Responsiveness to interferon alpha treatment in patients with chronic hepatitis C coinfected with hepatitis G virus

BACKGROUND/AIMS: Patients with chronic hepatitis C are often coinfected with the new identified Flaviviridae-like agent, termed hepatitis G virus (HGV). The aim of the study was to investigate the responsiveness of hepatitis G virus to interferon alpha and to evaluate whether a hepatitis G virus coinfection negatively influences the outcome of treatment in chronic hepatitis C. METHODS: One hundred and fifteen patients with histologically proven chronic hepatitis C were treated with interferon alpha and investigated for the presence of hepatitis G virus coinfection by nested polymerase chain reaction with primers from the helicase region of hepatitis G virus. All patients received at least 3 MU (range 3-6) interferon alpha thrice weekly for at least 6 months (mean 8, range 6-12). Polymerase chain reaction products of seven pre- and post-treatment hepatitis G virus positive patients were directly sequenced for identification of sequence variability during the follow-up. RESULTS: Eighteen (16%) patients were coinfected with hepatitis G virus. Although nine (50%) of these patients became HGV RNA negative during interferon alpha therapy, only three patients (17%) remained HGV RNA negative at the end of follow-up (mean 24 months). The rate of sustained response of chronic hepatitis C was not significantly different between patients with hepatitis C virus infection and HCV/HGV coinfection (19% vs 28%). Severity of liver disease as determined by alanine aminotransferase levels, histology and hepatitis C virus viremia was not significantly different in patients with hepatitis C virus or HCV/HGV coinfection. Sequence analysis of the helicase region revealed that our isolates all belonged to the hepatitis G virus and not to the GBV-C like genotype. No amino acid exchanges during the observation period of up to 48 months were observed, indicating that this region is highly conserved. CONCLUSIONS: The responsiveness of hepatitis G virus to interferon alpha in chronic HCV/HGV coinfected patients is similar to that observed in chronic hepatitis C. Hepatitis G virus coinfection seems not to interfere with the efficacy of interferon alpha treatment in patients with chronic hepatitis C.     

Neuronal activity in MST and STPp, but not MT changes systematically with stimulus-independent decisions

Recurrent infection with hepatitis C virus (HCV) is almost universal following orthotopic liver transplantation although clinical severity varies. Data on 135 patients who underwent transplantation for hepatitis C cirrhosis were reviewed. We describe a progressive, severe cholestatic form of hepatitis occurring in a subgroup of patients with recurrent hepatitis C. Ten patients with severe recurrent hepatitis C were identified; 1 has died, 1 awaits retransplantation, and 8 have undergone retransplantation. All 10 developed severe progressive cholestatic hepatitis, with a mean rise in bilirubin to 24.7 mg/dL at the time of retransplantation. Histology at initial recurrence was of mild hepatitis without evidence of rejection. The failed grafts showed either cirrhosis or confluent hepatic necrosis. The onset of cholestasis preceded retransplantation by less than 5 months. Our study suggests that a minority of patients with recurrent hepatitis C after undergoing liver transplantation develop a severe progressive cholestatic hepatitis and liver failure.     

Detection of hepatitis E virus genome and gene products in two patients with fulminant hepatitis E

Non-isotopic in situ hybridization (digoxigenin-labeled probe directed towards hepatitis E virus ORF1) and immunohistochemistry (against hepatitis E virus ORF2 and ORF3) were applied to detect hepatitis E virus genome and gene product in the liver tissue of two patients with fulminant hepatitis E seropositive for hepatitis E virus RNA. Both hepatitis E virus RNA and hepatitis E virus antigens were detected exclusively in the cytoplasm of hepatocytes and not detected in other cell types. In both patients, more than 50% of the hepatocytes were positive for both hepatitis E virus RNA and hepatitis E virus antigens, most of which showed degenerative changes. This is consistent with the histological appearance of marked loss of hepatocytes with acinar collapse. Interestingly, denaturation of the RNA before in situ hybridization was found to enhance hepatitis E virus RNA detection. We conclude that: (1) hepatitis E virus RNA and hepatitis E virus antigens can be demonstrated in the liver in hepatitis E virus-related fulminant hepatitic failure, (2) hepatitis E virus is hepatocyte-tropic within the liver, (3) cytoplasmic localization of hepatitis E virus RNA and hepatitis E virus antigens is consistent with cytoplasmic replication, and (4) the presence of degenerative changes in hepatitis E virus positive cells, together with the histological appearance of hepatocyte loss in the absence of significant inflammatory infiltrate, suggests that hepatitis E virus-related fulminant hepatitic failure is mediated by a cytopathic mechanism.     

