慢性乙型肝炎相关性肝细胞癌的危险因素研究进展

慢性乙型病毒性肝炎是我国肝癌的最主要病因,肝癌的早筛早治有利于改善患者的预后。目前还没有可以直接诊断的早期标志物,因此对慢性乙型肝炎患者发生肝细胞癌的危险因素研究,具有重要意义。本篇综述主要总结了慢性乙型肝炎进展至肝癌的危险因素。慢乙肝患者在HBsAg阴转后仍需监测肝癌的发生。     

NAFLD与肝细胞癌的相关性研究进展*

非酒精性脂肪性肝病（NAFLD）已成为世界范围内最常见的慢性肝脏疾病,被认为是代谢综合征在肝脏的表现,其疾病谱从轻微肝细胞脂肪变性到非酒精性脂肪性肝炎（NASH）,进一步可发展为肝硬化或肝细胞癌（HCC）。随着肥胖及胰岛素抵抗问题的日益严重,NAFLD、NASH及其相关肝硬化、肝癌患者也日益增多。近年来研究表明,NASH可不经肝硬化阶段直接发展为HCC,具体机制尚不明确。     

肝细胞癌患者癌组织miRNA-30c水平变化及其临床意义探讨*

目的 探讨肝细胞癌（HCC）患者癌组织微小RNA（miRNA）-30c（miRNA-30c）水平变化及其与预后的关系。方法 2010年2月~2012年11月我院收治的HCC患者35例,经外科手术切除肿瘤获得癌组织标本。采用RT-PCR法检测癌组织miRNA-30c相对水平。不同临床和病理因素患者癌组织miRNA-30c水平高低的风险比（OR）和95%可信区间（CI）采用Logistic二项回归分析。采用Kaplan-Meier最小乘积法评价患者的生存率,不同miRNA-30c水平患者生存率的差异比较采用Log-Rank检验。结果 35例HCC患者癌组织miRNA-30c相对水平为0.6,95%CI为0.3~0.6,其中癌组织miRNA-30c相对水平低于0.6者13例,大于0.6者22例;不同性别、年龄、肿瘤大小、分化程度、TNM分期、有无肝炎病史和血清甲胎蛋白（AFP）水平高低患者癌组织miRNA-30c水平差异无统计学意义（P>0.05）,但17例存在淋巴结转移患者癌组织miRNA-30c水平为（0.2±0.0）,显著低于18例无淋巴结转移患者【（0.8±0.1）,P<0.05】;调整后的风险比（OR）=5.4,95%CI：1.2~20.1;癌组织miRNA-30c高水平患者总生存期为（14.5±6.7）个月,95%CI为11.0~28.4个月,显著长于低水平患者【（7.9±1.5）个月,95%CI为3.2~10.7个月,P<0.05】。结论 本研究结果表明,HCC患者癌组织miRNA-30c相对水平与患者预后有关,其是否可作为潜在的PLC诊断和预后判断的生物学标志物还需进一步研究。     

慢性乙型肝炎和肝硬化患者血浆miR-181a水平变化*

目的 探讨慢性HBV感染者血浆微小RNA(miRNA)-181a的变化。方法 采用实时荧光定量PCR法检测20例乙型肝炎病毒携带者（ASC）、20例慢性乙型肝炎（CHB）患者、20乙型肝炎肝硬化（LC）患者和20例健康人血浆miR-181a水平,常规检测血清HBV DNA。结果 NC组、ASC组和LC组血浆miR-181a水平分别为（1.01±0.03）、（0.97±0.02）、（0.91±0.02）,而CHB组患者为（0.74±0.03）,显著低于前三组（P<0.001）;ASC组和LC组血清HBV DNA（3.86±2.89）lg copies/ml和（2.47±3.26）lg copies/ml,而CHB组患者为（8.96±1.63）lg copies/ml（P<0.001）;CHB患者血浆miR-181a水平与HBV DNA水平呈负相关（r=0.76,P<0.001）,ASC组和LC组血浆miR-181a水平与HBV DNA水平无显著相关性。结论 CHB患者血浆miR-181a水平降低,其意义还需要进一步探讨。     

