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糖尿病性黄斑水肿危险因素研究进展

Research progress on risk factors for diabetic macular edema

来源期刊： 眼科学报 | 2024年7月 第39卷 第7期： 352-364 发布时间：2024-07-28 收稿时间：2024/9/19 10:14:25 阅读量：553
作者：
李梓敬,
金陈进,
关键词：
糖尿病性黄斑水肿危险因素全身因素眼部因素
diabetic macular edema risk factors systemic factors ocular factors
DOI：
10.12419/24070303
收稿时间：
2024-06-05 
修订日期：
2024-06-25 
接收日期：
2024-07-15 
糖尿病性黄斑水肿(diabetic macular edema, DME)是糖尿病最常见和最严重的并发症之一，也是中青年劳动人群常见的致盲原因。DME病理生理机制复杂，是多种因素相互作用的结果，控制这些危险因素是降低发病率的关键。DME是全身病相关性眼病，其发生与发展受众多危险因素的影响，但此前文献对其总结不足，本文从全身因素及眼部因素两个方面就DME的危险因素进行综述。全身危险因素主要包括血糖控制欠佳、糖尿病病程长、高血压、血脂代谢紊乱、肥胖、肾功能异常、妊娠状态、降糖药物使用、贫血、阻塞性睡眠呼吸暂停低通气综合征、遗传因素、吸烟、饮酒、高血钙、低血镁等；而其眼部危险因素主要包括白内障、青光眼及玻璃体切割术、全视网膜激光光凝术、合并视网膜静脉阻塞和相关细胞因子等。深入认识和理解这些危险因素，有助于更好地预防和早期治疗DME，同时为治疗糖尿病视网膜病变过程中控制DME进展提供指引和参考。但是，其中一部分因素还存在一定争议，更多的DME危险因素仍有待进一步探索，期望在不久的将来，更多基础和前瞻性临床研究为DME危险因素及治疗提供高质量的证据。
Diabetic macular edema (DME) is one of the most common and severe complications of diabetes, and it is a leading cause of blindness in the working-age population. The pathophysiology of DME is complex, resulting from the interplay of various factors. Controlling these risk factors is crucial in reducing the incidence of DME. As a systemic diseaserelated ocular condition, the onset and progression of DME are influenced by numerous risk factors. However, previous literature has provided insufficient summaries of these factors. This review aims to summarize the risk factors for DME from both systemic and ocular perspectives. The systemic risk factors primarily include poor glycemic control, prolonged duration of diabetes, hypertension, dyslipidemia, obesity, renal dysfunction, pregnancy, the use of hypoglycemic medications, anemia, obstructive sleep apnea-hypopnea syndrome, genetic factors, smoking, alcohol consumption, hypercalcemia, and hypomagnesemia. On the other hand, ocular risk factors include cataracts, glaucoma and vitrectomy, panretinal photocoagulation, coexisting retinal vein occlusion, and related cytokines. A deeper understanding of these risk factors will aid in the better prevention and early treatment of DME, while also providing guidance and reference for controlling the progression of DME during the treatment of diabetic retinopathy. However, some of these factors remain controversial, and additional DME risk factors still need to be explored. It is hoped that, in the near future, more 
foundational and prospective clinical studies will provide high-quality evidence on DME risk factors and treatments.

文章亮点

1. 关键发现

• 文章从全身因素及眼部因素两个方面就糖尿病性黄斑水肿（diabetic macular edema, DME）的危险因素进行综述，为 DME 的防治提供更多理论支持。

2. 已知与发现

• DME 是全身病相关性眼病，其发生与发展受众多危险因素的影响，但此前文献对其总结不足，本文从全身因素及眼部因素两个方面就 DME 的危险因素进行综述。全身危险因素主要包括血糖控制欠佳、糖尿病病程长、高血压、血脂代谢紊乱、肥胖、肾功能异常、妊娠状态、降糖药物使用、贫血、阻塞性睡眠呼吸暂停低通气综合征、遗传因素、吸烟、饮酒、高血钙、低血镁等；而其眼部危险因素主要包括白内障、青光眼及玻璃体切割术、全视网膜激光光凝术、合并视网膜静脉阻塞和相关细胞因子等。

3. 意义与改变

• 深入认识和理解这些危险因素，有助于更好地预防和早期治疗 DME，同时为治疗糖尿病视网膜病变过程中控制 DME进展提供指引和参考。期望在不久的将来，更多基础和前瞻性临床研究为DME 危险因素及治疗提供高质量的证据。

