Incidence and risk factors for hepatocellular carcinoma in 967 patients with cirrhosis

Purpose: To determine the incidence of hepatocellular carcinoma in cirrhosis and to examine the influence of age and sex, and the contribution of etiological factors. Methods: 967 patients with liver cirrhosis and free of hepatocellular carcinoma were enrolled in this longitudinal, retrospective and observational study. Monitoring for hepatocellular carcinoma was scheduled at 3- to 6-month intervals. The mean (±SD) length of follow-up was 60.3 ± 51.7 months (range 6–258). Results: During the observation period, hepatocellular carcinoma developed in 64 patients. The calculated annual incidence was 2.1%. The probability of being free of liver cancer was 92% at 5 years, 80% at 10 years, and 69% at 15 years. Age was the only independent risk factor for the development of malignancy in the multivariate analysis. There were no differences according to male sex, alcohol abuse, and chronic hepatitis B and C virus infection. Conclusions: The annual incidence of hepatocellular carcinoma was 2.1%. These results, although confirming that age is a risk factor for hepatocellular carcinoma in cirrhosis, indicate that alcohol abuse, male sex, and concurrent hepatitis B and C virus infection do not involve a higher risk of developing liver cancer.     

Human hepatitis B virus and hepatocellular carcinoma II. Experimental induction of hepatocellular carcinoma in tree shrews exposed to hepatitis B virus and aflatoxin B1

On the basis of the successful establishment of an animal model in tree shrews experimentally infected with human hepatitis B virus (HBV), a study on the hepatocarcinogenic effects of HBV and/or aflatoxin B1 (AFB1) was conducted. The results showed that the incidence of hepatocellular carcinoma (HCC) was significantly higher in the animals both infected with HBV and exposed to AFB1 (52.94%) than in those solely infected with HBV (11.11%) or exposed to AFB1 (12.50%). No HCC of precancerous lesions were found in the controls that were neither HBV-infected nor AFB1-exposed. Precancerous lesions, including liver cell dysplasia and enzyme-altered hyperplastic hepatocyte foci, were observed before the occurrence of HCC, and the frequency of their appearance correlated well with the incidence of HCC. HBV DNA and the protein it encodes were detected in the cancer cells and/or the surrounding hepatocytes. Integration of HBV DNA inot the host liver genome was found during hepatocarcinogenesis among the animals infected by HBV. These results suggest that exposure to HBV and AFB1 may play a synergistic role in the development of HCC, and support the viewpoint of an aetiological relationship between HBV and HCC.Abbreviations HCC hepatocellular carcinoma - HBV human hepatitis B virus - AFB1 aflatoxin B1 - GGT foci hyperplastic hepatocyte foci positive for -glutamyltranspeptidase - LCD liver cell dysplasia     

Hepatitis B virus infection and the risk of hepatocellular carcinoma

Epidemiological studies have provided overwhelming evidence for a causal role of chronic hepatitis B virus(HBV) infection in the development of hepatocellular carcinoma(HCC).However,the pathogenesis of HBV infection and carcinogenesis of HBV-associated HCC are still elusive.This review will summarize the current knowledge on the mechanisms involved in HBV-related liver carcinogenesis.The role of HBV in tumor formation appears to be complex,and may involve both direct and indirect mechanisms.Integration of H...     

Differences in characteristics of patients with and without known risk factors for hepatocellular carcinoma in the United States

AIM： To examine the clinical characteristics of a subgroup of patients with hepatocellular carcinoma （HCC） and compare them to those with known risk factors. METHODS： We used the HCC database of 306 patients seen at our institution from January 1, 1995 to December 31, 2001. Of the 306 patients, 63 （20%, group 1） had no known risk factors （hepatitis C virus, hepatitis B virus, alcohol, hemochromatosis or cirrhosis from any cause） and 243 （group 2） had one or more risk factors. RESULTS： The median age was similar in both groups, but there were disproportionate numbers of younger （〈 30 years old）, older （〉 80 years） patients, women （33% vs 18%）, and Caucasians （81% vs 52%） in group 1 as compared to group 2. There were fewer Asians （2% vs 11%） and African Americans （13% vs 27%） in group 1. Abdominal pain （70% vs 37%） was more common while gastrointestinal bleeding （0% vs 11%） and ascites （4% vs17%） were less common in group i compared to group 2. Group 1 had larger tumor burden （median size 9.4 cm vs 5.7 cm） at the time of presentation, but there were no differences in the site （right, left or bilateral lesions）, or number of tumors between the two groups. CONCLUSION： HCC patients without identifiable risk factors have different characteristics and clinical presentation compared to those with known risk factors.Absence of cirrhosis and larger tumor burden may explain the differences in the presenting symptoms.     