Serum hepatitis G virus RNA in patients with chronic viral hepatitis

OBJECTIVES: The hepatitis G virus (HGV) is a newly described flavivirus that affects a high proportion of patients with chronic viral hepatitis: our objective was to determine what role HGV might play in the course of disease. METHODS: We evaluated stored serum samples from 108 patients with chronic hepatitis B and 99 patients with chronic hepatitis C who participated in trials of alpha-interferon or ribavirin for the presence of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA by branched DNA and for the presence of HGV RNA by polymerase chain reaction (PCR), using primers from the NS5 region of the genome. RESULTS: Initially, 20 (19%) patients with hepatitis B and 11 (11%) with hepatitis C had HGV RNA in their serum. Patients with and without HGV infection were similar with regard to clinical features, laboratory tests, and hepatic histology. HGV RNA levels fell during interferon therapy and became undetectable in those receiving the highest doses; however, HGV RNA levels returned to pretreatment values when therapy was stopped. With ribavirin therapy, HGV RNA levels did not change. Two- to 12-yr follow-up serum samples were available from 17 initially HGV RNA-positive patients, of whom only 10 (59%) were still positive. CONCLUSIONS: HGV infection is common among patients with chronic hepatitis B and C but has little effect on the short-term course of disease or response to therapy. HGV RNA levels are suppressed but not eradicated by alpha-interferon and are unaffected by ribavirin treatment. Spontaneous loss of HGV RNA occurs over time in a proportion of patients.     

Importance of health education at a secondary school: experience with a course on viral hepatitis

The hepatitis C virus is the main causative agent for sporadic as well as parenteral cases of non-A non-B hepatitis. Alpha interferon is a biologically active protein produced by B lymphocytes and monocytes which can be manufactured by recombinant DNA technology. Treatment of chronic hepatitis C with interferon in adults is associated with a sustained response in 20-25% of treated cases. First studies provide encouraging results for the use of interferon in the treatment of chronic hepatitis C in children, but controlled trials using this drug in a larger population of children are needed.     

A histopathological study of alcoholics with chronic HCV infection: comparison with chronic hepatitis C and alcoholic liver disease

To clarify the relationship between hepatitis C virus infection and excessive alcohol intake, we carried out histological examination of the liver in 46 alcoholics with chronic hepatitis C virus infection and compared the findings in 55 patients with chronic hepatitis C, 38 with alcoholic liver disease, and 27 with chronic hepatitis B. The majority of alcoholics with chronic hepatitis C virus infection displayed virus-related histological changes very similar to those in chronic hepatitis C, including frequent lymphoid follicles (34.7%) or aggregates (93.3%) in the portal tracts, mild necroinflammatory change (76.1%) in the parenchyma, and lymphocytosis in sinusoids (83.7%). Liver cell dysplasia and irregular regenerative activity of hepatocytes were rarely observed. The effects of alcohol on the liver were found to be minimal in the majority. These findings could suggest that the hepatic injury in the majority of alcoholics with chronic hepatitis C virus infection in Japan is due to persistent hepatitis C virus infection rather than to alcoholic injury. In addition, our study disclosed that the perivenular fibrosis which is designated as a histological characteristic of alcoholic liver disease is frequently observed in chronic hepatitis C. These similarities suggest that a similar fibrogenesis is present in chronic hepatitis C and alcoholic liver disease.     

