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Concept: Cirrhosis

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& Aims: Little is known about whether the antiviral agent entecavir is more effective than a less potent drug, lamivudine, in reducing the risk of death and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).

Concepts: Cirrhosis, Hepatitis, Hepatocellular carcinoma, Antiviral drug, Hepatitis C, Hepatitis B, Hepatitis A, Hepatitis D

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The liver is the first line of defence against continuously occurring influx of microbial-derived products and bacteria from the gut. Intestinal bacteria have been implicated in the pathogenesis of alcoholic liver cirrhosis. Escape of intestinal bacteria into the ascites is involved in the pathogenesis of spontaneous bacterial peritonitis, which is a common complication of liver cirrhosis. The association between faecal bacterial populations and alcoholic liver cirrhosis has not been resolved.

Concepts: Cirrhosis, Liver, Ascites, Gastroenterology, Hepatic portal vein, Hepatic encephalopathy, Spontaneous bacterial peritonitis, Alcoholic liver disease

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Specialist physician concentration in urban areas can affect access and quality of care for rural patients. As effective drug treatment for hepatitis C (HCV) becomes increasingly available, the extent to which rural patients needing HCV specialists face access or quality deficits is unknown. We sought to determine the influence of rural residency on access to HCV specialists and quality of liver care.

Concepts: Medicine, Cirrhosis, City, Physician, Illness, Hepatitis C, Hepatitis A, Internal medicine

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Nanoparticle drug delivery systems using polymers hold promise for clinical applications. We synthesized dual-ligand modified chitosan (GCGA) nanoparticles using lactic acid, glycyrrhetinic acid, and chitosan to target the liver in our previous studies. We then synthesized the GCGA/5-FU nanoparticles by conjugating 5-fluorouracil (5-FU) onto the GCGA nanomaterial, which had a mean particle size of 239.9 nm, a polydispersity index of 0.040, a zeta potential of +21.2 mV, and a drug loading of 3.90%. GCGA/5-FU nanoparticles had good slow release properties, and the release process could be divided into five phases: small burst release, gentle release, second burst release, steady release, and slow release. Inhibitory effects of GCGA/5-FU on tumor cells targeted the liver, and were time and dose dependent. GCGA nanoparticles significantly prolonged the efficacy of 5-FU on tumor cells, and alleviated the resistance of tumor cells to 5-FU. GCGA/5-FU nanoparticles were mostly concentrated in the liver, indicating that the GCGA nanoparticles were liver targeting. GCGA/5-FU nanoparticles significantly suppressed tumor growth in orthotopic liver transplantation mouse model, and improved mouse survival.

Concepts: Cirrhosis, Liver, Polymer, In vivo, Nanotechnology, Sol-gel, Colloid, In vitro

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Hepatitis C virus (HCV) infection exacerbates alcoholic liver injury by mechanisms that include enhanced oxidative stress. The forkhead box transcription factor FOXO3 is an important component of the antioxidant stress response that can be altered by HCV. To test whether FOXO3 is protective for alcoholic liver injury, we fed alcohol to FOXO3(-/-) mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity. This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2(+/-)) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol. These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury.

Concepts: DNA, Gene, Gene expression, Transcription, Superoxide dismutase, Cirrhosis, Alanine transaminase, Hepatitis C

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Many liver transplantation (LT) programs require substance abuse (SA) treatment for candidates with a history of alcohol abuse. However, there are no data indicating that SA treatment prevents post-LT alcohol relapse. We examined 118 adults who underwent LT from May 2002 to February 2011 to explore the relationship between SA treatment and post-LT relapse to any alcohol use. Sixty-one patients (52%) with a history of alcohol abuse or dependence received SA treatment before LT. Relapse to any alcohol use was identified in 40 LT recipients (34%). Patients who received SA treatment before LT did not differ significantly in the rate of post-LT alcohol relapse from patients who did not receive treatment before transplantation (30% versus 39%, P = 0.20). However, patients who received SA treatment both before and after transplantation had significantly lower rates of alcohol relapse (16%) than patients who received no SA treatment (41%) or SA treatment only before LT (45%, P = 0.03). Our findings suggest that LT programs should consider placing more emphasis on the continuation of some type of SA treatment after transplantation. Future research should prospectively examine the optimal timing for SA treatment that will attenuate the risk of alcohol relapse after transplantation. Liver Transpl 000:000-000, 2013. © 2013 AASLD.

Concepts: Cirrhosis, Alcoholism, Drug addiction, Addiction

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Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix components, ultimately leading to fibrosis and liver failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33’s profibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.

