乙型肝炎相关性肝癌术后抗病毒治疗的临床意义

目的探讨抗病毒治疗对HBV相关性肝癌术后的影响。方法回顾性分析113例HBV相关性肝癌并行根治性切除患者的病例资料,术后接受抗病毒治疗的为治疗组44例,单纯手术切除的为对照组69例。比较两组1、3、5年无瘤生存率及肝癌复发时肝功能的差异。结果治疗组和对照组的1、3、5年无瘤生存率分别为81.8%、38.6%、26.7%和73.9%、26.5%、13.6%,两组比较差异有统计学意义(P=0.038)。至随访终点,共有88例肝癌复发,治疗组(n=32)相对于对照组(n=56)的ALT、Child-Pugh评分、HBV DNA在肝癌复发时明显降低,分别为[(38.2±20.9)U/L比(48.0±20.3)U/L,P=0.046]、[(5.41±0.76)lg拷贝/mL比(6.14±1.55)lg拷贝/mL,P=0.014]、[2.70 lg拷贝/mL比(5.23±1.49)lg拷贝/mL,P0.01]。结论抗病毒治疗能够改善HBV相关性肝癌切除术后的无瘤生存率,并有助于肝癌患者术后残肝功能的恢复,为肝癌复发的综合治疗创造条件。     

Clinical features of hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer death,and chronic hepatitis B is a serious worldwide problem.The epidemiology of HCC is distinctive.Hepatitis B virus (HBV) plays a major role in hepatocarcinogenesis.Prevention of HBV-related HCC is a key issue in current hepatology.This paper describes the prevention and clinical features of HBVrelated HCC,along with a short review of the disease.     

Safety of hepatectomy for elderly patients with hepatocellular carcinoma

The number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. Characteristics of elderly HCC patients are a higher proportion of females, a lower rate of positive hepatitis B surface antigen, and a higher rate of positive hepatitis C antibodies. Careful patient selection is vital for performing hepatectomy safely in elderly HCC patients. Treatment strategy should be decided by not only considering tumor stage and hepatic functional reserve, but also physiological status, including comorbid disease. Various assessment tools have been applied to predict the risk of hepatectomy. The reported mortality and morbidity rates after hepatectomy in elderly HCC patients ranged from 0% to 42.9% and from 9% to 51%, respectively. Overall survival rate after hepatectomy in elderly HCC patients at 5 years ranged from 26% to 75.9%. Both short-term and long-term results after hepatectomy for strictly selected elderly HCC patients are almost the same as those for younger patients. However, considering physiological characteristics and the high prevalence of comorbid disease in elderly patients, it is important to assess patients more meticulously and to select them strictly if scheduled to undergo major hepatectomy.     

High-dose hepatitis B immunoglobulin therapy in hepatocellular carcinoma with hepatitis B virus-DNA/hepatitis B e antigen-positive patients after living donor liver transplantation

AIM: To investigate the impact of high-dose hepatitis B immunoglobulin(HBIG) on hepatocellular carcinoma(HCC) and hepatitis B virus(HBV) recurrence and overall survival after living donor liver transplantation(LDLT).METHODS: We investigated 168 patients who underwent LDLT due to HCC, and who were HBV-DNA/hepatitis B e antigen(HBe Ag)-positive, from January 2008 to December 2013. After assessing whether the patients met the Milan criteria, they were assigned to the low-dose HBIG group and high-dose HBIG group. Using the propensity score 1:1 matching method, 38 and 18 pairs were defined as adhering to and not adhering to the Milan criteria. For each pair, HCC recurrence, HBV recurrence and overall survival were analyzed by the Kaplan-Meier method and the log rank test according to the HBIG dose. RESULTS: Among those who met the Milan criteria, the 6-mo, 1-year, and 3-year HCC recurrence-free survival rates were 88.9%, 83.2%, and 83.2% in the low-dose HBIG group and 97.2%, 97.2%, and 97.2% in the high-dose HBIG group, respectively(P = 0.042).In contrast, among those who did not meet the Milan criteria, HCC recurrence did not differ according to the HBIG dose(P = 0.937). Moreover, HBV recurrence and overall survival did not differ according to the HBIG dose among those who met(P = 0.317 and 0.190, respectively) and did not meet(P = 0.350 and 0.987, respectively) the Milan criteria. CONCLUSION: High-dose HBIG therapy can reduce HCC recurrence in HBV-DNA/HBe Ag-positive patients after LDLT.     

