中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

Research advances in liver failure associated with hepatitis B virus reactivation

DOI: 10.3969/j.issn.1001-5256.2021.04.002
  • Received Date: 2020-12-23
  • Accepted Date: 2021-03-01
  • Published Date: 2021-04-20
  • Hepatitis B virus (HBV) infection is a major public issue in the world. Although currently used antiviral drugs can effectively control virus replication, they cannot clear HBV and HBV reactivation is still observed after the withdrawal of anti-HBV drugs. Meanwhile, experimental studies and clinical research have shown that after HBV infection, although 95% of the adult patients can achieve clinical cure spontaneously, virus genome still exists in host hepatocytes, and when immunosuppressants or chemotherapeutic drugs are used for the treatment of underlying diseases such as solid tumor, hematological malignancies, rheumatic immune diseases, and HCV infection, HBV replication might be reactivated. HBV reactivation may lead to severe clinical outcomes, and some patients may experience liver failure or even death. Retrospective studies in China show that 9%-30% of the cases of acute-on-chronic hepatitis B liver failure are caused by HBV reactivation, and therefore, it is of great importance to identify the population at risk of HBV reactivation and develop reasonable preventive measures, which may help to reduce the development of acute-on-chronic hepatitis B liver failure. This article reviews the definition and basis of HBV reactivation, elaborates on the predisposing factors and mechanism of HBV reactivation in inducing liver failure, and summarizes the population requiring prevention and related preventive measures.

     

  • 肝细胞癌(HCC)是全球引起肿瘤相关死亡的第三大原因1-3,目前,肝移植是HCC的最佳治疗方案4-6,但仅少数患者能够接受肝移植7-8。因此,肝切除(hepatic resection,HR)仍然是HCC的首选方案9-10。但遗憾的是,HR后3年复发率高达50%,5年总生存率(OS)只有40%~60%11-13。微波消融(microwave ablation,MWA)与HR相比具有类似的疗效,但其具有创伤小、不良反应少、对肝功能影响小等特点14-16

    然而,HR与MWA的疗效仍存在争议17-20。HCC多由肝硬化发展而来,这意味着患者肝功能储备更差,疗效更具不确定性,且肝硬化是影响HCC复发的独立因素21-23,所以,MWA与HR治疗HCC合并肝硬化的效果及安全性更具有争议,且无相关Meta分析。近年来,关于MWA与HR疗效对比的临床研究越来越丰富24-31,因此,本研究旨在收集MWA和HR治疗HCC合并肝硬化的相关文献,系统评价其临床疗效及安全性,为临床决策提供依据。

    本研究根据PRISMA指南完成,PROSPERO注册号:CRD42024509185。

    计算机检索PubMed、Cochrane Library、EMBASE、Web of Science、中国知网、维普、万方数据库,时间均为从建库至2023年11月。同时手工检索已发表的会议论文等。采用主题词+自由词的方式,英文检索词:resection、hepatectomy、surgery、ablation、liver cancer、liver neoplasm、primary hepatic carcinoma、hepatocellular carcinoma、cirrhosis、cirrhotic、hepatocirrhosis。中文检索词:微波消融、热消融、肝癌、肝肿瘤、原发性肝癌、肝细胞癌、肝硬化、外科切除、切除。

    1.3.1   研究类型

    随机对照试验(randomized controlled trial,RCT)或回顾性队列研究(retrospective cohort study,RCS)或前瞻性队列研究。

    1.3.2   研究对象

    HCC合并肝硬化患者。

    1.3.3   干预措施

    观察组采用MWA,对照组采用HR。

    1.3.4   结局指标

    (1)OS;(2)局部复发(local recurrence,LR);(3)无复发生存率(DFS);(4)肝功能;(5)不良反应;(6)手术时间;(7)出血量;(8)住院时间。

    (1)转移性肝癌或复发性肝癌;(2)不同语言撰写的同一篇文章;(3)个案报道;(4)无法提取结局指标的文献;(5)单臂研究。

    由两名研究者独立筛选文献、提取资料并交叉核对,如有分歧,则由第三方协商解决。提取(1)一般信息:第一作者、年份、类型、国家、干预措施;(2)临床数据:患者年龄、男女比例、病例数、肝功能、肿瘤大小等基线信息、随访时间、上述结局指标。

    两名研究者独立进行文献质量评价、讨论,直至获得一致的结果。非RCT使用Newcastle-Ottawa量表(NOS)评价32:≥8分为高质量,6~7分为中等质量,<6分为低质量。RCT采用Cochrane系统评价员手册5.1.0推荐的RCT偏倚风险评估工具33