Concepts: DNA, Medicine, Gene expression, Asthma, Cirrhosis, Liver, Organ, Hepatic encephalopathy

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There is a high prevalence of metabolic syndrome in liver transplant recipients, a population that tends to be physically inactive. The aim of this study was to characterize physical activity and evaluate the relationship between physical activity and metabolic syndrome after liver transplantation. A cross-sectional analysis was performed in patients more than 3 months after transplantation. Metabolic syndrome was classified according to National Cholesterol Education Panel Adult Treatment Panel III guidelines. Physical activity, including duration, frequency, and metabolic equivalents of task (METs), was assessed. The study population consisted of 204 subjects, with 156 more than 1 year after transplantation. The median time after transplantation was 53.5 months (range = 3-299 months). The mean duration of exercise was 90 ± 142 minutes, and the mean MET score was 3.6 ± 1.5. Metabolic syndrome was observed in 58.8% of all subjects and in 63.5% of the subjects more than 1 year after transplantation. In a multivariate analysis involving all subjects, metabolic syndrome was associated with a time after transplantation greater than 1 year [odds ratio (OR) = 2.909, 95% confidence interval (CI) = 1.389-6.092] and older age (OR = 1.036, 95% CI = 1.001-1.072). A second analysis was performed for only patients more than 1 year after transplantation. In a multivariate analysis, metabolic syndrome was associated with lower exercise intensity (OR = 0.690, 95% CI = 0.536-0.887), older age (OR = 1.056, 95% CI = 1.014-1.101), and pretransplant diabetes (OR = 4.246, 95% CI = 1.300-13.864). In conclusion, metabolic syndrome is common after liver transplantation, and the rate is significantly higher in patients more than 1 year after transplantation. The observation that exercise intensity is inversely related to metabolic syndrome after transplantation is novel and suggests that physical activity might provide a means for reducing metabolic syndrome complications in liver transplant recipients. Liver Transpl, 2013. © 2013 AASLD.

Concepts: Obesity, Median, Cirrhosis, Liver, Organ transplant, Arithmetic mean, Liver transplantation, Metabolic equivalent

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Infection with hepatitis B virus (HBV) may lead to acute or chronic hepatitis. HBV infections were previously much more frequent but there are still 240 million chronic HBV carriers today and ca. 620,000 die per year from the late sequelae liver cirrhosis or hepatocellular carcinoma. Hepatitis B was recognized as a disease in ancient times, but its etiologic agent was only recently identified. The first clue in unraveling this mystery was the discovery of an enigmatic serum protein named Australia antigen 50 years ago by Baruch Blumberg. Some years later this was recognized to be the HBV surface antigen (HBsAg). Detection of HBsAg allowed for the first time screening of inapparently infected blood donors for a dangerous pathogen. The need to diagnose clinically silent HBV infections was a strong driving force in the development of modern virus diagnostics. HBsAg was the first infection marker to be assayed with a highly sensitive radio immune assay. HBV itself was among the first viruses to be detected by assay of its DNA genome and IgM antibodies against the HBV core antigen were the first to be selectively detected by the anti-mu capture assay. The cloning and sequencing of the HBV genome in 1978 paved the way to understand the viral life cycle, and allowed development of efficient vaccines and drugs. Today’s hepatitis B vaccine was the first vaccine produced by gene technology. Among the problems that still remain today are the inability to achieve a complete cure of chronic HBV infections, the recognition of occult HBV infections, their potential reactivation and the incomplete protection against escape mutants and heterologous HBV genotypes by HBV vaccines.

Concepts: Immune system, Virus, Cirrhosis, Hepatitis, Hepatitis C, Hepatitis B, Hepatitis B virus, Hepatitis B vaccine

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The transforming growth factor-beta (TGF-β) is an important regulatory suppressor factor in hepatocytes. However, liver tumor cells develop mechanisms to overcome its suppressor effects and respond to this cytokine inducing other processes, such as epithelial-mesenchymal transition (EMT), which contribute to tumor progression and dissemination. Recent studies have placed chemokines and their receptors at the centre not only of physiological cell migration but also of pathological processes, such as metastasis in cancer. In particular, CXCR4 and its ligand, stromal cell-derived factor 1α (SDF-1α)/chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we show that autocrine stimulation of TGF-β in human liver tumor cells correlates with a mesenchymal-like phenotype, resistance to TGF-β-induced suppressor effects and high expression of CXCR4, which is required for TGF-β-induced cell migration. Silencing of the TGF-β Receptor1 (TGFBR1), or its specific inhibition, recovered the epithelial phenotype and attenuated CXCR4 expression, inhibiting cell migratory capacity. In an experimental mice model of hepatocarcinogenesis (diethylnitrosamine-induced), tumors showed increased activation of the TGF-β pathway and enhanced CXCR4 levels. In human hepatocellular carcinoma (HCC) tumors, high levels of CXCR4 always correlated with activation of the TGF-β pathway, a less differentiated phenotype and a cirrhotic background. CXCR4 concentrated at the tumor border and perivascular areas, suggesting its potential involvement in tumor cell dissemination. Conclusion: A cross-talk exists among the TGF-β and CXCR4 pathways in liver tumors, reflecting a novel molecular mechanism that explains the pro-tumorigenic effects of TGF-β and opens new perspectives for tumor therapy. (HEPATOLOGY 2013.).

Concepts: Gene, Cancer, Oncology, Cirrhosis, Anatomical pathology, Benign tumor, Tumor, Neoplasm