Hepatocarcinogenesis In Chronic Hepatitis Research Articles

Association of Common Polymorphisms in the Interleukin-1 Beta Gene with Hepatocellular Carcinoma in Caucasian Patients with Chronic Hepatitis B

Interleukin-1 beta (IL-1β) promotes liver disease progression and hepatocarcinogenesis in chronic hepatitis B (CHB). Single nucleotide polymorphisms (SNPs) within the promotor region of the IL-1β gene can affect the progression towards liver cirrhosis and hepatocellular carcinoma (HCC). Aims: We aimed to investigate the association of three common IL-1β SNPs with hepatitis B virus (HBV)-related HCC in Caucasian patients. Method: A Caucasian cohort of 99 patients with HBe antigen (Ag)-positive CHB, 255 patients with HBeAg-negative CHB and 278 inactive carriers (IC) were enrolled. 105 patients were diagnosed with liver cirrhosis, and 64 with HCC and cirrhosis. Genotyping of the IL-1β rs1143623, rs1143627 and rs16944 was performed. Results: The rs1143627 TT and rs16944 CC genotypes were more frequent in patients with HCC compared to patients without liver tumours (48% vs. 33%, p = 0.018 and 47% vs. 31%, p = 0.001, respectively). In multivariate analysis, the rs16944 CC genotype was independently associated with HCC (OR = 6.44 [95% CI 1.50-27.59] p = 0.012). The haplotype, including rs1143623 TT and rs16944 CC, was a risk factor for HCC development (OR = 1.55 [95% CI 1.04-2.32] p = 0.031). Conclusions: We identified an association of common IL-1β SNPs with HBV-related HCC in a Caucasian population. The effect was independent of the phases of chronic HBV infection, which are currently regarded as important HCC risk factors.

FRI552 - Hippo inactivation drives BMI1-associated proliferative hepatocarcinogenesis in chronic hepatitis B virus infection

FRI552 - Hippo inactivation drives BMI1-associated proliferative hepatocarcinogenesis in chronic hepatitis B virus infection

Serum PreS1 and HBsAg ratio reflects liver fibrosis and predicts the development of hepatocellular carcinoma in chronic hepatitis B patients.

While the preS1 region of the large hepatitis B surface protein plays an essential role in hepatitis B virus (HBV) infection, the effect of preS1 on liver fibrosis and hepatocarcinogenesis in chronic hepatitis B (CHB) patients is not well known. In this study, we measured serum preS1levels by chemiluminescent immunoassay technology in 690 CHB patients and evaluated the correlation between serum preS1levels and HBV, liver function markers and liver inflammation, fibrosis assessed by histological findings. Predictive factors for hepatocellular carcinoma (HCC) development in patients who had no previous history of HCC at the time of preS1level measurement were also analysed. Median hepatitis B surface antigen (HBsAg) and preS1levels were 3.08log IU/mL and 98ng/mL, respectively. PreS1values were significantly correlated with serum HBsAg (p <0.001), hepatitis B core-related antigen (HBcrAg) (p <0.001) and HBV DNA levels (p <0.01). PreS1values were also significantly correlated with serum alanine aminotransferase levels (p <0.001) and were significantly higher in patients who had higher grading of liver inflammatory activity (p <0.05). HBsAg level was correlated, but preS1/HBsAg ratio reflected liver fibrosis staging more directly than HBsAg alone. Multivariate analysis identified age ≥53years (hazard ratio [HR], 18.360 for <53years; p = 0.021) and preS1/HBsAg ratio ≥0.12 (HR, 6.205 for <0.12; p = 0.040) as significant and independent factors for HCC development in CHB patients. The preS1/HBsAg ratio directly reflects liver fibrosis, and the ratio might be a predictive marker for HCC development in CHB patients.

SAT-251-The association of serum IFN-λ3 levels with liver fibrosis and hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents

SAT-251-The association of serum IFN-λ3 levels with liver fibrosis and hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents

Association of serum interferon-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents.

