non-HCC Group Research Articles

High hepatitis B virus load is associated with hepatocellular carcinomas development in Chinese chronic hepatitis B patients: a case control study

BackgroundPersistent hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC) development. This study aimed to clarify whether the high HBV DNA level is associated with HCC development by comparing HBV DNA levels between HBV infected patients with and without HCC.ResultsThere were 78 male and 12 female patients in each group and there was no statistical difference between these two group patients' average ages. The HBV DNA level in the HCC patients was 4.73 ± 1.71 Log10 IU/ml while 3.90 ± 2.01 Log10 IU/ml in non-HCC patients (P < 0.01). The HBeAg positive rate was 42.2% (38/90) in the HCC group while 13.3% (12/90) in the non-HCC group (P < 0.001). Compared with patients with HBV DNA level of < 3 Log10 IU/ml, the patients with level of 3 to < 4, 4 to < 5, 5 to < 6, or ≥ 6 Log10 IU/ml had the odds ratio for HCC of 1.380 (95% CI, 0.544-3.499), 3.671 (95% CI, 1.363-9.886), 5.303 (95% CI, 1.847-15.277) or 3.030 (95% CI, 1.143-8.036), respectively.ConclusionsHBV-related HCC patients had higher HBV DNA level than non-HCC counterparts. Our findings imply that active HBV replication is associated with the HCC development.

Assessment of disease progression in patients with transfusion-associated chronic hepatitis C using transient elastography.

To evaluate the relationship between liver stiffness and duration of infection in blood transfusion-associated hepatitis C virus (HCV) patients with or without hepatocellular carcinoma (HCC). Between December 2006 and June 2008, a total of 524 transfusion-associated HCV-RNA positive patients with or without HCC were enrolled. Liver stiffness was obtained noninvasively by using Fibroscan (Echosens, Paris, France). The date of blood transfusion was obtained by interview. Duration of infection was derived from the interval between the date of blood transfusion and the date of liver stiffness measurement (LSM). Patients were stratified into four groups based on the duration of infection (17-29 years; 30-39 years; 40-49 years; and 50-70 years). The difference in liver stiffness between patients with and without HCC was assessed in each group. Multiple linear regression analysis was used to determine the factors associated with liver stiffness. A total of 524 patients underwent LSM. Eight patients were excluded because of unsuccessful measurements. Thus 516 patients were included in the current analysis (225 with HCC and 291 without). The patients were 244 men and 272 women, with a mean age of 67.8 ± 9.5 years. The median liver stiffness was 14.3 kPa (25.8 in HCC group and 7.6 in non-HCC group). The patients who developed HCC in short duration of infection were male dominant, having lower platelet count, with a history of heavier alcohol consumption, showing higher liver stiffness, and receiving blood transfusion at an old age. Liver stiffness was positively correlated with duration of infection in patients without HCC (r = 0.132, P = 0.024) but not in patients with HCC (r = -0.103, P = 0.123). Liver stiffness was significantly higher in patients with HCC than in those without in each duration group (P < 0.0001). The factors significantly associated with high liver stiffness in multiple regression were age at blood transfusion (P < 0.0001), duration of infection (P = 0.0015), and heavy alcohol consumption (P = 0.043). Although liver stiffness gradually increases over time, HCC develops in patients with high stiffness value regardless of the duration of infection.

Hepatocellular carcinoma in Budd-Chiari syndrome: A single center experience with long-term follow-up in South Korea

To evaluate long-term clinical course of Budd-Chiari syndrome (BCS) and predictive factors associated with the development of hepatocellular carcinoma (HCC) and survival. We analyzed 67 patients with BCS between June 1988 and May 2008. The diagnosis of BCS was confirmed by hepatic venous outflow obstruction shown on abdominal ultrasound sonography, computed tomography, magnetic resonance imaging, or venography. The median follow-up period was 103 ± 156 [interquartile range (IQR)] mo. The median age of the patients was 47 ± 16 (IQR) years. At diagnosis, 54 patients had cirrhosis, 25 (37.3%) Child-Pugh class A, 23 (34.3%) Child-Pugh class B, and six (9.0%) patients Child-Pugh class C. During the follow-up period, HCC was developed in 17 patients, and the annual incidence of HCC in patients with BCS was 2.8%. Patients in HCC group (n = 17) had higher hepatic venous pressure gradient (HVPG) than those in non-HCC group (n = 50) (21 ± 12 mmHg vs 14 ± 7 mmHg, P = 0.019). The survival rate of BCS patients was 86.2% for 5 years, 73.8% for 10 years, and 61.2% for 15 years. In patients with BCS and HCC, survival was 79% for 5 years, 43.1% for 10 years, and 21.5% for 15 years. The incidence of HCC in patients with BCS was similar to that in patients with other etiologic cirrhosis in South Korea. The HVPG is expected to provide additional information for predicting HCC development in BCS patients.

