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Biomedical subjects

A L Zignego

Publications and source records attributed to A L Zignego.

At least 37 records · Page 2Linked to original sources
PubMed1997

Chronic viral hepatitis induced by hepatitis C but not hepatitis B virus infection correlates with increased liver angiogenesis.

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections lead to cirrhosis and increase the risk for the development of hepatocellular carcinoma (HCC). Angiogenesis is an essential step in oncogenesis and contributes to tumor progression in adult organs; however, to what extent angiogenesis occurs in the liver during chronic viral hepatitis has not been studied. Ninety-nine matched patients affected by chronic hepatitis due to either HBV or HCV were studied together with 13 controls (5 patients were affected by familial hyperbilirubinemia with normal liver histology; 6 patients with stage II primary biliary cirrhosis; and 2 patients with pseudo inflammatory tumor). Microvessel density was assessed in liver biopsies by immunostaining using two different antibodies against endothelial cell antigens, QB-END/10 and Factor VIII. In addition, the liver homogenates and sera of HCV- or HBV-positive patients and controls were tested for their capacity to stimulate the migration and proliferation of freshly isolated human endothelial cells in vitro. Evidence of angiogenesis was significantly more frequent in HCV-positive patients compared with HBV-infected subjects or controls (74% vs. 39% vs. 8%) (chi2 = 20.78; P < .0001) (HCV+ vs. HBV+ vs. controls). The degree of microvessel density was also higher in HCV- than in HBV-positive patients or controls (chi2 = 12.28; P < .005). In addition, HCV-positive sera and liver homogenates stimulated a higher migration and proliferation of human endothelial cells in vitro compared with HBV-positive or control sera and liver homogenates. These observations indicate that angiogenesis is particularly linked to HCV infection, suggesting a possible contribution to HCV-related liver oncogenesis.

Adolescent↗
PubMed1997

Impaired response to alpha interferon in patients with an inapparent hepatitis B and hepatitis C virus coinfection.

The possibility of hepatitis B virus (HBV) infection in HBsAg-negative patients has been shown. However, an "inapparent" coinfection by HBV in hepatitis C virus (HCV)-positive patients generally is not taken into account in clinical practice. Mechanisms responsible for resistance to interferon (IFN) have not been completely clarified. The aim of this study was to investigate whether an "inapparent" coinfection by HBV in anti-HCV-positive chronic liver disease patients may influence IFN response. Fourteen anti-HCV positive, HBsAg-negative but serum HBV DNA-positive patients by PCR and 111 anti-HCV-positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis were treated with 3 MU of recombinant alpha-2a IFN 3 times weekly for 12 months. Serum HBV DNA and HCV RNA were determined before treatment, after 6-12 months and in coincidence with ALT flare-up by PCR. HBV PCR was performed using primers specific for the S region of the HBV genome and HCV PCR with primers localised in the 5'NC region of HCV genome. IgM anti-HBc was tested using IMx Core-M Abbott assay. By the end of treatment, ALT values had become normal in 4/14 HBV DNA-positive patients (28%), but all "responders" (4/4) relapsed between 2 and 5 months after therapy. All but one patient were HCV RNA-positive before treatment, 6 were also both HBV DNA and HCV RNA-positive during ALT flare-ups. In 5 patients, only HBV DNA and in 3 patients, only HCV RNA was detected when transaminase values increased. All patients remained HBsAg-negative and anti-HCV-positive. IgM anti-HBc was detected both before treatment and during ALT elevation in 3 patients and only during ALT relapse in 3 others. Of the 111 anti-HCV positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis, a biochemical response to IFN treatment was observed in 54% of the cases. Relapse of ALT values was observed in 47% of the cases during a follow-up of 1 year after treatment. "Inapparent" HBV/HCV coinfection may be implicated in cases of resistance to IFN treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by IFN treatment. The pathogenic role of HBV in liver disease was confirmed by detection of IgM anti-HBc in some cases; the appearance of these antibodies only after IFN treatment suggests that IFN may exert a selective role in favour of HBV. Further studies will show the effect of different treatment schedules. HBV DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding interviral relationships and mechanisms involved in multiple hepatitis virus infections.

