Incidence of autoimmune thyroiditis in interferon-alpha treated and untreated patients with chronic hepatitis C virus infection.

OBJECTIVES: To clarify the relationship between interferon-alpha (IFN-alpha) therapy and autoimmune thyroiditis in chronic hepatitis C virus (HCV) infection, we investigated a selected number of patients without basal thyroid dysfunctions. MATERIALS AND METHODS: 130 patients (average age: 20-70), with chronic HCV infection and without basal clinical and laboratory signs of autoimmune thyroiditis were divided into two groups: IFN-alpha treated (A) and untreated (B) patients. Group A received IFN-alpha (three million U.I./3 times a week) for six months; group B was followed for the same period. Thyroid peroxidase and thyroglobulin autoantibodies were measured by radioimmunoassay; thyroid function was measured by radioimmunoassay (free thyroxine and triiodothyronine) and immunoradiometric assay (thyroid stimulating hormone). RESULTS: After a 6-month period, thyroid autoantibodies positivity was documented in 21.1% of group A and in 10.3% of group B patients, both statistically relevant (p<0.001 and p<0.011, respectively). The comparison between the two groups was not statistically relevant (p=0.142). CONCLUSIONS: Our study showed a prevalence of de novo thyroid autoimmunity in chronic HCV patients treated with IFN-alpha, confirming previous data in literature. The lack of a significant difference between treated and untreated patients strongly suggests that the anti-thyroid autoimmune response is linked to the HCV infection itself. Moreover, IFN-alpha therapy probably does not represent a risk factor in renewing the autoimmune processes of the thyroid gland. Thyroid function and autoantibodies must be systematically monitored in patients with HCV infection, especially in female and IFN-alpha treated population, not only to verify the possible thyroid abnormalities but also to rule out concomitant autoimmune diseases.

Virus-specific CD8(+) T cells with type 1 or type 2 cytokine profile are related to different disease activity in chronic hepatitis C virus infection.

The present study demonstrates that the quality of the virus-specific CD8(+) T cell responses, as detected by both enzyme-linked immunospot assay and specific MHC-peptide tetramers, changed in relation to the different disease activity in chronically hepatitis C virus-infected patients. Indeed, both the serum alanine transaminase and the hepatic flogosis levels were related directly to the frequencies of peripheral memory effector CD8(+) T cells producing IFN-gamma (Tc1), but inversely to the frequencies of those producing both IL-4 and IL-10 (Tc2). Longitudinal studies highlighted that Tc1 or Tc2 responses fluctuate in relation to the different phases of the disease in the same individual. Furthermore, the Tc1 or Tc2 phenotype correlates with tetramer-positive cells expressing either CXCR3 or CCR3, promoting differential tissue localization of these cells and the maintenance of T cell homeostasis. Finally, studies at the level of liver-infiltrating lymphocytes indicated that they produced both IFN-gamma and IL-4 with an evident bias towards the Tc1-like phenotype. Our studies suggest that the progressive fluctuation of Tc1 and Tc2 responses may play a fundamental role in maintaining a long-lasting low-level liver inflammation, and may constitute the basis for new therapeutic strategies of immune regulation.

Different reactivity against HCV proteins (RIBA 3) according to progression of liver damage.

BACKGROUND: Aim of the study was to assess the correlation between clinical stage of HCV-related liver disease and viraemia to immune response to different viral antigens. METHODS: We considered 1330 patients with HCV chronic infection followed up from 6 months up to 6 years divided into two groups according to RIBA 3 (Abbott) response: Group I, 1231 patients with positivity for at least two bands (83 subjects with asymptomatic infection, 941 with chronic hepatitis, 201 with cirrhosis and 6 with HCC); Group II, 99 patients with positivity at only one band (45 with asymptomatic infection, 53 with chronic hepatitis and 1 cirrhotic). RESULTS: We noticed a major percentage of positive patients for at least three bands in more severe clinical forms (90% of chronic hepatitis or cirrhosis versus 60% of asymptomatics, p < 0.005, chi 2 test). Moreover we noticed a percentage increase of positivity for antibodies anti-c100 and anti-NS5 with the progression of liver damage, statistically significant differences between asymptomatics and patients with chronic forms. We also observed that viraemia is related neither to clinical stage nor to different reactivity to RIBA 3, albeit viraemia is usually detected more frequently among patients with liver damage, but unrelated to different reactivities. CONCLUSIONS: Our results show a clear correlation between number of reactivities towards HCV proteins and progression of liver damage, pointing out that immune response plays a direct role in the long-term outcome of HCV infection.

IgM anti-hepatitis C virus in patients with chronic non-A, non-B hepatitis and their relationship to viral replication.

