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Background/Aims: We evaluated patients with nonalcoholic fatty liver disease (NAFLD) and compared the clinical and pathological features to identify the risk factors for NAFLD with severe fibrosis. Methods: One hundred and eighty-two patients with biopsy-confirmed NAFLD from various medical centres were recruited into this study. Results: The variables that were significantly associated with severe steatosis were male gender (mild:severe=36%:53%, P=0.02), younger age (mild:severe=57%:82%, P>0.001) and absence of type 2 diabetes (mild:severe=43%:71%, P>0.001). There was no significant difference in the degree of inflammation among the clinical groups. The variables that were significantly associated with severe fibrosis were female gender (mild:severe=54%:84%, P=0.002), older age (≥60 years old) (mild:severe=29%:53%, P=0.020), type 2 diabetes (mild:severe=42%:71%, P=0.020) and hypertension (mild:severe=24%:53%, P=0.002). Although there were more obese patients in the group with severe fibrosis, the association was not statistically significant (mild:severe=67%:78%, P=0.229). The prevalence of high serum triglyceride levels was similar between the two groups. The N (Nippon) score (total number of risk factor) could significantly predict severe fibrosis in NAFLD patients (1.48 ± 1.14 vs. 2.66 ± 0.94, P

Efficacy of interferon (IFN) therapy during the acute phase of hepatitis C infection is promising, although the optimal regimen has yet to be determined. It is not known whether the known prognostic factors for chronic hepatitis C (CHC) influence the effect of IFN in acute hepatitis C (AHC). Seventeen patients with AHC were analyzed for hepatic IFN α receptor 2 (IFNAR2) prior to IFN treatment. All patients were subsequently treated with either 168 million units (MU) or 336 MU of natural IFN α. Seventeen age-matched samples of CHC were provided as controls. The overall sustained response rate was 64.7% (11/17). In patients who received a total dose of 168 MU IFN, the sustained response rate was 28.6% (2/7), and in those who received 336 MU of IFN, the sustained response rate was 90.0% (9/10). The peaks of ALT and HCV-RNA quantity were not associated with the response to IFN. The hepatic IFNAR2 levels were 1.52±0.34 densitometry units and 0.92±0.16 in AHC and CHC, respectively (P = 0.042). There was no difference in hepatic IFNAR2 levels between sustained virological responders (SVR) and nonsustained virological responders (NR). The hepatic receptor levels were higher in AHC than in CHC patients. The levels of hepatic IFNAR2 did not differ in SVR and NR, indicating that high-dose natural IFN α treatment is effective for AHC, irrespective of the levels of hepatic IFNAR2.

The role of host genetic factors in chronic hepatitis B virus (HBV) infection is not fully understood. We studied the influence of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) gene promoter polymorphisms on disease progression in HBV carriers.The sample population included 213 Japanese HBV carriers and 52 healthy volunteers. Of 213 HBV carriers, 66 were considered to be asymptomatic carriers based on the sustained normalization of serum ALT together with seropositivity for the antibody to hepatitis B e antigen (anti-HBe), and 147 were found to have chronic progressive liver disease including cirrhosis. Five biallelic polymorphisms in the TNF-alpha gene promoter and three biallelic polymorphisms in the IL-10 gene promoter were analyzed by polymerase chain reaction in combination with direct sequencing or restriction fragment length polymorphism assay.Allelic distributions of both gene promoters were not significantly different between HBV carriers and healthy volunteers. In HBV carriers, the TNF-alpha gene promoter polymorphisms were not linked to disease progression. In contrast, allelic frequencies of T and A at positions -819 and -592, respectively, in the IL-10 gene promoter, as well as the frequencies of ATA haplotype at positions -1082/-819/-592 (which is characterized with low capacity for IL-10 production), were significantly higher in asymptomatic carriers than in patients with chronic progressive liver disease. Even after adjusting for individuals positive for anti-HBe, such a relationship could be found between the two groups.In chronic HBV infection, inheritance of the IL-10 gene promoter polymorphisms is involved in a host genetic factor that is relevant to disease progression.

Lamivudine (100mg/日) が投与されたB型慢性肝炎患者34例の治療終了後の長期経過を検討した. 投与期間は16～52週間, 治療後の平均観察期間は151週 (42～172週) であった. 34例中8例 (24%) は最終観察時点でALT値が正常であった. 8例中の3例は投与前のHBV DNA量が低値であったが, この3例はいずれもALT値が投与中に正常化し, 投与終了後も正常値を維持した. 他の5例は, 投与終了後にALT値が一過性に上昇した後に正常化した. 他の26例はいずれもALT値の異常変動が持続しており, Lamivudine によって肝機能の正常, 安定化を得るには長期投与が必要と考えられた. また Lamivudine 投与終了の必要条件は治療前のHBV DNA量が低値であること, 治療中のHBe抗体の出現及びHBV DNAの持続陰性化を得ることなどが考えられたが投与中止の条件については, 今後さらに症例数を増やし検討する必要があると考えられた.

Objective Fulminant hepatitis is a rare but fatal disease. In the present study, we examined the changes in etiology and prognosis of fulminant hepatitis in Nagasaki Prefecture, Japan between 1980 to 1999. Methods Eighty-one patients with fulminant hepatitis admitted to our hospitals from 1980 to 1999 were examined with respect to the etiology and prognosis. Results Fulminant hepatitis was due to hepatitis A virus in 2 (12%) cases, hepatitis B virus in 18 (22%) cases, unknown etiology in 50 (62%) cases, and drug-induced in 11(14%) cases. The number of cases in the first half of the study (1980-1989) was 47 and that of the latter half (1990-1999) was 34 cases. The incidence of fulminant hepatitis type B also decreased from 14 cases (30%) to 4 cases (12%) during these periods. The overall survival rate of fulminant hepatitis was 32%; it was equal in fulminant hepatitis type B, fulminant hepatitis of unknown etiology and fulminant drug-induced hepatitis. The survival rate of fulminant hepatitis type A was 100%, though only two cases were identified. Retrospectively, the survival rate in patients with a pre-encephalopathy period of ≤10 days and aged ≤39 years was significantly higher than in patients ≥40 years of age (p

