Koya Nakashima

IL-1 β and TNF-α produced by peripheral blood mononuclear cells before and during interferon therapy in patients with chronic hepatitis C

We investigated the spontaneous and phytohemagglutinin-stimulated production of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) by peripheral blood mononuclear cells in patients with chronic hepatitis C during treatment with interferon-α (IFN-α). Spontaneous productions of these were significantly higher in patients with chronic hepatitis C than in healthy subjects. For patients prescribed interferon, stimulated production of TNF-α was significantly higher in complete responders than in partial responders, but the differences were small between the other cytokine levels and outcome of IFN treatment. Spontaneous production of these cytokines was higher in patients with genotype III with complete response than in genotype III patients with a partial response, but this was not the case in patients with genotype II. There was a negative correlation between these cytokines and histological activity index. Spontaneous production of cytokines was decreased only in complete responders after the administration of interferon. These data suggest that the elevated production of cytokines in patients with chronic hepatitis C may be due to host response to the virus, and monitoring cytokines along with alanine aminotransferase and hepatitis C virus RNA during treatment may provide more precise information of the effectiveness of therapy.

Detection of HCV RNA in subjects with antibody to hepatitis C virus among the general population of Fukuoka, Japan.

Volunteer blood donors and aged people who came to hospitals for a thorough physical checkup were surveyed to evaluated the exact prevalence of hepatitis C virus (HCV) infection in the general population of Fukuoka, Japan. We tested for antibody to HCV (anti-HCV) by second-generation assay and, to distinguish active HCV infection from past resolved infection, we tested for HCV RNA in reactive serum samples by polymerase chain reaction. The prevalence of anti-HCV was 286 (2.0%) of 14341 subjects, increasing with advancing age, from 0.4% in the under-29 age group to 12.0% in the over-70 age group. There were no differences between sexes. HCV RNA was detected in 170 of 286 (59.4%) anti-HCV-positive subjects. The ratio of HCV RNA-positive to anti-HCV-positive subjects was higher in males than in females (P<0.05) and decreased with advancing age, from 72.2% to 46.5%. The prevalence of elevated alanine aminotransferase (ALT) was only 15.9% in subjects with HCV RNA, higher in males (21.4%) than in females (8.3%) (P<0.05). This study revealed that the prevalence of anti-HCV was high in the aged population, but that the ratio of HCV RNA-positive to anti-HCV-positive subjects was low, and most of the HCV RNA-positive subjects had normal ALT levels.

Prevalence and role of hepatitis C viraemia in haemodialysis patients in Japan

A second generation assay for antibody to hepatitis C virus (anti-HCV) was used in order to establish the exact prevalence of HCV infection in haemodialysis patients. HCV RNA was sought by the polymerase chain reaction in order to determine whether haemodialysis patients with anti-HCV had been infected with HCV in the past or were presently infected. Of 357 patients, 198 (55.5%) were positive for anti-HCV, compared to 113 (31.7%) positive for original antibody to c100-3 protein (P < 0.001). HCV RNA was detected in 171 (86.4%) of the 198 patients with anti-HCV. Liver dysfunction was found in 63 (17.6%) of all haemodialysis patients. Of these, 55 (87.3%) had HCV infection, one (1.6%) hepatitis B virus infection while, in the remaining seven, the origin was unknown. Thus, in almost all anti-HCV-positive patients, HCV viraemia was present. We conclude that HCV is an important cause of liver disease in haemodialysis patients.

Improved detection of antibodies to hepatitis C virus by the second-generation assay in patients with chronic non-A, non-B liver disease

Serum samples from 337 Japanese patients with chronic non-A, non-B liver disease were tested for antibodies to hepatitis C virus (HCV) by means of first-generation (c100-3; anti-c100) and second-generation (pHCV-34, pHCV-31, c100-3; anti-HCV II) enzyme linked immunosorbent assays (ELISA) and for antibody to the GOR epitope (anti-GOR) also by ELISA. Anti-HCV II was detected in 314 (93.2%), anti-c100 in 247 (81.3%) and anti-GOR in 211 (62.6%) samples. Thus, anti-HCV II was more sensitive in detecting HCV infection than either anti-c100 or anti-GOR (P < 0.001). All serum samples reactive with anti-c100 or anti-GOR reacted with anti-HCV II. Among 314 anti-HCV II-positive patients, we found that 185 (58.9%) were positive for both anti-c100 and anti-GOR while 14 (4.5%) were positive for anti-HCV II alone. Nine (64.3%) of the 14 are presently infected with HCV, as revealed by detection of HCV RNA in their serum; the remaining five may have been infected in the past with HCV. These findings indicate that HCV is a major causative agent of chronic non-A, non-B liver disease in Japan and that detection of anti-HCV II is a specific and more sensitive diagnostic test for HCV infection.

