Yoshishige Miyake

Transmission of hepatitis B virus from hepatitis B core antibody- positive donors in living related liver transplants

BACKGROUND In order to clarify the risk of hepatitis B virus (HBV) transmission from hepatitis B core antibody-positive (HBcAb(+)) donors and to evolve a new strategy to counter such a risk, we undertook a retrospective (1990-1995) and prospective (1995-1996) analysis of our experience with living related liver transplantation involving HBcAb(+) donors. METHODS Between June 15, 1990, and June 30, 1995, HBcAb(+) individuals were not excluded as donor candidates at our institutions. For 171 liver transplants, 16 donors were HBcAb(+). Between July 1, 1995, and June 30, 1996, HBcAb(+) individuals were generally excluded as donor candidates; however, three recipients were given liver grafts from HBcAb(+) donors because other donor candidates presented even higher risks. In the latter period, recipients with transplants from HBcAb(+) donors underwent prophylactic passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG). The serum of 10 HBcAb(+) donors was examined by nested polymerase chain reaction for the presence of HBV-DNA, but it was not detected in any of them. However, the same examination of the liver tissue of five such donors yielded positive results in all cases. RESULTS In the first 5-year period, out of 16 recipients with HBcAb(+) donors, 15 became hepatitis B surface antigen-positive after transplant. The three recipients with HBcAb(+) donors during the second 1-year period, who were treated by prophylactic passive immunization with HBIG, remained hepatitis B surface antigen-negative and negative for serum HBV-DNA after transplant. CONCLUSIONS HBV exists in the liver of healthy HBcAb(+) individuals, but not in the blood. Therefore, HBV is thought to be transmitted to recipients by liver grafts from the HBcAb(+) donors at a significantly high rate. The prevention of viral activation and clinical disease development by means of passive immunization with HBIG seems promising, although the follow-up period in our study may be too short for any definitive conclusions.

Prevalence of hepatitis E virus infection in Japanese children

Background: Recently, sporadic cases of acute hepatitis and fulminant hepatitis caused by hepatitis E virus (HEV) have been reported in Japan. However, few reports have addressed the issue of HEV infection during childhood. Methods: This study included 5 patients with fulminant hepatitis, 30 patients with acute hepatitis, and 309 patients without history of hepatic dysfunction or hepatitis in childhood as control. RNA was extracted from each serum sample, and HEV specific reverse-transcriptase polymerase chain reaction was performed. Anti-HEV immunoglobulin (Ig)M and IgG were measured by enzyme-linked immunoadsorbent assay. Results: HEV RNA, anti-HEV IgM, and anti-HEV IgG were not detected in the sera of any of the five patients with fulminant hepatitis. In the 30 patients with acute hepatitis, only one (3.3%) was positive for anti-HEV IgG, and all were negative for anti-HEV IgM and HEV RNA. Of the 309 control patients, 8 (2.6%) were positive for anti-HEV IgG, and 2 (0.6%) were positive for anti-HEV IgM, respectively. Conclusion: The result of patients with fulminant hepatitis suggests that HEV is an unlikely cause of fulminant hepatitis in children. However, the detection rate of anti-HEV IgG shows that a history of HEV infection is not so rare among children in Japan.

Age at Time of Hepatitis Be Antibody Seroconversion in Childhood Chronic Hepatitis B Infection and Mutant Viral Strain Detection Rates

BACKGROUND Investigations of adult patients have demonstrated that with seroconversion, changes occur from wild-type strains of the infecting virus to mutant strains. However, to date, there have been few reports and insufficient investigation of this issue in children. METHODS The presence or absence of nucleotide base and amino acid sequence mutations in a portion of the X region containing the core promoter region, the pre-C region, and the C region of HBV genomic DNA were investigated using a polymerase chain reaction-direct sequencing method on serum samples collected from 14 children who were hepatitis Be antibody (HBeAb)-positive carriers. Samples from three children who were HBe antigen (HBeAg)-positive carriers served as the control subjects. RESULTS When patients were grouped based on whether they had had documented seroconversion before age 6 or at age 6 or older, differences in mutant viral detection rates involving the core promoter region and the pre-C region were apparent. Specifically, a mutant strain showing a G-to-A substitution at nucleotide 83 in the pre-C region, or a mutant strain showing an A-to-T substitution at nucleotide 1762 and a G-to-A substitution at nucleotide 1764, was detected in only two of eight cases (25%) from the HBeAb-positive carriers with documented seroconversion before age 6. In contrast, these findings were present in six of six patients (100%) with documented seroconversion at age 6 or older. CONCLUSIONS The results of the present study suggest that the mechanism of onset of HBeAb seroconversion differs between children aged less than 6 years and those who are aged 6 or more.