Time-dependent intrahepatic recurrence of hepatocellular carcinoma is frequent after different treatment modalities, including percutaneous ethanol injection. We attempted to prospectively analyze the possible risk factors for early intrahepatic recurrence of hepatocellular carcinoma after percutaneous ethanol injection.Sixty-five patients with 65 solitary hepatocellular carcinoma nodulesor =6 cm in diameter underwent initial treatment with percutaneous ethanol injection and were examined to ascertain the factors related to recurrence, local and distant, within the liver. A number of clinical and tumor parameters were analyzed.Cumulative overall recurrence rates 12 and 24 months after percutaneous ethanol injection were 15.6% and 45.1%, respectively, irrespective of clinical and tumor parameters. Overall recurrence rates 12 and 24 months after percutaneous ethanol injection were 40% and 67.5%, for tumoror =3 cm and 7.5% and 37.5%, for tumor3 cm. Cumulative local recurrence rates at 12 and 24 months were 26.3% and 43.5%, respectively, for tumoror =3 cm and 11.7% and 18.2%, respectively, for tumor3 cm. The log-rank test indicated that a tumor size ofor =3 cm and the presence of capsule for a tumor of3 cm in diameter were significant risk factors for intrahepatic recurrence. A pretreatment serum PIVKA-II level ofor =0.02 AU/ml was the only clinical parameter associated with overall recurrence (p=0.0041) and distant intrahepatic recurrence (p=0.0307). Distant intrahepatic recurrence rates 12 and 24 months after percutaneous ethanol injection were 22.5% and 31.4%, respectively, for PIVKA-II levels ofor =0.02 AU/ml and 8% and 17.8%, for PIVKA-II of0.02 AU/ml. Cox's proportional hazard model identified that tumor size, tumor capsule and baseline serum PIVKA-II levels were independently related to intrahepatic recurrence.These data demonstrate that tumor size and peritumoral capsule were associated with overall and local recurrence of hepatocellular carcinoma. Moreover, pretreatment serum levels of PIVKA-II can indicate the risk of early intrahepatic recurrence and may assist in patient selection and appropriate therapy.

Abdominal sonography is a routinely used noninvasive modality for screening and treatment of liver diseases. We attempted to establish a morphological sonographic staging to predict the severity of liver diseases with their consequent analysis with morphological staging of peritoneoscopy and histology. In all, 136 patients were enrolled for the final confirmation of disease state by peritoneoscopy and histology preceded by abdominal sonography. All patients were categorized from stage 0 to stage 5, depending on a proposed criterion of sonographic features based on surface pattern of liver and the appearance of internal echogenic bands relating to the irregularity of the liver texture. A digitized computer quantitation of histogram-based standard deviation (sd) values from different stages of sonographic images was analyzed, and their values were justified by correlation with the definite appearance of an internal echogenic band. The association of different sonographic stages with disease progression was also demonstrated by their relation with peritoneoscopy and histology. In all patients, the different sonographic staging results were significantly correlated with hepatic surface features of peritoneoscopic staging (r = 0.939, P < 0.0001) graded from stage 0 to stage 5 and were also correlated with biopsy-proven staging of fibrosis (r = 0.739, P < 0.0001). The greater sd values of histogram-based echo levels, as analyzed from digitized sonographic images of 90 patients, were associated with the appearance of internal echogenic bands (P < 0.0001). Furthermore, the corresponding sds were significantly correlated with the qualitative staging of sonographic features (r = 0.781, P < 0.0001), peritoneoscopy (r = 0.786, P < 0.0001) and histology (r = 0.779, P < 0.0001). We concluded that our proposed sonographic staging is well correlated with peritoneoscopic and histological staging of liver diseases, with only a small discrepancy, and can be used clinically to demonstrate the ongoing severity of liver diseases.

Background/Aims: Recently, a novel DNA virus was isolated from the serum of a patient with post-transfusion non-A–G hepatitis and named TT virus. The aim of this study was to determine the prevalence and clinical characteristics of TT virus infection in patients with sporadic acute hepatitis of unknown etiology. Methods: TT virus was investigated in the serum of 66 patients with sporadic acute hepatitis non-A–G and 50 healthy controls by semi-nested PCR with previously published primers. Results: TT virus was detected in 17 (26%) of the 66 patients with sporadic acute hepatitis non-A–G and in a slightly higher rate (34%,17/50) in the control group. No significant differences in alanine aminotransferase or bilirubin concentrations were observed between the groups of patients with or without TT virus infection. Eighty per cent (12/15) of patients for whom follow up was possible had persistent viremia from 4 to 36 months, and 67% (8/12) of these patients had already normalized their levels of alanine aminotransferase. A phylogenetic tree constructed by the Neighbor Joining Method revealed that all isolates in this study were grouped within genotype 1a and 1b, without showing any association between genetic type and development of hepatic disease. Conclusions: Our results suggest that TT virus DNA is present not only in patients with sporadic acute hepatitis non-A–G but also in a large proportion of the general population. This virus was not likely to be the causative agent of hepatitis among the patients in this study.

Perinatal transmission of hepatitis B virus (HBV) is a common cause of chronic infection. In the present study, we evaluated the long-term efficacy of immunization against HBV in infants at high-risk, by using polymerase chain reaction (PCR). Two hundred and fifty-one infants received hepatitis B immunoglobulin at birth and a course of hepatitis B vaccine within 6 months of age between 1981 and 1993. Of 251 infants, 203 (81%) and 97 (39%) were followed until 1 and 4-6 years of age, respectively. HBV-DNA was detected by PCR in 74 (36%) of 203 children at 1 year of age, while the prevalence rate of children positive for HBV-DNA decreased to 14 (14%) of 97 children at 4-6 years of age, including 2 children who had the breakthrough variants of HBV. Our results indicate that most of HBV infections occur early, during the first year, and that immunization against HBV effectively protects infants at high-risk against viral transmission, at least up to 4-6 years of age.

This study aimed to determine the expression level of interferon alpha/beta (IFN-alpha/beta) receptor in the liver immunohistochemically and evaluate its usefulness in predicting the outcome to IFN therapy in patients with chronic hepatitis C.The level of IFN-alpha/beta receptor expression was determined in immunoperoxidase-stained pretreatment sections of 55 chronic hepatitis C patients later treated with IFN. We used liver biopsy specimens and mouse monoclonal anti-human IFN-alpha/beta receptor antibody. Quantitative analysis of immunostaining was performed by image analysis software. The level of IFN-alpha/beta receptor was expressed as Unit (U). Sustained responders were patients who showed persistent disappearance of serum HCV-RNA during the 6-month period after treatment, while non-responders showed persistence of viremia after therapy.Positive immunostaining was observed in the cytoplasm of hepatocytes. The mean expression level of hepatic IFN-alpha/beta receptor in sustained responders (2.65+/-1.11 U, n = 15) was significantly (p0.001) higher than in non-responders (1.61+/-1.05 U, n = 40). A significant decrease in IFN-alpha/beta receptor expression level was observed in patients with advanced liver fibrosis. In patients with low level viremia (pretreatment serum HCV-RNA1 Meq/ml, n = 18), the level of IFN-alpha/beta receptor in sustained responders (2.89+/-1.12 U, n = 11) was significantly (p0.01) higher than in non-responders (0.93+/-0.33 U, n = 7).Our results suggest that measurement of the level of hepatic IFN-alpha/beta receptor in patients with chronic hepatitis C might be useful for predicting the response to IFN therapy. Resistance to IFN therapy in patients with chronic hepatitis C might be due to low levels of hepatic IFN-alpha/beta receptor.

