Yoshihide Fukuda

Transmission of hepatitis C in an isolated area in Japan : community-acquired infection

Abstract Background/Aims: The spread of hepatitis C virus (HCV) infection not due to drug needle sharing or transfusion is largely unknown in communities. A search for risk factors for HCV infection in an endemic area might elucidate inapparent modes of transmission. Methods: We conducted screening for hepatitis virus markers and parenteral exposures to blood among 435 inhabitants in an isolated area known for its endemicity for non-A, non-B hepatitis and in a nonendemic area with 1542 inhabitants. Results: The prevalence of hepatitis B surface antigen was the same in both areas. The prevalence of antibody to HCV verified by the recombinant immunoblot assay was 32.4% in the highly endemic area and 2.3% in the nonendemic area ( P Conclusions: Folk remedies such as acupuncture and cutting of the skin using nonsterilized knives should be considered as possible routes of HCV transmission not associated with blood transfusion or sharing of drug paraphernalia.

EFFECT OF GB VIRUS C/HEPATITIS G VIRUS COINFECTION ON THE COURSE OF HIV INFECTION IN HEMOPHILIA PATIENTS IN JAPAN

OBJECTIVE A novel virus, GB virus C (GBV-C)/hepatitis G virus (HGV), has been isolated. This virus is parenterally transmissible, but its effect on various diseases remains to be disclosed. We investigated the effect of GBV-C/HGV coinfection on the course of HIV infection. METHODS GBV-C/HGV RNA was measured by nested reverse transcription polymerase chain reaction (RT-PCR) in 41 HIV-infected hemophilia patients in Japan. Patient characteristics, HIV RNA concentrations, and rates of progression to AIDS and to death were compared in patients with and without GBV-C/HGV coinfection. HIV RNA was quantified by the Amplicor HIV Monitor test (Roche Molecular Systems, Somerville, NJ, U.S.A.), and progression to AIDS and to death was analyzed using Kaplan-Meier plots. RESULTS GBV-C/HGV infection was present in 11 of 41 of patients (26.8%). Mean HIV RNA concentration was lower in patients with GBV-C/HGV coinfection (3.52+/-4.81 x 10(4) copies/ml) than in patients without coinfection (5.76+/-14.78 x 10(4) copies/ ml) and progression to AIDS and to death were slower in patients with GBV-C/HGV coinfection than patients without it, although the differences were not statistically significant. CONCLUSION In Japanese hemophilia patients, coinfection with GBV-C/HGV does not have an adverse effect on the course of HIV infection.

Hepatic vascular endothelial cells heterogenously express surface antigens associated with monocytes, macrophages and T lymphocytes

During studies of the antigenic and functional properties of hepatic sinusoidal lining cells in situ, we found that only the sinusoidal endothelial cells share antigens with a peripheral blood macrophage subset capable of presenting soluble antigens and triggering autologous mixed lymphocyte reactions. They were HLA-DR+, OKM1−, OKM5+. Vascular endothelial cells in the portal areas and central veins were HLA-DR+, OKM1− and OKM5−. The sinusoidal endothelial cells also expressed an antigen found on helper/inducer (OKT4 and Leu3 a) T lymphocytes. Thus, the present study suggests that endothelial cells in different anatomic compartments in the liver heterogenously express surface antigens associated with monocytes, macrophages and T lymphocytes and possess distinct immunological functions.

Clinical evaluation of serum tissue inhibitor of metalloproteinases‐1 levels in patients with liver diseases

Serum levels of the tissue inhibitor of metalloproteinases‐1 (TIMP‐1) were measured in 268 patients with liver diseases by means of a one‐step sandwich enzyme immunoassay. In the cases of acute hepatitis, chronic active hepatitis (CAH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC), the levels of TIMP‐1 were higher than those of the control group. Tissue inhibitor of metalloproteinases‐1 levels correlated with type III procollagen peptide and with type IV collagen, indicating TIMP‐1 as a useful marker for hepatic fibrosis. Levels of TIMP‐1 also correlated with aspartate aminotransserase and alanine aminotransferase levels and showed the highest levels in acute hepatitis. Thus, TIMP‐1 might also reflect hepatic inflammation. Serum levels of α‐fetoprotein and TIMP‐1 had a significant positive correlation in patients with HCC. A cut‐off level of TIMP‐1 between LC and HCC was set at 440 ng/mL, having a low sensitivity and a high specificity. These results suggest the usefulness of TIMP‐1 as a tumour marker in cases of HCC where α‐fetoprotein levels are not elevated.

Elevation of serum cystatin C concentrations in patients with chronic liver disease.

Objective We examined serum cystatin C concentrations in patients to explore the possible clinical application of cystatin C as a marker of disease severity in cases of chronic liver diseases. Methods Serum cystatin C concentrations were determined by an enzyme-linked immunosorbent assay kit in 103 patients with various chronic liver diseases and compared with concentrations in healthy control volunteers. Results The mean cystatin C concentration was 0.68 ± 0.03 mg/l in chronic hepatitis patients, 1.13 ± 0.09 mg/l in liver cirrhosis patients and 1.16 ± 0.10 mg/l in hepatocellular carcinoma patients, all significantly higher than concentrations in the control volunteers (P < 0.0001). Significant correlations were observed between cystatin C concentrations and total bilirubin levels, albumin levels, platelet levels, type IV collagen levels and hyaluronic acid levels. Serum cystatin C concentrations correlated well with histological stages despite the lack of correlation with histological grades. Conclusion Our results show that serum cystatin C increases with the progression of chronic liver disease and that it is a potential marker for liver fibrosis.

Long-term follow-up of sustained responders to interferon therapy, in patients with chronic hepatitis C.