       糖尿病视网膜病变(diabetic retinopathy, DR)是糖尿病(diabetes mellitus, DM)最常见和最严重的并发症之一，也是中青年劳动人群常见的致盲原因。其中，糖尿病性黄斑水肿(diabetic macular edema, DME)可发生于DR中的任何阶段，是DR影响视功能的最重要原因之一[1]。DME在我国DR患者中的发病率可高达33.62%[2]，给家庭和社会带来了沉重的经济负担。DME的主要病理生理机制：1)当血-视网膜色素上皮(retinal pigment epithelium, RPE)屏障受损，毛细血管渗透性增加，蛋白质和水进入视网膜实质层，并在视网膜的内丛状层和外核层之间积聚，使视网膜增厚、外周毛细血管渗出，从而导致DME；2)血管内皮生长因子(vascular endothelial growth factor, VEGF)在DME过程的血-视网膜屏障破坏中起关键作用[3]。长期的DME使光感受器的结构发生变化，导致视功能受损。除此以外，DME还存在其他复杂机制，有待研究者进一步探索。因此，为了更好地预防和治疗DME，本文从全身因素及眼部因素两个方面就DME的危险因素进行相关综述。

1 全身因素

1.1 血糖控制

       血糖控制与DME的发生和发展密切相关。持续的高血糖损伤视网膜血管内皮细胞，影响血-视网膜屏障(blood-retinal barrier, BRB)的完整性，从而使血管通透性增加，蛋白质和水渗漏至视网膜层间。另外，高血糖也导致自由基、糖基化终产物等毒性物质的累积，同样对BRB的结构和功能造成一定损伤 [4]。
       糖化血红蛋白(Glycated Hemoglobin A1c, HbA1c)代表了近三个月以来血浆葡萄糖的平均水平，是评估血糖控制的重要指标。HbA1c基线水平越高，发生DME的风险越高。根据Wisconsin等[5-6]进行的流行病学研究(Wisconsin epidemiologic study of diabetic retinopathy, WESDR)，HbA1c>12.1% 的DM患者发生DME风险是HbA1c<9.4%的DM患者的3倍。Hammes等[7]纳入德国和奥地利166个研究中心的85 813例患者进行多元回归分析，也得到相似结论：HbA1c>8%是黄斑水肿及DR进展的重要危险因素。但有趣的是，一项来自丹麦的研究[8]显示，高于正常值的HbA1c会同时增加增殖期DR(proliferative diabetic retinopathy, PDR)和DME的风险；与之相反，低于正常值的HbA1c却仅增加PDR的风险。具体的机制尚未阐明。然而，低水平HbA1c是否在抗VEGF药物治疗DME中具有协同作用？在不同研究中，结果有所差异。在一项为期3年的研究中，Bansal等[9]对DME患者进行雷珠单抗眼内注射治疗。但是，视力、中心视网膜厚度(central macular thickness, CMT)和DR严重程度的改善与HbA1c的水平并无明显相关。Wong等[10]则发现，较低的HbA1c(<7%)能使CMT在首次抗VEGF药物治疗中下降得更多。
       Hirsch等[11]首次提出血糖变异性的概念，血糖变异性既可以指日间的血糖波动(如空腹血糖、餐后2 h血糖的波动)，也可以指长期血糖的波动(如HbA1c的波动)。有关血糖变异性和DME关系的研究较少，仅有一项来自中国台湾的前瞻性研究[12]。该研究指出，空腹血糖高变异性是2型DM患者发生DME的危险因素。而其他研究显示，在1型DM 患者中，HbA1c高变异性是DR的危险因素，但空腹血糖高变异性并非DR的危险因素[13-14]。这些差异可能与DM类型、病情进展速度等多种因素相关。
       血糖的短期内迅速改善也可能会导致DR或DME的加重。在减重手术后、接受胰岛素强化治疗后、胰腺移植术后等情况中均可出现[15-16]。其可能的机制：HbA1c的快速下降，会降低血管内渗透压，在细胞内外产生渗透梯度，导致体液从高渗透压水平移动到低渗透压水平，而视网膜血管正是较敏感的低压区域[17]；同时也会减少视网膜血流量，使血液供应不足，同时自身血流调节受损[18]。所以，高水平的HbA1c、高血糖变异性和血糖的短期改善均是DME的危险因素。

1.2 糖尿病病程

       糖尿病病程是DME较明确的危险因素。众多流行病学证据显示，糖尿病病程越长，DME发生风险越高[6, 19-22]。根据一项美国研究显示，糖尿病病程>10年的患者患DME的风险是糖尿病病程<10年患者的8.5倍[20]。英国DR筛查项目相关数据显示，基线时无DR的2型DM患者在随访5年以后出现DR、PDR和DME的累积发病率分别为36%、0.7%和0.6%，而在随访10年以后，累积发病率分别上升至66%、1.5%和1.2%[22]。在WESDR1型DM患者队列25年随访过程中，97%的患者随时间的推移发展为DR，而1/3~1/2的患者又陆续发展为PDR(42%) 或DME(29%)[6, 21]。但是，上述累积发病率的增长速度随患者年龄增长先快后慢，可能是因为随着年龄增长，竞争性死亡风险随之增加。因此，加强宣教，减少DM患病，对防止DME的发生和延缓发展具有极其重要的意义。

