Hepatitis: Sakaguchi H

Motoyama H, Enomoto M, Yasuda T, Fujii H, Kobayashi S, Iwai S, Morikawa H, Takeda T, Tamori A, Sakaguchi H, Kawada N. · Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #18679001 No free full text.

Abstract: A 37-year-old woman was admitted to a hospital with jaundice. Within a couple of weeks, her liver function improved with only symptomatic therapy. About 30 to 60 days before admission, she had taken a herbal medicine, bofu-tsu-sho-san. A diagnosis of drug-induced liver injury was made according to the diagnostic scale proposed at the Digestive Disease Week-Japan 2004. A drug-lymphocyte stimulation test for each ingredient of bofu-tsu-sho-san; the results were positive for Cnidii Rhizoma, Angelicae Radix and Menthae Herba. The liver biopsy specimen revealed features of acute hepatitis. Physicians should be aware that bofu-tsu-sho-san can cause liver injury, as this drug is commonly used as an over-the-counter medicine.

Enomoto M, Tamori A, Kohmoto MT, Hayashi T, Jomura H, Habu D, Sakaguchi H, Takeda T, Kawada N, Seki S, Shiomi S, Koh N, Nishiguchi S. · Department of Hepatology, Osaka City University Medical School, Osaka 545-8585, Japan. · J Interferon Cytokine Res. · Pubmed #17348818 No free full text.

Abstract: Sequential treatment with lamivudine and interferon (IFN) has induced sustained biochemical and virologic responses in the majority of patients with chronic hepatitis B in France. However, the efficacy of sequential treatment in patients with chronic hepatitis B virus (HBV) genotype C infection has not been evaluated. Twenty-four HBe antigen-positive patients were treated with 100 mg lamivudine alone for 16-32 weeks, then with both 6 MU IFN-beta and lamivudine for 4 weeks, and lastly with IFN-beta alone for 20 weeks. Sustained response was achieved in 7 (29%) patients 24 weeks after the end of therapy. No lamivudine-resistant variants emerged in any patient. Hepatitis flare occurred in 3 patients after the withdrawal of lamivudine, but none had decompensation. The patients with sustained response were significantly younger at baseline (p = 0.033) and had a significantly lower HBV DNA level at the start of IFN (p = 0.020) than those without sustained response. In conclusion, the rate of response to sequential therapy with lamivudine and IFN in HBe antigen-positive patients with HBV genotype C infection was lower than the rate reported previously. Patients who were young or who had a favorable virologic response to lamivudine were more likely to have a sustained response.

Takeda T, Yasuda T, Nakayama Y, Nakaya M, Kimura M, Yamashita M, Sawada A, Abo K, Takeda S, Sakaguchi H, Shiomi S, Asai H, Seki S. · Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi Abeno-ku, Osaka 545-8585, Japan. · World J Gastroenterol. · Pubmed #17203518 links to  free full text

Abstract: AIM:To evaluate the method of noninvasive transient elastography for assessment of histological stage of liver fibrosis in patients with chronic hepatitis C (CHC). METHODS: Two hundred and thirty-seven patients with CHC were included in this study. Liver biopsy was performed under ultrasonography on 217 of the patients, excluding twenty with clear clinical evidence of liver cirrhosis. Fifty subjects without liver disease were enrolled as a control group (stage 0). Twenty-five patients with sustained virological response (SVR) to interferon (IFN) therapy were also enrolled. These patients underwent liver biopsy before IFN therapy. Examination of liver stiffness (LS) was performed by elastography. RESULTS: Medians (50% levels) of LS were 4.1 (3.5-4.9), 6.3 (4.8-8.5), 8.8 (6.8-12.0), 14.6 (10.5-18.6), and 22.2 (15.4-28.0), respectively, in the fibrosis stages 0-4 (P < 0.001). LS was significantly correlated with four serum fibrosis markers. LS values in patients with SVR were 3.8 (3.5-5.6), 5.2 (4.4-6.8), 6.8 (6.1-7.6), and 6.1 (3.6-7.9), respectively, in the fibrosis stages 1-4. In all stages, LS for patients with SVR was significantly lower than that for patients who did not undergo IFN therapy. LS was significantly correlated with serum concentrations of hyaluronic acid, type IV collagen, type IV collagen 7S, and type III procollagen N peptide. CONCLUSION: LS correlated well with the histological stage of fibrosis. Changes in liver fibrosis stage may thus be estimated noninvasively using transient elastography.

Tamori A, Hayashi T, Shinzaki M, Kobayashi S, Iwai S, Enomoto M, Morikawa H, Sakaguchi H, Shiomi S, Takemura S, Kubo S, Kawada N. · Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan. · J Med Virol. · Pubmed #19382258 No free full text.

