8-hydroxy-2--deoxyguanosine and Hepatitis-C--Chronic

Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established.. We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera.. Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p<0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation.. Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients.. UMIN 000001031.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Deoxyguanosine; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis C, Chronic; Humans; Interferon-alpha; Iron Metabolism Disorders; Leukocytes, Mononuclear; Liver; Liver Neoplasms; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Oxidative Stress; Polyethylene Glycols; Proportional Hazards Models; Recombinant Proteins; Ribavirin; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome

Coffee is associated with a reduced risk of hepatocellular carcinoma in patients with chronic C hepatitis. This prospective trial was aimed at assessing the mechanisms underlying coffee-related protective effects.. Forty patients with chronic hepatitis C were randomized into two groups: the first consumed 4 cups of coffee/day for 30 days, while the second remained coffee "abstinent". At day 30, the groups were switched over for a second month.. At baseline, aspartate aminotransferase and alanine aminotransferase were lower in patients drinking 3-5 (Group B) than 0-2 cups/day (Group A) (56 ± 6 vs 74 ± 11/60 ± 3 vs 73 ± 7 U/L p=0.05/p=0.04, respectively). HCV-RNA levels were significantly higher in Group B [(6.2 ± 1.5) × 10(5)vs (3.9 ± 1.0) × 10(5)UI/mL, p=0.05]. During coffee intake, 8-hydroxydeoxyguanosine and collagen levels were significantly lower than during abstinence (15 ± 3 vs 44 ± 16 8-hydroxydeoxyguanosine/10(5)deoxyguanosine, p=0.05 and 56 ± 9 vs 86 ± 21 ng/mL, p=0.04). Telomere length was significantly higher in patients during coffee intake (0.68 ± 0.06 vs 0.48 ± 0.04 Arbitrary Units, p=0.006). Telomere length and 8-hydroxydeoxyguanosine were inversely correlated.. In chronic hepatitis C coffee consumption induces a reduction in oxidative damage, correlated with increased telomere length and apoptosis, with lower collagen synthesis, factors that probably mediate the protection exerted by coffee with respect to disease progression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Alanine Transaminase; Aspartate Aminotransferases; Caffeine; Coffee; Collagen; Cross-Over Studies; Deoxyguanosine; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Male; Middle Aged; Prospective Studies; RNA, Viral; Telomere

Eicosapentaenoic acid (EPA) has been shown to exert anti-inflammatory actions. To evaluate the effects of EPA on chronic hepatitis C, we administered EPA ethyl ester capsules to patients receiving the combination therapy of interferon alpha-2b and ribavirin. EPA (1,800 mg/d) was supplemented in combination with vitamin E (300 mg/d) and C (600 mg/d) to 5 chronic hepatitis C patients (EPA group). Five patients were administered vitamin E and C but not EPA (control group). Blood samples were obtained before and after 4, 8, 12 and 24 wk of therapy and analyzed for fatty acid compositions of erythrocyte and plasma and serum 8-hydroxy-2'-deoxyguanosine. EPA in erythrocyte membrane rose to 3 fold the basal level in the EPA group, while it decreased significantly in the control group after 24 wk of therapy. Lymphocyte counts in the EPA group increased to 120.8 +/- 25.4% after 4 wk of therapy and maintained the basal level throughout therapy, whereas the counts decreased significantly in controls. The serum alanine aminotransferase level was improved significantly in the EPA group. Changes in lymphocyte counts following 24 wk of therapy correlated with the EPA level in erythrocyte. The serum 8-hydroxy-2'-deoxyguanosine level at 24 wk in the EPA group was significantly lower than that in controls. These observations may suggest the beneficial effect of EPA supplementation in the treatment of chronic hepatitis C patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Deoxyguanosine; Dietary Supplements; Eicosapentaenoic Acid; Erythrocyte Membrane; Erythrocytes; Fatty Acids; Fatty Acids, Unsaturated; Female; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lymphocyte Count; Male; Middle Aged; Phospholipids; Recombinant Proteins; Ribavirin

Accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA, which may result from the continuous reactive oxygen species (ROS) generation associated with chronic inflammation, has been reported in various human preneoplastic lesions and in cancerous tissues. However, no direct causative relationship between the 8-OHdG formation and carcinogenesis has been thus far demonstrated in humans. Directly proving the causality requires showing that depletion of 8-OHdG levels in tissue by interfering with ROS generation results in a reduction in cancer. Chronic hepatitis C virus (HCV) infection is associated with a high risk of hepatocellular carcinoma (HCC). Several studies on patients with chronic HCV have shown that hepatic iron overload is attributable to liver injury and that iron depletion improved serum aminotransferase levels. Excess iron is known to generate ROS within cells, which causes mutagenic lesions, such as 8-OHdG. In this study, therefore, we have evaluated whether therapeutic iron reduction (phlebotomy and low iron diet) with a long-term follow-up (6 years) would decrease the hepatic 8-OHdG levels and the risk of HCC development in patients with chronic HCV. Patients (34) enrolled were those who had undergone standard IFN therapy but had no sustained response. Quantitative immunohistochemistry using the KS-400 image analyzing system and electrochemical detection was used for 8-OHdG detection. With this treatment, elevated hepatic 8-OHdG levels in patients with chronic hepatitis C (8.3 +/- 4.6/10(5) dG) significantly decreased to almost normal levels (2.2 +/- 0.9/10(5) dG; P < 0.001) with concomitant improvement of hepatitis severity, including fibrosis, whereas HCV titers were unaffected. None of these patients developed HCC. Thus, long-term iron reduction therapy in patients with chronic hepatitis C may potentially lower the risk of progression to HCC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Deoxyguanosine; Female; Ferritins; Hepatitis C, Chronic; Humans; Iron; Iron, Dietary; Liver; Male; Middle Aged; Phlebotomy

Free iron in the liver is believed to facilitate the formation of reactive oxygen species (ROS), including hydroxyl radicals (*OH), which cause oxidative damage of numerous cellular components such as lipids, proteins, and nucleic acids, and also upregulate collagen synthesis. The *OH radical is known to generate promutagenic bases such as 8-hydroxy-2-deoxyguanosine (8-OHdG). In cases with chronic hepatitis C, long-term iron reduction therapy reduced the activity of hepatitis, suppressed fibrosis, and prevented hepatocarcinogenesis. In nonalcoholic steatohepatitis (NASH) livers, hepatic iron accumulation as well as oxidative DNA damage significantly increased. Humoral factor(s) in NASH serum may upregulate DMT1 expression in small intestine. Iron reduction therapy for NASH patients has a potential to reduce disease activity as well as hepatic oxidative damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; Hepatitis C, Chronic; Humans; Iron; Jejunum; Non-alcoholic Fatty Liver Disease; Oxidative Stress

The significance of antibodies to cardiolipin (anti-CL) remains uncertain in patients with chronic hepatitis C (CH-C). The main purpose of this study was to elucidate the clinical characteristics of patients with CH-C seropositive for anti-CL. The prevalence of anti-CL and clinical parameters associated with anti-CL in those patients were examined. Six of the 45 (13%) patients with CH-C had anti-CL. However, none of these six CH-C patients fulfilled the criteria for antiphospholipid syndrome. Serum triglyceride and apolipoprotein B (ApoB) levels in CH-C patients with anti-CL were significantly higher than those in CH-C patients without anti-CL. Serum triglyceride levels positively correlated with serum ApoB levels. CH-C patients with anti-CL had significantly more progressive hepatic fibrosis than those without anti-CL. The degree of 8-hydroxy 2'-deoxyguanosine (8-OHdG) expression in the liver tissue was more severe in CH-C patients with anti-CL than in those without it. However, the emergence of anti-CL in CH-C patients was independent of insulin resistance, hepatic steatosis, and iron overload. These findings suggest that the emergence of anti-CL is associated with oxidative stress and that CH-C patients seropositive for anti-CL have clinical characteristics of hypertriglyceridemia, which derives from the facilitation of ApoB synthesis, and progressive hepatic fibrosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antibodies, Anticardiolipin; Apolipoproteins B; Deoxyguanosine; Fatty Liver; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; Histocytochemistry; Humans; Liver; Male; Middle Aged; Prevalence; Triglycerides

