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Aims/Hypothesis: Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. Methods: We performed a twostep (1.5 and 6 pmol min −1 kg −1 ) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2 H 2 ]glucose and [ 2 H 5 ] glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. Results: In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48±12 vs 63±13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. Conclusions/interpretation: Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.

Treatment with peginterferon-alpha2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks.

SUMMARY A new antigen-antibody system associated with the hepatitis B virus and immunologically distinct from the HB surface, core, and e systems is reported. The new antigen, termed 3, was detected by direct immunofluorescence only in the liver cell nuclei of patients with HBsAg positive chronic liver disease. At present, the intrahepatic expression of HBcAg and 6 antigen appears to be mutually exclusive. No ultrastructural aspect corresponding to the antigen could be identified under the electron microscope. 8 antibody was found in the serum of chronic HBsAg carriers, with a higher prevalence in patients with liver damage. The nuclear fluorescence patterns of HBcAg and antigen were similar; it is only possible to discriminate between the two antigens by using the respective specific antisera.While studying liver biopsies from patients who were seropositive for the hepatitis B surface antigen (HBsAg) in direct immunofluorescence, it was noted that an antiserum against the hepatitis B core antigen (HBcAg), as well as staining specimens in which core particles could be demonstrated by the electron microscope (EM), also reacted with additional biopsies which did not contain core particles (at electron microscopy) and were negative with other reference antisera against HBcAg.When the EM core positive and core negative specimens were tested with several HBsAg positive sera, it soon became apparent that some sera reacted with either one or the other liver substrate; this suggested that there were two distinct nuclear antigenic specificities.The identification of this new antigen and of its antibody as an immunological system independent of other known reactions associated with the HB virus is reported in this communication. Provisionally, we propose that it should be called 6.

The hepatitis B virus-associated , antigen was found in the serum of experimentally infected chimpanzees as an internal component of a discrete subpopulation of hepatitis B surface antigen (HBsAg) particles. The 35-to 37-nm particles banded in CsCl at 1.24-1.25 g/cm3 and sedimented with a mobility intermediate between that of the hepatitis B virion and that of the 22-nm form of HBsAg. The particles contained only indistinct internal structure by electron microscopy and were not unique to 5 agent infection, similar particles without 5-antigen activity being observed in the preinfection serum of HBsAg carrier chimpanzees. A small RNA (Mr, 5 X 105) was temporally associated with 5 antigen in the serum of infected chimpanzees and copurified with the -antigen-associated particles. This RNA is smaller than the genomes of known RNA viruses but larger than the viroids of higher plants. The 3 antigen (6-Ag), a relatively new specificity, first was detected by immunofluorescence in the liver of human subjects with chronic hepatitis B surface antigen (HBsAg) hepatitis (1). Ultrastructural studies have failed to demonstrate components of hepatitis B virus (HBV) in b-Ag-positive nuclei (2) and the b-Ag-anti-b-Ag system is distinct from the known antigenantibody systems of HBV (3). Prevalence studies of b-Ag-anti-3-Ag in human populations (4,5) and transmission experiments in chimpanzees (6) indicate that b-Ag is associated with a transmissible pathogenic agent, 3 agent, that is either a HBV mutant with characteristics of a defective interfering particle or a new agent which requires helper functions of HBV for its expression.After extraction from hepatocyte nuclei with guanidine hydrochloride, b-Ag was characterized as a protein with a molecular weight of approximately 68,000 (2). Although b-Ag has not been detected in the sera of patients with intrahepatic b-Ag, such individuals develop high titers of anti-3-Ag which might interfere with the available solid-phase radioimmunoassay for b-Ag. The analysis of serial specimens from chimpanzees to which 3-agent was transmitted revealed 6-Ag in the sera during the acute phase of infection and prior to the development of anti-3-Ag (6). We report here the association of 3-Ag in serum with a discrete subpopulation of HBsAg and a low molecular weight RNA. MATERIALS AND METHODSSource of 5Ag. Two chronic HBsAg-carrier chimpanzees (nos. 29 and 800) were infected with 3 agent by inoculation with serum from a patient with chronic type B hepatitis and intrahepatic b-Ag. Serum samples and percutaneous liver biopsies were taken from each animal before inoculation and weekly thereafter and analyzed for markers of b-Ag and HBV. TheseThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 6124 chimpanzees were part of a transmission study of the 3 agent and experimental details are reported elsewhere (6). Serum samples containing b-Ag...