HBV DNA不同载量的CHB患者的HBeAg和ALT水平比较

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沈云岳, 宁小晓, 王蕾. HBV DNA不同载量的CHB患者的HBeAg和ALT水平比较. 26(12): 823-825
SHEN Yunyue, NING Xiaoxiao, WANG Lei. Comparison of HBeAg and ALT levels among CHB patients with different HBV DNA loads. Labratory Medicine, 26(12): 823-825 复制到剪切板

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《检验医学》编辑部

HBV DNA不同载量的CHB患者的HBeAg和ALT水平比较

沈云岳¹, 宁小晓¹, 王蕾²

1.上海交通大学附属第六人民医院检验科,上海 200233

2.上海中医药大学附属龙华医院检验科,上海 200032

通讯作者:王蕾,联系电话:021-64385700-3206

作者简介:沈云岳,男,1980年生,学士,主管技师,主要从事分子生物与临床免疫检验工作。

摘要

目的

探讨乙型肝炎病毒(HBV)DNA不同载量的慢性乙型肝炎(CHB)患者乙肝病毒e抗原(HBeAg)与丙氨酸氨基转移酶(ALT)的关系,为临床治疗提供依据。

方法

分别比较214例ALT正常的CHB患者中HBeAg(+)、HBeAg(-)患者与200名HBsAg(-)、ALT正常的健康对照者ALT水平的差异。将ALT水平正常的214例CHB患者HBV DNA载量按HBV DNA载量分为3组(Ⅰ组:HBV DNA<10³ IU/mL;Ⅱ组:10³ IU/mL≤HBV DNA<10⁴ IU/mL;Ⅲ组:HBV DNA≥10⁴ IU/mL)。比较各组间ALT水平和HBeAg阳性率。

结果

214例ALT正常的CHB患者中HBeAg(+)组及HBeAg(-)组ALT水平均高于正常对照组(P<0.01),且HBeAg(+)组ALT水平明显高于HBeAg(-)组(P<0.05);Ⅰ组CHB患者HBeAg阳性率明显低于Ⅱ组和Ⅲ组(P<0.05),Ⅲ组CHB患者的ALT水平明显高于Ⅰ组和Ⅱ组(P<0.05)。

结论

HBV DNA≥10⁴ IU/mL且ALT水平正常的CHB患者其ALT水平处于正常范围的上限, HBeAg阳性率较高,提示临床应予以更多的关注。

关键词: 丙氨酸氨基转移酶; 乙肝e抗原; 慢性乙型肝炎; 聚合酶链反应

中图分类号:Q555 文献标志码:A 文章编号:1673-8640(2011)12-0823-03

Comparison of HBeAg and ALT levels among CHB patients with different HBV DNA loads

SHEN Yunyue¹, NING Xiaoxiao¹, WANG Lei²

1.Department of Clinical Laboratory, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China

2.Department of Clinical Laboratory, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China

Abstract

Objective

To investigate the relationship between hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) levels among chronic hepatitis B (CHB) patients with different loads of hepatitis B virus (HBV) DNA, and to provide the reference for clinical treatment.

Methods

A total of 214 CHB patients with ALT within normal range and 200 healthy subjects with HBsAg-negtive and normal ALT levels were enrolled. The ALT levels' differences were compared among HBeAg(+) group of CHB patients, HBeAg(-) group of CHB patients and healthy subjects. The 214 cases of CHB patients with normal ALT levels were classified into 3 groups according to HBV DNA load (GroupⅠ: HBV DNA<10³ IU/mL, Group Ⅱ:10³ IU/mL≤HBV DNA<10⁴ IU/mL and Group Ⅲ: HBV DNA≥10⁴ IU/mL). ALT levels and the positive rate of HBeAg of these groups were analyzed.

Results

Among the 214 CHB patients, the ALT levels of HBeAg(+) group and HBeAg(-) group were higher than that of the healthy group (P<0.01), and the ALT levels of HBeAg(+) group were higher than those of HBeAg(-) group (P<0.05). The positive rate of HBeAg of Group Ⅰwas significantly lower than those of Group Ⅱ and Group Ⅲ (P<0.05). The ALT levels of Group Ⅲ were significantly higher than those of Group Ⅰ and Group Ⅱ (P<0.05).