To determine whether alteration of the mitochondria DNA (mtDNA) copy number and its oxidative damage index (mtDNA(∆CT)) can be detected by analysis of peripheral blood cells in hepatitis C virus (HCV)-infected patients.. This study enrolled two groups of patients aged 40-60 years: a control group and an HCV-infected group in Department of Gastroenterology and Hepatology in Changhua Christian Hospital. Patients with co-infection with hepatitis B virus or human immunodeficiency virus, autoimmune disease, malignant neoplasia, pregnancy, thyroid disease, or alcohol consumption > 40 g/d were excluded. HCV-infected patients who met the following criteria were included: (1) positive HCV antibodies for > 6 mo; (2) alanine aminotransferase (ALT) levels more than twice the upper limit of normal on at least two occasions during the past 6 mo; and (3) histological fibrosis stage higher than F1. The mtDNA copy number and oxidative damage index of HCV mtDNA (mtDNA(∆CT)) were measured in peripheral blood leukocytes. The association between mtDNA copy number and mtDNA(∆CT) was further analyzed using clinical data.. Forty-seven normal controls (male/female: 26/21, mean age 50.51 ± 6.15 years) and 132 HCV-infected patients (male/female: 76/61, mean age 51.65 ± 5.50 years) were included in the study. The genotypes of HCV-infected patients include type 1a (n = 3), type 1b (n = 83), type 2a (n = 32), and type 2b (n = 14). Liver fibrosis stages were distributed as follows: F1/F2/F3/F4 = 1/61/45/25 and activity scores were A0/A1/A2/A3 = 7/45/55/25. There were no age or gender differences between the two groups. HCV-infected patients had higher hepatitis activity (aspartate transaminase levels 108.77 ± 60.73 vs 23.19 ± 5.47, P < 0.01; ALT levels 168.69 ± 93.12 vs 23.15 ± 9.45, P < 0.01) and lower platelet count (170.40 ± 58.00 vs 251.24 ± 63.42, P < 0.01) than controls. The mtDNA copy number was lower in HCV-infected patients than in controls (173.49 vs 247.93, P < 0.05). The mtDNA(∆CT) was higher in HCV-infected patients than in controls (2.92 vs 0.64, P < 0.05). To clarify the clinical significance of these results in HCV-infected patients, their association with different clinical parameters among HCV-infected patients was analyzed. A negative association was found between mtDNA copy number and elevated aspartate transaminase levels (r = -0.17, P < 0.05). Changes in mtDNA copy number were not associated with HCV RNA levels, HCV genotypes, liver fibrosis severity, or inflammatory activity in the liver biopsy specimen. However, a correlation was observed between mtDNA(∆CT) and platelet count (r = -0.22, P < 0.01), HCV RNA level (r = 0.36, P < 0.01), and hepatitis activity (r = 0.20, P = 0.02). However, no difference in the change in mtDNA(∆CT) was observed between different fibrosis stages or HCV genotypes.. Oxidative stress and mtDNA damage are detectable in patient's peripheral leukocytes. Increased leukocyte mtDNA(∆CT) correlates with higher HCV viremia, increased hepatitis activity, and lower platelet count.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Deoxyguanosine; DNA Damage; DNA, Mitochondrial; Female; Gene Dosage; Hepatitis C, Chronic; Humans; Male; Middle Aged; Oxidative Stress; RNA, Viral

