隐匿性HBV感染与肝细胞肝癌关系的研究进展

乙型肝炎病毒（hepatitis B virus,HBV）和原发性肝癌（hepatocelluar carcinoma,HCC）的发病密切相关,随着研究的深入,人们开始关注乙肝病毒感染的特殊形式（隐匿性HBV感染）和原发性肝癌的联系。现综述隐匿性HBV感染和原发性肝癌的发病关系和机制的研究进展。     

Isoflavone consumption and subsequent risk of hepatocellular carcinoma in a population‐based prospective cohort of Japanese men and women

The incidence of hepatocellular carcinoma (HCC) is much higher in men than in women. Several experiment and epidemiological studies have suggested that estrogen might play an inhibitory role in the development of HCC. Because isoflavones have a similar structure as 17β‐estradiol and appear to have an anti‐estrogenic effect in women and estrogenic effect in men, we hypothesized that the effect of isoflavones on HCC differs by sex. We investigated the association between isoflavones (genistein and daidzein) and soy products and HCC in Japan in a population‐based prospective study in 19,998 Japanese (7,215 men and 12,783 women) aged 40–69 years. During 11.8 years of follow‐up, 101 subjects (69 men and 32 women) were newly diagnosed with HCC. Case patients were grouped according to consumption of isoflavones and soy products and stratified by hepatitis virus infection. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC were calculated by Cox proportional‐hazards modeling. In women, genistein and daidzein were dose‐dependently associated with an increased risk of HCC, with multivariable HRs for the highest versus lowest tertile of 3.19 (95%CI = 1.13–9.00, p_trend = 0.03) and 3.90 (95% CI = 1.30–11.69, p_trend = 0.01), respectively. No association between isoflavones and HCC was observed in men. These results persisted when analysis was restricted to subjects positive for either or both hepatitis C and B virus. In conclusion, isoflavone consumption may be associated with an increased risk of HCC in women. Women with hepatitis virus infection may be advised to abstain from isoflavone consumption. Further studies are warranted to confirm these findings. © 2008 Wiley‐Liss, Inc.     

多发性骨髓瘤与乙型肝炎病毒感染的临床观察

目的 探讨多发性骨髓瘤（MM）患者乙型肝炎病毒（HBV）的感染状况及乙肝表面抗原（HBsAg）阳性MM患者的临床特点。方法 应用ELISA法测定196例MM患者以及48 697例健康体检者（对照组）的HBV标记物,PCR法测定HBV-DNA拷贝数。结果 196例MM 患者中HBsAg阳性者有5例（2.6％）,与对照组的3.4%比较差异无统计学意义（P>0.05）。5例HBsAg阳性MM患者的HBV血清学标记均为HBsAg、HBeAb、HBcAb三者阳性,其中2例HBV-DNA拷贝数＞1000,给予拉米夫定治疗。5例患者均给予抗MM治疗,未见HBV激活和肝功能异常。结论 HBV感染可能与MM发病无关,抗MM治疗对HBV的病毒激活及肝功能的影响可能不明显,仍有待于进一步研究。     

Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review

We combined information published worldwide on the seroprevalence of hepatitis B surface antigen (HbsAg) and antibodies against hepatitis C virus (anti-HCV) in 27 881 hepatocellular carcinomas (HCCs) from 90 studies. A predominance of HBsAg was found in HCCs from most Asian, African and Latin American countries, but anti-HCV predominated in Japan, Pakistan, Mongolia and Egypt. Anti-HCV was found more often than HBsAg in Europe and the United States.     

