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Lamivudine treatment of chronic hepatitis B (CHB) is associated with frequent resistance and loss of clinical benefit. We present outcomes of lamivudine-refractory Japanese patients treated with entecavir for 3 years.Eighty-two patients refractory to lamivudine therapy received entecavir 0.5 or 1 mg daily for 52 weeks in phase II study ETV-052, directly entered rollover study ETV-060, and received entecavir 1 mg daily. Responses were evaluated among patients with available samples.After 96 weeks in ETV-060 (148 weeks total entecavir treatment time), 55%(36/65) of patients had hepatitis B virus(HBV) DNA of\400 copies/mL, 85% (52/61) had alanine aminotransferase (ALT) of ≤1 × upper limit of normal (ULN), and 14.6% (7/48) achieved HBe seroconversion.A subset of 42 patients received entecavir 1 mg from phase II baseline through 148 weeks: 54% (19/35) had HBV DNA of400 copies/mL, 84% (27/32) had ALT of ≤1 × ULN, and 15% (4/27) achieved HBe seroconversion.Sixteen patients in the 1-mg subset had baseline and week 148 evaluable biopsy pairs: 81% (13/16) showed histologic improvement and 38% (6/16) showed improvement in fibrosis. Genotypic resistance to entecavir emerged in 31 patients for a 3-year cumulative resistance probability of 35.9%. Entecavir was generally well tolerated during ETV-060, with no on-treatment ALT flares.Long-term entecavir treatment of lamivudine-refractory CHB resulted in virologic suppression, ALT normalization, and improvements in liver histology. Resistance was consistent with that observed in worldwide studies.

Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis B virus (HBV) infections is 6.5% and accounts for 60% of hepatocellular carcinoma. HBV has nine genotypes that have been identified by molecular genetic analysis. HBV genotypes are associated with several clinical features. We reviewed the prevalence of HBV genotypes in Myanmar and neighboring countries. We also reviewed HBV genotypes in refugees from Myanmar. HBV subgenotype C1 is predominant in Myanmar. As HBV genotype C is associated with hepatocellular carcinoma (HCC), it is important to screen for cirrhosis and HCC and to prevent their development in HBV-infected individuals of Myanmar.

Background/Aims: Hepatitis E virus (HEV) in Bangladesh has not been adequately documented. We report HEV RNA and genotype detection in Bangladesh. Methods: In total, 82 samples were used; 36 sporadic acute hepatitis (AH), 12 fulminant hepatitis (FH), 14 chronic liver disease (CLD) and 20 from an apparently healthy population (HP) positive for both immunoglobulin (Ig) M and IgG specific anti-HEV antibodies (anti-HEV). The male/female ratio was 61/21, ages 12–67 (mean 30.4) years. RNA was extracted, transcribed to cDNA and amplified in nt 6345–6490 (ORF2) of HEV. Nucleic and amino acid sequences were determined. Homology comparison between Bangladesh clones and other representative HEV clones and phylogenetic tree analyses were done. Relations between HEV RNA-positivity and clinical factors were analyzed. Results: HEV RNA was positive in 9/36 (25.0%) of AH cases, 4/12 (33.3%) FH, 3/14 (21.4%) CLD and 0/20 (0%) HP samples; total 16/82 (19.5%). Four factors correlated significantly with HEV RNA-positivity (Mann-Whitney U test); alanine aminotransferase (ALT) (P = 0.0229), aspartate aminotransferase (AST) (P = 0.0448), and titers of IgG (P = 0.0208) and IgM (P = 0.0095) specific anti-HEV. The 16 HEV clones were divided mainly into two groups, A and B, including six different cDNA sub-groups. Conclusion: HEV RNA was found in sporadic AH and FH and sub-clinical CLD cases, but not in HP. HEV RNA-positivity was significantly related to values of ALT and AST and titers of IgG and IgM specific anti-HEV, with IgM specific anti-HEV showing the most significant relationship. All clones were genotype I, which is prevalent in South Asia.

Capsaicin has beneficial pharmacological properties, such as the ability to improve appetite and digestion. However, capsaicin has been reported to suppress gastric acid output, but to increase secretion; no consensus as to its effects on gastric acid output has been reached, and the underlying mechanisms remain to be elucidated. Rat gastric lumen was perfused with capsaicin. Basal acid output and gastric acid secretion stimulated by vagal nerve activation and bethanecol, a muscarinic receptor agonist, were measured. After intravenous infusion of calcitonin gene-related peptide (CGRP), the measurements were repeated. The secretion of gastrin, somatostatin, and histamine was measured in isolated vascularly perfused rat stomach after vagal nerve and bethanecol stimulation, and under the influence of capsaicin. Capsaicin administration had no effect on basal gastric acid output, but inhibited acid secretion resulting from vagal stimulation. Capsaicin had no effect on acid secretion resulting from stimulation with bethanecol. Administration of high-dose CGRP inhibited basal acid output and gastric acid secretion from both vagal nerve and bethanecol stimulation. Low-dose CGRP inhibited gastric acid secretion because of vagal stimulation, but had no effect on basal secretion or acid secretion following stimulation with bethanecol. Capsaicin administration inhibited the stimulated gastrin and histamine secretion and reversed the suppression of somatostatin secretion mediated by vagal stimulation. However, capsaicin had no effect on stimulated gastrin secretion, suppression of somatostatin secretion, or stimulated histamine secretion because of bethanecol. Capsaicin inhibited gastric acid output, and the mechanism underlying this effect appears to involve vagal nerve inactivation.

Background and Aim: Entecavir has demonstrated clinical efficacy for chronic hepatitis B. This study evaluated the efficacy and safety of entecavir in nucleoside-naive Japanese chronic hepatitis B patients. Methods: In this multicenter, double-blind study, 66 nucleoside-naive Japanese chronic hepatitis B patients were randomized to 0.1 mg entecavir (n = 32) or 0.5 mg entecavir (n = 34) daily for 52 weeks. The primary endpoint was the proportion of patients whose serum hepatitis B virus (HBV) DNA decreased from baseline by ≥2 log10 copies/mL or became undetectable (

The overexpression of murine double minute 2 (MDM2) is found in several human tumors, and increased expression of MDM2 inactivates the apoptotic and cell cycle arrest function of p53. Interleukin-16 (IL-16) is a pleiotrophic cytokine and the properties of IL-16 suggest that it involve in the pathophysiological process of chronic inflammatory diseases. In this study, we investigated the expression of MDM2 in intestinal metaplasia and gastric cancer as well as the effect of H. pylori infection and IL-16 on epithelial cell proliferation and MDM2 expression in gastric cells in vitro. The expression of MDM2 on gastric biopsies was studied immunohistochemistry. AGS cells were incubated with a combination of IL-16 and Helicobacter pylori (H. pylori). Gastric epithelial cell proliferation was studied by BrdU uptake and the expressions of MDM2 were studied by ELISA. There was no significant difference on the expression of MDM2 between with and without H. pylori infected chronic gastritis. In H. pylori infected gastric mucosa; the MDM2 expression was higher on intestinal metaplasia and gastric cancer than chronic gastritis. IL-16 administration was increased MDM2 expression and cell proliferation on AGS cells, which was decreased by H. pylori infection. In conclusion, the expression of MDM2 in long-term H. pylori infected gastric mucosa may indicate a risk for carcinogenesis. IL-16 secretion in H. pylori infected mucosa is one of the factors for gastric cancer. The expression of MDM2 on mucosa can be a mediator for gastric cancer.

