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Hepatic iron contents and response to interferon-alpha in patients with chronic hepatitis C. Relationship to genotypes of hepatitis C virus.

Recent reports have shown that response to interferon treatment is influenced by hepatic iron contents in patients with chronic hepatitis C. In those reports, however, hepatitis C virus (HCV) genotypes and serum HCV-RNA levels were not examined. The aim of the present study was to investigate whether hepatic iron contents influence the response to interferon in patients with chronic hepatitis C and whether HCV genotypes and serum HCV-RNA levels play a role in this relationship. Among 65 patients with chronic hepatitis C, hepatic iron contents were significantly high in patients with a history of excess drinking of alcohol (more than 80 g/day) compared to those without, and significantly low in female patients before menopause. Having excluded these patients, hepatic iron contents were significantly higher in patients with genotype 1b infection than those with genotype 2a and 2b infection. There was no significant correlation between hepatic iron contents and plasma HCV-RNA levels. Among the patients with genotype 1b infection, hepatic iron contents were significantly lower in the responders to interferon than those in the nonresponders (429 +/- 100 vs 875 +/- 110 micrograms/g liver, P < 0.05). From these results, it is concluded that response to interferon is mainly influenced by HCV genotypes, while hepatic iron contents may play an important role in response to interferon in patients with genotype 1b infection.

Adolescent↗

Prevalence of antibodies to hepatitis C virus in Chinese patients with viral hepatitis and hepatic failure.

Anti-HCV assay with ORTHO kits was done in 100 blood donors and recipients and 374 cases of viral hepatitis, including 65 cases of fulminant, subacute and chronic hepatic failure. None of the 100 blood donors and recipients showed positive anti-HCV response. Anti-HCV was positive in 7.6% of the patients with chronic persistent hepatitis, 9.7% of the patients with chronic active hepatitis and 23.1% of the patients with liver cirrhosis. High prevalence of anti-HCV was observed in subacute hepatic failure (60.8%) and chronic hepatic failure (53.9%). Fifty-two (83.9%) of 62 anti-HCV positive cases were infected concurrently with HBV. The incidence of HBV replicating marker in patients with HCV or co-infected with HBV was lower than that of those with HBV alone. It is suggested that HCV might inhibit the replication of hepatitis B virus. The mortality rate of patients with anti-HCV positive hepatic failure was higher than that of those with HBV infection. Therefore, anti-viral therapy for anti-HCV positive hepatic failure should be considered.

Adolescent↗

Hepatitis C virus eradication associated with hepatitis B virus superinfection and development of a hepatitis B virus specific T cell response.

BACKGROUND/AIMS: Specific T cell responses during acute hepatitis B and during chronic hepatitis C have been described in detail. However, the T cell responses during the rare setting of acute hepatitis B virus (HBV) infection in the course of chronic hepatitis C that eventually lead to clearance of both viruses are completely unknown. METHODS: We analyzed the virus specific CD4+ and CD8+ T cell response during an acute HBV superinfection in a patient with chronic hepatitis C. RESULTS: The patient eliminated hepatitis C virus (HCV)-RNA and HBV-DNA from serum soon after the clinical onset of acute hepatitis B. The HBV specific T cell response found in this patient corresponds to the typical response that has been described in acute hepatitis B without chronic HCV infection. In contrast the hepatitis C specific immune response was similar to that generally found in chronic hepatitis C despite the fact that the patient also eliminated HCV-RNA. CONCLUSIONS: We hypothesize that the acute HBV infection induced a HBV specific T cell response which was associated with elimination HBV DNA and HCV-RNA, the latter possibly by bystander mechanisms, e.g. via secretion of cytokines. If such a non-specific bystander mechanism which has proven to be effective in the experimental setting and which is formally described here for a single patient can be shown to be a more general phenomenon, it may support the approach with new antiviral strategies, e.g. the induction of non-specific defense mechanisms against HCV.

Acute Disease↗

Concurrent emergence of hepatitis B e antigen-negative hepatitis B virus variant and autoimmune hepatitis cured by adenine arabinoside monophosphate.

