Search

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown., Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD., Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023., Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months., Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified., Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn., Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

Nonalcoholic fatty liver disease (NAFLD) affects up to 70% of children with obesity and has become the number one etiology for liver transplant in the United States. Early, effective intervention is critical to prevent disease progression into adulthood. Yet, it is seldom achieved through lifestyle modification alone. Thus, children must be included in NAFLD pharmacology trials, which, to date, continue to focus primarily on adult populations. This commentary serves as a call to action., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background & Aims: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis., Methods: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points., Results: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated., Conclusions: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis., Lay Summary: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS., Gov Identifier: NCT03205345., Competing Interests: Conflict of interest James Robinson, Jean L. Chan and David Hagerty were employees of Conatus Pharmaceuticals, Inc., during the conduct of the study. Nicole Wedick was a consultant employed by Conatus Pharmaceuticals, Inc., and reports personal fees from SimulStat, Inc., during the conduct of the study. Catherine Frenette reports research funding from Conatus Pharmaceuticals, Inc., during the conduct of this study and personal fees from Conatus Pharmaceuticals, Inc., outside of the submitted work. Kris Kowdley reports grants from Conatus Pharmaceuticals, Inc., during the conduct of the study; personal fees from Abbvie, Gilead and Intercept, outside of the submitted work; grants from Enanta, Genfit, Gilead, CymaBay, HighTide, Intercept, Allergan and LaJolla, outside of the submitted work; royalties from UpToDate, outside of the submitted work. Kris Kowdley was on the Advisory Board of Assembly Biosciences, Blade, Enanta, Genefit, Gillead, CymaBay and Merck and was a consultant for HighTide and Intercept, outside of the submitted work. Guy Neff reports grants from Echosens and personal fees from Intercept, outside the submitted work. Parvez Mantry reports personal fees from Gilead, Intercept, Salix, Eisai, Abbvie and grants from Allergan, Genfit, Bristol-Myers, Galmed, Viking, Pfizer, Merck, outside the submitted work. Ethan Weinberg reports personal fees from Mallinckrodt Pharmaceuticals and from Sequana, outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease., Approach and Results: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients., Conclusions: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH., (© 2020 by the American Association for the Study of Liver Diseases.)

Chronic liver disease is reaching epidemic proportions with the increasing prevalence of obesity, nonalcoholic liver disease, and alcohol overuse worldwide. Most patients are not candidates for liver transplantation even if they have end-stage liver disease. There is growing evidence of a gut microbial basis for many liver diseases, therefore, better diagnostic, prognostic, and therapeutic approaches based on knowledge of gut microbiota are needed. We review the questions that need to be answered to successfully translate our knowledge of the intestinal microbiome and the changes associated with liver disease into practice., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Hepatitis C virus (HCV) and its sequelae present a significant source of economic and societal burden. Introduction of highly effective curative therapies has made HCV elimination attainable. The study used a predictive model to assess the clinical and economic impact of implementing national screening and treatment policies toward HCV elimination in Korea., Methods: A previously validated Markov disease progression model of HCV infection was employed to analyze the clinical and economic impact of various strategies for HCV diagnosis and treatment in Korea. In this analysis, the model compared the clinical and economic outcomes of current HCV-related interventions in Korea (7,000 patients treated and 4,200 patients newly diagnosed annually, starting in 2017) to four elimination scenarios: 1) initiating sufficient diagnosis and treatment interventions to meet the World Health Organization's GHSS elimination targets by 2030, 2) delaying initiation of interventions by one year, 3) delaying initiation of interventions by two years and 4) accelerating initiation of interventions to meet elimination targets by 2025. Modelled historical incidence of HCV was calibrated to match a viremic HCV prevalence of 0.44% in 2009. Elimination scenarios required 24,000 treatments and 34,000 newly diagnosed patients annually, starting in 2018, to reach the 2030 targets., Results: Compared to current "status quo" interventions, elimination (or accelerated elimination by 2025) would avert 23,700 (27,000) incident cases of HCV, 1,300 (1,400) liver-related deaths (LRDs) and 2,900 (3,100) cases of end-stage liver disease (ESLD) over the 2017-2030 time period. Postponing interventions by one (or two) years would avert 21,100 (18,600) new HCV infections, 920 (660) LRDs and 2,000 (1,400) cases of ESLD by 2030. Following elimination or accelerated elimination strategies would save 860 million USD or 1.1 billion USD by 2030, respectively, compared to the status quo, requiring an up-front investment in prevention that decreases spending on liver-related complications and death., Conclusions: By projecting the impact of interventions and tracking progress toward GHSS elimination targets using modelling, we demonstrate that Korea can prevent significant morbidity, mortality and spending on HCV. Results should serve as the backbone for policy and decision-making, demonstrating how aggressive prevention measures are designed to reduce future costs and increase the health of the public., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests. Homie Razavi is an employee of Center for Disease Analysis (CDA). CDA has received funding from AbbVie Inc. for this project. CDA has also received research funding from AbbVie, Gilead, Intercept, and Pfizer. Ellen Dugan, Kwang-Hyub Han, Sang Hoon Ahn, Mi Young Jeon and Do Young Kim have nothing to declare. Yuri Sanchez Gonzalez, Kyung Sik Kang, Yong Kyun Won are employees of AbbVie and may own stock/stock options.