Aims/Background: Autoimmune cholangitis/cholangiopathy (AIC) is an enigmatic disease marked by chronic cholangitis, antinuclear antibodies (ANA) and sero-negativity for conventionally detected anti-mitochondrial antibodies (AMA). We examined whether AIC is a distinct entity, an AMA-negative variant of primary biliary cirrhosis (PBC), or a cholangiopathic variant of autoimmune hepatitis (AIH) by comparing the clinical, laboratory and autoantibody profiles of 21 cases of AIC, 37 cases of PBC and 16 cases of AIH from selected Japanese patients. Methods: The specificities of AMA and ANA were determined by immunofluorescence, immunoblotting and enzyme inhibition assays using various mitochondrial and nuclear autoantigens, and the frequencies for these groups were compared. Results: By clinical, biochemical and histological data, AIC and PBC were similar and both were clearly distinct from AIH. Serologically, by immunofluorescence of AMA and ANA, there was polarisation. By immunoblotting, and notwithstanding the negative test for AMA, a proportion of the AIC sera reacted with the E2 subunits of the 2-oxo-acid dehydrogenase enzyme complexes, but more particularly with the lower molecular weight E2 subunits. The antinuclear reactivity in AIC was with centromere, Sp100 and nuclear pore complex proteins as in PBC, but preferentially with the nuclear pore complex. Conclusion: Our results demonstrate that AIC and PBC are similar diseases. However this duo is of interest because, usually, among sets of autoimmune syndromes, differences in serological targetting are matched by differences in clinical presentation: AIC and PBC are an exception to this.

The presence of α-fetoprotein (AFP) mRNA in mononuclear cells of the peripheral blood was examined in patients with hepatocellular carcinoma (HCC), liver cirrhosis, chronic hepatitis and normal volunteers using nested reverse transcription polymerase chain reaction (RT-PCR). Then, the AFP mRNA levels were quantitatively analyzed in AFP mRNA-positive patients with HCC. AFP mRNA was detected in 23 of 38 (60.5%) cases with HCC, 2 of 12 (16.7%) cases with cirrhosis, and 1 of 9 (11.1%) cases with chronic hepatitis, respectively. AFP mRNA was not demonstrated in six healthy volunteers. The frequency of positive cases in TNM stage III–IV (16/21, 76.2%) was significantly higher than that in stage I–II (7/17, 41.2%)(P

A total of 1, 889 voluntarily donated blood from five provinces in northern Thailand were investigated for the prevalences of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection. The average positive rates of HBs-Ag, anti-HBs, IgM anti-HBc, anti-HCV and anti-HIV were 8.7, 42.6, 0.5, 1.6 and 1.7%, respectively. The highest positive rates of HBs-Ag, anti-HBs, IgM anti-HCV and anti-HIV were found in the age group under 19 years (13.3%), 40-49 year old group (47.6%), 20-29 year old group (0.6%), 30-39 year old group (2.6%) and 20-29 year old group (2.9%), respectively. We found only two cases that were anti-HIV and HBs-Ag positive. There are no cases that were anti-HIV and IgM anti-HBc positive, and that were anti-HIV and anti-HCV positive. These results suggest that in northern Thailand, most of the HBV infections are due to vertical transmission from mother to child, although HBV infection is a major cause of viral hepatitis, HCV infection will become an important public health problem in the near future and that the prevalence of HIV infection is quite high among sexually active generations. Therefore, there is a need for more medical attention to these blood-borne virus diseases, and we strongly recommend routine blood screening for HCV in every medical institutions in northern Thailand.

A questionnaire survey was conducted of members of the NANB Hepatitis Research Group of the Japanese Ministry of Health and Welfare on the incidence of GBV-C/HGV RNA-positivity among HCV, HBV, and non-B-C infected patients to clarify the involvement of the newly discovered GBV-C/HGV in hepatic diseases in Japan. As a result, GBV-C/HGV RNA was detected in about 10% of HCV-infected patients, 5% of HBV-infected patients, and 5% of patients with non-B non-C hepatitis. With HBs antigen-positive patients, the GBV-C/HGV positivity rate increased with the progression of liver disease from 3.9% with chronic hepatitis, 5.4% with liver cirrhosis, and 9.1% with hepatocellular carcinoma. This increase was not observed with HCV RNA-positive and non-B, non-C patients. Also no GBV-C/HGV RNA-positive patients were seen among HCV RNA-positive fulminant hepatitis patients having no history of use of blood or blood products. These results suggest that although GBV-C/HGV may possibly be involved as a causative virus in some non-A-E hepatitis in Japan, it is not a main cause. If HBV-infected patients are excluded, it is almost possible to conclude that GBV-C/HGV is not involved in the progression of chronic liver disease. Although a very slight possibility exists that GBV-C/HGV infection may be a cause of fulminant hepatitis, the data suggest that it is not a major cause.

It was recently reported that mutations in the precore and core promoter region of hepatitis B virus (HBV) are associated with fulminant hepatitis. The aim of this study was to investigate the association of mutations in the precore and core promoter region of HBV with fulminant and severe acute hepatitis. We studied Japanese patients with acute HBV infection, including seven patients with fulminant hepatitis, 12 with severe acute hepatitis and 41 with acute self-limited hepatitis. The presence of HBV mutants was examined by using a point mutation assay to detect a G to A transition at position 1896 in the precore region and an A to T transition at position 1762 and a G to A transition at position 1764 in the core promoter region. Significant differences in the proportion of mutations in the precore or core promoter region were present between patients with fulminant hepatitis and self-limited acute hepatitis (7/7 (100%) vs 4/41 (9.8%), P < 0.01) and between severe acute hepatitis and self-limited acute hepatitis (6/12 (50.0%) vs 4/41 (9.8%), P < 0.01). The frequency of mutation increased proportionately with the severity of disease in patients with acute HBV infection. Fulminant hepatitis B in Japan is closely associated with mutations in the core promoter and precore gene of HBV. Point mutation assays for HBV precore and core promoter analysis may be useful to predict the outcome of liver disease in patients with acute HBV infection.

We analysed the expression of interferon (IFN) alpha/beta receptor mRNA in the liver of patients with chronic hepatitis C and examined the relationship between the expression of this receptor gene and the level of hepatitis C virus (HCV)-RNA as well as the response to 16 weeks of 6 x 10(6) units IFN. The mean level of IFN alpha/beta receptor mRNA in patients with chronic HCV infection (expressed as delta cycle; 10.8 +/- 1.9 (mean +/- SD); n = 39) was significantly higher than that of control subjects (9.4 +/- 0.5; n = 6; P0.01). There was a significant negative correlation between the level of IFN alpha/beta receptor mRNA and serum HCV-RNA in 39 patients with chronic hepatitis C (R = -0.546; P0.01). The mean level of IFN alpha/beta receptor mRNA in six patients who showed a complete response to IFN therapy (12.3 +/- 1.6) was higher than that of 15 patients who failed to respond to therapy (10.1 +/- 1.5; P0.01). Our results are consistent with the suggestion that the anti-viral activity of IFN depends on the level of the IFN alpha/beta receptor on hepatocytes in patients with chronic hepatitis C.