Conclusions

The ALT level is at the upper limit of normal range, and the positive rate of HBeAg is rather high in CHB patients with ALT within the normal range and HBV DNA≥10⁴ IU/mL, which suggests that more attention should be paid for the patients in the clinical course of treatment.

Keyword: Alanine aminotransferase; Hepatitis B virus e antigen; Chronic hepatitis B; Polymerase chain reaction

Show Figures

据报道,全球约3.5亿人为慢性乙型肝炎病毒(HBV)感染者,每年约有100万人死于HBV感染所致的肝功能衰竭、肝硬化和原发性肝细胞癌(HCC)^{[ 1]}。我国HBV的携带者约1.2亿,是我国常见的传染病,其传染性和病死率均居高不下,严重危害人们的健康。临床上慢性乙型肝炎(CHB)患者的诊断、抗病毒药物的应用、疗效的观察主要依靠乙肝血清学指标、肝功能[丙氨酸氨基转移酶(ALT)]和HBV DNA检测。目前,血清ALT水平仍是评价肝脏功能的最常用指标之一^{[ 2]},是临床评价CHB患者肝功能损害程度最重要的依据。那么是否只要CHB患者ALT在正常范围内就说明肝脏损害程度减轻、不需要进行抗病毒治疗呢?关于这个问题我们对部分ALT结果正常的CHB患者结合其乙型肝炎e抗原(HBeAg)和HBV DNA的结果进行了相关的分析研究。

材料和方法

一、研究对象

1.CHB^{[ 3 ]}组收集上海交通大学附属第六人民医院肝炎门诊2010年1月至2010年5月检测HBV标志物且ALT<65 U/L的血清样本,共214例。根据HBeAg结果分为HBeAg(-)组和HBeAg(+)组。其中HBeAg(-)组130例,男96例,女34例,年龄19~92岁;HBeAg(+)组84例,男62例,女22例,年龄17~81岁。

2.正常对照组选取乙型肝炎表面抗原(HBsAg)、乙型肝炎e抗体(HBeAb)和乙型肝炎核心抗体(HBcAb)均阴性、ALT<65 U/L的健康体检者样本作为正常对照组,共200名,其中男91例、女109例,年龄20~70岁。

二、仪器和试剂

i2000全自动化学发光仪及HBV血清标志物检测试剂盒为美国雅培公司产品;ABI7000全自动基因扩增检测仪为美国应用生物公司产品;HBV DNA荧光定量试剂盒为上海克隆生物技术有限公司产品;HITACHI 7600-020全自动生化分析仪为日本日立公司产品;ALT检测试剂盒为上海科华东菱诊断用品有限公司产品。

三、方法

1.HBV血清标志物检测采用化学发光法,严格按照i2000全自动化学发光仪操作规程进行。HBsAg≥0.05 IU/mL为阳性;乙型肝炎表面抗体(HBsAb)≥10 mIU/mL为阳性;HBeAg≥1.00 S/CO为阳性;HBeAb<1.00 S/CO为阳性;HBcAb>1.00 S/CO为阳性。

2.HBV DNA定量检测采用荧光定量聚合酶链反应(PCR),严格按标准操作程序(SOP)操作。试剂的检测敏感性为10³ IU/mL,检测范围为10³~10⁸ IU/mL。检测样本HBV DNA ≥1×10³ IU/mL时,按实际检测结果报告;HBV DNA<1×10³ IU/mL时,均报告“小于最低检测限”。

3.ALT检测 ALT采用酶法和化学法检测,全自动操作,按照仪器及项目操作规程进行。ALT正常参考范围:0~65 U/L。

四、统计学方法

使用SPSS 13.0统计软件进行统计学分析,计量资料以 ±s表示,组间比较采用非参数检验, P<0.05表示差异有统计学意义。

结果

一、ALT正常的CHB患者HBeAg(-)组、HBeAg(+)组与正常对照组ALT水平比较

ALT正常的CHB患者中HBeAg(-)组、HBeAg(+)组ALT水平均高于正常对照组( P<0.01),且HBeAg(+)组ALT水平高于HBeAg(-)组( P<0.05), 见表1。

表1 ALT正常的CHB患者与正常对照组ALT水平的比较(

±s,U/L)