Clinical course of sub-centimeter-sized nodules detected during surveillance for hepatocellular carcinoma

To evaluate the outcome of sub-centimeter-sized nodules (SCSNs) detected during surveillance for hepatocellular carcinoma (HCC) in patients at risk. We retrospectively analyzed a total of 142 patients with liver cirrhosis or chronic hepatitis B or C without a prior history of HCC in whom a SCSN was detected during HCC surveillance. We calculated the rate of HCC development from SCSNs in the study population and analyzed the differences in the baseline clinical characteristics and imaging features between the patients with SCSNs that eventually developed into HCC and patients with SCSNs that did not develop into HCC. During 667 person-years of follow-up, HCC developed in 33 patients. The calculated HCC development rate was 4.9% per year. The cumulative one-, two-, three- and five-year HCC development rates were 5.6%, 10.6%, 14.1% and 20.4%, respectively. Upon baseline comparison, the HCC group was older (54.4 ± 8.3 years vs 48.9 ± 9.4 years; P = 0.003) and had lower albumin levels (3.56 ± 0.58 g/dL vs 3.84 ± 0.55 g/dL; P = 0.012) and higher baseline alpha-fetoprotein (AFP) levels (8.5 ng/mL vs 5.4 ng/mL; P = 0.035) compared to the non-HCC group. Nodule pattern and initial radiologic diagnosis also differed between the two groups. Multivariate analysis revealed that age [P = 0.012, odds ratio (OR) =1.075, 95% confidence interval (CI) =1.016-1.137], sex (P = 0.009, OR = 3.969, 95% CI: 1.403-11.226), and baseline AFP level (P = 0.024, OR = 1.039, 95% CI: 1.005-1.073) were independent risk factors for developing HCC. The overall risk of HCC development in patients with SCSNs is similar to that in liver cirrhosis patients. Patients with these risk factors need to be closely monitored during follow-up.

Hepatitis B virus core promoter mutations G1613A and C1653T are significantly associated with hepatocellular carcinoma in genotype C HBV-infected patients

BackgroundHepatitis B virus (HBV) is a major cause of hepatocarcinogenesis.To identify mutations relevant to hepatocellular carcinoma (HCC) development, we compared the full genome sequences of HBV from the sera of patients with and without HCC.MethodsWe compared the full genome sequences of HBV isolates from 37 HCC patients (HCC group 1) and 38 patients without HCC (non-HCC group 1). We also investigated part of the core promoter region sequences from 40 HCC patients (HCC group 2) and 68 patients without HCC. Of the 68 patients who initially did not have HCC, 52 patients remained HCC-free during the follow-up period (non-HCC group 2), and 16 patients eventually developed HCC (pre-HCC group 2). Serum samples collected from patients were subjected to PCR, and the HBV DNA was directly sequenced.ResultsAll patients had genotype C. A comparison of the nucleotide sequences of the HBV genome between HCC group 1 and non-HCC group 1 revealed that the prevalence of G1613A and C1653T mutations in the core promoter region was significantly higher in the HCC group. These mutations tended to occur simultaneously in HCC patients. Multivariate analysis with group 2 revealed that the presence of HCC was associated with aging and the double mutation. Future emergence of HCC was associated with aging and the presence of a single G1613A mutation.ConclusionsG1613A and C1653T double mutations were frequently found in patients with HCC. A single G1613A mutation was associated with future emergence of HCC. These mutations may serve as useful markers in predicting HCC development.

