对138例HBeAg阴性慢性乙型肝炎患者血清学指标的探讨

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应晟, 杨美云. 对138例HBeAg阴性慢性乙型肝炎患者血清学指标的探讨. 25(5): 418-419
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对138例HBeAg阴性慢性乙型肝炎患者血清学指标的探讨

应晟, 杨美云

奉化人民医院检验科,浙江奉化 315500

作者简介：应晟,女,1976年生,主管技师,主要从事免疫学检验工作。

摘要

关键词: 乙型肝炎e抗原; 阴性; 慢性乙型肝炎; 血清学指标

中图分类号:R446.62 文献标志码:B 文章编号:1673-8640(2010)05-0418-02

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在乙型肝炎感染的自然史中, 乙型肝炎e抗原(HBeAg)转阴, e抗体(抗-HBe)产生或阴性, 乙型肝炎病毒(HBV)DNA水平下降或消失, 往往代表炎症缓解, 传染性小, 但有一部分患者仍保持一定水平复制, 慢慢发展成为肝硬化或肝癌^[1]。本研究选取HBeAg阴性的慢性乙型肝炎患者138例, 通过与101例HBeAg阳性的慢性乙型肝炎患者对比, 进行临床特点、血清学指标分析。

一、材料和方法

1.血清标本收集奉化人民医院2007年6月至2008年6月间慢性乙型肝炎患者239例。经酶联免疫吸附试验(ELISA)检测HBeAg阳性101例(男66例, 女35例), 年龄(42.4± 10.5)岁, HBeAg阴性138例(抗-HBe阳性或阴性, 男98例, 女40例), 年龄(35.0± 12.0)岁, HBV DNA均> 1× 10³拷贝/mL。诊断符合2000年9月中华医学会西安会议修订的《病毒性肝炎防治方案》中的标准^[2]。所有患者均排除甲、丙、丁、戊型肝炎病毒混合感染, 酒精性肝炎, 药物性肝炎和自身免疫性肝炎。

2.仪器自动荧光定量聚合酶链反应(PCR)仪(PE5700)、生化全自动仪(日立7180)、电发光分析仪(罗氏2010)。

3.HBV抗原抗体的ELISA检测试剂购自上海科华生物有限公司, 操作及结果判读按试剂说明书进行。

4.HBV DNA荧光定量PCR检测试剂购自中山大学达安基因股份有限公司。

5.血清生化指标检测测定丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、白蛋白(Alb)、总胆红素(TBil), 试剂盒购自上海东菱诊断用品有限公司。

6.肝纤维化指标检测血清铁蛋白(SF)采用德国罗氏试剂, 血清透明质酸酶(HA)、Ⅳ 型胶原肽的测定由迪安公司协助完成, 试剂由北京北方生物研究所提供。

7.统计学方法用SPSS 11.0统计软件进行统计分析, 计量资料用 $\begin{matrix} \bar{x} \end{matrix}$ ± s表示, 组间比较采用t检验。

二、结果

1. HBV DNA含量比较 HBeAg阳性组HBV DNA含量高于HBeAg阴性组, 差异有统计学意义(P< 0.01)。见表1。

2.血清生化指标分析 HBeAg阳性组血清ALT高于HBeAg阴性组, 差异有统计学意义(P< 0.01), 而AST、TBil、Alb两组差异无统计学意义(P> 0.05)。见表1。

表1 HBeAg阴性组与HBeAg阳性组各项生化指标及HBV DNA含量的比较

3.血清肝纤维化指标比较 HBeAg阳性组与阴性组间SF、HA、Ⅳ 型胶原肽水平差异均无统计学意义(P> 0.05)。见表2

表2 HBeAg阴性组与HBeAg阳性组血清肝纤维化指标比较

三、讨论

以往认为, 慢性乙型肝炎患者发生HBeAg转阴, 伴随HBV DNA水平降低或消失且转氨酶正常, 提示HBV复制停止、传染性小。本研究中138例HBeAg阴性患者的血清生化指标与肝纤维化指标均存在异常。HBeAg消失并不能代表病毒水平的完全降低或病情恢复, HBeAg阴性慢性乙型肝炎由不能产生HBeAg的HBV病毒株引起, 主要为HBV前C区或核心区启动子变异, 是HBeAg阴性慢性乙型肝炎发生的主要机制。常见的变异包括前C区第1 896位核苷酸G被A替换而出现终止密码子TAG, 导致蛋白翻译停止, HBeAg不能合成。HBV核心区启动子区域在1 762位和1 764位的A-T和G-A突变, 影响前C区mRNA转录, 减少HBeAg合成而表现为HBeAg阴性, 核心区启动子区域和前C区突变可同时存在^[3]。