Objective: Severe acute respiratory syndrome (SARS) is a severe pulmonary infectious disease caused by a novel coronavirus. To develop an effective and specific medicine targeting the SARS-coronavirus (CoV), a chimeric DNA-RNA hammerhead ribozyme was designed and synthesized using a sequence homologous with the mouse hepatitis virus (MHV). Method: Chimeric DNA-RNA hammerhead ribozyme targeting MHV and SARS-CoV were designed and synthesized.To confirm its activity, in vitro cleavage reactions were performed with the synthesized ribozyme. Effects of the chimeric ribozyme were evaluated on multiplication of MHV. Effects of the chimeric ribozyme on expression of SARS-CoV were evaluated in cultured 3T3 cells. Result: The synthetic ribozyme cleaved the synthetic target MHV and SARS-CoV RNA into fragments of predicted length. The chimeric DNA-RNA hammerhead ribozyme targeting SARS-CoV significantly inhibited multiplication of MHV in DBT cells by about 60%. The chimeric DNA-RNA hammerhead ribozyme targeting SARS-CoV significantly inhibited the expression of SARS-CoV RNA in 3T3 cells transfected with the recombinant plasmid. The chimeric DNA-RNA ribozyme targeting SARS-CoV significantly inhibited MHV viral activity and expression of recombinant SARS RNA in vitro. Conclusion: These findings indicate that the synthetic chimeric DNA-RNA ribozyme could provide a feasible treatment for SARS.

Objective We have observed alterations of quantitative (q)-EEG findings occurring in interferon (IFN)-α treated chronic hepatitis C (CH-C) patients, and found patient's age to be one factor influencing such EEG alterations. In the present study we evaluated the correlation between q-EEG alterations during IFN-α treatment and the severity of hepatitis based on liver biopsies. Methods A total of 102 CH-C patients underwent blind, prospective and serial q-EEG examinations. The IFN-α was administered under the same therapeutic regimen to all patients. Serial EEGs were obtained before, at 2 and 4 weeks, and at 2-3 days after the conclusion of treatment. The absolute powers of each frequency band in different periods were determined by q-EEG. Staging (of fibrosis) and grading (of inflammatory cell infiltration) were scaled according to Desmet's classification. We evaluated the relationship between q-EEG and scales of staging or grading. Results Age distributions did not differ significantly among stages or grades. As the stage or grade increased, the alterations of EEG during IFN-α treatment became more pronounced, and significant (repeated-measures analysis of variances; both, p

It has been reported that levels of soluble intercellular adhesion molecule-1 (ICAM-1) in the blood are elevated in hepatocellular carcinoma patients. In the present study, serial observations of the localization of ICAM-1 in the liver were made by light and electron microscopy in rats with carcinogen-induced cancer. Male Fisher rats were given diethylnitrosamine (DEN) orally in their drinking water. Rats were sacrificed at 6, 8, 12, or 14 weeks after the start of DEN administration and the liver tissue was collected. ICAM-1 expression in liver was assessed using indirect immunoperoxidase staining with anti-rat ICAM-1 antibody. Although ICAM-1 expression by endothelial cells in livers of DEN-treated rats was lower than in the control group at 8 weeks, it was higher in the membrane and cytoplasm of hepatocytes. The expression of ICAM-1 in mesenchymal cells was decreased, paralleling development of cellular atypia, whereas in hepatocyte membranes and cytoplasm it was increased in these atypia. ICAM-1 was localized to the cytoplasm of cancer cells, but to the membrane of hepatocytes in the treated livers at 14 weeks. Furthermore, the levels of ICAM-1 in mesenchymal cells tended to be lower in the cancerous area than in the atypical hyperplastic nodule, and were reduced as the density of cell atypia increased, in comparison to cells in areas without cancerous nodules. We concluded that ICAM-1 may be influenced the development of cancer induced in the rat liver by a chemical carcinogen.

We treated patients with C-viral chronic hepatitis (CH) and liver cirrhosis (LC) with polaprezinc and determined prospectively the effect on long-term outcome. 62 patients were enrolled. Of these, 32 were administered 1.0 g polaprezinc and the remainder were not administered polaprezinc. We measured the serum zinc concentrations using conventional atomic absorption spectrometry and conducted a prospective study to determine the long-term outcome of the polaprezinc therapy. Changes of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the polaprezinc administration group were significantly lower than those of the untreated group. The decrease in platelet count was clearly less than that of the untreated group. The factors that inhibited increases in serum zinc concentrations following administration of polaprezinc included low serum zinc concentration states. Furthermore, the reductions of AST and ALT levels in the low zinc group were significantly greater than those of the high zinc group. When the patients who were administered polaprezinc were divided into two groups whose zinc concentrations increased (zinc responders) or remained stable or decreased (zinc non-responders), the zinc responders had a clearly lower cumulative incidence of HCC than the zinc non-responders. We conclude zinc supplementation improved the long-term outcome in C-viral CH and LC patients.

The expression of large (pre-S1), middle (pre-S2), major S (S) polypeptides of the envelope (HBs) and X peptides of hepatitis B virus (HBV) was investigated in 37 liver specimens with chronic hepatitis B by indirect immunoperoxidase staining. Primary antisera utilized were polyclonal ones against HBs (poly-HBs), core (HBc) and X and monoclonal ones against pre-S1, pre-S2 and S with (particle-S) or without (peptide-S) conformational structure. The localization of HBs proteins in hepatocytes was classified into three types: diffuse, membranous and inclusion. The peptide-S and pre-S2 were expressed at nearly the same frequency as poly-HBs in all types, whereas particle-S was found less frequently (18/29 cases) in the inclusion type, and pre-S1 was recognized relatively rarely (9/33 cases) in the membranous type. As for staining intensity, peptide-S and pre-S2 were almost identical to poly-HBs which stained the most strongly among all three staining types. Particle-S was similar to poly-HBs in the membranous type, but was weak in the inclusion type in the majority. While pre-S1 was stained in a similar intensity to poly-HBs in the diffuse and inclusion types, it was weak or negative in the membranous type. Thus, envelope particles indicated by particle-S staining appeared to be located most frequently in the membranous type, but their assembly might be suppressed in the inclusion type where pre-S1 was well expressed. The X peptide was more frequently detected in the liver with serum HBe antigen and/or HBV DNA. The X peptide was stained exclusively in the cytoplasm of hepatocytes and was correlated with the cytoplasmic HBc antigen. The X peptide was not observed differently between cases with and those without cirrhosis. This suggests that the expression of X peptide tends to occur with virus replication but not with disease progression.

