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Biomedical subjects

H Yotsuyanagi

Publications and source records attributed to H Yotsuyanagi.

At least 19 recordsLinked to original sources
PubMed1998

Precore wild-type DNA and immune complexes persist in chronic hepatitis B after seroconversion: no association between genome conversion and seroconversion.

Precore hepatitis B virus (HBV) mutants may gradually prevail during or after seroconversion (SC) from hepatitis B e antigen (HBeAg) to hepatitis B e antigen antibody (anti-HBe) status in many chronic hepatitis B (CH-B) patients. However, patients with CH-B still produce anti-HBe more than several years after SC, and the relationship between SC and genome conversion in the precore region has not been clarified. Therefore, in patients with CH-B who had a sustained loss of HBeAg and complete remission of hepatitis after SC, the precore region was sequenced in paired serum samples from 1 year before SC to 3 years after SC. Mutant precore defective HBV DNA was found in only 6 (19%) of 31 CH-B patients who had a complete remission of hepatitis after SC. Mixed-type HBV DNA (precore wild-type and mutant-type) was found in 4 (13%) patients. Wild-type HBV DNA was found in 21 (68%) CH-B patients after SC. Longer-term follow-up of 11 CH-B patients indicated that 3 of 11 patients experienced precore genome conversion 2 to 3 years after SC. E-plus DNA or e-minus DNA was semiquantitated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays before and after SC. E-plus DNA levels decreased from 10(5.56+/-1.58) to 10(2.45+/-1.61). Similarly, e-minus DNA levels declined from 10(4.25+/-1.56) to 10(1.86+/-1.37). By dot-blot assay, serum HBV DNA became negative soon after SC, as did serum HBeAg. In contrast, HBeAg-containing immune complexes were still detected after SC. Anti-HBe antibody was produced throughout SC and thereafter, as determined by a sensitive experimental assay. Therefore, we conclude that genome-conversion in the precore region is a separate event from HBeAg/anti-HBe seroconversion.

Acute Disease↗
PubMed1998

Persistent viremia after recovery from self-limited acute hepatitis B.

To define the duration of viremia in the course of acute hepatitis B, we semiquantitatively determined the levels of hepatitis B virus (HBV) DNA in the sera, using polymerase chain reaction (PCR) coupled with Southern blotting, of non-immunocompromised patients with self-limited acute hepatitis B. In the sera of 10 of 11 patients, HBV DNA, which was presumably coated with viral proteins, was detected for a long period after recovery, even at the final observation times, which ranged from 6 to 19 months after disease onset. To characterize the mode of HBV that was present in serum, we immunoprecipitated immune complexes in sera by the addition of anti-human immunoglobulin G (IgG) and determined the levels of HBV DNA separately in the supernatants and pellets. In the acute phase of hepatitis B, high levels of HBV DNA were detected both in the supernatants and pellets at comparative levels. After the convalescent phase, the amount of HBV DNA in the supernatant decreased with respect to that in the pellets. It is notable that, in most cases, serum HBV persisted as a form of immune complex even after the seroconversion to antibody to hepatitis B surface antigen (anti-HBs). These data suggest that the replication of HBV may persist in some organs, most likely in the liver or peripheral blood cells, for a long period after recovery from acute hepatitis B, and the data indicate the possible transmission of HBV from organ transplantation donors who exhibit serological markers of past infection only.

Acute Disease↗
PubMed1998

Regulation of Fas gene expression in HeLa cells as determined by modified RT-PCR.

We determined human Fas messenger RNA (mRNA) levels in HeLa cells using a 'mutagenic' reverse transcription-polymerase chain reaction, which quantitates mRNA levels using the corresponding genomic DNA as an internal control. The expression level of Fas mRNA was very low in serum-deprived quiescent HeLa cells. In conjunction with the start of cell-cycle progression upon the addition of serum to culture medium, the Fas mRNA level gradually increased, reached its peak at 36 h and returned to the basal level after 48 h. HeLa cells at 36 h exhibiting a high level of Fas mRNA expression were more susceptible to the anti-Fas antibody apoptotic signal. Thus, the regulation of Fas expression is associated with cell-cycle progression, and this method for Fas mRNA detection may be useful, particularly for the analysis of small amounts of samples.

Antibodies↗
PubMed1998

The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice.