Anisonucleosis is defined as a morphological manifestation of nuclear injury characterized by variation in the size of the cell nuclei. It has been described in variety of benign conditions and is most pronounced in dysplasia and malignancy. To better understand the pathogenesis of anisonucleosis in liver diseases, this study focused on hepatocyte anisonucleosis in biopsies of liver transplant recipients who developed recurrent chronic hepatitis C virus (HCV) infection. Post transplant surveillance liver biopsy specimens were evaluated employing light microscopy, immunohistochemistry, digital image analysis, and nucleometry for histopathological analyses, measurement of nuclear size, and quantification of tissue expression of oxidative marker 8-hydroxy-2'deoxyguanosine (8-OHdG). Our aim in this study was to determine whether there were any independent associations between hepatocyte anisonucleosis and various clinicopathological parameters. These features included patient age, body mass index, gender, race, donor age, live versus cadaveric donor status, history of diabetes mellitus, history of tacrolimus and cyclosporine therapy, duration post transplant and parameters of hepatitis activity index, fibrosis index, steatosis, and oxidative tissue damage in formalin fixed paraffin embedded (FFPE) liver biopsies as determined by immunohistochemistry using 8-OHdG, an indicator of hydroxyl radical mediated tissue damage. Our findings suggested that in liver transplant recipients with recurrent chronic HCV infection, hepatocyte anisonucleosis is more pronounced in individuals with diabetes mellitus (p = 0.0016), and among those who have heightened hepatic expression of the oxidative damage marker 8-OHdG (p = 0.0053). Further studies are necessary to determine whether anisonucleosis is an independent marker for diabetes or oxidative damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Aged; Biopsy; Cell Nucleus; Deoxyguanosine; Diabetes Mellitus; Female; Hepatitis C, Chronic; Hepatocytes; Humans; Image Interpretation, Computer-Assisted; Immunohistochemistry; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Oxidative Stress; Young Adult

Liver steatosis and hepatic oxidative stress are the histopathological features of chronic hepatitis C. Hepatitis C virus (HCV) genotype 1 core protein induces hepatic steatosis and reactive oxygen species production in transgenic mice. The amino acid substitutions in the HCV core region appear to be related to hepatocarcinogenesis.. The aim of this study was to clarify the impact of mutations in the HCV core region on oxidative stress and lipid metabolism in patients with chronic hepatitis C.. Sixty-seven patients (35 men, 32 women; mean age, 58.4 +/- 10.2 years) with chronic hepatitis C with high titres (>5 log IU/ml) were enrolled. Substitutions in amino acids 70, 75 and 91 of the HCV genotype 1b core region, the percentage of hepatic steatosis, and hepatic 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were investigated in all patients. Urinary 8-OHdG levels were measured in 35 patients.. Body mass index, alanine aminotransferase, gamma-glutamyl transferase, and triglyceride levels and substitutions of amino acid 70/Q (glutamine) were significantly associated with the presence of steatosis on univariate analysis. Multivariate analysis showed that substitution of amino acid 70 of glutamine and triglyceride levels were the independent factors related to liver steatosis. Hepatic and urinary 8-OHdG levels were significantly higher in patients with methionine at amino acid 91 of the HCV core region than in those with leucine.. Substitutions in the amino acids of the HCV genotype1b core region are associated with hepatic steatosis and oxidative stress in patients with chronic hepatitis C.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Amino Acid Substitution; Antiviral Agents; Biopsy, Needle; Cohort Studies; Deoxyguanosine; Fatty Liver; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Immunohistochemistry; Liver Function Tests; Logistic Models; Male; Middle Aged; Multivariate Analysis; Oxidative Stress; Polymerase Chain Reaction; Prognosis; Retrospective Studies; Risk Assessment; RNA, Viral; Severity of Illness Index; Statistics, Nonparametric; Viral Core Proteins

Increased production of reactive oxygen species, which cause oxidative DNA damage, is considered to be related to hepatocarcinogenesis. 8-Hydroxy-2'-deoxy-guanosine (8-OHdG) is a useful marker of DNA damage induced by oxidative stress. The aim of this study was to determine whether expression of 8-OHdG is a risk factor for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection.. The expression of 8-OHdG in liver biopsy specimens was assessed immunohistochemically. In total, 104 patients with chronic HCV infection who were diagnosed on liver biopsy between January 1987 and December 2002 were studied retrospectively. Univariate and multivariate analyses using age, gender, habitual drinking, tobacco exposure, diabetes mellitus, serum alanine aminotransferase level, HCV genotype, hepatic fibrosis, inflammation, steatosis, and 8-OHdG expression in liver biopsy specimens were conducted to identify factors related to the development of HCC.. On multivariate analysis, 8-OHdG and fibrosis were independent and significant risk factors for HCC development (relative risk, 2.48; P = 0.023; relative risk, 5.35; P = 0.001, respectively). Furthermore, the cumulative incidence rate of HCC in 39 patients with high 8-OHdG expression levels was significantly greater than that in 65 patients with low 8-OHdG expression levels (P = 0.043). In addition, liver 8-OHdG expression was correlated with hepatic inflammation.. 8-OHdG is a risk factor for the development of HCC in patients with chronic HCV infection. Patients with chronic HCV who express 8-OHdG should be monitored carefully for the development of HCC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers, Tumor; Biopsy; Carcinoma, Hepatocellular; Deoxyguanosine; DNA Damage; Female; Hepatitis C, Chronic; Humans; Incidence; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Oxidative Stress; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Up-Regulation