乙型肝炎和肝癌患者乙型肝炎病毒前C区1896位点突变的研究

为探索乙型肝炎病毒前Ｃ区突变是否与肝损程度及肝癌发生有关，对１３９例ＨＢｓＡｇ、ＨＢＶＤＮＡ和抗－ＨＢｅ阳性，ＨＢｅＡｇ阴性的慢性ＨＢＶ感染者和肝癌患者的血清标本，采用３＇碱基特异性聚合酶反应进行了第１８９６位核苷酸突变的检测分析。     

Intrahepatic distribution of hepatitis B virus antigens in patients with and without hepatocellular carcinoma

AIM: To study the intrahepatic expression of hepatitis B surface antigen(HBs Ag) and hepatitis B core antigen(HBc Ag) in chronic hepatitis B patients with and without hepatocellular carcinoma. METHODS: A total of 33 chronic hepatitis B patients(mean age of 40.3 ± 2.5 years), comprising of 14 HBe Ag positive and 19 HBe Ag negative patients; and 13 patients with hepatitis B virus related hepatocellular carcinoma(mean age of 49.6 ± 4.7 years), were included in our study. Immunohistochemical staining for HBc Ag and HBs Ag was done using standard streptavidin-biotin-immunoperoxidase technique on paraffin-embedded liver biopsies. The HBc Agand HBs Ag staining distributions and patterns were described according to a modified classification system. RESULTS: Compared to the HBe Ag negative patients, the HBe Ag positive patients were younger, had higher mean HBV DNA and alanine transaminases levels. All the HBe Ag positive patients had intrahepatic HBc Ag staining; predominantly with "diffuse" distribution(79%) and "mixed cytoplasmic/nuclear " pattern(79%). In comparison, only 5% of the HBe Ag-negative patients had intrahepatic HBc Ag staining. However, the intrahepatic HBs Ag staining has wider distribution among the HBe Ag negative patients, namely; majority of the HBe Ag negative cases had "patchy" HBs Ag distribution compared to "rare" distribution among the HBe Ag positive cases. All but one patient with HCC were HBe Ag negative with either undetectable HBV DNA or very low level of viremia. Intrahepatic HBc Ag and HBs Ag were seen in 13(100%) and 10(77%) of the HCC patients respectively. Interestingly, among the 9 HCC patients on anti-viral therapy with suppressed HBV DNA, HBc Ag and HBs Ag were detected in tumor tissues but not the adjacent liver in 4(44%) and 1(11%) patient respectively. CONCLUSION: Isolated intrahepatic HBc Ag and HBs Ag can be present in tumors of patients with suppressed HBV DNA on antiviral therapy; that may predispose them to cancer development.     

Expression of B7-H4 and hepatitis B virus X in hepatitis B virus-related hepatocellular carcinoma

AIM: To investigate the expression and clinical significance of B7-H4 and hepatitis B virus X(HBx) protein in hepatitis B virus-related hepatocellular carcinoma(HBV-HCC).METHODS: The expression of B7-H4 in the human HCC cell lines Hep G2 and Hep G2.2.15 were detected by western blot, flow cytometry, and immunofluorescence. The expression of B7-H4 and HBx in 83 HBV-HCC was detected by immunohistochemistry, and the relationship with clinicopathological features was analyzed. Paraffin sections were generated from 83 HBV-HCC patients(22 females and 61 males) enrolled in this study. The age of these patients ranged from 35 to 77 years, with an average of 52.5 ± 11.3 years. All experiments were approved by the Ethics Committees of the Second Affiliated Hospital, Zhejiang University School of Medicine.RESULTS: B7-H4 was significantly upregulated in Hep G2.2.15 cells compared to Hep G2 cells. Specifically, the protein expression of B7-H4 in the lysates of Hep G2 cells was more than that in Hep G2.2.15 cells. In addition, HBx was expressed only in Hep G2.2.15 cells. Similar data were obtained by flow cytometry. The positive rates of B7-H4 and HBx in the tissues of 83 HBV-HCC patients were 68.67%(57/83) and 59.04%(49/83), respectively. The expression of HBx was correlated with tumor node metastases(TNM) stage, and the expression of B7-H4 was positively correlated with HBx(rs = 0.388; p 0.01). The expression level of B7-H4 in HBx-positive HBV-HCC tissues was substantially higher than that in HBx-negative HBV-HCC tissues. The expression level of B7H4 was negatively related to tumor TNM stage.CONCLUSION: Higher expression of HBx and B7-H4 was correlated with tumor progression of HBV-HCC, suggesting that B7-H4 may be involved in facilitating HBV-related hepatocarcinogenesis.     