Cholestatic liver diseases encompass a broad spectrum of pathologies, with the core injury occurring at the level of cholangiocytes and progressing to hepatic fibrosis and liver dysfunction. Primary biliary cholangitis and primary sclerosing cholangitis are the most significant progressive cholangiopathies in adults. Although rare, they commonly evolve to liver failure and need for liver transplantation. Despite recent advances in the basic knowledge of these cholangiopathies, the pathogenesis is still elusive. Targeted treatments to prevent disease progression and to preclude malignancy are not yet available. This review will address the general clinical features of both diseases, analyze their commonalities and differences, and provide a state-of-the art overview of the currently available therapeutics.

Nonalcoholic fatty liver disease (NAFLD) represents the most common liver disease, and it is expected to become the leading cause of end-stage liver disease in the near future. Bariatric operations have beneficial effects on NAFLD, inducing histological resolution of liver damage through weight loss-dependent and weight loss-independent mechanisms. Due to lack of randomized controlled trials, no specific guidelines have been established so far. Yet there is growing evidence that NAFLD will eventually become a formal indication for metabolic surgery. Data regarding the choice of procedure are conflicting, although gastric bypass seems to be slightly superior to sleeve gastrectomy. The purpose of this review is to provide an update on the ongoing research regarding the role of metabolic surgery in NAFLD management.

Background and Aims: While the association between platelet activation and hepatic fibrosis has been previously demonstrated in animal studies; the utility of anti-platelet agents in reversing the progression of hepatic fibrosis requires further review. Utilizing systematic review methods, we provide to our knowledge the first meta-analysis combining evidence from all studies aimed to establish the effect of anti-platelet agents in the prevention of hepatic fibrosis., Methods: We searched Medline, EMBASE and PubMed databases from inception to October 2018 to identify all studies aimed at evaluating the role of anti-platelet agents in the prevention of hepatic fibrosis. The primary outcome was hepatic fibrosis. The initial title, abstract, and full-text screening were performed in duplicate. Risk of bias was evaluated using the Newcastle-Ottawa Scale. A fixed-effect generic inverse variance method was used to create a pooled estimate of the odds of hepatic fibrosis in patients with anti-platelet agents versus without anti-platelet agents., Results: Among the 2310 unique articles identified during the title screening, 4 studies with a combined population of 3141 patients were deemed eligible for inclusion into the meta-analysis establishing the effect of anti-platelet agents on hepatic fibrosis. One study failed to report their findings in the entire cohort, electing to instead summarize the effects of anti-platelets within subgroups categorized by fibrotic risk factors. Use of anti-platelets was associated with 32% decreased odds of hepatic fibrosis, (adjusted pooled OR 0.68; CI 0.56-0.82, p ≤ 0.0001). The statistical heterogeneity among the studies was insignificant., Conclusion: Use of anti-platelet agents is associated with the decreased odds of hepatic fibrosis. Due to limited evidence, future high-quality randomized controlled trials with larger comparative samples are required to further delineate the potential beneficial effects of these drugs in preventing hepatic fibrosis.