Although the efficacy of hepatitis C virus (HCV) treatment is improved dramatically by direct-acting antiviral agents (DAAs), the assessment of hepatocellular carcinoma (HCC) remains important. Interferon lambda 3 (IFN-λ3) is associated with liver fibrosis and inflammation in chronic hepatitis C (CHC) patients, but its impact on carcinogenesis remains controversial and little is known about its effects after viral clearance. To determine the contribution of IFN-λ3 to hepatocarcinogenesis after HCV clearance, we analyzed IFNL3 genotypes and serial serum IFN-λ3 levels in CHC patients who achieved sustained virologic responses (SVR). This study comprised 201 CHC patients treated with DAAs. Serum samples were collected sequentially and IFN-λ3 levels were quantified by chemiluminescence enzyme immunoassay. The IFNL3 polymorphism (rs8099917) was genotyped in 195 patients. One hundred and twenty-five patients were rs8099917 T/T and 70 were non-T/T. Serum IFN-λ3 levels did not differ significantly with IFNL3 genotype, dropped markedly by 1week and remained low up to 24weeks after the end of treatment. Interferon-λ3 levels were significantly higher after viral clearance in patients who developed HCC and were associated with a higher potential for hepatocarcinogenesis, such as a higher frequency of non-hypervascular hypointensive nodules (P = 0.046), higher stages of liver fibrosis (P < 0.001), and higher post-treatment levels of Wisteria floribunda agglutinin positive Mac-2 binding protein (P < 0.001) and alanine aminotransferase (P < 0.001). Serum IFN-λ3 levels after HCV clearance are associated with the potential for HCC development. Interferon-λ3 could be helpful for elucidating the relationships among immunologic status, liver fibrosis, liver inflammation, and hepatocarcinogenesis, after achieving SVR.

On the potential role of intestinal microbial community in hepatocarcinogenesis in chronic hepatitis B.

The chronic infection of hepatitis B virus (HBV) is the most potent risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The association of intestinal microbiota alteration with progressive liver disease has been investigated in recent studies. Overgrowth of potentially pathogenic bacteria of gram‐negative species and, in particular, a significant increase in the fecal count of Escherichia coli (E. coli) are characterized in the presence of HCC. This study was conducted to describe the characteristics of the intestinal microbiota related to the presence of HCC in HBV‐carrier patients. The available literature indicates the colonization of E. coli as principal source of portal vein lipopolysaccharide (LPS), in the gut may contribute to the carcinogenesis process by inducing chronic inflammation. This understanding could help to predict the clinical outcomes in HBV‐carrier patients and innovative strategies to reduce the virulence of liver disease from intestinal dysbiosis.

Hepatitis C virus infection triggers a tumor-like glutamine metabolism.

Our data suggest that HCV establishes glutamine dependence, which is required for viral replication, and, importantly, that glutamine addiction is a hallmark of tumor cells. While HCV induces glutaminolysis to create an environment favorable for viral replication, it predisposes the cell to transformation. Glutaminolytic enzymes may be interesting therapeutic targets for prevention of hepatocarcinogenesis in chronic hepatitis C. (Hepatology 2017;65:789-803).

Impact of serum ferritin level on hepatocarcinogenesis in chronic hepatitis C patients.

To elucidate the impact of the serum ferritin level, a surrogate indicator of hepatic iron accumulation, on hepatocarcinogenesis in chronic hepatitis C patients. Serum ferritin was measured in 487 chronic hepatitis C patients without history of hepatocellular carcinoma (HCC) after excluding patients in phlebotomy, those with overt chronic gastrointestinal bleeding and those who achieved sustained virological response before enrollment. Patients were divided into four groups (G1-G4) by quartile points of serum ferritin, with sexes separated. The serum ferritin level was positively correlated with total bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), γ-glutamyltransferase, hemoglobin and AFP, and inversely correlated with prothrombin activity in both sexes. A significant difference in HCC incidence was observed only in male patients; the incidence was higher in G1 (≤80 ng/mL, n = 54) and G4 (≥323 ng/mL, n = 54) compared with that of G2 (81-160 ng/mL, n = 54) and G3 (161-322 ng/mL, n = 52). The spline curve indicating the relationship between the hazard ratio and serum ferritin level took the form of a J-shape for male patients. In multivariate analysis, G1 and G4 showed higher incidence of HCC among men with a hazard ratio of 2.19 (95% confidence interval, 1.02-4.70; P = 0.045) compared with G2 and G3, together with older age, lower serum albumin and ALT above the normal upper limit. The serum ferritin level is an independent risk factor for HCC development in male patients with chronic hepatitis C when the level is extremely high or low.

