotectants will advance therapeutic development for hepatic injury.

In vitro cytochrome p450 activity decreases in children with high pediatric end-stage liver disease scores.

To improve the modeling and simulation of pharmacokinetics in pediatric patients, research into developmental and disease-specific determinants is needed. This article describes the evaluation of the activity of in vitro cytochrome P450 (P450), an important enzyme family in drug metabolism, in children with hepatic dysfunction. The activity of six P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) was evaluated in 31 patients with different pathologies, predominantly biliary atresia (n = 23). Hypervariable activity was observed for all the isoforms. Compared with average adult activity, low activity levels were seen for CYP1A2, 2C19, 2E1, and 3A4. For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed. Age, comedication, and genotype could not be used as predictors for P450 activity in this patient population. In contrast, the pediatric end-stage liver disease score was negatively correlated with the ln(activity). This finding suggests a decrease in P450 activity with deteriorating hepatic function. Moreover, the activity of all isoforms was correlated, demonstrating a concomitant decrease of all isoforms in young patients with liver disease. To our knowledge, this is the first study to evaluate P450 activity in children with hepatic impairment. The presented data may provide support in the further optimization of a disease-specific model in this patient population.

Expression of genes involved in xenobiotic metabolism and transport in end-stage liver disease: up-regulation of ABCC4 and CYP1B1.

BACKGROUND: Expression of drug-metabolizing enzymes and drug transporters in liver is mainly regulated by a system of nuclear receptors. The aim of the current study was to investigate the expression of nuclear receptors, as well as these enzymes and transporters, in liver samples from patients suffering from end-stage liver disease of various etiologies (HCV infection, alcohol liver disease, and primary sclerosis cholangitis). METHODS: Gene expression was measured using quantitative real-time PCR with surgical specimens from livers of patients with end-stage liver disease, and non-tumoral liver tissue that served as control. RESULTS: Our study confirmed that the expression of most phase I enzymes is suppressed in end-stage liver disease, and is correlated with a decrease in NR1I2 and NR1I3, the main regulators of xenobiotic metabolism. While mRNA levels of phase II enzymes were generally unchanged, some ABC transporters were up-regulated. The most spectacular increases in expression were observed with ABCC4 (MRP4) - at the mRNA level, and CYP1B1 - at both the mRNA and protein levels. We also demonstrated that IL-6 can induce CYP1B1 expression independently of CYP1A1, in a human hepatocellular liver carcinoma cell line. CONCLUSIONS: As CYP1B1 is an enzyme which converts various substrates into carcinogenous metabolites, its overexpression in liver may be one of the factors increasing the risk of hepatic cancers in patients with liver disease. CYP1A1 and CYP1B1 are often referred to as model AHR target genes, but CYP1A1 was down-regulated in diseased liver samples. This points to the existence of differences in regulation of these two genes.

Analysis of 83 consecutive liver transplants performed at a tertiary care reference hospital in the interior of the state of Sao Paulo / Analise de 83 transplantes hepáticos consecutivos realizados em hospital universitário de referência terciária do interior do estado de São Paulo

PURPOSE: To analyze pre-, intra- and immediate postoperative parameters of patients submitted to liver transplantation. METHODS: Eighty-three consecutive orthotopic liver transplants performed from January 2009 to July 2011 were analyzed. The patients were divided into 2 groups: A, survivors (MELD between 9 and 60) and B, non-survivors (MELD between 14 and 40), with 30.6 percent of group A patients being CHILD C, 51℅ CHILD B and 18,4℅ CHILD A. In group B ,32.1℅ of the patients were CHILD C, 42,9℅ CHILD B, and 25℅ CHILD A. All orthotopic liver transplantations were performed using the piggyback technique without a portacaval shunt. Systemic arterial pressure and serum ALT and AST levels were determined preoperatively and 5, 60 and 1440 minutes after arterial graft revascularization. Serum ALT and AST profiles were evaluated for seven days after surgery. RESULTS: Systemic arterial blood pressure levels, time of hot and hypothermic ischemia and time of graft implant were statistically similar for the two groups (p>0.05). Serum levels (U/L) of ALT and AST at the 5, 60 and 1440 minute time points after arterial revascularization of the graft were also similar for the two groups studied, as also were the serum ALT and AST profiles. CONCLUSIONS: No statistically significant difference in any of the parameters studied was detected between the two groups. Under the conditions of the present study and on the basis of the parameters evaluated, no direct relation was detected between the intraoperative period and the type of patient outcome in the two groups studied.

OBJETIVO: Analisar parâmetros do pré, intra e pós-operatório imediato de pacientes submetidos ao transplante de fígado. MÉTODOS: Foram analisados 83 transplantes ortotópicos de fígado realizados consecutivamente no período janeiro de 2009 a julho de 2011. Os pacientes foram dividos em dois grupos: A, survivors (MELD entre 16 e 60), e B, non-survivors (MELD entre 14 e 40) sendo que 30,6℅ dos pacientes do grupo A eram CHILD C, 51℅ CHILD B e 18,4℅ CHILD A. No grupo B, 32,1℅ dos pacientes eram CHILD C, 42,9℅ CHILD B, e 25℅ CHILD A. Todos os transplantes ortotópicos de fígado foram feitos com a técnica de piggyback sem "shunt" porto cava. Foram analisados os valores de pressão arterial sistêmica e os níveis séricos de ALT e AST, no pré-operatório, 5, 60 e 1440 minutos após revascularização arterial do enxerto. Avaliaram-se os perfis séricos da ALT e AST durante sete dias de pós-operatorio. RESULTADOS: Verificou-se que em ambos os grupos, os níveis de pressão arterial sistêmica, os tempos de isquemia normotérmica, hipotérmica e de implante do enxerto foram estatisticamente semelhantes (p>0,05). Os níveis séricos (U/L) de ALT e AST nos tempos de 5, 60 e 1440 minutos após a revascularização arterial do enxerto também foram semelhantes nos grupos estudados. Os perfis séricos da ALT e AST foram semelhantes nos dois grupos estudados. CONCLUSÕES: Não se verificou diferença estatisticamente significante entre todos os parâmetros estudados, em ambos os grupos. Nas condições do presente estudo, não se verificou relação direta do intra-operatório com o tipo de evolução (outcome) dos pacientes nos dois grupos estudados.