Liver transplantation for hepatitis B virus: Decreasing indication and changing trends

AIM: To evaluate the indication and outcome of hepatitis B virus(HBV)-related liver transplantation(LT) in the era of newer antiviral agents.METHODS: We collected data on all patients who underwent transplantation at King Faisal Specialist Hospital and Research Center.These data included demographic,perioperative and long-term postoperative follow-up data including viral serological markers,HBV DNA,and repeated liver imaging.Between January 1990 and January 2012,133 patients(106 males and 27 females) underwent LT for HBV-related cirrhosis at our center.All patients were followed up frequently during the first year following transplantation,according to our standard protocol; follow-up visits occurred every 3-6 mo thereafter.Breakthrough infection was definedas re-emergence of HBV-DNA or hepatitis B surface antigen(HBs Ag) while on treatment.Five patients transplanted prior to 1992 did not receive immediate posttransplant anti-HBV prophylaxis; all other patients were treated with HBIG and at least one nucleos(t)ide analog.RESULTS: One hundred and thirty-three patients underwent LT for HBV and were followed for a median of 82 mo(range: 1-274).The rates of post-LT survival and HBV recurrence during the follow-up period were 89% and 11%,respectively.The following factors were associated with disease recurrence: younger age(44.3 ± 16.2 years vs 51.4 ± 9.9 years,P = 0.02),positive pretransplant hepatitis B e antigen(HBe Ag)(60% vs 14%,P 0.0001),detectable pretransplant HBV DNA(60% vs 27%,P = 0.03),positive posttransplant HBs Ag(80% vs 4%,P 0.0001) and positive posttransplant HBe Ag(27% vs 1%,P 0.0001).Forty-four(33%) patients had hepatocellular carcinoma(HCC).In the first(pre-2007) group,HBV was the second leading indication for LT after hepatitis C virus infection.A total of 64 transplants were performed,including 46(72%) for decompensated HBV cirrhosis,12(19%) for decompensated cirrhosis complicated by HCC and 6(10%) for compensated cirrhosis complicated by HCC.In the second group,nonalcoholic steatohepatitis surpassed HBV as the second leading indication for LT.A total of 69 HBV related transplants were performed,including 43(62%) for decompensated HBV cirrhosis,7(10%) for decompensated cirrhosis complicated by HCC and 19(27.5%) for compensated cirrhosis complicated by HCC.There was a significant(P = 0.007) increase in the number of transplants for compensated cirrhosis complicated by HCC.CONCLUSION: The use of potent anti-HBV agents has led to a changing trend in the indications for LT.HBV is currently the third leading indication for LT in this hyperendemic area.     