Potential associations between perihepatic lymph node enlargement and liver fibrosis, hepatocellular injury or hepatocarcinogenesis in chronic hepatitis B virus infection.

Although perihepatic lymph node enlargement (PLNE) is frequently observed in chronic liver disease, little is known about PLNE in chronic hepatitis B virus (HBV) infection. We aimed to evaluate this issue. We originally enrolled a consecutive 502 patients with chronic HBV infection. Among them, 288 patients without history of interferon-based or nucleoside analog treatment and hepatocellular carcinoma (HCC) were primarily analyzed. PLNE was detected in 27 of 288 (9.4%) patients, which was fewer than that in chronic hepatitis C patients but more than that in subjects undertaking a general health examination as previously reported. The presence of PLNE was significantly associated with a higher probability of having an aspartate aminotransferase (AST) platelet ratio index of more than 1.5 (11.1% vs 1.5%, P = 0.01), a higher AST level (38.0 vs 26.8 U/L, P = 0.001), a higher alanine aminotransferase level (50.1 vs 28.0 U/L, P < 0.0001), and a lower platelet count (18.6 vs 20.6 × 10(4) /μL, P = 0.048) after adjustment for sex and age. However, in our original sample (n = 502), PLNE was observed in 1.4% of the patients with HCC and/or its history whereas 9.2% of the patients without HCC, and the proportion was significantly lower in patients with HCC and/or its history (P = 0.03). PLNE was associated with liver fibrosis and hepatocellular injury, but was negatively associated with HCC in chronic HBV infection.

Increased serum mitochondrial creatine kinase activity as a risk for hepatocarcinogenesis in chronic hepatitis C patients

Serum mitochondrial creatine kinase (MtCK) activity was reportedly increased in cirrhotic patients although less prominent than that in hepatocellular carcinoma (HCC) patients. To elucidate the clinical significance of serum MtCK activity in chronic liver disease, 171 chronic hepatitis C patients were enrolled. Serum MtCK activity in study subjects was correlated with serum albumin, platelet counts, liver stiffness values and serum aspartate and alanine aminotransferase. In mouse fibrotic liver induced by bile duct ligation, ubiquitous MtCK mRNA and protein expressions were significantly enhanced and its immunoreactivity was increased, predominantly in hepatocytes. During the mean follow-up period of 2.7 years, HCC developed in 21 patients, in whom serum MtCK activity was significantly higher than that in patients without HCC development. Multivariate Cox regression analysis revealed that higher serum MtCK activity was a risk for HCC development. A cutoff value of MtCK for the prediction of HCC development was determined as 9.0 U/L on receiver operating characteristics analysis, where area under receiver operating characteristics curve was 0.754, with a sensitivity of 61.9%, a specificity of 92.8% and a high negative predictive value of 94.2%. Cumulative incidence of HCC was significantly higher in patients with serum MtCK activity of >9.0 U/L compared to those with serum MtCK activity of ≤ 9.0 U/L even in patients with elevated liver stiffness value, >15 kPa. In conclusion, serum MtCK activity may be increased correlatively with the stage of liver fibrosis and hepatocellular damage. Increased serum MtCK activity is an independent risk for hepatocarcinogenesis in chronic hepatitis C patients.

