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G Fattovich

Publications and source records attributed to G Fattovich.

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

Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.

BACKGROUND & AIMS: Few data are available concerning the long-term prognosis of chronic liver disease associated with hepatitis C virus infection. This study examined the morbidity and survival of patients with compensated cirrhosis type C. METHODS: A cohort of 384 European cirrhotic patients was enrolled at seven tertiary referral hospitals and followed up for a mean period of 5 years. Inclusion criteria were biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of hepatitis A and B viruses and of metabolic, toxic, or autoimmune liver diseases. RESULTS: Antibodies against hepatitis C virus were positive in 98% of 361 patients tested. The 5-year risk of hepatocellular carcinoma was 7% and that of decompensation was 18%. Death occurred in 51 patients (13%), with 70% dying of liver disease. Survival probability was 91% and 79% at 5 and 10 years, respectively. Two hundred five patients (53%) were treated with interferon alfa. After adjustment for clinical and serological differences at baseline between patients treated or not treated with interferon, the 5-year estimated survival probability was 96% and 95% for treated and untreated patients, respectively. CONCLUSIONS: In this cohort of patients, life expectancy is relatively long, in agreement with the morbidity data showing a slowly progressive disease.

Carcinoma, Hepatocellular↗
PubMed1997

Hepatitis B virus core protein mutations are concentrated in B cell epitopes in progressive disease and in T helper cell epitopes during clinical remission.

The distribution and temporal and clinical features of amino acid substitutions of the core protein of hepatitis B (HB) virus were analyzed, using at least 2 sequential samples from 27 patients. Six patients seroconverted from HBe antigen (HBeAg)-positive to anti-HBe-positive (3 went into remission), and 21 were continuously anti-HBe positive with progressive hepatitis. Precore mutations, which terminate HBeAg translation, all appeared by the second sample. Most core mutations occurred between the first and second samples; significantly fewer occurred after the second. In seroconverters who went into remission, mutations occurred in the T helper epitope from aa 50 to 69 (P = .00045); for anti-HBe-positive patients with ongoing disease, mutations occurred in B cell epitopes (P = .0007 for aa 74-83). An ineffective anti-HBc B cell response accounts for ongoing disease and selection of mutations after seroconversion. In those who remit, mutations in the major T helper epitope allow immune escape, thus minimizing immune-mediated hepatitis.

Adult↗
PubMed1997

Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.

To assess prevalence and incidence of cholecystolithiasis in cirrhosis, 356 consecutive cirrhotics and 247 consecutive cases of chronic hepatitis without cirrhosis were studied by ultrasonography. Cholecystolithiasis was significantly more frequent in cirrhotics than in patients with chronic hepatitis (p < 0.001) after stratification for age and for alcohol abuse, and its prevalence in the former was affected by Child's class (p < 0.001) and duration (p < 0.001) of cirrhosis and was higher in HBsAg-negative as compared with HBsAg-positive cases (36.2 vs. 11.9%) and in patients with previous alcohol abuse (41.5 vs. 28.3%), while no difference was noted in relation to sex. By multivariate analysis, duration and Child's class of cirrhosis and HBsAg-negative status were statistically associated with cholecystolithiasis. One hundred and eighty-two of the 356 cirrhotic patients without gallstones at inclusion were followed prospectively, and 21 (11.5%) of them developed cholecystolithiasis, and duration of cirrhosis and past alcohol abuse were found to be independent risk factors for gallstone development by multivariate analysis. Cirrhosis is a significant risk factor for cholecystolithiasis, except for HBsAg-positive patients who have prevalence and incidence similar to noncirrhotics. Severity and duration of cirrhosis and previous alcohol abuse are associated with an increased risk of gallstone formation.

Aged↗
PubMed1996

Hepatitis C genotypes in patients with dual hepatitis B and C virus infection.

