柳慶華，許方程，寶彩芹，李永芬，馬 佳

結(jié)直腸癌患者血清D-dimer與C-反應(yīng)蛋白的檢測及其臨床意義

柳慶華1，許方程2，寶彩芹1，李永芬2，馬 佳1

目的 評估結(jié)直腸癌(colorectal carcinoma，CRC)患者血清D-dimer與C-反應(yīng)蛋白(C-reactive protein, CRP)檢測的臨床意義。方法 收集53例CRC患者與30例健康者對照，患者術(shù)前及術(shù)后1、3、7 d采集血樣，對照在體檢時采集的血樣；檢測血清D-dimer與CRP并對淋巴結(jié)轉(zhuǎn)移、血管浸潤和TNM分級不同病理參數(shù)間檢測值進行對比分析；對開腹手術(shù)和腹腔鏡手術(shù)術(shù)后檢測值進行對比分析；對患者術(shù)前CRP與D-dimer檢測值進行相關(guān)性分析。結(jié)果 CRC患者D-dimer、CRP顯著高于健康人群(P<0.01)；淋巴結(jié)轉(zhuǎn)移和血管浸潤陽性患者D-dimer[(2.33±0.72) mg/L]與CRP[(16.0±1.5) mg/L]水平高于陰性患者(P<0.01)；TNM分級各級患者間D-dimer與CRP水平有統(tǒng)計學(xué)差異，隨病理等級增加而升高(P<0.01)。D-dimer和CRP在術(shù)后均升高(P<0.05)，隨后降低，D-dimer術(shù)后1周降至正常水平，而CRP在1周后仍高于術(shù)前水平(P<0.05)。腹腔鏡組CRP水平顯著低于開腹手術(shù)組(P<0.01)。術(shù)前CRP與D-dimer間具有正相關(guān)性(r=0.432，P<0.05)。結(jié)論 血清D-dimer、CRP水平與CRC及其病變程度相關(guān)，可能對CRC的早期診斷、預(yù)后判斷以及術(shù)后炎性反應(yīng)判斷具有指導(dǎo)意義。

C-反應(yīng)蛋白；D-dimer；結(jié)直腸癌

癌癥常伴有凝血和纖維蛋白溶解途徑的改變，有50%的患者和95%的腫瘤轉(zhuǎn)移患者會出現(xiàn)凝血參數(shù)異常[1]。血栓栓塞與出血是癌癥死亡的第二大原因。目前，惡性腫瘤患者血液高凝性和血栓栓塞并發(fā)癥的研究報道雖然較多，但癌癥引起的血液凝固與纖溶活化機制仍不清楚[2]。D-Dimer由交聯(lián)纖維蛋白XIIIa被纖溶酶降解產(chǎn)生，其濃度變化為腫瘤細胞誘導(dǎo)的凝固與纖溶系統(tǒng)的活化提供了有力證據(jù)[3]。此外，C-反應(yīng)蛋白(C-reactive protein, CRP)是典型的炎性標(biāo)志分子，以CRP升高為標(biāo)志的慢性炎性反應(yīng)可能與結(jié)直腸癌(colorectal carcinoma, CRC)的危險性相關(guān)[4]。為此，本研究檢測CRC患者血漿D-dimer和CRP水平，并評估兩者與CRC病理學(xué)分型及其臨床意義。

1 對象與方法

1.1 對象 選取2009-01至2014-04我院普外科接受擇期結(jié)直腸切除術(shù)治療的CRC患者53例為病例組，其中男35例，女18例；中位年齡61歲，范圍29～80歲。開腹手術(shù)20例，腹腔鏡切除術(shù)33例。選擇同時期在本院體檢中心進行健康體檢的30名健康人群為對照組，其中男20名，女10名，中位年齡59歲，范圍30～79歲。病例組與對照組間年齡、性別無統(tǒng)計學(xué)差異，兩組具有可比性。