慢性乙型肝炎病毒感染者肝细胞癌筛查和监测

肝细胞癌是我国常见恶性肿瘤,疾病负担十分沉重。筛查和监测是提高肝细胞癌患者早诊早治和生存率的有效措施。慢性乙型肝炎病毒感染是我国肝细胞癌的主要病因,有必要制定专门的筛查和监测策略。中国肝炎防治基金会组织国内有关专家,参考国内外相关指南,并结合当前研究进展和临床实践经验共同讨论后达成一致意见,旨在为规范开展慢性乙型肝炎病毒感染者肝细胞癌的筛查和监测提供参考,进而改善我国肝细胞癌的防控效果和患者预后。     

老年CHC临床特点及抗病毒治疗策略研究进展

由于患者老龄化和病程不断延长,老年慢性丙型肝炎（chronic hepatitis C,CHC）患者的治疗越来越受到关注。由于老年患者感染丙型肝炎病毒（HCV）的时间较长,罹患肝硬化和肝癌的风险较高。老年丙型肝炎患者可能还伴有多种肝外基础疾病,如恶性肿瘤、肾脏疾病、糖尿病、心血管疾病和神经认知障碍等。目前,新型直接抗病毒药物（DAA）对老年CHC患者的抗病毒治疗效果和相关并发症情况尚不明了。有限的有关DAA治疗老年CHC患者的研究资料表明,年龄不应成为DAA治疗的障碍。     

Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma

IntroductionUse of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC).MethodsThis was a bicentric retrospective study including all patients ≥75 years and treated with sorafenib for advanced HCC between January 2010 and March 2014.ResultsOf the 51 patients included (median age: 78 years, range: 75–92; performance status (PS) 0–1: 98%; cirrhosis: 88.2%; Child–Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3–4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients ≥80 years were associated with severe AE (OR: 13.3; p = 0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS ≥1 at baseline (OR: 10.4; p = 0.01), or other cardiovascular histories (OR: 30.9; p = 0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p < 0.0001).ConclusionTolerance of Sorafenib seems to be low in elderly, especially for patients aged ≥80 years or with PS ≥1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival.     

Safety and efficacy of lamivudine after radiofrequency ablation in patients with hepatitis B virus-related hepatocellular carcinoma

Background Antiviral treatments for hepatitis B virus (HBV) are not established in patients with HBV-related hepatocellular carcinoma (HCC). Aim To investigate the safety and efficacy of lamivudine (LAM) in patients with HBV-related HCC who were treated with radiofrequency ablation (RFA). Methods RFA-treated patients with HBV-related HCC were retrospectively divided into those who received LAM (LAM group) and those who did not (nontreatment group). The first-year changes in serum alanine aminotransferase (ALT), total bilirubin (TBIL), and albumin (ALB) levels were compared in corresponding subsets based on Child-Pugh classification (Mann–Whitney U test) and between one-to-one matched pairs (Wilcoxon signed rank test), who were selected on the basis of their propensity scores for receiving LAM. Overall and recurrence-free survival was also compared. Results Complete ablation of HCC was achieved in 104 patients with HBV-related HCC between January 2000 and December 2005. LAM was administered to 33 patients after RFA. Serum HBV-DNA became negative by TMA method in 24 (73%) patients. Four patients showed redetection of HBV-DNA with ALT elevation. Subset analysis based on initial Child-Pugh class and paired analysis with matching revealed significant decreases in ALT and bilirubin levels and increases in ALB levels in the first year in the LAM group (ΔALT = −17, ΔALB = +0.3, and ΔTBIL = −0.2) compared with controls (ΔALT = +5, ΔALB = ±0.0, and ΔTBIL = +0.3). Overall survival and recurrence-free survival did not differ between the two groups. No specific adverse effect was observed in the LAM group. Conclusion LAM after RFA for HBV-related HCC was safe and improved liver function. Further studies are needed to evaluate its effect on survival.     

Risk calculators for hepatocellular carcinoma in patients affected with chronic hepatitis B in Asia

Risk calculators are widely used in many clinical fields, and integrate several important risk factors through the conversion of a risk function into a single measure of risk. Several studies have been carried out to create risk calculators for the prediction of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Most of them were hospital-based, with limited sample sizes and insufficient external validation. These study groups collaborated to establish the REACH-B risk score, which incorporated five clinical variables to predict HCC risk. This risk score was then validated in international clinical cohorts. Evidence suggests that quantitative serum HBsAg level provides additional predictability of HCC, especially in patients with low levels of hepatitis B virus DNA. This novel marker was incorporated into a risk calculator and was internally validated. This tool will hopefully be externally validated in the near future. Risk calculators can be used to support clinical practice, and to establish preventive measures; several “off-label” extension usages have also been implemented. Albeit beneficial, several precautions and discussions should be noted in using the risk calculators. The future development of risk calculators for CHB patients can be extended by applying them to additional CHB-related outcomes, and by incorporating emerging risk parameters.     