In patients with chronic hepatitis B and C virus (HBV, HCV) infection, an inverse relationship in the replicative activity of the two viruses has been reported. In the present study the genotype of HCV was evaluated in 34 consecutive cases found with hepatitis B surface antigen (HBsAg) and anti-HCV in the serum, in order to identify its possible influence in determining the pattern of HBV/HCV interaction. Nineteen patients were HCV-RNA positive and could be genotyped: 8 were infected by HCV-1 (3 by HCV-1a and 5 by HCV-1b), 10 by HCV-2, and only 1 by HCV-3. Among these, 3 were HBV-DNA positive, compared to 10 of 15 HCV-RNA-negative patients (P = 0.003), and all 3 were coinfected with HCV-2. Mean alanine aminotransferase (ALT) levels were similar between patients infected with HCV-1 and HCV-2. Among 7 patients with cirrhosis 5 were infected by HCV-2, while 6 of 12 of those without cirrhosis had HCV-1 infection. In conclusion, HBV replication was inhibited more efficiently by HCV-1 than by HCV-2. Cirrhosis was frequently found in patients with dual HBV and HCV-2 infection.

Adult↗
PubMed1996

Serum procollagen type III peptide in chronic hepatitis B. Relationship to disease activity and response to interferon-alpha therapy.

The clinical significance of serum procollagen type III peptide, a marker of active fibrogenesis, was evaluated in 110 hepatitis B surface antigen positive patients with chronic hepatitis (32 chronic persistent hepatitis, 60 chronic active hepatitis, and 18 active cirrhosis), selected on the basis of active viral replication and biochemical activity, including 54 cases treated with interferon-alpha. At presentation the procollagen type III peptide level serum was above normal in 48 (44%) of the 110 patients and the median value was significantly higher than that of healthy carriers with normal transaminases and histology (P < 0.000005). Semiquantitative histological evaluation showed a significant correlation between serum procollagen type III peptide levels and necrosis/inflammation in the subgroup of patients with chronic active hepatitis, but no relationship with the score of fibrosis. Among patients treated with interferon-alpha and with increased fibrogenic activity (indicated by high pretreatment serum levels of procollagen type III peptide), peptide levels were significantly decreased when pretreatment levels were compared with those at 12 months after therapy withdrawal, both in responders to interferon (P = 0.022) and non-responders (P = 0.012). However, serum procollagen type III peptide levels normalized in 75% of responders to interferon with sustained serological and histological remission of liver disease, but in only 21% of non-responders (P = 0.02). These results obtained in a well-defined population suggest that serum procollagen type III peptide is a better marker of active fibrogenesis and inflammation than an indicator of the extent of fibrosis, and that interferon may reduce active liver fibrogenesis in chronic hepatitis B independently of its effect on viral replication. However, a consistent proportion (56%) of our chronic hepatitis B patients had normal serum procollagen type III peptide levels at presentation, thus precluding the clinical use of this marker both for diagnosis of liver injury and for monitoring the therapeutic response to interferon.

Adult↗
PubMed1996

Liver stellate cells in chronic viral hepatitis: the effect of interferon therapy.

BACKGROUND/AIMS: Liver stellate cell proliferation and differentiation into myofibroblast-like cells is related to the development of liver fibrosis. Several cytokines, including interferons, regulate liver stellate cell proliferation and phenotypic modulation. Recent studies indicate that human liver stellate cells express the alpha-isotype of actin, specific to smooth muscle cell differentiation. We aimed to evaluate the expression of alpha-smooth muscle actin-positive liver stellate cells in patients with chronic viral hepatitis and to evaluate whether and how such expression can be modified by alpha-interferon treatment. METHODS: Using immunohistochemistry, and a semi-quantitative scoring method, we evaluated alpha-smooth muscle actin expression in liver stellate cells before and after alpha-interferon therapy in a series of liver biopsies from 44 patients with chronic viral hepatitis. RESULTS: Before therapy, a large number of liver stellate cells expressing alpha-smooth muscle actin were present throughout all acinar zones. A significant reduction in alpha-smooth muscle actin expression by liver stellate cells was demonstrated in biopsies performed after suspending the interferon treatment. The drop in the number of alpha-smooth muscle actin-labelled cells after therapy correlated closely with the improvement in the histological index of activity. CONCLUSIONS: The results suggest a specific effect of interferon on liver stellate cells, possibly related to its anti-inflammatory action.