Hepatitis B virus with X gene mutation is associated with the majority of serologically "silent" non-b, non-c chronic hepatitis

Hepatitis B virus (HBV) with X gene mutations has been a putative pathogen of chronic hepatitis without serological markers of known hepatitis viruses. The aim of this study was to reconfirm whether the HBV with the X gene mutation is associated with these serologically "silent" non-B, non-C (NBNC) chronic hepatitis, alcoholic liver disease (ALD) and autoimmune hepatitis (AIH). HBV DNA was amplified from serum and sequenced in 30 patients with NBNC chronic hepatitis in comparison with 20 patients with ALD and 5 patients with AIH. HBV DNA was identified in 21 patients (70%) in NBNC chronic hepatitis by nested polymerase chain reaction while only one patient (5%) in ALD and none in AIH showed HBV DNA. Eighteen (85.7%) of the 21 identified HBV DNAs had an identical 8-nucleotide deletion mutation at the distal part of the X region. This mutation affected the core promoter and the enhancer II sequence of HBV DNA and created a translational stop codon which truncated the X protein by 20 amino acids from the C-terminal end. All the HBV DNAs had a precore mutation at the 83rd nucleotide resulting in disruption of HBe antigen synthesis. These results indicate that HBV mutants are closely associated with the majority of serologically "silent" NBNC chronic hepatitis cases and the population of such mutant HBV DNAs is not uniform.     

Dilated cardiomyopathy associated with hepatitis C virus infection

BACKGROUND: Myocarditis is thought to be commonly caused by various viruses, and accumulating evidence links viral myocarditis with the eventual development of dilated cardiomyopathy. In many cases, however, the evidence is only circumstantial, and direct conclusive proof is not available. Polymerase chain reaction (PCR) has been used to detect enterovirus RNA in myocardial tissue, but the wide discrepancy in results emphasizes the need for further study. METHODS AND RESULTS: We investigated hepatitis C virus infection in patients with dilated cardiomyopathy. The presence, type, and quantity of hepatitis C virus RNA were evaluated in the sera, and the presence of positive and negative strands of hepatitis C virus RNA in the heart was investigated with the PCR technique. Anti-hepatitis C virus antibody was present in the sera of 6 of 36 patients (16.7%) with dilated cardiomyopathy and in 1 of 40 patients (2.5%) with ischemic heart disease, showing a statistically significant (P < .05) difference. At an earlier time, acute myocarditis was suspected in 3 patients who had developed acute onset of heart failure, and the diagnosis was confirmed by endomyocardial biopsy in 1 patient. Hepatitis C virus RNA was present in the sera of 4 of the 6 patients, and all 4 had hepatitis C virus type II. The copy number of hepatitis C virus RNA in the serum was 8 x 10(2) to 2 x 10(3) genomes per 1 mL serum. Positive strands of hepatitis C virus were found in the hearts of 3 patients, and negative strands of hepatitis C virus were detected in the heart of 1 patient. CONCLUSIONS: The results suggest that hepatitis C virus infection is frequently found in patients with dilated cardiomyopathy and that hepatitis C virus is an important causal agent in the pathogenesis of the disease. Antiviral therapy against hepatitis C virus may be indicated in these patients.     

GB virus C infection in patients with primary antibody deficiency

Sera from 77 patients with common variable immunodeficiency (CVID) were tested for GB virus C (GBV-C) RNA, because they are prone to unexplained chronic hepatitis, and from 28 patients with X-linked agammaglobulinemia (XLA) who have a similar primary antibody deficiency but are not prone to hepatitis. Eight CVID and 8 XLA patients were positive; 6 positive CVID and 3 XLA patients had abnormal liver enzymes, explained in 3 by either hepatitis B or C virus infection. Most patients tested had antibodies to the E2 antigen of GBV-C, apparently passively acquired from their immunoglobulin therapy. The high prevalence of GBV-C viremia in CVID and XLA patients is probably explained by their long-term exposure to blood products. Our data indicate that GBV-C does not cause chronic hepatitis in immunocompromised XLA patients and is not the cause of chronic non-B or -C hepatitis in the majority of CVID patients.     