Hepatocarcinogenesis in chronic hepatitis C patients achieving a sustained virological response to interferon: significance of lifelong periodic cancer screening for improving outcomes

Due to advances in interferon (IFN) therapy for chronic hepatitis C, most elderly patients, and even many of those with advanced hepatic fibrosis, now achieve a sustained virological response (SVR). However, carcinogenesis remains problematic in these patients. Hence, we aimed to elucidate risk factors for hepatocarcinogenesis in SVR patients and to present an appropriate follow-up protocol for improving outcomes. We retrospectively studied 562 consecutive SVR patients for a median observation period of 4.8 years. Hepatocellular carcinoma was diagnosed in 31 patients (5.5%). Respective cumulative incidences were 3.1, 10.1, and 15.9% at 5, 10, and 15 years after completion of IFN therapy. The proportional hazards model identified moderate or advanced fibrosis stage, advanced age, habitual alcohol consumption, and alpha-fetoprotein elevation as determinants of carcinogenesis, with hazard ratios of 10.7 (p < 0.001), 4.1 (p < 0.01), 3.9 (p < 0.01), and 2.6 (p < 0.05), respectively. Carcinoma was diagnosed in 26% of patients more than 10 years after completion of IFN therapy. Unexpectedly, F2 fibrosis was detected in 42% of these patients. The 5-year survival rate was 93% in the patients who had received periodic cancer screening but only 60% in those who had not. We recommend that SVR patients be observed at 6-month intervals, at a minimum, to facilitate diagnosis at an early stage, for as long as possible after completion of therapy even if not at an advanced stage of fibrosis.

Iron metabolic disorder in chronic hepatitis C: Mechanisms and relevance to hepatocarcinogenesis

The liver is the major iron storage organ in the body, and therefore, iron metabolic disorder is sometimes involved in chronic liver diseases. Chronic hepatitis C is one of the liver diseases that show hepatic iron accumulation, even though its level should be recognized to be basically mild to moderate and sometimes within the normal range. The mechanisms underlying hepatic iron accumulation in chronic hepatitis C have not been fully elucidated. Reduction of the hepcidin transcription activity by hepatitis C virus (HCV)-induced reactive oxygen species may in part account for it, but the regulation of hepcidin is very complex and may depend on many variables, including the particular stage of the systemic and/or hepatic inflammatory conditions and the circulating transferrin-bound iron and intracellular iron stores. This might explain the variations in hepatic iron concentrations reported among patients with HCV-related chronic liver disease. However, even mild-to-moderate iron overload in the liver contributes to disease progression and hepatocarcinogenesis in chronic hepatitis C probably by reinforcing the HCV-induced oxidative stress through Fenton reaction. The present review highlights the current concept of hepatic iron overload status in chronic hepatitis C and discusses how iron metabolic disorder develops in this disease and the impact of hepatic iron overload on disease progression and its relevance to hepatocarcinogenesis.

α-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C

The effects of interferon (IFN) treatment and the post-IFN treatment α-fetoprotein (AFP) levels on risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC) are unknown. To determine the relationship between AFP and alanine transaminase (ALT) levels and HCC risk, a cohort consisting of 1,818 patients histologically proven to have CHC treated with IFN were studied. Cumulative incidence and HCC risk were analyzed over a mean follow-up period of 6.1 years using the Kaplan-Meier method and Cox proportional hazard analysis. HCC developed in 179 study subjects. According to multivariate analysis, older age, male gender, advanced fibrosis, severe steatosis, lower serum albumin levels, non sustained virological response (non-SVR), and higher post-IFN treatment ALT or AFP levels were identified as independent factors significantly associated with HCC development. Cutoff values for ALT and AFP for prediction of future HCC were determined as 40 IU/L and 6.0 ng/mL, respectively, and negative predictive values of these cutoffs were high at 0.960 in each value. The cumulative incidence of HCC was significantly lower in patients whose post-IFN treatment ALT and AFP levels were suppressed to less than the cutoff values even in non-SVR patients. This suppressive effect was also found in patients whose post-IFN treatment ALT and AFP levels were reduced to less than the cutoff values despite abnormal pretreatment levels. Post-IFN treatment ALT and AFP levels are significantly associated with hepatocarcinogenesis. Measurement of these values is useful for predicting future HCC risk after IFN treatment. Suppression of these values after IFN therapy reduces HCC risk even in patients without HCV eradication.

Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: A propensity score analysis

Some patients with chronic hepatitis B virus (HBV) infection progress to hepatocellular carcinoma (HCC). However, the long-term effect of nucleos(t)ide analogue (NA) therapy on progression to HCC is unclear. Therefore, we compared chronic hepatitis B patients who received NA therapy to those who did not, using a propensity analysis. Of 785 consecutive HBV carriers between 1998 and 2008, 117 patients who received NA therapy and 117 patients who did not, were selected by eligibility criteria and propensity score matching. Factors associated with the development of HCC were analyzed. In the follow-up period, HCC developed in 57 of 234 patients (24.4%). Factors significantly associated with the incidence of HCC, as determined by Cox proportional hazards models, include higher age (hazard ratio, 4.36 [95% confidence interval, 1.33-14.29], p=0.015), NA treatment (0.28 [0.13-0.62], p=0.002), basal core promoter (BCP) mutations (12.74 [1.74-93.11], p=0.012), high HBV core-related antigen (HBcrAg) (2.77 [1.07-7.17], p=0.036), and high gamma glutamyl transpeptidase levels (2.76 [1.49-5.12], p=0.001). NA therapy reduced the risk of HCC compared with untreated controls. Higher serum levels of HBcrAg and BCP mutations are associated with progression to HCC, independent of NA therapy.

Iron metabolic disorder in chronic hepatitis C: insights from recent evidence.

The liver is the major iron storage organ in the body, and therefore iron metabolic disorder is sometimes involved in chronic liver diseases. Chronic hepatitis C is one of the liver diseases that show hepatic iron accumulation. The present review highlights the current concept of hepatic iron overload status in chronic hepatitisC and discusses how iron metabolic disorder develops in this disease, and the impact of hepatic iron overload on disease progression and its relevance to hepatocarcinogenesis. The level of hepatic iron accumulation in chronic hepatitis C should be recognized to be basically mild to moderate and sometimes within the normal range. However, even mild to moderate iron overload in the liver contributes to disease progression and hepatocarcinogenesis in chronic hepatitis C, probably by reinforcing the oxidative stress induced by hepatitis C virus (HCV) protein. The mechanisms by which hepatic iron overload develops in chronic hepatitis C have not been fully elucidated. Reduction of the transcription activity of hepcidin by HCV-induced reactive oxygen species may in part account for it, but the regulation of hepcidin is very complex and may depend on many variables, including the particular stage of the systemic and/or hepatic inflammatory conditions and the circulating transferrin-bound iron and intracellular iron stores. This might explain the variations in hepatic iron concentrations reported among patients with HCV-related chronic liver disease.

Molecular mechanisms of hepatocarcinogenesis in chronic hepatitis C virus infection

Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) and chronic liver disease worldwide. Recent developments and advances in HCV replication systems in vitro and in vivo, transgenic animal models, and gene expression profiling approaches have provided novel insights into the mechanisms of HCV replication. They have also helped elucidate host cellular responses, including activated/inactivated signaling pathways, and the relationship between innate immune responses by HCV infection and host genetic traits. However, the mechanisms of hepatocyte malignant transformation induced by HCV infection are still largely unclear, most likely due to the heterogeneity of molecular paths leading to HCC development in each individual. In this review, we summarize recent advances in knowledge about the mechanisms of hepatocarcinogenesis induced by HCV infection.

Serum IL‐6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: An analysis based on gender differences

