Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C

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 10⁵ μm², 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.     

Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients

BACKGROUND: Occult hepatitis B virus (HBV) infection frequently occurs in patients with HBV surface antigen (HBsAg)-negative chronic liver disease, and much evidence suggests that it is a risk factor for hepatocellular carcinoma (HCC) development. However, to the authors' knowledge, no follow-up study has been performed to date evaluating HCC occurrence over time in chronic hepatitis patients with or without occult HBV infection. METHODS: A cohort of the 380 HBsAg-negative chronic hepatitis patients attending the study institution between 1991-2000 were evaluated and tested for occult HBV DNA by analysis of liver biopsy specimens. RESULTS: There were 135 patients (35.5%) with occult HBV and 245 patients (64.5%) without occult HBV. Cirrhosis was significantly associated with occult HBV infection (P = 0.01). One hundred thirty-four of these patients were followed for a minimum of 50 months (median, 82.8 +/- 32.6 mos). Fifty-three patients (39%) were occult HBV carriers and 81 (61%) were not. Nine patients developed HCC during the follow-up; eight were positive and one was negative for occult HBV (P = 0.002). CONCLUSIONS: The current observational cohort study showed that, among the HBsAg-negative patients with chronic hepatitis, HCC develops for the most part in carriers of occult HBV. Therefore, the evaluation of HBV genomes in chronic hepatitis patients appears to be a powerful tool for the identification of individuals at higher risk of HCC development.     

Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis

BACKGROUND: Chronic hepatitis C can result in fatty changes in the liver. Previous studies have suggested that hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with hepatitis C virus (HCV) infection. The authors sought to determine whether hepatic steatosis is associated with hepatocellular carcinoma (HCC) in a cohort of patients with hepatitis C-related cirrhosis. METHODS: The authors retrospectively identified 94 consecutive patients with hepatitis C cirrhosis who underwent liver transplantation from 1992 to 2005 and had pathology available for review. Of these, 32 had evidence of HCC, and 62 had no HCC on explant histology. All explant specimens were graded again for steatosis by a single, blinded pathologist. Steatosis, age, sex, body mass index, HCV RNA, HCV genotype, Model for End-Stage Liver Disease (MELD) score, chronic alcohol use, and diabetes were examined in univariate and multivariate analyses for association with HCC. RESULTS: In total, 69% of patients in the HCC group and 50% of patients in the control group had evidence of steatosis (1+) on histology. Odds ratios for the development of HCC for each grade of steatosis compared with grade 0 were as follows: grade 1 (1.61 [0.6-4.3]), grade 2 (3.68 [1.1-12.8]), and grade 3 or 4 (8.02 [0.6-108.3]) (P = .03 for the trend). In univariate analysis, there was a significant association between increasing steatosis grade (P = .03), older age (56 years vs 49 years; P < .02), higher aspartate aminotransferase (122.5 U/L vs 91.5 U/L; P = .005), higher alanine aminotransferase (95.8 U/L vs 57.2 U/L; P = .002), higher alpha-fetoprotein (113.5 ng/mL vs 17.8 ng/mL; P < .001), lower median HCV RNA (239,000 IU/mL vs 496,500 IU/mL; P = .02), higher biologic MELD score (21.8 vs 20.3; P = .03), and risk of HCC. In multivariate analysis, age (P = .02), AFP (P = .007), and steatosis (P = .045) were significantly associated with HCC. CONCLUSIONS: In patients with HCV-related cirrhosis, the presence of hepatic steatosis is independently associated with the development of hepatocellular carcinoma. These findings suggest that steatosis poses an additional risk for HCC and that increased vigilance should be practiced in surveillance of persons with both HCV and steatosis.     

Prevention of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Chronic hepatitis B (CHB) accounts for approximately 50% of the underlying etiologies for the development of hepatocellular carcinoma (HCC) worldwide. We reviewed the primary, secondary, and tertiary measures for the prevention of HCC in CHB patients. First, the most effective method is preventing the acquisition of CHB through global vaccination of infants. However, in patients already chronically infected, antiviral treatment using interferon or nucleoside analogs can prevent disease progression to cirrhosis or HCC. Studies have found viral replications indicated by a HBV DNA level to be a strong predictor for cirrhosis and HCC, irrespective of other viral and biochemical factors. Additionally, periodic surveillance using ultrasonography and serum α-fetoprotein every 3-6 months for earlier detection of HCC is also important so that curative treatments can be used. Once HCC occurs, hepatic resection is the mainstay of curative treatments. To prevent tumor recurrence after resection, adjuvant interferon treatments have been tried with promising results based on the assumption that they not only suppress viral activity but also have tumoricidal, antiangiogenetic, and antiproliferative effects. Using nucleoside analogs also has its rationale for preventing de novo tumor development in remnant liver, considering that viral replications are a strong risk factor for HCC. Optimal preventive plans should be further investigated in future studies.     