Background & Aims: Cirrhosis and its clinical consequences can be aggravated by bacterial infections, ultimately leading to the development of acute on chronic liver failure (ACLF), characterized by acute decompensation, organ failure, and high mortality within 28 days. Little is known about cellular and molecular mechanisms of ACLF in patients with cirrhosis, so no therapeutic options are available. We developed a sepsis-associated preclinical model of ACLF to facilitate studies of pathogenesis and evaluate the protective effects of simvastatin., Methods: Male Wistar rats inhaled CCl 4 until they developed cirrhosis (at 10 weeks) or cirrhosis with ascites (at 15-16 weeks). Male Sprague-Dawley rats received bile-duct ligation for 28 days or intraperitoneal thioacetamide for 10 weeks to induce cirrhosis. After induction of cirrhosis, some rats received a single injection of lipopolysaccharide (LPS) to induce ACLF; some were given simvastatin or vehicle (control) 4 hours or 24 hours before induction of ACLF. We collected data on changes in hepatic and systemic hemodynamics, hepatic microvascular phenotype and function, and survival times. Liver tissues and plasma were collected and analyzed by immunoblots, quantitative polymerase chain reaction, immuno(fluoro)histochemistry and immunoassays., Results: Administration of LPS aggravated portal hypertension in rats with cirrhosis by increasing the severity of intrahepatic microvascular dysfunction, exacerbating hepatic inflammation, increasing oxidative stress, and recruiting hepatic stellate cells and neutrophils. Rats with cirrhosis given LPS had significantly shorter survival times than rats with cirrhosis given the control. Simvastatin prevented most of ACLF-derived complications and increased survival times. Simvastatin appeared to increase hepatic sinusoidal function and reduce portal hypertension and markers of inflammation and oxidation. The drug significantly reduced levels of transaminases, total bilirubin, and ammonia, as well as LPS-mediated activation of hepatic stellate cells in liver tissues of rats with cirrhosis., Conclusions: In studies of rats with cirrhosis, we found administration of LPS to promote development of ACLF, aggravating the complications of chronic liver disease and decreasing survival times. Simvastatin reduced LPS-induced inflammation and liver damage in rats with ACLF, supporting its use in treatment of patients with advanced chronic liver disease., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Prevailing dietary guidelines recommend regular fish consumption. However, the associations of fish and long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFAs) intakes with mortality remain unclear., Objectives: To examine the associations of fish and LCn-3 PUFAs intakes with total and cause-specific mortality., Methods: A total of 240 729 men and 180 580 women from NIH-AARP Diet and Health Study were prospectively followed-up for 16 years. Dietary intakes were assessed using a validated NIH Diet History Questionnaire., Results: A total of 54 230 men and 30 882 women died during 6.07 million person-years of follow-up. Higher fish and LCn-3 PUFAs intakes were significantly associated with lower total mortality (P < 0.0001). Comparing the highest with lowest quintiles of fish intake, men had 9% (95% confidence interval, 6-11%) lower total mortality, 10% (6-15%) lower cardiovascular disease (CVD) mortality, 6% (1-10%) lower cancer mortality, 20% (11-28%) lower respiratory disease mortality and 37% (17-53%) lower chronic liver disease mortality, while women had 8% (5-12%) lower total mortality, 10% (3-17%) lower CVD mortality and 38% (20-52%) lower Alzheimer's disease mortality. Fried fish consumption was not related to mortality in men whereas positively associated with mortality from all causes (P = 0.011), CVD and respiratory disease in women. LCn-3 PUFAs intake was associated with 15% and 18% lower CVD mortality in men and women across extreme quintiles, respectively., Conclusion: Consumption of fish and LCn-3 PUFAs was robustly associated with lower mortality from major causes. Our findings support current guidelines for fish consumption while advice on non-frying preparation methods is needed., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Chronic liver disease (CLD) is frequently seen in the hemophilia population. The ADVANCE Working Group conducted a cross-sectional study in which people with hemophilia (PWH) aged ≥40 years were included. This study aimed to assess the associations between CLD and its risk factors using data from the H3 study, and to suggest implications for optimal care.Data from 13 European countries were collected at a single time-point (2011-2013). Univariate and multivariate logistic regression (MLR) analyses were performed.A total of 532 PWH were included with either hemophilia A (n = 467) or hemophilia B (n = 65). A total of 127 (24%) were diagnosed with CLD. Hepatitis C virus (HCV), human immunodeficiency virus (HIV), total cholesterol, and severe hemophilia were significant risk factors in univariate logistic regressions. In MLR, HCV Ab+/PCR+ (OR = 17.6, P < .001), diabetes (OR = 3.0, P = .02), and HIV (OR = 1.9, P = .049) were positively associated with CLD. Total cholesterol (OR = 0.6, P = .002) was negatively associated with CLD. We found no evidence of interaction effects among the explanatory variables. No significant associations with age and type of or severity of hemophilia were observed in MLR.The main risk factors for CLD in this European cohort also apply to the general population, but the prevalence of HCV and HIV is considerably larger in this cohort. With new and improved treatment options, intensified eradication therapy for HCV seems justified to prevent CLD. Similarly, intensified monitoring and treatment of diabetes seem warranted.

Hepatitis B virus vaccination, while effective in reducing incident chronic hepatitis B in endemic regions, will not have the desired impact on the rates of end-stage liver disease in chronically infected persons. A large reservoir of chronic infection remains and needs to be managed effectively. Over three decades, interferon alpha (IFNα), and nucleoside analogue therapies have reduced the morbidity and mortality associated with chronic hepatitis B by suppressing viral replication and retarding the progression to cirrhosis and the development of hepatocellular carcinoma (HCC). The preferential preservation of covalently closed circular (cccDNA) and capsid reverse transcriptase-cccDNA interactions during nucleoside analogue therapy currently prevent cure; the majority of patients require continuous maintenance suppressive therapy. In selected patients nucleoside analogues may be stopped. New targets for drug therapy need to be directed at inhibiting intracellular HBV replication, transcription and translation pathways to enhance the likelihood of a cure in the host. Such cures for chronic hepatitis B infection will require several synergistic therapies to achieve either complete eradication of replicative intermediates from the host (cure), or more probably, a functional cure defined as loss of hepatitis B surface antigen. Hampering such development is the lack of a proven serological surrogate for cccDNA to evaluate treatment efficacy. This review outlines the pathophysiology of the virus, the host immunological responses and current therapies. Understanding the interactions between HBV and the host remains fundamental to guide correct sequencing and combinations of treatment with either host or viral-targeting agents to achieve higher rates of cure.