Hepatitis C virus (HCV) is the main cause of chronic hepatitis worldwide. Chronic hepatitis ultimately results in the development of hepatocellular carcinoma (HCC). However, the mechanism of hepatocarcinogenesis in chronic HCV infection is still unclear. The ability of the core protein of HCV to modulate gene transcription, cell proliferation and cell death may be involved in the pathogenesis of HCC. Here, we report the development of HCC in two independent lines of mice transgenic for the HCV core gene, which develop hepatic steatosis early in life as a histological feature characteristic of chronic hepatitis C. After the age of 16 months, mice of both lines developed hepatic tumors that first appeared as adenomas containing fat droplets in the cytoplasm. Then HCC, a more poorly-differentiated neoplasia, developed from within the adenomas, presenting in a 'nodule-in-nodule' manner without cytoplasmic fat droplets; this closely resembled the histopathological characteristics of the early stage of HCC in patients with chronic hepatitis C. These results indicate that the HCV core protein has a chief role in the development of HCC, and that these transgenic mice provide good animal models for determining the molecular events in hepatocarcinogenesis with HCV infection.

Animals↗
PubMed1998

Acute exacerbation of autoimmune liver disease associated with hantaviral infection.

Hantavirus is known to cause haemorrhagic fever with renal syndrome (HFRS). Although liver dysfunction has been reported in HFRS, hepatic manifestations of hantaviral infection have not been well described. We describe a case of autoimmune cholangitis in which an exacerbation of hepatitis was associated with hantaviral infection. Seroconversion of both IgG- and IgM-class antibodies to hantavirus was noted coincident with acute exacerbation of hepatitis, which was resolved promptly by treatment with corticosteroid. No extrahepatic manifestations were noted. This case suggests that hantavirus may trigger acute exacerbation of autoimmune liver disease without extrahepatic manifestations and that it may cause community-acquired hepatitis.

Antibodies, Antinuclear↗
PubMed1997

Sialadenitis histologically resembling Sjogren syndrome in mice transgenic for hepatitis C virus envelope genes.

Hepatitis C virus (HCV), a major causative agent of non-A, non-B chronic hepatitis, is also suggested to be associated with extrahepatic manifestations such as mixed cryoglobulinemia and glomerulonephritis. Two independent lines of transgenic mice carrying the HCV envelope genes have been shown previously to express the HCV envelope proteins in organs, including the liver and salivary glands, which results in no pathological changes in the liver. Further analysis of these animals now has revealed that they develop an exocrinopathy involving the salivary and lachrymal glands. This pathology resembles Sjogren syndrome, which also is suggested to have a possible association with chronic hepatitis C. These observations suggest that HCV might be involved in the pathogenesis of sialadenitis in humans and that this transgenic mouse system would be a good animal model for the study of HCV infection.

Age Factors↗
PubMed1997

Hepatitis C virus core protein induces hepatic steatosis in transgenic mice.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide, which finally leads to development of hepatocellular carcinoma. Chronic hepatitis C is characterized by several histological features in the liver which discriminate it from other forms of hepatitis: bile duct damage, lymphoid follicles and steatosis (fatty change). Little is known, however, about the role of HCV or its viral proteins in the pathogenesis of hepatitis. Recently, the core protein of HCV has been suggested to have a transcriptional regulatory function, and thereby to be involved in inducing phenotypic changes in hepatocytes. To clarify whether or not the HCV core protein has an effect on pathological phenotypes in the liver, two independent transgenic mouse lines carrying the HCV core gene were established. These mice developed progressive hepatic steatosis, indicating that the HCV core protein plays a direct role in the development of hepatic steatosis, which characterizes hepatitis C. This transgenic mouse system would be a good animal model for the study of pathogenesis in human HCV infection.

Animals↗
PubMed1996

Chronic hepatitis A with persistent viral replication.

Hepatitis A virus (HAV) usually causes an acute self-limited illness. This report describes a patient with hepatitis A whose serum aminotransferase activities remained above normal and whose serum was persistently positive for immunoglobulin (Ig) M class anti-hepatitis A 31 months after the onset of hepatitis. Liver biopsy carried out 11 months after the onset of hepatitis showed histological changes consistent with chronic hepatitis of moderate severity. HAV RNA was detected by polymerase chain reaction (PCR) in feces collected at the time of the liver biopsy. Furthermore, the patient developed esophageal varices 25 months after the onset of hepatitis. We believe this to be the first reported case in which persistent replication of HAV is implicated in chronic hepatitis with the potential to develop into liver cirrhosis.

Hepatitis A↗
PubMed1996

Prolonged fecal excretion of hepatitis A virus in adult patients with hepatitis A as determined by polymerase chain reaction.

