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儿童慢性乙型肝炎肝组织HBsAg、HBcAg的表达与抗病毒疗效的关系
DOI: 10.3969/j.issn.1001-5256.2021.01.010
Association of the expression of HBsAg and HBcAg in liver tissue with antiviral response in children with chronic hepatitis B
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摘要:
目的 探索性研究慢性乙型肝炎(CHB)儿童肝组织HBsAg和HBcAg不同表达与抗病毒疗效的关系。 方法 收集2014年1月—2017年12月在解放军总医院第五医学中心青少年肝病科住院并明确诊断为CHB的276例6月~16岁儿童患者的病例资料，比较肝组织HBsAg和HBcAg免疫组化染色阳性和阴性组(HBsAg阳性组249例, HBsAg阴性组27例; HBcAg阳性组163例，HBcAg阴性组113例)患者的临床特点，以及肝组织HBsAg和HBcAg不同表达模式下抗病毒疗效的差异。计量资料组间比较采用Mann-Whitney U检验；计数资料组间比较采用χ2检验或Fisher精确检验。以肝组织HBsAg和HBcAg染色阳性和阴性为应变量，以可能影响其表达强度有意义的相关因素为自变量，进行logistic回归分析。 结果 276例患者年龄0.5~16岁，男性占60.51%(167例)。HBeAg阴性14例(5.07%)。肝脏炎症程度分级(G)：2级52.54%，2~3级6.88%，3级7.61%。肝纤维化分期(S)：3期7.25%, 3~4期1.45%，4期3.62%。肝组织HBsAg阳性组儿童年龄及血清HBsAg定量高于阴性组(Z值分别为1.854、2.447, P值均＜0.05)。肝组织HBcAg阳性组HBeAg阳性率高于阴性组(χ2=2.650)，ALT(Z=2.473)、AST(Z=1.813)、肝组织纤维化分期S≥3期的比例(χ2=2.086)均低于阴性组(P值均＜0.05)。logistic回归分析显示，影响肝组织HBsAg染色阳性的因素为血清HBsAg定量(P＜0.05)，影响肝组织HBcAg染色阳性的因素为HBeAg阴性或阳性(P＜0.05)。276患者中186例完成IFNα或单用拉米夫定抗病毒治疗停药后6个月的随访，155例(83.33%)获得HBeAg血清学转换，其中76例(40.86%)HBsAg阴转。肝组织的HBsAg阳性表达强度越高，血清HBsAg阴转率越低。肝组织的HBcAg阳性表达强度越高，HBeAg血清学转换率越低。肝组织HBsAg及HBcAg均阴性表达模式的儿童HBsAg阴转率最高(100%)，HBsAg阳性及HBcAg阴性的儿童HBsAg阴转率(32.31%)最低。 结论 肝组织HBsAg及HBcAg阴性的CHB儿童抗病毒治疗HBsAg阴转率最高 Abstract:Objective To investigate the association of the expression of HBsAg and HBcAg in liver tissue with antiviral response in children with chronic hepatitis B (CHB). Methods Clinical data were collected from 276 children, aged 6 months to 16 years, who were hospitalized and diagnosed with CHB in Department of Adolescent Liver Diseases in The Fifth Medical Center of Chinese PLA General Hospital from January 2014 to December 2017, and based on the results of immunohistochemical staining for HBsAg and HBcAg, there were 249 children in the positive HBsAg group, 27 in the negative HBsAg group, 163 in the positive HBcAg group, and 113 in the negative HBcAg group. Clinical features were compared between groups, as well as the difference in antiviral response between the children with different expression patterns of HBsAg and HBcAg in liver tissue. The Mann-Whitney U test was used for comparison of continuous data between groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. A logistic