Background and Aim: Entecavir is a potent inhibitor of both wild-type and lamivudine-resistant hepatitis B virus (HBV) with proven clinical efficacy. We conducted a randomized, double-blind, multicenter study in Japan (ETV-052) evaluating the efficacy and safety of two doses of entecavir in adult patients with lamivudine-refractory chronic hepatitis B infection. Methods: Eighty-four patients with chronic hepatitis B who were refractory to lamivudine therapy were switched from lamivudine to daily oral doses of 0.5 mg entecavir (41 patients) or 1 mg entecavir (43 patients) for 52 weeks. Results: The proportions of patients achieving the primary end-point (≥2 log10 reduction in HBV-DNA from baseline by polymerase chain reaction assay or undetectable HBV-DNA levels [

We examined prospectively the influence of occult hepatitis B virus (HBV) infection on the histopathological features and clinical outcome of HCV RNA-positive chronic hepatitis (CH-C) and detected hepatitis B core (HBc) particles in hepatocytes. The subjects were 468 patients with CH-C or liver cirrhosis (LC) who were negative for serum hepatitis B surface antigen (HBsAg) by enzyme-linked immunosorbent assay. HBV DNA was detected in serum by nested PCR. HBsAg and HBc antigen (HBcAg) in liver were investigated using immunohistochemical techniques and light (LM) and electron microscopy (EM). Serum HBV DNA was detected in 43.6% of the patients studied. There were no significant differences between HBV DNA-positive and DNA-negative patients in terms of their clinical profiles. For HBV DNA-positive patients, the degree of inflammatory cell infiltration and irregular regeneration of hepatocytes was significantly greater than for HBV DNA-negative patients. The cumulative probability of development of hepatocellular carcinoma (HCC) was significantly higher for HBV DNA-positive patients than for HBV DNA-negative patients. HBV DNA positivity was a risk factor for the occurrence of HCC according to multivariate analysis. HBsAg and HBcAg were detected in 8.5 and 72.3%, respectively, of the livers of serum HBV DNA-positive individuals. Core particles were detected in the nuclei of the hepatocytes by IEM. The histopathological features and long-term outcome of CH-C or LC could be affected by occult HBV infection.

症例は58歳，男性．不明熱，肝機能障害精査のため入院．血液検査，画像診断・各種培養を行ったが，原因不明であった．肝生検により肉芽腫性肝炎と診断された．入院時の胸部単純レントゲン・CTでは異常所見を認めなかったが，経過中に再検したところ両肺野にび慢性に広がる粒状影が認められ，transbronchial lung biopsy，骨髄からも肉芽腫病変を認めた．膀胱癌に対してBacillus Calmette-Guerin膀胱内注入療法の既往があったことより，粟粒結核を疑い抗結核療法を施行した結果，解熱し，肝機能も改善して軽快退院となった．Bacillus Calmette-Guerin播腫による重症例，死亡例も少なからず存在することから，早期診断，治療が必要と思われる．本症のように入院時肺所見が乏しく肝機能障害を認める症例は，積極的な肝生検診断が重要で不明熱検索目的の肝生検では結核を念頭においたPCRや培養目的の凍結組織などの検体採取も必要と思われた．

Aim With advent of reverse-transcription (RT)/polymerase chain reaction (PCR) for detection of the hepatitis E viral genome, we carried out retrospective examinations. Methods Serum samples collected from 68 patients diagnosed as viral hepatitis with unknown etiology were tested for viral markers of hepatitis virus. Results Two of them were found positive for hepatitis E viral RNA. While the clinical course of one patient (patient 1) was typical as acute hepatitis E, another patient (patient 2) was persistently infected with HEV. Patient 2 was infected with the virus via blood transfusion during chemotherapy against T-cell lymphoma. The entire viral genome from the donor was identical with that from the serum of patient 2 obtained on day 170 after the transfusion of the implicated red blood cell (RBC) product, confirming the transmission of HEV by transfusion. The patient remained negative for anti-HEV antibodies for the follow-up period of six months, probably due to immune suppression by lymphoma and chemotherapy. Conclusion We report here an unusual case of long-term HEV infection in a patient with T-cell lymphoma. Persistent infection with HEV was probably due to the absence of anti-HEV antibodies, which was caused by lymphoma and chemotherapy.

Treating latent tuberculosis infection is a strategy for eliminating tuberculosis, and isoniazid is recommended as preventive therapy. However, concerns have been raised regarding the application of isoniazid due to its toxicity, particularly hepatotoxicity; however, biochemical monitoring is not routinely performed during treatment. We herein present a case of fatal isoniazid-induced acute liver failure. The patient's liver function was not periodically examined and isoniazid therapy was continued for 10 days despite the onset of symptoms associated with hepatitis. The patient died four months after hospitalization. It is essential to consider the potential toxicities of isoniazid and establish strategies to prevent acute liver failure.

OBJECTIVE To determine the impact of phlebotomy on the laboratory values and the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. METHODS Study patients with chronic hepatitis C were treated with glycyrrhizin injection and oral ursodeoxycholic acid and either with (n=52) or without (n=50) phlebotomy during the period of 2005-2012. Six phlebotomized patients had previously received interferon therapy and were subsequently excluded from the data analysis. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, lactate dehydrogenase, ferritin, iron and albumin, as well as the hemoglobin concentration, platelet count and prothrombin time, were determined. We compared the long-term outcomes based on the incidence of HCC and laboratory values, including the baseline serum ferritin levels, in patients treated with versus without phlebotomy. RESULTS In the phlebotomy group, the mean AST and ALT levels decreased significantly at each one-year interval over five years (p

We performed balloon-occluded retrograde transvenous obliteration (B-RTO) before hepatocellular carcinoma (HCC) therapy in cases with HCC and gastric varices (GV) containing porto-systemic shunts. We conducted retrospective analyses on effects of B-RTO on hepatic functional reserve and HCC, as well as associated complications, and verified HCC treatment timing.B-RTO was performed before HCC therapy after confirming disappearance or shrinkage of gastro-renal shunt with 3-dimensional computed tomography (3D-CT). Hepatic resection (HR) was performed in 7 of 12 cases, and transcatheter chemo-embolization (TACE) was used in 5 cases.B-RTO significantly improved GV (P=0.002). Improvement in grade/form was observed by endoscopy after 84.1 days, and that in gastro-renal shunt was observed by 3D-CT after 13.9 days. HCC size (P=0.862) and stage didn't change after B-RTO. Two cases showed improved Child-Pugh classification, and no deterioration in hepatic functional reserve was observed. B-RTO was performed 37.9 days before HCC therapy in surgical cases, and 45 days in TACE cases.Performing B-RTO before HCC therapy did not exacerbate HCC and allowed its safe performance. Evaluation with 3D-CT after B-RTO to determine HCC therapy timing was possible after 2 weeks. However, care is needed as esophageal varices worsened in some cases.