Actins↗
PubMed1996

A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon.

AIMS: The aim of this study was to assess the incidence of fatal, life-threatening side effects and the de novo appearance of non-hepatic morbidity during interferon alfa therapy for chronic viral hepatitis. The relationship of these adverse events to actual total dose and duration of interferon was also evaluated. METHODS: We conducted a retrospective study at 73 Italian centers of 11,241 consecutive patients with chronic viral hepatitis who underwent interferon alfa treatment. RESULTS: Five patients died during interferon therapy due to liver failure (n = 4) or complications arising from sepsis. Life-threatening side effects were observed in eight patients: two cases where depression developed and led to a suicide attempt and six patients with bone marrow suppression (granulocytes < 500/mm3 or platelets < 25,000/mm3). These symptoms and signs completely disappeared after interferon withdrawal. During interferon treatment, 131 patients developed the following de novo non-hepatic disorders: symptomatic thyroid disease (n = 71), impotence (n = 5), systemic autoimmune disease (n = 5), immune-mediated dermatologic disease (n = 14), diabetes mellitus (n = 10), cardiovascular disease (n = 7), psychosis n = 10), seizures (n = 4), peripheral neuropathy (n = 3) and hemolytic anemia (n = 2). Most of these complications are reversible or can be ameliorated. Fatal or life-threatening side effects were not related to actual total dose or duration of interferon alfa, while the majority of patients with de novo non-hepatic morbidity received medium/high doses (> 200 million units) of interferon alfa or were treated for periods longer than 16 weeks (68% and 80%, respectively). CONCLUSIONS: Treatment with interferon alfa may have fatal or life-threatening side effects, their incidence in this study being low (0.04% and 0.07%, respectively) and perhaps no different than in untreated patients with chronic viral hepatitis. Moreover de novo non-hepatic morbidity occurred in 1.2% of patients, and the dose and duration of interferon therapy seem important in determining the frequency of this complication. The development of clinically-overt thyroid disease was most common.

Adolescent↗
PubMed1996

Serum levels of soluble CD30 in chronic hepatitis B virus infection.

There is evidence that both cellular and humoral components of the immune response are required for viral clearance to occur in chronic hepatitis B. Recent studies demonstrated that CD30 molecule, a member of the tumour necrosis factor superfamily of membrane cytokine receptors, is expressed on, and released as a soluble molecule (sCD30) by activated T cells producing T helper 2 (Th2) cytokines, which modulate antibody responses. To better characterize the immunoregulatory mechanisms in chronic hepatitis B virus (HBV) infection, sCD30 values were evaluated by an ELISA in 90 hepatitis B surface (HBsAg)-positive patients with chronic hepatitis, selected on the basis of active viral replication and biochemical activity. At presentation abnormal levels (> 20 U/ml) of sCD30 were detected in 57 (63%) out of 90 patients with chronic hepatitis B, and median value was significantly higher in this group of patients compared with that of healthy HBsAg carriers (26.7 versus 10.5 U/ml, P < 0.000 05) and with normal controls (26.7 versus 3 U/ml P < 0.000 01). Sequential studies of chronic hepatitis B did confirm the association of raised sCD30 levels with the active phase of the illness. On the other hand, a significant decrease was noted when sCD30 levels at diagnosis and after termination of HBV replication and biochemical remission of hepatitis were compared in 10 untreated patients (median, 28 U/ml at entry versus 8 U/ml at remission, P < 0.01) and in six patients responding to interferon-alpha therapy (median, 29.5 U/ml at entry versus 6 U/ml at remission, P < 0.05). The high serum sCD30 levels reported during the active phase of HBsAg-positive chronic hepatitis suggest a certain degree of immune competence of these patients, at least with respect to a Th2-type response. These data are in agreement with recent serologic surveys showing that most chronic hepatitis B patients do demonstrate ongoing humoral immune response to HBV antigens, using novel immunoassays designed to detect antibody in the presence of excess serum viral antigen. Th2 functions that mainly promote humoral immunity to HBV antigens may be critical, in association with a competent virus-specific cytotoxicity, for efficient termination of HBV replication in chronic hepatitis B.