    应用Stata 12.0软件进行Meta分析。计数资料采用相对危险度(RR)为效应量,计量资料采用标准化均数差(SMD)为效应指标,各效应量均给出其点估计值和95%CI。通过χ2I2检验评估异质性,P<0.1和I2≥50%提示有异质性,采用随机效应模型评估效应量,否则采用固定效应模型。如存在异质性,通过亚组分析对异质性来源进行探讨。采用Egger和Begg检验及剪补法进行发表偏倚评估。P<0.05为差异有统计学意义。

    初检获得1 255篇文献,经逐层筛选后,根据纳入和排除标准等,最终纳入8篇文献24-31,文献筛选流程见图1

    图  1  文献筛选流程图
    Figure  1.  Literature screening flow chart

    纳入研究共953例患者,其中3项RCT,5项RCS,经皮MWA(PMWA)4篇,经腹腔镜MWA(LMWA)1篇,未分类3篇,最长随访时间为104个月,单发肿瘤最大直径≤5 cm,多发肿瘤个数≤3且最大直径≤3 cm。纳入文献特征见表1

    表  1  纳入文献的基本特征
    Table  1.  The characteristics of studies
    纳入研究 国家

    例数

    (T/C)

    研究类型

    年龄(岁)

    (T/C)

    男女比例

    (T/C)

    MWA方式 HBsAg阳性率(T/C,%) Child-Pugh分级 肿瘤个数及大小(cm) 随访时间(月) 结局指标 NOS(分)
    Zhang等201724 中国 31/42 RCS

    51.2±6.93/

    54.1±7.23

    20∶11/

    29∶13

    PMWA 45.2/61.9 A或B 单发且直径≤5或3个且最大直径≤3 >60 ①④ 6
    Zhang等201625 中国 68/122 RCS

    55.4±9.9/

    49.5±8.6

    57∶11/

    111∶11

    PMWA 92.6/91.8 A 单个且直径<3 9~104 ①②③④⑧ 7
    杨藩等201626 中国 98/152 RCS

    55.4±7.9/

    52.5±8.0

    82∶16/

    133∶19

    PMWA 91.8/91.4 A或B 单发且直径≤3 9~96 ①③④⑧ 8
    黄炎等201727 中国 26/24 RCS

    57.6±6.0/

    58.1±5.5

    15∶11/

    15∶9

    LMWA - A或B 2.36±0.41/2.46±0.36;个数≤2 13~63/16~65 ①②④⑤⑥⑦⑧ 8
    廖凌峰等201828 中国 40/68 RCT

    52.36±8.62/

    52.20±8.60

    28∶12/

    50∶18

    PMWA 90.00/88.24 A或B

    2.32±0.64/

    2.12±0.60

    12~36 ①③④
    陈红健等201829 中国 46/46 RCT 29~78 68∶24 UNK 100 A或B 单发且直径≤3或2个且直径之和≤3 24 ①④⑤⑥⑦⑧
    王辉坡等201930 中国 45/45 RCT

    53.8±3.2/

    54.3±2.9

    23∶22/

    18∶27

    UNK - - - - ⑥⑦⑧
    黄志明等201631 中国 47/53 RCS

    60.0±12.4/

    55.8±11.3

    42∶5/

    48∶5

    UNK - A或B 单发且直径≤3或3个且最大直径≤3 3~44 ①②④⑥⑧ 9

    注:T,MWA组;C,HR组;UNK,未分类或未确定。①OS;②LR;③DFS;④不良反应;⑤肝功能;⑥手术时间;⑦术中出血量;⑧住院时间。-,未提供数据。

    下载: 导出CSV 
    | 显示表格

    3项RCT中,1项报告了具体随机方法30,3项研究结果数据完整28-30,2项未选择性报告研究结果28-29,1项不清楚30,所有研究分配隐藏不清楚、其他偏倚来源不清楚。5项RCS中,NOS评分提示3项研究≥8分,2项研究≥6分,超过50%为高分(表1)。

    2.4.1   OS

    分别有7/4/5/3项研究报道1/2/3/5年OS,结果表明MWA与HR均无统计学差异(RR=0.99,95%CI:0.96~1.01,P=0.308,I2=0.0%;RR=0.95,95%CI:0.87~1.04,P=0.284,I2=0.0%;RR=0.94,95%CI:0.87~1.01,P=0.069,I2=0.0%;RR=0.98,95%CI:0.83~1.15,P=0.822,I2=0.0%)(图2a~d)。