Background: Hepatitis C virus (HCV) RNA titer and HCV genotype are two major determinants of the outcome of interferon (IFN) monotherapy. To clarify the usefulness of combination therapy with IFN and ribavirin in Japanese hepatitis C patients, we treated patients with a relatively high dose of IFN in combination with ribavirin for 24 weeks and examined the effects in relation to the viral parameters. Methods: Two hundred and ninety-five patients were enrolled in the study. The patients received either 6 or 10 million units (MU) of interferon α-2b every day for 2 weeks and then three times a week for 22 weeks with a daily dose of either 600 or 800 mg of ribavirin. The treatment response and safety of this treatment were examined. Results: The sustained virologic response (SVR) rates were 26.8% in genotype 1 and 76.5% in genotype 2 (P

Combination therapy with polyethylene glycosylated IFN-alpha2a or IFN-alpha2b and ribavirin is currently the standard therapy for chronic hepatitis C. However, even with this therapy, hepatitis C virus cannot be eradicated in 50% of patients with refractory chronic hepatitis C. In addition, withdrawal or dose reduction occurs in approximately 40% of patients due to adverse effects. This treatment is also a contraindication in some patients, such as in patients with coexisting diseases or in elderly patients. For these patients, standard IFN-alpha monotherapy is even safer and more effective. In patients with chronic hepatitis C, IFN-alpha monotherapy results in a significant increase in the cumulative survival rate by suppressing the progression to hepatocellular carcinoma or liver failure. In addition, other efficacious therapeutic regimens have been employed, such as prolonged administration of standard IFN-alpha in elderly patients; prolonged low-dose continuous administration in patients with decompensated cirrhosis or hepatocellular carcinoma postoperative patients; and combination therapy with 5-fluorouracil and standard IFN-alpha for advanced hepatocellular carcinoma. Monotherapy with standard IFN-alpha should thus be recognised as one of the important therapeutic strategies for chronic hepatitis C.

This study was performed to evaluate any improvement in the nutritional state and clinical symptoms in patients with liver failure and advanced cirrhosis after consumption of a liver diet with restricted energy and protein, in combination with a branched chain amino acids (BCAA)-enriched elemental diet.A BCAA-enriched elemental diet, in combination with a liver diet, characterized by restricted energy and protein, was administered in divided meals to 20 patients with liver failure associated with ascites or hepatic encephalopathy for 4 weeks.The symptom of ascites abated as a result of increased total serum protein and albumin levels after the nutritional intervention in comparison with baseline levels. Ammonia levels were slightly increased without exacerbating hepatic encephalopathy, and the protein nutrition state consequently improved.Divided meals of a BCAA-enriched elemental diet combined with a liver diet improved the nutritional state and clinical symptoms of patients with liver failure.

Background/Aims: This investigation compared the histological findings in the livers of chronic hepatitis C patients who were or were not co-infected with SEN virus (SEN-V) to determine the histological and clinical characteristics of SEN-V infection in Japan. Methods: Three hundred and ninety-two patients with hepatitis C virus-associated chronic hepatitis (CH) or liver cirrhosis (LC) were included in the study. Serum samples were tested for the presence of SEN-V DNA by nested polymerase chain reaction. The liver biopsy specimen of each patient was examined and scores were assigned to indicate the severity of each of the following features: inflammatory cell infiltration in the periportal, parenchymal, and portal areas; F stage; portal sclerotic change; perivenular fibrosis; pericellular fibrosis; damage to the bile ducts; steatosis and irregular regeneration of hepatocytes (IR). Results: Of the 473 patients, 194 (41.0%) were positive for SEN-V DNA. The rate of progression of F stage correlated with SEN-V DNA positivity. The blood biochemical parameters did not differ significantly between the SEN-V DNA-positive and -negative patients. The histological features of the livers of SEN-V DNA-positive patients included more severe parenchymal inflammatory cell infiltration and more IR. In particular, among those at the F2, F3 and F4 stages, the degree of IR of the SEN-V DNA-positive patients was significantly greater than that of the SEN-V DNA-negative patients. The cumulative probability of hepatocellular carcinoma (HCC) incidence and survival rate did not differ between the SEN-V DNA-positive and-negative patients. Conclusions: SEN-V co-infection may influence the histopathological features of the livers of patients with type C CH and LC but does not affect the outcome of patients with type C chronic liver disease.

Aim: The incidence of hepatocellular carcinoma (HCC) in C-viral chronic hepatitis (CH) and liver cirrhosis (LC) patients after interferon (IFN) therapy was evaluated according to alanine aminotransferase (ALT) levels. Patients: Two hundred sixty-nine patients with C-viral CH and LC were treated with natural IFN-α. The efficacy of IFN therapy was evaluated based on virologic response and ALT levels using the following groups: virologic-sustained responders (VSR); biochemical-sustained responders (BSR); partial responders (PR), which consisted of BSR patients whose serum ALT levels later relapsed; non-responders (NR)1, which included patients with serum ALT levels that were usually less than 80 IU/l; and NR2, NR with ALT levels persistently more than 80 IU/l. Results: Of the 269 patients, 22 (8.2%) developed HCC after IFN therapy. The incidence of HCC (%/patient/year) was 0.78%, 0%, 0%, 0.17%, 4.68% in VSR, BR, PR, NR1, NR2, respectively. Multivariate analysis revealed that an increase in ALT levels to more than 80 IU/l is an important risk factor for the occurrence of HCC. Conclusions: We concluded that the patients with ALT levels less than twice the upper limit of normal after IFN therapy have a reduced risk of progression to HCC from C-viral chronic liver disease.