Adolescent↗
PubMed1995

Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis.

To examine the morbidity of compensated cirrhosis type B, a cohort of 349 Western European, white patients (86% men; mean age, 44 years) with biopsy-proven cirrhosis was followed up for a mean period of 73 months and was studied for occurrence of hepatocellular carcinoma (HCC) and decompensation. At entry into the study all patients were tested for hepatitis B e antigen (HBeAg; 34% of patients were HBeAg-positive) and antibody to hepatitis delta virus (anti-HDV; 20% of patients were anti-HDV-positive); 48% of 252 patients tested were hepatitis B virus (HBV)-DNA-positive. During follow-up HCC developed in 32 (9%) of the 349 patients and decompensation was observed in 88 (28%) of 317 tumor-free patients. Five years after diagnosis, the probability of HCC appearance was 6% and the probability of decompensation was 23%. After the first episode of decompensation the probability of survival was 35% at 5 years. Cox's regression analysis identified three variables that independently correlated with HCC: age, serum levels of platelets, and liver firmness on physical examination. HBV (HBeAg or HBV-DNA) and HDV (anti-HDV) markers at presentation had no prognostic value for the development of HCC. In conclusion, a high proportion of patients with HBsAg-positive compensated cirrhosis do not experience worsening of their condition for several years, but once decompensation occurs life expectancy is poor. European, white patients with compensated cirrhosis type B are at consistent risk for HCC. Prognostic factors for HCC reflect an advanced stage of cirrhosis and support the hypothesis that development of a tumor could be the likely consequence of long-standing hepatic disease.

Aged↗
PubMed1995

Hepatitis B e antigen negative chronic active hepatitis: hepatitis B virus core mutations occur predominantly in known antigenic determinants.

In chronic hepatitis B virus (HBV) infection seroconversion from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb) may be followed either by remission of the disease with low-level viraemia, or by continuing inflammation with high-level viraemia. In both situations the virus may acquire a mutation in the precore sequence which prevents it from encoding HBeAg. We now show that the number of amino acid substitutions in the HBV core is low in viral sequences from patients with HBeAg positive chronic liver disease and HBeAg negative HBeAb positive patients in remission, but the frequency of substitutions is high in HBeAg, negative HBeAb positive patients with active liver disease. Furthermore we show that these substitutions cluster in the promiscuous CD4+ T-helper-cell epitope and in HBV core/e antibody binding determinants, but are not found in regions recognized by major histocompatability complex (MHC) restricted cytotoxic T lymphocytes. Sequential viral sequences from patients before and after HBeAg/HbeAb seroconversion shows that core mutations arise either at the same time or after the precore stop mutation which prevents the virus from encoding HBeAg. These results are consistent with the hypothesis that after clearance of HBeAg, mutations in regions of the virus recognized by CD4+ helper T cells and B cells allow persistence of the HBe negative virus in HBeAb positive patients with viraemia and active hepatitis.

CD4-Positive T-Lymphocytes↗
PubMed1995

HLA-DR expression in liver in human HIV infection.

In order to clarify the relationship between HLA-DR antigen expression in the liver and human HIV infection, we studied 66 non-autopsy specimens obtained from HIV-infected patients with and without AIDS; 33 biopsies from HIV-negative patients were considered for control purposes. All biopsies were immunohistochemically tested with monoclonal antibody TAL-1B5, reacting with the alpha-chain subunit of HLA-DR in the avidin biotin complex method. We found occasional and usually weak HLA-DR expression on hepatocytes and biliocytes. By comparison with controls, HIV-positive cases showed a significantly higher percentage of HLA-DR immunoreactivity on hepatic artery and portal vein endothelial cells. No relationship was demonstrated between HLA-DR endothelial expression and the CD4+ lymphocyte count or grade of portal/periportal inflammation in the liver. The biological significance of HLA-DR expression on intrahepatic vascular endothelial cells in HIV infection still remains to be clarified.

Adult↗
PubMed1995

Hepatitis B virus precore/core variation and interferon therapy.