二、CHB患者不同HBV DNA病毒载量组中HBeAg阳性率与ALT水平的关系

将214例CHB患者根据血清HBV DNA载量分为3组(Ⅰ组:HBV DNA<10³ IU/mL;Ⅱ组:10³ IU/mL≤HBV DNA<10⁴ IU/mL;Ⅲ组:HBV DNA≥10⁴ IU/mL)。Ⅰ 组的HBeAg阳性率明显低于Ⅱ、Ⅲ组( P<0.05),而Ⅱ组与Ⅲ组之间无明显差异( P>0.05)。Ⅲ组的ALT水平高于Ⅰ组和Ⅱ组( P<0.05),而Ⅰ组与Ⅱ组之间无明显差异( P>0.05)。

表2 HBV DNA不同载量的CHB患者HBeAg阳性率与ALT水平的比较

讨论

本研究结果发现,正常对照组的ALT水平明显低于CHB患者(包括HBeAg(-)组和HBeAg(+)组)。现今上海大多数医院基本上都是采用酶速率法检测ALT,参考值上限均在65 U/L左右。然而很多研究都提示现行的ALT正常参考范围上限可能偏高,特别是对于CHB患者。根据Prati等^{[ 4]}2002年对初次献血者进行研究,发现其ALT正常参考范围上限显著低于现行的ALT正常参考范围。随后的一项以95 533名男性和47 522名女性为对象的研究^{[ 5]}也表明, 若以Prati等得出的正常参考范围上限为标准,ALT轻度升高者(但仍处于现行的正常范围)因肝病死亡的相对危险性较高;与ALT<20 U/L者相比,ALT为20~29 U/L的患者的肝病死亡相对危险性要高2.9倍,ALT为30~39 U/L的患者的肝病死亡相对危险性高9.5倍。因此,对于CHB患者来说,ALT<65 U/L并不能说明肝脏功能正常,特别是ALT处于正常参考范围上限的患者,往往由于ALT在正常参考范围,容易被临床忽视,从而延误患者的进一步治疗。由于ALT 水平与肝组织坏死炎症及纤维化程度有时并不一定相关。因此,单纯依赖ALT水平来确定慢性HBV感染者是否需要治疗存在很大的局限性^{[ 6]}。Wang等^{[ 7]}认为,在亚洲,相当一部分处于“免疫耐受期”的慢性HBV感染者尽管ALT水平正常,但已经出现肝纤维化。Keeffe等^{[ 8]}认为在决定慢性HBV感染者是否需要治疗时, 应采用男性30 U/L、女性19 U/L作为ALT正常参考范围上限的标准。

临床上对CHB患者抗病毒治疗的原则是HBV DNA≥10⁴ IU/mL,无论ALT水平正常与否,均应作抗病毒治疗。本研究结果显示,在ALT正常的CHB患者中,HBV DNA≥10⁴ IU/mL的患者的HBeAg阳性率和ALT水平均高于HBV DNA<10³ IU/mL的患者。所以HBV DNA≥10⁴ IU/mL的CHB患者,特别是HBeAg(+)的患者更应引起临床重视。虽然其ALT处于正常水平,但是体内病毒仍在复制,ALT也处于正常上限,提醒临床医生不应盲目停止用药,应密切注意患者情况制定相应的治疗方案。HBeAg(-)的CHB可潜在引起肝纤维化,特别对于HBeAg(-)、血清高病毒载量的CHB患者,尽管ALT水平正常,临床也应予以高度重视。Kumar等^{[ 9]}报道,持续ALT正常、HBV DNA<10⁵ IU/mL的HBeAg(-)患者,约有21%的病例有活动性肝炎。虽然ALT水平持续正常的患者发生肝组织学病变的比例显著低于ALT水平升高者,但多数ALT水平“正常”的患者并不能长期保持正常的ALT水平,我们不能仅根据HBeAg阴转与否来判断病毒的复制状态,也不能看到ALT在正常范围就停止治疗或放松警惕^{[ 10]}。

总之, 临床应将ALT多少作为判定标准以决定慢性HBV感染者是否需要进一步的治疗,这个问题还有待于进行更深入地探讨。本研究中部分CHB患者ALT水平处于正常范围的上限,这种现象提示这部分人群可能仍存在病毒复制和肝功能的损伤,临床在治疗过程中应予以更多的关注^{[ 11]}。

The authors have declared that no competing interests exist.