In hepatitis A virus (HAV) infection, fecal excretion of the virus has been reported to cease shortly after symptoms occur. Although there have been several reports on detection of HAV in feces using polymerase chain reaction (PCR), the duration of fecal HAV shedding in human adult hepatitis A has not been well described. In the present study, we applied the reverse-transcription (RT)-PCR system to the detection of fecal HAV RNA in 10 patients with sporadic hepatitis A. The viral genomic RNA was detected in the stools from five patients after the onset of clinical symptoms. All stool samples collected within 10 days of onset of illness were HAV-RNA-positive, and the duration of positivity lasted from a few days to as long as 3 months. In four patients, HAV RNA was detected in the stool even after the serum alanine transaminase (ALT) levels had peaked, and in one patient well after ALT levels fell to normal. These results show that fecal shedding of HAV can last for months after resolution of symptoms and such patients could be a source of further spreading of the virus in the community.

Adult↗
PubMed1995

Hepatitis C virus genotypes and development of hepatocellular carcinoma.

BACKGROUND: Among several genotypes of hepatitis C virus (HCV), genotypes 1b (or II) and 2a (or III) are predominant in Japan. Although it has been shown that the efficacy of interferon treatment of patients with chronic hepatitis C varies with the HCV genotype, the relationship between HCV genotype and the development of hepatocellular carcinoma (HCC) has not been well described. METHODS: The genotypes and serum levels were determined for HCV-RNA in 72 patients with HCC and 131 patients without HCC, all of whom were positive for second-generation HCV antibody and HCV-RNA. In addition, clinical data from 34 patients with HCC who each had a history of blood transfusion were analyzed. RESULTS: Fifty-seven (79.2%) of 72 patients with HCC had genotype 1b HCV, whereas 101 (77.1%) of 131 patients without HCC had genotype 1b, indicating that there was no significant difference in the prevalence of genotype 1b HCV between the patients with and without HCC. Furthermore, comparison of patients with HCC with genotype 1b HCV with those with genotype 2a who had a history of blood transfusion did not differ significantly in the number of years from blood transfusion to diagnosis of HCC. Levels of HCV-RNA were not significantly different among patients with liver diseases of various stages. CONCLUSIONS: Hepatocellular carcinoma develops in patients with either genotype 2a HCV or genotype 1b HCV. A difference in genotype is not likely to be responsible for the difference in development of HCC.

Carcinoma, Hepatocellular↗
PubMed1995

Dominant replication of either virus in dual infection with hepatitis viruses B and C.

To characterize the state of dual infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), HBV-DNA and HCV-RNA levels were determined by spot hybridization or polymerase chain reaction in the sera of patients who were positive for both hepatitis B surface antigen and HCV antibody. Among 27 patients who showed evidence of double infection, 21 (77.8%) had detectable levels of only either HBV or HCV genome in their sera, 2 (7.4%) showed none of the viral genomes, and 4 (14.8%) had both HBV-DNA and HCV-RNA. In the 4 patients with both HBV-DNA and HCV-RNA, the titers of HCV-RNA or HBV-DNA were lower than those in the patients with HCV-RNA or HBV-DNA alone. In some patients with chronic hepatitis, the viruses appeared to replicate in turn in the course of the disease. These results indicate that the viruses show alternating dominance in replication in most of the patients who have dual infection with HBV and HCV, probably due to interference of the viruses.

Adolescent↗
PubMed1995

Takayasu's arteritis in prepulseless stage manifesting lymph node swelling and hepatosplenomegaly.

A 17-year-old male had fever of unknown origin (FUO) for 3 months with positive c-reactive protein, lymph node swelling, and hepatosplenomegaly. Biopsy specimens of the liver and lymph node disclosed nonspecific inflammation. Lymph node swelling and hepatosplenomegaly subsided gradually, while vascular murmur and pulselessness appeared. Computerized tomography and magnetic resonance imaging showed thickened arterial wall, while angiography disclosed arterial narrowing. From these findings he was diagnosed to have Takayasu's arteritis. The therapy with prednisolone was effective. Takayasu's arteritis is rarely manifested by hepatosplenomegaly and lymphadenopathy in its prepulseless stage.

Adolescent↗
PubMed1994

Induction of interstitial pneumonitis during interferon treatment for chronic hepatitis C.

A 48-year-old woman developed interstitial pneumonitis while receiving interferon treatment for chronic hepatitis C. Laboratory studies prior to treatment showed elevated serum alanine aminotransferase levels, but chest X-rays and physical examination revealed no abnormalities suggestive of interstitial pneumonitis. At the 9th week of interferon treatment (total dose, 380 MU of recombinant interferon-alpha, without other medications), the patient began to complain of cough and exertional dyspnea. A chest X-ray film revealed diffuse reticulo-nodular shadows in bilateral lung fields, suggesting a diagnosis of interstitial pneumonitis. A marked increase in lymphocyte count was observed in bronchoalveolar lavage fluid and a diagnosis of interstitial pneumonitis was made as a result of transbronchial lung biopsy. Her clinical symptoms and abnormal lung shadows were reversible, improving within a month of the discontinuation of interferon, and disappearing promptly after exogenous corticosteroid was instituted. This may be the first case of drug-induced interstitial pneumonitis occurring during the course of treatment with interferon alone. We should be aware of the possibility of interstitial pneumonitis developing during treatment of chronic hepatitis C with interferon.