Primary biliary cholangitis is a chronic inflammatory, autoimmune cholestatic liver disease, which untreated will usually progress to end-stage biliary cirrhosis. The aims of treatment and management of primary biliary cholangitis are the amelioration of associated symptoms, particularly pruritis and fatigue, and the prevention of end-stage liver disease. The presentation, natural history and clinical course are variable. Recent published European and UK clinical guidelines have emphasized the need for risk stratification and an individualized approach to patient management in primary biliary cholangitis. The bile acid, ursodeoxycholic acid, is established as the first-line treatment of primary biliary cholangitis. Assessment of clinical response to treatment is based on specified improvements in serum liver tests including near normalization of the serum alkaline phosphatase level at 1 year. At least two thirds of patients with primary biliary cholangitis should respond to ursodeoxycholic acid after 1 year's treatment. The correct dosage of ursodeoxycholic acid is determined by body weight viz 13-15 mg/kg/day. A significant number of patients with primary biliary cholangitis in the UK are being underdosed. Over a third of ursodeoxycholic acid partial responders become responders within 2 years after increasing the ursodeoxycholic acid doses to recommended levels. While transplant rates for primary biliary cholangitis have halved over the last 20 years, it is clear that optimizing the dose of ursodeoxycholic acid in partial responders would further decrease morbidity, mortality and the need for liver transplantation.

Introduction: Hepatitis B virus (HBV) infection is the major cause of cirrhosis worldwide. The ultimate goal of current antiviral treatments for chronic hepatitis B (nucleos(t)ide analogs and interferon-α) is to prevent the development of end-stage liver diseases. Areas covered: We present a review of the current literature on antiviral therapy in patients with chronic hepatitis B and cirrhosis. Medline search was performed to identify relevant literature from 1993 through January of 2017. Expert commentary: One randomized controlled trial and a number of observational studies have shown that nucleos(t)ide analogs can decrease the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis. Data from clinical trials of entecavir and tenofovir have shown that histological improvement and regression of fibrosis can be achieved in the majority of patients with chronic hepatitis B by successful viral suppression. Entecavir and tenofovir are the preferred antiviral agents for treatment of chronic hepatitis B in patients with cirrhosis due to their high antiviral potency and high genetic barrier to resistance. Pegylated interferon-α is another therapeutic option for chronic hepatitis B patients with well-compensated cirrhosis. However, interferon therapy is contraindicated in patients with decompensated cirrhosis, and evidence for reduced HCC is currently insufficient.

Background: To observe the effect of the combined administration of entecavir and adefovir dipivoxil to improve hepatic fibrosis in hepatitis B patients with interferon resistance., Methods: This study comprised 90 hepatitis B patients with hepatic fibrosis and interferon (IFN) resistance who were admitted in the hospital's department of infectious disease for diagnosis and treatment between January 2013 and September 2015. They were randomly divided into two groups in accordance with the random number table: the combination treatment group (N.=45) and the entecavir group (N.=45). They were observed for any variations in the indexes of liver function and fibrosis, as well as the Model for end-stage liver disease (MELD) scores, before and after treatment., Results: After treatment, the levels of the indexes in both groups (the combination treatment group vs. the entecavir group) were as follows: bilirubin (67.5±7.7 vs. 82.4±13.5 μmol/L); International Normalized Ratio (INR) (1.21±0.8 vs. 1.14±0.7); creatinine (147.3±12.4 vs. 287.4±21.6 mg/dL); GGT (67.4±23.2 vs. 88.4±23.7 U/L); and ALT (63.4±40.8 vs. 96.5±23.5 U/L). In comparison of the indexes of hepatic fibrosis between the two groups, we found the following differences: PCIII (67.5±7.7 vs. 82.4±13.5 μg/L); IV-C (61.3±18.7 vs. 74.5±17.9 μg/L); HA (147.3±12.4 vs. 87.4±31.6 μg/L); and LN (88.7±13.2 vs 102.5±23.4 μg/L). The results showed that the differences in comparison of the indexes before and after the treatment were statistically significant (P<0.05). After treatment, the MELD score of patients in the combination treatment group was significantly lower than that in the entecavir group (18.7±3.2 vs. 22.5±3.4), with a statistically significant difference (P<0.05)., Conclusions: In the chronic hepatitis B patients with interferon resistance, the combined administration of entecavir and adefovir dipivoxil can significantly improve liver function, hepatic fibrosis and MELD scores. The results highlight the need to promote the benefits of this drug combination in helping chronic hepatitis B patients with interferon resistance, and to promote its application in clinical practices.

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease and may progress to liver fibrosis, liver cirrhosis, decompensated cirrhosis, and even end-stage liver disease without effective treatment. The diagnosis of PBC is mainly based on the biochemical parameters indicating cholestatic hepatitis and the presence of specific autoantibody in circulation. The goals of the treatment and management of PBC are to prevent the development of end-stage liver disease, to improve related clinical symptoms, and to improve patients' quality of life. Since PBC has relatively strong heterogeneity and the clinical manifestations and course of PBC can be diverse, it is necessary to provide long-term individualized treatment and follow-up for such patients. Here we provide an interpretation of the 2017 EASL Clinical Practice Guidelines for the diagnosis and management of patients with PBC, in order to better understand recent clinical research evidence and updated recommendations. In particular, we focus on the key points in the diagnosis, treatment, and follow-up strategies of PBC and emphasizing that timely and accurate risk stratification and proper clinical research enrollment may bring benefits to patients with refractory PBC.

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 (CCl 4 )-induced hepatotoxicity. For acute model, rats were orally treated with GA and DGA for 7 d prior to CCl 4 by intraperitoneally (i.p.) injection. For the chronic model, rats were orally treated with GA or DGA and CCl 4 i.p. twice a week for four weeks. In both acute and chronic models, the CCl 4 -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.