本研究结果显示, 总体上HBeAg阳性组的HBV DNA水平高于HBeAg 阴性组(P< 0.01), 提示前者复制水平总体上高于后者, 与文献报道一致^[4]。HBeAg阳性组血清ALT 比HBeAg 阴性组高(P< 0.01), ALT虽是反应肝脏炎症的重要指标, 一次测定值只能反映某一时间点的肝脏损伤情况, 不能完全反应肝组织的炎症程度, 且其他生化指标AST、Alb、TBil等两组相比差异无统计学意义。

虽然作为金标法腹腔镜及肝活检是确诊肝硬化(肝纤维化分级)的可靠指标, , 但因具有创伤性不利于反复检查和被患者接受, 难以在基层医院推广。本研究选择血清HA、Ⅳ 型胶原肽、SF作为判断肝纤维化的观察指标。HA由肝内间质细胞合成经肝窦内皮细胞降解, 其升高反映肝内间质细胞增生或门体分流等, 肝窦内皮细胞摄取和分解HA减少, 检测HA是反映肝脏病变或纤维化程度的最敏感指标之一^[5]。Ⅳ 型胶原肽是基底膜网状结构的主要成分, 在细胞内合成后直接以前胶原形式参与细胞外基质的构成, 肝纤维化时可见其增高。SF主要在肝脏合成并储存, 升高程度与肝细胞损害的程度呈平行关系, 随着病程的进展逐渐升高^[6]。HBeAg阴性组与HBeAg阳性组相比, HA、Ⅳ 型胶原肽、SF等肝纤维化指标差异无统计学意义。

综上所述, HBeAg阴性的慢性乙型肝炎患者, HBV虽然处于低复制状态, ALT水平也较HBeAg阳性的慢性乙型肝炎患者低, 但肝纤维化程度却与HBeAg阳性的患者无明显差异。因此对HBeAg阴性的慢性乙型肝炎患者应引起重视, 虽然HBeAg阴性, 但并不意味肝组织病理变化停止, 应定期检查上述血清指标, 控制疾病进展, 以降低肝硬化、肝癌的发病率。

The authors have declared that no competing interests exist.

参考文献

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[1]	欧晓娟, 王晓明, 王宝恩, 等. e抗原阳性及阴性慢性乙型肝炎患者临床特点比较[J]. 中华肝脏病杂志, 2007, 15(6): 428-430. [本文引用:1]
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[3]	Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants[J]. J Viral Hepat, 2002, 9(1): 52-61. [本文引用:1] [JCR: 3.082]
[4]	Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection[J]. Hepatology, 2002, 36(6): 1408-1415. [本文引用:1]
[5]	刘霖敏. 血清HA、PCⅢ、Ⅳ-C、LN和内皮素在慢性肝病肝纤维化中的临床意义[J]. 江西医药, 2007, 42(9): 832-834. [本文引用:1]
[6]	裴豪, 陆忠华, 季瑞云, 等. 慢性乙肝患者血清铁蛋白与肝组织病理学的关系[J]. 临床肝胆病杂志, 2006, 22(3): 182-183. [本文引用:1]

2007

0.0

... 在乙型肝炎感染的自然史中,乙型肝炎e抗原(HBeAg)转阴,e抗体(抗-HBe)产生或阴性,乙型肝炎病毒(HBV)DNA水平下降或消失,往往代表炎症缓解,传染性小,但有一部分患者仍保持一定水平复制,慢慢发展成为肝硬化或肝癌^[1] ...

2000

0.0

... 诊断符合2000年9月中华医学会西安会议修订的《病毒性肝炎防治方案》中的标准^[2] ...