Interleukin-1β gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection

AIM: To examine the effect of interleukin-1-beta (IL-1beta) promoter region C-511T and IL-1 receptor antagonist (IL-1RN) polymorphism among the patients with chronic hepatitis B virus (HBV) infection (HCC and non-HCC). METHODS: Genomic DNA from 136 Thai patients with chronic HBV infection (HCC=46 and non-HCC=90) and 152 healthy individuals was genotyped for IL-1beta gene polymorphism (-511) using polymerase chain reaction with sequence specific primers (PCR-SSP). The variable number of tandem repeats (VNTR) of IL-1RN gene was assessed by a PCR-based assay. The association between these genes and status of the disease was evaluated by chi2 test. RESULTS: IL-1B-511 genotype C/C was found to be significantly different in patients with HCC when compared with healthy individuals (P=0.036, OR=2.29, 95%CI=1.05-4.97) and patients without HCC (P=0.036, OR=2.52, 95%CI=1.05-6.04). Analysis of allele frequencies of IL-1B-511 showed that IL-1B-511 C allele was also significantly increased in patients with HCC, compared to that in healthy control (P=0.033, OR=1.72, 95%CI=1.04-2.84). However, no significant association in IL-1RN gene was found between the two groups. CONCLUSION: IL-1B-511C allele, which may be associated with high IL-1B production in the liver, is a genetic marker for the development of HCC in chronic hepatitis B patients in Thai population.     

Interleukin-1β gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection

AIM: To examine the effect of interleukin-1-beta (IL-1β)promoter region C-511T and IL-1 receptor antagonist (IL-1RN) polymorphism among the patients with chronic hepatitis B virus (HBV) infection (HCC and non-HCC).METHODS: Genomic DNA from 136 Thai patients with chronic HBV infection (HCC=46 and non-HCC=90) and 152 healthy individuals was genotyped for IL-1β gene polymorphism (-511) using polymerase chain reaction with sequence specific primers (PCR-SSP). The variable number of tandem repeats (VNTR) of IL-1RN gene was assessed by a PCR-based assay. The association between these genes and status of the disease was evaluated by X2 test.RESULTS: IL-1B-511 genotype C/C was found to be significantly different in patients with HCC when compared with healthy individuals (P = 0.036, OR = 2.29,95%CI = 1.05-4.97) and patients without HCC (P=0.036,OR=2.52, 95%CI=1.05-6.04). Analysis of allele frequencies of IL-1B-511 showed that IL-1B-511 C allele was also significantly increased in patients with HCC, compared to that in healthy control (P=0.033,OR= 1.72, 95%CI=1.04-2.84). However, no significant association in IL-1RN gene was found between the two groups.CONCLUSION: IL-1B-511C allele, which may be associated with high IL-1B production in the liver, is a genetic marker for the development of HCC in chronic hepatitis B patients in Thai population.     

Association between PNPLA3 gene polymorphisms and risk of hepatitis B virus-related hepatocellular carcinoma in Han population in China:a case-control study

Background and aim: Several recent studies showed that the genetic polymorphisms in the PNPLA3 region (rs738408, rs738409, rs2294918, rs2294919 and rs2281135) were with related to various kinds of liver diseases. We analyzed the five single-nucleotide polymorphisms (SNPs) for major HBV outcomes in Han Chinese.

Methods: A total of 2410 samples were involved and peripheral blood samples were collected in this study. The SNPs in the PNPLA3 region were genotyped by using Matrix-assisted laser desorption/ionization time of flight mass spectrometry.

