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Presents information on a study that examined hepatitis C virus infection among hospital employees with needlestick injuries. Research methods; Results and discussion.

Background/objectives: It has been unknown if attenuated insulin sensitivity (Si) in non-alcoholic fatty liver disease (NAFLD) is a cause or a result. We examined the impact of attenuated Si on NAFLD evolution., Subjects/methods: We observed 4856 NAFLD- and diabetes-free participants for a mean 2.9 years. Si was indexed by single point insulin sensitivity estimator (SPISE = [600 × HDL-c 0.185 ]/[TG 0.2  × BMI 1.338 ]), correlating with 1/HOMA-IR in an independent cohort (n = 1537, Spearman rho = 0.519, P < 0.01). Fatty liver (FL) was diagnosed by ultrasonography and diabetes by fasting plasma glucose (FPG) ≥ 7 mmol/L and/or glycohemoglobin A1c ≥ 6.5%. Multinominal comparison was performed with incident FL (FL w/oDM , n = 486), diabetes (DM w/oFL , n = 171), and FL plus diabetes (FL/diabetes, n = 58) as targets; none of the above (n = 4,138) was the control. SPISE was taken as a predictor with adjustment for covariates. Trajectory of SPISE during the 5 years before development of each condition was also assessed., Results: With SPISE tertile 3 (>10.06) as the reference, tertile 1 (<8.07) was related to incident FL w/oDM and FL/diabetes with OR (95% CI) 3.47 (2.60-4.63) and 1.78 (1.10-2.87), respectively, and tertile 2 (8.07-10.06) related to FL w/oDM with OR (95% CI) 1.38 (1.03-1.85). Low SPISE was not significantly related to incident diabetes. At -5 years, SPISE was 12% (P < 0.05) and 13% (P < 0.01) lower in those developed FL w/oDM and FL/diabetes, respectively, than the control. At year 0, SPISE in the two groups was 18% and 21% lower than the control, respectively (P < 0.01)., Conclusions: Attenuation of Si indexed by SPISE was a risk factor for NAFLD.

Background . A new agent, potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer advantages over conventional H. pylori eradication therapies. We aimed to compare the eradication rate between VPZ-based treatment and PPI-based one. Methods . This randomized controlled trial was designed to assign 141 patients with H. pylori- positive gastritis to VPZ group (VPZ 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days) or PPI group (rabeprazole 20 mg or lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days). Primary endpoints were eradication rates and adverse events. Results . Seventy of 72 patients in VPZ group and 63 of 69 patients in PPI group completed the treatment after 7 days. The eradication rate was significantly higher in VPZ group than PPI group by intention-to-treat analysis (95.8% versus 69.6%, P = 0.00003, 95% confidence interval [CI] 88.3-99.1% versus 57.3-80.1%) and per-protocol analysis (95.7% versus 71.4%, P = 0.0002, 95% CI 88.0-99.1% versus 58.7-82.1%). The incidence of adverse events was not different between the groups (26.3% in VPZ group versus 37.7% in PPI group, P = 0.15). Conclusion . VPZ-based regimen is more useful than that PPI-based regimen as a first-line H. pylori eradication therapy., Competing Interests: The authors have no conflict of interests to disclose.

Background: The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients., Methods: After we assessed the trend of patients who were first diagnosed with HCC at 53 tertiary care centers in Japan from 1991 to 2010, we collected detailed data of 5326 patients with non-viral etiology. The etiologies were categorized as autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), unclassified, and other. Baseline characteristics at initial diagnosis, the modality of the initial treatment, and survival status were collected via a website. Survival of the patients was assessed by the Kaplan-Meier method and Cox proportional hazard regression., Results: The proportion of patients with non-viral etiologies increased from 10.0% in 1991 to 24.1% in 2010. Of the patients, 92% were categorized as ALD, NAFLD, or unclassified. Body mass index (BMI) was ≥ 25 kg/m(2) in 39%. Diabetes was most prevalent in NAFLD (63%), followed by unclassified etiology (46%) and ALD (45%). Approximately 80% of patients underwent radical therapy, including resection, ablation, or transarterial chemoembolization. Survival rates at 3, 5, 10, 15, and 20 years were 58.2, 42.6, 21.5, 15.2, and 15.2%, respectively. Multivariate analysis revealed that patients with BMI > 22 and ≤ 25 kg/m(2) showed the best prognosis versus other BMI categories, after adjusting by age, gender, tumor-related factors, and Child-Pugh score., Conclusions: Most cases of non-B, non-C HCC are related to lifestyle factors, including obesity and diabetes. Slightly overweight patients showed the best prognosis.

This prospective, non-randomized, multicenter cohort study analyzed the safety and efficacy of a steroid-free immunosuppressive (IS) protocol for hepatitis C virus (HCV)-positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid-free IS protocol (Fr group) and 29 the traditional steroid-containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p=0.013). Preemptive anti-HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p=0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p=0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p=0.022, p<0.0001, p=0.012, respectively). The steroid-free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post-transplant period and HCV recurrence in HCV-positive LDLT recipients., (© 2012 John Wiley & Sons A/S.)

Unlabelled: The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment., Conclusion: Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Immunoglobulin (Ig) G4-associated autoimmune hepatitis (AIH) is a recently identified and possibly new disease entity. However, the epidemiology and clinical features of IgG4-associated AIH remain uncertain. The aim of this study was to determine the prevalence and the clinical, serological, and histological characteristics of IgG4-associated AIH., Methods: We examined the clinical features, serum IgG4 concentration, liver biopsy histology, and IgG4-bearing plasma cell infiltration of 60 patients with type 1 AIH and 22 patients with autoimmune pancreatitis., Results: High serum IgG4 concentration (≥ 135 mg/dL) and IgG4-bearing plasma cell infiltration in the liver (≥ 10/high-power fields [HPFs]) were found in 2 of the 60 (3.3%) patients with type 1 AIH. These patients had high serum levels of IgE, giant cell change, and rosette formation in the liver. Although corticosteroid therapy reduced the serum IgG4 concentration and normalized liver enzymes and histology, one patient developed IgG4-related sclerosing cholangitis after 5 years of follow-up., Conclusions: Because IgG4-associated AIH was found in over 3% of Japanese patients with type 1 AIH in our cohort, further studies are needed on this possible new disease entity and its impact on the diagnostic guidelines of AIH.