3008例乙型肝炎肝硬化患者的并发症及死因分析

目的研究首都医科大学附属北京地坛医院乙型肝炎肝硬化住院患者的并发症、合并症及死亡的相关危险因素。方法分别回顾性分析本院2008年1月至2010年12月2568例和2011年1月至2014年9月3008例乙型肝炎肝硬化住院患者的相关资料。结果发现乙型肝炎肝硬化并发症发病率最高为原发性肝癌,不同时期比较发现发病率呈上升趋势(P=0.000),其余并发症如腹水、上消化道出血、自发性细菌性腹膜炎、肝性脑病、肝肾综合征发病率呈下降趋势(P=0.000)。2型糖尿病、高血压等合并症发病率前后比较无统计学差异(P=0.399,P=0.089)。除自发性细菌性腹膜炎外,肺部感染是肝硬化住院患者最易发的感染。对不同时期死亡的相关危险因素进行多元回归分析,肝癌、自发性细菌性腹膜炎、肝性脑病、肝肾综合征和上消化道出血均与病死显著相关(P=0.000)。结论原发性肝癌仍然是乙型肝炎肝硬化最常见并发症,也是乙型肝炎肝硬化最主要的病死原因,病死患者均伴发多种并发症。     

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     

Occult hepatitis B virus and hepatocellular carcinoma

Occult hepatitis B virus (HBV) infection (OBI) is a challenging pathobiological and clinical issue that has been widely debated for several decades. By definition, OBI is characterized by the persistence of HBV DNA in the liver tissue (and in some cases also in the serum) in the absence of circulating HBV surface antigen (HBsAg). Many epidemiological and molecular studies have indicated that OBI is an important risk factor for hepatocellular carcinoma (HCC) development. OBI may exert direct pro-oncogenic effects through the activation of the same oncogenic mechanisms that are activated in the course of an HBsAg-positive infection. Indeed, in OBI as in HBV-positive infection, HBV DNA can persist in the hepatocytes both integrated into the host genome as well as free episome, and may maintain the capacity to produce proteins-mainly X protein and truncated preS-S protein - provided with potential transforming properties. Furthermore, OBI may indirectly favor HCC development. It has been shown that the persistence of very low viral replicative activity during OBI may induce mild liver necro-inflammation continuing for life, and substantial clinical evidence indicates that OBI can accelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for HCC development.     

Key role of hepatitis B virus mutation in chronic hepatitis B development to hepatocellular carcinoma

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). The HBV mutations, which include point mutation, deletion, insertion and truncation mutation of HBV gene in 4 open reading frames (S, C, P, X), are closely associated with HCC pathogenesis. Some mutations accumulated during chronic HBV infection could be regarded as a biomarker to predict the occurrence of HCC. The detection of the mutations in clinical practice could be helpful for defining better preventive and therapeutic strategies and, moreover, predicting the progression of liver disease.     

Autophagy and microRNA in hepatitis B virus-related hepatocellular carcinoma

Approximately 350 million people worldwide are chronically infected by hepatitis B virus (HBV). HBV causes severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). In about 25% of affected patients, HBV infection proceeds to HCC. Therefore, the mechanisms by which HBV affects the host cell to promote viral replication and its pathogenesis have been the subject of intensive research efforts. Emerging evidence indicates that both autophagy and microRNAs (miRNAs) are involved in HBV replication and HBV-related hepatocarcinogenesis. In this review, we summarize how HBV induces autophagy, the role of autophagy in HBV infection, and HBV-related tumorigenesis. We further discuss the emerging roles of miRNAs in HBV infection and how HBV affects miRNAs biogenesis. The accumulating knowledge pertaining to autophagy and miRNAs in HBV replication and its pathogenesis may lead to the development of novel strategies against HBV infection and HBV-related HCC tumorigenesis.