2002

3.082

0.0

. 2002, 9(1):52-61

World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants

M. L. Funk 1,2 ,D. M. Rosenberg 3 andA. S. F. Lok 4

1 Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA, 2 Worldwide Epidemiology Department, GlaxoSmithKline, Research Triangle Park, USA, 3 Greenford, UK, 4 Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA * Dr Daniel M. Rosenberg, GlaxoSmithKline, Greenford Road, Greenford, Middlesex UB6 0HE, UK. E-mail: dr74409@gsk.com

> Hepatitis B is a serious disease that is endemic in many parts of the world. A significant proportion of patients with chronic hepatitis B (CHB) are infected with a variant form of the hepatitis B virus (HBV) which decreases or abolishes the production of hepatitis B e-antigen (HBeAg). The purpose of this literature review is to describe the epidemiology of HBeAg-negative CHB (e-CHB) worldwide. A literature search was conducted to identify studies pertaining to e-CHB and underlying variants (precore and core promoter). Fifty studies were included in our analysis. The median prevalence of e-CHB among patients with chronic HBV infection was 33% in the Mediterranean, 15% in Asia Pacific, and 14% in the USA and Northern Europe. The pre core stop codon variant was detected in a median of 60% (range 0–100%) of HBeAg-negative patients overall, 92% in the Mediterranean, 50% in Asia Pacific and 24% in the USA and Northern Europe. There were very few data on the prevalence of core promoter variants outside Asia where the median prevalence among HBeAg-negative patients was 77%. This literature review revealed that e-CHB is more common than previously suspected and that it is present worldwide with marked variations in the prevalence of associated HBV variants across different geographical regions. Additional research using population based samples of adequate size based on a consensus definition of e-CHB and using standardized HBV DNA assays is needed to better estimate the true prevalence of e-CHB and its associated HBV variants.

... HBV核心区启动子区域在1 762位和1 764位的A-T和G-A突变, 影响前C区mRNA转录,减少HBeAg合成而表现为HBeAg阴性,核心区启动子区域和前C区突变可同时存在^[3] ...

2002

0.0

. 2002, 36(6):1408-1415 DOI:10.1053/jhep.2002.36949

Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection

Abstract The goals of this retrospective study were to determine whether there is a threshold hepatitis B virus (HBV) DNA value associated with spontaneous or antiviral therapy–related hepatitis B e antigen (HBeAg) clearance. We also investigated whether there is an HBV DNA value that can be used for differentiating inactive carriers from patients with HBeAg-negative chronic hepatitis B. HBV DNA levels in sequential serum samples of 165 Chinese patients with different stages of chronic HBV infection were quantified by a polymerase chain reaction (PCR)–based assay. Our results showed that almost all of the patients (89%) who remained HBeAg-positive had HBV DNA levels that were persistently above 10 5 copies/mL. Serum HBV DNA levels decreased by a mean of 3 log 10 in patients with HBeAg loss, but 51% had levels above 10 5 copies/mL at the time HBeAg first became undetectable. Mean serum HBV DNA levels were significantly lower in HBeAg-negative patients. HBV DNA value above 10 5 copies/mL would exclude all inactive carriers, but 45% of patients with HBeAg-negative chronic hepatitis would also be excluded if testing were only performed at presentation and 30% would be excluded if testing were performed on 3 occasions. In conclusion, serum HBV DNA levels decreased significantly in patients with HBeAg loss, but there was no threshold HBV DNA level associated with HBeAg clearance. Given the fluctuating course of HBeAg-negative chronic hepatitis, it is not possible to define a single cutoff HBV DNA value for differentiating inactive carriers from patients with HBeAg-negative chronic hepatitis. (H EPATOLOGY 2002;36:1408-1415.)

... 01),提示前者复制水平总体上高于后者,与文献报道一致^[4] ...

2007

0.0

... HA由肝内间质细胞合成经肝窦内皮细胞降解,其升高反映肝内间质细胞增生或门体分流等,肝窦内皮细胞摄取和分解HA减少,检测HA是反映肝脏病变或纤维化程度的最敏感指标之一^[5] ...

2006

0.0

... SF主要在肝脏合成并储存,升高程度与肝细胞损害的程度呈平行关系,随着病程的进展逐渐升高^[6] ...