不同核苷（酸）类药物治疗乙型肝炎相关性肝癌患者成本效益分析*

目的 探讨不同核苷（酸）类药物治疗乙型肝炎相关性肝癌患者的疗效与成本-效益。 方法 采用随机数字表法将144例乙型肝炎相关性肝癌患者分为A、B、C、D四组,每组36例,在TACE术后分别口服恩替卡韦、拉米夫定、阿德福韦酯和替比夫定抗病毒治疗,观察48 w。采用Cochran Armitage 趋势检验进行成本-效益分析。 结果 A组和B组血清ALT复常率分别为94.4%和88.9%,均显著高于C组的77.8%和D组的75.0%（P<0.05）,HBV DNA 转阴率分别为100.0%和100.0%,均显著高于C组的91.6%和D组的91.6%（P<0.05）;A、B、C、D四组ALT复常率成本-效益分别为33.81%、36.29%、38.87%和75.71%,HBV DNA转阴成本-效益分别为114.82%、129.04%、155.88%和255.77,呈递增趋势。 结论 乙型肝炎相关性肝癌患者优选的核苷（酸）类药物是恩替卡韦和拉米夫定。     

慢性乙型肝炎患者发生肝细胞癌的危险因素分析

目的探究慢性乙型肝炎(CHB)患者发生肝细胞癌(HCC)的危险因素。方法收集2013年1月—2015年6月北京地坛医院确诊的CHB且随访超过3年的患者,共1239例。其中非肝硬化患者1108例,肝硬化患者131例。收集患者的一般资料及实验室检查指标并计算APRI、FIB-4及m FZB-4评分。符合正态分布的计量资料2组间比较采用t检验;非正态分布的计量资料2组间比较采用Mann-Whitney U检验。计数资料2组间比较采用χ~2检验。影响HCC发生的独立危险因素采用Cox回归分析。采用受试者工作特征曲线下面积(AUC)比较3种评分对CHB患者发生HCC的预测能力,采用DeLong检验对各个评分的AUC进行比较。通过拟合优度检验分析m FIB-4评分校准能力。使用Kalplan-Merier法对HCC发生进行分析,log-rank法进行比较。结果中位随访时间为4.6年,37例(3.0%)患者发生HCC。多因素Cox回归分析显示,年龄(HR=1.046,95%CI:1.018～1.074,P=0.001)、ALT (HR=0.995,95%CI:0.992～0.999,P=0.008)、AST (HR=0.994,95%CI:0.990～0.998,P=0.020)和PLT (HR=0.988,95%CI:0.981～0.994,P=0.001)是影响HCC发生的独立危险因素。m FIB-4、FIB-4、APRI评分的AUC分别为0.771、0.658、0.676,其中m FIB-4评分的AUC大于FIB-4评分(Z=5.629,P 0.000 1)及APRI评分(Z=4.243,P 0.000 1)。与m FIB-4 2.68的患者相比,m FIB-4≥2.68的患者HCC发生风险更高(Z=37.840,P 0.000 1)。结论年龄、ALT、AST和PLT是CHB患者发生HCC的独立危险因素。与FIB-4,APRI评分相比,m FIB-4评分对CHB患者发生HCC的预测价值更高。m FIB-4≥2.68的CHB患者是发生HCC的高危人群。     

肠道菌群失调与肝细胞癌*

大量研究表明,肝病,特别是肝硬化和肝癌患者,发生肠道菌群紊乱或细菌过度生长的机率增高,并且肠道菌群失调与肝细胞癌的发生、发展有着密切的联系;肠道菌群所产生的脂多糖（LPS）可与其识别受体Toll样受体4（TLR4）结合,通过细胞内信号转导通路介导一系列免疫炎症反应,进一步加重肝损伤,促进炎症相关的肝细胞癌发生;抗生素可通过调节肠道菌群,减少内毒素的产生等作用有可能减缓肝细胞癌的发生和发展。     