Analysis of 83 consecutive liver transplants performed at a tertiary care reference hospital in the interior of the state of Sao Paulo.

PURPOSE: To analyze pre-, intra- and immediate postoperative parameters of patients submitted to liver transplantation. METHODS: Eighty-three consecutive orthotopic liver transplants performed from January 2009 to July 2011 were analyzed. The patients were divided into 2 groups: A, survivors (MELD between 9 and 60) and B, non-survivors (MELD between 14 and 40), with 30.6% of group A patients being CHILD C, 51℅ CHILD B and 18,4℅ CHILD A. In group B, 32.1℅ of the patients were CHILD C, 42,9℅ CHILD B, and 25℅ CHILD A. All orthotopic liver transplantations were performed using the piggyback technique without a portacaval shunt. Systemic arterial pressure and serum ALT and AST levels were determined preoperatively and 5, 60 and 1440 minutes after arterial graft revascularization. Serum ALT and AST profiles were evaluated for seven days after surgery. RESULTS: Systemic arterial blood pressure levels, time of hot and hypothermic ischemia and time of graft implant were statistically similar for the two groups (p>0.05). Serum levels (U/L) of ALT and AST at the 5, 60 and 1440 minute time points after arterial revascularization of the graft were also similar for the two groups studied, as also were the serum ALT and AST profiles. CONCLUSIONS: No statistically significant difference in any of the parameters studied was detected between the two groups. Under the conditions of the present study and on the basis of the parameters evaluated, no direct relation was detected between the intraoperative period and the type of patient outcome in the two groups studied.

3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor use in chronic liver disease: a therapeutic controversy.

OBJECTIVE: To review efficacy and safety data of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) in adult patients with chronic liver disease. DATA SOURCE: A MEDLINE search (2005 to March 2011) was conducted with use of the keywords: statin, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatitis C, chronic liver disease, and HMG-CoA reductase inhibitor. STUDY SELECTION AND DATA EXTRACTION: All articles written in English identified from data sources were evaluated and reviewed for inclusion. Original research and retrospective cohorts were included in this review. The references of articles that we identified were examined for any additional studies appropriate for review. DATA SYNTHESIS: Cardiovascular disease is a major cause of morbidity and mortality worldwide. Reducing cholesterol levels has been shown to reduce the development of atherosclerosis and incidence of cardiovascular disease. The HMG-CoA reductase inhibitors (also known as statins) are the most effective agents available in the management of hyperlipidemia and prevention of major cardiovascular events. The most common hepatic adverse effect associated with statin use is a transient asymptomatic elevation of serum aminotransferases in the first 12 weeks of therapy. Although the positive benefits of statin therapy are well recognized, the concerns of potential hepatotoxicity with statin therapy have limited use not only in the general population but also in patients with a history of chronic liver disease. Clinical trials in which the authors evaluated statin therapy in patients with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and hepatitis C virus demonstrated improved and/or normalization of aminotransferases and improved lipid levels without any reported adverse effects attributable to statin therapy. CONCLUSIONS: Available clinical data suggest that statin therapy in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and hepatitis C virus is a safe option in the management of dyslipidemia.

Hepatocyte IKK2 protects Mdr2-/- mice from chronic liver failure.

UNLABELLED: Mice lacking the Abc4 protein encoded by the multidrug resistance-2 gene (Mdr2(-/-)) develop chronic periductular inflammation and cholestatic liver disease resulting in the development of hepatocellular carcinoma (HCC). Inhibition of NF-κB by expression of an IκBα super-repressor (IκBαSR) transgene in hepatocytes was shown to prevent HCC development in Mdr2(-/-) mice, suggesting that NF-κB acts as a tumour promoter in this model of inflammation-associated carcinogenesis. On the other hand, inhibition of NF-κB by hepatocyte specific ablation of IKK2 resulted in increased liver tumour development induced by the chemical carcinogen DEN. To address the role of IKK2-mediated NF-κB activation in hepatocytes in the pathogenesis of liver disease and HCC in Mdr2(-/-) mice, we generated Mdr2-deficient animals lacking IKK2 specifically in hepatocytes using the Cre-loxP system. Mdr2(-/-) mice lacking IKK2 in hepatocytes developed spontaneously a severe liver disease characterized by cholestasis, major hyperbilirubinemia and severe to end-stage fibrosis, which caused muscle wasting, loss of body weight, lethargy and early spontaneous death. Cell culture experiments showed that primary hepatocytes lacking IKK2 were more sensitive to bile acid induced death, suggesting that hepatocyte-specific IKK2 deficiency sensitized hepatocytes to the toxicity of bile acids under conditions of cholestasis resulting in greatly exacerbated liver damage. Mdr2(-/-)IKK2(Hep-KO) mice remarkably recapitulate chronic liver failure in humans and might be of special importance for the study of the mechanisms contributing to the pathogenesis of end-stage chronic liver disease or its implications on other organs. CONCLUSION: IKK2-mediated signaling in hepatocytes protects the liver from damage under conditions of chronic inflammatory cholestasis and prevents the development of severe fibrosis and liver failure.