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Gut 2004;53:587-592. doi: 10.1136/gut.2003.016766 Background and aim: Fatigue is the commonest symptom in primary biliary cirrhosis (PBC), affecting individuals at all stages of disease. The pathogenesis of fatigue in PBC [...]

Chronic hepatitis C virus (HCV) infection is associated with an increase in hepatic steatosis and a decrease in serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL) and apolipoprotein B (apoB), the main protein constituent of LDL and very low-density lipoprotein (VLDL). These changes are more marked in HCV genotype 3 infection, and effective treatment results in their reversal. Low lipid levels in HCV infection correlate not only with steatosis and more advanced liver fibrosis but also with non-response to interferon-based therapy. The clinical relevance of disrupted lipid metabolism reflects the fact that lipids play a crucial role in the life cycle of hepatitis C virus. HCV assembly and maturation in hepatocytes depend on microsomal triglyceride transfer protein and apoB in a manner that parallels the formation of VLDL. VLDL production from the liver occurs throughout the day with an estimated 10 particles produced every 24 h whilst the estimated hepatitis C virion production rate is 10 virions per day. HCV particles in the serum exist as a mixture of complete low-density infectious lipo-viral particles (LVP) and a vast excess of apoB-associated empty nucleocapsid-free sub-viral particles that are complexed with anti-HCV envelope antibodies. Apolipoprotein E (apoE) is also involved in HCV particle morphogenesis and is an essential apolipoprotein for HCV infectivity. ApoE is a critical ligand for the receptor-mediated removal of triglyceride rich lipoprotein (TRL) remnants by the liver. The dynamics of apoB-associated lipoproteins, including HCV-LVP, change post-prandially with an increase in large TRL remnants and very low density HCV-LVP which are rapidly cleared by the liver (at least three HCV receptors are cellular receptors for uptake of TRL remnants). In summary, HCV utilises triglyceride-rich lipoprotein pathways within the liver and the circulation to its advantage. [ABSTRACT FROM AUTHOR]

Background: Host genetic factors may significantly influence the ability to clear hepatitis C virus (HCV) following infection. HCV is associated with very low density lipoproteins (VLDL) and low density lipoproteins (LDL) in the host's circulation. Apolipoprotein E (APOE) is found in VLDL and binds to potential receptors involved in HCV entry into cells, the LDL receptor, and the scavenger receptor protein SR-B1. The APOE gene is polymorphic with three alleles coding for three isoforms: Apo-ϵ2, Apo-ϵ3, and Apo-ϵ4. The aim of this study was to assess if these functional polymorphisms determine disease outcome in HCV infected individuals. Methods: The APOE genotype was determined in 420 Northern European patients with evidence of exposure to HCV. Genotype and allele distribution were compared with those of 288 healthy controls and progression of liver disease and viral clearance were analysed according to APOE allele status. Results: The APOE*E2 and APOE*E4 alleles were both associated with a reduced likelihood of chronic infection (odds ratio (OR) 0.39 (95% confidence interval (CI) 0.211–0.728), p = 0.003; and OR 0.6 (95% CI 0.38–0.96), p = 0.032) and there was a notable absence of the E2E2 genotype in the HCV antibody positive group compared with the control population (p = 0.0067). Overall the genotypes carrying the E2 allele (E2,E3 and E2,E4) were associated with the equivalent of a 3–5-fold reduction in the risk of chronic HCV infection (genotype relative risk 0.36 and 0.20, respectively). Conclusion: This study indicates that functional APOE gene polymorphisms may be a determinant of outcome in HCV infection. We hypothesise that the E2 allele may protect against viral persistence via defective binding of HCV lipoviral particles to the cellular receptors involved in entry of these infectious particles. [ABSTRACT FROM AUTHOR]

ABSTRACT- A study has been undertaken to determine the incidence of serum markers of hepatitis B virus (HBV) infection in British caucasian patients with biopsy-proven alcoholic liver disease (n = 56), HBsAg negative chronic active liver disease (CALD) (n = 47) and primary liver cell cancer (PLCC) (n = 27), compared to a hospital control population without liver disease (n = 112). No increased incidence of any serum marker of HBV infection was found in alcoholic liver disease or in 'lupoid' CALD (antinuclear factor positive 1:40 and/or smooth muscle antibody positive > 1:40). In contrast, the incidence of antibody to HB surface and core antigens was significantly increased (p<0.05) in patients with cryptogenic CALD. The incidence of hepatitis B surface antigen and antibodies to HB core and 'e' antigens was significantly increased (p<0.005) in PLCC. [ABSTRACT FROM AUTHOR]

A retrospective review of 110 cases of hepatocellular carcinoma (HCC) from the North East of England was undertaken to examine clinical features and prognosis in the 52 patients 65 years of age or more at presentation in comparison with 58 patients under 65. Symptoms and signs at the time of presentation were similar in the two age groups. Only 25% of patients were known to be cirrhotic at the time of presentation, but this increased to 75% after investigation. Although tumour stage at diagnosis was no worse in the elderly group, these patients received less intensive investigation and were significantly more likely to receive conservative therapy (p = 0.03). Although median survival was significantly worse in those aged > or = 65 years than in those < 65 years (10.5 and 18.5 weeks respectively; p = 0.02) this adverse effect disappeared when adjusted for the effects of treatment. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PUC) is an autoimmune condition characterized by destruction of the intrahepatic bile ducts. Autoreactive CD4+ T cells have been reported both in the peripheral circulation and in the mononuclear cell infiltrate in the affected portal tracts. In this large study we have used two- and three-colour flow cytometry to determine the phenotypes of the CD4+ T cell subsets in the peripheral blood and liver-infiltrating lymphocytes of PBC patients (n = 43), normal controls (n= 19) and patients with alcoholic cirrhosis (n = 15), according to a novel classification based on the simultaneous expression of different isoforms of CD45. In PBC patients the proportion of peripheral blood CD4+ cells possessing the CD45ROhighRA- 'memory' phenotype was significantly increased, and the CD45RO- RAhigh 'naive' population was significantly decreased, compared with the two control groups. No significant differences In peripheral blood CD4+ T cell subsets were seen between patients with pre-cirrhotic and cirrhotic PBC. A similar, but more marked, shift towards the CD45ROhigh'RA- 'memory' phenotype was seen in the liver infiltrating CD4+ T cells in PBC patients compared with alcoholic cirrhotics. Cells within the CD4+ memory subpopulation were further subgrouped according to expression of CD45RB, the level of expression of which has been associated with functional differences in the memory subset. In peripheral blood no differences were seen between PBC patients and controls with respect to the proportion of CD45ROhighRBhigh and CD45RO'high'RBhigh memory subsets. A statistically significant difference in the distribution of these memory subsets, with an increased memory-2/ memory-1 ratio was observed in the liver-infiltrating CD4+ T cells of PBC patients compared with those from alcoholic cirrhotic patients. The potential implications of this observation are discussed. [ABSTRACT FROM AUTHOR]