To investigate correlations between the interval between blood transfusion and the start of IFN therapy, and IFN efficacy, we studied chronic hepatitis C patients with a history of blood transfusion. The subjects were 122 patients with chronic hepatitis C and a history of blood transfusion at 64 institutions. The patients were treated with high or low-dose IFN. High-dose therapy consisted of intramuscular injection of human lymphoblastoid interferon (HLBI), 6 x 10(6) IU daily for 2 weeks, then 3 times a week for 22 weeks, and low-dose interferon therapy of intramuscular injection of HLBI, 6 x 10(6) IU daily for 2 weeks, then 3 x 10(6) IU 3 times a week for 22 weeks. Normal serum ALT levels for 6 months or more after completing IFN (complete response) were found in 44/122 (36.2%) patients and HCV RNA was no longer detectable after completing IFN therapy in 19/68 (27.9%). Patients in whom the interval between blood transfusion and the start of IFN therapy was less than 20 years had significantly higher rates of HCV RNA-negative complete response than those in whom the interval was 20 years or more (p < 0.039). When chronic HCV infection is caused by blood transfusion, the efficacy of IFN depends on the duration of chronic HCV infection. Since the duration of HCV infection is a factor in predicting efficacy, early IFN therapy may be more effective.

Most patients infected with hepatitis C virus (HCV) develop chronic hepatitis. Unfortunately, the pathological evolution of this disease over time is not completely understood. We studied 70 HCV-positive patients, from whom 2 to 10 liver biopsy specimens (mean, 3.9) had been obtained during an interval of 1 to 26 years (mean, 8.8 years). Each biopsy specimen was evaluated independently by four pathologists who each provided a numerical score for the grade of portal/periportal necroinflammation (0-4), grade of lobular necroinflammation (0-4), their sum (final grade), and the stage of fibrosis (1-4). The scores were correlated with progression of disease, if any, and transition to cirrhosis. During follow-up, 35 patients (50%) developed cirrhosis. Cirrhosis developed in all patients with a high final grade (> or = 5) of necroinflammation on initial biopsy who were followed for 10 years and in 96% of patients with an intermediate final grade (3.5-4.9) who were followed for 17 years. Only 30.4% of patients with low final grade (< or = 3.4) on initial biopsy developed cirrhosis after 13 years. All patients with evidence of septal fibrosis with incomplete nodularity (stage 3.0-3.4) in the initial biopsy progressed to unequivocal cirrhosis by 10 years. The rate of progression to cirrhosis was accelerated in patients whose initial biopsies showed high-grade and -stage lesions. This study demonstrates the importance of grading and staging liver biopsy lesions in chronic hepatitis C, particularly for patients with high-grade necroinflammation, septal fibrosis, and regions of modularity on initial biopsy who are at high risk of developing advanced cirrhosis in the ensuing decade.

Background/Methods: The cause of fulminant hepatitis is still not fully understood. We studied 23 patients with fulminant hepatitis, using polymerase chain reaction to detect hepatitis virus genomes. Tests for HBsAg and IgM anti-HAV and IgM anti-HBc were performed in all patients. Serum samples were stored at −70°C for later analysis of anti-HCV and hepatitis virus genomes such as hepatitis B virus, hepatitis C virus and hepatitis D virus. Results: Of 23 patients, 17 (74%) had HBV-DNA and two (9%) had HCV-RNA. No patient was positive for both viruses or positive for HDV-RNA. Serological tests indicated that two patients, negative for HBV-DNA and HCV-RNA, were positive for IgM anti-HAV. In contrast, 8 of 17 (47%) HBV-DNA positive patients were negative for both IgM anti-HBc and HBsAg in conjunction with low levels of viremia. Four patients were positive for anti-HCV, but only one was positive for HCV-RNA. One patient, positive for HCV-RNA, was negative for anti-HCV. Conclusions: Our results indicate that analysis of hepatitis virus genomes using polymerase chain reaction allows accurate identification of the virus causing fulminant hepatitis

The discovery of hepatitis C virus (HCV) has enabled the diagnosis of type C chronic liver disease, which had in the past been diagnosed as part of non-A, non-B chronic liver disease. Although most cases with chronic liver disease are caused by hepatitis B virus (HBV) or HCV infection, there are still cases of non-B, non-C chronic liver disease. Forty patients with chronic liver disease, who were seronegative for hepatitis B surface antigen and antibody to HCV, were followed for a mean period of 72 months. The clinical manifestations in these patients were compared with those reported for type B and type C chronic liver disease. Of the 40 patients, 22 were diagnosed with chronic hepatitis, 14 with liver cirrhosis and 4 with hepatocellular carcinoma (HCC). Twenty-seven (67.5%) patients showed mild alanine aminotransferase activity profiles, and the natural clinical course of most patients showed a slow progression compared with that reported for type B and type C patients. The yearly incidence of HCC was 9.7% in patients with liver cirrhosis and 3.9% in chronic hepatitis. These rates were similar to those in type B or type C patients. This suggests that our population sample contained a number of patients with type B, type C or other etiologic agent(s), because 66.7% of the patients who developed HCC had some evidence of exposure to HBV or HCV. Our results suggest that more detailed and accurate tests for detecting HBV and HCV should be considered before making the diagnosis of non-B, non-C chronic liver disease, and that there is the need to reveal unknown etiologic agent(s).

With the increasing long-term use of interferon (IFN), several new adverse effects have been recognized. Very little attention, however, has been paid to auditory acuity. We encountered 3 cases of sudden hearing loss associated with IFN. We then conducted a prospective study to assess the auditory function of 73 patients receiving IFN. Auditory disability (tinnitus and/or hearing loss) occurred in 32 patients (43.8%) during IFN therapy, among which audiometry documented sensorineural hearing loss in 27 cases (36.9%); 17 (48.6%) of the 35 patients receiving IFN-beta had auditory disability, including hearing loss in 13 cases (37.1%), and 15 (39.5%) of 38 patients receiving IFN-alpha suffered from auditory disability. There was not much difference between the influences of IFN-alpha and -beta. Auditory disability frequently developed in the later stages of treatment, and most patients recovered 7-14 days after the discontinuation of IFN. The results demonstrate that sudden hearing loss can occur as a side effect of treatment with IFN. This may reveal the association between autoimmunity and sudden hearing loss.

We analyzed serum HCV-RNA levels using a newly developed quantitative nucleic acid hybridization (branched DNA probe) assay in 32 Japanese patients with chronic hepatitis C treated with β-interferon (β-IFN). The branched DNA probe assay was less sensitive than the polymerase chain reaction (PCR) method but it provided easy and accurate quantitative analysis of HCV-RNA levels in several samples. Eleven of 32 (34%) patients had a complete response (CR) to IFN treatment, defined as normalization of ALT levels. Six patients (19%) had a partial response (PR) and 15 (47%) had no response (NR). In only one of 11 (9%) patients with CR, the pre-treatment HCV-RNA level was marginally more than the detectable limit of 350 kequivalents/ml (keq/ml). However, serum HCV-RNA levels were detectable in four of six patients (67%) with PR and 13 of 15 (87%) patients with NR. There was a significant difference in HCV-RNA levels between CR and NR groups (9% vs. 87%, P ) using this method. We could not find a significant difference in the proportion of different genotypes of HCV-RNA between CR and NR groups. We conclude that determination of serum HCV-RNA levels prior to IFN treatment using a branched DNA probe assay is very useful in predicting the effect of IFN treatment.