Background: The Japanese Liver Transplantation Society presented its first report on donor morbidity in 2003. The Society has been continuing to survey outcomes in living liver donors in Japan., Methods: By using a uniform comprehensive medical record review process, data were collected on 3565 living liver donors who had donated grafts by the end of December 2006 at 38 Japanese centers., Results: Preoperative problems were reported in 2 donors, intraoperative problems in 27, and postoperative complications in 270. In total, 299 donors (8.4%) suffered complications related to liver donation. Postoperative complications included biliary complications in 3.0%, reoperation in 1.3%, severe after-effects in two (0.06%), and death (apparently related to donor surgery) in one donor (0.03%). The incidence of postoperative complications in left and right lobe donors was 8.7% and 9.4%, respectively., Conclusions: The accumulated experience indicates a reduction in the incidence of donor complications, especially for right lobe resection. One donor death and two cases of severe after effects related to liver donation have been reported during 18 years of living donor liver transplantation experience in Japan.

Primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), is ranked third in men and fifth in women as a cause of death from malignant neoplasms in Japan. The number of deaths and death rate of HCC began to increase sharply in 1975. These numbers peaked at 34,510 and 27.4/100,000, respectively, in 2004, but decreased to 33,662 annual deaths and a 26.7/100,000 death rate in 2006. Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are both major causes of HCC, HCV-related HCC represents 70% of all cases. The incidence of HCC without hepatitis B surface antigen (HBsAg) or antibodies to HCV (anti-HCV) accounts for 8%-15% of HCC patients nationwide. Geographically, HCC is more frequent in western than eastern Japan, and death rates of HCC in each prefecture correlate with anti-HCV, but not HBsAg, prevalence. Interferon therapy for chronic hepatitis C reduces the risk of development of HCC, especially among patients with sustained virological response. Further research should focus on the mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and preventative approaches. Better understanding of HCC unrelated to HCV and HBV, possibly caused by steatohepatitis and diabetes, should also be a major concern in future studies.

Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection was found in 23 (4%) of 552 newly hepatitis B surface antigen-positive patients in Japan. Because one-fourth of cases develop into fulminant hepatic failure and mortality is 100%, management of HBV reactivation in patients with resolved HBV infection should be discussed.

Objectives: Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well., Methods: Five CTLA4 polymorphisms, located at -1722, -658, and -318 in the promoter, +49 in exon 1, and +6230 in the 3' untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls., Results: Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64%vs 42%, odds ratio [OR] 2.48, P= 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR 0.49, P= 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR 5.45, P= 0.038 and OR 12.66, P= 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL, P < 0.001). The +6230 G/A polymorphism did not influence sCTLA4 levels in AIP patients., Conclusions: Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.

Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Although the HLA-DRB1*0405 allele is associated with type 1 AIH in Japanese, the exact genetic etiology of AIH remains undefined. Recently, polymorphisms of Fcgamma receptors (FcgammaR) and Fc receptor-like gene 3 (FCRL3) were linked to a variety of autoimmune diseases, and may be at least partially responsible for susceptibility to AIH. In this study, we genotyped FcgammaRIIA, FcgammaRIIB, and four FCRL3 polymorphisms in 87 Japanese patients with type 1 AIH and 97 ethnically matched controls using the TaqMan assay. Although we were able to detect significantly lower serum IgG concentrations in AIH patients specifically with the FCRL3-110A/A genotype, we observed no difference in the distribution of the genotypes between patients and controls, implying that susceptibility to type 1 AIH in Japanese patients is not influenced by FcgammaRIIA, FcgammaRIIB, or FCRL3 polymorphisms.

Unlabelled: Genetic predisposition to type 1 autoimmune hepatitis (AIH) is linked mainly to HLA class II genes. We previously searched the whole HLA region for AIH susceptibility genes using microsatellite markers and found only HLA-DR/DQ to be a candidate region for this suspected multifactorial disease. As such, the aim of this study was to broaden our search and screen the whole genome for additional genes that might contribute to type 1 AIH susceptibility. Eighty-one patients with type 1 AIH (15 men, 66 women, average age 55.9) and 80 healthy sex- and age-matched Japanese controls were enrolled in this study. We performed a case-control association study using 400 polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. Two markers, one on chromosome 11 (D11S902, Pc = 0.013) and one on chromosome 18 (D18S464, Pc = 0.008), were revealed to have statistically significant associations with AIH. An additional 7 markers (D2S367, D6S309, D9S273, D11S1320, D16S423, D17S938, and D18S68) were also found to be candidate susceptibility regions. In addition, our results showed there were 17 regions that may contain genes of resistance to AIH. No specific markers were detected in HLA-DR4-negative patients, and no differences were seen in the clinical courses of patients (severe versus mild to moderate)., Conclusion: This first genomewide scan of Japanese AIH patients revealed at least 26 candidate AIH susceptibility or resistance regions other than HLA class II loci. These results also suggested that the products of several genes interact to determine heritable susceptibility to AIH.