In this study, the serum concentrations of human hepatocyte growth factor (HGF) were examined to clarify the relationship between HGF and interferon (IFN) therapy for hepatitis C. The subjects were 94 patients with chronic hepatitis C who underwent liver biopsy at our institution from 1994 through 1996. These patients were treated with natural IFN-α, IFNα2a and IFNα2b for periods varying from 12 to 26 weeks. Serum levels of HGF were determined in individual patients just before and after the administration of IFN and at 6 months and 1 year thereafter. The serum concentration of HGF was evaluated using enzyme-linked immunosorbent assay kits. The intra-hepatic location of HGF was explored using an immunoperoxidase-staining method. A positive correlation was found between the degree of HGF expression in the liver and the serum HGF concentrations. The degree of HGF expression in the liver decreased in the virologically sustained responders (SVRs) following IFN therapy. The serum HGF concentrations immediately after IFN therapy were lower than those before therapy in 83% of the patients. The concentrations gradually rose thereafter in about 45% of the non-responders, while it remained low or declined further in about half of the patients in this group. In the SVRs, the serum HGF concentrations declined in 88% of patients immediately after IFN therapy. Thereafter, it remained equally low or declined further in 60% of the SVRs. The serum HGF concentrations at 6 months and 1 year after IFN therapy were significantly lower in the SVRs than in the non-responders. In conclusions, serum HGF concentrations declined following IFN treatment regardless of the virological outcome of treatment. The decrease in serum HGF concentrations results from a decrease in the number of mesenchymal cells producing HGF. Consequently, evaluation of the serum HGF concentration is of clinical value for assessing changes in liver tissues after IFN therapy.

Human hepatocellular carcinoma is one of the most common cancers in the world. We previously showed that dbpA, a member of the Y box family of proteins, could accelerate the process of inflammation-induced hepatocarcinogenesis, and that dbpA is more abundantly expressed in hepatocellular carcinoma than in non-tumorous tissue. In this study, to clarify the mechanism by which expression of dbpA is enhanced in the proliferative state, we examined the transcriptional activity of the dbpA promoter region. We focused on the sequence 5'-TTTGGGGC-3' (-8 to -1 in the promoter region) resembling the E2F binding site (one base mismatch, TFSEARCH score 86.2). By overexpressing E2F1 in Huh-7 cells, transcriptional activity of dbpA was significantly increased, and this increase was abolished by mutating or deleting this sequence. Thus, expression of dbpA was positively regulated by E2F1, suggesting that one of the effects of E2F1 on cell proliferation might be mediated by dbpA at the carcinogenesis step.

We investigated the clinical significance of serum and intrahepatic KL-6/MUC1 (KL-6) in patients with hepatitis C virus (HCV) antibody-positive hepatocellular carcinoma (HCC). The subjects included 76 patients diagnosed with anti-HCV positive HCC, 69 with, and 51 without, liver cirrhosis (LC). Frozen serum samples were obtained from each subject to determine the serum KL-6 levels using an enzyme-linked immunosorbent assay. Expression of KL-6 antigen in the liver was also investigated using immunoperoxidase staining. The mean serum KL-6 level in patients with HCC was [Formula: see text] U/ml (319U/ml for HCC with LC, 342.8U/ml for HCC without LC). Serum KL-6 levels in patients with HCC with LC and HCC without LC did not differ. Serum KL-6 levels were elevated with increases in the size of spaces occupied by tumors in the liver. Among patients with HCC, there was no correlation between serum KL-6 levels and alpha-fetoprotein (AFP) levels and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels. However, some patients with low levels of AFP and PIVKA-II possessed high levels of KL-6. Furthermore, serum KL-6 levels decreased after therapy for HCC nodules. Immunohistochemical staining showed KL-6 antigen was detected within the cell membrane and in the cytoplasm of cancer cells. KL-6 antigen was localized on the membrane and the endoplasmic reticulum of cancer cells in the cancerous foci by electron microscopy. Our results suggest that serum KL-6 levels represent a serological marker of HCC development, because KL-6 expression was localized to the cancer cells in HCC nodules.

We determine whether the serum KL-6/MUC1 (KL-6) levels in patients with type C liver disease can be used to assay inflammatory activity and the stage of fibrosis of patients, as well as to screen high-risk groups for the development of hepatocellular carcinoma (HCC). Study subjects included 130 patients with type C chronic hepatitis (CH), 15 patients diagnosed with type C acute hepatitis (AH) and 17 healthy control subjects. Frozen serum samples were obtained from each subject to determine the KL-6 levels using an enzyme-linked immunosorbent assay (EIA) method. The mean KL-6 levels in patients were as follows: 150.1 U/ml for healthy controls, 203.7 U/ml for AH patients, 225.7 U/ml for F0 stage, 207.4 U/ml for F1 stage, 235.8 U/ml for F2 stage, 193.3 U/ml for F3 stage, and 276.2 U/ml for F4 stage in CH patients. The mean serum KL-6 level in patients with F4 stage was significantly higher than that in healthy controls. No relationship was observed between the serum KL-6 levels and liver histology. However, the degree of irregular regeneration (IR) of hepatocytes and the levels of KL-6 were significantly correlated according to the progression of F stages. The cumulative incidence of HCC in the high KL-6 level group (>/=300 U/ml) was significantly greater than that in the low level group. Our results suggest that the determination of serum KL-6 levels may be useful in screening high-risk groups for the development of HCC.

Objectives: The aims of this study were to determine the hepatitis B virus (HBV) genotypes in hepatitis delta virus (HDV) RNA-positive patients and to characterize the HBV nucleotide sequences that may be found on a distant island of Japan. Methods: This study included three patients with chronic hepatitis who were positive for hepatitis B surface antigen (enzyme-linked immunosorbent assay; ELISA), HDV antibody (ELISA) and HDV RNA by polymerase chain reaction (PCR). The HBV genotype was determined by nested PCR using type-specific primers. The first-round PCR products from two patients were sequenced, followed by an investigation of nucleotide homology. Results: Viruses from all three patients in this study were classified as HBV genotype B. Comparison with HBV isolates from geographically neighboring regions revealed that the two HBV isolates had 97.9–98.6% identity at the nucleotide level to a Chinese isolate, 98.3–98.6% identity to the Okinawa isolate and 98.6–98.8% identity to a Japanese isolate of genotype B. On phylogenetic analysis, the HBV isolates from the two patients were classified as HBV genotype B. The HBV isolates of cases 1 and 3 clustered in the same group as isolates from the Chinese mainland and Japanese mainland, which are geographically near Miyako Island. Conclusion: The HBV isolates coinfected with HDV found on Miyako Island were of genotype B. The PCR method based on genotype-specific primers was useful in determining HBV genotypes.