Background. The development of hepatocellular carcinoma (HCC) is associated closely with cirrhosis. In the present study, the cumulative risk of HCC in patients with cirrhosis was investigated. Methods. A total of 401 patients were registered from April 1977 and followed for a mean of 4.4 years. Of 401 patients, 255 (64%) were tested for hepatitis B surface antigen (HBsAg) and antibody (anti-) to the hepatitis C virus (HCV); 87 (34%) patients were positive for HBsAg but were negative for anti-HCV (hepatitis B virus [HBV] group), 126 (49%) were negative for HBsAg but were positive for anti-HCV (HCV group), 10 (4%) were positive for both and 32 (13%) were negative for both (non-B non-C group) Results. By the end of March 1993, HCC was diagnosed in 127 (31.6%) patients. The cumulative risk of HCC in the HCV group was slightly higher than that in HBV group (P = 0.3, 5-year risk: 36.9 versus 21.2%). In contrast, the rate was significantly lower in the non-B non-C group than in the HBV or HCV groups (P < 0.05 and P < 0.01, respectively, 5 year risk: 12.4%). Conclusions. These results suggest that not only HBV infection but also HCV infection increase the risk for HCC in patients with cirrhosis.

We analyzed the evolution of the precore/core gene of hepatitis B virus (HBV) over a period of 6 to 11 years in seven patients with chronic HBV infection, who exhibited a variety of clinical features. Sequence analysis revealed the following results: (1) HBeAg to anti-HBe seroconversion was correlated roughly with the occurrence of precore-defective mutants, and several years appeared to be required for complete replacement of wild types by mutants; (2) core gene mutations preceded precore-defective mutations and tended to increase with time, although not cumulatively. They occurred not only during serum alanine aminotransferase (ALT) elevations but also after ALT returned to normal; (3) ALT fluctuations appeared to subside with complete replacement of the wild type by the mutant type and/or substantial accumulation of core gene mutations; (4) unexpectedly, the anti-HBe-positive “healthy” carrier was found to harbor the wild type precore gene, as did the HBeAg-positive “healthy” carrier; however, the core gene of the former evolved at a rapid rate; and (5) a partial deletion was recognized in the core gene at the onset of fatal hepatic failure in one patient. Thus, the precore/core mutation was closely related with the clinical features in the patients. © 1994 Wiley-Liss, Inc.

最近開発され臨床応用が予定されているE型肝炎血清診断用の特異的抗E抗体検出系を用いて,過去の非A非B非C型急性肝炎患者保存血清のスクリーニングを行ったところ,当院で経験した原因不明の急性肝炎患者血清中に特異的抗体が検出された.症例は24歳の男性.海外渡航歴・飲酒歴は共にない.発熱・発疹で発症し,近医で加療中に肝障害発見,症状増悪し当院入院となった.非A非B型肝炎の診断下経過観察され,肝炎症状は一峰性の良好な経過を辿り,発症より113日目に軽快退院した.経時的に保存されていた血清につき前述の抗E抗体力価の推移を検討した結果,トランスアミナーゼ値のピークより約1カ月遅れて頂値を示す特異的陽性の所見を得た.本邦においては今迄の所極めて稀な散発性発症した急性E型肝炎と思われる症例をA示した.

Effects of interferon (IFN) treatment on 91 patients with chronic HCV-related liver diseases in three hospitals were analyzed. HCV-RNA encoding the NS5 region of HCV was detected by the RT-PCR method, and HCV genotyping was performed by slot-blot hybridization using the type-specific cDNA probes on HCV-NS5. HCV titers in blood before treatment with IFN were determined by the multicyclic PCR method. HCV-NS5 was positive in 61 out of 91 patients and the HCV-K1 genotype was found in 40 patients, whereas the HCV-K2 genotype was found in 21. To summarize results from all three hospitals, 52.3% of patients recovered completely and 33.3% recovered partially in the K2 group, in each of these the percentage was significantly higher than in the K1 group. In addition, the percentage of the patients showing no response to IFN treatment was significantly higher in the K1 group than in the K2 group. In the HCV-NS5-negative group, the percentage of patients who did not respond was significantly lower than in the K1 group. In the K1 group, a complete recovery tended to be found more frequently in patients with lower titers of HCV. However, some patients with low titers of HCV did not respond to treatment. The differences of HCV titers between the groups showing different responses to IFN treatment was not statistically significant. In the K2 group, HCV titers were significantly lower than those in the K1 group; however, the effects of IFN were not related to the titers of HCV in K2 group. Two patients with liver cirrhosis in the K2 group had a complete or partial recovery, whereas four patients with liver cirrhosis in the K1 group did not respond to IFN treatment. These results indicate that the HCV genotype is the most important determinant of the effects of IFN treatment.

A cDNA clone, C8-2, derived from nonstructural (NS) protein 5 region of hepatitis C virus (HCV) genome hasbeen isolated and was expressed in Escherichia coli as a fusion protein with β -galactosidase ( β -Gal). The recombinant protein, β -Gal/C8-2, was partially purified and used for detection of anti-HCV antibody by enzyme-linked immunosorbent assay (ELISA). Anti-C8-2 antibody was detected in 47% of patients with post-transfusion non-A, non-B (NANB) acute hepatitis and in 55% of patients with NANB chronic liver diseases. Of 1491 normal blood donors, ten (0.7%) were positive for anti-C8-2 antibody, and three of these ten samples were negative for anti-C100-3 antibody. HCV RNA was detected in one of these three samples. These results suggest that the recombinant protein containing C8-2 peptide may be useful as another nonstructural protein epitope for diagnosis of hepatitis C and screening of blood donors.

To compare the seroepidemiology of hepatitis C and hepatitis B between Bangladesh and Japan, we tested the second generation antibody to hepatitis C virus (anti-HCV-2) and hepatitis B surface antigen (HBsAg) in serum samples from 163 professional blood donors (161 males and 2 females, mean age 28.6 yr.) and 83 voluntary blood donors from Bangladesh, and 7479 Japanese voluntary blood donors (5036 males and 2443 females; mean age 37.1 yr.). In Bangladesh, anti-HCV-2 is detected in 2.4% of professional blood donors and 0% of voluntary blood donors, furthermore, HBsAg is detected in 29% and in 2.4% of professional and voluntary blood donors, respectively. In Japan, anti-HCV-2 is detected in 0.6% in voluntary blood donors, and HBsAg also in 0.6%. These results indicate that professional blood donors in Bangladesh are highly contaminated by hepatitis B virus and moderately by hepatitis C virus, while voluntary blood donors in both countries are not so highly contaminated by either hepatitis viruses.

