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ABSTRACT: Several lines of evidence have suggested that oxidative stress plays an important role for the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, by using immunohistochemical staining of liver biopsy samples, we measured hepatic 7,8-dihydro-8-oxo-2' deoxyguanosine (8-oxodG), a DNA base-modified product generated by hydroxyl radicals, of 38 NASH patients and compared with 24 simple steatosis and 10 healthy subjects. Relation of hepatic 8-oxodG with clinical, biochemical, and histologic variables and changes after iron reduction therapy (phlebotomy plus iron-restricted diet) were also examined. Hepatic 8-oxodG levels were significantly higher in NASH compared with simple steatosis (17.5 versus 2.0 8-oxodG-positive cells/10(5) microm(2); P < 0.0001). 8-oxodG was significantly related to iron overload condition, glucose-insulin metabolic abnormality, and severities of hepatic steatosis in NASH patients. Logistic regression analysis also showed that hepatic iron deposit and insulin resistance were independent variables associated with elevated hepatic 8-oxodG. After the iron reduction therapy, hepatic 8-oxodG levels were significantly decreased (from 20.7 to 13.8 positive cells/10(5) microm(2); P < 0.01) with concomitant reductions of serum transaminase levels in NASH patients. In conclusion, iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH.
Cancer Epidemiology Biomarkers & Prevention 02/2009; 18(2):424-32. · 4.12 Impact Factor
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Ryosuke Sugimoto,
Naoki Fujita,
Naohisa Tomosugi,
Nagisa Hara,
Hirohide Miyachi,
Hideaki Tanaka,
Masaki Takeo, Naoki Nakagawa,
Motoh Iwasa,
Yoshinao Kobayashi,
Masahiko Kaito,
Yoshiyuki Takei
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ABSTRACT: Aim: This study was conducted to determine the clinical relevance of hepcidin, a recently identified key iron regulatory hormone, in patients with chronic hepatitis C virus (C-HCV). Methods: Serum hepcidin levels were measured in 9 C-HCV patients by surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS), and compared to those of healthy controls. Sequential changes of hepcidin were also investigated during phlebotomy. Results: Serum hepcidin and ferritin were significantly higher in C-HCV than in controls (P = 0.0002), these two variables were strongly related to each other (r = 0.658; P < 0.01), and phlebotomy significantly decreased serum hepcidin in C-HCV (P = 0.0007); all these results recollect the hepcidin response to iron signal. Hepcidin/ferritin ratio, an index of the appropriateness of hepcidin expression relative to iron overload, was significantly lower in C-HCV than in controls (0.33 +/- 0.41 vs. 0.73 +/- 0.36, P = 0.0068). This relative impairment of hepcidin expression was not reversible after phlebotomy (P = NS). Conclusions: Although the hepcidin expression responds to iron conditions in C-HCV, this response is relatively limited. This relative impairment of hepcidin expression may be relevant to disease progression, and thus correction of its regulation may be beneficial for these iron-overloaded C-HCV patients.
Hepatology Research 02/2009; 39(6):619-24. · 2.20 Impact Factor
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Masayoshi Konishi,
Motoh Iwasa,
Jun Araki,
Yoshinao Kobayashi,
Akira Katsuki,
Yasuhiro Sumida, Naoki Nakagawa,
Yuji Kojima,
Shozo Watanabe,
Yukihiko Adachi,
Masahiko Kaito
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ABSTRACT: Oxidative stress plays an important role in the pathogenesis of chronic liver diseases. The plasma level of 8-isoprostane, a product of lipid peroxidation, is a marker of oxidative stress in vivo. The aim of the present study was to clarify whether the degree of lipid peroxidation, as measured by the plasma level of 8-isoprostane, influences the progression of chronic liver diseases and hepatocarcinogenesis.
Plasma 8-isoprostane levels were investigated in 14 patients with non-alcoholic fatty liver disease (NAFLD), 75 with chronic hepatitis C (CH-C), 14 with cured CH-C, 14 with HCV-positive hepatocellular carcinoma (HCC-C) and 38 healthy volunteers. 8-Isoprostane was measured by enzyme immunoassay after affinity column purification.