Interleukin-6 (IL-6) may play a role in the pathogenesis of hepatocellular carcinoma (HCC). Recently, it was reported in mouse models that estrogen-mediated inhibition of IL-6 production explains the gender disparity in HCC. We conducted a retrospective cohort study to examine whether this hypothesis is applicable to human HCC. We enrolled 330 patients with chronic hepatitis C whose serum samples were collected between January 1994 and December 2002. Serum IL-6 concentrations were measured and patients were divided into three groups according to IL-6 levels: low, middle, and high. We evaluated the association between serum IL-6 levels and the risk of subsequent HCC development, including subgroup analysis on each gender. During the follow-up period (mean 9.0 yr), HCC developed in 126 patients. The incidence rates differed significantly among the three groups (p = 0.015), increasing in accordance with serum IL-6 levels. However, unexpectedly, this tendency was significant only in female patients. In a multivariate analysis, higher serum IL-6 level was an independent risk factor for HCC development in female patients, with a hazard ratio of 1.61. Although female patients showed a weak negative correlation between serum IL-6 levels and estradiol levels, the lower risk of HCC in female patients cannot be fully explained by estrogen-mediated inhibition of IL-6 production. In conclusion, higher serum IL-6 level was an independent risk factor for HCC development in female but not male chronic hepatitis C patients. Measurement of serum IL-6 levels may provide useful information for predicting future HCC development in female chronic hepatitis C patients.

Obesity Is an Independent Risk Factor for Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

It is not fully elucidated whether obesity enhances hepatocarcinogenesis in patients with chronic hepatitis C. The aim of this study was to investigate the relationship between body weight and risk of hepatocarcinogenesis in chronic hepatitis C patients. We enrolled 1431 patients with chronic hepatitis C who visited our liver clinic between 1994 and 2004, excluding those with hepatocellular carcinoma (HCC) at their visit or with a previous history of HCC. They were divided into 4 groups according to body mass index (BMI): underweight (< or =18.5 kg/m(2), N = 112); normal (18.5 to less than 25 kg/m(2), N = 1023); overweight (25 to less than 30 kg/m(2), N = 265); and obese (>30 kg/m(2), N = 31). We assessed the impact of obesity on the hepatocarcinogenesis adjusted by multivariate Cox proportional hazard regression with other risk factors found significant in univariate analysis. During the follow-up period (mean, 6.1 y), HCC developed in 340 patients, showing cumulative incidence rates of 10.5%, 19.7%, and 36.8% at 3, 5, and 10 years, respectively. The incidence differed significantly among the BMI groups (P = .007). Adjusting for other significant factors, overweight and obesity were shown to be an independent risk factor of HCC, with a hazard ratio of 1.86 (95% confidence interval, 1.09-3.16; P = .022) and 3.10 (95% confidence interval, 1.41-6.81; P = .005) as compared with the underweight patients. The risk of HCC in patients with chronic hepatitis C increases in proportion to BMI in a wide range of its values, from underweight to obese.

Clinical features of hepatitis C virus‐related hepatocellular carcinoma and their association with α‐fetoprotein and protein induced by vitamin K absence or antagonist‐II

We investigated the differences in clinical features between alpha-fetoprotein (AFP)-predominant hepatocellular carcinoma (HCC) and protein induced by vitamin K absence or antagonist-II (PIVKA-II)-predominant HCC, especially regarding host factors thought to contribute to hepatocarcinogenesis in chronic hepatitis C virus (HCV) infection. HCV-related HCC patients (n=306) were divided into four groups according to median AFP (48.1 ng/ml) and PIVKA-II (60 mAU/ml). Host factors, tumor factors, survival, and risk factors affecting survival were compared. Aspartate aminotransferase (AST; IU/L), alanine aminotransferase (ALT; IU/L), and platelet count (x 10(4)/ml) were, respectively, 81, 67, and 8.2 in AFP-predominant HCC (group A; n=66) vs. 50, 42, and 11.4 in PIVKA-II-predominant HCC (group P; n=52). Tumor sizes (mm) in groups A and P were 20 and 37, respectively. Significant differences were evident. Survival was identical between the two groups. Factors affecting survival were total bilirubin, portal tumor thrombus and number of nodule in group A, and albumin and tumor distribution in group P. PIVKA-II-predominant HCC had a milder hepatitis and a better-preserved platelet count compared with AFP-predominant HCC. Considering the strong relation between hepatocarcinogenesis and hepatic inflammation with chronic HCV infection, these differences indicate that hepatocarcinogenic mechanisms in PIVKA-II-predominant HCC may differ from those in AFP-predominant HCC.