We report the case of a hepatitis B virus chronic carrier in whom features of severe autoimmune hepatitis developed concurrently with the emergence of a hepatitis Be antigen-negative variant. Corticosteroid administration failed to normalize serum transaminase activity and resulted in increased viral multiplication. Adenine arabinoside monophosphate treatment allowed simultaneous inhibition of hepatitis B virus multiplication and remission of autoimmune features. This observation indicates that hepatitis Be antigen-negative variants can induce autoimmune hepatitis and adds support to the hypothesis that autoimmune hepatitis can be triggered by hepatotropic viruses. Patients with both features should first be treated with adenine arabinoside monophosphate. This observation indicates that hepatitis Be antigen-negative variants can induce autoimmune hepatitis and adds support to the hypothesis that autoimmune hepatitis can be triggered by hepatotropic viruses. Patients with both features should first be treated with adenine arabinoside monophosphate.

Antiviral Agents↗

Absence of hepatitis B virus DNA in patients with hepatitis C and non-A-E hepatitis in the State of São Paulo, Brazil.

Occult hepatitis B virus (HBV) infection has been reported as cases in which HBV DNA was detected despite the absence of any HBV serological markers or in cases in which anti-HBc antibody was the sole marker. The aim of the present study was to determine, using the polymerase chain reaction (PCR), whether HBV infection occurs in hepatitis C and non-A-E hepatitis patients without serological evidence of hepatitis B infection in Sao Paulo State. Two different populations were analyzed: 1) non-A-E hepatitis patients, including 12 patients with acute and 50 patients with chronic hepatic disorders without serological evidence of infection with known hepatitis viruses; 2) 43 patients previously diagnosed as hepatitis C with positive results for anti-HCV and HCV RNA. Among hepatitis C patients, anti-HBc was detected in 18.6% of the subjects. Three different sets of primers were employed for HBV DNA detection by nested PCR, covering different HBV genes: C, S and X. HBV-DNA was not detected in any sample, whereas the positive controls did produce signals. The lack of HBV DNA detection with these pairs of primers could be due to a very low viral load or to the presence of mutations in their annealing sites. The latter is unlikely as these primers were screened against an extensive dataset of HBV sequences. The development of more sensitive methods, such as real time PCR, to detect circular covalent closed DNA is necessary in order to evaluate this question since previous studies have shown that cryptic hepatitis B might occur.

Brazil↗

Polymerase chain reaction analysis for viral nucleic acids in acute sporadic hepatitis patients negative for serum hepatitis B surface antigen and antibodies to hepatitis C virus.

BACKGROUND: Polymerase chain reaction (PCR) is both very sensitive and very valuable in the clarification of the pathogenesis of viral hepatitis from type A to E (HAV to HEV). METHODS: This study was aimed to detect viral nucleic acids with PCR in 33 consecutive, acute sporadic hepatitis patients who were seronegative for hepatitis B surface antigen and antibody to hepatitis C virus by conventional radioimmununoassay or enzyme-linked immunoassay. RESULTS: Of the totals, 10 (30.3%) had detectable viral genomes. HBV DNA and HCV RNA were each detected in 2 (7.4%) of 27 patients with a self-limiting course. By contrast, HBV DNA was detected in the two (33.3%, p = 0.14) and HCV RNA in the three (50%, p = 0.03) of the six patents who became chronic; another one who had subsequent multiple exacerbations of hepatitis was positive for both HBV DNA and HCV RNA. HDV RNA was not detectable in all subjects. Although four (12.1%) were positive for antibody against HEV, none had detectable HEV RNA. Spontaneous disease resolution predominantly occurred in patients without detectable hepatitis B and hepatitis C genomes (100% of 23 patients vs 40% of 10 patients, p < 0.01). CONCLUSIONS: These results demonstrate that a combination of serological and molecular tests is mandatory for the appraisal of acute sporadic non-B non-C hepatitis and its clinical prognosis, they also raise the possibility of a hepatotrophic agent other than HAV to HEV. Recent documentation of the new GBV-C (hepatitis G virus) suggests the necessity of studying the unidentified pathogenesis in patients with non-A to E hepatitis.