China is an area of high endemicity for viral hepatitis, and the molecular epidemiological investigation of TT virus (TTV) infection is of interest. In the present study, we investigated the epidemiology, clinical significance and molecular characteristics of TTV infection in patients with chronic hepatitis B and C in Yanbian City, China. Serum samples obtained from 74 patients with hepatitis B and hepatitis C who visited Yanbian Hospital, located in northeast China, were analyzed in this study. The study group included 22 cases of chronic hepatitis B (B-CH), 17 cases of liver cirrhosis B (B-LC), 7 cases of hepatocellular carcinoma (B-HCC), 16 cases of chronic hepatitis C (C-CH), 11 cases of liver cirrhosis C (C-LC) and 1 case of hepatocellular carcinoma (C-HCC). Detection of TTV DNA was performed as described by Nishizawa et al. The second-round PCR products from 7 subjects were sequenced, followed by investigation of nucleotide homology and phylogenetic analysis. TTV DNA was present in 18.2, 5.9, 28.6, 6.3, 9.1 and 0% of the patients with B-CH, B-LC, B-HCC, C-CH, C-LC and C-HCC, respectively. The highest prevalence of TTV infection was seen in the groups aged 40–50 and over 60 years. There was no significant correlation between the presence of TTV DNA and the clinical parameters in patients with hepatitis B and C. The various isolates showed 97.9–100% with isolates reported previously from Japan and 98.4–100% with isolates reported previously from China. Nucleotide sequence analysis revealed that the Yanbian isolates could be classified in the same group as the Japan and China isolates. We concluded that chronic coinfection with TTV did not affect the serological features of chronic hepatitis B and C in China, as found in Tokyo, Japan.

Serum ferritin levels, and histological liver iron content were determined in 106 patients with chronic hepatitis C (CHC) to find out whether iron status is involved in the pathogenesis of CHC and to study the relationship between sexual differences and the liver function test and liver histology. The serum ferritin index (SFI) as an indicator when both male and female subjects are combined was calculated. SFI significantly correlated with serum aminotransferase levels. In a comparative study of the relationship between serum ferritin levels and histological liver iron content, serum ferritin levels most strongly correlated with sinusoidal iron score (SIS) in male. A study of the relationship between liver histology and serum ferritin levels, and histological liver iron content showed that in the male subjects, serum ferritin levels, the portal iron score (PIS), SIS, and total iron score significantly increased as activity increased and serum ferritin levels and PIS were significantly higher as the F stage increased. These findings indicate that serum ferritin levels reflect histological liver iron content. Serum ferritin levels and histological liver iron content reflect histological activity and the F stage in males; in females, however, no relationship was observed.

Aims: The relationship between the hepatitis G virus (HGV) RNA-positive state or the HGV anti-E2 antibody-positive state, and various clinical parameters among patients with C-viral chronic liver disease and blood donors, was examined. Patients and methods: The subjects consisted of 166 patients with hepatitis C virus (HCV) RNA-positive liver disease, and 157 blood donors. Serum samples were tested for the presence of HGV RNA by the polymerase chain reaction method. The HGV E2 antibody level was measured with an enzyme-linked immunosorbent assay kit. Results: HGV RNA was detected in 1.3% of the blood donors, and HGV E2 antibodies were detected in the sera of 2.5% of the blood donors. The detection rate of HGV RNA and HGV E2 antibodies among the patients with C-viral liver disease was 4.8 and 28.3%, respectively. The detection rates of HGV RNA and HGV E2 antibody among those in each F stage were 0 and 25.0% among those in the F1 stage, 2.6 and 34.2% among those in F2, 11.1 and 27.8% among those in F3, 12.5 and 29.2% among those in F4, and 11.1 and 27.8% among those with hepatocellular carcinoma (HCC). The detection rate of HGV RNA increased with the progression of the F stage and HCC, however, the detection rate of HGV E2 antibody among the four F stages and HCC did not significantly differ. In addition, the clinical parameters and background of those who did or did not have HGV E2 antibodies or HGV RNA, did not significantly differ. Conclusion: HGV exposure may promote the progression of liver fibrosis (F stage) in C-viral liver diseases.

The goal of the study was to evaluate the efficacy and safety of balloon-occluded transarterial chemoembolization (B-TACE) of hepatocellular carcinoma (HCC) using miriplatin (a lipophilic anticancer drug) and gelatin particles.B-TACE was performed for 62 HCC nodules in 33 patients who could not be treated by surgical resection or radiofrequency ablation. All 33 patients had a history of transarterial chemoembolization (TACE) treatment prior to B-TACE. As a historical comparison, we investigated 40 nodules in 28 patients treated by TACE using a conventional microcatheter (C-TACE), miriplatin and gelatin particles. The therapeutic effect per tumor was compared between the groups based on the Response Evaluation Criteria in Cancer Study Group of Japan (RECICL) and side-effects were compared based on the Common Terminology Criteria for Adverse Events (ver. 4.0).The therapeutic efficacy after 4-12 weeks was evaluated in 59 nodules in the B-TACE group and in 37 nodules in the C-TACE group. Of these nodules, TE4 occurred in 29 (49.2%) in the B-TACE group and in 10 (27%) in the C-TACE group. Local efficacy was significantly higher in nodules treated by B-TACE than by C-TACE. The side-effects on hepatic function were similar in the two groups.Our results suggest that B-TACE with miriplatin is a useful treatment for hepatocellular carcinoma.

In the present study, we compared the molecular epidemiology of GBV-C/HGV co-infection and the clinical profiles in patients diagnosed with either type B or type C hepatitis virus infection from Nanjing in Southeast China and Yanbian in Northeast China, with those at the Nihon University Hospital in Tokyo. The patients included 97 men in Nanjing, 66 men and women in Yanbian, and 249 men and women at the Nihon University Hospital. GBV-C/HGV RNA was detected using reverse transcriptase polymerase chain reaction as described by Abe et al. The prevalence of GBV-C/HGV co-infection in Nanjing, Yanbian, and Tokyo was 18.8, 23.3, and 3.5% in type B liver diseases, respectively, and 3.6, 11.1, 7.3% in type C liver diseases, respectively. A comparison of background factors between GBV-C/HGV RNA-positive and -negative patients revealed no significant differences in any parameter between Nanjing, Yanbian, and Tokyo. A phylogenic tree analysis of nucleotide sequences showed that the Nanjing strain was closely related to the Shanghai, Hong Kong, and Tokyo isolates, while the Yanbian isolate was closely related to the Korean, Mongolia, and Tokyo strains. These isolates were classified to the East Asian type of genotype 3. The results of the phylogenic tree analysis suggests that the GBV-C/HGV isolates from China and Japan have a common origin. Therefore, the prevalence of GBV-C/HGV infection may be geographically determined, irrespective of racial differences.

