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Concept: Cirrhosis

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Early age at infection with Hepatitis B virus (HBV) increases the risk of chronic infection. Moreover, early HBV infection may further independently increase the risk of hepatocellular carcinoma (HCC) beyond its effect on chronicity.

Concepts: Cirrhosis, Hepatitis, Hepatocellular carcinoma, Interferon, Hepatitis C, Hepatitis B, Hepatitis B virus, Hepadnaviridae

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The clinical perspective on hepatic growth is limited. The goal of the present study was to compare hepatic hypertrophy and the kinetic growth rate(KGR) in patients after the ALPPS (Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy) procedure, portal vein embolization (PVE) and living donor liver transplantation.

Concepts: Cirrhosis, Liver, Organ transplant, Hepatic portal vein, Liver transplantation, Liver dialysis, Portal venous system, Hepatic portal system

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We read with great interest the article published by Fagan KJ et al[1] entitled ELF score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. In the article the authors stated that the ELF manufacturer’s cut-off value (≥9.8) reliably identifies individuals with advanced fibrosis within patients with chronic liver diseases and that age and histological activity (HA) may influence its results. However, we think that there are some points to discuss about this study. This article is protected by copyright. All rights reserved.

Concepts: Medicine, Cancer, Medical terms, Cirrhosis, All rights reserved, Copyright, Liver biopsy, Prometheus

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The fixed dose combination of sofosbuvir and ledipasvir (SOF/LDV) has marked a new era for patients with chronic HCV because it is the first drug to be approved by the FDA that does not include peginterferon or ribavirin. The results of three clinical studies show that SOF/LDV has sustained virologic response of approximately 96% when given as once a day pill for 3 months to both treatment naive and treatment-experienced HCV-1 patients with the exception of prior null responder patients with cirrhosis. Moreover, emerging data in special populations (patients with decompensated cirrhosis, with post-transplant recurrence, with prior SOF-based therapy failure, and with HIV co-infection) show a good tolerance and high sustained virological profile. Many other emerging therapies are now available. Actually, the recommendations of the international guidelines are applicable only for selected patients followed-up by dedicated specialists, including hepatologists and infectologists, and are specifically individualized for patients with advanced fibrosis. We will expect that the landscape for management of HCV will include direct-acting antivirals for treatment of patients with different genotypes and low-grade fibrosis in order to interrupt the progression to late stage of disease and the complications of the infection, including renal disease, thyroid dysfunction, and some cancers.

Concepts: Pharmacology, Medicine, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B, Virology

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The gut microbial ecosystem plays an important role in the pathogenesis of liver diseases. However, the association of microbial community structure with the severity of liver dysfunction is not completely understood.

Concepts: Cirrhosis, Liver, Sociology, The Association, Organ transplant, Liver disease, Sunshine pop

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MicroRNAs (miRNAs) are small, non-coding RNAs that regulate various biological processes, including liver fibrosis. Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis. By microarray profiling and real-time PCR, we noted that micorRNA-31 (miR-31) expression in HSC from rat, mouse and human was all significantly increased during HSC activation in culture. Overall miR-31 expression levels were unchanged in the whole liver RNA extracts from fibrotic rat and human samples. Nevertheless, we found miR-31 was particularly upregulated in HSC but not in Hepatocyte during fibrogenesis. Thus, we hypothesized that miR-31 may mediate liver fibrosis. In our study, we found that inhibition of miR-31 expression significantly inhibited HSC activation while overexpression of its expression obviously promoted HSC activation. Moreover, overexpression of miR-31 promoted HSC migration by enhancing MMP-2 expression while inhibition of miR-31 has an opposite effect. And the biological function of miR-31 during HSC activation might be through targeting FIH1, a suppressor of hypoxia-inducible factor (HIF-1), as knockdown of FIH1 by short hairpin RNA (shRNA) could mimic the effects of miR-31. In addition, primary rat hepatic stellate cells were isolated and treated with different cytokines such as TGFβ, VEGF, PDGF-BB and so on, to evaluate upstream regulators of miR-31. We found that only TGFβ, a pivotal regulator in liver fibrosis, remarkably increased miR-31 expression in HSC. And the effects of TGFβ upon HSCs can be partially counteracted by inhibition of miR-31. Additionally, ChIP experiments and Luciferase reporter assay demonstrated that Smad3, a major TGF-β-downstream transcription factor, stimulated the transcription activity of miR-31 by binding directly to the promoter of miR-31. In conclusion, miR-31/FIH1 pathway associates with liver fibrosis, perhaps by participating TGFβ/Smad3 signaling in HSC.