Hepatitis B and C virus infections in children with congenital coagulation disorders

The prevalence of hepatitis B and C virus infections, transmitted by blood transfusions, was studied in 79 children with congenital coagulation disorders. Twenty nine percent had evidences of hepatitis B virus infection and 52% evidences of hepatitis C virus infection. Older children and those with the higher number of transfusions had the highest rates of infections. It is concluded that children with congenital coagulation disorders constitute a high risk group for hepatitis B and C virus infections.     

Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease

Acute hepatitis A superimposed on chronic liver disease (CLD) has been associated with severe or fulminant hepatitis. An open, multicenter study was performed to compare the safety and immunogenicity of an inactivated hepatitis A vaccine in patients with CLD with that in healthy subjects. A secondary objective was to compare the safety of the hepatitis A vaccine with that of a commercial hepatitis B vaccine in subjects with chronic hepatitis C. A total of 475 subjects over the age of 18 years were enrolled into 1 of 5 groups according to history, serological data, and previous diagnosis. Patients in groups 1 (healthy adults), 2 (chronic hepatitis B), 3 (chronic hepatitis C), and 5 (other CLD not caused by viral hepatitis) were vaccinated with two doses of inactivated hepatitis A vaccine, 6 months apart. Patients in group 4 (chronic hepatitis C) received 3 doses of a recombinant hepatitis B vaccine, according to a 0-, 1-, and 6-month schedule. Local injection-site symptoms were the most common reactions reported following vaccination in all groups (35.5% of all doses), with the hepatitis B vaccine eliciting fewer injection-site symptoms than the hepatitis A vaccine (19.8% compared with 37.5%). Although a higher percentage of healthy subjects (93%) seroconverted after a single dose of the hepatitis A vaccine than did subjects with chronic hepatitis C (73.7%) or CLD of nonviral etiologies (83.1%), more than 94% of all vaccinees were seropositive for anti-HAV after the complete vaccination course. At each time point, a lower geometric mean concentration of anti-HAV was observed for each group of CLD patients compared with the healthy control subjects. In conclusion, hepatitis A vaccine was well tolerated and induced a satisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.     

Serum hepatocyte growth factor activity and hepatocyte proliferation in Long-Evans with a cinnamon-like coat color rats with hepatic lesions

We classified hepatic lesions spontaneously developed by Long-Evans with a cinnamon-like coat color (LEC) rats into the following four stages: Normal liver, acute hepatitis, chronic hepatitis, and hepatoma, by biochemical tests of the sera, and anatomical and histopathological examination of the livers. Hepatocyte growth factor (HGF) activity in the sera of LEC rats which developed acute hepatitis, chronic hepatitis, and hepatoma was higher than that of normal LEC rats. In particular, HGF activity in the sera of the LEC rats with acute hepatitis was about 70-fold that of normal LEC rats. However, primary cultured hepatocytes of LEC rats with hepatic lesions were hardly proliferated by stimulation with EGF and insulin in vitro or with increased HGF in vivo. These results suggest that the hepatocytes of LEC rats with hepatic lesions disorder the signal transduction of growth factors.     

Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. A multicenter comparison study

To evaluate rectal mucosal hemodynamics in patients with chronic hepatitis, we employed reflectance spectrophotometry and examined the results in relation to the presence and severity of chronic hepatitis. Twenty-six patients with histologically diagnosed chronic hepatitis and 21 controls were examined for rectal vascular findings by endoscopy. Indices (I) of rectal mucosal oxygen saturation (ISO2) and rectal mucosal hemoglobin (IHb) concentration were measured. To minimize the effects of systemic anemia, the IHb was divided by blood Hb concentration, giving the rectal index for Hb (RHb). The relationship between rectal mucosal hemodynamics and the histological grade of chronic hepatitis was studied. Rectal vascular lesions were observed in three patients with chronic hepatitis (11.5%). The RHb in patients with chronic hepatitis was significantly higher than that in the controls (5.74 +/- 0.71 and 4.82 +/- 1.12, respectively; P < 0.01). There was no significant difference in ISO2 levels (44.23 +/- 5.84 and 41.94 +/- 4.91, respectively). No significant correlation was observed between rectal mucosal hemodynamics and the histological severity of chronic hepatitis, although rectal mucosal hemodynamics changed in patients with chronic hepatitis. Early vascular changes were observed in the rectal mucosa of patients with chronic hepatitis.     