肝细胞肝癌血清AFP值与HBV感染的关系

目的:探索肝细胞肝癌患者血清AFP值与HBV感染模式的关系.方法:回顾性分析2009年1月到2011年6月于我院就诊并手术的所有肝脏恶性肿瘤患者的临床资料.结果:共有217例肝脏恶性肿瘤患者纳入研究:肝细胞肝癌(HCC)组176例,非HCC组41例.HCC组中HBV感染模式前三位的分别是HBsAg,HBeAb和HBcAb阳性(小三阳)(30.7％),HBsAg和HBcAb阳性(25.6％)及HBsAg,HBeAg和HBcAb阳性(大三阳)(20.5％).HCC组血清AFP值高于非HCC组血清AFP值(P ＜0.001),但HCC组内HBV感染组与非HBV感染组之间血清AFP水平无统计学差异(P =0.147),三种主要HBV感染模式之间血清AFP值也无统计学差异(P=0.578).同样的,无论在AFP阴性组(＜20ng/ml)还是AFP阳性组(≥20ng/ml),三种主要的HBV感染模式之间的血清AFP值均无统计学差异.结论:HCC的血清AFP值明显高于其他类型的肝脏恶性肿瘤血清AFP值,但HCC组内HBV的各种感染模式之间AFP值水平无差异.     

Replication efficiency and sequence analysis of full-length hepatitis B virus isolates from hepatocellular carcinoma tissues

Prolonged replication of hepatitis B virus (HBV) in liver tissues of hepatitis B patients has been considered as an important risk factor for the development of malignancy. Few studies on full-length HBV sequencing in association with the replication efficiency of isolates from HCC tissues have been reported. To study the structural and functional genomics of HBV isolates from Chinese hepatocellular carcinoma (HCC) patients, full-length HBV genomes were amplified from 6 HBV-marker positive HCC tissues and used to transfect HepG2 cells. Five of 6 isolates showed high replicative efficiency. All isolates were of genotype C and "hot-spots" mutations were detected in the B cell and T helper (Th) cell epitopes of the envelope and the core region. In addition, the X region of 2 isolates contained a stop-codon mutation that was predicted to result in a truncated X protein. High replicative HBV immune escape mutants that persist in infected hepatocytes could be 1 of the important factors to initiate pathological processes for the development of HCC in Chinese patients.     

抗病毒治疗对肝癌患者围手术期胰岛素抵抗的改善作用

目的:探讨抗病毒治疗对肝癌患者围手术期胰岛素抵抗的改善作用。方法:110例肝癌切除术患者随机分为治疗组（60例）及对照组（50例）,检测两组患者围手术期空腹血糖(fasting plasma glucose,FPG)、血清胰岛素水平(fasting serum insulin,FINS)、白介素6（IL-6）、肿瘤坏死因子α（TNF-α）并计算胰岛素抵抗指数（hemeostasis model assement of insulin resistance,HOMA-IR）,观察两组胰岛素抵抗变化情况。结果:两组患者术后血清IL-6、TNF-α水平均较术前升高,但治疗组升高幅度低于对照组,两组比较有统计学差异（P＜0.05）。两组患者术前存在有不同程度胰岛素抵抗,术后胰岛素抵抗水平较术前加剧,但治疗组患者术后胰岛素抵抗情况及术后并发症发生率较对照组改善,两组比较有统计学差异（P＜0.05）。结论:抗病毒治疗可改善肝癌切除术患者围手术期胰岛素抵抗。     

HBV感染与hTERT基因表达在肝细胞癌组织中的相关性研究

目的 :研究hTERT基因在HBsAg阳性与阴性肝细胞癌 (hepatocellularcarcinoma ,HCC)患者组织中表达的差异 ,探讨HBV病毒感染与hTERT基因表达在HCC中的相关性。方法 :应用免疫组化 (SP法 )和半定量逆转录聚合酶链反应 (RT PCR)分别检测 73例HCC患者组织中hTERT蛋白及其mRNA的表达情况 ,其中HBsAg阳性 5 3例 ,HBsAg阴性 2 0例 ,比较二者表达的差异。结果 :hTERT蛋白在HBsAg阳性HCC组织中的阳性表达为 48/5 3 ,在HBsAg阴性HCC组织中阳性表达为 12 /2 0 ,两组病例hTERT蛋白表达阳性率差异有统计学意义 ,P <0 0 1;hTERTmRNA在HB sAg阳性HCC组织中阳性表达为 46/5 3 ,hTERTmR NA在HBsAg阴性HCC组织中阳性表达为 11/2 0 ,两组病例hTERTmRNA表达阳性率差异有统计学意义 ,P <0 0 5 ;统计学分析显示 ,HCC中HBsAg与hTERTmRNA的表达有显著关联性 ,与hTERT蛋白的表达强度成系统性的线性趋势 ,P <0 0 1。结论 :HBsAg阳性HCC组织中hTERT基因表达的阳性率和阳性强度均明显高于HBsAg阴性HCC组织 ,差异有统计学意义 ,P <0 0 5 ;HCC中HBV病毒感染与hTERT基因表达之间具有相关性 ,提示在HCC发生发展中可能存在二者的相互作用     