In Japanese blood donors, positivity for antibodies to hepatitis C virus (HCV) ranges from 0.2% in subjects under 20 to 3.9% in those over 50 years. It is estimated that at least 2.3 million Japanese have contracted HCV infection through contaminated blood. HCV carrier state was confirmed by polymerase chain reaction for HCV-RNA in subjects positive for antibodies to more than one viral protein (70% of cases). Subjects positive for core antibody alone, however, were found to be HCV-RNA negative with normal liver function, and are considered to have only a past history of HCV infection (30% of cases). Acute hepatitis C progresses to chronic infection in about 90% of cases. In comparison with hepatitis B, chronic hepatitis C leads more frequently to cirrhosis and liver cancer, and rarely remits spontaneously. In typical HCV infection, aminotransferase activities fluctuate markedly in the early stages, then become relatively stable for 10 years or more, with chronic persistent hepatitis shown by histological examination. Thereafter, aminotransferase activities may change dramatically, with progression to chronic active hepatitis and rapid development of cirrhosis and hepatocellular carcinoma. On average, it takes about 30 years for chronic hepatitis C to progress from initial infection to cirrhosis and cancer, but the disease progresses much more rapidly in elderly patients.

In Japan, hepatocellular carcinoma (HCC) is one of the most prevalent cancers, with a reported fatality rate showing a consistent and significant increase in the last decade. At most, only 25% of HCC cases are positive for the hepatitis B surface antigen (HBsAg). To investigate a potential role for hepatitis C virus (HCV) in the development of HCC, sera from 105 HBsAg-negative HCC patients were collected from five districts of Japan and assayed for antibody to HCV antigen (HCVAb). A large number of these patients (76.2%) were found to be positive for the HCVAb in comparison with the reported prevalence in sera from blood donors (1.1%). A history of blood transfusion was found in 39.6% of the cases positive for HCVAb, which was significantly different to the lower rate (4.7%) observed in HCC patients who were both positive for HBsAg and negative for HCVAb (P less than 0.001).

A lambda gt11 cDNA library was constructed from RNA purified from hepatitis B viral surface antigen-negative human plasma with high alanine aminotransferase activity. A cDNA clone, designated as C8-2, was isolated by immunoscreening with mixed sera from non-A, non-B hepatitis (NANBH) carrier and convalescent chimpanzees. The recombinant protein produced by C8-2 reacted specifically with sera of patients in the chronic phase of NANBH. The sequence of C8-2, 269 bp, did not hybridized with any human or chimpanzee genomic DNA, and had no homology with those of primates and viruses. The existence of this sequence in RNA of possibly infectious plasma was shown by RNA blot hybridization and by Southern blot analysis of products amplified by the polymerase chain reaction. These results strongly suggest that C8-2 is derived from the agent of this viral hepatitis.

We evaluated patients with nonalcoholic fatty liver disease (NAFLD) and compared the clinical and pathological features to identify the risk factors for NAFLD with severe fibrosis.One hundred and eighty-two patients with biopsy-confirmed NAFLD from various medical centres were recruited into this study.The variables that were significantly associated with severe steatosis were male gender (mild:severe=36%:53%, P=0.02), younger age (mild:severe=57%:82%, P0.001) and absence of type 2 diabetes (mild:severe=43%:71%, P0.001). There was no significant difference in the degree of inflammation among the clinical groups. The variables that were significantly associated with severe fibrosis were female gender (mild:severe=54%:84%, P=0.002), older age (or = 60 years old) (mild:severe=29%:53%, P=0.020), type 2 diabetes (mild:severe=42%:71%, P=0.020) and hypertension (mild:severe=24%:53%, P=0.002). Although there were more obese patients in the group with severe fibrosis, the association was not statistically significant (mild:severe=67%:78%, P=0.229). The prevalence of high serum triglyceride levels was similar between the two groups. The N (Nippon) score (total number of risk factor) could significantly predict severe fibrosis in NAFLD patients (1.48 +/- 1.14 vs. 2.66 +/- 0.94, P0.001).The N score can be used to predict severe fibrosis in cases of NAFLD.

Efficacy of interferon (IFN) therapy during the acute phase of hepatitis C infection is promising, although the optimal regimen has yet to be determined. It is not known whether the known prognostic factors for chronic hepatitis C (CHC) influence the effect of IFN in acute hepatitis C (AHC). Seventeen patients with AHC were analyzed for hepatic IFN alpha receptor 2 (IFNAR2) prior to IFN treatment. All patients were subsequently treated with either 168 million units (MU) or 336 MU of natural IFN alpha. Seventeen age-matched samples of CHC were provided as controls. The overall sustained response rate was 64.7% (11/17). In patients who received a total dose of 168 MU IFN, the sustained response rate was 28.6% (2/7), and in those who received 336 MU of IFN, the sustained response rate was 90.0% (9/10). The peaks of ALT and HCV-RNA quantity were not associated with the response to IFN. The hepatic IFNAR2 levels were 1.52 +/- 0.34 densitometry units and 0.92 +/- 0.16 in AHC and CHC, respectively (P = 0.042). There was no difference in hepatic IFNAR2 levels between sustained virological responders (SVR) and nonsustained virological responders (NR). The hepatic receptor levels were higher in AHC than in CHC patients. The levels of hepatic IFNAR2 did not differ in SVR and NR, indicating that high-dose natural IFN alpha treatment is effective for AHC, irrespective of the levels of hepatic IFNAR2.

Objective: The aim of this study was to identify clinical features and virological aspects of infectious sources that are related to the severity of sexually transmitted acute hepatitis B virus (HBV) infection in patients, especially in cases of genotype C. Methods: Nineteen patients with acute HBV infection, 10 classified with severe acute hepatitis (SH) (prothrombin time; PT 40%), and their infectious sources (all were sexual partners) were studied. Infectious source factors were analyzed in relation to the severity of hepatitis in the patients’ partners. Results: The nucleotide homology of HBV-DNA between each pair was ≧98.9%. Sixteen were infected with HBV genotype C. Among the 16 infectious sources, age, numbers with elevated alanine aminotransferase (ALT, 7/9 vs. 1/7), anti-HBe positivity (8/9 vs. 1/7) and core promoter mutations at nt 1762 (7/9 vs. 1/7), nt 1764 (8/9 vs. 1/7) and precore mutation at nt 1896 (8/9 vs. 1/7) were significantly higher in the sources of SH than in those of AH. Conclusion: Higher age, elevated ALT, anti-HBe positivity and core promoter/precore mutations were possible risk factors for an infectious source of the severe form of sexually transmitted acute hepatitis due to HBV genotype C.