Interferon (IFN) therapy has been proven to induce the normalization of serum alanine aminotransferase (ALT) levels and to eradicate the hepatitis C virus (HCV) in some patients with chronic hepatitis C, and these patients are usually defined as ‘sustained responders’. However, there have been some reports of hepatocellular carcinoma (HCC) in these patients, and the development of HCC remains life‐threatening in patients who clear HCV. We analysed the long‐term prognoses of patients with chronic hepatitis C in whom HCV was eradicated with IFN. We investigated 392 sustained responders to IFN therapy, from 1277 patients with chronic HCV infection who received IFN treatment at one of our institutions between April 1989 and March 1999. We analysed the medical records and looked for the development of HCC. About 30% of the sustained responders had been lost to follow‐up 3 years after the end of IFN therapy, and the follow‐up rate of sustained responders was significantly lower than that of non‐sustained responders (P < 0.0001). HCC were found in eight patients: in seven patients HCC developed within 5 years after completion of IFN therapy; but in one patient, a single HCC less than 3 cm in diameter was detected between 7 and 8 years after completion of IFN. Of the five patients who had regular medical follow‐up, the HCC was solitary, and the patients survived without any evidence of recurrence. Of the three patients who had not been followed‐up, two died from HCC and HCC recurred in the third. These results suggest that HCC can develop in sustained responders and that sustained responders should be followed‐up closely after completion of IFN so that HCC may be detected at an early stage. The optimal duration of the follow‐up period of the sustained responders remains unclear. Additional prospective studies are required in order to establish an appropriate follow‐up protocol for sustained responders to IFN.

Serum hyaluronic acid reflects the effect of interferon treatment on hepatic fibrosis in patients with chronic hepatitis C.

Changes in serum hyaluronic acid (HA) in 35 patients treated with interferon (IFN) were studied and the histological change in fibrosis was analysed. Serum HA levels and hepatitis C virus (HCV) RNA were followed from the start of therapy to 12 months after completion of treatment. Histological changes in pre‐ and post‐treatment liver biopsies were assessed using a modified Knodells scoring system. The serum levels of HA (r = 0.79; P<0.0001) correlated with the degree of fibrosis more closely than with that of amino terminal peptides of type III procollagen (PIIIP; r = 0.45; P<0.05) or type IV collagen (IV‐C; r = 0.42; P<0.05). Only complete responders (CR) had a significant decrease in serum levels of HA and IV‐C (P<0.05), in parallel with histological improvement (P<0.01). Neither partial responders (PR) nor non‐responders (NR) had significant changes in histological scores and in serum levels of fibrotic markers. Significant differences were observed between CR and NR, both in HA levels (P<0.01) and PIIIP levels (P<0.05) 12 months after the cessation of treatment. These results suggest that serum HA is an indicator of the extent of fibrosis in chronic hepatitis C. Serial determinations of serum HA levels may be of use for monitoring the histological response of hepatic fibrosis to IFN treatment in chronic hepatitis C.

Reactive lymphoid hyperplasia of liver coexisting with chronic thyroiditis: radiographical characteristics of the disorder.

Background: Reactive lymphoid hyperplasia of the liver is an extremely rare entity, with six cases reported so far.

Serum Hyaluronan as a Marker of Liver Fibrosis in Hemophiliacs with Hepatitis C Virus-Associated Chronic Liver Disease

We measured serum type III procollagen peptide, type IV collagen (IV-C), and hyaluronan (HA) in 36 hemophiliacs with hepatitis C virus (HCV)-related chronic liver disease. We also measured these markers in 19 interferon (IFN)-treated patients before and after a 6-month course of IFN-α. The serum concentrations of IV-C and HA were correlated with the stage of fibrosis (IV-C r = 0.38; HA r = 0.78). These markers fell only in complete responders showing sustained clearance of serum HCV RNA by IFN. These results suggest that, in hemophiliacs with chronic liver disease, serum HA measurement might be an alternative to liver biopsy and reflect the response to IFN.

Changes in blood supply in small hepatocellular carcinoma: correlation of angiographic images and immunohistochemical findings

BACKGROUND/AIMS To assess the changes occurring in blood flow with growth in small hepatocellular carcinomas, we analyzed the angiographic features and immunohistochemical findings in 35 hepatocellular carcinomas less than 2 cm in diameter. METHODS Hepatocellular carcinomas were evaluated by digital subtraction angiography (DSA), ultrasound angiography with intraarterial CO2 microbubbles (USAG), and computed tomography during arterial portography (CTAP). Immunohistochemically, hepatocellular carcinomas were evaluated using QB-end/10 (QB) monoclonal antibody. RESULTS All 18 moderately-differentiated hepatocellular carcinomas stained positively with QB antibody. No hepatocellular carcinomas without attenuation on CTAP were positive by immunohistochemistry, and two hepatocellular carcinomas with attenuation on CTAP also lacked staining. We observed four hepatocellular carcinomas without hypervascularity on DSA or USAG, which stained positively with QB antibody; these hepatocellular carcinomas had fatty metamorphosis. CONCLUSIONS 1. Immunohistochemical findings are closely associated with angiographic findings regarding changes in blood supply. 2. All moderately-differentiated hepatocellular carcinomas have characteristics of hypervascularity, both by angiographic images and by immunohistochemistry. 3. The increase in arterial blood supply occurs later than the decrease in portal perfusion, which may indicate that the decrease in portal perfusion may not be the direct result of replacement by angiogenesis. 4. Some hepatocellular carcinomas with fatty metamorphosis, which are often hypovascular by angiographic evaluation, have hypervascular immunohistochemical characteristics.