Abstract: Hepatocellular carcinoma (HCC) develops several years after the eradication of hepatitis C virus (HCV) by interferon therapy. Risk factors for the development of HCC are only partly understood. To elucidate the role of occult hepatitis B virus (HBV) infection in hepatocarcinogenesis in patients with sustained virologic response, the prevalences of HBV-related makers were examined. Study group comprised 16 patients with sustained virologic response (group A) and 50 with HCV (group B). Anti-HBc and anti-HBs in serum were examined by enzyme-linked immunoassay. HBV DNA in liver was examined by nested polymerase chain reaction, using primers specific for genes encoding for HBx, HBsAg, HBcAg, and HBV cccDNA. Sequence of the amplified HBV DNA for 'a' determinant of HBsAg was determined in HCC. Anti-HBc was positive in 10 of 16 in group A and 25 of 50 in group B. HBV DNA in liver was detected in 12 of 16 in group A and 21 of 50 in group B (P = 0.044). In group A, HBV DNA in liver was detected frequently in patients without cirrhosis and in those with a longer period from the time of HCV eradication to the development of HCC. Mutation in 'a' determinant of HBsAg was found in three HCC of group A. Occult HBV infection may be one of the most important risk factors in hepatocarcinogenesis of Japanese patients with sustained virologic response.

Fujii H, Enomoto M, Fukushima W, Ohfuji S, Mori M, Kobayashi S, Iwai S, Morikawa H, Tamori A, Sakaguchi H, Ikura Y, Ueda M, Kawada N. · Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. · J Gastroenterol. · Pubmed #19360373 No free full text.

Abstract: BACKGROUND: Several noninvasive tests have been proposed to predict cirrhosis in patients with chronic hepatitis C, but not in patients with non-alcoholic steatohepatitis (NASH). We assessed whether noninvasive laboratory tests designed to predict the risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection could be used in patients with NASH. METHODS: The subjects were 50 patients with biopsy-proved NASH and 100 age- and sex-matched patients with HCV. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), age-platelet (AP) index, AST-to-platelet ratio index (APRI), cirrhosis discriminant score (CDS), and the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) model were calculated. RESULTS: The areas under the receiver-operating characteristic curves of the AAR, AP index, APRI, CDS, and HALT-C model for predicting cirrhosis were respectively 0.813, 0.877, 0.786, 0.949, and 0.908 in patients with NASH and 0.555, 0.652, 0.761, 0.782, and 0.782 in patients with HCV. A CDS cutoff value of less than 5 misclassified none of the 9 patients with NASH who had cirrhosis, while a value of more than 8 misclassified none of the 41 patients with NASH without cirrhosis. With the HALT-C model, a cutoff value of less than 0.6 classified non-cirrhotic NASH, while a cutoff value of 0.97 or higher classified cirrhotic NASH. The use of CDS and HALT-C model could avoid liver biopsy for predicting cirrhosis in 60 and 48% of the patients with NASH, respectively. CONCLUSIONS: Noninvasive laboratory tests designed to predict cirrhosis in patients with HCV are also useful in patients with NASH.

Ohfuji S, Fukushima W, Tanaka T, Habu D, Takeda T, Tamori A, Sakaguchi H, Seki S, Kawada N, Nishiguchi S, Shiomi S, Hirota Y. · Department of Public Health, Osaka City University Graduate School of Medicine, Osaka, Japan. · Hepatol Res. · Pubmed #18507689 No free full text.

Abstract: Aim: Some studies have suggested that nutritional support might protect against the recurrence of hepatocellular carcinoma (HCC) among postoperative HCC patients. However, no epidemiological studies have evaluated the effect of nutritional support on HCC incidence. This study aimed to investigate the association between a late evening meal and HCC. Methods: We conducted a hospital-based, case-control study comparing 73 cases with HCC to 253 matched controls among patients with chronic hepatitis C. A questionnaire elicited information on the consumption of a late evening meal, which was defined as a snack or meal within 2 h before bedtime. The odds ratios (OR) and 95% confidence intervals (CI) were calculated by the conditional logistic regression model. Results: After adjustment for potential confounders, patients who consumed a late evening meal had a lower OR as compared to those who did not consume one (OR, 0.08; 95% CI, 0.01-0.48). In terms of frequency of intake, a clear inverse exposure-response relationship was observed (trend P = 0.009). In addition, a negative association between a late evening meal and HCC was more pronounced among patients with an alpha-fetoprotein level of less than 20 ng/mL and those with a body mass index of less than 25 kg/m(2). Conclusion: A late evening meal might protect against HCC, particularly among patients with a normal alpha-fetoprotein level and who are not obese, although these relations might be accounted for other factors, including total energy intake. Further studies with larger study sizes are needed to corroborate these findings.

Enomoto M, Tamori A, Kohmoto MT, Hayashi T, Morikawa H, Jomura H, Sakaguchi H, Habu D, Kawada N, Shiomi S, Nishiguchi S. · Department of Hepatology, Graduate School of Medicine, Osaka City University Medical School, Osaka, Japan. · Hepatol Res. · Pubmed #18498358 No free full text.