Etiology of hepatocellular carcinoma in West Africa,a case–control study

Hepatocellular carcinoma (HCC) is a leading cause of cancer in West Africa where HBV infection is endemic. However, limited information is available on other risk factors such as alcohol use, HCV and HIV infection. A case–control study was conducted in referral hospitals of Abidjan (Cote d'Ivoire), Bamako (Mali) and Lome (Togo). Cases were matched with controls on age, gender and participating site. The diagnosis of HCC relied on the combination of one or more space‐occupying lesions suggestive of an HCC on a standardized abdominal ultrasound and an α‐fetoprotein level ≥400 ng/ml. HIV, HBV and HCV serology were performed. Hazardous alcohol use was assessed using the AUDIT questionnaire. A conditional logistic regression model was used to measure odds ratio (OR) with their 95% confidence intervals (CI). A total of 160 cases and 320 controls were included. Cases were predominantly men (80.0%) with a median age of 47 years (IQR 38–57). Hazardous alcohol use (OR = 4.5 [CI 1.1–18.5]), HBV infection (OR = 62.5 [CI 20.5–190.7]) and HCV infection OR = 35.9 [CI 10.0–130.3]) were independently associated with HCC. Combining the effect of HBV infection and alcohol, HBV‐infected hazardous drinkers had an OR = 149.8 (CI 13.5–1 667.0), HBV mono‐infected had an OR = 57.4 (CI 18.8–175.3) (ref: HBV‐negative). Aside the independent association of alcohol use and HBV and HCV infection with HCC, a synergic effect between alcohol use and HBV infection was identified. Timely screening and care of HBV infection and hazardous drinking might prevent a significant number of HCC in West Africa.     

Effects of interferon treatment on development and progression of hepatocellular carcinoma in patients with chronic virus infection: a meta-analysis of randomized controlled trials

Available literature on the effects of interferon (IFN) treatment on development and progression of hepatocellular carcinoma (HCC) in patients with chronic virus infection reports controversial results. The primary objective of this meta-analysis was to evaluate the effect of IFN on HCC risk in patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; IFN's efficacy on local tumor progression and survival of advanced HCC patients was also assessed. All randomized controlled trials (RCTs) comparing IFN with no antiviral treatment were selected. Finally, we identified 11 RCTs including 1,772 patients, who met our inclusion criteria to perform this meta-analysis. Our analysis results showed that IFN significantly decreased the overall HCC incidence in HCV-infected patients [relative risk (RR)=0.39; 95% confidence interval (CI)=0.26-0.59; p=0.000], subgroup analysis indicated that IFN decreased HCC incidence in HCV-related cirrhotic patients evidently (RR=0.44; 95% CI=0.28-0.68; p=0.000); but HCC incidence in nonresponders to initial antiviral therapy did not reduce by maintenance IFN therapy (RR=0.96; 95% CI=0.59-1.56; p=0.864). Analysis results also demonstrated that IFN did not significantly affect the overall rate of HCC in HBV-infected patients although there was a trend favoring IFN therapy (RR=0.23; 95% CI=0.05-1.04; p=0.056). Besides, IFN did not improve one-year overall survival of advanced HCC patients significantly (RR=1.61; 95% CI=0.96-2.69; p=0.072); however, a quantitative analysis on local tumor progression could not be performed owing to lack of unified definitions among trials included in our study. By this meta-analysis, we conclude that IFN therapy is effective in reducing overall HCC risk in chronic HCV-infected patients; using it in this subpopulation seems promising, but its administration in other subpopulations still requires further exploration.     