regression analysis was performed with positive or negative staining of HBsAg and HBcAg in liver tissue as dependent variables and related significant factors affecting their expression intensity as independent variables. Results The age of 276 children ranged from 0.5 to 16 years, and there were 167 boys, accounting for 60.51%. Of all children, 14 (5.07%) had negative HBeAg. As for liver inflammation grade (G), 52.54% had G2 inflammation, 6.88% had G2-3 inflammation, and 7.61% had G3 inflammation; as for liver fibrosis stage (S), 7.25% had S3 fibrosis, 1.45% had S3-4 fibrosis, and 3.62% had S4 fibrosis. The positive HBsAg group had significantly higher age and serum HBsAg quantification than the negative HBsAg group (Z=1.854, Z=2.447, both P < 0.05). Compared with the negative HBcAg group, the positive HBcAg group had a significantly higher positive rate of HBeAg (χ2=2.650, P < 0.05) and significantly lower ALT (Z=2.473, P < 0.05), AST (Z= 1.813, P < 0.05), and proportion of children with S≥3 liver fibrosis (χ2=2.086, P < 0.05). The logistic regression analysis showed that serum HBsAg quantification was an influencing factor for positive HBsAg staining in liver tissue (P < 0.05) and negative or positive HBeAg was an influencing factor for positive HBcAg staining in liver tissue (P < 0.05). Among the 276 children, 186 completed the 6-month follow-up after antiviral therapy with IFNα or lamivudine alone, and 155 (83.33%) achieved HBeAg seroconversion, among whom 76 (40.86%) had HBsAg seroconversion. The higher the expression intensity of HBsAg in liver tissue, the lower the seroconversion rate of serum HBsAg; the higher the expression intensity of HBcAg in liver tissue, the lower the seroconversion rate of serum HBeAg. The children with negative expression of HBsAg and HBcAg in liver tissue had the highest HBsAg seroconversion rate of 100%, and the children with positive HBsAg and negative HBcAg in liver tissue had the lowest HBsAg seroconversion rate of 32.31%. Conclusion CHB children with negative HBsAg and HBcAg in liver tissue had the highest HBsAg seroconversion rate after antiviral therapy. -
Key words:
- Hepatitis B, Chronic /
- Hepatitis B Surface Antigens /
- Hepatitis B Core Antigens /
- Child