Intestinal non-Hodgkin's lymphoma (NHL), especially the T-cell type, is well known to be associated with celiac disease (CD), an enteropathic disorder with a propensity for certain racial and genetic backgrounds. CD is typically characterized by gastrointestinal (GI) symptoms, anti-transglutaminase antibodies in the sera, and microscopical findings of the intestinal mucosa, which resolve with a gluten-free diet (GFD). In Asian populations, including the Japanese, CD and the associated NHL have been supposed to be quite rare, and studies concerning the frequency of CD or its relationship with NHL are scarce. We describe a Japanese middle-aged man with intestinal diffuse large B-cell lymphoma associated with CD. Following multi-combined chemotherapy, the patient's lymphoma has been in a state of complete response, and his GI symptoms have improved with a GFD. This case suggests that the possibility of CD and its association with intestinal NHL should be kept in mind, even in Asian populations.

Aim: To investigate the clinical significance of KL-6 as a tumor marker of HCC in two different ethnic groups with chronic liver disease consecutively encountered at outpatient clinics., Methods: Serum KL-6 was measured by the sandwich enzyme immunoassay method using the KL-6 antibody (Ab) as both the capture and tracer Ab according to the manufacturer's instructions (Eisai, Tokyo, Japan). Assessment of alpha fetoprotein (AFP) and protein induced vitamin K deficiency or absence (PIVKA-II) was performed in both groups using commercially available kits., Results: A significantly higher mean serum KL-6 (556+/-467 U/L) was found in HCC in comparison with non-HCC groups either with (391+/-176 U/L; P<0.001) or without (361+/-161 U/L; P<0.001) liver cirrhosis (LC). Serum KL-6 level did not correlate with either AFP or PIVKA-II serU/Levels. Using receiver operating curve analysis for KL-6 as a predictor for HCC showed that the area under the curve was 0.574 (95%CI = 0.50-0.64) and the KL-6 level that gave the best sensitivity (61%) was found to be 334 U/L but according to the manufacturer's instructions; a cut-off point of 500 U/L was used that showed the highest specificity (80%) in comparison with AFP and PIVKA-II (78% vs 72% respectively). Combining the values of the three markers improved specificity of AFP for HCC diagnosis from 78% for AFP alone; 93% for AFP plus PIVKA-II to 99% for both plus KL-6 value (P<0.001). Mean serum alkaline phosphatase level was significantly higher in KL-6 positive (564+/-475) in comparison with KL-6 negative (505+/-469) HCC patients (P = 0.021), but such a difference was not found among non-HCC corresponding groups., Conclusion: KL-6 is suggested as a tumor for HCC. Its positivity may reflect HCC-associated cholestasis and/or local tumor invasion.

We investigated the presence of antibodies to hepatitis E virus (anti-HEV) and hepatitis A virus (anti-HAV) by enzyme immunoassays in sera from 1015 individuals collected in 1974, 1984 and 1994. Age-specific profiles of anti-HEV remained unchanged with a peak at 40-49 years, while those of anti-HAV started to increase in individuals aged 20-29 years in 1974, 30-39 years in 1984 and 40-49 years in 1994. These results suggest that a silent HEV infection has been taking place in the last 20 years or so in Japan, while HAV infection has been terminated at least since 1974.

Background/aims: Genetic predisposition to type 1 autoimmune hepatitis (AIH) is linked mainly to HLA-class II genes. The aim of this study is to scan the HLA region for additional genes which may contribute to type 1 AIH susceptibility., Methods: We performed association analysis using HLA class I and II alleles and 18 polymorphic microsatellite markers distributed throughout the HLA region. We specifically assessed tumor necrosis factor (TNF)-alpha gene polymorphisms., Results: The frequencies of HLA-DRB1*0405, DRB4 and DQB1*0401 alleles were significantly higher in AIH patients. The association study revealed the presence of three segments in the HLA region showing significantly low P (Pc) values. The first segment was located around the HLA-DR/-DQ subregion, the second was around the HLA-B54 allele, and the third was around two microsatellites near the TNF gene cluster. However, stratification analysis for the effect of DRB1*0405 eliminated association of the latter two segments. Haplotype D of the TNF-alpha promoter gene polymorphisms was weakly associated with susceptibility, but was found to be not significant after stratification analysis., Conclusions: The most influential gene on type 1 AIH pathogenesis in Japanese is the HLA-DRB1. Other genes in the HLA region, including TNF-alpha, have little or no association with type 1 AIH susceptibility.

During the past 20 years, primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), has ranked third in men and fifth in women as a cause of death from malignant neoplasm in Japan. The numbers of deaths and death rate from HCC showed a sharp increase beginning in 1975. Although both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important causes, HCV-related HCC has accounted for most of the recent increase and now represents 75% of all HCC in Japan. Geographically, HCC is more frequent in western than eastern Japan, and the death rate of HCC in each prefecture correlates with prevalence of anti-HCV. Among patients with HCV-related HCC, a history of blood transfusion was a relatively important source of infection in the 1990s, whereas community-acquired infections increased after 2000. There was a negative correlation between the duration from onset of infection to development of HCC and the age at onset. Interferon therapy for chronic hepatitis C has reduced the risk for HCC, indicating that early detection of HCV carriers and better treatment will contribute to improved outcomes. Nationwide screening for HCV and HBV began in 2002 in Japan, and reduction of HCC is anticipated. Further research should focus on mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and treatment approaches. Better understanding of HCC unrelated to HCV and HBV and possibly because of steatohepatitis and diabetes should also be a major concern in future studies.

SEN virus (SENV) has been tentatively linked to transfusion-associated non-A-E hepatitis. We investigated SENV's role in unexplained hepatitis in other settings. Polymerase chain reaction amplification was used to detect 2 SENV variants (SENV-D and SENV-H) in 1706 patients and control subjects. SENV was detected in 54 (22%) of 248 patients with acute or chronic non-A-E hepatitis, 9 (35%) of 26 patients with hepatitis-associated aplastic anemia, and 0 of 17 patients with cryptogenic acute liver failure, compared with 150 (24%) of 621 control subjects with liver disease and 76 (10%) of 794 healthy control subjects. When controlling for geographic region, the prevalence of SENV among case and control subjects was not significantly different. The severity of acute or chronic hepatitis A, B, or C was not influenced by coexisting SENV infection. No etiological role for SENV in the cause of cryptogenic hepatitis could be demonstrated.