BACKGROUND Des-γ-carboxy prothrombin (DCP) has been reported to be an important prognostic factor in patients with hepatocellular carcinoma (HCC). Recently, a monoclonal antibody, 19B7, which recognizes the Gla domain of DCP, has been identified. The 19B7 antibody recognizes an epitope different from that recognized by MU-3, which is another antibody against DCP. In this study, the authors investigated the measurement of DCP using the antibodies MU-3 and 19B7, respectively, as a prognostic factor for patients with HCC who had solitary, small tumors and or Child Stage A HCC. METHODS One hundred four patients with HCC who had solitary, small tumors or Child Stage A tumors were enrolled in the study between 1991 and 2001. All patients were treated and were followed for a mean of 3.2 years. The authors analyzed the correlation between the DCP Index (DCP measured by MU-3 and DCP measured by 19B7) and patient prognosis. The patients were classified into 3 groups based on their DCP Index: 1) DCP negative (DCP < 40 milli arbitrary unit (mAU)/mL)); 2) low DCP Index (DCP ≥ 40 mAU/mL; MU-3:19B7 ratio, < 3.0; and 3) high DCP Index (DCP ≥ 40 mAU/mL; MU-3:19B7 ratio, ≥ 3.0). RESULTS The survival rate for patients in the high DCP Index group was lower compared with the survival rate for patients in the DCP-negative group and was significantly lower compared with the survival rate for patients in the low DCP Index group. In a univariate Cox proportional hazards model, the positive factors were high DCP Index and low DCP Index. Among the positive predictive factors that were analyzed using a multivariate Cox proportional hazards model were age (hazard ratio, 3.27; P = 0.006), low DCP Index (hazard ratio, 2.87; P = 0.012), and high DCP Index (hazard ratio, 12.3; P < 0.0001). CONCLUSIONS The prognosis of patients who had a high DCP Index score was poorer compared with patients who had a low DCP Index score and patients who were classified as DCP negative. The authors concluded that the DCP Index is a prognostic indicator for patients with HCC. Cancer 2003;98:2671–7. © 2003 American Cancer Society.

A 57-year-old woman was referred to our hospital because of a liver mass detected by computed tomography. She had taken oral contraceptives for only one month at the age of thirty. Physical examination revealed no abnormalities, and laboratory data, including hepatic function tests, were within the normal range, with the exception of elevated levels of those serum proteins induced by the absence of vitamin K or by raised levels of the antagonist (PIVKA)-II (3,502 AU/ml). Abdominal ultrasonography revealed a hyperechoic mass measuring 10 X 10 cm in the left posterior segment of the liver. Because hepatocellular carcinoma could not be completely excluded, this mass was resected. The tumor consisted of sheets of uniform cells with clear cytoplasm, perinuclear eosinophilic granules and round nuclei. These histological findings were consistent with liver cell adenoma. Background hepatic tissue appeared normal. After resection of the tumor, serum PIVKA-II fell to within the normal range. An area of hepatocellular carcinoma (HCC) with a mid-trabecular pattern was immunohistochemically found, which was positive for PIVKA-II. Sinusoidal endothelial cells were CD34-positive, containing scattered PIVKA-II positive cells. This tumor was therefore finally diagnosed as liver cell adenoma with focal malignant transformation to HCC.

BACKGROUND/AIMS: this study aimed to determine the viremia status after clinical, biochemical and serological recovery from acute hepatitis B viral (HBV) infection. METHODS: we detected serum HBV-DNA in 19 patients with acute hepatitis B during followed-up 6-43 months after onset, and analyzed HBV genotypes. RESULTS: 13 (72%) of 19 patients had detectable HBV DNA at the point of 6 months after onset, and four (33%) of 12 patients had persisted viremia for more than 1 year although they were recovery with normalization of alanine transaminase (ALT), disappearance of hepatitis B surface antigen (HBsAg) and appearance of antibody against HBsAg (anti-HBs). Eighteen (95%) of 19 patients were infected with HBV genotype C, one (5%) with genotype B. CONCLUSIONS: these results suggest genotype C of HBV is the predominant genotype of acute hepatitis B in Nagasaki region in Japan. HBV can persist in the serum for more than one year after complete clinical and serological recovery from acute viral hepatitis.

Background & Aims: The effects of interferon therapy in chronic hepatitis C patients on survival are unclear. Our objective was to analyze survival among a large cohort of chronic hepatitis C patients. Methods: We used a retrospective cohort study design in the setting of 7 university hospitals and 1 regional core hospital in Japan. Our study included 2889 patients with histological-proven chronic hepatitis C: 2430 patients received interferon therapy, and 459 patients were untreated. For intervention, the median dose and duration of interferon administration was 480 million units and 137 days, respectively. For measurements, survival status was confirmed by medical records or direct questionnaires. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality among the Japanese general population and by risk ratio calculated by proportional hazards regression. Results: Thirty of 459 untreated patients, 7 of 817 virologic sustained responders, and 49 of 1613 nonresponders died in 5.4-years follow-up. Fifty-eight (67%) of 86 patient deaths were due to liver diseases (39 to hepatocellular carcinoma). Compared with the general population, overall mortality was high among untreated patients (SMR: 1.9; CI: 1.3–2.8) but not among interferon-treated patients (SMR: 0.9; CI: 0.7–1.1). The risk of death was reduced, compared with untreated patients, among interferon-treated patients (risk ratio for overall death: 0.367; CI: 0.236–0.596; for liver-related death: 0.284; CI: 0.164–0.494) and among sustained responders (risk ratios: 0.148; CI: 0.064–0.343 and 0.050; CI: 0.012–0.216). The risk of liver-unrelated deaths remained unchanged. Conclusions: Interferon therapy improved survival of chronic hepatitis C patients by preventing liver-related deaths. GASTROENTEROLOGY 2002;123:483-491

BACKGROUND Hepatitis C virus (HCV) infection is a heterogeneous disease, the natural history of which remains controversial. There is solid evidence that chronic HCV infection is responsible for the occurrence of hepatocellular carcinoma (HCC). The aim of the current cohort study was to determine the rate of the development of HCC from the time of primary HCV infection and to assess the risk factors for the development of HCC in chronic posttransfusion hepatitis C patients. METHODS Four hundred sixty-nine patients with clinically compensated HCV, who had undergone a single blood transfusion comprised the current study cohort. Patients with other risk factors for chronic liver disease were excluded. All patients were referred to the liver center at the National Nagasaki Medical Center between December 1980 and December 1998 and were followed prospectively until the end of the analysis (June 2000). RESULTS Follow-up data were obtained for 445 patients. The mean duration from HCV infection to the end of the observation was 28 years. Fifty-two patients (11.1%) progressed to HCC. The mean duration from the time of blood transfusion to the diagnosis of HCC was 31 years. Multivariate Cox regression analyses revealed age, fibrosis, duration from HCV infection to study entry, and alcohol consumption to be the independent factors affecting the development of HCC. The risk of developing HCC in patients age ≥ 56 years was increased 7.8-fold compared with that in patients age < 56 years. The mean age of patients at the time of HCC diagnosis was 65 years (range, 58–79 years). CONCLUSIONS At the time of diagnosis, 92% of the 52 HCC patients were age > 60 years and 38 of the HCC patients (73%) were in their 60s. There was a significantly negative correlation between the duration from HCV infection to the development of HCC and the age of the patient at the time of infection (correlation coefficient = 0.702; P < 0.0001; Y = 61.1–0.82X), indicating that the age of patients, rather than the duration of HCV infection, is more significant for HCC development in patients with posttransfusion HCV. Moreover, these data may contribute to the design of an optimal follow-up schedule for patients with posttransfusion HCV. Cancer 2002;95:331–9. © 2002 American Cancer Society. DOI 10.1002/cncr.10662