The goal in patients with immune active hepatitis B virus (HBV) infection is to significantly suppress viral replication and prevent progression of fibrosis to cirrhosis and liver decompensation and decrease the incidence of hepatocellular carcinoma. This is achievable by the highly active antivirals, entecavir and tenofovir, which are considered first-line therapy in most patients with immune active hepatitis C virus and after liver transplantation to prevent HBV recurrence. Patients with decompensated cirrhosis should be referred for liver transplantation and treated with first-line antivirals as early as possible, with the goal of achieving complete viral suppression in the shortest time possible., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Chronic liver disease and cirrhosis are a leading cause of morbidity and mortality in the United States. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis and which has been designated an orphan condition, is a chronic autoimmune disease resulting in the destruction of the small bile ducts in the liver. Without effective treatment, disease progression frequently leads to liver failure and death. Until May 2016, the only FDA-approved treatment for PBC was ursodiol (UDCA), an oral hydrophilic bile acid, which can slow progression of liver damage due to PBC. However, 1 out of 3 patients taking UDCA has an inadequate biochemical response, leading to increased risk of disease progression, liver transplantation, and mortality. Given this unmet clinical need, new therapies are in development for the treatment of PBC. To provide pharmacists with an overview of the latest research on the pathophysiology of PBC and potential new treatment options and to highlight medical and specialty pharmacy approaches to managing access to drugs to treat orphan diseases such as PBC, a 2-hour satellite symposium was presented in conjunction with the 2015 Academy of Managed Care Pharmacy (AMCP) Nexus meeting. Although obeticholic acid was approved by the FDA for the treatment of PBC in May 2016, this development occurred after the symposium presentation. The symposium was supported by an independent educational grant from Intercept Pharmaceuticals and was managed by Analysis Group. Robert Navarro, PharmD, moderated the CPE-accredited symposium titled "Medical and Specialty Pharmacy Management Update on Primary Biliary Cirrhosis." Expert panelists included Christopher L. Bowlus, MD; James T. Kenney, RPh, MBA; and Gary Rice, RPh, MS, MBA, CSP., Objective: To summarize the educational satellite symposium presentations and discussions., Summary: Autoimmune liver diseases, including PBC, are responsible for 15% of all liver transplants performed and an equal percentage of deaths related to liver disease. UDCA is the only FDA-approved therapy for treatment of PBC and is considered the standard of care. Nevertheless, many patients do not respond to UDCA, creating the need for new therapeutic options to improve clinical outcomes for PBC patients with inadequate response to treatment. While several agents are being studied in combination with UDCA, monotherapy with the novel agent obeticholic acid, a farnesoid X receptor agonist, has also shown promising results. Health plans are anticipated to assign any newly introduced therapy for the treatment of PBC to specialty pharmacy given its orphan disease status. This assignment enables the health plan to receive disease education, which is particularly important when new drugs are indicated for orphan diseases, and assistance with designing appropriate prior authorization criteria. The clinical value of any new therapeutic options that will inform formulary decisions and prior authorization criteria will be assessed based on evidence of efficacy, safety, and tolerability, among other factors, such as the potential to reduce or delay medical resource utilization (e.g., liver transplant). Key considerations for prior authorization of a new therapy will be determining which PBC patients are appropriate candidates for the new therapy and developing criteria for that determination. These are likely to include clinical diagnostic criteria and degree of response to prior treatment with UDCA. Initially, any new therapy would likely be positioned as noncovered until appropriate prior authorization criteria are established., Conclusions: PBC is a chronic liver disease with significant morbidity and mortality, as well as a significant burden on the health care system if the disease progresses to the point at which a liver transplant is needed. Although UDCA, the current standard of care, has improved outcomes for many patients, others have an inadequate response to this treatment. This symposium discussed these issues and also addressed the overall treatment paradigm for orphan drug therapies, key implications for patient management, and the role of specialty pharmacy management and any associated needs both in general and specifically for new therapeutic options for PBC.

Primary biliary cholangitis (PBC; previously "primary biliary cirrhosis") is a cholestatic, putatively autoimmune-mediated liver disease with a clear female preponderance affecting the intrahepatic small and medium-size bile ducts and resulting in bile duct destruction, ductopenia and portal fibrosis that progresses slowly to biliary cirrhosis. Despite suboptimal response in one third of patients treated with ursodeoxycholic acid (UDCA), this remains the only FDA-approved agent for this disease. In this review, we cover recent advances in research that have yielded numerous agents currently at different stages of the drug pipeline, some of which are expected to be approved in the near future. We also discuss accumulating evidence supporting the use of older agents (fibrates and glucocorticoids) as an adjunctive therapy to UDCA in non-responsive patients. We suggest that with the imminent expansion of the therapeutic armamentarium for PBC, a more comprehensive approach - ideally taking into account not only biochemical markers of disease stage - is needed to better select patients in whom these strategies might be most useful. Studies are also needed to compare the relative efficacy of different proposed second-line treatments not only against UDCA monotherapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease. Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo., Areas Covered: This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database., Expert Opinion: If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.