Although the oxidative stress frequently occurs in patients with chronic hepatitis C, its role in future hepatocellular carcinoma (HCC) development is unknown. Hepatic 8-hydroxydeoxyguanosine (8-OHdG) was quantified using liver biopsy samples from 118 naïve patients who underwent liver biopsy from 1995 to 2001. The predictability of 8-OHdG for future HCC development and its relations to epidemiologic, biochemical and histological baseline characteristics were evaluated. During the follow-up period (mean was 6.7+/-3.3 years), HCC was identified in 36 patients (30.5%). Univariate analysis revealed that 16 variables, including 8-OHdG counts (65.2+/-20.2 vs 40.0+/-23.5 cells per 10(5) microm2, P<0.0001), were significantly different between patients with and without HCC. Cox proportional hazard analysis showed that the hepatic 8-OHdG (P=0.0058) and fibrosis (P=0.0181) were independent predicting factors of HCC. Remarkably, 8-OHdG levels were positively correlated with body and hepatic iron storage markers (vs ferritin, P<0.0001 vs hepatic iron score, P<0.0001). This study showed that oxidative DNA damage is associated with increased risk for HCC and hepatic 8-OHdG levels are useful as markers to identify the extreme high-risk subgroup. The strong correlation between hepatic DNA damage and iron overload suggests that the iron content may be a strong mediator of oxidative stress and iron reduction may reduce HCC incidence in patients with chronic hepatitis C.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Carcinoma, Hepatocellular; Deoxyguanosine; DNA Damage; Female; Hepatitis C, Chronic; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Oxidative Stress; Reactive Oxygen Species

8-Hydroxydeoxyguanosine (8-OHdG) is a promutagenic DNA lesion produced by hydroxyl radicals and is recognized as a useful marker in estimating DNA damage induced by oxidative stress. The aim of this study was to clarify the clinical significance of hepatic 8-OHdG levels in patients with chronic viral hepatitis. Hepatic 8-OHdG accumulation was investigated in patients with chronic hepatitis C (CH-C) (n = 77) and chronic hepatitis B (CH-B) (n = 34) by immunohistochemical staining of liver biopsy samples. 8-OHdG positive hepatocytes were significantly higher in patients with CH-C compared to CH-B (median 55.0 vs 18.8 cells/10(5) mum(2), P < 0.0001). The number of positive hepatocytes significantly increased with the elevation of serum aminotransferase levels, especially in CH-C patients (8-OHdG vs alanine aminotransferase (ALT)/aspartate aminotrasferase (AST) were r = 0.738/0.720 in CH-C and 0.506/0.515 in CH-B). 8-OHdG reactivity was strongly correlated with body and hepatic iron storage markers in CH-C (vs serum ferritin, r = 0.615; vs hepatic total iron score, r = 0.520; vs hepatic hepcidin mRNA levels, r = 0.571), although it was related to serum HBV-DNA titers (r = 0.540) and age of patients (r = -0.559) in CH-B. These results indicate that hepatic oxidative DNA damage is common in chronic viral hepatitis, in particular chronic HCV-infected patients, suggesting a possible link between chronic hepatic inflammation and hepatocarcinogenesis. The strong positive correlation between hepatic DNA damage and iron overload suggests that iron content is one of the most likely mediators of hepatic oxidative stress and iron reduction may be beneficial to reduce the incidence of hepatic cancer in CH-C patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Aspartate Aminotransferases; Deoxyguanosine; DNA Damage; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Iron Overload; Liver; Male; Middle Aged; Oxidative Stress

