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

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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