Objectives: Organs for transplantation are scarce, but new medical therapies can prevent organ failure and the need for transplants. We sought to describe the unique value created by treatments that spare organs from failure and thus conserve donated organs for transplant into others, using hepatitis C virus (HCV) as a case study., Study Design: Epidemiologic-economic model., Methods: Using data on trends in chronic liver disease, liver disease progression, and liver transplant allocation models, as well as the effectiveness of new HCV treatments, we estimate the potential effects of systematic HCV screening and treatment on the demand for liver transplants in the United States. We estimate the spillover benefits to patients with all-cause liver disease in terms of increased availability of transplants and life-years gained., Results: We estimated that systematic HCV screening and treatment could spare 10,490 liver transplants to HCV-infected patients from 2015 to 2035. An estimated 7321 transplants would accrue to patients with end-stage liver disease without HCV and 3169 transplants to those with uncured HCV, providing approximately 52,700 and 22,800 additional life-years, respectively., Conclusions: Treatment advances for HCV have the potential to generate considerable spillover benefits to patients awaiting transplants for non-HCV-mediated liver failure. For other diseases in which organ transplants are in short supply, our study provides a novel pathway by which positive spillovers may accrue from treatments that prevent end-stage organ disease.

Primary biliary cirrhosis (PBC) is characterized by progressive nonsuppurative destruction of small bile ducts, resulting in intrahepatic cholestasis, fibrosis and ultimately end-stage liver disease. Timely intervention with ursodeoxycholic acid is associated with excellent survival, although approximately one-third of all patients fail to achieve biochemical response, signifying a critical need for additional therapeutic strategies. Obeticholic acid (OCA) is a potent ligand of the nuclear hormone receptor farnesoid X receptor (FXR). Activation of FXR inhibits bile acid synthesis and protects against toxic accumulation in models of cholestasis and facilitates hepatic regeneration in preclinical studies. Data from recent Phase II and III controlled trials suggest a therapeutic impact of OCA in PBC biochemical nonresponders, as evidenced by change in proven laboratory surrogates of long-term outcome. Dose-dependent pruritus is a common adverse effect, but may be overcome through dose-titration. Longer term studies are needed with focus on safety and long-term clinical efficacy.

The Share 35 policy for organ allocation, which was adopted in June 2013, allocates livers regionally for candidates with Model for End-Stage Liver Disease scores of 35 or greater. The authors analyzed the costs resulting from the increased movement of allografts related to this new policy. Using a sample of nine organ procurement organizations, representing 17% of the US population and 19% of the deceased donors in 2013, data were obtained on import and export costs before Share 35 implementation (June 15, 2012, to June 14, 2013) and after Share 35 implementation (June 15, 2013, to June 14, 2014). Results showed that liver import rates increased 42%, with an increased cost of 51%, while export rates increased 112%, with an increased cost of 127%. When the costs of importing and exporting allografts were combined, the total change in costs for all nine organ procurement organizations was $11 011 321 after Share 35 implementation. Extrapolating these costs nationally resulted in an increased yearly cost of $68 820 756 by population or $55 056 605 by number of organ donors. Any alternative allocation proposal needs to account for the financial implications to the transplant infrastructure., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose of Review: The aim of this review was to define the implication of hepatitis C virus (HCV) eradication in patients with cirrhosis., Recent Findings: Sustained virologic response (SVR) is associated with a favourable outcome in patients with cirrhosis especially in the presence of regression of cirrhosis but also with extrahepatic outcomes regarding health-related quality of life, risk of diabetes, risk of cardiovascular diseases and control of HIV replication by antiretroviral therapy. In patients with decompensated cirrhosis identifying the point of no return where viral eradication is not followed by clinical improvement is extremely relevant. A strict follow-up is needed in order to early diagnose HCC and signs of liver dysfunction, even after SVR, not only in patients with histological diagnosis of cirrhosis but also in those with advanced disease identified by liver stiffness measurements or by noninvasive methods., Summary: Eradication of HCV is associated with regression or 'freezing' of cirrhosis even if it is still unknown the point of no return where this has no benefit for the patient. Nevertheless, in patients with cirrhosis, follow-up should be pursued after eradication of HCV. In addition, HCV eradication has several extrahepatic benefits.

Unlabelled: A national viral hepatitis therapy program was launched in Taiwan in October 2003. This study aimed to assess the impact of the program on reduction of end-stage liver disease (ESLD) burden. Profiles of national registries of households, cancers, and death certificates were used to derive incidence and mortality of ESLDs from 2000 to 2011. Age-gender-adjusted incidence and mortality rates of hepatocellular carcinoma (HCC) and chronic liver diseases (CLDs) and cirrhosis of adults ages 30-69 years were compared before and after launching the program using Poisson's regression models. A total of 157,570 and 61,823 patients (15%-25% of those eligible for reimbursed treatment) received therapy for chronic hepatitis B and C, respectively, by 2011. There were 42,526 CLDs and cirrhosis deaths, 47,392 HCC deaths, and 74,832 incident HCC cases occurred in 140,814,448 person-years from 2000 to 2011. Male gender and elder age were associated with a significantly increased risk of CLDs and cirrhosis and HCC. Mortality and incidence rates of ESLDs decreased continuously from 2000 to 2003 (before therapy program) through 2004-2007 to 2008-2011 in all age and gender groups. The age-gender-adjusted rate ratio (95% confidence interval; P value) in 2008-2011 was 0.78 (0.76-0.80; P < 0.001) for CLDs and cirrhosis mortality, 0.76 (0.75-0.78; P < 0.005) for HCC mortality, and 0.86 (0.85-0.88; P < 0.005) for HCC incidence using 2000-2003 as the reference period (rate ratio = 1.0)., Conclusions: The national viral hepatitis therapy program has significantly reduced the mortality of CLDs and cirrhosis and incidence and mortality of HCC., (© 2014 by the American Association for the Study of Liver Diseases.)