Monitoring of antiviral therapy with quantitative evaluation of HBeAg: a comparison with HBV DNA testing

The serological endpoint of response in the treatment of chronic hepatitis B is the loss of hepatitis B virus DNA and HBeAg. Because the quantitative measurement of hepatitis B virus DNA in serum has been shown to be useful for monitoring and predicting response to interferon-alpha therapy, we decided to evaluate whether changes in HBeAg concentration could also be used in this manner. Twenty-nine patients who were initially positive for HBeAg and HBV DNA were serially evaluated for HBeAg concentration with a microparticle-capture enzyme immunoassay. HBeAg levels in serum were calculated by means of comparison with a standard curve of fluorescence rate vs. HBeAg concentration. The results, expressed in milliunits per milliliter, were compared with hepatitis B virus DNA levels determined by means of solution hybridization. The baseline HBeAg concentration proved to be the best independent predictor of response on stepwise Cox regression analysis (p = 0.026). Similar disappearance curves were observed for the two markers, although hepatitis B virus DNA became undetectable at an earlier interval in 13 of 16 cases (81%). In the 16 responders, a decline in HBeAg concentration of more than 90% was observed by wk 12 of therapy (mean +/- S.D., 95% +/- 13%). Nonresponders did not demonstrate such steep declines in HBeAg values by wk 12 (mean +/- S.D., 45% +/- 27%), and levels tended to increase at subsequent time points. We conclude that serial monitoring of HBeAg concentration with a technique that should be readily adaptable to clinical laboratories may be useful in the initial evaluation and monitoring of patients undergoing antiviral therapy.     

Functional analysis of HBV genomes from patients with fulminant hepatitis

Two previous case reports suggest that hepatitis B virus (HBV) core promoter variants with a high replication competence contribute to the pathogenesis of fulminant hepatitis B (FHB). We recently found in HBV genomes from patients with FHB an accumulation of mutations within the core promoter region. Therefore, the aim of this study was to investigate the phenotype of these HBV variants. Replication competence and expression of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) of viral genomes from seven patients with FHB and one patient with fulminant recurrent hepatitis after liver transplantation were analyzed by transfection experiments in human hepatoma cells. Compared with wild-type virus, the HBV variants from the seven patients with FHB produced similar or slightly lower levels of intracellular replicative intermediates and extracellular viral particles. In contrast, the HBV genomes from the patient with fulminant recurrent hepatitis synthesized and secreted significantly more HBV DNA. All genomes tested expressed similar or even higher levels of HBeAg compared with wild-type virus, except for those from four patients with a precore stop codon mutation in the respective dominant viral populations. The level of HBsAg produced by all variant genomes was similar or reduced compared with wild-type virus. These data indicate that in some cases HBV variants with enhanced replication competence and/or a defect in HBeAg expression may contribute to the development of FHB. However, neither phenotype is an essential prerequisite; thus, an additional role of other viral or host factors in the pathogenesis of FHB is suggested.     

Hepatitis G virus co-infection in liver transplantation recipients with chronic hepatitis C and nonviral chronic liver disease

Hepatitis G virus (HGV) is a newly described RNA virus that is parenterally transmitted and has been found frequently in patients with chronic hepatitis C infection. To determine the impact of hepatitis G virus co-infection on morbidity and mortality following liver transplantation, we measured HGV RNA by polymerase chain reaction in pre and posttransplantation sera from a cohort of patients transplanted for chronic hepatitis C and a control group of patients transplanted for nonviral causes who were negative for hepatitis C virus (HCV) RNA in serum. The overall prevalence rate of HGV RNA in transplanted patients with chronic hepatitis C was 20.7%. HGV infection was present before transplantation in 13% while it appeared to have been acquired at the time of transplantation in 7.4%. Mean serum alanine aminotransferase activity, hepatic histological activity, and patient and graft survival were similar between HGV-positive and HGV-negative patients. The prevalence rate of HGV RNA in transplanted controls was 64% (P < .01) with a significantly higher rate of acquisition of HGV infection following transplantation (53%, P < .001) when compared with patients with chronic hepatitis C. Mean serum alanine aminotransferase activity was significantly lower in the control patients with HGV infection alone following transplantation than in patients co-infected with hepatitis C (37 +/- 9 vs. 70 +/- 33 U/L, P < .01). Thus, HGV is frequently found in transplantation patients co-infected with hepatitis C although it appears to have minimal clinical impact. In patients transplanted for nonviral causes of end-stage liver disease, a high rate of hepatitis G acquisition at the time of transplantation may occur but does not appear to predispose to chronic hepatitis.     