Abstract: Aim: The endpoint of treatment with nucleoside analogs remains unclear for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We report the results of a randomized trial to determine the optimal duration of additional therapy after response to lamivudine in HBeAg-negative patients. Methods: Twenty-two patients with HBeAg-negative chronic hepatitis B who exhibited biochemical and virological responses to lamivudine were enrolled. When patients responded to treatment, they were randomly assigned to receive 12 more months of therapy (Group A, 11 patients) or 24 more months of therapy (Group B, 11 patients). Results: The baseline characteristics of the patients were similar in the two groups. Biochemical and virological responses were obtained in all patients within 6 months. Drug resistance developed in one patient in Group A during month 7 of additional therapy, and in five patients in Group B from months 13-23 of additional therapy. Ten patients in Group A and six in Group B completed the protocol and were included in analysis. Eight of the 10 patients in Group A experienced relapse between months 2 and 14 after the discontinuation of therapy, while three of the six patients in Group B experienced relapse between months 2 and 24. There was no difference in cumulative relapse rate between the groups (P = 0.275). Conclusion: Additional therapy with lamivudine for longer than 12 months after biochemical and virological responses in patients with HBeAg-negative chronic hepatitis B could increase the risk of drug resistance, but did not reduce the rate of relapse.

Hayashi T, Tamori A, Nishikawa M, Morikawa H, Enomoto M, Sakaguchi H, Habu D, Kawada N, Kubo S, Nishiguchi S, Shiomi S. · Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan. · Liver Int. · Pubmed #18492017 No free full text.

Abstract: BACKGROUND/AIMS: The mechanism of hepatocarcinogenesis remains unclear in patients in whom hepatitis C virus (HCV) disappears after interferon (IFN) therapy. We compared molecular alterations in hepatocellular carcinoma (HCC) between patients with a sustained virological response (SVR) to IFN and patients with HCV. METHODS: The study group comprised 44 patients with HCV and 13 patients with SVR. One patient in the SVR group had two tumour nodules, both of which were examined. Mitochondrial DNA (mtDNA) mutations in displacement-loop lesions were directly sequenced. Mutation of the TP53 gene was examined by direct sequencing. The methylation status of p16, p15, p14, RB and PTEN genes was evaluated by a methylation-specific polymerase chain reaction. RESULTS: The average number of mtDNA mutations was 4.2 in 44 HCCs with HCV and 2.0 in 14 HCCs with SVR (P=0.0021). mtDNA mutation was less frequently detected in HCCs from patients with SVR than in patients with HCV. TP53 mutations were detected in 12 (27%) of 44 HCCs with HCV and 2 (14%) of 14 SVR-HCCs. Hypermethylation of the p16, p15, p14, RB and PTEN promoters was, respectively, detected in 34, 13, 8, 12 and 11 of 44 HCCs from patients with HCV and 14, 0, 0, 2 and 2 of 14 HCCs from patients with SVR (P=0.049, 0.021, 0.085, 0.322 and 0.402). Hypermethylation of p16 was one of the most important alterations in SVR-HCC. CONCLUSIONS: Molecular alterations in hepatocarcinogenesis of patients with SVR-HCC were different from those of patients with continuous HCV infection.

Enomoto M, Tamori A, Kohmoto MT, Morikawa H, Habu D, Sakaguchi H, Takeda T, Seki S, Kawada N, Shiomi S, Nishiguchi S. · Department of Hepatology, Osaka City University Medical School, Asahimachi, Abeno-ku, Osaka, Japan. · J Med Virol. · Pubmed #17854034 No free full text.

Abstract: It remains unclear whether mutational patterns of the hepatitis B virus (HBV) genome are associated with the development of severe hepatitis after the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) variants during lamivudine treatment. Thirty patients with chronic hepatitis B who had YMDD variants during lamivudine therapy and were followed up subsequently while receiving lamivudine alone for at least 6 months were examined retrospectively. The lamivudine resistant mutations in the HBV polymerase gene were detected by a line probe assay, and the full-length sequences of HBV DNA were determined in some patients. Between months 5 and 33 of therapy, mutations from methionine to isoleucine at rt204 (rtM204I) were detected in 18 patients, and mutations from methionine to valine at rt204 (rtM204V) were detected in 12. The rtM204V mutations were always accompanied by mutations from leucine to methionine at rt180 (rtL180M), while rtM204I mutations were not. Baseline characteristics, alanine aminotransferase (ALT) levels, and HBV DNA levels within 6 months after the emergence of YMDD variants did not differ significantly between patients with rtM204I alone and those with rtL180M/rtM204V. No specific mutation was identified on full-length sequence analysis in three patients with a hepatitis flare. During long term follow-up, the addition of rtL180M to rtM204I was found in four patients 7-31 months after detecting the change at rt204 and was linked to increased ALT levels. In conclusion, mutational patterns of HBV DNA at the time of emergence of YMDD variants were apparently unrelated to the clinical outcomes in Japanese patients with chronic hepatitis B during lamivudine therapy.