Hepatic oxidative stress occurs in chronic hepatitis C (CH-C), but little is known about its producing mechanisms and precise role in the pathogenesis of the disease. To determine the relevance of hepatic oxidatively generated DNA damage in CH-C, 8-hydroxy-2'-deoxyguanosine (8-OHdG) adducts were quantified in liver biopsy specimens by immunohistochemical staining, and its relationship with clinical, biochemical, and histological parameters, and treatment response was assessed in 40 CH-C patients. Hepatic 8-OHdG counts were significantly correlated with serum transaminase levels (r=0.560, p=0.0005) and histological grading activity (p=0.0013). Remarkably, 8-OHdG levels were also significantly related to body and hepatic iron storage markers (vs serum ferritin, r=0.565, p=0.0004; vs hepatic total iron score, r=0.403, p=0.0119; vs hepatic hepcidin messenger RNA, r=0.516, p=0.0013). Baseline hepatic oxidative stress was more prominent in nonsustained virological responder (non-SVR) than in SVR to interferon (IFN)/ribavirin treatment (50.8 vs 32.7 cells/10(5) microm2, p=0.0086). After phlebotomy, hepatic 8-OHdG levels were significantly reduced from 53.4 to 21.1 cells/10(5) microm2 (p=0.0125) with concomitant reductions of serum transaminase and iron-related markers in CH-C patients. In conclusion, this study showed that hepatic oxidatively generated DNA damage frequently occurs and is strongly associated with increased iron deposition and hepatic inflammation in CH-C patients, suggesting that iron overload is an important mediator of hepatic oxidative stress and disease progression in chronic HCV infection.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Alanine Transaminase; Antimicrobial Cationic Peptides; Antiviral Agents; Aspartate Aminotransferases; Deoxyguanosine; DNA Adducts; DNA Damage; Drug Therapy, Combination; Female; Ferritins; Hepatitis C, Chronic; Hepcidins; Humans; Interferons; Iron Overload; Liver; Male; Middle Aged; Oxidative Stress; Ribavirin

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; Guanine; Hepatitis C, Chronic; Homeostasis; Humans; Immunohistochemistry; Iron; Iron Overload; Iron, Dietary; Liver; Phlebotomy

Nucleic acid damage by reactive nitrogen and oxygen species may contribute to inflammation-related carcinogenesis. To investigate the extent of nucleic acid damage in hepatitis C virus infection and its change after interferon treatment, we measured 8-nitroguanine and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the liver of patients with chronic hepatitis C (CHC) before and after interferon therapy.. Hepatic accumulation of 8-nitroguanine and 8-OHdG was immunohistochemically evaluated in 20 CHC patients and 7 control patients with non-alcoholic fatty liver.. Immunoreactivities of 8-nitroguanine and 8-OHdG were strongly detected in the liver from patients with CHC, but not in control livers. 8-Nitroguanine accumulation was found not only in infiltrating inflammatory cells, but also hepatocytes particularly in the periportal area. The accumulation of 8-nitroguanine and 8-OHdG increased with inflammatory grade (8-nitroguanine; P = 0.0019, 8-OHdG; P = 0.0009). In the sustained virological responder group after interferon therapy, 8-nitroguanine and 8-OHdG accumulation were markedly decreased in the liver (8-nitroguanine; P = 0.018, 8-OHdG; P = 0.018).. In this study, we demonstrated for the first time that 8-nitroguanine accumulated in the liver of patients with CHC. 8-Nitroguanine is a useful biomarker to evaluate the severity of HCV-induced chronic inflammation in relation to hepatocellular carcinoma.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Carcinoma, Hepatocellular; Deoxyguanosine; DNA Damage; Female; Guanine; Hepatitis C, Chronic; Humans; Inflammation; Liver; Liver Neoplasms; Male; Middle Aged; Reactive Oxygen Species