Results: Our study indicated the clear relationship between the PNPLA3 rs2294918, rs2294919 and HBV-related HCC after control for the effects of sex, drinking and smoking. Health subjects with the PNPLA3 rs2294919?TC genotype would have a 0.605 (95% CI: 0.413, 0.886; p?=?.010) times lower odds of having HCC, and those with the rs2294918 AG genotype would have a 1.872 (95% CI: 1.256, 2.792; p?=?.002) times higher odds of having HCC, whereas the values of sex, age, drinking and smoking were fixed. In addition, CA haplotype of the haplotype block of rs738409 and rs2281135 was also associated with HBV-related HCC.

Conclusions: Our study suggested that PNPLA3 loci (rs2294918, rs2294919) were associated with HBV-related HCC in Han Chinese.     

Epidemiologic risk factors of hepatocellular carcinoma in a rural region of Egypt

Background  

Hepatocellular carcinoma (HCC) is a major health problem worldwide, including Egypt. In the recent past, HCC has become the second most prevalent cancer among men in Egypt. Since HCC has not been well studied in the rural population of Egypt, this case–control study was conducted to investigate the epidemiologic risk factors of HCC in the predominantly rural region of Gharbiah, Egypt.     

乙肝肝硬化患者并发肝癌的危险因素研究

探讨乙型肝炎肝硬化患者短期内原发性肝癌的发生情况及其发生的危险因素。对180例乙型肝炎肝硬化患者作了4年随访,应用Kaplan—Meier法计算其原发性肝癌的发生情况,Cox风险模型分析发生原发性肝癌的独立的危险因素。共有30例并发原发性肝癌,第一年肝癌的发病率为2．2％,第二年为5．5％,第三年为5．7％,第四年为6．8％。平均每年发病率为4．8％。并发原发性肝癌的危险因素有以下几个：年龄大于50岁、有长期饮酒史（饮酒量大于75g／天）、有出血史、甲胎蛋白大于50μg／L、凝血酶原活动度小于70％、血小板计数小于60×10^9／、凝血酶原活动度小于70％为独立的危险因素。根据独立的危险因素可建立并发原发性肝癌的预测公式,其预测值为0—4．84。预测值大于2．57的患者为发生原发性肝癌的高风险人群,其4年中肝癌的累积发生率为61％。预测值小于2．57的患者为低风险人群,其4年中肝癌的累积发生率为8．1％。     

Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

Hepatocellular carcinoma(HCC)is a grave primary liver cancer that has a limited therapeutic option because it is generally diagnosed later in an advanced stage due to its aggressive biologic behavior.The early detection of HCC has a great impact on the treatment efficacy and survival of patients at high risk for cancer.Potential host,environmental,and virus-related risk factors have been introduced.Hepatitis B virus(HBV)is a major cause of end-stage liver diseases such as liver cirrhosis or HCC in endemic areas,and its serologic or virologic status is considered an important risk factor.HCC risk prediction derived from the identification of major risk factors is necessary for providing adequate screening/surveillance strategies to high-risk individuals.Several risk prediction models for HBV-related HCC have been presented recently with simple,efficient,and readily available to use parameters applicable to average-or unknown-risk populations as well as high-risk individuals.Predictive scoring systems of risk estimation to assess HCC development can provide the way to an evidence-based clinical approach for cost-and effort-effective outcomes,capable of inducing a personalized surveillance program according to risk stratification.In this review,the concepts and perspectives of the risk prediction of HCC are discussed through the analysis of several risk prediction models of HBV-related HCC.     

Risk factors for hepatocellular carcinoma in a cohort infected with hepatitis B or C

Background and Aim: The incidence of hepatocellular carcinoma ( HCC) has increased in Australia in recent decades, a large and growing proportion of which occurs among a population chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). However, risk factors for HCC among these high‐risk groups require further characterization. Methods: We conducted a population‐based cohort study using HBV and HCV cases notified to the New South Wales Health Department between 2000 and 2007. These were linked to cause of death data, HIV/AIDS notifications, and hospital records. Proportional hazards regression was used to identify significant risk factors for developing HCC. Results: A total of 242 and 339 HCC cases were linked to HBV (n = 43 892) and HCV (n = 83 817) notifications, respectively. For both HBV and HCV groups, being male and increasing age were significantly associated with risk of HCC. Increasing comorbidity score indicated high risk, while living outside urban areas was associated with lower risk. Hazard ratios for males were two to three times those of females. For both HBV and HCV groups, cirrhosis, alcoholic liver disease, and the interaction between the two were associated with significantly and considerably elevated risk. Conclusion: This large population‐based study confirms known risk factors for HCC. The association with older age highlights the potential impact of HBV and HCV screening of at‐risk groups and early clinical assessment. Additional research is required to evaluate the impact of improving antiviral therapy on HCC risk.     