We compared the seroepidemiologic patterns of Helicobacter pylori and hepatitis A virus (HAV) infections among participants in 2 independent cross-sectional studies conducted in Japan in 1986 and 1994. Subgroups were monitored with successive blood sampling. H. pylori and HAV infection status was defined by results of enzyme-linked immunosorbent assay. In 1986, the prevalence of H. pylori infection and HAV infection, respectively, were 80% and 70% among adults and 31% and 5% among children. The prevalence of both infections increased with age. Concordant infections were found in 74.5% of adults (kappa=0.2) versus 2% of children (kappa=0.05). During the 9-year study period, the incidence of H. pylori infection was 1.1% among adults and 2% among children. The seroprevalence of HAV remained constant. The disparity between the increase in prevalence of H. pylori and HAV infection with age is likely associated with improvements in hygienic practices. The discordance between the presence of the infections among younger persons is evidence against a common source and/or vehicle for transmission.

Background: Deaths of living liver donors have been reported in western countries, whereas the morbidity and mortality of such donors in Japan, one of the leading countries for living liver transplantation, have not been reported in detail. We aimed to review the operative morbidity and mortality of such donors in Japan., Methods: 1853 donors of 1852 living liver transplants done in 46 liver transplant centres, and registered in the database of the Japanese Liver Transplantation Society, were assessed for eight donor-related factors of morbidity and mortality. Data for 1841 donors were analysed., Findings: No perioperative mortality was recorded since inception of the liver transplantation programme in Japan from Nov 13, 1989, to April 11, 2002. 244 postoperative complications were reported in 228 (12%) donors. The frequency of complications was significantly higher in donors of the right liver lobe than in those involving the lateral segment, and left lobe graft (p<0.0001, and p<0.0001, respectively). Postoperative hospital stay was significantly longer in donors of the right lobe (mean 19.7 [SD 13.0]) than in those of the lateral segment (14.2 [7.6]), left lobe (14.0 [6.5]), and left lobe and caudate lobe (16.3 [12.1]). Re-operation related to donor hepatectomy was done in 23 donors., Interpretation: By contrast with western countries, no perioperative mortality was recorded in living liver donors in Japan. However, a proportion of these donors developed serious complications. This morbidity should be reduced to maintain zero mortality in living liver donors.

The association between cryoglobulinemia and hepatitis C virus (HCV) infection has been reported. However, the factors underlying its wide variation of occurrence have not yet been well identified. To investigate this, cryoglobulinemia was studied in four cohorts of Egyptian and Japanese patients. Fifty Egyptian patients with chronic hepatitis C, infected with genotype 4 (the predominant HCV genotype in Egypt), were compared with 50 age- and sex-matched Japanese patients, infected with HCV genotype 1b (the predominant HCV genotype in Japan). Thirty-two Egyptian and 30 age- and sex-matched Japanese patients with chronic hepatitis B were included as controls. All patients were noncirrhotic. Antinuclear antibody (ANA), immunoglobulins (Ig), and cryoglubulins were assessed. Results showed a significantly higher prevalence of cryoglobulinemia in chronic hepatitis C Japanese genotype 1b (40%) as compared with Egyptian genotype 4 (14%), P = 0.003, while no difference was found between Japanese (17%) and Egyptian chronic hepatitis B controls (13%). Symptomatic cryoglobulinemia was more prevalent in the Japanese than in the Egyptian chronic hepatitis C group (10% vs. 4%), but the difference was not statistically significant. Univariate analysis showed no association between cryoglobulinemia and either age, sex, alanine aminotransferase level, or HCV viral load in Japanese or Egyptian patients, while the mean IgM level was significantly higher in the cryoglobulin-positive than in the cryoglobulin-negative chronic hepatitis C patients in each group (P = 0.003 and 0.017, respectively). Cryoglobulinemia was found to be significantly associated with both high IgG level (P = 0.020), and positive ANA (P < 0.001) in Japanese patients with chronic hepatitis C, genotype 1b but not in Egyptians with genotype 4. Multivariate analysis showed that the only factors predisposing to cryoglobulinemia were Japanese ethnicity with HCV genotype1b (P = 0.002, OR = 2.56), high IgM level of >245 mg/dl (P = 0.018, OR = 2.05) and female gender (P = 0.040, OR = 1/0.66). In conclusion, cryoglobulinemia is prevalent in Japanese patients with chronic hepatitis C infected with genotype 1b, but cryoglobulinemia is not common in Egyptians with HCV genotype 4. Although it was not possible to evaluate ethnicity and HCV genotype separately in this study, HCV genotype 1b appears to predispose more to cryoglobulinemia than does genotype 4. Female gender and high serum IgM level were also related., (Copyright 2003 Wiley-Liss, Inc.)

Hepatitis C virus (HCV) causes various grades of chronic liver disease, ranging from an asymptomatic state to cirrhosis. To assess genetic factors of disease severity, we selected two HCV patient groups according to the following stringent criteria: (i) asymptomatic carrier state (ASC) defined by HCV infection for more than 20 years, normal alanine aminotransferase levels for the past 5 years as well as normal liver histology and/or shape and (ii) liver cirrhosis (LC) as diagnosed by clinical symptoms, liver biopsy and/or ultrasonography. A total of 103 chronically infected Japanese HCV patients (43 ASC and 60 LC) were analyzed. HLA class I and II alleles were established using low resolution DNA typing. HLA-DRB1 and DQB1 genotypes were inferred upon polymerase chain reaction-restriction fragment length polymorphism analysis. Two hundred and one anti-HCV-negative ethnically matched controls were included. The frequencies of DRB1*12 (*1201 and *1202), DQB1*0301 and DRB3*03 alleles were higher in patients with ASC than in those with LC (odds ratio (OR) 11.23, OR 4.25, and OR 3.22, respectively). The frequency of DQB1*0503 were lower in ASC patients compared to LC patients (OR 0.05). No significant differences between groups were observed for age, sex, source of infection, HCV genotype or viral loads. Our findings establish that certain HLA class II alleles strongly influence disease progression following HCV infection.

