结直肠癌患者血清D-dimer与C-反应蛋白的检测及其临床意义

2014-07-18柳庆华许方程宝彩芹李永芬

武警医学 2014年11期

柳庆华，许方程，宝彩芹，李永芬，马佳

柳庆华1，许方程2，宝彩芹1，李永芬2，马佳1

目的评估结直肠癌(colorectal carcinoma，CRC)患者血清D-dimer与C-反应蛋白(C-reactive protein, CRP)检测的临床意义。方法收集53例CRC患者与30例健康者对照，患者术前及术后1、3、7 d采集血样，对照在体检时采集的血样；检测血清D-dimer与CRP并对淋巴结转移、血管浸润和TNM分级不同病理参数间检测值进行对比分析；对开腹手术和腹腔镜手术术后检测值进行对比分析；对患者术前CRP与D-dimer检测值进行相关性分析。结果 CRC患者D-dimer、CRP显著高于健康人群(P<0.01)；淋巴结转移和血管浸润阳性患者D-dimer[(2.33±0.72) mg/L]与CRP[(16.0±1.5) mg/L]水平高于阴性患者(P<0.01)；TNM分级各级患者间D-dimer与CRP水平有统计学差异，随病理等级增加而升高(P<0.01)。D-dimer和CRP在术后均升高(P<0.05)，随后降低，D-dimer术后1周降至正常水平，而CRP在1周后仍高于术前水平(P<0.05)。腹腔镜组CRP水平显著低于开腹手术组(P<0.01)。术前CRP与D-dimer间具有正相关性(r=0.432，P<0.05)。结论血清D-dimer、CRP水平与CRC及其病变程度相关，可能对CRC的早期诊断、预后判断以及术后炎性反应判断具有指导意义。

C-反应蛋白；D-dimer；结直肠癌

癌症常伴有凝血和纤维蛋白溶解途径的改变，有50%的患者和95%的肿瘤转移患者会出现凝血参数异常[1]。血栓栓塞与出血是癌症死亡的第二大原因。目前，恶性肿瘤患者血液高凝性和血栓栓塞并发症的研究报道虽然较多，但癌症引起的血液凝固与纤溶活化机制仍不清楚[2]。D-Dimer由交联纤维蛋白XIIIa被纤溶酶降解产生，其浓度变化为肿瘤细胞诱导的凝固与纤溶系统的活化提供了有力证据[3]。此外，C-反应蛋白(C-reactive protein, CRP)是典型的炎性标志分子，以CRP升高为标志的慢性炎性反应可能与结直肠癌(colorectal carcinoma, CRC)的危险性相关[4]。为此，本研究检测CRC患者血浆D-dimer和CRP水平，并评估两者与CRC病理学分型及其临床意义。

1 对象与方法

1.1 对象选取2009-01至2014-04我院普外科接受择期结直肠切除术治疗的CRC患者53例为病例组，其中男35例，女18例；中位年龄61岁，范围29～80岁。开腹手术20例，腹腔镜切除术33例。选择同时期在本院体检中心进行健康体检的30名健康人群为对照组，其中男20名，女10名，中位年龄59岁，范围30～79岁。病例组与对照组间年龄、性别无统计学差异，两组具有可比性。

排除标准：1个月内有感染或炎性疾病；术前接受过放疗化疗；缺血性心脏病史。所有患者均签署知情同意书。所有患者利用切除样本，依TNM分级标准进行分级[5]。

1.2 血清D-dimer与CRP检测与判断标准患者术前2 d，术后1 d、3 d和7 d分别采集清晨空腹静脉血3 ml，注入枸橼酸钠抗凝管，在2 h内以3000 r/min离心20 min后，取上层血浆分装后-70 ℃储存备用。血清CRP 检测采用散射比浊法(DADE DEHRING公司试剂盒，特种蛋白分析仪)检测，D-dimer检测用免疫比浊法(Sysmex公司试剂盒，Sysmex CA1500全自动血凝分析仪)测定。

2 结果

2.1 术前血清D-dimer、CRP水平与临床病理学参数关系直结肠癌患者术前D-dimer与CRP血清浓度检测结果见表1。患者D-dimer与CRP水平高于

健康人群(P<0.01)；淋巴结转移和血管浸润阳性患者D-dimer与CRP水平高于阴性患者(P<0.01)；TNM分级各级间比较有显著差异，D-dimer与CRP水平随病理等级增加而升高(P<0.01)。

表1 结直肠癌术前血清D-dimer与CRP水平与临床病理学特征关系；mg/L)

注：与健康对照组比较，①P<0.01；与淋巴结转移阴性者比较，②P<0.01；与血管浸润阴性者比较，③P<0.01；与TNM分级Ⅰ级患者比较，④P<0.01

2.2 切除术对血清CRP与D-dimer水平的影响由表2可见，所有手术患者血清D-dimer浓度在术后1 d明显升高(P<0.05)，随后又降低，至术后1周降至健康对照水平；腹腔镜手术与开腹手术组间未见统计学差异。血清CRP术后1 d有急剧升高(P<0.01)，随后有所降低，术后1周时仍高于术前水平(P<0.05)；腹腔镜组CRP水平低于开腹手术组(P<0.01)。

2.3 血清CRP与D-dimer相关性分析经直线相关分析，发现CRC患者术前CRP与D-dimer具有正相关性(r=0.432，P<0.05)。

表2 结直肠癌术后血清CRP与D-dimer浓度变化；mg/L)