This study was undertaken to detect TTV DNA in serum samples from patients with non-A, non-B, non-C, non-E, and non-G (non-A–G) liver diseases and from blood donors, and to investigate the clinicopathological features of TTV infection including its prevalence and influence on liver disease. The study population consisted of 20 patients with non-A–G liver diseases (nine with chronic hepatitis (CH), six with liver cirrhosis (LC), and five with hepatocellular carcinoma (HCC), as well as 47 blood donors. Detection of TTV DNA was conducted with 200 μl of serum by the nested polymerase chain reaction. The detection rate of TTV DNA by subject category was CH 55.9; LC 66.7; HCC 60%; and blood donors 28%. Regarding blood biochemistry, TTV DNA-positive patients tended to show higher levels of aspartate aminotransferase and alanine aminotransferase, as well as lower levels of platelet counts. Long-term follow-up revealed that TTV DNA-positive patients exhibited characteristic, multiple peaks of alanine aminotransferase (ALT) levels. The histologic findings in the livers of TTV DNA-positive patients with CH consisted of moderate necro-inflammatory reactions. In conclusion, it is possible that the TTV genotype 1b infection caused liver injury.

The present investigation compared the histological findings in the liver of chronic hepatitis C patients who were or were not co-infected with TT virus (TTV) to determine the histological and clinical characteristics of TTV infection. One hundred eighty patients with chronic hepatitis or liver cirrhosis type C were included in this study. Serum samples were tested for the presence of TTV DNA by a nested polymerase chain reaction. The liver biopsy specimen of each patient was examined, and scores were assigned to indicate the severity of each of the following features: inflammatory cell infiltration in the periportal, parenchymal, and portal areas; fibrous stage; lymphoid reaction in the portal area; portal sclerotic change; perivenular fibrosis; pericellular fibrosis; damage of bile duct; and irregular regeneration of hepatocytes. Sixty-four (34.4%) of the 180 patients were positive for TTV DNA. The histological features of the liver and the blood biochemical parameters of the TTV DNA-positive and TTV DNA-negative patients, did not differ significantly except for the score of irregular regeneration (IR) of hepatocytes. Among those in the F4 stage of fibrosis, the score of IR of the TTV DNA-positive patients was significantly higher than that of the TTV DNA-negative patients. In conclusion, chronic TTV infection does not modify the biochemical features of chronic hepatitis type C patients. TTV may be a risk factor, however, for the development of hepatocellular carcinoma in patients with type C liver disease in the F4 stage.

The organ where the GB virus (GBV)-C/hepatitis G virus (HGV) localizes and proliferates is not known. We examined the digestive organs for HGV RNA to determine the localization of the HGV. Two cases of patients with serum-positive HGV RNA were investigated. We embedded surgically excised materials and digestive secretion materials from cases 1 and 2 in paraffin blocks. The tissue specimens investigated included lymph nodes No. 201 and 202, ascending colon (nontumor and tumor area), ileocecum, appendix, liver (nontumor and tumor area) and gall bladder. We made cDNA after extraction of total RNA from thin tissue sections and detected HGV RNA with a reverse transcription polymerase chain reaction method. No HGV RNA was detected in liver, colon and gall bladder tissues. HGV RNA was only detected in the appendix tissue. Comparison of nucleotide sequences of PCR products from serum and appendix was almost the same. Homology between US type (PNF2161) and the serum and appendix PCR products was 92.6 and 93.6%, respectively. These results suggest that HGV proliferates in the appendix and is carried by the portal blood flow to the liver, and may cause a hepatitis reaction in the liver.

We determined hepatocyte growth factor (HGF) levels in the serum and liver of patients with hepatitis C and assessed the relationship to histological findings of the liver and hepatitis C virus-related markers in the serum in patients with type C liver diseases. The subjects were 108 patients with chronic hepatitis C (CH), 70 patients with liver cirrhosis C (LC), 38 patients with hepatocellular carcinoma (HCC) and 20 patients with acute hepatitis (AH). As normal controls 20 subjects were studied. The serum HGF levels were measured using an enzyme-linked immunosorbent assay kit. Intrahepatic HGF was investigated by immunoperoxidase staining using monoclonal HGF antibody. The serum HGF level was highest in patients with AH. The serum HGF levels tended to be higher in patients with LC and HCC than those with CH. Further, the serum HGF level was related to the degree of intrahepatic inflammatory cell infiltration and fibrosis, and intrahepatic HGF was noted primarily in the cell membrane of mesenchymal cells in focal necrosis. The degree of intrahepatic HGF expression tended to be higher in patients with high serum HGF levels. In patients with HCC, however, HGF showed little localization in cancer cells, but was noted in infiltrating mesenchymal cells in both cancerous and noncancerous regions. In conclusion, the measurement of serum HGF levels may be useful for estimating the degree of intrahepatic inflammatory reaction and fibrosis. Although further study is necessary, the high serum level of HGF revealed high carcinogenic states in chronic hepatitis and liver cirrhosis type C.

Persistent hepatitis C virus (HCV) infection is associated with the development of human hepatocellular carcinoma (HCC), although the mechanism of HCV-related hepatocarcinogenesis remains unclear. Recently, however, the close relationships between the development of HCC and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) cascade have been described. In the present study, we investigated the effects of HCV core protein on this MAPK/ERK cascade. HCV core protein significantly activated the MAPK/ERK cascade, including Elk1. We also examined whether HCV core protein acted synergistically along with hepatocyte mitogen-mediated MAPK/ERK activation. Interestingly, Elk-1 activities were further enhanced by the tumor promoter, 12-O-tetradecanoyl phorbol 13-acetate (TPA), but not by hepatocyte mitogens (epidermal growth factor [EGF] and transforming growth factor alpha [TGF-alpha]) in NIH3T3 cells and HepG2 cells expressing HCV core protein. Moreover, the MAPK/ERK activation by HCV core protein was blocked in the presence of the specific MEK1 inhibitor, PD98059. These results indicate that ERK activation by HCV core protein may be independent of hepatocyte mitogen-mediated signaling but synergistic with TPA, and HCV core protein may function at MEK1 or farther upstream of that component.

Aims/Background: The present investigation compared the histological features of the liver of chronic hepatitis C patients who are or are not coinfected with hepatitis G virus (HGV) to determine the histological and clinical characteristics of HGV infection. Subjects and Methods: This study included 194 patients with chronic hepatitis C who visited our institution between 1993 and 1995. Detection of serum HGV RNA was performed by nested reverse transcription-polymerase chain reaction. Scores were assigned to indicate the severity of each of the following features on the liver biopsy of a patient: inflammatory cell infiltration in the periportal, parenchymal, and portal area; fibrous stage; lymphoid aggregates in the portal area; portal sclerotic change; perivenular fibrosis; pericellular fibrosis; bile duct damage; bridging necrosis; and irregular regeneration of hepatocytes (IR). Results: HGV RNA was detected in the sera of 18 (9.3%) of the 194 patients. The histological features of the HGV RNA-positive patients show significantly more severe bile duct damage, perivenular fibrosis, pericellular fibrosis and IR than the liver of the HGV RNA-negative patients. The biochemical results in the two groups did not significantly differ. Conclusion: Our data suggest that chronic HGV coinfection worsens the histological features of liver disease.