Plasma 8-isoprostane was significantly elevated in NAFLD (11.9 [3.8-56.8] pg/mL), CH-C (10.1 [4.2-134.5] pg/mL) as compared to controls (6.3 [3.6-11.1] pg/mL). Plasma 8-isoprostane values were positively correlated with body mass index in NAFLD (P < 0.05) and with total cholesterol in cured CH-C (P < 0.01). 8-Isoprostane levels were not significantly related to sex, age, biochemical data or iron metabolism markers in all liver diseases. In addition, after the administration of peg-interferon, the values of 8-isoprostane improved in almost all patients, reaching values of healthy subjects.
8-Isoprostane values are elevated in patients with NAFLD and CH-C as compared to healthy controls. Oxidative stress caused by increased lipid peroxidation is involved in the pathogenesis of NAFLD and CH-C.
Journal of Gastroenterology and Hepatology 12/2006; 21(12):1821-5. · 2.87 Impact Factor
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Journal of Gastroenterology 10/2006; 41(9):921-2. · 4.16 Impact Factor
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ABSTRACT: The intravenous administration of interferon-beta may be effective for the treatment of chronic hepatitis C, as is intramuscular interferon-beta. We compared the efficacy and safety of twice-a-day versus once-a-day of natural interferon-beta for the initial treatment of patients with chronic hepatitis C.
Forty-nine patients with chronic hepatitis C, with less than 5 Meq/mL serum hepatitis C virus-RNA, were randomly assigned into one of the two treatment groups A and B and treated with natural interferon-beta following two different protocols. Twenty-two patients were treated with twice-a-day interferon-beta (3 MU) for 3 weeks followed by once-a-day interferon-beta (6 MU) for 5 weeks (group A), and 20 patients were treated with once-a-day interferon-beta (6 MU) for 8 weeks (group B). Seven patients did not complete the treatment protocol. Efficacy was assessed by measuring the serum levels of hepatitis C virus-RNA and aminotransferase.
The rate of sustained virological response was significantly higher in group A (14 of 22 patients, 63.6%) than in group B (6 of 20 patients, 30.0%) (P < 0.05). Among patients with hepatitis C virus-RNA level less than 1 Meq/mL, the sustained virological response rate was significantly higher in group A (13 of 15 patients, 86.7%) than in group B (5 of 12 patients, 41.7%) (P < 0.05). However, the sustained virological response rate in patients with hepatitis C virus levels more than 1 Meq/mL was not significantly different between group A (1 of 7 patients, 14.3%) and group B (1 of 8 patients, 12.5%).
Twice-a-day interferon-beta therapy is more effective than once-a-day interferon-beta for the treatment of chronic hepatitis C patients with hepatitis C virus-RNA levels less than 1 Meq/mL.
Hepato-gastroenterology 50(51):775-8. · 0.66 Impact Factor
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ABSTRACT: Measurement of des-gamma-carboxy prothrombin by conventional methods is of limited use for the early detection of hepatocellular carcinoma for its low sensitivity. The aim of the present study was to investigate the usefulness of measuring des-gamma-carboxy prothrombin by a highly sensitive assay for the early diagnosis of hepatocellular carcinoma in patients with chronic liver disease and for the detection of recurrence after treatment of hepatocellular carcinoma.
Des-gamma-carboxy prothrombin levels by a sensitive assay and alpha-fetoprotein levels were sequentially measured in 188 patients with type B or C chronic liver disease and in 63 patients with hepatocellular carcinoma.
The positive rate of des-gamma-carboxy prothrombin was 62% in all of hepatocellular carcinoma patients. Hepatocellular carcinoma was detected in 14 of 188 chronic liver disease patients during their follow-up period, the positive rate of des-gamma-carboxy prothrombin and of alpha-fetoprotein being 57% and 71% in these 14 patients, respectively. Des-gamma-carboxy prothrombin level normalized in 67% of 39 patients after the treatment of hepatocellular carcinoma. Of the 19 patients with tumor recurrence, 84% showed re-elevation of des-gamma-carboxy prothrombin level.
Measurement of des-gamma-carboxy prothrombin by this highly sensitive assay combined with alpha-fetoprotein is useful for detecting hepatocellular carcinoma in chronic liver disease patients and for monitoring recurrence after treatment of hepatocellular carcinoma.
Hepato-gastroenterology 49(43):235-8. · 0.66 Impact Factor