注：与术前比较，①P<0.05，②P<0.01；与术后1 d比较，③P<0.01；与腹腔镜组比较，④P<0.01

3 讨论

D-Dimer水平在肺癌、前列腺癌、宫颈癌、卵巢癌、乳腺癌和结肠癌等实体瘤中都较健康人群高[6]。Oya等[7]发现，CRC患者的D-dimer水平与手术切除时肿瘤浸润程度相关。Yoshinori等[8]认为，高水平的CRP与CRC或结肠癌无显著关联。Helzlsouer等[9]发现，在结肠癌患者，CRP浓度显著高于对照，直肠癌和前列腺癌患者CRP与对照无显著差异。Volkova等[10]最近却发现，血清CRP和Ang-2浓度高的CRC患者，生存率显著较低。Zhang等[11]对27 913例45岁以上健康女性进行近11年的随访研究发现，CRP基线水平与直结肠癌危险性无显著关系，血清高CRP与CRC癌变部位、癌症分级也无显著关系。Heikkila等[12]对公开发表的相关论文进行分析，发现在90项独立研究报告中，有9项为大项前瞻性研究，其中5项研究结果认为，CRP循环水平与CRC和肺癌有关，4项研究发现CRP循环水平与乳腺癌、前列腺癌和CRC无关；多项研究发现，CRP在癌症患者中的浓度高于良性肿瘤和健康对照。Kwon等[13]研究发现，CRC患者CRP水平显著高于对照组，而CRP 与患者无疾病生存和总生存率无显著相关性。以上研究显示，血清CRP、D-dimer水平与CRC等实体癌的相关性尚需进一步研究论证。

本研究对53例CRC患者和30名健康人群的对比分析发现，患者血清CRP与D-dimer浓度显著高于健康对照。癌症TNM分级、淋巴结转移和血管浸润等不同病理学参数患者对比分析显示，血清CRP与D-dimer浓度随癌症恶化程度增加而升高，该结果与多项报道结果一致[6,7,12]。本研究还发现，术后D-dimer浓度有短暂的升高，说明手术损伤对凝血和纤溶系统有显著影响，而由于肿瘤对凝血和纤溶带来的变化随着切除术的实施而消除，D-dimer术后很快又降至正常水平。CRP的检测结果显示，无论是开腹手术还是腹腔镜手术，都有明显的术后炎性反应，但腹腔镜手术反应轻于开腹手术，充分显示了腹腔镜手术微创伤的优势，也提示CRP的检测在判断术后炎性反应中可发挥重要作用。患者术前血清CRP与D-dimer浓度的相关性分析发现，两者呈显著正相关。

可能由于因果关系倒置、经济社会学、生活方式，以及癌症伴发的血栓和炎性反应等诸多因素影响，当前对CRP、D-dimer与CRC的相关性研究还存在诸多分歧，CRP、D-dimer对CRC早期诊断与病因判断中的应用还缺乏足够证据。本研究对血清CRP和D-dimer的检测，为相关研究提供了数据补充。然而，阐明CRP和D-dimer与癌症关系的有效途径，是开展CRP和D-dimer功能性基因变异与癌症关系的研究。根据孟德尔随机化法则，对基因多态性进行研究，有利于排除经济社会学或生活方式等混杂因素的影响，提供更准确的依据[14,15]。

总之，根据有限的数据不难推断，血清D-dimer和CRP水平与CRC及其病变程度相关，对两者进行联合检测，可能对CRC的早期诊断、预后判断，以及术后感染判断具有指导意义。

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(2014-06-20收稿 2014-08-10修回)

(责任编辑武建虎)

Detection of serum D-dimer and CRP in patients with colorectal cancer and its clinical significance

LIU Qinghua1, XU Fangcheng2, BAO Caiqin1, LI Yongfen2, and MA Jia1.

1. Medical Department，2. Department of General Surgery，Yunnan Provincial Corps Hospital，Chinese People’s Armed Police Forces，Kunming 650111，China

Objective To evaluate the clinical significance of serum D-dimer and C-reactive protein (CRP) detection in patients with colorectal carcinoma. Methods Fifty-three patients and thirty healthy controls were enrolled and bloods were sampled from controls at examination and patients pre-operation and on days 1, 3, 7 post-operation respectively. Serum D-dimer and CRP were detected. The results were analyzed considering the pathologic parameters such as TNM staging, lymph nodes metastasis and vascular invasion. Contrastive analyses were performed between the measurements of laparoscopic and open resection cases. Results D-dimer and CRP levels in patients were significantly higher than in controls(P<0.01). D-dimer and CRP levels in patients with lymph nodes metastasis or vascular invasion were significantly higher than in negative cases. Serum D-dimer and CRP were increased by the TNM stages promotion. Serum D-dimer and CRP were both increased post-operation and then decreased. D-dimer was attenuated to normal level and CRP was still significantly higher than pre-operation at 7 days post-operation. CRP in patients undergoing laparoscopic resection were significantly lower than in those undergoing open resection. Pre-operative CRP and D-dimer were positively correlated(r=0.432，P<0.05). Conclusions Serum D-dimer and CRP are correlated with pathologic degrees in CRC; combined measurements of these two indexes may be significant in early diagnosis, prognosis and post-operative inflammation judgment in CRC.

C-reactive protein；D-dimer；colorectal carcinoma

柳庆华，本科学历，医师，E-mail：279960529@qq.com

650111昆明，武警云南总队医院：1.医务处，2.外二科

许方程， E-mail：37861833@qq.com

R735.3