Past exposure to hepatitis B virus as a risk factor for hepatocellular carcinoma in patients with chronic liver disease.

The aim of the study was to determine whether past exposure to hepatitis B virus (HBV) influences the risk of the development of hepatocellular carcinoma (HCC) in Japanese patients with chronic liver disease (CLD). We conducted a hospital-based case-control study of 141 HCC patients with CLD and 151 controls with CLD but without HCC. Past exposure to HBV was assessed by antibody to hepatitis B core antigen (anti-HBc) positivity. Ninety-two patients (65%) with HCC were anti-HBc positive compared with 65 patients (43%) with CLD alone (P < 0.01). A multivariate analysis using logistic regression modelling revealed that anti-HBc positivity significantly increased the risk of the development of HCC [odds ratio (OR) 2.0, P = 0.01]. In the anti-HBc-positive patients, a significantly increased risk of HCC was seen among the patients positive for anti-HBc alone (OR, 2.6; P < 0.01). However, a significant OR was not obtained among the patients with a transient HBV infection implied by positivity for both antibody to hepatitis B surface antigen and anti-HBc (OR, 1.5; P = 0.48). These results indicate that past exposure to HBV is a risk factor for HCC in Japanese CLD patients, especially when they have no serological evidence of immunity to HBV.     

Direct acting antivirals therapy and hepatocellular carcinoma risk in patients with hepatitis C virus

The estimated number of people with active hepatitis C virus infection worldwide is about 70 million. The estimated number of people with active hepatitis C vir...     

Clinical significance of prior hepatitis B virus infection in patients with hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND: The effect of prior hepatitis B virus (HBV) infection on the clinicopathologic findings for patients with hepatitis C virus (HCV) RNA and hepatocellular carcinoma (HCC) is still unclear. METHODS: Of 59 patients who underwent liver resection for HCV-related HCC (相似文献   

High prevalence of hepatitis C virus infection in schistosomiasis japonica patients associated with hepatocellular carcinoma

Schistosomiasis japonica (SCJ) patients frequently develop hepatocellular carcinoma (HCC). This study investigated relationship between SCJ infection, hepatitis virus infection, and incidence of HCC, in 25 patients with chronic SCJ infection and HCC (SCJ with HCC group), 51 patients with chronic SCJ infection without HCC (SCJ group) and 65 HCC patients without SCJ (HCC group). Number of patients who were positive to HBsAg or hepatitis B virus DNA were 4 (16.0%) in the SCJ with HCC group, none (0%) in the SCJ group, and 5 (7.9%) in the HCC group; while number of patients who were positive to anti-hepatitis C virus antibody were 21 (87.5%) in the SCJ with HCC group, 3 (5.9%) in the SCJ group, and 58 (84.6%) in the HCC group. Biopsy was performed for all patients, and background histological features of each specimen were evaluated based on the histological activity index scoring system. Mean scores of inflammatory changes in both the portal area and parenchyma in the SCJ with HCC group were significantly higher than those in the SCJ group. Nodular formation which is common in post-viral hepatitis was frequently observed in the SCJ with HCC group, and histological changes in non-cancerous area of the SCJ with HCC group showed the characteristics of chronic viral hepatitis. We conclude that infection of hepatitis virus, particularly hepatitis C virus, affects synergistically on the hepatocarcinogenesis in patients having SCJ infection.     

Expression of bile duct-type cytokeratin in hepatocellular carcinoma in patients with hepatitis C virus and prior hepatitis B virus infection

The clinicopathologic findings in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) positive for biliary markers, those related to the hepatic progenitor cells, were investigated. Cytokeratin (CK) 19 was reactive for HCCs only in patients with prior hepatitis B virus (HBV) infection. The proportions of patients with prior HBV infection and poorly differentiated HCC were significantly higher among those with CK 19-positive HCC than among those with CK 19-negative HCC. Some HCCs develop from the hepatic progenitor cells in patients with HCV infection and prior HBV infection, which may affect the clinicopathologic findings of HCV-related HCCs.     