Adult↗
PubMed1997

Hepatitis C virus infection in mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma: evidence for a pathogenetic role.

We investigated the pathogenetic relevance of hepatitis C virus (HCV) infection in mixed cryoglobulinemia (MC) with or without complicating B-cell Non-Hodgkin's lymphoma (NHL) in comparison with other immunological and lymphoproliferative disorders. The following groups of patients were studied: A) 25 patients with MC in 7 cases evolved into B-cell NHL; B) 25 healthy subjects; C) 22 patients with different systemic immune diseases; D) 24 patients with chronic HCV infection without MC; E) 25 patients with B-cell idiopathic NHL. Methods used included: i) Polymerase chain reaction (PCR) for HCV RNA detection in serum and peripheral blood mononuclear cells (PBMC) (uncultured or mitogen-stimulated); ii) Branched DNA (b-DNA) for HCV RNA quantification; iii) HCV genotyping by genotype-specific primers localized in the core region and by hybridization of amplification products of the 5' untranslated region (5'UTR), obtained with universal primers, using genotype-specific probes. Serum anti-HCV and HCV RNA were detected in 88% and 73% of MC patients, respectively, and in a significantly lower percentage of healthy controls and patients with autoimmune diseases. HCV RNA concentration was significantly lower in supernatants than in corresponding whole sera (p < 0.001). Plus-strand HCV RNA was detected in 81% of peripheral blood mononuclear cell (PBMC) samples and minus-strand in the majority of fresh or mitogen stimulated cells. All MC patients with NHL had HCV RNA sequences in PBMC. HCV genotype 2a/III was detected in MC patients with a prevalence that was significantly higher than in HCV infected patients without MC. Surprisingly, HCV markers (anti-HCV and/or HCV RNA) were found in 32% of patients with idiopathic NHL. These data suggest that HCV infection is involved in the pathogenesis of MC through both direct participation in the immune complex related vasculitis and by triggering the lymphoproliferative disorder underlying the disease. This latter disorder seems to be related to HCV lymphotropism which could also be responsible for the evolution of MC to malignant lymphoma. This study also suggests that HCV infection may be involved in the pathogenesis of idiopathic B-cell NHL through a similar pathogenetic mechanism.

Aged↗
PubMed1997

Different cytokine profiles of intraphepatic T cells in chronic hepatitis B and hepatitis C virus infections.

BACKGROUND & AIMS: The cytokine pattern secreted by T cells at the site of viral replication may influence the final outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. The aim of this study was to assess whether a cytokine imbalance oriented toward T helper (Th) 1 or Th2-type responses may play a role in chronic hepatitis B or C. METHODS: Production of interferon (IFN)-gamma, interleukin (IL)-4, and IL-5 by wide series of T-cell clones derived from the liver of 6 patients with chronic hepatitis B (291 clones) and 9 patients with chronic hepatitis C (260 clones) was studied. T-cell clones were generated by limiting dilution from freshly isolated mononuclear cells derived from liver tissue to give a reliable representation of the intrahepatic inflammatory infiltrates. RESULTS: The majority of liver-infiltrating T cells in chronic hepatitis C were Th1 cells able to secrete IFN-gamma but unable to secrete IL-4 or IL-5, whereas in hepatitis B, most CD4+ and CD8+ liver T cells were ThO-like cells able to produce not only IFN-gamma but also IL-4 and IL-5. CONCLUSIONS: The different cytokine profiles of T cells within the liver in chronic HBV and HCV infections illustrate a different behavior of the local immune response in these two infections that may have pathogenetic implications.

Adult↗
PubMed1997

Serum HCV-RNA and liver histologic findings in patients with long-term normal transaminases.