Patients with hepatitis C virus (HCV) infection may have different patterns of antibody response to various structural and non-structural viral antigens. We have correlated the serological patterns to the clinical features of chronic infection and to viral replication in 68 HCV-Ab-positive patients with chronic liver disease at different stages (19 with cirrhosis-hepatocellular carcinoma, 38 with chronic active hepatitis and 11 with chronic persistent hepatitis). Serum samples from each patient were assayed for HCV-IgM by enzyme immunoassay and for HCV-RNA by the polymerase chain reaction using primer sets derived from the 5'-non-coding region. The prevalence of HCV-IgM was high (54 patients (79.4%)) and the study showed a good correlation between high values of anti-HCV-IgM and the presence of HCV-RNA in serum, since HCV-RNA was detected in 35 of the 54 IgM-positive patients (64.8%) and notably in 19 of the 20 subjects with high levels of specific IgM. Conversely, all the 35 sera containing HCV-RNA were also reactive for HCV-IgM, while none of the HCV-IgM-negative sera was HCV-RNA reactive. Positivity rates for both HCV-RNA and IgM anti-HCV were higher in the more advanced stages of disease; thus, the clinical pattern of HCV chronic hepatitis seems to be strictly related to the serological pattern and the presence of HCV-RNA.

Prevalence of anti-HCV in two Tanzanian villages.

The presence of anti-HCV antibodies was investigated in sera from a total of 123 inhabitants of two Tanzanian villages. In one of the villages, 72.2% of the sera and in the other village, 82.6% of the sera were found to be anti-HCV positive. These values are dramatically higher than other reported prevalences, whereby cross-reactivity between HCV and Flaviviruses as well as possible transmission by arthropod vectors cannot be ruled out.

HBV infection in Italian family groups.

Intrafamilial spread of HBV infection was evaluated in 85 Italian family groups. Secondary infected cases were observed in 43% of these families, of which 73% showed clusters of HBs positive members, with a prevalence among the family members (children-siblings) of the mother/wife index cases, and no strict relation to their "e" system. The presence of the delta agent in the index case was correlated to a higher percentage of secondary HBs-positive cases, but the intrafamilial spread of delta agent was a rare event. A similar higher incidence of HBV markers was observed among the relatives of the index cases positive for auto-antibodies. The evidence presented suggests the importance of genetic factors in the acquisition and clearance of HBV and delta infections.

Non-A, non-B hepatitis: positive and negative considerations on 138 cases.

In 138 patients with NANB H no correlations were observed regarding types of exposure (PTH: 19.5%, DA: 18.1%, Sporadic cases: 62.4%), age groups and periods of incubation. Precipitin lines were detected assaying by ID and/or CEP onset and recovery sera with heterologous reference sera positive for Ab or Ag, respectively, or with autologous sera; "Ag"' was present during acute phase of illness, "Ab" appeared with decrease of aminotransferases, and in most cases seroconversion was observed in accord with clinical course. In few patients double precipitin lines were evidenced (heterogeneity of Ag?), while one patient reacted with all reference sera and many others with two/three sera (two NANB viruses or two Ag/Ab systems?). Tendency towards chronicity emerged in four cases, and in these Ag/Ab systems had a different behaviour.

Preliminary results of immune response to hepatitis B (HB) vaccine (Pasteur) in adults.

Antibody responses were estimated in 42 healthy high risk volunteers submitted to three monthly intradeltoid inoculations of a 5 micrograms HBs vaccine containing both subtypes adw and ayw. The presence and concentration of anti-HBs varied according to individual responses and the number of injections. One month after the 1st dose those responding numbered 19%, one month after the 2nd the number rose to 83,3%, and reached 100% one month after the 3rd dose. In a few cases antibody levels were low (less than or equal to 50 mIU/ml), while in most subjects they rose after the 2nd dose, reaching high titres. Concordance and comparability of anti-HBs concentration were achieved by three different measurements (S/N, RIA Units, mIU/ml). No important side effects were observed. The timing of booster doses is discussed.

Post-transfusion hepatitis: antigen/antibody systems correlated with non-A, non-B hepatitis.

In seven patients post-transfusion hepatitis (PTH) was due to non-A, non-B virus(es) (38.9% of all PTH, while 61.1% were due to hepatitis B virus (HBV). No clinical or biochemical differences were observed in non-A, non-B PTH when compared with PTH due to HBV, while incubation period was very ample, from 15 days to nine months (generally 45 days to two months). An antigen/antibody system was shared by five of our patients (their sera showed precipitin lines when assayed by immunodiffusion with known sources of antigen or antibody), while in one patient an antigen/antibody system was detected when onset serum was assayed with self-recovery serum but not when assayed with known sources of antigen and antibodies, nor with sera of the other five patients. Antigen was detected during the first weeks of illness, antibody at recovery, for both systems. The results suggest that there may be at least two antigen/antibody systems correlated to non-A, non-B hepatitis not necessarily linked to incubation period.