MDM2 promoter SNP309 is associated with the risk of hepatocellular carcinoma in patients with chronic hepatitis C.

PURPOSE: A single nucleotide polymorphism (SNP) in the promoter region of MDM2 gene, SNP309, has recently been shown to be associated with accelerated tumor formation in both hereditary and sporadic cancers in humans. However, the association of SNP309 with hepatocellular carcinoma is unknown. We evaluated the association of SNP309 with the risk of hepatocellular carcinoma development among Japanese patients with chronic hepatitis C virus infection. EXPERIMENTAL DESIGN: We genotyped the SNP309 at the MDM2 promoter in 435 Japanese patients with chronic hepatitis C virus infection, including 187 patients with hepatocellular carcinoma and 48 healthy subjects, using a fluorogenic PCR. Presence of SNP was also confirmed by direct sequencing of the MDM2 promoter region. RESULTS: The proportion of G/G genotype of the SNP309 in patients with hepatocellular carcinoma (33%) was significantly higher than that in patients without hepatocellular carcinoma (23%), with an odds ratio (95% confidence interval) of 2.28 (1.30-3.98). A multivariate analysis revealed that MDM2 SNP309 (G/G versus T/T), age >60 years, male gender, presence of cirrhosis, serum alpha-fetoprotein >20 mug/L, and serum albumin <3.2 g/dL were independently associated with the hepatocellular carcinoma development at odds ratio of 2.27, 2.46, 3.08, 4.15, 4.87, and 6.33, respectively. CONCLUSIONS: The MDM2 promoter SNP309 is associated with the presence of hepatocellular carcinoma in Japanese patients with chronic hepatitis C.     

Analysis of the complete hepatitis B virus genome in patients with genotype C chronic hepatitis and hepatocellular carcinoma

Hepatitis B virus (HBV) genotype C and the basic core promoter (BCP) mutations were reported to be associated with the development of hepatocellular carcinoma (HCC). In this study the full sequences of HBV genomes were analyzed in order to find the other predictors of HCC development. We determined the full sequences of HBV genomes in 24 genotype C carriers who developed HCC (HCC group) at the beginning of follow-up and at the time of HCC diagnosis, and 20 patients who did not develop HCC (non-HCC group) served as a control. The number of nucleotide and amino acid substitutions in most regions was higher in the HCC group than in the non-HCC group, and the following substitutions and deletions were found more frequently in the HCC group than in the non-HCC group: G1317A and T1341C/A/G in the X promoter region were detected in 13 and six of the HCC cases, four and none of the non-HCC cases, respectively; and pre-S2 deletion was detected in eight HCC and none of the non-HCC cases. Compared with the wild type X promoter, the mutant type X promoters, M1 (G1317A), M2 (T1341C), and M4 (T1341G) showed increases in activity of 2.3, 3.8, and 1.4 times, respectively, in HepG2 cells. Substitutions and deletion of nucleotides of the HBV genome, especially the pre-S2 deletion and G1317A and T1341C/A/G mutations may be useful markers for predicting the development of HCC. ( Cancer Sci 2007; 98: 1921–1929)     

Association of hepatitis B virus infection with hepatocellular carcinoma in American patients

Thirty-four patients from the Philadelphia area with hepatocellular carcinoma (HCC) were matched with colon cancer patients, lung cancer patients and blood donors according to age and sex. Sera from the four groups were tested to determine the prevalence of hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). Five of the HCC patients (14.7%) and none of the controls were positive for HBsAg. At least one of the three serologic markers of hepatitis B virus (HBV) infection was found in 51.5% of the HCC patients, 5.3% of the colon cancer patients, 11.1% of the lung cancer patients, and 10.7% of the blood donors. Twelve of the seventeen seropositive HCC patients (70.6%) were positive for anti-HBc alone, while all of the seropositive lung cancer patients and donors were positive for anti-HBs alone. Sera positive for any HBV marker were also tested for e antigen (HBeAg) and its antibody (anti-HBe). Four of the HCC patients (23.5% of the seropositives) had anti-HBe, while none of the sera tested had HBeAg. A history of alcoholism did not appear to influence HBV seropositivity in the HCC patients. This study supports the hypothesis that HBV infection is closely associated with HCC even in areas where both conditions are uncommon. The wide disparity between seropositivity for HBsAg and anti-HBc in the HCC patients is an unusual feature, for which an age effect may be the best explanation.     