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肝细胞癌(HCC)是常见的消化系统恶性肿瘤之一, 其恶性程度高, 增殖能力强, 患者预后差。2018年, 全球新发肝癌84.1万例, 在恶性肿瘤发病率排名第6位, 死亡78.1万例[1]; 2015年我国的新发肝癌约37.0万例, 死亡人数约32.6万例[2]。因此, 寻找肝癌预后评估的生物标志物具有重要的临床意义。
葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase, G6PD是参与磷酸戊糖途径(pentose phosphate pathway, PPP)的第一种酶, 也是PPP的限速酶, 糖酵解产生的6-磷酸葡萄糖在G6PD的催化下进入PPP, 产生细胞活动所需要的能量[3]。研究发现, G6PD在黑色素瘤[4]、乳腺癌[5]、肺癌[6-7]、肝癌[8-9]、结直肠癌[10]等恶性肿瘤中表达升高, 在肿瘤的发生发展中起重要作用。
淋巴细胞/单核细胞比值(LMR)是反映机体炎症和免疫状态的一项敏感指标, 已被证实可用于预测卵巢癌[11]、肺癌[12]和肝癌[13]等实体肿瘤的预后。本文通过分析G6PD在肝癌组织中的表达与预后的关系, 以及不同G6PD表达水平患者的临床指标差异, 探讨G6PD表达在HCC预后评估中的临床价值。
1. 资料与方法
1.1 研究对象
收集2016年6月—2018年1月在本院就诊的44例首诊HCC患者的肝癌组织和相应的癌旁组织标本, 及其临床信息和实验室检查结果。纳入标准: (1)所有患者均符合《原发性肝癌诊疗规范(2019年版)》[14]; (2)有完整的基本资料和实验室检测结果(肝肾功能、血常规、凝血指标和肿瘤标志物)。排除标准: (1)合并其他恶性肿瘤或有全身感染症状; (2)术前接受过其他方式治疗。
1.2 仪器试剂
采用贝克曼奥林巴斯5800全自动生化分析仪检测肝肾功能, 贝克曼库尔特全自动血细胞分析仪H750检测血常规。贝克曼ACLTOP检测凝血指标。BeckmanDX1800全自动化学发光仪测定AFP。BIO-RAD荧光定量PCR系统CFX ConnectTM检测基因表达。
1.3 方法
使用Trizol(美国Thermo公司)提取组织RNA。逆转录试剂盒FSQ-301(日本TOYOBO公司)合成cDNA。β-actin为内参基因, 进行qPCR。G6PD: 上游5′-AACATCGCCTGCGTTATCCTC-3′, 下游5′-ACGTCCCGGATGATCCCAA-3′; β-actin: 上游5′-CCTCGCCTTTGCCGATCC-3′, 下游5′-GGATCTTCATGAGGTAGTC AGTC-3′。
用Gene Expression Profiling Interactive Analysis(GEPIA)数据库分析G6PD在HCC组织中的表达。Kaplan Meier Plotter(KM plotter)数据库评估HCC组织中G6PD表达水平与预后。
1.4 伦理学审查
本研究方案经由武汉大学中南医院伦理委员会审批, 批号: 2017058。
1.5 统计学方法
采用SPSS 21.0软件进行数据分析。正态分布的计量资料以x±s表示, 2组间比较采用t检验; 偏态分布的计量资料以M(P25~P75)表示, 2组间比较采用Mann-Whitney U检验。计数资料2组间比较采用Fisher确切概率法; Spearman相关用来分析G6PD与LMR的相关性; 采用Kaplan-Meier法绘制生存曲线。P＜0.05为差异有统计学意义。
2. 结果
2.1 肝癌组织中G6PD mRNA表达
运用RT-qPCR检测44例HCC患者肝癌组织和癌旁肝脏组织中G6PD的mRNA表达水平。结果发现, G6PD mRNA在癌组织中表达明显高于癌旁组织(Z=-3.221, P=0.001), 癌组织G6PD表达水平是癌旁组织的2.09倍(图 1a)。
图 1 肝癌组织中G6PD mRNA表达及其与预后评估注: a, HCC患者癌组织和癌旁组织G6PD mRNA表达水平比较; b, GEPIA数据库中G6PD在肝癌组织中表达; c, G6PD高表达和低表达患者总生存曲线; d, G6PD高表达和低表达患者无进展生存曲线。2.2 低G6PD组和高G6PD组的HCC患者基本资料
根据G6PD mRNA表达水平中位数, 将患者分为G6PD高表达组(n=22)及低表达组(n=22)。两组患者在年龄、性别、HBV DNA检测阳性率和TNM分期上差异均无统计学意义(P值均＞0.05)(表 1)。
表 1 HCC患者低G6PD组和高G6PD组的基本资料指标 低G6PD组(n=22) 高G6PD组(n=22) P值 年龄(岁) 57.04±9.88 52.00±8.74 0.080 男/女(例) 17/5 17/5 1.000 HBV DNA(例) 0.537 ＜500 IU/ml 7 10 ≥500 IU/ml 15 12 TNM分期(例) 0.736 Ⅰ~Ⅱ 15 17 Ⅲ~Ⅳ 7 5 2.3 肝癌患者预后与G6PD表达的关系分析
运用GEPIA数据库分析肝癌组织(n=369)和癌旁组织(n=160)中的G6PD表达。结果发现, G6PD在癌组织中表达明显高于癌旁组织(P＜0.01)(图 1b)。运用KM plotter数据库, 分析两组患者预后差异。结果发现, G6PD高表达是不良预后的危险因素: 总生存期(HR=1.84, 95%CI: 1.30~2.61; P=0.000 52)和无进展生存期(HR=1.75, 95%CI: 1.27~2.42;P=0.000 54), 即G6PD高表达患者预后不良(图 1c、d)。