Hepatitis B virus (HBV) DNA has been detected in the sera of hepatitis patients who are negative for hepatitis B surface antigen (HBsAg) by polymerase chain reaction (PCR). The purpose of the present study was to clarify the clinical characteristics of patients with chronic hepatitis C who are negative for serum HBsAg and positive for HBV DNA. The subjects included 49 patients with chronic hepatitis C who were negative for serum HBsAg and 119 blood donors who served as healthy controls. Serum samples were tested for the presence of HBV DNA by the nested PCR method. Serum HBV DNA was detected in 18 (37.7%) of the 49 chronic hepatitis C patients and in none (0%) of the 119 blood donors. Among the hepatitis C patients, HBV DNA was detected in 20.7% of those who were negative for all HBV-associated markers and in 57.1% of those who were positive for one or more HBV-associated marker. The HBV DNA-positive rate among those in each F stage did not significantly differ. The liver function parameters of the HBV DNA-positive and the HBV DNA-negative chronic hepatitis C patients did not significantly differ. These results suggest that hepatitis C virus is frequently coinfected with serum HBsAg-negative HBV, and that the incidence of HBV infection in blood donors is low. However, it is considered that HBsAg-negative HBV infection does not modify the blood biochemical features of chronic hepatitis C.

We tested the sera of patients with non-A, non-B, non-C, non-G (non-A to -G) hepatocellular carcinoma (HCC) for the presence of TT virus (TTV) DNA and clinicopathologically elucidated the relationship between TTV infection and hepatocarcinogenesis. The study cohort consisted of 19 patients with non-A to -G HCC. Detection of TTV DNA was performed by the nested polymerase chain reaction according to a previously published method. TTV DNA was detected in the sera of 9 (47.4%) of the 19 patients with non-A to -G HCC. The clinical background factors and blood biochemical parameters of the TTV-DNA-positive and -negative HCC patients did not significantly differ. Three TTV-DNA-positive and 2 TTV-DNA-negative patients underwent surgical resection of the HCC. The histological findings in the non-cancerous liver tissue of the TTV-DNA-positive and -negative patients did not significantly differ. In conclusion, TTV infection does not affect the features of non-A to -G HCC.

Objectives - To estimate the effect of brain function due to IFN-alpha in chronic hepatitis C patients by the quantitative EEG. Methods - 56 chronic hepatitis C patients were administered IFN-alpha intramuscularly at 9×10 6 IU daily for the first 4 weeks and then 3 times/week for the next 20 weeks. Serial EEGs were obtained in each subject before, at 2 and 4 weeks, and after completing the treatment. Resting EEG without artifacts was selected for quantitative EEG analysis, which was performed blindly. The frequency range was divided into delta to beta. The absolute and relative powers of each frequency band in each subject were calculated and the differences of these powers at different stages were analyzed statistically. Results - The absolute powers of slow waves (delta, theta 1, and theta 2) increased while alpha 2 and fast wave (beta) decreased significantly at all locations during IFN-alpha administration. The total power and alpha 1 values revealed no significant alterations. The relative power revealed the same alteration during treatment. These changes disappeared following the treatment. Such diffuse slowing in the EEG was revealed by the total change in the whole subjects. Conclusions - Diffuse slowing in the EEG was induced by IFN-alpha, was reversible, and was evident as the total change in the subjects. These findings suggested mild IFN-alpha-induced encephalopathy.

Hypervariable region 1 (HVR1) of hepatitis C virus (HCV) is known to contain neutralizing epitopes. We previously found that murine antibodies against HVR1-#6 captured a different isolate, HCV-#7, and cross-reacted with the HVR1 peptide of HCV-#7. We investigated the inducibility and generality of cross-reaction of animal anti-HVR1 antibody responses in this study. Anti-HVR1-#7 antibodies, which were induced in mice and a chimpanzee by immunization, were found to be cross-reactive to HVR1-#6 peptide. Antibody responses against HVR1-#6-1 and HVR1-#7 peptides were detected in 11/165 (6.7%) and 26/165 (15.8%) HCV-infected individuals, respectively. Nine HVR1 sequences from six individuals, who were strongly positive for anti-HVR1-#7 antibodies, were only 50–64.5% identical to that of HVR1-#7. All nine of these HVR1 peptides were reactive to sera from the six patients and/or to antisera against HVR1-#6 and HVR1-#7 produced in mice and chimpanzees. Cross-inhibition tests of chimpanzee antisera indicated that a given species of anti-HVR1 antibodies was reactive to multiple HVR1 sequences. Fine epitope mapping of polyclonal and monoclonal anti-HVR1 antibodies showed that conserved subregions in HVR1 sequences determined the observed immunological cross-reactivity. Our data demonstrate that cross-reacting anti-HVR1 antibodies are inducible by a single peptide immunization.

We report a case of acute hepatitis C that appears to have been sexually transmitted. The patient was a 21-year-old female with no history of blood transfusion and no personal or family history related to hepatic decease. The patient first had sexual intercourse with her male partner in November 1994 and she visited our hospital with a chief complaint of general weakness in March 1995. She was admitted because of abnormal liver function test results (ALT 329; AST 152 IU l −1 ). She was negative for serum second-generation anti-hepatitis C virus (HCV) antibody, anti-hepatitis A IgM antibody, anti-hepatitis B core IgM antibody, anti-Epstein–Barr virus IgM antibody, anti-nuclear antibody, anti-DNA antibody and anti-mitochondrial antibody at admission. A serum HCV RNA test gave a positive result on the 7th day after admission; her HCV RNA level was 10 3.5 copies 50 μl −1 serum on the 21st day. Her anti-HCV antibody status became positive on the 30th day after admission. A liver needle biopsy specimen taken on the 35th day showed well-preserved lobular architecture and mild necroinflammation within the parenchyma without accompanying fibrosis. Abdominal ultrasound and computed tomography did not show significant change in the liver or spleen. Taking the above findings together a diagnosis of acute hepatitis C was maden. Treatment by interferon-β succeeded in eradicating the HCV and the patient was free of HCV RNA 1 year later. The patients partner had untreated chronic hepatitis C. The HCVs isolated from the patient and her partner both had the 2b genotype and single-strand conformation polymorphism analysis revealed three virtually identical bands. The nucleotide sequences (E1-E2/NS1 region) of the two HCVs showed 98% homology. These genetic findings suggest that the sexual transmission of HCV occurred in this case.