In this study we aimed to correlate liver histology and the presence of hepatitis C virus (HCV) viremia, genotype, and quantity of HCV genome in 19 positive and 11 RIBA II indeterminate patients presenting persistently normal ALT values over 24 months before biopsy. In addition, after biopsy serum ALT values were monitored monthly for a mean follow-up period of 24.8 months, after which patients were reevaluated for RIBA II and the presence of viremia. Sixteen patients (53%) were serum HCV-RNA-positive; 13 of them (68%) were confirmed positive and 3 (27%) indeterminate on RIBA II. Histology of the HCV-RNA-positive patients showed eight cases of CPH (one case of genotype 1a; four cases type 1b; three cases type 2), six cases of CAH (three cases type 1b, three cases type 2), one case of CLH (type not determined), and one case of normal liver (NL) (type 1b). Histology of the HCV-RNA-negative patients showed four cases of CPH, one case of CAH, two cases of CLH, and seven cases of NL. During the follow-up period nine patients (30%) presented slight increases in ALT values (< 2 x N), and in particular, flares of ALT were observed four times in the CAH and five times in the CPH patients, who were all viremic, but never in the NL subjects. These results indicate that subjects positive on RIBA II, but with persistently normal ALT values, had a high probability of being serum HCV-RNA-positive and that almost all these viremic subjects presented histologic signs of liver disease. In contrast, RIBA II indeterminate subjects had a moderate probability of being HCV-RNA-positive, but a number of these may present signs of liver disease. In both cases there was no association with genotype or HCV-RNA serum levels. The other nonviremic cases included subjects with hepatic changes going toward resolution or with normal liver in whom hepatic biopsy can be avoided. Only one case was a true carrier since he was viremic with normal liver and persistently normal ALT values.

Adult↗
PubMed1997

Viruses and cancers: possible role of hepatitis C virus.

Oncogenesis is a multifactorial process in which environmental, genetic and infectious factors are variably involved. A possible role of specific viruses has been suggested in at least 15% of human cancers. Hepatitis C virus (HCV), which is both hepato- and lymphotropic, is responsible for various liver disorders, i.e. chronic hepatitis, cirrhosis and hepatocelluar carcinoma, as well as for a constellation of extrahepatic immune-mediated manifestations, among which is mixed cryoglobulinaemia. This is a systemic disorder secondary to a chronic, benign B-lymphocyte proliferation, which in some subjects may evolve to a malignant non-Hodgkin's lymphoma (NHL). Interestingly, recent studies reported the appearance of malignant B-cell neoplasias in patients with type C chronic hepatitis; moreover, in a significant number (from 22% to 50%) of 'idiopathic' NHLs, the presence of HCV infection has been demonstrated. The presence of a geographical etherogeneity in the prevalence of HCV-positive NHL suggests that other co-factors, i.e. genetic and environmental, could be involved in the lymphomagenesis. HCV may exert its oncogenic potential in two different directions, leading to liver cancer or B-cell lymphoma.

B-Lymphocytes↗
PubMed1997

Interstitial lung fibrosis and rheumatic disorders in patients with hepatitis C virus infection.