Oxidative stress (OS) plays a major role in chronic hepatitis C. Various OS markers have been found to be elevated in hepatitis C virus (HCV)-related liver disease. This study detected the presence of OS in serum and liver biopsy specimens of HCV patients. Reactive oxygen molecules (ROM) in sera of 54 HCV patients were compared with 23 controls. OS markers 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal, malondialdehyde, and thioredoxin were measured in liver biopsy specimens of 18 HCV patients with fibrosis staging F1 (six); F2 (two), F3 (four), and F4 (six). The interferon (IFN) response and hepatocellular carcinoma (HCC) occurrence in the presence of OS markers were also evaluated. The level of ROM in HCV patients was 318 +/- 56.7 Carr compared with 248 +/- 40.8 Carr in controls (p=0.032). Multivariate analysis found age (p=0.0236) to be the only independent variable associated with increase in ROM in sera. In liver biopsy specimens, OS markers were found mainly around the area of piecemeal necrosis or the periportal area. The presence of OS markers seemed to increase with fibrosis staging, although not significantly. The OS DNA damage marker 8-OHdG was detected in the nucleus of hepatocytes. Thirteen patients received IFN therapy. During the 4-year follow-up period, HCC developed in four nonresponders to IFN and in one untreated patient. OS markers were stained in both HCC cells and non-HCC cells in HCC patients. OS markers were found in serum and liver specimens of HCV-associated liver disease and in HCC tissue. Detection of OS markers may be important for monitoring disease progression in HCV patients. Antioxidant therapy in combination with antiviral therapy may minimize liver damage and aid in the prevention and subsequent development of HCC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age Factors; Aldehydes; Biomarkers; Carcinoma, Hepatocellular; Deoxyguanosine; Disease Progression; Female; Hepatitis C, Chronic; Humans; Immunohistochemistry; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Malondialdehyde; Oxidative Stress; Reactive Oxygen Species; Thioredoxins

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.. Hepatic expression of 8-OHdG was immunohistochemically investigated in control and diseased human livers.. 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.. 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.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Bile Duct Diseases; Biomarkers; Deoxyguanosine; DNA Damage; Hepatitis; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunohistochemistry; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Liver Diseases, Alcoholic; Middle Aged; Mitotic Index; Necrosis; Oxidation-Reduction

Chronic hepatitis C virus (HCV) infection is associated with an increased production of reactive oxygen species within the liver that are responsible for the oxidation of intracellular macromolecules. To ascertain whether the increased risk of hepatocellular carcinoma in individuals with chronic HCV infection is related to an accumulation of oxidative DNA damage, the 8-hydroxydeoxyguanosine (8-OHdG) content in the DNA of liver tissue and leukocytes of 87 individuals with HCV- or HBV-related liver disease and of 10 healthy controls was measured. Serum levels of thiobarbituric acid reactive substances (TBARS) were also assessed as an index of lipid peroxidation.. The 8-OHdG content in the circulating leukocytes correlated with that of liver tissue (r = 0.618, p < .0004). HCV patients had the highest median 8-OHdG levels (p < .0004). 8-OHdG leukocyte levels in HCV patients were higher than in HBV patients (p < .04) and they significantly correlated with the clinical diagnosis (p < .025), the serum ferritin levels (p < .05), and the amount of liver steatosis (p < .001). No correlation was found with age, gender, history of drinking or smoking, ALT or GGT levels, ESR, alpha-1, or gamma-globulin level and Ishak score. TBARS levels were significantly higher in cirrhotics than in noncirrhotics (p < .01).. The 8-OHdG level in circulating leukocytes is a reliable marker of oxidative stress occurring in the liver of individuals with chronic HCV infection. DNA oxidative damage appears to be an early and unique event in the natural history of HCV-related hepatitis. This injury increases the risk of genomic damage and may be one of the important factors involved in the carcinogenic process in cases of HCV-related chronic liver disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Deoxyguanosine; DNA; DNA Damage; Fatty Liver; Female; Ferritins; Hepatitis C, Chronic; Humans; Leukocytes; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Middle Aged; Oxidation-Reduction; Thiobarbituric Acid Reactive Substances