HBsAg subtypes among HBsAg carriers in Okinawa, Japan. Evidence of an important relationship in seroconversion from HBeAg to anti-HBe

In Okinawa, Japan 1261 hepatitis B surface antigen (HBsAg) carriers were investigated for clinical differences among HBsAg subtypes. Among the 854 for whom they could be determined, subtype adw was found in 604 (70.7%), adr in 232 (27.2%) and others in 18 (2.1%). The overall prevalence of hepatitis B e antigen (HBeAg) was significantly lower in subtype adw (11.9%) than in adr (17.7%) (P < 0.01). The mean age of HBeAg-positive carriers was significantly lower in adw (20.4 years) than in adr (26.9 years) (P < 0.05). Seroconversion from HBeAg to antibody to HBeAg (anti-HBe) occurred in 43 carriers. The seroconversion rate was higher in adw (43.1%) than in adr (29.3%) and the seroconversion age was younger in adw (22.7 years) than in adr (27.9 years). These results suggest that carriers with subtype adw tend to seroconvert from HBeAg to anti-HBe at a higher rate and a younger age than do those with adr. HBsAg subtypes may be closely associated with the HBeAg/anti-HBe status.

Prevalence of hepatitis C virus infection among female prostitutes in Fukuoka, Japan

To assess the risk of sexual transmission of hepatitis C virus (HCV), we surveyed female prostitutes to determine the prevalence of antibody to HCV (anti-HCV) and HCV RNA. Anti-HCV was examined with a second generation anti-HCV test employing a passive hemagglutination assay. HCV RNA was detected by two-stage polymerase chain reaction with primers deduced from the 5′-noncoding region of the HCV genome. All studies were performed in Fukuoka, Japan, from 1989 through 1992 and all subjects were Japanese and had no history of intravenous drug abuse. The prevalence of anti-HCV was significantly higher in the prostitutes (10.1%; 61/604) than in the controls (female blood donors; 0.8%; 52/6632) (P<0.001). HCV RNA was found in 73.2% of the anti-HCV-positive prostitutes. The prevalence of anti-HCV among prostitutes increased with the number of years spent in prostitution (P<0.05). Prostitutes with a history of syphilis had a higher prevalence of anti-HCV than those with no history of syphilis, irrespective of the number of years in prostitution. In a longitudinal study of 244 prostitutes, 2 of the 218 initially seronegative subjects showed anti-HCV and HCV RNA over the study period of 3 years. These two persons had no history of percutaneous exposure. Sexual transmission of HCV presents a risk for female prostitutes.

Low prevalence of hepatitis C virus infection among hospital staff and acupuncturists in Kyushu, Japan.

During 1987 and 1988, samples of serum were collected from 1097 members of the staff of four prefectural hospitals in Miyazaki prefecture and from 183 acupuncturists in Fukuoka City, Japan. The staff included both surgical and non-surgical doctors, radiographers, physiotherapists, nurses, laboratory technicians and others. The samples were tested for the following hepatitis C virus (HCV) markers; antibodies to c100 (anti-c100) by means of enzyme-linked immunosorbent assay (ELISA) with supplementary recombinant immunoblot assay as well as antibodies to the GOR epitope (anti-GOR), also by means of ELISA. Anti-c100 was present in 1.7% of the doctors, radiographers and physiotherapists, in 1.3% of the nurses and in 2.2% of the acupuncturists. These prevalences were slightly higher than those in the controls but the differences were not statistically significant. Anti-c100 was not detected in any laboratory technician or other member of the hospital staff. For an accurate determination of the prevalence of HCV infection, the combined rate of anti-c100 and/or anti-GOR was also calculated. The combined prevalence of HCV infection was 4.3% in medical staff, 2.2% in nurses and 5.5% in acupuncturists. The prevalence of HCV infection among those with direct contact with patients was higher than that of the controls but without statistical significance. In the cohort we examined, the occupational risk of HCV infection was low.