Prevalence of GB Virus C/Hepatitis G Virus Ribonucleic Acid and Anti-Hepatitis G Virus-E2 Antibodies among Japanese Children with Histories of Transfusions or with Liver Diseases

To clarify the prevalence of Japanese children thought to be at a risk for infection with GB virus-C (GBV-C)/hepatitis G virus (HGV), we investigated the detection rates of serum GBV-C/HGV ribonucleic acid (RNA) by reverse transcription-seminested PCR and serum anti-HGV-E2 antibody by ELISA in 162 children with histories of blood or plasma product transfusions or with liver diseases and performed phylogenetic analysis of the 5′ noncoding region sequences of GBV-C/HGV genomes. Children with histories of transfusions were divided into those who had been treated with antineoplastic agents for malignant diseases (malignant group) and those who had received transfusions for nonmalignant diseases (nonmalignant group). Children with liver diseases were divided into hepatitis B (HBV), hepatitis C (HCV), and non-A-C hepatitis groups. We detected GBV-C/HGV RNA in 11 of 33 (33.3%) and anti-HGV-E2 in 1 of 27 (3.7%) children in the malignant group and in 3 of 56 (5.4%) and 1 of 53 (1.9%) children, respectively, in the nonmalignant group. Neither GBV-C/HGV RNA nor anti-HGV-E2 was detected in the HBV and non-A-C hepatitis groups. GBV-C/HGV RNA and anti-HGV-E2 were detected in 7 of 23 (30.4%) and in 1 of 18 (5.6%) children, respectively, in the HCV group. All children positive for either GBV-C/HGV RNA or anti-HGV-E2, except one whose route of GBV-C/HGV infection suggested mother-to-infant transmission, had histories of transfusions. The phylogenetic analysis showed that all isolates in this study were divisible into three groups and that most of them were clustered into group 3 (Asian group).

SECOND GENERATION HEPATITIS C VIRUS ANTIBODY-POSITIVE RATE IN CHILDREN : INVESTIGATION OF THE ROUTE OF HEPATITIS C VIRUS INFECTION IN CHILDREN WITH NO HISTORY OF TRANSFUSION

Hepatitis C virus (HCV) antibody and HCV‐RNA screening was undertaken in 1864 children, aged from 0 to 15 years who did not have a history of transfusion. Anti‐HCV was tested by the second generation enzyme‐linked immunosorbent assay (ELISA). HCV RNA was examined by reverse transcriptase‐nested polymerase chain reaction (PCR). Two of the 1864 children were positive for serum HCV RNA. They had no history of transfusion, no episodes of horizontal transmission, but the mother in each case was positive for serum HCV RNA, implying mother‐to‐infant infection. Eleven children who were positive for HCV antibody with low values and negative for serum HCV RNA were classified as belonging to the high bovine milk (composed primarily of casein)‐specific IgG4 value group. This suggested that many of the children who were falsely positive for HCV antibody using ELISA had antibodies to casein.

Prevalence of GBV‐C/HGV infection in pregnant Japanese women

Recently, a novel viral agent, hepatitis G virus, was identified by independent researchers from the serum of patients with liver disease, and termed GBV-C or HGV. At present, GBV-C and HGV are considered to be separate isolates of the same virus; however, the role of this virus in acute and chronic liver disease remains uncertain. Although vertical transmission is known to be one of the routes of transmission, the prevalence of GBV-C/HGV viremia in pregnant Japanese women is unknown. Thus, we determined this prevalence using the reverse transcription polymerase chain reaction (RT-PCR).

Analysis of the hypervariable region of hepatitis C virus E2/NS1 gene in an infant infected by blood transfusion

We investigated the sequential change in the hypervariable region 1 (HVR1) of hepatitis C virus (HCV) E2/NS1 gene in an infant. He was transfused with 160 mL of blood containing the HCV (0.7 Meq/mL) on the 6th d after birth and subsequently developed chronic viremia. At 16 mo, the HVR1 amino acid sequences of HCV observed in the infants sera were very similar to those from the donor (his maternal grandfather) on the day of transfusion. However, highly variable amino acid sequences of HVR1 were observed throughout infancy. These results demonstrate that an adaptive response of HCV to evade host immunity seems to occur, as in adult cases, even in early infancy when the ability to produce humoral immunoglobulin is thought to be low.

Clinical and serological courses of a newborn with post-transfusion hepatitis C

Summary. The clinical and serological course of a haemophilic baby who was transfused with 160 ml of blood containing the hepatitis C virus (HCV) (0.70 Meq. ml‐1) on the sixth post‐natal day is described. He is the infant of an HCV‐negative mother. One month after the transfusion, there was a marked increase in HCV RNA and a small amount of HCV antibody was detected. This case provides evidence that a newborn is capable of producing HCV antibodies.

Methylxanthines inhibit late-onset circulatory collapse in preterm infants.

Several drugs, when used chronically in very preterm infants, are considered to be associated with the development of late‐onset circulatory collapse (LCC), which can lead to neurodevelopmental impairment. Despite its clinical importance, conclusive risk factors for LCC have yet to be identified. The aim of the present study was to investigate the relationship between LCC and diuretics, methylxanthines, levothyroxine, and sodium chloride.

Natural emergence of an anti-hepatitis B s escape mutant in a young female hepatitis B virus carrier.

determinant of the S region of the hepatitis B virus (HBV) genome abolish expression of determinant ‘a’ and the resultant anti-hepatitis B surface (anti-HBs) escape mutant HBV are able to survive in the presence of anti-HBs.1 Several types of anti-HBs escape mutant HBV have been reported.1–10 These mutations arise in children infected with HBV after they have received either immunoprophylaxis with hepatitis B (HB) immunoglobulin and HB vaccine1,2,4,6,8,10 or monoclonal antibodies to HBV after orthotopic liver transplantation.5 In addition, anti-HBs escape mutant HBV have also been found in chronic HBV carriers who are seropositive for anti-HBs due to host immune pressures.3,7,9 In the present report, we present a girl with chronic hepatitis B in whom an anti-HBs escape mutant HBV has emerged naturally.