Concomitant and isolated expression of TGF-alpha and EGF-R in human hepatoma cells supports the hypothesis of autocrine,paracrine, and endocrine growth of human hepatoma

Single and double immunohistochemical staining for transforming growth factor (TGF)-alpha and epidermal growth factor-receptor (EGF-R) was done in order to identify the localization of TGF-alpha and EGF-R in human hepatocellular carcinoma (HCC). Single immunohistochemical staining for TGF-alpha showed immunoreactivity in the cytoplasm of hepatoma cells in 22 of 30 cases of HCC. The localization of TGF-alpha was heterogeneous from HCC cells to HCC cells. In the surrounding regenerative nodules, the hepatocytes were mildly to moderately positive for TGF-alpha. The proliferating bile ductules and peripheral nerves were also immunopositive for TGF-alpha. Single immunohistochemical staining for EGF-R demonstrated a linear localization of EGF-R along the cell membrane of the HCC cells in 21 of the 30 cases of HCC. In the regenerative nodules, the hepatocytes also showed linear staining along the cell membrane. Double staining for TGF-alpha and EGF-R in 12 cases of HCC showed a concurrent localization of TGF-alpha and EGF-R in some hepatoma cells and isolated localization of the two substances of other HCC cells. These combinations either abruptly moved around or intermingled with each other. These immonohistochemical results thus support the theory of an autocrine, paracrine, and endocrine mechanism of TGF-alpha and EGF-R on the proliferation of human hepatocellular carcinoma. © 1995 Wiley-Liss, Inc.     

The treatment choices and outcome of hepatocellular carcinoma in hemophilic patients with human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection due to contaminated blood products in Japan

BackgroundHuman immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection through unheated blood product for hemophilia caused in early 1980s has been significantly serious problem in Japan. After the development of HIV treatment in 1990s, HCV-related hepatocellular carcinoma (HCC) has been one of the most significant problem in these population. Treatment choices for HCC might be limited in hemophilia patients because of their bleeding tendency. The aim of this study was to elucidate the treatment choices and outcome of HCC in hemophilic patients coinfected with HIV/HCV due to contaminated blood products.MethodsWe asked 444 Japanese centers that specialize in treating HIV patients for participation, whether they have HIV/HCV coinfected cases with HCC, and the patient characteristics, treatments for HCC and survival after treatments were retrospectively reviewed according to each institutional medical records.ResultsOf 444 centers, 139 centers (31%) responded to the first query, and 8 centers (1.8%) ultimately provided 26 cases of HCC in coinfected hemophilic patients, diagnosed between December 1999 and December 2017. All 26 were male hemophilic patients, with a median age at HCC diagnosis of 49 (range, 34–73) years. Thirteen cases (50%) were HCV-RNA positive, and 14 cases (54%) had a solitary tumor. Even in the cases of Child-Pugh grade A, only 1 case underwent resection, and 18 cases (69%) did not receive the standard treatment recommended by the Japanese Society of Hepatology.ConclusionsHemophilic HCC patients with HIV/HCV coinfection may not routinely receive standard treatment due to their bleeding tendency and several complications related to HIV/HCV coinfection.     