参考文献

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2005

0.0

... 5亿人为慢性乙型肝炎病毒(HBV)感染者,每年约有100万人死于HBV感染所致的肝功能衰竭、肝硬化和原发性肝细胞癌(HCC)^[1] ...

2000

0.0

... 目前,血清ALT水平仍是评价肝脏功能的最常用指标之一^[2],是临床评价CHB患者肝功能损害程度最重要的依据 ...

2007

0.0

... CHB^{[ 3 ]}组收集上海交通大学附属第六人民医院肝炎门诊2010年1月至2010年5月检测HBV标志物且ALT#cod#x0003C ...

2002

13.976

0.0

... 根据Prati等^[4]2002年对初次献血者进行研究,发现其ALT正常参考范围上限显著低于现行的ALT正常参考范围 ...

2004

0.0

... 随后的一项以95 533名男性和47 522名女性为对象的研究^[5]也表明, 若以Prati等得出的正常参考范围上限为标准,ALT轻度升高者(但仍处于现行的正常范围)因肝病死亡的相对危险性较高 ...

2007

0.0

... 因此,单纯依赖ALT水平来确定慢性HBV感染者是否需要治疗存在很大的局限性^[6] ...

0.0

... Wang等^[7]认为,在亚洲,相当一部分处于#cod#x0201c ...

2006

0.0

. 2006, 4(8):936-962 DOI:10.1016/j.cgh.2006.05.016

A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update

Chronic hepatitis B (CHB) is an important public health problem worldwide and in the United States, with approximately 25% of patients infected as neonates dying prematurely from cirrhosis or liver cancer. A treatment algorithm for CHB previously developed and published by a panel of United States hepatologists was revised based on new developments in the understanding of CHB, the availability of more sensitive molecular diagnostic testing, the addition of new treatments, and better understanding of the advantages and disadvantages of approved therapies. This updated algorithm is based on available evidence using a systematic review of the scientific literature. Where data are lacking, the panel relied on clinical experience and consensus expert opinion. Serum HBV DNA can be detected at levels as low as 10 IU/mL using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest levels possible. The threshold level of HBV DNA for determination of candidacy for therapy is 20,000 IU/mL or more for patients with hepatitis B e antigen–positive CHB. A lower serum HBV DNA threshold of 2000 IU/mL or more is recommended for patients with hepatitis B e antigen–negative CHB, and 200 IU/mL or more for those with decompensated cirrhosis. Interferon alfa-2b, lamivudine, adefovir, entecavir, and peginterferon alfa-2a all are approved as initial therapy for CHB and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost.

... Keeffe等^[8]认为在决定慢性HBV感染者是否需要治疗时, 应采用男性30 U/L、女性19 U/L作为ALT正常参考范围上限的标准 ...

2008

12.821

0.0

... Kumar等^[9]报道,持续ALT正常、HBV DNA#cod#x0003C ...

2008

2.642

0.0

. 2008, 2(2):179-184 DOI:10.1007/s12072-008-9065-2

Should chronic HBV infected patients with normal ALT treated: debate

1.Department of Gastroenterology, G.B. Pant Hospital, New Delhi, 110002 India<br/>

Alanine aminotransferase (ALT) levels have traditionally been used for treatment decisions in chronic hepatitis B virus (CHBV) infected patients. But recent data have raised doubts on this wisdom, as a significant proportion of CHBV infected patients with normal ALT have high HBVDNA levels and significant liver injury at presentation especially in areas of intermediate to high endemicity. A normal ALT value only identifies patients less likely to respond to current treatments, rather than patients who are not in need of the treatment. Patients with CHBV infection with normal ALT should be considered for treatment based on the HBV DNA levels and histological injury.

... 的患者并不能长期保持正常的ALT水平,我们不能仅根据HBeAg阴转与否来判断病毒的复制状态,也不能看到ALT在正常范围就停止治疗或放松警惕^[10] ...

2007

0.0

... 本研究中部分CHB患者ALT水平处于正常范围的上限,这种现象提示这部分人群可能仍存在病毒复制和肝功能的损伤,临床在治疗过程中应予以更多的关注^[11] ...