Suppressive effects of entecavir on hepatitis B virus and hepatocellular carcinoma

We investigated the efficacy and effectiveness of entecavir in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. We enrolled 231 nucleoside-naïve chronic hepatitis B (CHB) patients primarily treated with entecavir 0.5 mg/day for at least 6 months in our institution. Of these, 71 patients had HCC at the start of entecavir treatment (HCC group) and 160 did not (non-HCC group). We compared antiviral responses to entecavir in the two groups, and evaluated the effects of entecavir on the clinical outcomes of curatively-treated HCC patients. The HCC and non-HCC groups had similar cumulative rates of HBV-DNA negativity, alanine aminotransferase normalization, and hepatitis e antigen loss in year 2 (100% vs 95.4%, 94.7% vs 97.3%, and 40.8% vs 41.8%, respectively; P > 0.05). Entecavir treatment for 12 months decreased mean Model for End-Stage Liver Disease scores in patients with cirrhosis and HCC (7.2 vs 5.6, P < 0.001). Of the 71 HCC patients, 16 underwent curative therapies concurrently with entecavir; hepatectomy in six and radiofrequency ablation in 10, and the 55 remaining patients received transarterial chemoembolization or conservative treatment. In a subgroup of 16 HCC patients receiving curative treatments, patients who became serum HBV DNA negative by week 24 had better overall survival (P = 0.039), but not recurrence-free survival (P = 0.961), than those who did not. First-line entecavir monotherapy is comparably effective in CHB patients with and without HCC, and improves hepatic function in HBV-related HCC patients. An early virological response to entecavir is prognostic of improved survival following curative therapy against HBV-related HCC.

Combination of preS Deletions and A1762T/G1764A Mutations in HBV Subgenotype C2 Increases the Risk of Developing HCC

Background: The interactions among hepatitis B virus (HBV) mutations in developing hepatocellular carcinoma (HCC) remain unclear and thus we investigated the risk of HCC related with single or multiple HBV mutations in Korean patients infected with HBV subgenotype C2. Methods: From January 2003 to December 2008, HBV isolates from 135 patients with HCC were compared with those from 135 patients without HCC, matching for age, gender, and HBeAg status. The prevalence of preS deletions and G1896A and A1762T/G1764A mutations was evaluated. Results: The frequency of preS deletions significantly differed between the non-HCC and HCC groups, with 6 (4.4%) versus 25 (18.5%) patients, respectively (p < 0.001). Additionally, the frequency of A1762T/G1764A mutations was higher in the HCC than the non-HCC group [82 (60.7%) versus 30 (22.2%), p < 0.001]. For combined mutations, the odds ratio (OR) was highest in patients with both preS deletions and the A1762T/G1764A mutation, with 1 (0.7%) versus 11 (8.1%) patients (p = 0.005; OR 11.887). Conclusions: HCC was associated with preS deletions and A1762T/G1764A mutations, and the combination of both mutations had a stronger association with HCC in Korean patients infected with HBV subgenotype C2.

Analysis of viral amino acids sequences and the IL28B SNP influencing the development of hepatocellular carcinoma in chronic hepatitis C

The association between hepatitis C virus (HCV) sequences with interleukin 28B (IL28B) single-nucleotide polymorphism (SNP) in the development of hepatocellular carcinoma (HCC) has not been well clarified. Complete HCV open-reading frame sequences were determined in 20 patients developing HCC and 23 non-HCC patients with HCV-1b infection in two distant time points. An additional 230 patients were studied cross-sectionally for core and NS5A sequences with HCC development. Among them, 98 patients with available samples were investigated for changes in viral core sequences over time. Finally, IL28B SNPs and HCC development were investigated in 228 patients. During observation period (HCC for 10.8years, and non-HCC for 11.1years), changes in core a.a. 70 and three amino acid positions in NS5A were characteristics of the patients developing HCC. In 230 patients, Q (glutamine) or H (histidine) to R (arginine) ratio at core a.a. 70 was significantly higher in the HCC group (HCC group 43:22 vs. non-HCC group 66:99, p=0.001). A change in core R70Q was observed over time in 11 patients associated with a decrease in platelets (p=0.005) and albumin (p=0.005), while a Q70R change was observed in 4 patients without associated changes in platelets (nonsignificant) and albumin (nonsignificant). IL28B SNP showed significant correlation with the core a.a. 70 residue. There was no evident link between IL28B SNPs and the occurrence of HCC. Hepatitis C virus core a.a. 70 residue is associated with liver disease progression and is independent factor for HCC development in genotype-1b infection. IL28B SNPs are related to core a.a. 70 residue, but not to HCC. The functional relevance of core a.a. 70 residue in hepatitis C pathogenesis should be further investigated.