Acute Disease↗

Diagnostic advances in viral hepatitis: the discovery of hepatitis C virus and genetic heterogeneity of hepatitis B virus.

The discovery of hepatitis C virus (HCV) and its serological markers represents a new milestone in the history of viral hepatitis and allows a specific diagnosis of viral hepatitis in more than 90 percent of cases. In addition, testing for anti-HCV plays a crucial role in prevention of post-transfusion non-A, non-B hepatitis. The multifaceted spectrum of liver disease associated with hepatitis B virus (HBV) infection, spanning from a healthy carrier state to severe forms of chronic hepatitis, was traditionally attributed to variability of host's antiviral immune response. The finding that a peculiar natural course and response to interferon of chronic hepatitis B is associated with the infection of a defective HBV unable to secrete the "e" antigen (HBeAg-minus) emphasizes the clinical implications of the genetic heterogeneity of hepatitis viruses.

Biomarkers↗

Prospective assessment of donor blood screening for antibody to hepatitis C virus and high-titer antibody to hepatitis B core antigen as a means of preventing post-transfusion hepatitis.

Since November 1989, the Japan Red Cross has been screening blood donors for hepatitis C virus antibody (anti-HCV) with 1st generation assay and high-titer antibody to hepatitis B virus core antigen (HBcAb). To clarify the effectiveness of the new screening tests for the prevention of post-transfusion hepatitis, the incidence of post-transfusion hepatitis after the introduction of new tests (December 1989 to September 1990) was compared with the incidence before the in introduction (January 1982 to December 1987). The incidence of "definite" post-transfusion hepatitis was 10.3% (205/1991) with a mean transfusion volume of 10.2 units before the screening, and 3.9% (11/282) with a mean transfusion volume of 14.6 units after the introduction of the new screening tests. Statistical analysis revealed a significant decrease of post-transfusion non-A, non-B hepatitis after the introduction of new tests (chi 2 = 10.9, P < 0.01). The incidence of "probable" post-transfusion hepatitis was 12.4% (246/1991) and 11.7% (33/282) respectively. No significant change was observed between the rates of "probable" post-transfusion hepatitis before and after the introduction of the new tests. It was concluded that anti-HCV and high-titer anti-HBc screening of volunteer blood donors could contribute to the prevention of the post-transfusion non-A, non-B hepatitis in Japan.

Blood Donors↗

[The relationship between hepatic expression, serum level of TGFbeta1 and the hepatic fibrosis in patients with viral hepatitis].

OBJECTIVE: To detect the hepatic tissue and serum level of TGFbeta1 in patients with viral hepatitis, in order to clarify their relationship of the starting, developing of hepatic fibrosis. METHODS: This study included 92 patients with viral hepatitis. Liver puncture was performed in 31 patients. Hepatic collagen staining (Masson's three colors) and TGFbeta1 immunohistochemistry staining of the liver tissue specimens were performed, morphometric quantitative measurements of hepatic histological collagen and TGFbeta1 were made. The serum level of TGFFbeta1 was detected by ELISA. RESULTS: The surface density of hepatic TGFbeta1 increased linearly with the elevation of fibrosis stage (P < 0.05), there were no significant differences between every two groups of G1, G2, G3 and G4 (P > 0.005). There was a closely positive correlation between the levels of TGFbeta1 in hepatic tissue and serum, the coefficient was 0.896 (P < 0.01). The levels of TGFbeta1 in tissue and serum both had positive correlation with hepatic collagen, coefficients were 0.863 and 0.667 (P < 0.001). The level of TGFbeta1 in tissue and serum both had positive correlation with serum levels of PCIII, HA, LN, CIV (P < 0.001). CONCLUSIONS: There was a closely relationship between the levels of TGFbeta1 in hepatic tissue and serum and liver fibrosis. The detection of TGFbeta1 in liver and serum are more sensitive than HA, LN, CIV in early period of hepatic fibrosis.

Adolescent↗

Regulation of biliary cholesterol output in the rat: dissociation from the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, and the hepatic uptake of chylomicron cholesterol.