The present study was designed to determine the frequency of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in patients with hepatocellular carcinoma (HCC) in Nagasaki Prefecture, Japan. We examined the clinical features of 1019 patients with HCC who visited our hospitals between January and December 1999. The ratio of men to women was 709 : 310, and the peak incidence of HCC was in the seventh decade of life in both men and women. In the majority of the patients, HCC showed association with HCV infection (74%) compared with HBV infection (17%). HBV-associated HCC was more common in young patients, while HCV-associated HCC was more common in patients with a history as a "daily drinker", or with a history of blood transfusion, liver cirrhosis, and persistently high serum transaminases before the diagnosis of HCC. HCC was initially suspected by ultrasonography or computed tomography in 776 of the 874 patients for whom there was a history of mode of detection of HCC (89%). Tumor size at the time of diagnosis of HCC in patients who had been regularly followed up for liver diseases at our hospitals was significantly smaller than that in patients who were not followed up regularly before the diagnosis (P < 0.01). Our results indicate that the proportions of patients with HBV or with HCV infection among HCC patients in Nagasaki Prefecture are similar to those found in a nationwide survey in Japan, and there are some differences between the clinical manifestations of HBV- and HCV-associated HCC. Our results emphasize the importance of close follow-up for the high-risk group (i.e. those with HBV- or HCV-associated chronic liver diseases) for the early detection of HCC.

To assess the possible influence of human immunodeficiency virus type 1 (HIV-1) infection on the clinical course of acute hepatitis A virus (HAV) infection, 15 HIV-1-infected homosexual men and 15 non-HIV-infected age-matched subjects were compared. HAV load was higher in HIV-1-infected than in non-HIV-infected patients (P

Objective The diagnostic criteria of autoimmune hepatitis (AIH) were recently modified by the International Autoimmune Hepatitis Group. This study was performed to assess the impact of the revised scoring system on the diagnosis of AIH. Patients and Methods We re-analyzed the clinical features of 89 patients diagnosed as AIH in Nagasaki Prefecture, Japan, using the revised scoring system, and compared the scores and final diagnosis with our previously published results using the original system. Results Of the 89 patients with AIH, 40 (45%) were classified using the new system as "definite" AIH, 41 (46%) as "probable" AIH, and 8 (9%) patients were categorized as "others". Of these, 37 (42%), 35 (39%), and 4 (4%) patients who were classified as "definite", "probable", and "others" by the original system remained in the same category by the revised system, respectively. However, 3, 4, and 6 patients were re-categorized as "definite" from "probable", "others" from "probable", and "probable" from "definite", respectively. The difference in aggregate scores between the above two systems ranged from -5 to +2. The main contributing factors to the changes in aggregate AIH score were "other autoimmune disease(s)" and "interface hepatitis without lobular involvement and bridging necrosis on liver histology". However, the main contributing factors to the demotions from "definite" to "probable" and form "probable" to "others" were those related to the characteristics of biliary diseases, i.e., antimitochondrial antibody positive, biliary changes in liver histology, and alkaline phosphatase: aspartate aminotransferase ratio between 1.5 and 3.0. Moreover, two patients who had no histological evidence of AIH were both re-categorized as "others" from "probable" AIH. Conclusion Our results indicated that the diagnosis, whether based on the revised or original system, was the same in the majority of AIH patients, but the revised scoring system excluded cases who had features suggestive of biliary diseases from "definite" AIH, and also confirmed that a diagnosis of "definite" AIH should not be made without liver histology.(Internal Medicine 39: 1008-1012, 2000)

The natural history of chronic hepatitis C is one of a slow progression from early stage chronic hepatitis without fibrosis to cirrhosis or hepatocellular carcinoma (HCC). The disease progresses to advanced stage chronic hepatitis C over 10–30 years. Data from Japan indicate that mortality associated with chronic hepatitis C results mainly from the development of HCC. We studied 186 patients referred between 1968 and 1994. The mean follow-up interval was 8.6 (2–23) years. HCC developed in 34 patients (18%). The cumulative probability of HCC development was 4% at 5 years, 18% at 10 years and 45% at 15 years. Univariable analysis indicated that age at entry, fibrosis stage, inflammation activity and the status of IFN treatment (treated vs untreated) were predictive risk factors for developing HCC in patients with chronic hepatitis C. Multivariable analysis of these risk factors indicated that age at entry (> 50 vs < 50; Risk Ratio = 3.2, P < 0.005) and fibrosis stage (F3 vs F0; Risk Ratio = 5.6, P < 0.005) are independent risk factors for HCC. From these results it was concluded that (1) 20% of patients referred to liver clinics with chronic hepatitis C in Japan can be expected to develop HCC over a 10 year period; (2) the risk of HCC increases with progression of liver fibrosis (F3, F4) and age (greater than 50 years old) at the time of diagnosis and (3) the degree of liver fibrosis is a critical predictive factor for the occurrence of HCC.

We examined RNA of hepatitis B virus (HBV) in peripheral blood mononuclear cells (PBMCs) by the reverse transcription polymerase chain reaction (RT PCR) in 61 patients associated with HBV infection, in order to analyze the relationship between the transcriptional activity of HBV in PBMCs and the clinical characteristics. The presence of HBV RNA in PBMCs was detected in 19/51(37.1%) patients with HBsAg positive and in 1/10 (10.0%) patient with HBsAg negative patients. Six healthy controls were all negative. The frequency of HBV RNA positivity was detected in patients with high ALT level (P

Short-term histologic improvement in hepatitis C-related hepatic fibrosis has been noted in studies with more than 2 years of follow-up, but the long-term effects of interferon therapy on hepatic fibrosis remain unclear.To assess changes in hepatic fibrosis after interferon therapy in patients with chronic hepatitis C.Retrospective cohort study.7 university hospitals and 1 national hospital in Japan.593 patients with chronic hepatitis C who underwent a paired liver biopsy from 1987 to 1997. Of these, 487 patients received interferon therapy and 106 patients were untreated.Patients in the treatment group received a 2- to 6-month course of interferon within 6 months after the initial biopsy.Fibrosis and inflammatory activity in paired biopsy samples obtained a median of 3.7 years apart (range, 1 to 10 years) were graded by using the criteria of Desmet and colleagues (F0 to F4) and those of the French METAVIR Cooperative Study Group (A0 to A3), respectively. Changes in fibrosis staging and activity scores and yearly rates of fibrosis progression and regression were calculated.183 of the 487 interferon-treated patients showed a sustained virologic response. Activity grade was unchanged in most of the untreated patients and improved in 89% (CI, 83% to 93%) of patients with a sustained virologic response. A sustained response to interferon was associated with a mean (+/-SE) reduction in fibrosis score of -0.60+/-0.07 at less than 3 years of follow-up and -0.88+/-0.08 at 3 years or more of follow-up. The rate of fibrosis progression was -0.28+/-0.03 unit/y (regression) in patients with sustained response, 0.02+/-0.02 unit/y in patients with nonsustained response (P0.001), and 0.10+/-0.02 unit/y in untreated patients.Although the time between biopsies partly affected the patient's clinical course, the differences observed here suggest that in patients with chronic hepatitis C, regression of fibrosis is associated with sustained virologic response to interferon therapy.