2.4 肝癌组织中G6PD表达与临床指标的关系
为了进一步比较肝癌患者中G6PD mRNA表达与临床指标的关系, 比较HCC患者低G6PD组(n=22)和高G6PD组(n=22)的肝功能、血常规、凝血功能和AFP差异。
结果显示, LMR在高G6PD组患者中明显低于低G6PD组(P=0.011), 其他指标两组间差异均无统计学意义(P值均＞0.05)(表 2)。
表 2 肝癌患者G6PD表达水平与术前临床指标关系指标 低G6PD组(n=22) 高G6PD组(n=22) 统计值 P值 ALT(U/L) 41.09±28.89 43.64±39.56 t=-0.244 0.809 AST(U/L) 49.00±33.74 47.23±30.33 t=0.183 0.855 总胆红素(μmol/L) 16.60±6.83 20.44±8.93 t=-1.604 0.116 直接胆红素(μmol/L) 4.49±2.82 4.94±2.20 t=-0.579 0.566 间接胆红素(μmol/L) 12.35±4.96 15.05±7.87 t=-1.335 0.187 TP(g/L) 66.80±5.96 67.58±6.27 t=-0.422 0.675 Alb(g/L) 39.66±3.75 39.65±5.63 t=0.006 0.995 Glb(g/L) 27.14±4.17 27.92±4.82 t=-0.575 0.568 GGT(U/L) 61.00±46.68 66.05±43.69 t=-0.366 0.716 ALP(U/L) 103.82±52.41 108.05±56.92 t=-0.256 0.799 WBC(×109/L) 5.35±1.66 5.61±2.34 t=-0.413 0.682 RBC(×1012/L) 4.24±0.85 4.41±0.70 t=-0.691 0.494 HGB(g/L) 129.59±25.11 135.34±18.16 t=-0.844 0.404 PLT(×109/L) 150.10±54.03 173.19±82.75 t=-1.052 0.229 中性粒细胞计数(×109/L) 3.41±1.64 3.80±1.80 t=-0.717 0.478 淋巴细胞计数(×109/L) 1.39±0.55 1.19±0.59 t=1.116 0.271 单核细胞计数(×109/L) 0.42±0.14 0.50±0.21 t=-1.531 0.134 LMR 3.49±1.44 2.45±0.96 t=2.681 0.011 PT(s) 11.59±1.06 11.70±0.88 t=-0.348 0.730 INR 1.06±0.10 1.07±0.08 t=-0.295 0.770 PTTA(%) 97.81±14.29 97.15±15.26 t=0.143 0.887 APTT(s) 32.20±2.78 32.63±3.65 t=-0.433 0.668 TT(s) 14.97±1.22 14.30±1.77 t=1.438 0.158 FIB(mg/dl) 286.61±56.74 308.19±81.70 t=-0.994 0.326 AFP(μg/L) 143.80(6.22~2 386.96) 1 481.35(56.20~4 453.63) Z=-1.723 0.085 2.5 G6PD表达与LMR相关性分析
进一步分析G6PD mRNA表达量与LMR相关性, 结果显示G6PD表达水平与LMR呈负相关(r=-0.439, P=0.005)(图 2), 提示G6PD表达与免疫功能、炎症状态有关。
3. 讨论
HCC是一种进展迅速, 恶性程度高, 预后极差的肿瘤[15]。随着各种分子生物学层面的研究深入, 越来越多的研究表明肝癌的发生发展常伴随着糖代谢紊乱[16]、多种基因表达改变和信号通路异常[17]。
肿瘤细胞由于瓦伯格效应(Warburg effect)主要通过糖酵解的方式分解葡萄糖获能, 所产生的6-磷酸葡萄糖可以通过PPP为核苷酸、脂质等生物分子合成提供前体以及NADPH[16, 18]。本研究发现G6PD基因在HCC中表达明显高于配对癌旁组织。相关研究指出, PI3K/Akt、Ras和Src等促癌信号通路的过度激活, 可通过翻译后调控机制促进G6PD激活[3], 从而引起肿瘤组织中G6PD表达升高, 产生的高水平NADPH可以减少细胞活性氧(ROS)的生成[19]。ROS在多种癌症中被检测到, 一方面被认为可以激活肿瘤信号, 但同时ROS累积也能启动氧化应激诱导肿瘤细胞的死亡, 肿瘤细胞G6PD表达升高, 可以减少升高的ROS, 建立氧化还原平衡[20]。同时细胞内ROS累积会引起NF-κB的激活, 可引起大量细胞因子如IL-6、IL-24、IL-32等的释放, 细胞因子招募单核细胞、巨噬细胞到肿瘤部位, 引起肿瘤微环境炎症反应, 促进肿瘤发展[21]。
已经有研究证实HBV感染会引起G6PD的升高[22], 同时HBV感染可能会引起肿瘤微环境炎症反应, 引起免疫细胞数量和状态改变[23]。而高LMR是多种癌症预后的保护因素[9, 24], 在肝癌的相关研究[25]中, 肝癌术前LMR可分为高值组(≥3.03)和低值组(＜3.03), 高LMR组患者肝癌切除术后5年生存率较好。也有学者[26]指出肝移植术后LMR＜2.75的患者的5年生存率明显低于LMR≥2.75的患者。而本研究发现LMR在G6PD高表达组中明显低于G6PD低表达组, 且肝癌组织中G6PD表达水平与LMR呈负相关, 提示G6PD高表达的HCC患者不良预后可能与肿瘤微环境炎症有关。