Precore/core genes from hepatitis B e antigen (HBeAg)-positive and antibody to HBeAg (anti-HBe) positive individuals with active hepatitis have been analyzed to search for correlations with response to interferon before and after treatment. Pretreatment, no precore stop codon mutants were detected, even at the 3% level, in HBeAg-positive responders or nonresponders. In anti-HBe-positive patients, precore mutants did not influence response. No significant core amino acid variability was observed in HBeAg-positive patients, irrespective of interferon response. However, anti-HBe-positive cases had multiple core protein substitutions, mostly in B- ant T-helper cell epitopes, but responders had fewer (P = .02 for responders versus nonresponders and reactivators). None of four responders, three of seven reactivators, and three of three nonresponders had mutations within the major T-helper epitope from aa50 to aa69 (P = .03). Precore mutants appeared in eight of nine natural seroconverters compared with 3 of 10 interferon-induced anti-HBe seroconverters (P = .01). Those in whom precore wild-type remained after treatment often tested negative in the last available sample using polymerase chain reaction (PCR), whereas emergence of mutants led to ongoing viremia in all cases. In anti-HBe-positive cases, precore sequences remained stable during therapy, except for 2 cases in whom a precore mutant appeared accompanied by reactivation. In the core protein, anti-HBe-positive cases selected a mean of 3.5, 1.6, and 1.7 amino acid substitutions in responders, nonresponders, and reactivators respectively (P = NS). In conclusion, core but not precore sequence before therapy may predict response. Appearance of precore mutants during therapy usually predicts failure to clear virus but substitution in core does not influence outcome.

Adolescent↗
PubMed1995

The interaction between hepatitis B virus and hepatitis C virus in acute and chronic liver disease.

Infections by the hepatitis B or C virus are extremely common causes of acute and chronic liver disease, and coexistence of the two viruses in the same patient is not rare. Evidence has been found that such interaction may play an important role in fulminant hepatitis and in the development of hepatocellular carcinoma in cirrhotic patients. Liver disease activity and prognosis have been reported to be generally more serious in the presence of double infection, although an inverse relationship in the replicative levels of the two agents has been noted, suggesting viral interference, particularly in cases of chronic hepatitis. Thus, the two viruses seem to inhibit each other at the molecular level, while cytopathic effects appear to be enhanced. Further studies are needed to explain the mechanisms of these apparently contrasting effects.

Acute Disease↗
PubMed1994

Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study.

BACKGROUND: Patients with cirrhosis have a high risk of hepatocellular carcinoma (HCC) but it is unclear how the etiology of liver disease influences tumor development. The authors evaluated hepatitis B and C virus (HBV, HCV) infection in cirrhosis in relation to the risk of HCC. METHODS: Two hundred and ninety consecutive cirrhotic patients were followed prospectively with periodic ultrasound examination. At entry, patients were tested for markers of HBV and HCV to assess relation to tumor development during follow-up. RESULTS: Twenty and five-tenths percent of patients were hepatitis B surface antigen (HBsAg) positive and 68.9% were positive for HCV antibodies. Previous alcohol abuse was present in 26.2%. During follow-up (46.3 +/- 21.4 months), HCC developed in 32 patients (11.0%) (annual incidence approximately 3%) including 19.6% of HBsAg-positive patients, 12.2% of HCV antibody positive patients and 14.4% of patients with a history of alcohol abuse. The highest rate of HCC was in patients with dual HBsAg and anti-HCV positivity with or without previous alcohol abuse, whereas the lowest incidence (0%) was in cases without risk factors. By univariate analysis, age older than 59 years (P < 0.005), longer duration of cirrhosis (P < 0.005), serum alpha-fetoprotein levels higher than 20 ng/ml (P < 0.05), and dual HBsAg and HCV positivity (P < 0.02) appeared to be associated with HCC. By multivariate analysis, age (P < 0.01), positivity for HBsAg and HCV antibodies (P < 0.05), male sex (P < 0.05), and previous alcohol abuse (P < 0.08) were independently related to tumor appearance. CONCLUSIONS: These results, although confirming that male sex and previous alcohol abuse are risk factors for hepatocellular carcinoma in cirrhosis, indicate that concurrent hepatitis B and C virus infection determines the highest risk of developing hepatocellular carcinoma.