    注: a,1年OS;b,2年OS;c,3年OS;d,5年OS。
    图  2  OS森林图
    Figure  2.  Forest plots of OS
    2.4.2   LR

    有2项研究报道1年LR,结果表明MWA与HR无统计学差异(RR=1.45,95%CI:0.63~3.33,P=0.383,I2=0.0%)(图3a)。各有1项研究报道2/3/5年LR,结果表明MWA与HR 2/5年LR无统计学差异2731P>0.05);MWA 3年LR高于HR25RR=1.59,95%CI:1.08~2.33,P=0.017)。

    注: a,1年LR;b,1年DFS;c,3年DFS;d,5年DFS。
    图  3  LR和DFS森林图
    Figure  3.  Forest plots of LR and DFS
    2.4.3   DFS

    分别有3/3/2项研究报道1/3/5年DFS,结果表明MWA 1、3、5年DFS均低于HR(RR=0.94,95%CI:0.89~0.99,P=0.018,I2=0.0%;RR=0.84,95%CI:0.72~0.98,P=0.023,I2=25.4%;RR=0.75,95%CI:0.58~0.98,P=0.032,I2=34.6%)(图3b~d)。1项研究28报道了2年DFS,MWA与HR无统计学差异(P>0.05)。

    2.4.4   肝功能

    分别有2/2/2项研究报道ALT、AST和Alb,结果表明MWA与HR无统计学差异(SMD=-2.02,95%CI:-0.45~0.01,P=0.051,I2=95.7%;SMD=-3.66,95%CI:-9.15~1.82,P=0.191,I2=98.8%;SMD=1.11,95%CI:-0.52~2.75,P=0.183,I2=94.1%)(图4a~c)。1项研究29报道TBil,MWA对TBil的影响低于HR(SMD=-1.43,95%CI:-1.89~-0.97,P=0.001)。

    注: a,ALT; b,AST; c,Alb。
    图  4  肝功能森林图
    Figure  4.  Forest plots of liver function
    2.4.5   不良反应

    7项研究报道不良反应,主要表现为胸水、腹水、出血、疼痛、胆瘘、肺部感染、肝脓肿、肝包膜下积液、短暂性心律失常、切口感染等。结果显示MWA不良反应率低于HR(RR=0.42,95%CI:0.30~0.59,P<0.001,I2=0.0%)(图5a)。

    注: a,不良反应;b,术中出血量;c,手术时间;d,住院时间。
    图  5  不良反应及手术相关指标森林图
    Figure  5.  Forest plots of adverse reaction and operation related indexes
    2.4.6   其他

    分别有3/4/6项研究报道术中出血量/手术时间/住院时间,结果显示MWA上述指标均优于HR(SMD=-2.31,95%CI:-2.64~-1.97,P<0.001,I2=3.1%;SMD=-3.38,95%CI:-4.05~-2.71,P<0.001,I2=73.8%;SMD=-2.54,95%CI:-3.27~-1.80,P<0.001,I2=92.8%)(图5b~d)。

    2.5.1   消融方式亚组分析

    消融方式分为PMWA、LMWA、未分类。结果显示(表2):在PMWA和未分类组,MWA 1年LR与HR无统计学差异(P值均>0.05)。在PMWA、LMWA和未分类组,MWA 1/2年OS与HR均无统计学差异(P值均>0.05)。在PMWA和LMWA组,MWA 3年OS与HR无统计学差异(P值均>0.05)。在PMWA和未分类组,MWA不良反应低于HR(P值均<0.05),在LMWA组,两者无统计学差异(P>0.05)。在LMWA和未分类组,MWA手术时间短于HR(P值均<0.05)。在PMWA、LMWA和未分类组,MWA住院时间短于HR(P值均<0.05)。在LMWA和未分类组,MWA术中出血量少于HR(P值均<0.05)。在LMWA和未分类组,MWA对ALT和AST的影响低于HR(P值均<0.05)。在LMWA组,MWA对Alb的影响低于HR(P<0.05),在未分类组,两者无统计学差异(P>0.05)。