A possible aetiopathogenetic role of hepatitis C virus (HCV) has been reported in various immune-mediated disorders, such as mixed cryoglobulinaemia, which may be complicated by interstitial lung involvement; moreover, different viruses, including HCV, have been correlated with idiopathic pulmonary fibrosis. Here, a cohort of eight HCV-positive patients (M/F = 4/4, mean age 61 +/- 8 S.D. yr) with interstitial lung fibrosis and a variable number of rheumatic disorders are described. Interstitial lung involvement appeared medially 4.5 +/- 3.2 S.D. yr after the clinical onset of chronic hepatitis. During the clinical follow-up, some rheumatic symptoms were also recorded: articular involvement (four patients): mild sicca syndrome (one patient); severe polymyositis and cranial neuropathy (one patient); serum cryoglobulins and/or autoantibodies (eight patients). In all patients, a moderate (four patients) or severe (four patients) lung fibrosis was evaluated by means of high-resolution computed tomography. The presence of parenchymal radiotracer uptake on 67Ga scan (7/7 patients) and increased percentages of neutrophils (4/4 patients) and lymphocytes (2/4) at bronchoalveolar lavage suggested an active lung involvement. Different degrees of reduction of single breath diffusing capacity for carbon monoxide (DLco) (mean value 57.6 +/- 15%, range 37-80) were observed in all cases, while spirometric abnormalities, consistent with a global restrictive pattern, were less frequently found. In all cases, anti-HCV antibodies and HCV viraemia were demonstrated: viral genome was also detected in peripheral lymphocytes from 4/4 subjects and in one case in lung biopsy specimens. A desquamative interstitial pneumonia pattern was demonstrated in two cases by lung biopsy. The present work supports the hypothesis that HCV chronic infection could represent a trigger factor for interstitial lung fibrosis and various rheumatic disorders.

Aged↗
PubMed1997

Lymphotropic virus infection of peripheral blood mononuclear cells in B-cell non-Hodgkin's lymphoma.

Some lymphotropic viruses such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been proposed as causative agents of B cell non-Hodgkin's lymphoma (NHL). More recently, the presence of hepatitis C virus (HCV), which is both a hepatotropic and lymphotropic virus, has been reported in one third of B cell NHL patients. The aim of this study was to investigate in a series of B cell NHL the prevalence of three lymphotropic viruses, i.e. EBV, HHV-6 and HCV, in peripheral blood mononuclear cells (PBMC). Eighteen unselected B cell NHL patients (10 men, 8 women; mean age 62 +/- 12 years, range 31-77 years; mean disease duration 1.8 +/- 1.4 years) and 40 age- and sex-matched healthy controls were included in the study. In all cases, an acquired-immunodeficiency-syndrome-related lymphoma was excluded. By means of the polymerase chain reaction technique, EBV DNA, HHV-6 DNA and HCV RNA were detected in PBMC. HCV genomic sequences were significantly more frequent in PBMC of NHL patients than in controls (33 vs. 2.5%; p < 0.01); on the other hand, in the same two groups EBV DNA (39 vs. 60%; p = not significant) and HHV-6 DNA (22 vs. 32%; p = not significant) were present in a comparable percentage of individuals in the same two groups. The infection of PBMC by HCV alone was present in the majority (5 of 6) of HCV-positive NHL. These data support the implication of HCV infection in a statistically significant number of B cell NHL, whereas a possible co-operation between HCV and other well-known lymphotropic viruses seems to be excluded.

Adult↗
PubMed1997

Long course and prognostic factors of virus-induced cirrhosis of the liver.

OBJECTIVE: Chronic infection by hepatitis B virus (HBV) and hepatitis C virus (HCV) is now recognized as a major cause of liver cirrhosis. This study was aimed at evaluating the natural history of the disease in a large series of Italian patients with HBV- and HCV-related cirrhosis without portal hypertension at entry. METHODS: The clinical records of 405 patients (233 males, mean age 54 +/- 9 yr) with histologically proven cirrhosis (321 with HCV-related and 84 with HBV-related cirrhosis) and no clinical evidence of portal hypertension at entry were retrospectively examined to evaluate the occurrence of complications and the cumulative mortality rate during follow-up. RESULTS: Patients had a mean follow-up of 8 +/- 3 yr. The cumulative survival rate was 99.1% at 5 yr, 76.8% at 10 yr, and 49.4% at 15 yr. The age-adjusted death rate was 3.14 and 2.84 times higher than in the general Italian population in men and women, respectively. Only the bilirubin level was an independent indicator of survival. Esophageal varices, ascites, jaundice, hemorrhage, hepatic encephalopathy, and hepatocellular carcinoma significantly reduced the survival rate (major complications), whereas thrombocytopenia, diabetes, and cholelithiasis did not affect survival (minor complications). The incidence of hepatocellular carcinoma was similar in patients with either HBV- or HCV-related disease and was quite frequent, especially in males. CONCLUSIONS: This study demonstrates that the course of virus-induced liver cirrhosis is not influenced by the etiology of the disease and that the occurrence of complications significantly shortens life expectancy. The longer survival rate observed in this study is probably due to the fact that cirrhosis was here recognized by liver biopsy in the absence of clinical evidence of portal hypertension.