排除標(biāo)準(zhǔn)：1個月內(nèi)有感染或炎性疾??；術(shù)前接受過放療化療；缺血性心臟病史。所有患者均簽署知情同意書。所有患者利用切除樣本，依TNM分級標(biāo)準(zhǔn)進行分級[5]。

1.2 血清D-dimer與CRP檢測與判斷標(biāo)準(zhǔn) 患者術(shù)前2 d，術(shù)后1 d、3 d和7 d分別采集清晨空腹靜脈血3 ml，注入枸櫞酸鈉抗凝管，在2 h內(nèi)以3000 r/min離心20 min后，取上層血漿分裝后-70 ℃儲存?zhèn)溆?。血清CRP 檢測采用散射比濁法(DADE DEHRING公司試劑盒，特種蛋白分析儀)檢測，D-dimer檢測用免疫比濁法(Sysmex公司試劑盒，Sysmex CA1500全自動血凝分析儀)測定。

2 結(jié) 果

2.1 術(shù)前血清D-dimer、CRP水平與臨床病理學(xué)參數(shù)關(guān)系 直結(jié)腸癌患者術(shù)前D-dimer與CRP血清濃度檢測結(jié)果見表1。患者D-dimer與CRP水平高于

健康人群(P<0.01)；淋巴結(jié)轉(zhuǎn)移和血管浸潤陽性患者D-dimer與CRP水平高于陰性患者(P<0.01)；TNM分級各級間比較有顯著差異，D-dimer與CRP水平隨病理等級增加而升高(P<0.01)。

表1 結(jié)直腸癌術(shù)前血清D-dimer與CRP水平與臨床病理學(xué)特征關(guān)系 ；mg/L)

注：與健康對照組比較，①P<0.01；與淋巴結(jié)轉(zhuǎn)移陰性者比較，②P<0.01；與血管浸潤陰性者比較，③P<0.01；與TNM分級Ⅰ級患者比較，④P<0.01

2.2 切除術(shù)對血清CRP與D-dimer水平的影響 由表2可見，所有手術(shù)患者血清D-dimer濃度在術(shù)后1 d明顯升高(P<0.05)，隨后又降低，至術(shù)后1周降至健康對照水平；腹腔鏡手術(shù)與開腹手術(shù)組間未見統(tǒng)計學(xué)差異。血清CRP術(shù)后1 d有急劇升高(P<0.01)，隨后有所降低，術(shù)后1周時仍高于術(shù)前水平(P<0.05)；腹腔鏡組CRP水平低于開腹手術(shù)組(P<0.01)。

2.3 血清CRP與D-dimer相關(guān)性分析 經(jīng)直線相關(guān)分析，發(fā)現(xiàn)CRC患者術(shù)前CRP與D-dimer具有正相關(guān)性(r=0.432，P<0.05)。

表2 結(jié)直腸癌術(shù)后血清CRP與D-dimer濃度變化 ；mg/L)

注：與術(shù)前比較，①P<0.05，②P<0.01；與術(shù)后1 d比較，③P<0.01；與腹腔鏡組比較，④P<0.01

3 討 論

D-Dimer水平在肺癌、前列腺癌、宮頸癌、卵巢癌、乳腺癌和結(jié)腸癌等實體瘤中都較健康人群高[6]。Oya等[7]發(fā)現(xiàn)，CRC患者的D-dimer水平與手術(shù)切除時腫瘤浸潤程度相關(guān)。Yoshinori等[8]認為，高水平的CRP與CRC或結(jié)腸癌無顯著關(guān)聯(lián)。Helzlsouer等[9]發(fā)現(xiàn)，在結(jié)腸癌患者，CRP濃度顯著高于對照，直腸癌和前列腺癌患者CRP與對照無顯著差異。Volkova等[10]最近卻發(fā)現(xiàn)，血清CRP和Ang-2濃度高的CRC患者，生存率顯著較低。Zhang等[11]對27 913例45歲以上健康女性進行近11年的隨訪研究發(fā)現(xiàn)，CRP基線水平與直結(jié)腸癌危險性無顯著關(guān)系，血清高CRP與CRC癌變部位、癌癥分級也無顯著關(guān)系。Heikkila等[12]對公開發(fā)表的相關(guān)論文進行分析，發(fā)現(xiàn)在90項獨立研究報告中，有9項為大項前瞻性研究，其中5項研究結(jié)果認為，CRP循環(huán)水平與CRC和肺癌有關(guān)，4項研究發(fā)現(xiàn)CRP循環(huán)水平與乳腺癌、前列腺癌和CRC無關(guān)；多項研究發(fā)現(xiàn)，CRP在癌癥患者中的濃度高于良性腫瘤和健康對照。Kwon等[13]研究發(fā)現(xiàn)，CRC患者CRP水平顯著高于對照組，而CRP 與患者無疾病生存和總生存率無顯著相關(guān)性。以上研究顯示，血清CRP、D-dimer水平與CRC等實體癌的相關(guān)性尚需進一步研究論證。