慢性乙型肝炎患者HBV基因型分布及其耐药基因突变分析*

目的 探讨慢性乙型肝炎（CHB）患者HBV基因型及其耐药突变发生情况。方法 纳入240例接受核苷（酸）类似物单药或联合或序贯治疗的CHB患者,采用PCR扩增HBV逆转录（RT）区和序列测定鉴定耐药基因突变,采用HBV S基因测序法鉴定基因型。结果 在35例单用拉米夫定治疗的CHB患者中,发生耐药突变14例（40.0%）,突变位点为rtL80I/V、rtVl73L、rtLl80M、rtM204V/I和rtV207I,23例单用阿德福韦治疗者发生耐药突变11例（47.8%）,突变位点为rtAl81T/V、rtS213T/N、rtV214A、rtQ215S/H/P、rtl233V、rtN236T、rtP237H和rtN/H238A/K/D/S,70例单用恩替卡韦治疗者发生耐药突变10例（14.3%）,突变位点为rtM204I,12例单用替比夫定治疗者发生耐药突变5例（41.7%）,突变位点为rtI169T、rtL180M、rtT184G/S/A/I/L/F、rtS202I/G、rtM204V和rtM250V/I/L,100例接受联合或序贯治疗者发生耐药突变51例（51.0%）,突变位点为rtA194T,恩替卡韦治疗患者耐药突变发生率最低（P<0.05）;240例CHB患者中,HBV基因B型21例（8.8%）、C型216例（90.0）和D型3例（1.2%）;在发生耐药突变的91例患者中,B型6例（6.6%）、C型83例（91.2%）和D型2例（2.2%,x²=1.22,P>0.05）;在发生耐药突变的6例B型感染者中有2例（33.3%）和83例C型感染者中有15例（18.1%）发生了多重耐药突变。结论 检测CHB患者感染HBV基因型并及时获得耐药突变基因分布,将有助于指导临床治疗。     

荧光定量聚合酶链反应检测乙型肝炎患者血清HBV DNA及临床价值

目的探讨荧光定量聚合酶链反应法定量检测乙型肝炎病毒(HBV)核酸的临床应用价值。方法应用荧光定量聚合酶链反应定量检测1962例乙型肝炎患者血清HBV DNA水平并与血清HBV标志物进行比较,并对35例乙型肝炎患者在拉米夫定治疗前后血清HBV DNA含量及相关指标作动态观察。结果乙型肝炎患者HBVDNA定量范围在6.79×102～1.95×109拷贝/毫升之间,在HBeAg阳性患者,其检出率和定量拷贝数较高。拉米夫定治疗后患者外周血HBV DNA载量下降明显。结论荧光定量PCR法是一种相对准确、灵敏度高、特异性强的定量检测HBV DNA的技术,对乙型肝炎诊断、指导、临床用药和疗效监测方面具有实用价值。     

HBeAg阴性和阳性慢性乙型肝炎患者血清HBV DNA水平与肝组织炎症的关系

目的:探讨HBeAg阴性和HBeAg阳性慢性乙型肝炎(CHB)HBVDNA水平和肝组织炎症损害的关系.方法:采用荧光定量聚合酶链反应分别对331例CHB(101例HBeAg阴性和230例HBeAg阳性)患者进行血清HBVDNA定量检测和肝组织活检病理炎症分级,对比分析结果.结果:331例CHB患者血清HBVDNA水平与肝组织炎症活动度及肝纤维化程度之间无明显相关性;101例HBeAg阴性CHB患者中31例(31%)血清HBVDNA>108copies/L,随着G1-G4肝组织炎症损害级别的增高其所占例数也相应增高.HBVDNA水平与肝组织炎症病理分级的相关性有显著意义(r=0.271,P<0.005);在230例HBeAg阳性的患者中,血清HBVDNA水平与肝组织炎症呈明显的负相关(r=-0.659,P<0.001).结论:血清HBVDNA水平可作为判断HBeAg阴性CHB患者肝组织炎症损害程度的指标,在HBeAg阳性的患者中,血清HBVDNA水平与肝组织炎症呈负相关.     

慢性乙型肝炎患者血清抗卯抗体检测及其与年龄变化、病毒载量和病毒基因型的关系分析

目的探讨幽门螺杆菌（HP）在慢性乙型肝炎中的作用。方法采用病例对照研究的方法分析376例慢性乙型病毒性肝炎患者的HP感染状况与年龄、乙型肝炎病毒（HBV）DNA定量和分型的关系。结果HP感染率随年龄变化无明显差异（P〉0．05），HP感染率在慢性乙型肝炎组（56．2％）、乙型肝炎肝硬化组（69．9％）、乙型肝炎合并肝癌组（75．0％）明显高于健康对照组（43．4％）（P〈0．01），各组与慢性胃炎组（57．9％）相比较无明显差异（P〉0．05），其中肝硬化组和合并肝癌组HP感染率均高于肝炎组（P〈0．05）。不同病毒载量慢性乙型肝炎患者的HP感染率均明显高于健康对照组（P〈0．01），但不同病毒载量之间无明显差异（P〉0．05）。慢性乙型肝炎患者B基因型、C基因型和D基因型HP感染率分别为61．3％、63．3％和50．0％，三组之间比较无统计学意义（P〉0．05）。结论慢性乙型肝炎患者HP感染率明显增加，且HP感染率随着肝病病变程度的进展而增加。     

