中性粒细胞与淋巴细胞比值标志物在2型糖尿病及并发症中的诊断价值

发布时间:2020-06-18       作者:牛文彦       来源:临床实验室        浏览:2542       收藏: 0

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作者:牛文彦 王雅茹 张诗田

单位:天津医科大学朱宪彝纪念医院检验科

【摘要】2型糖尿病(type 2 diabetes mellitus,T2DM)目前已成为世界性健康问题,多项研究发现,T2DM及其并发症的发生与系统性慢性低度炎症有关。中性粒细胞介导固有免疫,淋巴细胞介导适应性免疫,中性粒细胞与淋巴细胞比值(neutrolphil to lymphocyte ratio,NLR)可作为提示系统性炎症的指标。大量临床研究发现,NLR与T2DM及其并发症如糖尿病肾病、糖尿病神经病变、糖尿病心血管病变相关,可作为这些疾病的预测因子。NLR作为简便易得的检测指标可在T2DM及其并发症的诊断中发挥作用。

2型糖尿病(type 2 diabetes mellitus,T2DM)已成为全球性健康问题,预计到2030年,T2DM患病人数将达到3.66亿[1,2]。如果不能及时诊断和有效控制T2DM,将会出现严重并发症,最终导致患者死亡。因此,早期预测和诊断对于控制T2DM及其并发症的发生发展极为重要。多项研究发现,T2DM及其并发症的发生发展与系统性慢性低度炎症有关[3-5]。中性粒细胞和淋巴细胞作为机体抵抗外界病原体入侵的第一道防线,是重要的炎症调节分子,是参与激活涉及急性和慢性炎症反应的主要细胞类型[6]。中性粒细胞主要介导固有免疫,淋巴细胞主要介导适应性免疫。中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratiao,NLR)可从血常规分析中获得,用于评价炎症反应的预后[6]。许多研究发现,NLR可用作炎症标志物,是重大心脏事件后死亡的危险因素和癌症预后的预测因子[7,8],它与多种疾病(心肌梗死、冠心病、冠状动脉粥样硬化、慢性阻塞性肺疾病、肥胖患者的高分化肾癌)的不良预后有关[9-15]。近来,一些临床研究发现,NLR也是T2DM及其并发症的潜在炎症生物标志物[16,17],可作为T2DM及其并发症的预测因子。

一、T2DM

T2DM以胰岛素抵抗、慢性高血糖为特征。大量研究报道糖尿病患者炎症细胞因子(C反应蛋白、IL-1、IL-6、TNF-α)水平升高[18]。最近, NLR已成为T2DM新的炎症标志物[19]。NLR可从全血细胞计数(CBC)中获得,可作为内皮功能异常和急性或慢性全身性炎症的指标[20]。中性粒细胞分泌炎性因子,可引起血管壁变性;淋巴细胞具有抗动脉粥样硬化的作用,从而调节炎症应答[21]。NLR升高与胰岛素抵抗[22]、葡萄糖不耐受程度相关[16],且NLR在糖尿病前期和糖尿病患者中显著升高[19]。Palella E等人也发现,T2DM患者的白细胞数量和中性粒细胞数量显著高于健康对照组,糖化血红蛋白(HbA1c)水平较高的患者的NLR更高,提示白细胞在糖尿病患者炎症状态评估中起支持作用,且NLR是预测T2DM患者血管并发症的辅助预后指标[23]。Duman TT等人的研究也显示T2DM患者的NLR水平升高,并与HbA1c水平呈正相关[24]。目前,临床上认为代谢手术是T2DM伴肥胖患者的一种治疗选择,Aldo Bonaventura 等人通过logistic回归分析发现,NLR≤1.97可预测T2DM患者5年内的缓解,且与BMI无关。在接受代谢手术的肥胖患者中,低NLR与T2DM长期缓解相关,这表明循环的炎症细胞(即中性粒细胞)可能与T2DM缓解呈负相关[25]。以上结果表明, NLR可作为T2DM前期、糖尿病和代谢手术后长期缓解的预测指标,以及胰岛素抵抗的预后指标。

二、糖尿病心脑血管病变

炎症反应是动脉粥样硬化及其进展的关键机制,晚期糖基化终产物(AGEs)具有促炎症和潜在致动脉粥样硬化功能,在动脉粥样硬化的发展过程中,血液中性粒细胞数量增加,并被吸引到斑块中,分泌炎症产物,导致血管壁持续损伤和内皮功能受损[26]。在T2DM中,心血管疾病的部分风险是由于一些病理生理变化导致的血栓前状态,包括内皮功能障碍、止血过程的改变(血小板高反应性、凝血因子合成增加、纤溶功能降低)以及炎症等[23]。糖尿病患者仍有较高的心血管事件发生率和较差的预后,尤其是急性冠状动脉综合征(ACS)的发生[11]。Roglic等人发现,糖尿病占北美地区死亡人数的15.7%,在这些死亡中,绝大多数是由心血管或肾脏并发症引起的[27]

有研究表明,ACS患者术前NLR值越高,院内死亡率越高,NLR 5.0可能是ACS风险的一个临界值[28],约5.5%-18.2%的ACS患者死于医院,长期随访死亡率高达近15%[28]。M.Verdoia等人发现,糖尿病患者的NLR值较高,这种NLR的增加是糖尿病患者冠状动脉病变程度和严重程度的独立预测因子,NLR显著升高与血糖水平直接相关,但与HbA1c无相关性[11]。Azab等人根据T2DM病人NLR(NLR<1.6、1.6<NLR<2.4、NLR>2.4)将其分成三组,通过4年随访,统计发生主要心血管不良事件(MACEs,包括冠状动脉旁路移植术、急性心肌梗死、经皮冠状动脉介入治疗或心脏相关死亡)的比例,结果显示,NLR>2.4的患者中,20.5%的患者经历过MACEs,NLR值为1.6-2.4和NLR<1.6患者的MACEs率分别为12.4%和5.3%,在校正高血压、性别、吸烟、年龄、血糖控制和充血性心力衰竭等混杂因素后,NLR依旧是T2DM患者发生MACEs的重要预测因子[29]。对2559名因急性心肌梗死入院的患者进行了回顾性研究发现,T2DM患者1年内再次梗死或死亡的比例比非糖尿病患者明显增高,比例分别为28%和16.6%,且NLR≥5.0对预测再梗死和死亡有重要意义,提示NLR是T2DM伴急性心肌梗死患者死亡率和1年内再梗死的独立预测因子[30]