A case–control study on sequence variations in the enhancer II/core promoter/precore and X genes of hepatitis B virus in patients with hepatocellular carcinoma

To evaluate the sequence variations in the enhancer II (EnhII)/basal core promotor (BCP)/precore (PC) and X genes of hepatitis B virus (HBV) in Thai patients with hepatocellular carcinoma (HCC) by conducting a cross-sectional case-control study. As much as 60 patients with HCC and 60 patients without HCC, who were matched for sex, age, hepatitis B e antigen (HBeAg) status, and HBV genotype, were included. Viral mutations in the EnhII/BCP/PC and X regions were characterized by direct sequencing in serum samples. The prevalence of T1753C/A, A1762T/G1764A and G1899A mutations were significantly higher in the HCC group compared to the non-HCC group (43.3 vs. 23.3%, P=0.02; 88.3 vs. 53.0%, P<0.001; and 35.0 vs. 8.3%, P=0.001, respectively). No significant difference between groups was found with respect to G1613A, C1653T, C1766T/T1768A, A1846T/C, T1858C, and G1896A mutations. By multiple logistic regression analysis, the presence of cirrhosis, A1762T/G1764A and G1899A mutations were independently associated with the risk of HCC. These data suggested that A1762T/G1764A and G1899A mutations were associated with the development of HCC in Thai patients.

Hepatitis B virus BCP, precore/core, X gene mutations/genotypes and the risk of hepatocellular carcinoma in India

The study aims to characterize mutations of the HBV genome involving BCP, Precore/core and X regions and also defines HBV genotypes in patients of hepatocellular carcinoma (HCC). The study involved 150 HBV-related HCC cases and 136 HBV-related chronic liver disease patients without HCC as controls. HBV DNA was subjected to mutational analysis using SSCP technique, genotyping by RFLP, and direct nucleotide sequencing. HBV DNA was found in 58.7% (88/150) of the HCC cases and 74.3% (101/136) of controls. HBV mutants were observed in 44.3% of HCC cases and 43.2% of controls. HBV/D was prevalent amongst the patients and controls, followed by HBV/A. The prevalence of the TT1504 mutation in the X gene, the V1753 and T1762/A1764 mutations in the BCP region, and G1914 mutation in the core gene were significantly higher in the HCC group than in the non-HCC group. Multivariate analyses showed that the TT1504, V1753, A1762T/G1764A, and the G1914 mutations and the patient's age, sex, and HBeAg status increased the risk of HCC development significantly. Also, patients with HCC had lower levels of serum albumin, viral load, and platelet counts but higher values of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, and Alpha feto-protein than those of controls (P < 0.001 for all comparisons). HBV/D was the predominant genotype associated with HCC cases seen in India. The presence of different types of HBV mutations, age, sex, HBeAg status, and viral load was found to increase significantly the risk of HCC development in India.

Identification of three potential biomarkers in early resectable hepatocellular carcinoma.

4131 Background: Current surveillance programs employing routine serum alpha-fetoprotein and abdominal ultrasound for patients at-risk for HCC have not demonstrated significant improvement in patient clinical outcome due to their low sensitivity and specificity. The aim of this study was to identify novel serum biomarkers that might potentially improve on the current surveillance modalities. Methods: Serum proteins of 58 patients with surgically resected HCC (39 patients stage I and 19 patients stage III) and 11 non-HCC patients with chronic hepatitis B were profiled using RayBio L-Series 507 Antibody Array that simultaneously detects the levels of 507 proteins. To validate the data from the L-Series 507 array analysis, significantly modulated markers in the array analysis were quantified using multiplex sandwich ELISA. All samples were run in triplicates and analysis was repeated at least once. The results were compared with clinico-pathological parameters. Results: We identified three novel biomarkers confirmed by ELISA, namely TIMP-4, MCP-1 and Prolactin, which were all significantly overexpressed in the resected HCC patients compared to the non-HCC group. The lower limit of detection were 2.4 ng/mL (Prolactin), 72 pg/mL (TIMP-4) and 18 pg/mL (MCP-1). The median serum concentrations in non-HCC patients were 14.49 ng/mL, 1.36 ng/mL and 628 pg/mL compared to 47.95 ng/mL (p = 0.0003), 5.73 ng/mlL(p < 0.0001) and 1,099.2 pg/mL (p = 0.002) in the stage I HCC. The concentrations were further elevated to 56.12 ng/mL (p = 0.0001), 6.76 ng/mL (p < 0.0001) and 1240.6 pg/mL (p = 0.001) in the stage III HCC. TIMP-4 and MCP-1 were significantly higher in patients with larger tumors (p = 0.02 and p = 0.009 respectively). Elevated levels of all three novel biomarkers above median cut-off value portend a poorer relapse-free survival in resected HCC patients (p = 0.02). TIMP4 levels above median cut-off was also associated with reduction in relapse-free survival (p = 0.05). No association was noted between serum levels of TIMP- 4, MCP-1 and Prolactin with liver cirrhosis or inflammation. Conclusions: These serum proteins can be useful as complementary biomarkers for early detection of HCC in patients at-risk and may play a role in liver carcinogenesis. No significant financial relationships to disclose.

