Long-term liver histology improvement in patients with chronic hepatitis C and sustained response to interferon.

A retrospective multicentre survey was conducted to evaluate, in patients with chronic hepatitis C, the long-term liver histological changes induced by interferon (IFN). A total of 112 patients (mean age 46.4 years) were studied. All patients had received a 6-12-month IFN-alpha course (6-18 MU/week) and had successively undergone clinical, biochemical and virological follow-up for at least 36 months (range: 36-76). In each patient, two liver biopsies had been performed: 1-6 months before treatment and, 12-76 months after its completion. In 87 patients with biochemical and virological sustained response persisting for 12 months after therapy, post-treatment liver necroinflammation and fibrosis mean(+/-SD) scores (Knodell index) were significantly lower than pretreatment scores (2.9 +/- 2.2 vs 6.8 +/- 2.9 and 0.8 +/- 1.0 vs 1.2 +/- 1.1, respectively; P < 0.01). In 25 patients who relapsed within 1 year, necroinflammation and fibrosis post-treatment mean scores were similar to pretreatment scores (7.4 +/- 3.2 vs 6.9 +/- 3.1 and 1.8 +/- 1.3 vs 1.6 +/- 1.2, respectively; P > 0.05). On an individual basis, necroinflammation decreased in 87% of sustained responders but only in 36% of relapsers (P < 0.001), whereas fibrosis decreased in 44% of sustained responders but only in 14% of relapsers (P < 0.001). In sustained responders with biopsies performed 12-23 months (n=34), 24-35 months (n=26) or more than 36 months (n=27) after treatment, a progressive decrease of mean necroinflammatory score was observed (-2.6 +/- 2.1, -4.1 +/- 3.4 and -5.2 +/- 3.7 points, respectively; P < 0.01). A similar pattern was observed in fibrosis score (-0.3 +/- 0.6, -0.3 +/- 0.7 and -0.7 +/- 0.9 points, respectively; P < 0.05). Hence, among chronic hepatitis C patients treated with IFN, those with a 12-month sustained response, unlike those who relapse, have a long-term progressive reduction and, in some cases, a complete regression of liver histological damage.

Doppler sonography measurement of portal blood flow velocity after glucagon injection in patients with chronic HCV infection.

Doppler sonography measurement of portal flow velocity (PFV) after glucagon injection was performed in 45 patients with chronic hepatitis C virus (HCV) infection. Patients were divided into three groups: group 1 = no or mild liver fibrosis; group 2 = moderate to severe liver fibrosis, and group 3 = liver cirrhosis. All patients were examined using a Doppler ultrasound (US) multipurpose equipment and a convex 3.5-MHz probe, 10 min before (baseline), as well as 5 and 10 min after, IV administration of 1 mg of glucagon chloride. No significant differences were found in mean baseline PFV among group 1 (19.4 +/- 2.4 cm/s), group 2 (20.1 +/- 3.6 cm/s) and group 3 (17.5 +/- 3.7 cm/s). Five minutes after glucagon injection, all three groups showed significantly increased values of mean PFV (25.6 +/- 4.8, 23.7 +/- 4.0 and 19.5 +/- 5.0 cm/s, respectively; p < 0.05 vs. baseline). The mean increase of PFV above baseline was significantly higher in group 1 (7.9 +/- 3.7 cm/s) than in group 2 (4.5 +/- 3.9 cm/s) (p < 0.05) or in group 3 (2.7 +/- 2.3 cm/s) (p < 0.05). A significant inverse correlation was found between individual values of fibrosis score and of individual increase of PFV. In patients with chronic HCV infection, Doppler sonography measurement of PFV after glucagon injection could be useful in assessing the severity of liver histological damage.

Leukocyte and platelet lowering by some interferon types during viral hepatitis treatment.