Biopsy↗
PubMed1994

Induction of cell cycle progression by hepatitis B virus HBx gene expression in quiescent mouse fibroblasts.

The HBx gene of hepatitis B virus has been shown to induce hepatic tumors in transgenic mice and is implicated in hepatocarcinogenesis in human hepatitis B virus infection. To further characterize the role of HBx gene in carcinogenesis, we established mouse fibroblast cell lines in which the expression of HBx gene could be controlled by glucocorticoid hormone and examined the effect of HBx gene expression on cell growth in vitro. Along with the expression of HBx gene, most cells in the G0/G1 phase moved into the S phase in 24 h, and the cell cycle progressed further toward 48 h. Induction of DNA synthesis was also demonstrated by bromo-deoxyuridine labeling analysis. These results indicate that HBx gene has a function to trigger the synthesis of cellular DNA and suggest that HBx gene may play a role in hepatocarcinogenesis in human infection by driving deregulated cell cycle progression.

3T3 Cells↗
PubMed1994

High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice.

We studied the development of liver tumors in male HBx gene transgenic mice. Of two lineages studied, in the lineage with the lowest HBx gene expression liver tumors developed only in an incidence comparable with that in normal CD-1 strain, whereas 84% of male mice with a high level of the HBx gene product succumbed to liver neoplasia, indicating that continued HBx gene expression higher than a certain threshold level may be necessary for the development of hepatic neoplasia. Sixty-five mice from a lineage with a high level of HBx expression were then followed throughout their 24-mo lifespan. The livers of transgenic mice showed foci of cellular alteration with cytoplasmic vacuolations around the central veins from the age of 2 mo, but these foci did not expand progressively by the age of 12 mo. Immunostaining demonstrated such hepatocytes had higher expression of HBx protein than surrounding cells. Neoplastic lesions including liver cell adenomas and hepatocellular carcinomas developed from the age of 13 mo. By bromodeoxyuridine labeling analysis, hepatocytes in altered foci were found to have increased DNA synthesis, whereas no labeling was observed in age- and sex-matched nontransgenic littermate controls. Furthermore, DNA content analysis revealed the existence of several small aneuploid peaks in the transgenic liver before the age of tumor development. These results suggest that the continued expression of HBx gene may initiate a complex process to hepatocellular carcinoma by inducing DNA synthesis and placing large numbers of hepatocytes subjective to secondary events for transformation.

Adenoma, Liver Cell↗
PubMed1993

Duration of viremia in human hepatitis A viral infection as determined by polymerase chain reaction.

Viremia in hepatitis A viral (HAV) infection is said to be limited to pre-symptomatic period. However, it is not clear how long viremia lasts in human infection due to the lack of a simple and sensitive detection system. In an attempt to find HAV genome in patients' sera, we used the RT-PCR method by setting a pair of primers in the 5' non-coding region. While in most cases HAV-RNA was detected only before alanine aminotransferase (ALT) reached peak levels with this sensitive system, the viral genome was observed in some patients' sera even after ALT reached peak levels. Some patients also had HAV viremia after seroconversion to HAV antibody. These results show that viremia in HAV infection lasts longer than has been previously thought, and give a warning of possible secondary blood-borne infection.

Adult↗
PubMed1991

Interferon therapy for non-A, non-B chronic hepatitis.

We report the results of our study on 8-week consecutive interferon (IFN) treatment for chronic non-A, non-B hepatitis. In the 6 MIU/day group, most cases had continuously normalized alanine-aminotransferase (ALT) levels even after IFN treatment was discontinued. In responders whose ALT levels remained normal, not only the degree of inflammation, as seen from HAI scores, but also liver histopathological features were improved. Moreover, antibody to hepatitis C virus (anti-HCV) titer in responders was continuously decreased. Antiviral effects of IFN were observed by detection of HCV-RNA using the PCR technique. HCV-RNA became negative with IFN treatment, however, in some patients who relapsed after discontinuation of IFN treatment, re-elevation of ALT levels was usually preceded by re-appearance of HCV-RNA.

Alanine Transaminase↗