Hepatitis C virus (HCV) infects an estimated 170 million persons worldwide, and 2 million persons in Japan. HCV is a major cause of chronic liver diseases, especially hepatocarcinogenesis, and the number of patients with HCV-related hepatocellular carcinoma (HCC) is increasing worldwide as well as in Japan. Most patients with acute hepatitis C develop chronic hepatitis. Spontaneous disappearance of HCV in patients with type C chronic liver disease is uncommon, and it tends to progress to further advanced and more severe liver disease, ultimately to HCC over a period of 30 years in most cases. Chronic liver disease due to HCV infection is commonly associated with extrahepatic manifestation, for example cryoglobulinemia. Antiviral treatment for HCV infection with interferon alone during 24 weeks was associated with a low rate (less than 10%) of sustained virologic response (SVR), especially in patients infected with HCV genotype 1b and high HCV RNA concentration. However, combination therapy of interferon and ribavirin raises the SVR rate. More recently, pegylated interferon used for treatment of chronic hepatitis C resulted in a high SVR rate. These modalities of antiviral treatment will reduce HCC occurrence. So far, there is no HCV vaccine in spite of many efforts.

Background & Aims: Autoimmune pancreatitis is a distinctive disease entity characterized by high serum immunoglobulin G4 concentrations. Because of the close association between some autoimmune diseases and particular alleles of major histocompatibility complex genes, we investigated the association between HLA alleles and autoimmune pancreatitis., Methods: HLA-A, -B, -C, -DR, and -DQ gene typing and HLA-DRB1, -DQB1, and -DPB1 allele typing were performed by the polymerase chain reaction sequence-specific primers method and the restriction fragment length polymorphism method, respectively, in 40 patients with autoimmune pancreatitis, 43 patients with chronic calcifying pancreatitis, and 201 healthy subjects., Results: In patients with autoimmune pancreatitis compared with healthy subjects, we found a significant increase in DR4 (73% vs. 44%, corrected P = 0.01) and DRB1*0405 (58% vs. 21%, corrected P = 0.000026) and DQ4 (58% vs. 26%, corrected P = 0.001) and DQB1*0401 (58% vs. 21%, corrected P = 0.000017). The DRB1*0405-DQB1*0401 haplotype in autoimmune pancreatitis showed no significant association with any HLA class I antigens, in contrast to the B54-DRB1*0405-DQB1*0401 haplotype reported in autoimmune hepatitis. The frequencies of DRB1*0405 and DQB1*0401 were significantly high in patients with autoimmune pancreatitis compared with chronic calcifying pancreatitis., Conclusions: It is probable that DRB1*0405-DQB1*0401 haplotype is associated with autoimmune pancreatitis in the Japanese population.

Malignant neoplasias are the leading cause of death in Japan at present, of which hepatocellular carcinoma (HCC) ranks the third most frequent in men and the fourth most frequent in women. Annual deaths due to HCC are rising sharply and amounted to 33,000 in 1999. Chronic hepatitis C is the most frequent etiology of HCC in Japan and accounts for nearly 90% of cases. The recent rapid increase of HCC in Japan is a long-term sequel of hepatitis C virus infection that affected many individuals in the past, and manifests itself currently as HCC. Infection with the hepatitis C virus has prevailed since the end of World War II for reasons inherent in the socioeconomic background in Japan.

There is a strong association between 2 SEN virus (SENV) variants (SENV-D and SENV-H) and transfusion-associated non-A-E hepatitis. In total, 200 subjects from a Japanese region where hepatitis C virus (HCV) is highly endemic and 194 persons from a contiguous area where HCV is not endemic were tested for SENV-D and SENV-H DNA by polymerase chain reaction. SENV DNA was detected equally in subjects from each area (56% prevalence in the area of high endemicity vs. 61% in the nonendemic area). Age-specific prevalence of SENV was similar to that of TT virus, with equal distribution at all ages in both areas; HCV was predominant in the elderly population. Alanine aminotransferase levels were significantly associated with HCV viremia but not with SENV viremia. SENV is a common infection that appears to have transmission routes and age-related prevalence that are distinct from those of HCV. No evidence was found that SENV caused hepatitis or worsened the course of hepatitis C.

Though patients with chronic hepatitis C after blood transfusion hepatitis decrease dramatically during the past decade, patients with it after non-transfused acute hepatitis C are still in existence. This means that new patients with chronic hepatitis C are on the decrease but not diminish. To the contrary, the number of patients with chronic hepatitis C is increasing. This depends on mainly dig up the undiscovered patients. These result in increasing the patients with hepatocellular carcinoma.

Purpose: A seroepidemiological study of hepatitis E virus (HEV) infection was conducted in Japan, where HEV infection is not considered endemic., Methods: IgG and IgM class antibodies to HEV were measured with a newly developed enzyme-linked immunosorbent assay in which recombinant virus-like particles were used as an antigen. A total of 1253 individuals (401 males and 852 females; age range, 6-89 years) were enrolled from two different areas: area 1 (n = 478), in which hepatitis C was endemic; and area 2 (n = 775), in which it was not endemic., Results: The HEV antibody (IgG class) positive rate was 6.7% in area 1 and 4.6% in area 2. Similarly, the HAV antibody (IgG class) positive rates were 65.3% and 72.3%. The age- and sex-specific prevalence of both HAV and HEV antibodies was quite similar in the two areas, and the HAV antibody positive rate clearly increased with age in both males and females. On the other hand, the HEV antibody positive rate showed a slight tendency to increase with age in males, but not in females. None of the 32 individuals with the HEV antibody who were interviewed had a history of visiting countries in which hepatitis E was endemic. In both areas, the mean age, percentage of males, and HAV antibody positive rate were significantly higher in the group of individuals with the HEV antibody than in the group of those without it, according to conventional statistical analyses. Of the three factors age, male sex, presence of HAV antibody, and the area factor, only male sex was statistically significant (P < 0.001) on multivariate logistic regression analysis. Two (0.2%) of the total of 1253 individuals were positive for the IgM class antibody to HEV., Conclusions: Our results suggest the possibility that HEV infection is circulating in Japan at a low level. HEV infection was associated with male sex, but not with HAV infection.