基于多数据库分析肝细胞癌组织FAM49B基因水平及其临床意义

目的 利用多数据库分析肝细胞癌(HCC)组织FAM49B基因水平及其临床意义。方法 利用Oncomine和GEPIA数据库分析HCC组织与正常肝组织FAM49B基因水平,从TCGA获取临床病例资料,应用SPSS 21.0软件统计分析不同临床和病理学特征的HCC组织FAM49B基因水平的异同。自Kaplan Meier Plotter数据库分析不同FAM49B基因水平的HCC患者预后的异同,自MethHC数据库分析FAM49B启动子区甲基化水平,利用String数据库分析与FAM49B相互作用的蛋白网络,采用基因集富集分析(GSEA)预测FAM49B在HCC发病过程中可能的信号调控通路。结果 对Oncomine和GEPIA数据库分析显示HCC组织FAM49B基因水平显著高于正常肝组织(P均<0.01);不同性别(P=0.001)、有无肝硬化(P=0.003)、不同肿瘤分化程度(P=0.004)的HCC组织FAM49B基因水平显著不同,而不同年龄、肿瘤大小、病理学分期、甲胎蛋白水平和有无脉管侵犯者无显著性差异(P均>0.05);与FAM49B低水平患者比,FAM49B高水平患者总体生存期显著缩短,具有统计学意义(HR=1.8,P=0.0012);与正常肝组织相比,HCC组织FAM49B启动子区甲基化水平显著降低(P＜0.005);与FAM49B相互作用的蛋白有SERPINA1、ISLR和FERMT3;在FAM49B mRNA高水平组织富集到细胞凋亡、细胞周期、调节自噬和P53信号通路等相关基因集(P均<0.05)。结论 FAM49B在HCC组织呈高水平,其基因水平与HCC恶性程度和患者不良预后相关,可能作为癌基因在HCC发生发展过程中发挥作用,有望成为HCC诊断及预后评估的新靶点。     

Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

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Genetic variants of heat shock protein A1L2437 and A1B1267 as possible risk factors for hepatocellular carcinoma in India

To study the role of heat shock protein A1L (HSPA1L) and A1B (HSPA1B) polymorphisms and subsequent risk of hepatocellular carcinoma (HCC) in India. Subjects enrolled included 185 cases of HCC, 182 cases of chronic hepatitis (CH) and 200 healthy controls. Genomic DNA was typed for HSPA1L2437 and HSPA1B1267 SNP using polymerase chain reaction with restriction fragment length polymorphism. Other risk factors were also analysed. Hepatitis B virus (HBV) infection, older age >35 years and high aflatoxin level in urine increased the risk of HCC. The frequencies of HSPA1L BB genotype and B allele in HCC were more than in CH [odds ratio (OR): 9.83; P = 0.000], but also in HBV‐related HCC than Chronic Hepatitis B (CHB) [OR: 3.44; P = 0.004] and HCV‐related HCC compared to CHC [OR: 6.32; P = 0.010]. The frequency of HSPA1B genotype in the homozygous state was more in CH [OR: 6.01; P = 0.001] and is a good marker to predict the risk of HCV‐related CH (CHC) compared to controls. HCV‐related HCC has a higher frequency of the B allele of HSPA1B than healthy controls [OR: 3.95; P = 0.000] and CHC [OR: 2.35; P = 0.000], respectively. The frequencies increased further significantly in CHC compared to healthy controls [OR: 9.26; P = 0.000]. The risk for the development of CH and HCC compared to healthy controls irrespective of the aetiology was significant in terms of the HSPA1B marker than HSPA1L in the Indian population.