Kobayashi S, Takeda T, Enomoto M, Tamori A, Kawada N, Habu D, Sakaguchi H, Kuroda T, Kioka K, Kim SR, Kanno T, Ueda T, Hirano M, Fujimoto S, Jomura H, Nishiguchi S, Seki S. · Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan. · Liver Int. · Pubmed #17311612 No free full text.

Abstract: BACKGROUND: Interferon (IFN) improves hepatic inflammation/fibrosis and reduces the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CH-C). However, HCC develops in some patients who have a sustained virological response (SVR) to IFN therapy. We designed this study to establish a follow-up protocol for patients with CH-C who have SVR to IFN therapy. METHODS: We retrospectively studied 1124 patients with CH-C who received IFN. RESULTS: HCC developed in 3.5% of patients with SVR to IFN. As compared with SVR patients without HCC, SVR patients with HCC were predominantly male (P=0.003), older at the initiation of IFN therapy (P=0.002), and at a more advanced histologic stage of disease (P<0.001). However, three of the 13 SVR HCC patients had mild fibrosis. The mean interval from IFN therapy to the detection of HCC in SVR HCC patients was 5.8 years and did not differ significantly from that in non-SVR HCC patients (P=0.304). Although most patients with HCC received curative therapy, the prognosis of some SVR HCC patients was poor, probably because of insufficient follow-up, resulting in delayed detection of HCC. CONCLUSIONS: SVR patients with CH-C who are elderly, male, or have an advanced histologic stage are at a high risk for the development of HCC after IFN therapy. We recommend that SVR patients should be observed carefully for more than 10 years after the completion of IFN therapy, even if they only have early fibrosis.

Kubo S, Tanaka H, Takemura S, Yamamoto S, Hai S, Ichikawa T, Kodai S, Shinkawa H, Sakaguchi H, Tamori A, Habu D, Nishiguchi S. · Departments of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan. · Hepatol Res. · Pubmed #17300703 No free full text.

Abstract: Aim: Patients with high serum hepatitis B virus (HBV) DNA concentrations are at high risk of tumor recurrence after liver resection for HBV-related hepatocellular carcinoma (HCC). Methods: Among 24 patients with high serum HBV DNA concentrations who underwent liver resection for HBV-related HCC, postoperative lamivudine therapy was chosen by 14 (lamivudine group). The other 10 patients were controls. Results: Clinicopathologic findings did not differ between the groups. Tumor-free survival rate after surgery was significantly higher in the lamivudine than the control group (P = 0.0086). By univariate analysis, multiple tumors were also a risk factor for a short tumor-free survival. By multivariate analysis, lack of lamivudine therapy and multiple tumors were independent risk factors for a short tumor-free survival. In four patients YMDD mutant viruses were detected after beginning lamivudine administration; in two of them, adefovir dipivoxil was administered because of sustained serum alanine aminotransferase elevations. Conclusion: Lamivudine therapy improved tumor-free survival rate after curative resection of HBV-related HCC in patients with high serum concentrations of HBV DNA, although careful follow up proved necessary for the detection of YMDD mutant viruses.

Tamori A, Shinzaki M, Kosaka S, Hayashi T, Iwai S, Enomoto M, Habu D, Sakaguchi H, Kawada N, Hino M, Shiomi S, Nishiguchi S. · Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan. · Liver Int. · Pubmed #17241387 No free full text.

Abstract: BACKGROUND AND AIM: Thiopurine S-methyltransferase (TPMT) genotypes or phenotypes may be a predictive factor for azathioprine-induced toxicities. We investigated the genotypic status of TPMT to evaluate the risk of azathioprine-related adverse effects in Japanese patients with different liver diseases, including autoimmune hepatitis (AIH). METHODS: 49 patients with AIH, 67 with primary biliary cirrhosis (PBC), and 120 with hepatitis C virus (HCV) were examined. TPMT genotypes were determined by PCR-restriction fragment length polymorphism-based assays. RESULTS: The distribution of TPMT genotypes was 90% TPMT*1/TPMT*1, 8% TPMT*1/TPMT*3C, and 2% TPMT*3C/TPMT*3C in AIH, and 94% TPMT*1/TPMT*1, 4.5% TPMT*1/TPMT*3C, and 1.5% TPMT*3C/TPMT*3C in PBC. All except 1 patient with HCV had the TPMT*1/TPMT*1 genotype. Severe myelosuppression occurred in two of nine patients with AIH who received azathioprine, one of whom was homozygous for TPMT*3C. CONCLUSIONS: TPMT*3C variants are more frequent in patients with AIH or PBC than in patients with viral hepatitis or healthy volunteers in Japan. Pharmacogenetic screening for TPMT polymorphisms before commencing azathioprine therapy may help to prevent severe hematotoxicity in patients with TPMT deficiency.