Introduction: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive., Areas Covered: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids., Expert Opinion: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.

Pyrrole-imidazole (PI) polyamide is a novel gene regulating agent that competitively inhibits transcription factor binding to the promoter of the specific target gene. Liver fibrosis is an integral stage in the development of chronic liver disease, and transforming growth factor β (TGFβ) is known to play a central role in the progression of this entity. The aim of this study was to evaluate the effect of PI polyamide targeting TGFβ1 on rat liver fibrosis. PI polyamide was designed to inhibit activator protein 1 (AP-1) transcription factor binding to the TGFβ1 gene promoter. The effect of PI polyamide on hepatic stellate cells was evaluated by real time polymerase chain reaction (PCR) in RI-T cells. To determine the effect of PI polyamide in vivo, PI polyamide was intravenously administered at a dose of 3 mg/kg/week in dimethylnitrosamine (DMN)-induced rat model of liver fibrosis. Treatment of RI-T cells with 1.0 µM PI polyamide targeting TGFβ1 significantly inhibited TGFβ1 mRNA expression. Azan staining showed that DMN treatment significantly increased areas of fibrous materials compared with controls. PI polyamide targeting TGFβ1 significantly decreased the fibrous area compared with DMN group. mRNA expression levels of α-smooth muscle actin and matrix metalloproteinase-2 were significantly increased in DMN-treated group compared with control. Treatment with TGFβ1 PI polyamide significantly decreased mRNA expression of these genes compared with DMN group. The novel gene regulator PI polyamide targeting TGFβ1 may be a feasible therapeutic agent for the treatment of chronic liver disease.

Background & Aims: Hepatitis C (HCV) related disease in England is predicted to rise, and it is unclear whether treatment at current levels will be able to avert this. The aim of this study was to estimate the number of people with chronic HCV infection in England that are treated and assess the impact and costs of increasing treatment uptake., Methods: Numbers treated were estimated using national data sources for pegylated interferon supplied, dispensed, or purchased from 2006 to 2011. A back-calculation approach was used to project disease burden over the next 30 years and determine outcomes under various scenarios of treatment uptake., Results: 5000 patients were estimated to have been treated in 2011 and 28,000 in total from 2006 to 2011; approximately 3.1% and 17% respectively of estimated chronic infections. Without treatment, incident cases of decompensated cirrhosis and hepatocellular carcinoma were predicted to increase until 2035 and reach 2290 cases per year. Treatment at current levels should reduce incidence by 600 cases per year, with a peak around 2030. Large increases in treatment are needed to halt the rise; and with more effective treatment the best case scenario predicts incidence of around 500 cases in 2030, although treatment uptake must still be increased considerably to achieve this., Conclusions: If the infected population is left untreated, the number of patients with severe HCV-related disease will continue to increase and represent a substantial future burden on healthcare resources. This can be mitigated by increasing treatment uptake, which will have the greatest impact if implemented quickly., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Patients with cirrhosis who experience hepatic decompensation, such as the development of ascites, SBP, variceal hemorrhage, or hepatic encephalopathy, or who develop HCC, are at a higher risk of mortality. Management should be focused on the prevention of recurrence of complications, and these patients should be referred for consideration of liver transplantation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Aims: Chronic liver disease affects 855 people per million in the UK. Previous studies have reported that coffee appears protective against the development of abnormal liver enzymes, hepatic fibrosis and cirrhosis. The aim of this study, the first in a Scottish population, was to compare coffee consumption in patients with liver disease and that of control populations to determine correlations between coffee intake and the incidence of non-cancerous liver disease and with Child's-Pugh and model for end-stage liver disease (MELD) scores., Methods and Results: Two hundred and eighty-six patients attending the liver outpatient department at the Royal Infirmary of Edinburgh completed a questionnaire regarding coffee consumption and lifestyle factors. Control questionnaires were also completed by 100 orthopaedic outpatients and 120 medical students. Patients with cirrhosis (n = 95) drank significantly less coffee than those without cirrhosis (p = <0.001). There was no correlation between Child's-Pugh (-0.018) and MELD scores (-0.132) with coffee consumption., Conclusion: Coffee drinking is associated with a reduced prevalence of cirrhosis in patients with chronic liver disease. However, there was no significant difference in the amount of coffee drunk by liver patients and the control groups. It is possible that by changing the amount of coffee drunk, the development of cirrhosis in liver disease could be postponed.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the pediatric population. Increased recognition of this form of liver disease parallels the dramatic rise in childhood and adolescent obesity over the past 2 decades. Like adults, most children with NAFLD are obese, and comorbidities include insulin resistance, hypertension, and dyslipidemia. Unfortunately, pediatric NAFLD is not always a benign condition, with some children progressing to hepatic fibrosis and even cirrhosis in severe cases. The etiology of nonalcoholic steatohepatitis is not yet fully understood; however, hepatic steatosis in the context of insulin resistance and increased oxidative stress may lead to progressive disease. Although physical examination, laboratory evaluation, and radiographic findings provide clues to the potential presence of fatty liver disease, liver biopsy remains the gold standard for diagnosis. Lifestyle modification, including slow and steady weight loss, improved dietary habits, and increased daily, aerobic physical activity, remains the first-line approach in treating pediatric fatty liver disease. Antioxidant pharmacologic therapy such as use of vitamin E has shown some benefit in patients with biopsy-proven steatohepatitis. Nutrition plays an essential role not only in the development of fatty liver disease but also potentially in the treatment and prevention of progression to more severe disease.