BACKGROUND/AIMS: The hematologic toxicity (leukothrombocytopenia) of interferon therapy is well known and frequently observed; it may vary, however, according to the type of interferon administered. METHODOLOGY: We retrospectively assessed 158 patients with chronic viral hepatitis treated for 6-12 months with alpha (recombinant, lymphoblastoid or leukocyte) or beta interferon to monitor leukothrombocytopenia. RESULTS: During treatment, a significant decrease in leukocyte and platelet counts was detected in 48% and 43% of patients, respectively. The maximum decrease (31% and 26% of pre-treatment values; p<0.01) occurred after 4.9 and 4.2 months of treatment. No patient showed clinical symptoms of leukopenia or thrombocytopenia. Beta-interferon yielded the smallest decreases in leukocyte and platelet counts (-21% and -16% of pre-treatment values, respectively). Among alpha interferons, the lymphoblastoid (9 MU/week) produced the largest decrease both in leukocyte (38%; p<0.05 vs any other type) and in platelet (32%) number. The same dose of leukocyte interferon had the smallest effect (leukocytes: -27%; platelets: -2%), while recombinant interferon showed intermediate toxicity (-32% and -26% respectively). CONCLUSIONS: From this retrospective study, the hematologic toxicity of alpha and alpha interferons usually emerges as mild. However, leukopenia and thrombocytopenia may be induced more frequently by some of these interferon types.

[Glucagon test for Doppler sonography measurement of portal flow in chronic HCV infections] / Il test al glucagone nello studio eco-Doppler del flusso portale nell'infezione cronica da HCV.

Purpose - To evaluate whether Doppler sonography measurement of portal flow velocity (PFV) after glucagon injection can be useful in assessing the severity of liver damage in chronic HCV infection. Methods - Forty-five patients (32 males and 13 females; mean age 54.1 14.8 years) with biochemical (raised serum ALT levels), virological (positive serum HCV RNA test) and histological (liver biopsy) evidence of chronic HCV infection were included in the study. According to hepatitis staging (degree of liver fibrosis), as assessed by Knodell histological activity index, patients were divided into three groups: group 1 (n.=17), with no or mild fibrosis (fibrosis score: 0-1); group 2 (n.=11), with severe fibrosis (score: 3); and group 3 (n.=17), with liver cirrhosis (score: 4). For sonographic measurements of PFV, a Doppler ultrasound multi-purpose equipment and a convex 3.5 MHz probe were used. All patients were examined after an 8-hour fast, in supine position, 10 min before (baseline), as well as 5 and 10 min after, intravenous administration of 1 mg of glucagon chloride (Novo Nordisk). Statistical analysis was performed by ANOVA test, Bonferroni t test and Spearman rank correlation test. Results - No significant differences were found in mean basal PFV of group 1 (19.4 2.4 cm/sec), group 2 (20.1 3.6 cm/sec) and group 3 (17.5 3.7 cm/sec) (p > 0.05). Five minutes after glucagon injection, all the three groups showed a significant increase in PFV (25.6 4.8,23.7 4.0 and 19.5 5.0 cm/sec, respectively; p < 0.05 vs baseline). The peak increase in PFV after glucagon injection was significantly higher in group 1 (7.9 3.7 cm/sec; 40.7% of basal value) than in group 2 (4.5 3.9 cm/sec; 22.4%) (p < 0.05) and in group 3 (2.7+2.3 cm/sec; 15.4%) (p < 0.05). A significant (p< 0.001) inverse correlation was also found between the patients fibrosis scores and peak increments of PFV induced by glucagon. Conclusions - In some patients with chronic HCV infection, Doppler sonography measurement of PFV after glucagon injection can be useful, in combination with other non invasive ultrasound investigations, both in staging of liver disease and in monitoring the progression of liver histological damage.

Comparison of treatment with two different doses of leukocyte interferon alpha in patients with chronic hepatitis C.