The -5 C/T polymorphism of platelet glycoprotein (GP) Ib alpha is a major determinant of the level of GP Ib/V/IX complex surface expression. We investigated the frequency of this polymorphism among Asian populations. The gene frequencies of cytosine (C) in this polymorphism were 0.283 and 0.219 in Japanese and Korean populations respectively. The C allele is linked with human platelet antigen (HPA)-2a and smaller types of variable number of tandem repeats (VNTR). A novel allele, C-HPA-2a-D of VNTR, was found. No association was observed between these alleles and coronary artery disease in this case-control study. The clinical relevance of this polymorphism in the thrombotic status remains undetermined.

We examined the longitudinal changes of Helicobacter pylori infection within 46 families with children and 48 couples without children living in Japan. The study cohort was monitored from 1986 to 1994. H. pylori status was assessed by the presence of anti-H. pylori immunoglobulin G antibodies. At study entry, H. pylori prevalence in children with positive mothers was 23% versus 5% in children with negative mothers (odds ratio = 5.3; 95% confidence interval = 0.6 to 42.8). Seroconversion (rate of 1.5%/year) was evident only among children living with positive mothers and did not differ among adults living with or without children. These data strongly support the cluster phenomenon of H. pylori infection among families, the key role of the infected mothers in the transmission within families, and the importance of adult-child transmission and not vice versa.

The 150 male patients exposed to Thorotrast who were confirmed by a 1975-1978 national survey with diagnostic X rays of 50,860 war-wounded soldiers were followed up between 1979 and 1998 (Aichi series or second series). Age-adjusted rate ratios of deaths from all causes were 3.0 times higher in Thorotrast patients compared to controls; this was statistically significant. Rate ratios for liver cancer, liver cirrhosis and leukemia were 35.0, 7.5 and 18.2, respectively.

Updated data from two series in a cancer mortality study for a total of 412 Japanese Thorotrast patients were combined. The rate ratio for all deaths of Thorotrast patients, compared to controls, started to increase after a latent period of 20 years after injection of Thorotrast. Rate ratios for liver cancer, liver cirrhosis, leukemia and lung cancer were 35.9, 6.9, 12.5 and 2.0 times higher, respectively, than those for controls.

Objective: The age groups most susceptible to infection and the mode of transmission of Helicobacter pylori (H. pylori) are not yet clear. To contribute to a better understanding of this disease, this study was undertaken to evaluate changes in the seroepidemiological pattern of H. pylori in a group of Japanese people over the last 20 yr sampled in 1974, 1984, and 1994 in comparison with that of the hepatitis A virus (HAV), which was used as a marker of the fecal-oral route of transmission., Methods: A total of 1015 serum samples were obtained from the National Institute of Infectious Diseases in Tokyo. All of these samples were from healthy persons aged 0-89 yr (442 male and 573 female; median age 35.6 yr), living in seven prefectures in the central part of Japan in 1974, 1984, and 1994. All serum samples were assayed for H. pylori IgG by means of enzyme-linked immunosorbent assay (ELISA). Further, anti-HAV antibodies were assayed by blocking ELISA in the same samples. We investigated the prevalence of H. pylori and HAV for all ages, and the positive rate of H. pylori for infants and children separately., Results: The overall prevalence of H. pylori antibodies was 72.7% (CI 95%, 68.0-77.3) in 1974, 54.6% (CI 95%, 49.1-60.0) in 1984 and 39.3% (CI 95%, 34.1-44.4) in 1994. That of HAV was 57.7% (CI 95%, 52.5-62.8) in 1974, 41.7% (CI 95%, 36.3-47.0) in 1984, and 23.4% (CI 95%, 18.9-27.8) in 1994. The prevalence of both H. pylori and HAV was found to increase with age, whereas there have been clear cohort shifts in the seroepidemiological patterns of both infections over the last 20 yr in Japan. This study shows that there is a slight similarity in the concordance of positive and negative populations between H. pylori and HAV. However, it was very difficult to determine the concordance between H. pylori and HAV infection in this study., Conclusions: Our data strongly suggest that the highest infection rates for both H. pylori and HAV occur among infants and children in Japan. This study provides evidence that H. pylori and HAV may share a common mode of transmission but that changes in environmental conditions make this very difficult if not impossible to prove with seroepidemiological data.

TT virus (TTV) was recently identified as a candidate for a new hepatitis virus. In the present study, the clinical features and transmission routes of TTV infection were analyzed in an area highly endemic for hepatitis C virus (HCV) infection, and compared to those in an area not endemic. In conclusion, the prevalence of TTV infection was as high as 58% in the high-endemicity area for HCV infection. The main transmission route for TTV appeared to be different from that of HCV and HGV. TTV infection showed a reciprocal association with HCV infection, and had limited pathogenetic effect on hepatitis.

Iy alloantigen system is the first polymorphism of platelet glycoprotein Ib beta reported to cause neonatal alloimmune thrombocytopenic purpura. We investigated the allelic frequency of Iy alloantigen among Japanese and Korean populations by polymerase chain reaction-restriction fragment length method to determine the possibility of alloimmunization against Iy. Two hundred and nine Japanese and 97 Korean subjects were examined. All 306 individuals were homozygous for glycine at amino acid position 15 and negative for Iy. The allelic frequency of Iy in these populations was calculated to be less than 0.0016. Alloimmunization associated with Iy antigen in Asian populations seems unlikely from these results.