    表  2  消融方式的亚组分析
    Table  2.  Subgroup analysis-method of ablation
    亚组 结局指标 纳入研究数量 效应值[RRSMD (95%CI)] 异质性(I2 P 优势组
    PMWA 1年OS 4 0.99(0.96~1.01) 0.0% 0.326
    2年OS 1 0.94(0.83~1.08) 0.406
    3年OS 4 0.93(0.97~1.00) 0.0% 0.067
    1年LR 1 1.79(0.46~6.95) 0.397
    不良反应 4 0.44(0.29~0.66) 24.0% <0.001 MWA
    住院时间 2 -2.33(-2.84~-1.82) 75.4% <0.001 MWA
    LMWA 1年OS 1 - -
    2年OS 1 0.97(0.80~1.16) 0.704
    3年OS 1 0.97(0.75~1.26) 0.813
    ALT 1 -0.99(-1.58~-0.40) 0.001 MWA
    AST 1 -0.88(-1.46~-0.30) 0.003 MWA
    Alb 1 1.97(1.29~2.65) <0.001 MWA
    不良反应 1 0.42(0.17~1.03) 0.059
    手术时间 1 -2.62(-3.39~-1.86) <0.001 MWA
    住院时间 1 -2.25(-2.97~-1.54) <0.001 MWA
    术中出血量 1 -1.89(-2.56~-1.22) <0.001 MWA
    未分类 1年OS 2 0.98(0.91~1.07) 0.0% 0.711
    2年OS 2 0.95(0.83~1.10) 0.0% 0.529
    1年LR 1 1.25(0.43~3.59) 0.683
    ALT 1 -3.06(-3.67~-2.45) <0.001 MWA
    AST 1 -6.48(-7.51~-5.45) <0.001 MWA
    Alb 1 0.30(-0.11~0.71) 0.153
    不良反应 2 0.33(0.14~0.77) 0.0% 0.011 MWA
    手术时间 3 -3.61(-4.34~-2.89) 71.8% <0.001 MWA
    住院时间 3 -2.82(-4.73~-0.90) 96.9% 0.004 MWA
    术中出血量 2 -2.45(-2.83~-2.06) 0.0% <0.001 MWA
    下载: 导出CSV 
    | 显示表格
    2.5.2   研究类型亚组分析

    研究类型分为RCT和RCS。结果显示(表3),在RCT和RCS组,MWA 1/2年OS与HR均无统计学差异(P值均>0.05)。在RCS组,MWA 3年OS低于HR(P<0.05),但在RCT组,二者无统计学差异(P>0.05)。在RCT和RCS组,MWA 1年DFS与HR无统计学差异(P值均>0.05),MWA 3年DFS在RCS组低于HR(P<0.05),但在RCT组二者无统计学差异(P>0.05)。关于手术时间、术中出血量、住院时间、不良反应、ALT、AST,在RCT和RCS组,MWA均优于HR(P值均<0.05)。关于Alb,在RCS组MWA优于HR(P<0.05),但在RCT组,二者无统计学差异(P>0.05)。

    表  3  研究类型的亚组分析
    Table  3.  Subgroup analysis-type of research
    亚组 结局指标 纳入研究数量 效应值[RRSMD (95%CI)] 异质性(I2 P 优势组
    RCT 1年OS 2 0.97(0.91~1.04) 0.0% 0.437
    2年OS 2 0.95(0.85~1.06) 0.0% 0.324
    3年OS 1 1.02(0.74~1.41) 0.904
    1年DFS 1 0.92(0.81~1.04) 0.175
    3年DFS 1 1.05(0.64~1.70) 0.855
    ALT 1 -3.06(-3.67~-2.45) <0.001 MWA
    AST 1 -6.48(-7.51~-5.45) <0.001 MWA
    Alb 1 0.30(-0.11~0.71) 0.153
    不良反应 2 0.36(0.15~0.90) 20.4% 0.029 MWA
    手术时间 2 -3.93(-4.67~-3.19) 53.2% <0.001 MWA
    术中出血量 2 -2.45(-2.83~-2.06) 0.0% <0.001 MWA
    住院时间 2 -3.69(-5.17~-2.20) 89.1% <0.001 MWA
    RCS 1年OS 5 0.99(0.96~1.02) 0.0% 0.495
    2年OS 2 0.96(0.83~1.13) 0.0% 0.652
    3年OS 4 0.93(0.87~0.99) 0.0% 0.026 HR
    1年DFS 2 0.95(0.89~1.00) 0.0% 0.050
    3年DFS 2 0.81(0.69~0.95) 45.4% 0.009 HR
    ALT 1 -0.99(-1.58~-0.40) 0.001 MWA
    AST 1 -0.88(-1.46~-0.30) 0.003 MWA
    Alb 1 1.97(1.29~2.65) <0.001 MWA
    不良反应 5 0.43(0.29~0.62) 0.0% <0.001 MWA
    手术时间 2 -2.88(-3.34~-2.42) 0.0% <0.001 MWA
    术中出血量 1 -1.89(-2.56~-1.22) <0.001 MWA
    住院时间 4 -2.00(-2.65~-1.35) 89.1% <0.001 MWA
    下载: 导出CSV 
    | 显示表格