220 STEREOTACTIC BODY RADIATION THERAPY ON PORTAL VEIN TUMOR THROMBUS OF HEPATOCELLULAR CARCINOMA

Background and Aims: Lamivudine had comparable antiviral effects both in patients with chronic hepatitis B (CHB) and hepatits B virus (HBV)-related hepatocellular carcinoma (HCC). We aimed to investigate the antiviral and antitumoural effects of entecavir (ETV) in HBV-related HCC patients. Methods: From January 2007 to December 2007, 271 chronically HBV-infected patients were primarily treated with ETV 0.5mg/day for at least 6 months in our institution. Among these, 94 had HCC at the initiation of ETV treatment (HCC group) and 177 did not (non-HCC group). We compared antiviral responses to ETV between the two groups, and also evaluated the influence of ETV on post-treatment outcomes of HCC. Results: At baseline, the HCC group was older, and had higher Child–Pugh score and liver cirrhosis rate than the non-HCC group (all P < 0.05). 33% of the HCC group and 62% of the nonHCC group were positive for Hepatitis B e antigen (HBeAg) (P < 0.05). There were no differences in serum HBV DNA and alanine aminotransferase (ALT) levels between the two groups. The cumulative rates of HBV DNA negativity (<300 copies/ml), ALT normalization, and HBeAg loss at 48 weeks were similar for both groups (86.2%, 85.1% and 43.8%, respectively for the HCC group and 81.4%, 87.6% and 36.4%, respectively for the non-HCC group). After 48 weeks, the HCC group showed significant decreases in mean Child–Pugh and MELD scores, compared with baseline (6.9 vs. 5.8 and 10.1 vs. 8.7, respectively; both P < 0.001). Of the 94 HCC patients, 33 received curative therapies for HCC, simultaneously with ETV: hepatectomy in 9 and radiofrequency ablation in 24. For these subgroup, median recurrence-free survival was 27.9 months in the 21 patients who achieved HBV DNA negativity at week 24, significantly longer than 17.6 months in those who did not (27.9 vs. 17.6 months, P = 0.01), similar to overall survival (P = 0.067): all pretreatment characteristics of patients and tumors did not differ. Conclusions: First-line ETV was comparably efficacious in either CHB patients with or without HCC. ETV treatment improved hepatic function in HCC patients, and early virological response to ETV markedly produced a delay of post-treatment recurrence of HCC.

219 ASSESSMENT OF THE LIVER FUNCTION OF THE NAIVE PATIENT WITH HEPATOCELLULAR CARCINOMA OVER 80 YEARS OLD

Background and Aims: Lamivudine had comparable antiviral effects both in patients with chronic hepatitis B (CHB) and hepatits B virus (HBV)-related hepatocellular carcinoma (HCC). We aimed to investigate the antiviral and antitumoural effects of entecavir (ETV) in HBV-related HCC patients. Methods: From January 2007 to December 2007, 271 chronically HBV-infected patients were primarily treated with ETV 0.5mg/day for at least 6 months in our institution. Among these, 94 had HCC at the initiation of ETV treatment (HCC group) and 177 did not (non-HCC group). We compared antiviral responses to ETV between the two groups, and also evaluated the influence of ETV on post-treatment outcomes of HCC. Results: At baseline, the HCC group was older, and had higher Child–Pugh score and liver cirrhosis rate than the non-HCC group (all P < 0.05). 33% of the HCC group and 62% of the nonHCC group were positive for Hepatitis B e antigen (HBeAg) (P < 0.05). There were no differences in serum HBV DNA and alanine aminotransferase (ALT) levels between the two groups. The cumulative rates of HBV DNA negativity (<300 copies/ml), ALT normalization, and HBeAg loss at 48 weeks were similar for both groups (86.2%, 85.1% and 43.8%, respectively for the HCC group and 81.4%, 87.6% and 36.4%, respectively for the non-HCC group). After 48 weeks, the HCC group showed significant decreases in mean Child–Pugh and MELD scores, compared with baseline (6.9 vs. 5.8 and 10.1 vs. 8.7, respectively; both P < 0.001). Of the 94 HCC patients, 33 received curative therapies for HCC, simultaneously with ETV: hepatectomy in 9 and radiofrequency ablation in 24. For these subgroup, median recurrence-free survival was 27.9 months in the 21 patients who achieved HBV DNA negativity at week 24, significantly longer than 17.6 months in those who did not (27.9 vs. 17.6 months, P = 0.01), similar to overall survival (P = 0.067): all pretreatment characteristics of patients and tumors did not differ. Conclusions: First-line ETV was comparably efficacious in either CHB patients with or without HCC. ETV treatment improved hepatic function in HCC patients, and early virological response to ETV markedly produced a delay of post-treatment recurrence of HCC.