Studies of the pattern of change in the epidemiology of Helicobacter pylori infection are scarce. A longitudinal cohort study consisted of 644 children and adults, and two independent cross-sectional surveys were conducted in rural Japan between 1986 and 1994. The anti-H. pylori IgG seroconversion rates were 1.1% and 1% per year for children and adults, respectively. The seroreversion rate per year was 1.8% for children and 1.5% for adults. The cohort study was confirmed by the two cross-sectional studies. H. pylori prevalence fell in all age groups in both children (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.2-1.0, P = .05) and adults (OR = 0.4, 95% CI = 0.3-0.6, P = .001). The rate of loss of H. pylori infection was greater than the acquisition. Data regarding acquisition and loss of H. pylori infection are critical to understanding the epidemiology of the infection and to developing treatment and vaccination strategies.

A prospective follow-up study on hepatitis C virus (HCV) infection was conducted in seven haemodialysis units from April 1990 to March 1995. A total of 634 patients were undergoing maintenance haemodialysis in the seven units. Of those, 302 patients participated in the follow-up study; 179 were initially HCV antibody negative and 123 were initially positive. Nine of the 179 initially negative patients became positive for HCV antibody during the follow-up period. In accordance with the appearance of HCV antibody, indicating new infection of HCV, all nine of these patients were diagnosed with HCV viraemia. As no other routes were apparent, HCV infection in all nine patients was likely due to nosocomial transmission. Prevalence of HCV antibody at the start of follow up was significantly higher (P < 0.001) in haemodialysis units A-C (37.9%) than in haemodialysis units D-G (17.0%). Incidence of new HCV infection was significantly higher (P = 0.005) in the former units (2.2% per year) than in the latter (0.2% per year). Ten of the 123 patients who were initially positive for the HCV antibody exhibited a loss of reactivity during the follow-up period; of these 10 patients, nine were negative for HCV-RNA from the start of the study. In conclusion, the incidence of new HCV infection seen in patients undergoing haemodialysis suggests that their risk of acquiring HCV infection is directly related to the prevalence of HCV antibody positive patients being treated in the units.

Background/aims: A nationwide survey of autoimmune hepatitis (AIH) was carried out in Japan., Methods: Four hundred and ninety-six patients were enrolled by questionnaires sent to 101 hospitals with hepatology specialists., Results: The clinical features of Japanese AIH were as follows: most patients were middle-aged women; serum autoantibodies, especially antinuclear antibody, were frequently positive, serum IgG level was high, and HLA-DR4 was the major HLA allotype. Liver-kidney microsomal type 1 antibody was positive in nine of 79 patients tested. Eight of these antibody positive patients were also positive for antinuclear antibody and five for anti-smooth muscle antibody. Ninety-two percent of the patients showed piecemeal necrosis and 60% bridging necrosis; plasma cell infiltration in the portal areas was observed in 50% of the patients. Only 12.3% were diagnosed as having liver cirrhosis. A favorable effect of corticosteroid, normalization of serum transaminases, was observed in 89% of 317 patients, who were treated with an initial dose of over 30 mg/day. Sixty-two patients were positive for hepatitis C virus (HCV) markers. In these patients, however, only one patient was liver-kidney microsomal type 1 antibody positive. Corticosteroid was effective in 30 (81%) of 37 HCV-marker-positive patients treated with this agent. Thus the efficacy of corticosteroid did not differ from that in AIH patients without HCV infection (90%). Similarly, interferon treatment was used in 20 patients, all of whom were positive for HCV-RNA, and resulted in 50% efficacy as determined by normalization of the serum transaminase level 6 months after treatment. The International Diagnostic Scoring System for the diagnosis of AIH worked well in these patients, except for HCV-infected individuals, that is, approximately 10% of the total of AIH patients.

We report a case of primary ileal carcinoma in a young woman, which was diagnosed definitively before operation. A 29-year-old woman presented with abdominal pain, diarrhoea and bloody stools. Colonoscopic and radiographic studies revealed that there was a 7.5 x 7 cm tumour (well-differentiated adenocarcinoma) at the terminal ileum, forming an ulcerated lesion at the centre. The tumour had invaded the caecum, the right urinary tract, the right ovary and a portion of the sigmoid colon. Fifty-three cases of primary ileal carcinoma were reported in Japan between 1982 and 1994 and their clinical features are reviewed herein.

It has been clarified that hepatitis C virus(HCV) is the major cause of acute and chronic non-A, non-B hepatitis. However, it is also clear that there still exist a group of patients with viral hepatitis who are seronegative for hepatitis A, B, C, D or E virus infections. In this article, epidemiological studies on such non-A-E hepatitis in Japan are reported. Since the introduction of blood screening with hepatitis B virus(HBV) core antibody and HCV antibody in addition to HBV surface antigen, incidence of posttransfusion hepatitis decreased remarkably to a level less than 1%. Therefore, occurrence of non-A-E posttransfusion is rare in Japan. As for acute sporadic hepatitis, about 20% of the patients were diagnosed as type non-A-E. Those patients with non-A-E acute sporadic hepatitis showed relatively mild hepatitis. About 5% of patients with chronic hepatitis was negative for both markers of HBV and HCV infections. Hepatitis G virus, a newly discovered hepatitis virus, accounted for only a minor part of acute and chronic non-A-E hepatitis.