本研究對53例CRC患者和30名健康人群的對比分析發(fā)現(xiàn)，患者血清CRP與D-dimer濃度顯著高于健康對照。癌癥TNM分級、淋巴結(jié)轉(zhuǎn)移和血管浸潤等不同病理學(xué)參數(shù)患者對比分析顯示，血清CRP與D-dimer濃度隨癌癥惡化程度增加而升高，該結(jié)果與多項報道結(jié)果一致[6,7,12]。本研究還發(fā)現(xiàn)，術(shù)后D-dimer濃度有短暫的升高，說明手術(shù)損傷對凝血和纖溶系統(tǒng)有顯著影響，而由于腫瘤對凝血和纖溶帶來的變化隨著切除術(shù)的實施而消除，D-dimer術(shù)后很快又降至正常水平。CRP的檢測結(jié)果顯示，無論是開腹手術(shù)還是腹腔鏡手術(shù)，都有明顯的術(shù)后炎性反應(yīng)，但腹腔鏡手術(shù)反應(yīng)輕于開腹手術(shù)，充分顯示了腹腔鏡手術(shù)微創(chuàng)傷的優(yōu)勢，也提示CRP的檢測在判斷術(shù)后炎性反應(yīng)中可發(fā)揮重要作用?；颊咝g(shù)前血清CRP與D-dimer濃度的相關(guān)性分析發(fā)現(xiàn)，兩者呈顯著正相關(guān)。

可能由于因果關(guān)系倒置、經(jīng)濟社會學(xué)、生活方式，以及癌癥伴發(fā)的血栓和炎性反應(yīng)等諸多因素影響，當(dāng)前對CRP、D-dimer與CRC的相關(guān)性研究還存在諸多分歧，CRP、D-dimer對CRC早期診斷與病因判斷中的應(yīng)用還缺乏足夠證據(jù)。本研究對血清CRP和D-dimer的檢測，為相關(guān)研究提供了數(shù)據(jù)補充。然而，闡明CRP和D-dimer與癌癥關(guān)系的有效途徑，是開展CRP和D-dimer功能性基因變異與癌癥關(guān)系的研究。根據(jù)孟德爾隨機化法則，對基因多態(tài)性進行研究，有利于排除經(jīng)濟社會學(xué)或生活方式等混雜因素的影響，提供更準(zhǔn)確的依據(jù)[14,15]。

總之，根據(jù)有限的數(shù)據(jù)不難推斷，血清D-dimer和CRP水平與CRC及其病變程度相關(guān)，對兩者進行聯(lián)合檢測，可能對CRC的早期診斷、預(yù)后判斷，以及術(shù)后感染判斷具有指導(dǎo)意義。

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(2014-06-20收稿 2014-08-10修回)

(責(zé)任編輯 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

柳慶華，本科學(xué)歷，醫(yī)師，E-mail：279960529@qq.com

650111昆明，武警云南總隊醫(yī)院：1.醫(yī)務(wù)處，2.外二科

許方程， E-mail：37861833@qq.com

R735.3