218 SUPPRESSIVE EFFECTS OF ENTECAVIR ON VIRAL REPLICATION AND TUMOR PROLIFERATION IN PATIENTS WITH HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA

Background and Aims: Lamivudine had comparable antiviral effects both in patients with chronic hepatitis B (CHB) and hepatits B virus (HBV)-related hepatocellular carcinoma (HCC). We aimed to investigate the antiviral and antitumoural effects of entecavir (ETV) in HBV-related HCC patients. Methods: From January 2007 to December 2007, 271 chronically HBV-infected patients were primarily treated with ETV 0.5mg/day for at least 6 months in our institution. Among these, 94 had HCC at the initiation of ETV treatment (HCC group) and 177 did not (non-HCC group). We compared antiviral responses to ETV between the two groups, and also evaluated the influence of ETV on post-treatment outcomes of HCC. Results: At baseline, the HCC group was older, and had higher Child–Pugh score and liver cirrhosis rate than the non-HCC group (all P < 0.05). 33% of the HCC group and 62% of the nonHCC group were positive for Hepatitis B e antigen (HBeAg) (P < 0.05). There were no differences in serum HBV DNA and alanine aminotransferase (ALT) levels between the two groups. The cumulative rates of HBV DNA negativity (<300 copies/ml), ALT normalization, and HBeAg loss at 48 weeks were similar for both groups (86.2%, 85.1% and 43.8%, respectively for the HCC group and 81.4%, 87.6% and 36.4%, respectively for the non-HCC group). After 48 weeks, the HCC group showed significant decreases in mean Child–Pugh and MELD scores, compared with baseline (6.9 vs. 5.8 and 10.1 vs. 8.7, respectively; both P < 0.001). Of the 94 HCC patients, 33 received curative therapies for HCC, simultaneously with ETV: hepatectomy in 9 and radiofrequency ablation in 24. For these subgroup, median recurrence-free survival was 27.9 months in the 21 patients who achieved HBV DNA negativity at week 24, significantly longer than 17.6 months in those who did not (27.9 vs. 17.6 months, P = 0.01), similar to overall survival (P = 0.067): all pretreatment characteristics of patients and tumors did not differ. Conclusions: First-line ETV was comparably efficacious in either CHB patients with or without HCC. ETV treatment improved hepatic function in HCC patients, and early virological response to ETV markedly produced a delay of post-treatment recurrence of HCC.

Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection

Diabetes mellitus is frequently seen in hepatitis C patients and is often treated with antidiabetic agents that increase serum insulin levels. Because insulin is a growth-promoting hormone, antidiabetic agents could pose a risk for hepatocellular carcinoma (HCC). The aim of this study was to investigate an association between antidiabetic therapies and the incidence of HCC in hepatitis C patients with diabetes mellitus. A nested case-control study was conducted. Participants were recruited from a cohort study, in which patients with hepatitis C were consecutively registered. Participants were assigned to an HCC group (n=138) or a non-HCC group (n=103). To identify independent factors, variables including use of antidiabetic agents were analysed by logistic regression analysis. Besides ageing, being male, cirrhosis and hypoalbuminaemia, use of exogenous insulin and a second-generation sulphonylurea were significant independent factors associated with an incidence of HCC [odds ratio (OR) 2.969, 95% confidence interval (CI) 1.293-6.819, P<0.0103 and OR 6.831, 95% CI 1.954-23.881, P<0.0026 respectively). In stratified analyses, the impact of these antidiabetic agents was more evident in patients who were non-cirrhotic than in those who were cirrhotic. Exogenous insulin and a second-generation sulphonylurea were independent variables associated with an incidence of HCC in hepatitis C patients with diabetes mellitus. This association was evident in patients who were non-cirrhotic. To verify a causal relationship between these antidiabetic agents and the development of HCC, a prospective cohort study is required.