Autoimmune hepatitis with antibodies against liver cytosol (anti-LC1)

Antibody against liver cytosol (anti-LC1) was proposed in 1988 as a new and very specific immunoserologic marker of autoimmune hepatitis of childhood and young age. In adults, anti-LC1 might be masked by the presence in serum of anti-LKM1, usually associated with antibodies to hepatitis-C virus. We report the case of a 60-year-old woman who had active chronic hepatitis not related to infection by hepatitis C virus, with autoantibody reacting against liver cytosol as the unique marker of autoimmune hepatitis. Treated with corticosteroids (prednisone, 1 mg/kg per day), coagulation disorder, bilirubin, transaminase activity and immunoglobulins normalized in the following months. A year and a half later, autoantibodies anti-LC1 and p-ANCAs were no longer detected. We have only found one report of a young patient with anti-LC1 autoimmune hepatitis who had cirrhosis and portal hypertension, in national publications.     

Serum IL-8 levels and localization of IL-8 in liver from patients with chronic viral hepatitis

BACKGROUND/AIMS: Interleukin 8 is known as a chemotactic factor for neutrophils and T cells. Such inflammatory cells are observed in the liver tissue in chronic viral hepatitis. However, it is not known whether interleukin 8 relates to hepatic injury in patients with chronic viral hepatitis. Therefore, we determined serum interleukin 8 levels and identified the cells related to interleukin 8 production in liver tissue. METHODOLOGY: Studies were performed on 29 patients with chronic viral hepatitis and 20 normal controls. Serum interleukin 8 levels were assayed using a sandwich ELISA. Immunohistochemical examination was performed to identify the cells related to interleukin 8 production by using a rabbit polyvalent antibody to human interleukin 8. RESULTS: Serum interleukin 8 levels were found to be increased significantly (p<0.05) in patients with chronic viral hepatitis compared with normal controls. They were also increased significantly in patients with chronic active hepatitis compared with chronic persistent hepatitis (p<0.05), and during exacerbation stages compared with remission stages (p<0.05). Out of the 10 patients examined immunohistochemically, interleukin 8 positive cells in the liver tissue were visualized in 7 patients and observed mainly along sinusoids. There was significant correlation between serum interleukin 8 levels and intensity of staining for interleukin 8 in the liver tissue (p<0.05, r=0.869). CONCLUSIONS: Interleukin 8 plays a role in hepatic injury in patients with chronic viral hepatitis, and is mainly produced by nonparenchymal cells in the liver.     

Polyarteritis nodosa associated with hepatitis C virus

BACKGROUND: To study the seroprevalence of hepatitis C virus in a cohort of six patients with a diagnosis of polyarteritis nodosa (PAN). METHODS: There have been included six patients with a diagnosis of PAN, carrying out a serodiagnosis of hepatitis B virus (VHB) and C (VHC) this last one by means of the following methods: ELISA, RIBA-II and PCR. RESULTS: These cases (50%) showed exclusive positivity to VHC by means of the three ways of diagnosis, two cases showed positivity to VHB (33.3%), one case (16.6%) showed positivity to both virus (VHB and (VHC) and one case didn't show positivity virus. CONCLUSIONS: It is probable a ethipatogenic relation between hepatitis C virus and polyarteritis nodosa, our sample doesn't show any difference from that written in the literature. The positive rheumatoid factors can give false positive for VHC by means of the technique ELISA because of this it is necessary to confirm the positive by means of the techniques RIBA-II and PCR.