Aged↗
PubMed1994

Interferon therapy for the anti-HBe positive form of chronic hepatitis B.

Two distinct serologic types of chronic hepatitis B have been identified, namely the "classical" HBeAg positive form and the "atypical" HBeAg negative, anti-HBe positive variant which is due to infection by a mutant HBV having a pre-core stop codon that makes the virus unable to produce HBeAg. The anti-HBe positive form is currently the prevalent type of chronic hepatitis B in the Mediterranean area, being associated with a more severe clinical course compared to HBeAg positive cases. The response to interferon therapy in patients with anti-HBe positive chronic hepatitis B has been recently investigated in control trials. These studies have shown that normalization of ALT with efficient suppression of virus activity can be achieved in 50-80% of patients while treated with interferon alpha indicating that also the pre-core mutant of HBV is sensitive to the antiviral effect of interferon. However, reactivation of hepatitis occurs in a variable percentage of initial responders when interferon is stopped. The probability of reactivation increases when the disease is of long duration, when cirrhosis is present and particularly if the pre-core mutant of HBV has become the predominant type of circulating virus, indicating that this HBV variant is more resistant to immunoclearance compared to wild type HBV.

Chronic Disease↗
PubMed1994

A randomized controlled trial of thymopentin therapy in patients with chronic hepatitis B.

Strategies of treatment of chronic hepatitis type B are currently based on the use of either antiviral or immunomodulatory agents. A randomized, controlled trial was performed to assess the safety and efficacy of 6-month thymopentin therapy in 30 patients with chronic hepatitis B. Inclusion criteria were biopsy-proven chronic hepatitis, elevated alanine aminotransferase and serum HBsAg and HBV-DNA positivity for at least 12 months. At the conclusion of the study (1 year), HBV-DNA was negative and alanine aminotransferase had normalized in 13% and 20% of treated cases and in 20% and 27% of controls. None of the ten treated and one of the nine control patients who were initially HBeAg positive subsequently cleared HBeAg. None became HBsAg negative. A histologic improvement was noted in 27% of the treated patients compared with 18% of controls. These results indicate that this regimen of thymopentin therapy is not effective in treating chronic hepatitis B.

Adult↗
PubMed1994

Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP).

A multicenter longitudinal study was performed to assess the survival of hepatitis B surface antigen positive compensated cirrhosis, primarily in relation to hepatitis B virus replication and hepatitis delta virus infection, and to construct a prognostic index based on entry characteristics. This cohort study involved nine university medical centers in Europe. Three hundred and sixty-six Caucasian HBsAg positive patients with cirrhosis who had never had clinical manifestations of hepatic decompensation were enrolled and followed for a mean period of 72 months (6 to 202 months). Inclusion criteria were biopsy-proven cirrhosis, information on serum hepatitis B e antigen and antibody to hepatitis D virus at the time of diagnosis and absence of complications of cirrhosis. At entry 35% of the patients were HBeAg positive, 48% of the patients tested were HBV-DNA positive and 20% anti-HDV positive. Death occurred in 84 (23%) patients, mainly due to liver failure (45 cases) or hepatocellular carcinoma (23 cases). The cumulative probability of survival was 84% and 68% at 5 and 10 years, respectively. Cox's regression analysis identified six variables that independently correlated with survival: age, albumin, platelets, splenomegaly, bilirubin and HBeAg positivity at time of diagnosis. According to the contribution of each of these factors to the final model, a prognostic index was constructed that allows calculation of the estimated survival probability. No difference in survival of hepatitis D virus infected and uninfected patients was observed. Termination of hepatitis B virus replication and/or biochemical remission during follow up correlated with a highly significant better survival. These data show that in compensated cirrhosis B, hepatitis B virus replication, age and indirect indicators of poor hepatic reserve and established portal hypertension significantly worsen the clinical course of the disease, whereas hepatitis D virus infection does not influence the prognosis. The highly significant improvement in life expectancy following cessation of hepatitis B virus replication and biochemical remission favors antiviral therapy in those patients with a guarded prognosis, as estimated by a prognostic index.

Adult↗