X gene mutations in hepatitis B patients with cirrhosis, with and without hepatocellular carcinoma

Specific mutations in the hepatitis B virus (HBV) genome have been reported to be associated with the development of hepatocellular carcinoma (HCC). The goal of this study was to determine whether mutations in the HBV X gene are associated with the development of HCC in hepatitis B patients with cirrhosis. Forty-two patients infected with HBV genotype C2 with cirrhosis and HCC were compared with 46 patients with cirrhosis but without HCC. X gene mutations were determined by direct sequencing in all patients. The HCC and non-HCC groups were similar with respect to clinical characteristics, and the presence of T1762/A1764, T1653, and V1753 mutations was not significantly different between the two groups (P = 0.068, P = 0.097, P = 0.442, respectively). Only the B1499 mutation was associated significantly with HCC (P = 0.015) (odds ratio: 3.42, 95% CI: 1.24-9.48). In hepatitis Be antigen (HBeAg)-positive patients, advanced age was associated significantly with HCC (P = 0.038), whereas in HBeAg-negative patients, the B1499 mutation was associated more significantly with HCC (P = 0.01). Patients in the B1499 mutation group exhibited significantly higher AST and ALT levels compared with patients infected the wild-type virus. In conclusion, B1499 is a novel mutation associated with HCC in Korean patients with cirrhosis infected with HBV genotype C2.

T1015 Risk Factors for Hepatocellular Carcinoma in Patients with Nonalcoholic Steatohepatitis

Background: Hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) has been increasingly reported as the concept of NASH has received wide acceptance among clinicians in the intervening years. Moreover incidence of NASH itself is expected to increase reflecting age of gluttony. However it does not make sense from a cost-effectiveness point of view to screen HCC frequently in all patients with NASH because patients with NASH make up around 1% in overall Japanese population. Aim: This study was designed to assess risk factors for HCC in patients with NASH to develop effective screening methods. Patients and Methods: Our study included all the patients who were consecutively diagnosed at Gunma University Graduate School of Medicine and its affiliated hospitals as having NASH between 2000 and 2006, were followed up for at least 24 months. We evaluated incidence of HCC to date. We compared clinicopathological features (physical findings, laboratory findings, histological features and complications) between patients with HCC (HCC group) and patients without HCC (non-HCC group). The criteria for the diagnosis of NASH were compatible liver histology. We confirmed the diagnosis of HCC by ultrasonographic scanguided tumor biopsy except the treatment-resistant ascites or absence of informed consent in which an angiography or computed tomography showed typical characteristics of HCC. Results: The overall sample included 79 patients (26 men and 53 women, median age 63 years). The follow-up period ranged from 30 to 138 months with an average of 52 months. Fourteen patients (9 men and 5 women, median age 63 years) developed HCC. As for histological stage due to Blunt's classification, 1 and 16 had stage 1, 2 and 23 had stage 2, 3 and 12 had stage 3, and 8 and 14 had stage 4 in HCC group and non-HCC group, respectively. All cases accompanied either obesity or diabetes mellitus. Univariate analysis showed age, sex, histological stage, prothrombin time, serum total cholesterol level, and serum uremic acid level were significant different between HCC group and non-HCC group. Multiple logistic analysis showed male sex (odds ratio: 44.09, 95% Confidence interval: 3.564-545.4, p=0.032) and elder age (odds ratio: 1.134, 95% Confidence interval: 1.0181.265, p=0.029) were significant risk factors for HCC in patients with NASH. Conclusions: Though preliminary results, male sex and elder age were significant risk factors for HCC in patients with NASH and these patients have to be regularly monitored for early detection of HCC. At the same time, we should increase the sample size and follow-up periods and confirm our hypothesis in the near future.

Specific mutations in the enhancer II/core promoter/precore regions of hepatitis B virus subgenotype C2 in Korean patients with hepatocellular carcinoma