    除不良反应外,其余指标用Egger和Begg检验均无发表偏倚。Egger法提示不良反应存在偏倚,但剪补法显示结果稳定,提示不存在发表偏倚。

    MWA及HR是除肝移植外HCC最有效的治疗手段69,目前认为HR适用于CNLCⅠ‍a、Ⅰ‍b、Ⅱ‍a期肝癌,Ⅱb、Ⅲa期肝癌不宜首选HR,MWA适用于CNLCⅠa及部分Ⅰb期肝癌,且两者疗效无显著差异34。但HCC合并肝硬化的肝脏储备功能更差,二者是否同样有效?目前尚无相关Meta分析。因此,作者进行了该项研究,并获得了有价值的数据。

    本Meta分析发现,MWA 1/3/5年DFS低于HR,MWA 1/2/5年LR、1/2/3/5年OS与HR均无差异。该结果与熊琨等35(HCC未合并肝硬化)的研究结果相反,考虑与肝硬化是HCC复发的独立因素有关21-23。Zhang等36研究发现射频消融LR高于HR,3/5年OS低于HR,与本结果相反,考虑与MWA比射频消融具有更高的功率及单位时间肿瘤灭活率相关37。在手术时间、出血量、不良反应及住院时间方面,MWA显著优于HR。在肝功能方面,MWA后TBil更低,与既往研究16基本一致。MWA对ALT、AST和Alb的影响与HR无差异,与既往研究16不一致,从理论来讲,MWA时间更短,出血量更少,MWA对它们的影响应该更小,可能与纳入文献较少有关。但后续的亚组分析表明MWA对ALT等的影响更小,与既往研究16一致。因此,对于年龄≥75岁,或伴有高血压、糖尿病、心脏病等基础疾病的患者,MWA为HCC合并肝硬化的首选方案。

    为了进一步更全面地了解MWA与HR的临床疗效及安全性,本研究根据MWA方式进行了亚组分析,结果表明:无论是PMWA还是LMWA,MWA LR、OS与HR均无差异,结果未改变。在LMWA组,MWA不良反应和HR无差异,与亚组前结论相反,据此,本研究建议MWA方式首选PMWA。亚组后,MWA对ALT、AST、Alb的影响小于HR,故MWA后患者肝功能更好。

    同时本研究根据研究类型进行了亚组分析,结果表明:在RCT和RCS组,MWA 1/2年OS和HR无差异,与亚组前结论一致。在RCS组,HR 3年OS和3年DFS优于MWA,与亚组前结论一致,但在RCT组,二者无差异,与亚组前结论相反。考虑RCT比RCS有更高的方法学质量和证据等级,本研究更相信RCT结果,故认为MWA OS和DFS与HR无差异。对于手术时间、出血量、不良反应及住院时间,亚组后结论与亚组前一致。在RCT和RCS组,MWA的ALT、AST均优于HR。

    另外,Meta分析表明住院时间、手术时间、ALT、AST、Alb存在异质性,亚组分析表明MWA方式、研究类型不是异质性来源。本研究认为异质性与以下因素密切相关:(1)患者特征存在差异,如肿瘤大小、个数、部位,是否合并乙型肝炎、丙型肝炎,肝功能等级,是否合并腹水等不完全一致,而该类差异会直接影响HCC的预后。(2)手术能力、设备差异等均影响术后恢复。(3)RCT占比较少。(4)文献相对少,并受样本量及提取数据的限制,本研究未能进行更深入的亚组分析。以上也是本研究的局限性。

    因此,未来将进一步设计更好的研究来解决上述不足。多中心、大样本、包含更长随访时间及具有统一的患者和肿瘤特征的高质量RCT应该被开展,以帮助更全面和准确地了解MWA与HR的疗效及安全性,最终更好地指导临床应用。

    综上所述,MWA与HR在LR、DFS、OS方面无明显差异。MWA术中出血量更少,手术时间更短,不良反应更少,对肝功能影响更小,住院时间更短,尤其适合年龄大、基础疾病多、肝功能差的患者。然而,上述结论仍需高质量的临床研究进一步验证。

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