Concepts: DNA, Gene, Gene expression, Transcription, Molecular biology, RNA, Cirrhosis, Hepatic stellate cell

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Background Because male-to-female transplantations are related to exposure to H-Y antigen, sex matching may influence the outcomes after liver transplantation for autoimmune diseases. The purpose of this retrospective study was to evaluate the relevance of male-to-female mismatch in liver transplantation for primary biliary cirrhosis (PBC). Material and Methods This retrospective study was based on the data of 82 female liver transplant recipients with PBC from a single institution. The primary outcome measure was graft survival at 10 years. The negative effects of well-known risk factors for poor outcomes were evaluated separately and compared between the female-to-female and male-to-female transplantations. Results Graft survival was similar after female-to-female and male-to-female transplantations (74.7% versus 73.1% at 10 years, respectively, p=0.676). Regarding the differential impact of other risk factors, prolonged cold ischemia and increased amount of blood transfusions adversely influenced outcomes after male-to-female transplantation (p=0.039 and p=0.039, respectively) but not after female-to-female transplantation (p=0.843 and p=0.110, respectively). Sex mismatched transplantations were associated with lower 10-year graft survival in subgroups of patients with blood transfusions >4 units (61.4% versus 100.0%, p=0.063) and >8 hours of cold ischemia (54.7% versus 75.8%, p=0.418). Conclusions Although male-to-female sex mismatch does not seem to yield a direct negative impact on outcomes following liver transplantation for PBC, it can aggravate the negative effects of prolonged cold ischemia and blood transfusions.

Concepts: Cirrhosis, Liver, Gastroenterology, Hepatology, Organ transplant, Autoimmune disease, Primary biliary cirrhosis, Liver transplantation

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Acute and chronic hepatitis B virus (HBV) infections remain to present a major global health problem. The infection can be associated with acute symptomatic or asymptomatic hepatitis which can cause chronic inflammation of the liver and over years this can lead to cirrhosis and the development of hepatocellular carcinomas. Currently available therapeutics for chronically infected individuals aim at reducing viral replication and to slow down or stop the progression of the disease. Therefore, novel treatment options are needed to efficiently combat and eradicate this disease. Here we provide a state of the art overview of gene therapeutic approaches to inhibit HBV replication. We discuss non-viral and viral approaches which were explored to deliver therapeutic nucleic acids aiming at reducing HBV replication. Types of delivered therapeutic nucleic acids which were studied since many years include antisense oligodeoxynucleotides and antisense RNA, ribozymes and DNAzymes, RNA interference, and external guide sequences. More recently designer nucleases gained increased attention and were exploited to destroy the HBV genome. In addition we mention other strategies to reduce HBV replication based on delivery of DNA encoding dominant negative mutants and DNA vaccination. In combination with available cell culture and animal models for HBV infection, in vitro and in vivo studies can be performed to test efficacy of gene therapeutic approaches. Recent progress but also challenges will be specified and future perspectives will be discussed. This is an exciting time to explore such approaches because recent successes of gene therapeutic strategies in the clinic to treat genetic diseases raise hope to find alternative treatment options for patients chronically infected with HBV.

Concepts: DNA, Genetics, Virus, RNA, Cirrhosis, Hepatitis, Hepatitis C, Hepatitis B

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Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.

Concepts: Insulin, Diabetes mellitus, Obesity, Cirrhosis, Liver, Metabolic syndrome, Non-alcoholic fatty liver disease, Fatty liver