Recently, hepatitis B virus (HBV) genotypes and mutations have been reported to be related to hepatocellular carcinoma (HCC). This cross-sectional case-control study examined the relationship between HCC and mutations in the enhancer II/core promoter and precore regions of HBV by comparing 135 Korean HCC patients infected with HBV genotype C2 (HBV/C2; HCC group) with 135 age-, sex-, and hepatitis B e antigen (HBeAg) status-matched patients without HCC (non- HCC group). Age and sex were also matched between HBeAg-positive and -negative patients. The prevalence of T1653, A1689, V1753, T1762/A1764, T1846, A1850, C1858, and A1896 mutations was evaluated in this population. The prevalence of the T1653 mutation in the box alpha region, the T1689 [corrected] mutation in between the box alpha and beta regions, and the T1762/A1764 mutations in the basal core promoter region was significantly higher in the HCC group compared to the non-HCC group (8.9% vs. 2.2%, P = 0.017; 19.3% vs. 4.4%, P < 0.001; and 60.7% vs. 22.2%; P < 0.001). Among HBeAg-negative patients, the frequency of the T1653 mutation was higher in the HCC group. Regardless of HBeAg status, the prevalence of the T1689, [corrected] and T1762/A1764 mutations was higher in the HCC group than in the non-HCC group. However, no association was observed between mutations in the precore region and HCC. Upon multivariate analysis, the presence of the T1653, T1689, [corrected] and T1762/A1764 mutations was an independent predictive factor for HCC. The addition of the T1653 or T1689 [corrected] mutation to T1762/A1764 increased the risk of HCC. In conclusion, the T1653, T1689, [corrected] and/or T1762/A1764 mutations were associated with the development of HCC in Korean patients infected with HBV/C2.

The Risk Factors for Mortality in Patients with Hepatitis B Virus Infection and Hepatocellular Carcinoma Following Liver Transplantation

Purpose: Conflicting data exist regarding the impact of hepatocellular carcinoma (HCC) on survival following liver transplantation (LT). Previous hort-term studies have failed to demonstrate any correlation between HCC and survival. We studied risk factors for mortality in patients who underwent LT for chronic hepatitis B virus infection (HBV), either with or without HCC. Methods: We retrospectively reviewed all HBV-related liver transplants at our institution between February 1996 and July 2006. Patients with HBV and no evidence of HCC (non-HCC group) were compared to patients with HBV plus HCC (HCC group). The predictors of survival were examined using Cox proportional hazard regression. Results: We reviewed data from 67 patients who underwent LT for HBV alone (non-HCC group) and 31 patients with HBV plus HCC (HCC group). Post-transplant survival at 1-year, 3-years and 5-years was 94%, 65%, and 56% in the HCC group compared with 100%, 90%, and 88% in the non-HCC group. Median follow-up was 4.9 years. Mean survival for HCC patients was significantly shorter than in non-HCC patients (P= 0.04). Pre-transplant, of the 31 HCC patients: 10 had hepatic resection, 24 had at least one chemoembolization, and 11 had multiple chemoembolizations; 10 had both chemoembolization and hepatic resection. 8 HCC patients did not meet Milan criteria. Post-transplant, 7 patients had recurrent HCC. A total of 7 patients with HCC died by the end of follow-up: 4 died post-operatively and 3 died of metastatic HCC recurrence. Conclusion: Hepatitis B patients with HCC have shorter survival than patients without HCC when followed 5 years post-transplant. Our findings may be explained by a high pre-transplant tumor burden, as indicated by the size and number of lesions.Figure

MDM2 and p53 polymorphisms are associated with the development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

A single-nucleotide polymorphism (SNP) in the promoter region of MDM2, SNP 309, is associated with hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus infection. The effect of p53 codon 72 polymorphism Arg72Pro on HCC risk remains inconsistent. This study evaluated the association of MDM2 and p53 polymorphisms with the presence and early onset of HCC in Korean patients with chronic hepatitis B virus (HBV) infection. In total, 583 consecutive patients with chronic HBV infection were classified according to the presence (n = 287) or absence (n = 296) of HCC. The MDM2 SNP 309 and p53 Arg72Pro were genotyped using restriction fragment length polymorphism method. The MDM2 G/G and p53 Pro/Pro genotypes were more frequent in HCC group than in non-HCC group (P < 0.001 and P = 0.004, respectively). Multivariate analysis for the presence of HCC revealed that the odds ratio (OR) for MDM2 G/G over T/T was 4.89 (P < 0.001) and that of p53 Pro/Pro over Arg/Arg was 3.03 (P = 0.006). Combined MDM2 G/G and p53 Pro/Pro had a synergistic effect on HCC risk, with an OR of 20.78 (P < 0.001). The mean age of tumor onset in patients with MDM2 G/G genotype was 50.9 years compared with 55.1 with T/T genotype (P = 0.018) and that with p53 Pro/Pro was 49.7 years compared with 52.9 with Arg/Arg (P = 0.040). Thus, MDM2 SNP 309 and p53 Arg72Pro are associated with the early development of HCC in Korean patients with chronic HBV infection.