Mass health screening for liver disease was conducted in A.H areas in N Town which is known to be an endemic area for hepatitis since 1985. Subjects were about 1,000 inhabitants in A.H areas and 1795 inhabitants in non-endemic areas (control) 6 years or older in age. Informed consent was obtained from all inhabitants. All subjects were interviewed for demographic data including age, sex, occupation past medical history, surgical operation daily intake of alcohol, folk use of remedies such as acupuncture and family history of liver disease. Body weight and height were also recorded. Blood obtained from all individuals was analyzed for liver function enzyme and hepatitis virus markers including anti-HCV and HBV markers. Furthermore, health education on how to prevent hepatitis and how to treat liver diseases was provided. The results were as follows. 1. Overall, the prevalence of anti-HCV was 24.1% in A.H areas, and increased in older individuals over 50 years old. To the contrary, it was 2.3% in control areas. The prevalence of HBsAg was the same in both areas. 2. Prevalence of history of surgical operations, blood transfusion and acupuncture were similar in A.H. area sand control area. 3. Risk factors for HCV infection were blood transfusion, acupuncture, history of liver diseases and anti-HBs positive. 4. Death rate due to liver cirrhosis and hepatocellular carcinoma has been increasing year by year during recent years.

Unlabelled: A reverse transcriptase-polymerase chain reaction procedure (RT-PCR) for the detection of hepatitis G virus (HGV) RNA was used to examine the prevalence of HGV infection and HGV-related disease in Japan. Among 48 patients with acute non-A, B, C, D, E (non-A-E) hepatitis (five transfusion-associated cases and 43 sporadic cases), only one patient (2%), a transfusion recipient, was HGV RNA positive. Similarly, among 50 patients with established chronic non-A-E hepatitis, only two (4%) were positive for HGV RNA. These frequencies were not significantly different from those in 129 voluntary blood donors (0.8%). By contrast, HGV infection was relatively common among patients who were also infected with other hepatitis viruses. HGV co-infection or superinfection was found in seven of 53 (13%) patients with acute hepatitis C, in 15 of 126 (12%) patients with chronic hepatitis C, in three of 21 (14%) patients with acute hepatitis B and in four of 81 (5%) patients with chronic hepatitis B. Among the 29 dually infected patients, 15 (52%) had a history of blood transfusion. HGV was also detected in seven (10%) of 69 haemodialysis patients, of whom only one had a dual infection with hepatitis C virus (HCV) and an elevated aminotransferase level., In Conclusion: HGV RNA was found in only a low percentage of patients with either acute or chronic non-A-E hepatitis: HGV appears to co-infect or superinfect in 10-15% of HCV infections and in 5-15% of HBV infections; the prevalence of HGV infection (0.8%) among voluntary blood donors in Japan is similar to that for HCV infection; a history of blood transfusion was obtained in 22 (55%) of the total 40 HGV-positive subjects; and isolated HGV infection appears to have a low disease burden.

To clarify the origin of the Japanese, the Jomom and/or Yayol, we screened for HTLV-1 and -II antibodies among inhabitants of the Silk Road, the Han, Uygur and Kazaks. We also screened for HIV, HBV, and HCV. The HTLV-I, -II, HIV, and HCV antibody tests were uniformly negative in all the studied groups. In contrast, a significantly higher incidence of HBs antigen was observed in all the groups tested (Northern Han: 11.9%, Uygur: 6.0%, Kazak: 9.1%). These results indicate that these ethnic groups are not the origin of the indigenous Japanese (the Jomon), and that HBV is prevalent in the various groups along the Silk Road.

Platelet membrane glycoprotein Ib alpha has at least two polymorphisms which affect phenotype. One is the dimorphism at codon 145, and the other is a molecular weight polymorphism due to variable numbers of tandem repeats (TR) in the macroglycopeptide region. These two polymorphisms are in linkage disequilibrium. The frequencies of these polymorphisms differ considerably depending on race, and the largest variant with four TR is almost exclusively present in the Japanese population. We examined the genotypes of HPA-2 and TR polymorphism in three different races from Eastern Asia; the Japanese (n = 103), Korean (n = 101) and Chinese population (n = 177). The gene frequency of HPA-2 differed significantly among these three populations. Among HPA-2b-positive individuals, the A isoform with four TR and B with three TR were present in all three populations and A dominated over B. Individuals homozygous for the A isoform were found in both Japanese and Korean populations. These findings indicate that the largest haplotype is common in the Eastern Asian region.

Mass health screening (MHS) for detecting early cancer of hepatobiliary diseases is not common. However, as high risk factors for developing hepatocellular carcinoma (HCC) has been established in Japan, MHS for HCC is available, especially in high endemic areas of hepatitis C. Intrahepatic bile duct cancer often occur in patients with Thorotrastosis. Cohort study for detection of early cancer of intrahepatic bile duct has been conducting by the Japanese Government. Early detection of bile duct cancer in health screening is very rare. It will be helpful for perform MHS to clarify the high risk factors for bile duct cancers.

Sixteen medical institutions in Japan collaborated in this study of the epidemiology of hepatitis C virus (HCV) genotypes. A total of 4176 patients with type C chronic liver disease, from the four main islands of Japan, were evaluated. Of those evaluated, 2794 had chronic hepatitis, 727 had liver cirrhosis and 655 had hepatocellular carcinoma. The HCV genotype of the patients was determined by an enzyme-linked immunosorbent assay based on serological genotype 1- and 2-specific recombinant peptides (SG-1 and SG-2, respectively) of the NS4 region. The prevalence of SG-1 and SG-2 HCV was similar in the four main islands of Japan. SG-1 HCV predominated in each disease category (69-76%). The percentage of patients with SG-1 HCV increased by 7%, while that of patients with SG-2 HCV decreased by 7%, as liver disease progressed in severity from chronic hepatitis to carcinoma (P < 0.001). Patients with either SG-1 or SG-2 had a similar mean age and history of blood transfusion. In conclusion, SG-1 HCV was found to predominate in Japan, and the HCV genotype was found to be related to the stage of hepatitis C disease.