These studies were designed to determine the importance of the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, the amount of chylomicron cholesterol reaching the liver, and the rate of bile acid transport into bile as determinants of the rate of biliary cholesterol output. Female rats that had been subjected to diurnal light cycling, fasting for 48 hr, intravenous administration of chylomicrons, and diets containing either cholestyramine, cholesterol, or bile acid underwent total biliary diversion for 2 hr. The animals were then killed and the rates of hepatic cholesterol synthesis and levels of hepatic esterified cholesterol were measured along with biliary lipid concentrations. Despite a 1000-fold variation in the rate of hepatic cholesterogenesis and a 100-fold variation in the levels of cholesteryl esters, the output and molar percentage of cholesterol in bile remained essentially constant with the exception of an approximate doubling in the output of cholesterol, as well as of bile acid and phospholipid in those animals fed bile acid. However, in this latter group the molar percentage of each component was unchanged. The administration of a bolus of chylomicrons did not alter output or molar percentage of cholesterol. Total biliary diversion for 36 hr and bile acid infusion were used to markedly vary the rate of biliary bile acid output. Cholesterol and phospholipid output remained tightly coupled to bile acid output over almost a 40-fold range. In other experiments it was shown that biliary cholesterol output could be driven by bile acid infusion to a similar extent in rats in which the rate of hepatic cholesterogenesis had been varied over a 26-fold range. It was concluded that the rate of hepatic cholesterol synthesis, the level of hepatic cholesteryl esters, and the amount of cholesterol absorbed from the diet play no role in determining the rate of biliary cholesterol secretion, at least in this species.-Turley, S. D., and J. M. Dietschy. Regulation of biliary cholesterol output in the rat: dissociation from the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, and the hepatic uptake of chylomicron cholesterol.

Animals↗

19S and 7-8S forms of IgM antibody to hepatitis B core antigen in acute icteric hepatitis superimposed on hepatitis B surface antigen carriage.

The 19S and 7-8S forms of IgM antibody to hepatitis B core antigen (IgM anti-HBc) were separated by rate-zonal centrifugation from the serum of 20 Greek hepatitis B surface antigen (HBsAg) carriers with a superimposed acute icteric hepatitis positive for IgM anti-HBc by a radioimmunoassay. Serological markers of hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis D virus (HDV) infections were detected with radioimmunoassays and serum HBV DNA was detected with molecular hybridization techniques. Eighteen of the 20 carriers showed a predominance of one or the other form of IgM anti-HBc. Low molecular weight (7-8S) IgM anti-HBc was observed more frequently in HDV superinfection (5/9) and was related to a low mortality (1/9). In contrast, 19S IgM anti-HBc was observed more frequently in reactivation of chronic hepatitis B (6/9) and was related to a high mortality (5/9). These preliminary data show that in HBsAg carriers with a superimposed acute icteric hepatitis, predominance of 19S IgM anti-HBc is frequently associated with a severe clinical course; the opposite is true for predominance of 7-8S IgM anti-HBc.

Acute Disease↗

Hepatitis B prevention strategies: a benefit-cost analysis of immune serum globulin, hepatitis B immune globulin, and hepatitis B vaccine in the military.

The new hepatitis B vaccine is an effective method of preventing hepatitis B infection. However, its expense could contribute greatly to health care costs, with little marginal benefit if it is used indiscriminately. This study analyzes the relative risk of hepatitis among various health care workers to determine the relative merits of a vaccine strategy. It was found that the average cost of a hepatitis B vaccine in health care facilities is greatly reduced the closer the worker is to a dialysis unit. This might justify not using the vaccine at all in health care workers at facilities without dialysis. Analyzing the marginal cost of immune serum globulin (ISG) versus hepatitis B immune globulin (HBIG) and hepatitis B vaccine in a needle-stick protocol, it was determined that the increased protection provided by HBIG and hepatitis B vaccine comes at a cost that would be considered prohibitive by many prudent decision-makers. A separate analysis of the use of hepatitis B vaccine versus ISG in troops assigned to Korea found that most decision-makers might think the cost of hepatitis B vaccine prohibitive, with the benefits mostly speculative and unproved. Data are not available that would allow a benefit-cost analysis of hepatitis B vaccine in most dental personnel.(ABSTRACT TRUNCATED AT 250 WORDS)

Costs and Cost Analysis↗

Role of hepatitis C virus infection in spontaneous hepatitis B surface antigen clearance during chronic hepatitis B virus infection.