Impact of epidermal growth factor single‐nucleotide polymorphism on recurrence of hepatocellular carcinoma after hepatectomy in patients with chronic hepatitis C virus infection

Epidermal growth factor (EGF) gene single‐nucleotide polymorphism (SNP) is associated with an increased risk of hepatic tumors. The study aimed to elucidate the impact of EGF SNP and EGF receptor (EGFR) expression on the recurrence of hepatocellular carcinoma (HCC) after hepatectomy. To examine the impact of EGF SNP and EGFR on recurrent HCC, we retrospectively analyzed 141 HCC patients with chronic hepatitis C virus infection who underwent curative hepatectomy. The EGF *61 GG allele was present in 69 patients (48.9%), AG in 56 (39.7%) and AA in 16 (11.4%). The AA group had a significantly lower rate of intrahepatic metastasis (0% vs 16.5%, P = 0.02), lower serum EGF concentration (26.3 ± 15.9 pg/mL vs 43.4 ± 30.5 pg/mL, P = 0.02) and lower proportion of early recurrence (≤2 years; 28.6% vs 71.2%, P = 0.03) than the AG/GG group. The AA group had significantly higher recurrence‐free survival than the AG/GG group (P = 0.04), but there was no significant difference in overall survival between these two groups (P = 0.97). High versus low EGFR expression analyzed by immunohistochemical staining in cancer cells was not significantly associated with overall survival (P = 0.37) or recurrence‐free survival (P = 0.39). Therefore, EGF *61 AA was associated with a lower risk of recurrence after curative hepatectomy for HCC in patients with hepatitis C virus infection than other genotypes, but EGFR expression in cancer cells was not significantly associated with prognosis.     

Activity of sulfotransferase 1A1 is dramatically upregulated in patients with hepatocellular carcinoma secondary to chronic hepatitis B virus infection

The phase I metabolizing enzyme and phase II metabolizing enzyme play vital roles in carcinogenesis, but little is known about the changes of their activities in patients with hepatocellular carcinoma (HCC) secondary to chronic hepatitis B virus (HBV) infection. In this study phenacetin, a probe drug (1 g for men and 0.85 g for women orally), was applied for the detection of sulfotransferase 1A1 (SULT1A1) and cytochrome P4501A2 (CYP1A2) activities in 82 healthy participants and 148 HCC, 106 cirrhosis, and 41 chronic hepatitis B patients. In addition, a prospective cohort study for susceptibility to HCC was performed in 205 patients with cirrhosis secondary to chronic HBV infection. Compared with the healthy participants, SLUT1A1 activity increased by 9.7‐fold in the HCC patients (P < 0.01). CYP1A2 activity did not significantly differ between the healthy participants and HCC patients. CYP1A2 activity decreased by 91.2% (P < 0.01) and 67.7% (P < 0.05) in the patients with cirrhosis and chronic hepatitis B, respectively; SULT1A1 activity did not increase significantly. During an approximate 2‐year follow up, three of the 46 cirrhosis patients with elevated SULT1A1 activity and normal CYP1A2 activity developed HCC, but none of the 159 cirrhosis patients used as parallel controls did (P = 0.012). These results indicate that SLUT1A1 activity is dramatically upregulated in patients with HCC secondary to chronic HBV infection. The upregulation of SULT1A1 activity is not caused by the tumor itself. The interaction between SULT1A1 and CYP1A2 can play an important role in hepatocarcinogenesis in the Chinese population. (Cancer Sci 2009)     

Interferon for decreasing the incidence of hepatocellular carcinoma in patients with chronic hepatitis C

The incidence of hepatocellular carcinoma (HCC) in Japan has kept increasing during the past few decades. Persistent infection with hepatitis C virus (HCV) is the single most frequent cause of HCC in Japan at present. Interferon is the only reliable means of eradicating HCV infection, and by inference, preventing HCC associated with it. Since interferon is not effective in all the patients with chronic hepatitis C, it needs to be used with utmost discretion. The incidence of HCC is decreased not only in the patients who respond to interferon completely, accompanied by the loss of HCV RNA from serum, but also in those who obtain normal levels of aminotransferase while HCV persists after interferon. The patients who poorly respond to interferon need to be treated by other means of suppressing necroinflammatory processes in chronic hepatitis C, which is expected to retard the development of HCC.     

Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy

Background:

Interferon (IFN)-based therapies could eradicate hepatitis C (HCV) and reduce the risk of hepatocellular carcinoma (HCC). However, HCC could still happen after sustained virological response (SVR). We aimed to develop a simple scoring system to predict the risk of HCC development among HCV patients after antiviral therapies.

Methods:

From 1999 to 2009, 1879 patients with biopsy-proven HCV infection treated with IFN-based therapies were analyzed.

Results:

Multivariable analysis showed old age (adjusted HR (aHR)=1.73, 95% CI=1.13–2.65 for aged 60–69 and aHR=2.20, 95% CI=1.43–3.37 for aged ⩾70), Male gender (aHR=1.74, 95% CI=1.26–2.41), platelet count <150 × 10⁹/l (HR=1.91, 95% CI=1.27–2.86), α-fetoprotein ⩾20 ng ml⁻¹ (HR=2.23, 95% CI=1.58–3.14), high fibrotic stage (HR=3.32, 95% CI=2.10–5.22), HCV genotype 1b (HR=1.53, 95% CI=1.10–2.14), and non SVR (HR=2.40, 95% CI=1.70–3.38) were independent risk factors for HCC. Regression coefficients were used to build up a risk score and the accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC). Three groups as low-, intermediate-, and high-risk are classified based on the risk scores. One hundred sixty patients (12.78%) in the derivation and 82 patients (13.08%) in the validation cohort developed HCC with AUC of 79.4%, sensitivity of 84.38%, and specificity of 60.66%. In the validation cohort, the 5-year HCC incidence was 1.81%, 12.92%, and 29.95% in low-, intermediate-, and high-risk groups, with hazard ratios 4.49 in intermediate- and 16.14 in high-risk group respectively. The risk reduction of HCC is greatest in patients with SVR, with a 5-year and 10-year risk reduction of 28.91% and 27.99% respectively.

Conclusion:

The risk scoring system is accurate in predicting HCC development for HCV patients after antiviral therapies.     

Transition of antibody to hepatitis C virus from chronic hepatitis to hepatocellular carcinoma

Fifty-eight patients with chronic hepatitis C were followed for more than 7 years. Of them, 10 patients were found to develop hepatocellular carcinoma, 14 to develop liver cirrhosis, 30 to sustain chronic hepatitis, and 4 to show subsidence of hepatitis. Antibody to hepatitis C virus (anti-HCV) disappeared from the 4 patients whose hepatitis subsided, but it persisted in the remaining 54 patients. The mean titer of anti-HCV was almost the same at the stages of chronic hepatitis and of cancer in the 10 patients who developed hepatocellular carcinoma. These results indicate that chronic infection of hepatitis C virus may lead to hepatocellular carcinoma.     

Glycemic load in relation to hepatocellular carcinoma among patients with chronic hepatitis infection

BackgroundChronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are of paramount etiologic importance for hepatocellular carcinoma (HCC), but other factors are likely to be important. The association of diabetes mellitus and obesity with HCC raises the possibility that dietary glycemic load (GL) may interact with chronic hepatitis infection in the causation of HCC.Patients and methodsWe conducted a case–control study of 333 HCC patients and 360 controls in Athens, Greece. Third-generation assays were used to determine chronic HBV and HCV infection and information from a semiquantitative food frequency questionnaire to estimate dietary GL.ResultsAfter adjustment for possible confounding factors through multiple logistic regression, we found a nonsignificant positive association between GL and HCC, which was exclusively accounted for by a positive association between GL and HCC cases with chronic infection with hepatitis B and/or C. For the latter group of patients, the odds ratio at the highest compared with the lowest GL quintile was 1.95 (95% confidence interval 1.09–3.48). The association was strengthened after exclusion of subjects with diabetes.ConclusionOur results indicate that, among patients with chronic infection with HBV and/or HCV, reduction of dietary GL could reduce risk or delay development of HCC.