此外,NLR与冠状动脉疾病的复杂性以及接受直接经皮冠状动脉介入治疗(PCI)的ST段抬高心肌梗死(STEMI)患者较差预后也有关[11]。有研究显示冠心病、急性冠脉综合征和脑卒中患者的平均NLR显著高于对照组[31]。与健康人相比,脑卒中患者NLR显著升高,中/重度脑卒中患者的NLR也高于轻度脑卒中患者[32]。与非糖尿病患者相比,T2DM患者出血性脑卒中的风险更高,NLR升高与T2DM患者脑出血发生率呈正相关,NLR>2.58可作为危险阈值,有助于预测T2DM患者脑出血的风险,提示NLR作为系统炎症程度的指标,是T2DM患者脑出血的独立危险因素[26]

三、糖尿病肾病

糖尿病肾病导致25-40%的糖尿病患者出现严重不良后果,是导致终末期肾功能衰竭的主要原因[33]。炎症在糖尿病肾病的进展中发挥重要作用,许多炎症因子(IL-1、IL-6、IL-8、TNF-α)与糖尿病肾病的发病机理密切相关[34]。Kahraman等人对112名在内科和肾科进行治疗的T2DM患者做回顾性研究后发现,NLR与肾小球滤过率和总胆固醇水平呈负相关,与C反应蛋白、尿素、肌酐、随机尿微量白蛋白、红细胞分布宽度呈正相关[5]。24小时尿白蛋白排泄与中性粒细胞计数、NLR呈正相关,与淋巴细胞计数呈负相关[5]。随着24小时尿白蛋白排泄的平均值增加,NLR呈线性增加[5]。线性回归分析发现,NLR是尿白蛋白排泄的独立危险因素[5]。同时其他研究也发现,NLR的增高与24小时尿蛋白和尿白蛋白排泄呈独立相关[35],NLR是白蛋白尿的独立预测因子[17]。因此NLR可以用来提示糖尿病肾病的发生。

四、糖尿病视网膜病变

糖尿病视网膜病变是糖尿病微血管病变之一,约有28.5-40.3%的T2DM患者出现糖尿病视网膜病变[36]。根据视网膜病变的严重程度分为非增殖性和增殖性视网膜病变。Powell等人发现水杨酸类的抗炎药物可以抑制糖尿病视网膜病变的发生,说明炎症在视网膜病变的病理机制中发挥重要作用[37]。糖尿病合并视网膜病变患者的血清和玻璃体液中TNF-α、IL-6、IL-1β、ICAM-1显著升高[38,39]。中国医科大学陈蕾等人对247名T2DM患者进行研究后发现,与T2DM非视网膜病变患者相比,T2DM合并视网膜病变患者NLR显著升高[40]。但是,NLR在T2DM合并非增殖性视网膜病变组与T2DM合并增殖性视网膜病变组间没有显著差异,NLR与T2DM合并视网膜病变的严重性无关[40]。甘肃省人民医院刘静团队的meta分析中也论述了与上述发现一致的研究结果[41]。这说明NLR可能仅在糖尿病视网膜病变早期发挥作用,但是由于相关研究的病例数有限,所以今后仍需扩大样本量做进一步统计分析。

五、糖尿病周围神经病变

糖尿病周围神经病变是糖尿病主要并发症之一,约有45%的T2DM患者和54-59%的1型糖尿病(type 1 diabetes mellitus,T1DM)患者出现糖尿病周围神经病变[42, 43]。临床上认为,糖尿病周围神经病变的进展与血管畸形的进展有关[44]。复旦大学华山医院鹿斌团队根据NLR(NLR≤1.52、1.52<NLR≤2.20、NLR>2.20)将511名T2DM患者分为NLR低、中、高三组,高NLR组神经传导速率显著降低,振动感知阈值显著升高,糖尿病周围神经病变的严重程度随着NLR升高而加重[44]。与低NLR组相比,高NLR组空腹血糖、超敏C反应蛋白水平显著升高,中NLR组的糖化血红蛋白水平显著升高[44]。NLR与年龄、糖尿病周围神经病变诊断率、心脏收缩压、振动感知阈值、空腹血糖、维生素B12、超敏C反应蛋白、白细胞总数呈正相关,与神经传导速率、血磷水平呈负相关[44]。在校正了一些潜在影响因素(年龄、性别、病程、体重指数、收缩压、血糖、血脂、维生素B12、血磷、超敏C反应蛋白、白细胞总数等)后,NLR仍与糖尿病周围神经病变相关[44]。NLR最大约登指数的cutoff值为1.7时的敏感性为63.1%,特异性为72.1%;当NLR的cutoff值≥3.9时,特异性为95%[44]。因此NLR可以用来预测糖尿病周围神经病变的发生,可在临床上协助医生监测糖尿病周围神经病变的发生和进展。

综上所述,NLR简便易得,可能在T2DM及其并发症的发生发展中发挥重要的诊断作用。有望广泛应用于临床,有助于监控T2DM及其并发症的发生发展,提高患者生活质量。

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