BACKGROUND/AIMS: This study was carried in order to investigate whether human leukocyte interferon-alpha administered for 12 months at two different dosages, improves long-term responses in chronic hepatitis C and to see whether pre-treatment gamma-glutamyl transpeptidase values help to predict the clinical response to Interferon. METHODOLOGY: Forty-five patients were treated for 12 months with natural Interferon-alpha: 3 MU (group A: 31 cases); 6 MU (group B: 14 cases). Biochemical and virological responses were monitored during treatment and follow-up. RESULTS: Alanine aminotransferase was normalized in 58.1% (Group A) and 54.5% (Group B) of patients by the end of the treatment. Due to side effects 3 patients had to discontinue treatment. During follow-up, remission was maintained in 30.8% and 45.4% of patients respectively (p = 0.046). After 12 months of therapy, respectively 46.7% and 45.4% of patients with complete biochemical response, cleared virus from serum, as did, among long-term responders, 3/8 and 3/4 evaluated patients. Independently of dosage, a complete response was found more often in patients with normal pre-treatment gamma-glutamyl transpeptidase than in those with pre-treatment abnormal values. CONCLUSIONS: High dosage of IFN alpha was associated with a significantly greater rate of sustained biochemical response and with a better chance of viremia becoming negative. Pre-treatment gamma-glutamyl transpeptidase was able to predict the outcome of the treatment.

Radiological changes and circulating immune complexes in patients with urinary schistosomiasis.

The degree of infection and the urographic picture was correlated to the presence and level of circulating immune complexes (CICs) in 69 patients affected by urinary schistosomiasis. Patients were divided into 2 groups: those eliminating less and those eliminating more than 25 eggs/10 ml of urine. Radiological changes in the urinary tract were present in 67% of patients, the most frequent finding being single or multiple filling defects in the bladder. CICs were present in 39 patients. A positive correlation was found between the presence and level of CICs and the output of Schistosoma haematobium eggs, as well as between the presence of CIC and single or multiple filling defects of the bladder. Our findings indicated that CICs were present in patients with urinary schistosomiasis, but the different incidence in patients with a large egg output and radiological filling defects suggests a possible pathogenic role only in the earlier phase of the infection.

Immunological alterations associated with recurrent herpes simplex genitalis.

Immunological studies on 12 patients with culture-proven frequently recurrent herpes simplex genitalis were performed. All the patients were evaluated at three time intervals, initially without lesions and/or within 24 hr of lesion onset (acute illness); Days 5-7 from onset and after healing (convalescence); and between recurrences (quiescence). During the first 24 hr of lesions there was a decreased number of helper (CD4+) and an increased number of suppressor/cytotoxic (CD8+) cells with a resultant decrease in the CD4/CD8 ratio. An increased proportion of CD8+ cells coexpressing the CD11 marker (suppressor cells) was noted and correlated with a low proliferative response to HSV-2 antigens. Both the NK cells (CD16+) and the NK cell activity versus HSV-2-infected targets and the K562 cell line were decreased. Five to seven days after onset the number of CD8+ cells remained increased, although the expression of CD11 marker was decreased, indicating that the majority of CD8+ cells were cytotoxic (i.e., CD8+CD11-). At this time, the lymphoproliferative response to HSV-2 antigens and NK cell activity increased, correlating both with the number of CD16+ cells and with the expression of HLA-DR on this subset. In the interval between two recurrences, no significant alteration in any of the above immunological parameters was observed.

Detection of parasite related antigens associated with conglutinin binding immune complexes in patients with Schistosoma haematobium.

An ELISA assay was designed to detect the presence of parasite related antigens associated with circulating immune complexes in patients affected by urinary schistosomiasis. The assay makes use of bovine conglutinin as the immune complex recognition unit and of human anti-Schistosoma antibody as the antigen recognition unit. Using this method we showed that 10 of 15 (67%) patients with a positive polyethylene glycol assay had circulating immune complexes in which parasite antigens could be detected.