To examine the role of hepatitis C virus (HCV) infection in spontaneous hepatitis B surface antigen (HBsAg) clearance during the course of chronic hepatitis B virus (HBV) infection, serum specimens from 32 asymptomatic HBsAg carriers and 22 patients with chronic hepatitis type B who underwent spontaneous HBsAg clearance were studied for antibody to HCV (anti-HCV) using commercial EIAs. The results were compared with those of control groups matched for age, sex, hepatitis B e antigen, antibody to hepatitis delta virus, and cirrhosis. Eight (25%) of the asymptomatic carriers and 9 (41%) of the patients with chronic hepatitis were seropositive for anti-HCV in contrast to 1.6% and 9.1% of their respective control groups (P less than .01). Serum alanine aminotransferase level was persistently abnormal after HBsAg clearance in one asymptomatic carrier and in four patients with chronic hepatitis. These patients were seropositive for anti-HCV and at least one of them was negative for HBV-DNA by polymerase chain reaction. The data suggest that HCV superinfection may not only suppress HBV or terminate the HBsAg carrier state but may also assume the role of HBV as the cause of persistent hepatitis or transaminase elevation.

Adult↗

Long-term persistence of hepatitis B virus DNA in the serum of children with chronic hepatitis B after hepatitis B e antigen to antibody seroconversion.

To evaluate the prevalence and duration of viremia in relation to the features of liver disease, we investigated hepatitis B virus (HBV) DNA by the polymerase chain reaction in the serum of 39 children with chronic hepatitis B, after hepatitis B e antigen to antibody seroconversion. During a mean observation period of 8.2 +/- 3.8 years after seroconversion, all patients were asymptomatic; 36 had persistently normal alanine aminotransferase levels, and three had occasional mild alterations. Liver histology, checked in 21 patients, showed persistent hepatitis in nine, fibrosis in 10, and cirrhosis in two cases. HBV DNA was always undetectable by dot blot hybridization. Five children eventually cleared hepatitis B surface antigen, including one with cirrhosis who developed liver cancer at 19 years. HBV DNA was detected by polymerase chain reaction in 87% of children within 5 years of follow-up, in 58% of cases 6-10 years after seroconversion (p < 0.001), and in 50% of patients investigated later. Long-term viremia was found in two patients (40%) who cleared HBsAg, including the one who developed liver cancer. The chances of clearing viremia during follow-up were higher in children with acute hepatitis at the onset of illness (86%) than in those with asymptomatic onset (37%; p < 0.05). Our results show that low levels of HBV viremia, probably reflecting low levels of virus replication, persist for several years in children with chronic hepatitis B after hepatitis B e antigen to antibody seroconversion and remission of liver disease, even after the clearance of hepatitis B surface antigen. Persistent replication could support mild biochemical alterations and inflammatory liver lesions. It could allow late reactivation of liver disease and may play a role in the development of carcinoma.

Alanine Transaminase↗

Evolution of acute hepatitis B in homosexual men to chronic hepatitis B. Prospective study of placebo recipients in a hepatitis B vaccine trial.

To determine whether the frequency of chronic hepatitis B in homosexual men reflects the high rate of acute hepatitis B or an altered response to hepatitis B, 236 homosexual men were prospectively followed up after entry into the placebo group of a hepatitis B vaccine trial. Sixty-six participants (28.0%) developed hepatitis B ten to 18 months after entering the study. Only four (6.1%) of the 66 had persistence of hepatitis B beyond six months, similar to reports in nonhomosexual subjects. This study suggests that the high rate of acute hepatitis B is the major factor contributing to the high prevalence of chronic hepatitis B in homosexual men, rather than an altered host response. Clinical features of the acute illness could not be used to identify patients who developed chronic hepatitis B.

Acute Disease↗