综上, 在肝癌组织中高G6PD的表达与不良预后有关, G6PD高表达和低表达组的LMR有明显差异, 且G6PD的表达量与LMR呈负相关, 提示G6PD表达可能与肿瘤微环境炎症反应有关。本研究所用样本量较小, 具体的分子机制尚需进一步研究。
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表 1 儿童肝组织HBsAg与HBcAg不同分组各临床基线指标的比较
指标 HBsAg HBcAg 阳性组(n=249) 阴性组(n=27) 统计值 P值 阳性组(n=163) 阴性组(n=113) 统计值 P值 年龄(岁) 5.00(2.67~11.00) 4.25(2.08~7.00) Z=1.854 0.041 5.00(2.50~10.00) 4.83(2.58~7.67) Z=0.892 0.113 男性[例(%)] 151(60.64) 16(59.26) χ2=0.140 0.890 97(59.51) 70(61.95) χ2=0.407 0.683 母亲HBsAg阳性[例(%)] 191(76.71) 22(81.48) χ2=0.222 0.824 123(75.46) 90(79.65) χ2=0.815 0.417 ALT (U/L) 99.0(56.0~192.0) 98.0(64.5~153.0) Z=0.478 0.612 95.0(61.0~175.5) 113.0(50.0~214.0) Z=2.473 0.021 AST (U/L) 82.0(57.0~170.0) 75.0(58.0~110.5) Z=0.876 0.239 78.0(48.0~133.0) 91.0(53.0~177.0) Z=1.813 0.043 HBsAg定量(IU/ml) 11 155.5(4299.0~30 119.3) 3884.2(892.7~18 289.0) Z=2.447 0.023 18 195.0(5461.0~32 602.8) 7882.5(3002.0~16 083.3) Z=0.824 0.417 HBeAg阳性[例(%)] 223(89.56) 25(92.59) 1.0001) 153(93.87) 95(84.07) χ2=2.650 0.008 HBV DNA(lg IU/ml) 7.45 (6.83~8.65) 6.28 (5.14~8.05) Z=0.891 0.223 7.57(6.35~8.42) 7.05(6.11~8.11) Z=0.921 0.368 肝组织炎症分级[例(%)] χ2=0.904 0.366 χ2=0.848 0.396 G＜2 80(32.13) 11(40.74) 57(34.97) 34(30.09) G≥2 169(67.87) 16(59.26) 106(65.03) 79(69.91) 肝组织纤维化分期[例(%)] 0.5411) χ2=2.086 0.037 S＜3 217(87.15) 25(92.59) 148(90.80) 93(82.30) S≥3 32(12.85) 2(7.41) 15(9.20) 20(17.70) 注：1)为Fisher精确检验。 
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表 2 186例完成治疗的儿童治疗前肝组织HBsAg、HBcAg表达不同疗效的差异
项目 例数
(n=186)HBeAg转换
(n=155)HBsAg阴转
(n=76)HBsAg[例(%)] - 21(11.29) 20(95.24) 19(90.48) + 125(67.20) 100(80.00) 50(40.00) ++ 34(18.28) 31(91.18) 6(17.65) +++ 6(8.11) 4(66.67) 1(16.67) HBcAg[例(%)] - 74(39.78) 64(86.49) 30(40.54) + 101(54.30) 85(84.16) 41(40.59) ++ 9(4.84) 5(55.56) 4(44.44) +++ 2(1.08) 1(50.00) 1(50.00)
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表 3 肝组织HBsAg、HBcAg 4种表达方式抗病毒疗效的差异
组别 例数
(n=186)HBeAg转换
(n=155)HBsAg阴转
(n=76)HBsAg(-)HBcAg(-)[例(%)] 9(4.84) 9(100.00) 9(100.00) HBsAg(-)HBcAg(+)[例(%)] 12(6.45) 11(91.67) 10(83.33) HBsAg(+)HBcAg(-)[例(%)] 65(34.95) 55(84.62) 21(32.31) HBsAg(+)HBcAg(+)[例(%)] 100(53.76) 80(80.00) 36(36.00)
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