Risk stratification for hepatitis B virus related hepatocellular carcinoma

Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide, especially in the Asia–Pacific region. Several hepatitis B viral factors predictive of clinical outcomes in HBV carriers have been identified. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer‐HBV (REVEAL‐HBV) study from Taiwan illustrated the strong association between HBV‐DNA level at study entry and risk of HCC over time. In this community‐based cohort study, male gender, older age, high serum alanine aminotransferase level, positive hepatitis B e antigen, higher HBV‐DNA level, HBV genotype C infection, and core promoter mutation are independently associated with a higher risk of HCC. Another large hospital‐based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers cohort of Taiwanese patients further validated the findings of REVEAL‐HBV. The risk of HCC started to increase when HBV‐DNA level was higher than 2000 IU/mL. Both HBV‐DNA and HBsAg levels were shown to be associated with HCC development. While HBV‐DNA level had better predictive accuracy than HBsAg level, when investigating the overall cohort in patients with HBV‐DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL was identified as a new independent risk factor for HCC. With the results from REVEAL‐HBV, a risk calculation for predicting HCC in non‐cirrhotic patients has been developed and validated by independent cohorts (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B).Taken together, ample evidence indicates that HBsAg level can complement HBV‐DNA level in predicting HCC development, especially in HBV carriers with low viral load. In conclusion, HBV treatment guidelines should include the risk stratification of HCC to individualize the management of HBV carriers with different levels of HCC risk.     

Hepatitis B virus genotypes and hepatitis B surface antigen mutations in family contacts of hepatitis B virus infected patients with occult hepatitis B virus infection

Background:  The association and profile of surface gene mutations with viral genotypes have been studied in patients with chronic hepatitis B virus (HBV) but not in subjects with occult HBV infection.
Aim:  This study aimed to investigate the association of surface gene mutations with viral genotypes in occult HBV infection.
Materials & Methods:  Of 293 family contacts of 90 chronic HBV index patients, 110 consented for the study. Of 110 subjects, 97 were hepatitis B surface antigen (HBsAg) negative. HBV genotyping was done using direct DNA sequencing. The S-gene was also sequenced in 13 chronic hepatitis B patients to serve as controls.
Results:  Twenty-eight (28.8%) of the 97 subjects had occult HBV infection. Bidirectional sequencing of partial S-gene was successful in 13 of them. Seven (53.8%) of the viral sequences are genotype A1, two (15.3%) each having genotypes D5&D2 and one each (7.6%) having D1&G genotypes. Seven (53.8%) of the 13 HBsAg positive patients, had genotype D&6 (46.1%) genotype A. A128V & T143M mutations were observed in 5 of 13 (38.4%) subjects and A128V & P127S in 2 of 13 (15.3%) patients ( P  = 0.385). A128V mutation was seen in two (15.3%) subjects with D2 genotype, while T143M mutation was seen in three (23.07%) subjects with A1genotype. At aa125, three (23.07%) subjects with D5 genotype had methionine instead of threonine. There were wild type sequences in five (38.4%) subjects, one each of D1, G genotypes (20%) and four A1 (80%) genotypes. None of the subjects had G145R mutation.
Conclusions:  Occult HBV infection may be common in household contacts of chronic HBV infected patients. Equal prevalence of A&D sub-genotypes was present in occult HBV subjects and in chronic HBV patients. Mutations of the S-gene are genotype specific in both occult as well as chronic HBV infection.     