"Anti-Ia reactivity in sera from patients with chronic active hepatitis (CAH)".

Anti-Ia reactivity in sera from patients with chronic active hepatitis (CAH) were characterized by determining cross-reacting specificities with the antigen defined by anti-Ia monoclonal antibody (MoAb) and by studying the effect of CAH sera on the autologous mixed leukocyte reaction (MLR). Preincubation with autoimmune CAH sera lowered the percentage of Ia+ non-T cells stained by anti-Ia MoAb. HBsAg+ve/HBeAg+ve sera did not exert any blocking activity while 4 out of 11 HBsAg+ve/anti-HBe+ve sera exerted a significant blocking effect. Preincubation of cells with normal human serum (NHS) plus aggregated IgG did not block the binding of MoAb anti-Ia. Sera from patients with autoimmune or HBsAg+ve/anti-HBe+ve CAH, that blocked the binding of anti-Ia MoAb to Ia positive target cells by more than 20%, clearly inhibited the autologous mixed lymphocyte reaction (MLR). Both IgG and IgM fractions obtained by affinity chromatography from CAH sera inhibited the autologous MLR and blocked the binding of anti-Ia antibody to Ia positive target cells. A significant positive correlation (p less than 0.001) between serum anti-Ia reactivity and serum liver membrane antibodies (LMA) was observed. In 4 "autoimmune" CAH patients, steroid treatment induced a dramatic decrease in the anti-Ia reactivity.

Evaluation of circulating immune complexes (C.I.C.) in endometrial cancer.

We evaluated the presence of CIC in 32 patients with histological proven cancer of endometrium: 23 stage IA or IB (i.e. localized disease), 9 in stage II or III (i.e. advanced disease). The determination of CIC was done at the time of the diagnosis before the patients underwent any surgical or medical therapy. The presence of CIC was demonstrated in 17% (4/23) of the patients with localized disease and in 56% (9/9) of the patients with more advanced disease. Our findings indicate that the presence of CIC is higher in patients with advanced endometrial carcinoma (stage II, III), than in those suffering of a more limited disease (stage IA, IB) and this seems could be consistent with a possible role in modulating the immune response against tumour itself.

Peripheral blood mononuclear cells and regulatory T cells in acute viral hepatitis.

During acute viral hepatitis, we observed a significant decrease in OKT4/OKT8 ratio with a significant increase in the OKT8 positive subset in acute type B and non-A-non-B hepatitis. This altered ratio persisted in type B for a long time until HBsAg antibody became detectable, while it soon returned to normal in type A and non-A-non-B hepatitis. In the majority of acute hepatitis the altered ratio is because of an increase and not to a decrease in the whole T cell population, as described in chronic HBV infection. The number of HNK-1 positive cells remained raised during the recovery phase of type B and non-A-non-B hepatitis, a finding consistent with the hypothesis that NK cells play a role in the host defence against B and non-A-non-B virus infections. Serum beta 2-microglobulin concentrations were increased only in acute hepatitis B and non-A-non-B where immunological mechanisms are suspected to be involved, and showed a good correlation with the population of activated OKIa positive cells.

Follow-up of circulating immune complexes in the course of acute viral hepatitis, and correlation with serologically relevant parameters.

Type A, type B and type non-A, non-B hepatitis patients were followed up. Several parameters were checked at ten day intervals. Circulating immune complexes (CIC) were detected in a large percentage of patients by using the PEG test and an assay that makes use of bovine conglutinin (K) as recognition unit, and an enzymatically labelled immune complex as the probe. The decrease in the mean level of CIC in the patients correlated with the decrease in serum transaminases and bilirubinaemia in type A and type B hepatitis. Although the pattern of the mean values of the two assays was similar for type A and type B hepatitis, when the two CIC assays were compared for each patient, no significant correlation was found. In light of these and previous results, the necessity for performing CIC monitoring with more than one assay is also discussed.