Fujii H, Sakaguchi H, Enomoto M, Yamamori K, Inagawa M, Watanabe T, Kawada N, Seki S, Arakawa T. · Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan. · Gastrointest Endosc. · Pubmed #17185102 No free full text.

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Ohfuji S, Fukushima W, Tanaka T, Habu D, Tamori A, Sakaguchi H, Takeda T, Kawada N, Seki S, Nishiguchi S, Shiomi S, Hirota Y. · Department of Public Health, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. · Hepatol Res. · Pubmed #16916617 No free full text.

Abstract: Several studies have reported the role of coffee for hepatocellular carcinoma (HCC). However, no study investigated about the relation of coffee for HCC among individuals with a relevant risk factor, i.e., hepatitis C virus (HCV) infection. Thus, we conducted a hospital-based case-control study to assess an association between coffee and HCC, in which both 73 cases and 253 controls were patients with chronic type C liver disease. To consider potential changes in coffee intake due to progression of liver disease, the effect of coffee was estimated separately before and after first identification of liver disease. Odds ratios (OR) and 95% confidence intervals (CI) for HCC risk were calculated using the conditional logistic regression model. Coffee drinking on a daily basis (>/=1cup/day) revealed lowered ORs as compared with non-drinkers both before first identification of liver disease (OR 0.38; 95% CI: 0.13-1.12; P=0.078) as well as thereafter (OR 0.19; 95% CI: 0.05-0.71; P=0.032). Even after excluding subjects who reported a reduction in the frequency of coffee intake after first identification of liver disease, this negative correlation persisted (OR 0.35; 95% CI: 0.12-1.06; P=0.063). Taken together, coffee may be a protective factor for HCC among those infected with HCV.

Fukushima W, Tanaka T, Ohfuji S, Habu D, Tamori A, Kawada N, Sakaguchi H, Takeda T, Nishiguchi S, Seki S, Shiomi S, Hirota Y. · Department of Public Health, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. · Hepatol Res. · Pubmed #16427353 No free full text.

Abstract: We conducted a hospital-based case-control study to investigate the effects of alcohol drinking on hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV) infection, with special reference to the disease course and changes in drinking habits. From among 1159 HCV-RNA positive patients under clinical follow-up at Osaka City University Hospital (OCUH), we identified 73 cases newly diagnosed with HCC during the past 3 years and selected 253 matched controls without HCC. The odds ratios were calculated for cumulative and average daily ethanol consumption, during three different periods (lifetime, before, and after the first identification of liver disease), using a logistic regression model. Among all subjects, there was a trend towards an inverse association between HCC and lifetime ethanol consumption (P=0.059-0.066). The tendency was similar for ethanol consumption before the first identification of liver disease, while no associative trend was indicated after the first identification. Among those with minor changes on abdominal ultrasonography findings at the first OCUH visit, a positive association was suggested for ethanol intake after the first identification, although results were not statistically significant. In conclusion, our results did not demonstrate a strong positive association between alcohol drinking and HCV-related HCC in this population.

Habu D, Nishiguchi S, Enomoto M, Nakatani S, Minamitani S, Tamori A, Sakaguchi H, Takeda T, Seki S, Ogami M, Asai H, Shiomi S. · Department of Hepatology, Graduate School of Medicine, Osaka City University Medical School, Japan. · Hepatogastroenterology. · Pubmed #16334784 No free full text.

Abstract: BACKGROUND/AIMS: We propose a method, named US score, for semi-quantitative determination of the stage of chronic type C liver disease by ultrasonography. METHODOLOGY: The subjects were 454 patients with chronic type C liver disease. Of the patients with chronic hepatitis C, 208 underwent US-guided or laparoscopic liver biopsy. US score was the sum of the scores representing five morphological variables, to be evaluated semi-quantitatively, and change in US score with chronic liver disease progression was determined. RESULTS: The average US score was 2.5 +/- 0.4 for F0, 2.8 +/- 0.6 for F1, 3.0 +/- 0.6 for F2, 3.7 +/- 0.9 for F3 and 5.5 +/- 0.8 for F4. There was a significant correlation between US score and the degree of fibrosis of chronic hepatitis C as assessed by the new European classification (p<0.0001). The average US score was 5.6 +/- 0.9 for Child A, 6.6 +/- 1.1 for Child B, and 7.8 +/- 0.7 for Child C. There was a significant correlation between US score and the results of classification by Child-Turcotte criteria (p<0.0001). CONCLUSIONS: These results suggest that US score is a stable, convenient method of evaluating the degree of progression of chronic type C liver disease.

Enomoto M, Nishiguchi S, Tamori A, Kohmoto M, Habu D, Sakaguchi H, Takeda T, Kawada N, Seki S, Shiomi S. · Department of Hepatology, Osaka City University Medical School, Osaka, Japan. · J Med Virol. · Pubmed #16032731 No free full text.