Frequency of concurrence of hepatitis B surface antigen and antibody in a large number of carriers in Okinawa, Japan

SummaryA large number of chronic hepatitis B surface antigen (HBsAg) carriers in Okinawa, Japan were tested for antibody to HBsAg (anti-HBs), by both radioimmunoassay and enzyme immunoassay methods. Concurrence of HBsAg and anti-HBs was found in 166 (26.1% ). We found no clear predominance of either liver damage or hepatitis B e antigen (HBeAg) in the concurrent carriers studied. Antibody to pre-82 antigen (anti-pre-S2) was detected in 16 (9.6%) of 166 subjects with concurrent markers, 15 of these 16 carriers were positive for antibody to HBeAg (anti-HBe). Anti-pre-S2 was correlated wit anti-HBe rather than with anti-HBs. The distribution of HBsAg subtypes among carriers determined to have subtypes was 76.7% adw, 22.0% adr, 0.2% ayr, 0.9% adwr, and 0.2% adyr. The distribution of anti-HBs subtypes among concurrent carriers was 51.5% anti-r, 21.4% anti-w, 15.5% anti-d, and 10.7% anti-y. Concurrent carriers had HBsAg of one subtype and heterotypic anti-HBs. Because the HBsAg subtype ay is rare in this area, it is hard to believe that the concurrent carriers with anti-y were infected with hepatitis B virus of which the HBsAg subtype was ay. A dual infection was highly unlikely. It seems that some of the concurrent carriers correlate with compound subtypes adwr and adyr.

Antiviral Effect of Interferon Therapy for Patients with Chronic Hepatitis C

Thirty-two patients with chronic hepatitis who were positive for hepatitis C virus (HCV) RNA by polymerase chain reaction and had antibody to HCV (anti-HCV), were enrolled in this study. Twenty of them were also positive for antibody to the GOR epitope (anti-GOR). Sixteen of the enrolled patients were treated with human lymphoblastoid interferon for six months. Treatment was initiated with 3 million units of interferon daily for 2 weeks, followed by 3 million units three times a week for 6 weeks and 1.5 million units three times a week for 16 weeks. The efficacy of therapy was assessed by comparison with the results in 16 untreated patients. Aminotransferase values, titre of anti-HCV and anti-GOR antibodies showed significant decreases throughout the therapy compared with baseline levels and the untreated patients. After a 3 month follow-up, nine treated patients (56.3%) had normal aminotransferase activities and six of them eliminated HCV RNA from their sera (37.5%). Three of these six patients became negative for both anti-HCV and anti-GOR antibodies (18.8%). None of the untreated control patients had normal aminotransferase activities or became negative for HCV markers. The present study suggests that human lymphoblastoid interferon can control the disease activity and eliminate hepatitis C virus from patients with chronic hepatitis C.

Decrease of hepatitis A and B virus infections in the population of Okinawa, Japan.

In 1988 1282 serum samples were collected from healthy Japanese persons living on Hateruma Island (574 samples) and Iriomote Island (708 samples) in Okinawa, Japan. Serological markers of hepatitis B virus (HBV) infection [hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc) were investigated and the findings compared with samples taken in 1980 on Hateruma Island and in 1970 and 1980 on Iriomote Island. The samples collected in 1988 on Iriomote Island were also tested for antibody to hepatitis A virus (anti-HAV) and the findings compared with the results of the 1970 and 1980 surveys. The overall prevalence of HBsAg and anti-HBc was 3.7 and 64.8% for Hateruma Island and 3.8 and 44.9% for Iriomote Island. In both areas the overall prevalence of anti-HBc was lower than in 1980, the decrease being significant for the 10-19 year age group on Hateruma Island and the age groups under 39 years on Iriomote Island. The overall prevalence of anti-HAV had fallen to 50.9%. This remarkable decrease had occurred in children and young adults. These data suggest that Virus A (HAV) and HBV infections have dramatically decreased among children in Okinawa within the past 2 decades.