Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC.

Hepatitis C virus (HCV), a major cause of chronic liver disease, is a single-stranded positive sense virus of the family Flaviviridae. HCV cell entry is a multi-step process, involving several viral and cellular factors that trigger virus uptake into the hepatocyte. Tetraspanin CD81, human scavenger receptor SR-BI, and tight junction molecules Claudin-1 and occludin are the main receptors that mediate HCV entry. In addition, the virus may use glycosaminoglycans and/or low density receptors on host cells as initial attachment factors. A unique feature of HCV is the dependence of virus replication and assembly on host cell lipid metabolism. Most notably, during HCV assembly and release from the infected cells, virus particles associate with lipids and very-lowdensity lipoproteins. Thus, infectious virus circulates in patient sera in the form of triglyceride-rich particles. Consequently, lipoproteins and lipoprotein receptors play an essential role in virus uptake and the initiation of infection. This review summarizes the current knowledge about HCV receptors, mechanisms of HCV cell entry and the role of lipoproteins in this process. IntroductionHepatitis C virus (HCV) infection is a major world health problem; it has a prevalence of about 2 %, representing 130-170 million infected people worldwide (Shepard et al., 2005). In most cases (60-85 %), HCV infection progresses to chronic liver disease, which can lead to liver cirrhosis and hepatocarcinoma (Shepard et al., 2005). The current therapy, based on the combination of pegylated interferon with ribavirin, is effective in only 50-80 % of the patients, depending on the virus genotype, and has several serious side effects (Fried et al., 2002; Manns et al., 2001; Keam & Cvetkovic, 2008;Pawlotsky, 2006). A better understanding of the mechanisms leading to the initiation of infection is essential for the development of new therapeutic approaches targeting the early stage of the HCV replication cycle.HCV is a small, enveloped virus belonging to the family Flaviviridae (genus Hepacivirus). HCV has a singlestranded positive sense RNA genome of about 9.6 kb, encoding a polyprotein of about 3000 amino acids (aa), which is cleaved into structural (core, E1 and E2) and nonstructural (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins by host and viral proteases. Structural proteins form viral particles with the help of p7 and NS2, whereas non-structural proteins NS3 to NS5B are involved in genome replication (reviewed by Bartenschlager et al., 2004;Bartenschlager & Sparacio, 2007;Brass et al., 2006;Penin et al., 2004). The putative infectious virus particle is composed of a nucleocapsid or ribonucleoprotein complex bearing the HCV genome; this inner structure is surrounded by a phospholipid bilayer, into which E1 and E2 envelope glycoproteins are anchored. However, infectious HCV particles become tightly associated with verylow-density lipoproteins (VLDL) during virus assembly and are (co-)secreted with VLDL, although the exact nature of this association remains unclear (Gas...

Recent evidence implicates adaptive immunity as a key player in the mechanisms supporting hepatic inflammation during the progression of nonalcoholic fatty liver disease (NAFLD). In these settings, patients with NAFLD often show an increase in the circulating levels of antibodies against oxidative stress-derived epitopes (OSE). Nonetheless, the actual role of humoral immunity in NAFLD is still unclear. This study investigates the contribution of B-lymphocytes to NAFLD evolution. B-lymphocyte immunostaining of liver biopsies from NAFLD patients showed that B-cells were evident within cell aggregates rich in T-lymphocytes. In these subjects, B/T-lymphocyte infiltration positively correlated with both circulating IgG targeting oxidative stress-derived epitopes (OSE) and interferon-γ (IFN-γ) levels. Furthermore, high prevalence of lymphocyte aggregates identified patients with more severe lobular inflammation and fibrosis. In mouse models of NAFLD, the onset of steatohepatitis was characterized by hepatic B2-lymphocytes maturation to plasma cells and by an elevation in circulating anti-OSE IgG titers. B-cell responses preceded T-cell activation and were accompanied by the up-regulation in the hepatic expression of B-cell Activating Factor (BAFF). Selective B2-cell depletion in mice over-expressing a soluble form of the BAFF/APRIL receptor Transmembrane Activator and Cyclophilin Ligand Interactor (TACI-Ig) prevented plasma cell maturation and Th-1 activation of liver CD4 T-lymphocytes. Furthermore, TACI-Ig mice showed milder steatohepatitis and a decreased progression to fibrosis. Similarly, mice treatment with the BAFF-neutralizing monoclonal antibody Sandy-2 prevented hepatic B2-cell responses and ameliorated steatohepatitis. From these data we conclude that B2-lymphocyte activation is an early event in NAFLD evolution and contributes to the disease progression through the interaction with T-cells. Furthermore, combined clinical and experimental data suggest that elevated circulating anti-OSE IgG can identify a subset of NAFLD patients in whom adaptive immunity has a relevant role in the disease evolution toward fibrosis.

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