Abstract: This study evaluated an updated chemiluminescence enzyme immunoassay (CLEIA) for hepatitis C virus (HCV) core protein for monitoring viral kinetics during treatment with interferon (IFN)-alpha and ribavirin. Using the CLEIA, serum levels of HCV core protein were measured in 17 patients with genotype 1 and high baseline viral loads during the first 4 weeks of combination therapy. HCV RNA was measured by the Amplicor Monitor test for comparison. At the start of therapy, the median HCV level (interquartile range) was 700 (540-940) kIU/ml of viral RNA and 11,310 (5,528-14,238) fmol/L of core protein. HCV RNA was above the upper limit of the linear range of the Amplicor Monitor test in 13 of the 17 patients, while the core protein level was within the linear range of the CLEIA in all patients. During therapy, the proportion of patients with HCV levels below the cutoff values at each time point was less with the Amplicor Monitor test than with CLEIA. Serum HCV core protein level decreased rapidly during the first 24 hr of therapy and more slowly thereafter, with median exponential decays of 1.08 and 0.046 log10/day, respectively. In the second phase, between day 1 and 28, the median decrease in HCV core protein level was higher in four patients with sustained virologic response (0.13 log10/day) than in 13 patients with no response (0.028 log10/day, P = 0.042). The wide linear range of the HCV core protein assay is appropriate for measuring viral loads during therapy with IFN-alpha and ribavirin.

Kohmoto M, Enomoto M, Tamori A, Habu D, Takeda T, Kawada N, Sakaguchi H, Seki S, Shiomi S, Nishiguchi S. · Department of Hepatology, Osaka City University Medical School, Abeno-ku, Osaka, Japan. · J Med Virol. · Pubmed #15602726 No free full text.

Abstract: The usefulness of fully automated chemiluminescent microparticle immunoassay (Architect HBsAg QT) for monitoring serum levels of hepatitis B virus (HBV) during antiviral therapy remains unclear. Using this assay, hepatitis B surface antigen (HBsAg) was measured in 20 patients with chronic hepatitis B before and during lamivudine treatment. At the start of therapy, 12 patients had detectable hepatitis B e antigen (HBeAg) and 8 did not. The median serum HBV DNA level and HBsAg concentration (25th-75th centile) were 7.2 (6.1-7.8) log genome equivalents/ml and 3,932 (1,585-12,330) IU/ml, respectively. The HBsAg concentration was significantly higher in HBeAg positive than in HBeAg negative patients (P=0.031). There was a significant correlation between the HBsAg concentration and HBV DNA level (r=0.490, P=0.027). The HBsAg concentration negatively correlated with patient age (r=-0.395, P=0.085). After the start of lamivudine therapy, HBV DNA levels fell rapidly in all patients. Serum HBsAg concentrations also fell in most patients, but to a lesser extent. When drug-resistant variants emerged, serum HBsAg usually increased before biochemical breakthrough. Although HBV DNA was elevated persistently after the emergence of drug-resistant variants, the increase in HBsAg was transient. In some patients, the increase in HBsAg preceded the increase in HBV DNA. Monitoring of serum HBsAg concentrations with the use of Architect HBsAg QT, in addition to measurement of HBV DNA levels, is helpful for evaluating the response to lamivudine treatment and for the early detection of drug-resistant strains.

Seki S, Kitada T, Iwai S, Kadoya H, Yamada T, Kawada N, Sakaguchi H, Wakasa K. · Third Department of Internal Medicine, Osaka City University Medical School, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan. · Hepatogastroenterology. · Pubmed #14571717 No free full text.

Abstract: BACKGROUND/AIMS: Although Fas expression has been reported in liver with chronic viral hepatitis and primary biliary cirrhosis, little is known about Fas expression and apoptosis in type-1 autoimmune hepatitis. The aim of this study was to investigate whether the expression of Fas and apoptosis are found in liver with autoimmune hepatitis. The relationship between Fas expression and clinicopathological findings including the occurrence of apoptosis was also investigated. METHODOLOGY: Fas expression and apoptosis were immunohistochemically examined in liver tissues from 20 patients with autoimmune hepatitis and five control subjects using specific antibodies against Fas and single-stranded DNA. The grade of expression of Fas and apoptosis was evaluated and compared with histological findings and the results of liver function tests in each patient. RESULTS: Fas expression in hepatocytes was detected in all patients with autoimmune hepatitis, while Fas expression was not detected in control livers. The Fas-positive hepatocytes were particularly abundant in those areas facing piecemeal and confluent necrosis. In 30% of autoimmune hepatitis cases, bile-duct cells were faintly stained for Fas. A few hepatocytes positive for single-stranded DNA were found in the areas facing piecemeal necrosis and confluent necrosis. In 95% cases, many bile-duct cells were positive for single-stranded DNA. No relationship between the expression of Fas and single-stranded DNA was found in hepatocytes or bile-duct cells. However, the degree of Fas expression in hepatocytes significantly correlated with serum transaminase concentrations and was increased in parallel with the grade of activity but not with the stage of fibrosis. CONCLUSIONS: We have demonstrated that Fas expression is detected in hepatocytes of the liver with autoimmune hepatitis and that the level of Fas expression reflects the severity of inflammation in autoimmune hepatitis.