The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP) and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg α-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1-96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. α-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans.

Minimal encephalopathy was originally associated with chronic liver disease but is increasingly associated with most other chronic diseases and particularly with diabetes and also chronic disorders in other organs: kidneys, lungs, thyroid and with obesity. It is increasingly with dramatically increased and more or less permanent increase in systemic inflammation, most likely a result of Western lifestyle. Frequent physical exercise and intake of foods rich in vitamins, antioxidants, fibres, lactic acid bacteria etc in combination with reduction in intake of refined and processed foods is known to reduce systemic inflammation and prevent chronic diseases. Some lactic acid bacteria, especially Lb paracasei, lb plantarum and pediococcus pentosaceus have proven effective to reduce inflammation and eliminate encephalopathy. Significant reduction in blood ammonia levels and endotoxin levels were reported in parallel to improvement of liver disease. Subsequent studies with other lactic acid bacteria seem to demonstrate suppression of inflammation and one study also provides evidence of clinical improvement.

Liver transplantation has evolved over the past four decades into the most effective method to treat end-stage liver failure and one of the most expensive medical technologies available. Accurate understanding of the financial implication of recipient severity of illness is crucial to assessing the economic impact of allocation policies. A novel database of linked clinical data from the Organ Procurement and Transplantation Network with cost accounting data from the University HealthSystem Consortium was used to analyze liver transplant costs for 15,813 liver transplants. This data was then utilized to consider the economic impact of alternative allocation systems designed to increase sharing of liver allografts using simulation results. Transplant costs were strongly associated with recipient severity of illness as assessed by the MELD score (p < 0.0001); however, this relationship was not linear. Simulation analysis of the reallocation of livers from low MELD patients to high MELD using a two-tiered regional sharing approach (MELD 15/25) resulted in 88 fewer deaths annually at estimated cost of $17,056 per quality-adjusted life-year saved. The results suggest that broader sharing of liver allografts offers a cost-effective strategy to reduce the mortality from end stage liver disease., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Individuals infected with hepatitis C virus (HCV) need to be diagnosed well before developing end-stage liver disease to benefit from treatment. We aimed to ascertain what proportion of cases had been tested for HCV to inform on the effectiveness of current guidelines. Record linkage between national databases of HCV tests, hospital discharges and deaths identified 10,645 persons who were hospitalized or had died with mention of end-stage liver disease in Glasgow, Scotland, between 1993 and 2007. We estimated HCV test uptake and prevalence of HCV infection within the study population. The associations between both HCV test uptake and HCV-antibody status and sex, age group and deprivation quintile were estimated using logistic regression. We found that 43% of those hospitalized (n = 9153) and 23% of those who otherwise died (n = 1492) with first-time mention of end-stage liver disease had been tested for HCV during this period. Test uptake in those hospitalized increased from 13 (95% CI: 12-14%) in 1993-1997 to 58% (56-59%) in 2003-2007. The adjusted odds of being tested for HCV were significantly higher for men (OR=1.3, 95% CI: 1.2-1.5), for ages 25-54 (25-34 years: 2.7, 95% CI: 2.1-3.4; 35-44 years: 2.3, 95% CI: 2.0-2.6; 45-54 years: 1.5, 95% CI: 1.4-1.7) compared with 55+ years, and for those residing in the two most deprived quintiles (1.1, 95% CI: 1.0-1.2). Twenty-eight per cent of the HCV testees aged 25-44 years were HCV infected. These results highlight the continuing need for raising awareness among medical professionals for comprehensive HCV testing in patients with liver disease., (© 2010 Blackwell Publishing Ltd.)

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.

Unlabelled: The number of patients admitted to toxicological units due to acute liver failure (ALF) and acute-on-chronic liver failure (AoChLF) has been increasing in recent years. Various methods of extracorporeal liver support have been described in this paper, with particular emphasis on modified single pass albumin dialysis (SPAD)., Conclusions: 1. Single pass albumin dialysis (SPAD) is a promising method of extracorporeal liver support. 2. Due to widespread availability of continuous renal replacement therapy equipment it can be performed in most units providing intensive care. 3. No additional costs due to purchase of equipment or training of personnel are necessary to perform SPAD. 4. Further studies are necessary to establish optimal concentration of human albumin in dialysate and flow rates of blood and dialysate during the procedure. 5. Development of biocompatible replacement of human albumin would promote more frequent use of SPAD.