Level of hepatitis B surface antigen might serve as a new marker to predict hepatocellular carcinoma recurrence following curative resection in patients with low viral load

To investigate the association between preoperative HBsAg (hepatitis B surface antigen) level and risk of HCC (hepatocellular carcinoma) recurrence following curative resection, we enrolled 826 HBV-related HCC patients who underwent curative resection and received long-term follow-up at the Eastern Hepatobiliary Surgery Hospital (Shanghai, China). Multivariate analyses showed that serum HBsAg ≥ 2000 S/CO, seropositive hepatitis B e antigen (HBeAg), γ-glutamyl transpeptidase > 61 U/L, prothrombin time > 13 s, multinodularity, lager tumor size, and major portal vein invasion were independently associated with a increased risk of HCC recurrence. Compared with HCC patients with HBsAg level < 2000 S/CO, HCC patients with HBsAg level ≥ 2000 S/CO had a higher prevalence of seropositive HBeAg, antiviral therapy, and cirrhosis; were younger; and had a higher levels of alanine transaminase (ALT), aspartate aminotransferase (AST), and HBV viral load. Multivariable stratified analyses showed HCC patients with HBsAg level < 2000 S/CO tended to have a lower incidence of HCC recurrence in following subgroups of patients, including for noncirrhotic (HR, 0.561; 95% CI, 0.345-0.914), HBV DNA < 2000 IU/mL (HR, 0.604; 95% CI, 0.401-0.912), ALT ≤ 41 U/L (HR, 0.643; 95% CI, 0.440-0.942), AST ≤ 37 U/L (HR, 0.672; 95% CI, 0.459-0.983), and seronegative HBeAg (HR, 0.682; 95% CI, 0.486-0.958). When we evaluated HBeAg-negative patients with HBV DNA < 2000 IU/mL, HBsAg level still determined risk of HCC recurrence (p = 0.014), but not HBV DNA (p = 0.550) and ALT (p = 0.186). These results suggest high levels of HBsAg increase risk of HCC recurrence following curative resection. HBsAg level might serve as a new marker to complement HBV DNA level in predicting HCC recurrence, especially in HBeAg-negative patients with low viral load.     

N‐glycan based models improve diagnostic efficacies in hepatitis B virus‐related hepatocellular carcinoma

The early diagnosis of hepatocellular carcinoma (HCC) is of great clinical desirable due to lack of specific and sensitive markers. Alterations in the sugar chains of glycoprotein synthesized by the liver contribute to the molecular basis of abnormalities in carcinogenesis. This study aims to construct and assess the diagnostic value of N‐glycan based diagnostic model in HCC identification and follow‐up. A total of 393 subjects including HBV‐related HCC, liver fibrosis and healthy controls were recruited. Follow‐up was carried out before and after surgical treatment in HCC. N‐glycome of serum glycoprotein was profiled by DNA sequencer‐assisted fluorophore‐assisted carbohydrate electrophoresis (DSA‐FACE). Multiparameters diagnostic models were constructed based on N‐glycan markers. The result found that 2 N‐glycan structure abundances (NG1A2F, Peak 4; NA3Fb, Peak 9) were useful as N‐glycan markers. The diagnostic efficacy of the log ratio [log(p9/4)] was similar to that of AFP in differentiating HCC from fibrosis. The accuracy and sensitivity of the diagnostic model combining AFP and N‐glycan markers (Cscore B) were increased 7–10% compared with that of AFP. Log(p9/4) was more efficient in monitoring the progression of HCC with regarding to vascular invasion at improved specificity (16%) and accuracy (8%) compared with that of AFP. The N‐glycan markers were found to be changed significantly after surgical resection in HCC follow‐up. We conclude that the branching α (1,3)‐fucosylated triantennary glycan and a biantennary glycan are promising as N‐glycan markers. The diagnostic models based on the N‐glycan markers and AFP improve the efficacy in HCC diagnosis and progression monitoring.     

青年人与老年人原发性肝癌的临床分析

为提高青年人和老年人原发性肝癌临床诊断和防治水平，作者比较５５例青年人与７８例老年人原发性肝癌的临床病理特征，结果显示：血清ＨＢｓＡｇ阳性者青年组高于老年组；合并肝硬化者老年组较高；两组肿瘤类型和临床ＴＮＭ分期等亦有差异。两组原发性肝癌患者在某些临床特征方面存在差异。