Fujii H, Kitada T, Yamada T, Sakaguchi H, Seki S, Hino M. · Third Department of Internal Medicine, Osaka City University Medical School, 1-4-3, Asahimachi, Abenoku, Osaka, 545-8585, Japan. · Hepatogastroenterology. · Pubmed #12828100 No free full text.

Abstract: Although mild thrombocytopenia is a common adverse effect of interferon therapy, severe life-threatening thrombocytopenia is extremely rare. Here, we report a case of chronic hepatitis C patient that developed severe thrombocytopenia during alpha-interferon therapy, possibly due to an autoimmune mechanism. A 24-year-old female presented chronic hepatitis C in May, 1998. Based on the clinicopathological findings including a liver biopsy, administration of alpha-interferon was begun. In the fourth week of therapy, she experienced mild dyspnea and general fatigue. Complete blood count demonstrated thrombocytopenia (48,000/microL). Despite the immediate withdrawal of interferon, her platelet count further decreased to 1,100/microL. Bone marrow aspirate and elevated platelet-associated IgG antibodies were suggestive of immune thrombocytopenia. She was treated with intravenous and oral administration of steroids. Her platelet count returned to normal level 5 days later. Response to steroid treatment was consistent with the diagnosis of alpha-interferon-induced immune thrombocytopenia in this patient.

Nakatani K, Seki S, Kawada N, Kitada T, Yamada T, Sakaguchi H, Kadoya H, Ikeda K, Kaneda K. · Department of Anatomy, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. · Virchows Arch. · Pubmed #12447677 No free full text.

Abstract: Secreted protein, acidic and rich in cysteine (SPARC), which functions in tissue remodeling, has been reported to be expressed by myofibroblasts in liver cirrhosis and hepatocellular carcinoma. This study aimed to reveal its expression in chronic hepatitis. Immuno-light and electron microscopy demonstrated that SPARC was expressed by nerve fibers and hepatic stellate cells (HSCs) in the liver parenchyma and myofibroblasts in the fibrous septa. Reaction products were localized in the rough endoplasmic reticulum and nuclear envelope. Serial section analysis demonstrated that SPARC, platelet-derived growth factor receptor-beta, and alpha-smooth muscle actin were co-expressed by HSCs. Quantitative analysis demonstrated that, while SPARC-positive HSCs were sparse in control livers, they significantly increased in number in the livers with chronic hepatitis. There were, however, no significant differences in number among the grades of activity, the stages of fibrosis, or etiology (virus-infected or autoimmune, hepatitis B virus or hepatitis C virus). In liver cirrhosis, however, they significantly decreased in number. The present results indicate that SPARC is expressed by activated HSCs in chronic hepatitis, suggesting the involvement of SPARC in hepatic fibrogenesis after chronic injuries.

Seki S, Kitada T, Kawada N, Kadoya H, Sakaguchi H, Nakatani K, Satake K. · Third Department of Internal Medicine, Osaka City University Medical School, 1-4-3 Asahimachi, Abenoku, 545-8585 Osaka, Japan. · Hepatogastroenterology. · Pubmed #11995446 No free full text.

Abstract: BACKGROUND/AIMS: Evidence suggesting a relationship between fatty change in normal or malignant hepatocytes and hepatitis C virus has gradually accumulated, but less is known about the relationship between cell proliferation and fatty change in human hepatocellular carcinoma. METHODOLOGY: We studied the latter issue in two human hepatocellular carcinoma cell lines (OCUH-16 and Nuk-1) derived from hepatitis C virus-associated tumors. We examined the relationship between degree of fatty change assessed by oil-red-O staining and electron microscopy, actively proliferating cells counted using a monoclonal antibody to MIB-1 protein, and apoptotic cells counted using DNA nick-end labeling in the above two hepatocellular carcinoma cell lines with time lapse. RESULTS: On day 1 in culture, fatty change was present randomly in cytoplasm of some Nuk-1 cells, but was not found in OCUH-16 cells. Over time, fat droplets were found more frequently in large hepatocellular carcinoma cells in both Nuk-1 and OCUH-16 lines. Most of these cells were located in the periphery of hepatocellular carcinoma cell nests or islands as opposed to the small hepatocellular carcinoma cells located in the centers of nests in both lines. According to MIB-1 staining, these small cells proliferate more actively than the large, peripherally located hepatocellular carcinoma cells. Only a few apoptotic hepatocellular carcinoma cells were detected during culture. CONCLUSIONS: Fatty change in large hepatocellular carcinoma cells seems to be associated with less proliferative activity than was seen in small hepatocellular carcinoma cells without fatty change, located in more centrally cell nests, in these hepatocellular carcinoma cell lines.