慢性乙型肝炎患者血清HBV DNA载量与肝组织病理学变化关系研究

探讨慢性乙型肝炎轻度患者血清HBV DNA载量与肝组织病理学变化的关系。方法根据血清HBeAg状态将310例慢性乙型肝炎轻度患者分为HBeAg阳性和HBeAg阴性,应用荧光定量PCR技术检测血清HBV DNA水平,常规进行肝活检术和病理学观察,分析血清HBV DNA载量与肝组织病理学变化的关系。结果224例HBeAg阳性患者肝组织炎症程度以G0（42.0%）为主,纤维化程度以S0（58.0%）为主;86例HBeAg阴性患者炎症程度以G0（29.1%）、G1（30.2%）、G2（34.9%）为主,纤维化程度以S0（51.2%）为主;HBeAg阳性患者血清HBV DNA水平与肝组织炎症程度无明显相关（r=-0.098,P＞0.05）,与纤维化分期间存在负相关关系（r=-0.309,P＜0.01）;HBeAg阴性患者血清HBV DNA水平与肝组织炎症程度存在正相关关系（r=0.306,P＜0.01）,与纤维化程度无明显相关（r=0.112,P＞0.05）。结论 HBeAg阳性与HBeAg阴性患者血清HBV DNA载量与肝组织病理学变化的关系存在显著差别,应区别分析其临床意义。     

Prevention of hepatocellular carcinoma in patients with chronic hepatitis B

Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma(HCC). Globally,over half a million people each year are diagnosed with HCC,with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus(HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC,the molecular basis for this association has not been fully elucidated. In addition,a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis,recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agentsin achieving profound and durable suppression of HBV DNA levels while improving liver function and histology,robust evidence of other long-term clinical outcomes,such as prevention of HCC,are limited.     

A one-year trial of entecavir treatment in patients with HBeAg-positive chronic hepatitis B

To evaluate the efficacy and safety of entecavir （ETV） in hepatitis Be antigen （HBeAg）-positive chronic hepatitis B （CriB） patients who had not received a nucleoside analogue and who had failed in lamivudine （LVD） therapy. METHODS： Sixty-one patients were divided into three groups. Forty-two patients who had not received a nucleoside analogue were randomized into two groups： group A （n = 21） received LVD 100 mg/d and group B （n -- 21） received ETV 0.5 mg/d. The remaing 19 patients treated with LVD （n = 19）, who switched to ETV 1.0 mg/d served as group C. All patients were treated for 48 wk. HBV DNA levels were measured with polimerase- chain-reaction （PCR） analysis. Liver function tests, HBV serology and safety assessments were also conducted. RESULTS： Significantly more patients in group B （52.1% and 71.4%） had undetectable HBV DNA levels than in groups A （35.8% and 38%; P 〈 0.0001） and C （10.6% and 21.1%, P 〈 0.0001） at wk 24 and 48, respectively. At wk 48, ALT levels were normalized in more patients in group B （85.7%） than in groups A （76.2%） and C （74%）. CONCLUSION： ETV had a significantly higher response rate than LVD in patients with HBeAg-positive CriB who had not previously received a nucleoside analogue; ETV can effectively inhibit the replication of HBV DNA and normalize the levels of ALT in refractory CriB patients treated with LVD; and ETV is safe in clinical application.     

Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C

AIM:To study the potential association between hepatocellular carcinoma(HCC)in patients with chronic hepatitis C(CHC),cirrhosis and latent hepatitis B(LHB)infection,defined as the absence of detectable serum hepatitis B surface antigen(HBsAg)and the presence of hepatitis B core antibody(HBcAb).METHODS:This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody(HCV Ab)(+)and HBsAg(-)at Wayne State University between 1999 and 2008.From these,108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining(77)were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease.Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-)age,race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC.A subgroup of controls included 118matched patients with liver cirrhosis.χ2test and t test were used for data analysis.RESULTS:Seventy-seven percent of patients in all3 groups were African Americans.Patients with HCC had a significantly higher body mass index(P=0.03),a higher rate of co-infection with human immunodeficiency virus(HIV)(P=0.05)and a higher prevalence of alcohol abuse(P=0.03)than the controls.More patients with HCC had LHB than controls(78%vs39%,P=0.01).Sixty three percent of patients with HCC were both hepatitis B surface antigen(HBsAb)(-)and HBcAb(+)compared to 23%of controls(P<0.01).When compared to cirrhotic controls,the frequency of HBcAb(+)remained higher in patients with HCC(78%vs 45%,P=0.02).Patients with HCC were more likely to be both HBsAb(-)and HBcAb(+)than the cirrhotic controls(63%vs 28%,P=0.01).Although not statistically significant,100%of CHC and HIV coinfected patients with HCC(n=11)were HBcAb(+)when compared to controls(44%;n=9).CONCLUSION:These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.