Bilirubin↗
PubMed1997

Relevance of inapparent coinfection by hepatitis B virus in alpha interferon-treated patients with hepatitis C virus chronic hepatitis.

The aim of the study was to investigate whether an "inapparent" coinfection by hepatitis B virus (HBV) in anti-HCV-positive chronic liver disease patients may influence interferon (IFN) response. Fourteen anti-HCV-positive, hepatitis B surface antigen (HBsAg)-negative but serum HBV-DNA-positive patients and 111 anti-HCV-positive, HBsAg-negative, and HBV-DNA-negative patients with chronic hepatitis were treated with 3 MU of recombinant alpha-2a IFN 3/week for 1.2 months. Serum HBV-DNA and HCV-RNA were determined before treatment, after 6-12 months, and at the time of alanine aminotransferase (ALT) flare-up by HBV polymerase chain reaction (PCR) and HCV PCR, respectively. IgM anti-HBc were tested using the IMx Core-M assay (Abbott Laboratories, North Chicago, IL). By the end of treatment, ALT values had become normal in 4/14 HBV-DNA-positive patients (28%), but all "responders" (4/4) relapsed. IgM anti-HBc was detected both before treatment and during ALT elevation in three patients and only during ALT relapse in another three. In the remaining 111 patients, a biochemical response to IFN treatment was observed in 54% and relapse of ALT values in 47%. "Inapparent" HBV/HCV coinfection may be implicated in cases of resistance to IFN. HBV replication and HBV-related liver damage may persist in patients in whom HCV replication was inhibited by current doses of IFN, as suggested also by the presence of IgM anti-HBc in some cases. Further studies will show the effect of different treatment schedules. HBV-DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding of intervirus relationships and mechanisms involved in multiple hepatitis virus infections.

Adult↗
PubMed1996

Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia.

OBJECTIVE: To investigate the possible role of HCV variants in the pathogenesis of mixed cryoglobulinemia. SETTING: Medical service (rheumatology and hepatology units) of urban, university-affiliated teaching hospitals. DESIGN: Analysis of viral genotypes in a cohort of patients with hepatitis C virus (HCV) infection and mixed cryoglobulinemia. PATIENTS: 90 unselected HCV-positive (anti-HCV antibody-positive and HCV RNA-positive) patients consecutively recruited at routine ambulatory visits: 29 with and 61 without (control group) mixed cryoglobulinemia. MEASUREMENTS: Clinical and histologic data; HCV RNA detection in serum and peripheral blood mononuclear cells by polymerase chain reaction (PCR); HCV genotype determination by two methods based on genotype-specific primer PCR and genotype-specific probe hybridization, respectively. RESULTS: Persistent aminotransferase increases were found in 55% of patients with mixed cryoglobulinemia. Peripheral blood mononuclear cells were infected in 80% of cases. In serum samples, HCV genotype 2a/III was detected with a higher prevalence in patients with mixed cryoglobulinemia than in controls (41% compared with 15%). The overall prevalence of genotype 2a/III in mixed cryoglobulinemia increased to 52% when findings in peripheral blood mononuclear cells were also considered. Among patients with mixed cryoglobulinemia, this genotype was more frequent in those without clinical and biochemical signs of liver disease (85%) or with serum autoantibodies (75%). CONCLUSIONS: Mixed cryoglobulinemia may be related, at least in part, to the HCV genotype infecting the host.

Aged↗