Kitada T, Seki S, Iwai S, Yamada T, Sakaguchi H, Wakasa K. · Third Department of Internal Medicine, Osaka City University Medical School, Abeno-ku, Osaka, 545-8585, Japan. · J Hepatol. · Pubmed #11690707 No free full text.

Abstract: BACKGROUND/AIMS: 8-Hydroxydeoxyguanosine (8-OHdG) is a promutagenic DNA lesion produced by oxygen radicals and is recognized as a useful marker in estimating DNA damage induced by oxidative stress. METHODS: Hepatic expression of 8-OHdG was immunohistochemically investigated in control and diseased human livers. RESULTS: While no positive immunolabeling for 8-OHdG was observed in control livers, 8-OHdG was widely evident in diseased livers. Nuclear expression of 8-OHdG in the hepatocytes and bile duct cells were found in various forms of chronic hepatitis. 8-OHdG-positive hepatocytes were especially abundant in the periportal area with piecemeal necrosis and prominent cell infiltration. The number of positive hepatocytes significantly increased with the progression of severity of chronic hepatitis activity (r(s)=0.68, P<0.05). In alcoholic liver disease, nuclear expression of 8-OHdG was detected in the hepatocytes in the area of alcoholic hepatitis. Regarding primary biliary cirrhosis, 8-OHdG was preferentially detected in the nuclei of injured bile ducts (11 of 12 cases, 91.7%) and occasionally (2 of 12 cases, 16.7%) in the nuclei of hepatocytes around the bile duct lesions. CONCLUSIONS: These results indicate that oxidative DNA damage is common in various forms of chronic liver disease suggesting a possible link between chronic inflammation and hepatocarcinogenesis.

Kitada T, Seki S, Ikeda K, Nakatani K, Sakaguchi H, Kawada N, Kadoya H, Kaneda K. · Third Department of Internal Medicine, Osaka City University Medical School, Japan. · J Hepatol. · Pubmed #11097483 No free full text.

Abstract: BACKGROUND/AIMS: We recently demonstrated prion as a new marker for hepatic stellate cell activation in rats. Here, we have examined prion expression in normal and diseased human livers. METHODS: Prion expression was examined at protein level by immunohistochemistry and at mRNA level by in situ hybridization. RESULTS: While normal livers were negative for prion, all liver specimens but one from patients with chronic liver disease were positively stained. In chronic hepatitis, prion protein expression was found not only in the sinusoidal lining cells within the lobules but also in mesenchymal cells in expanded portal tracts. In alcoholic liver disease, prion-positive cells were found mainly in the areas of alcoholic hepatitis. Immunoelectronmicroscopy revealed that prion-positive cells were activated stellate cells. In situ hybridization demonstrated that the distribution of prion mRNA is similar to that of prion protein. In chronic hepatitis, the number of prion-positive cells correlated with the grade of activity but not with the stage of fibrosis. In alcoholic liver disease, levels of prion protein expression were significantly increased in the presence of alcoholic hepatitis. CONCLUSION: Prion as a novel marker of activated stellate cells correlates well with disease activity in human chronic liver diseases.

Seki S, Sakaguchi H, Kitada T, Tamori A, Takeda T, Kawada N, Habu D, Nakatani K, Nishiguchi S, Shiomi S. · Third Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan. · Clin Cancer Res. · Pubmed #10999730 links to  free full text

Abstract: The number of dysplastic nodules detected clinically has increased since patients with hepatitis virus-associated cirrhosis, who are at increased risk for hepatocellular carcinoma (HCC), began to undergo regular cancer surveillance. Although it is potentially important to determine which type(s) of nodule may be prone to progress to HCC, outcomes of dysplastic nodules have not been fully investigated. This prompted us to examine the outcomes of dysplastic nodules in cirrhotic patients clinicopathologically. We studied 33 dysplastic nodules of <20 mm in maximum diameter, diagnosed by fine needle aspiration biopsy under ultrasonography (US). These nodules were clinically followed, mainly by US examination, for up to 70 months. When the nodules enlarged or exhibited changes on US, they were histologically reexamined by second biopsy. Surprisingly, 15 of the 33 nodules (45.5%) disappeared, 14 nodules (42.4%) remained unchanged, and only 4 nodules (12.1%) progressed to HCC. The latter 4 nodules were all hyperechoic on US and were composed of clear cells with fatty change or small cells with increased nuclear density, and in all 4 patients serum was positive for hepatitis C virus antibody. Univariate analyses revealed that, although not significant, the hyperechoic nodules or nodules with small cell change showed a higher HCC progression rate in comparison with the hypoechoic nodules or the nodules without small cell change. In summary, most of the dysplastic nodules we followed disappeared or remained unchanged, but some progressed to HCC. Hyperechoic nodules in patients with hepatitis C virus-associated cirrhosis, which show small cell change with increased nuclear density, may be prone to progress to HCC.