1.3 高血压

       高血压是DME的另一重要危险因素。高血压可增加视网膜血管中的灌注压力，进一步损伤血管内皮，增加血管通透性，同时损伤视网膜血管的自身调节能力[23]。另外，高血压引起动脉基底膜增厚，容易引起附近静脉阻塞，从而进一步影响其与眼部动静脉的沟通[24]。临床研究表明，高血压与DME关系密切。在一项北欧的DR流行病学研究[8]中，收缩压和舒张压的升高都会增加DME进展的风险，而舒张压的升高仅增加PDR进展的风险。Martín-Merino等[25]的研究显示：收缩压>160 mmHg(1 mmHg=0.133 kPa)的患者发生DME的风险是收缩压≤160 mmHg患者的2倍。Lopes de Faria等[26]的研究指出当收缩压超过160 mmHg，每增加10 mmHg，DME风险增加23%。一项DME研究也发现，视网膜厚度与脉压水平(收缩压和舒张压之差)呈正相关[27]。高血压和动脉粥样硬化等因素使动脉壁弹性减弱，从而影响脉压，这也间接证明了高血压与DME存在一定的关系。
       另外，一些临床研究也提示，DME患眼可能存在血流动力学异常，这可能也是DME与高血压相关的重要证据。Park等[28]使用海德堡视网膜血流计测量单眼DME患者双眼的黄斑区血流量，并发现DME患眼的黄斑区血流量较对侧眼显著升高。与之相反，Sakata等[29]的研究却发现，有临床意义的黄斑水肿(clinically significant macular edema, CSME)的患眼、不伴CSME的患眼和对照组的患眼三组的中心凹旁毛细血管血流速度依次增加。这些差异可能与DME严重程度、病程的发展等因素有一定关系。Kase等[30]还指出，累及黄斑中心凹的DME(central-involved DME, CI-DME)患眼的脉络膜厚度/面积的平均值均高于无DME患眼，这可能与脉络膜血管的扩张和灌注变化密切相关，并且这些CI-DME患者的收缩压和舒张压比无DME患者高。因此，高血压可能通过直接或间接的方式增加DME发生或发展的风险。

1.4 血脂代谢紊乱

       血脂异常机制十分复杂。DM可促进血脂异常。DM通过中枢和视网膜组织特异性机制调节多种脂类摄取、重塑和清除的过程[31-32]。同时，胰岛素抵抗可升高低密度脂蛋白(low density lipoprotein, LDL)、总胆固醇(total cholesterol, TC)、甘油三酯(triglyceride, TG)和游离脂肪酸，降低高密度脂蛋白(high density lipoprotein, HDL)，并抑制反向胆固醇转运基因[33-35]。另一方面，血脂异常可通过多种方式影响视网膜血管系统。脂质沉积形成动脉粥样硬化斑块，可进一步阻塞血管，导致缺血、缺氧。此外，局部炎症反应和VEGF等也会导致内皮功能障碍，从而损害BRB，增加血管通透性，促进DME发生[36]。
       一项探究血脂异常和DME临床关系的荟萃分析显示，在DM患者中，有DME的患者的TC、TG和LDL水平比无DME的患者明显升高[37]；而HDL与是否发生DME无关。这可能是因为LDL颗粒对内皮细胞具有一定的毒性[35]，而HDL具有反向胆固醇转运、抗氧化、抗炎、扩张血管等作用[38]。一些研究也阐明了TC、LDL及TC/HDL比值与DME和硬性渗出的严重程度呈正相关[39-40]。近年有研究者指出，血清载脂蛋白(apolipoprotein, Apo)与DR或DME的联系可能比传统的血脂指标更强[41]。Wong等[10]的研究表明，ApoB与ApoA1比值越高，DME发生风险越高。
       多项临床研究证明，调脂药物可改善DME或降低DME发生率。Massin等[42]研究指出，在暂不需立即进行眼内注药治疗或激光治疗的DME患者中单独使用非诺贝特，治疗组的黄斑容量改善多于对照组。Gupta等[43]的研究则显示，2型DM伴血脂异常患者在接受黄斑局部格栅样光凝期间，口服阿托伐他汀可降低CSME中硬性渗出和中心凹下脂质迁移。然而，也有研究[44]指出，调脂药物与DME的发生或发展无明显关系。因此，还需要通过多中心、大样本量的前瞻性研究去证实它们之间的关系。

1.5 肥胖

       肥胖对DME的影响在不同研究中有所不同。最近，广州DM眼病研究[45]发现：腰/臀比与DR严重程度呈正相关，而腰/身高比和身体肥胖指数分别与DR/DME严重程度呈负相关。因此，在这项研究中，肥胖可能是DME的保护因素。另外的两项研究却有相反的结果。一项瑞典研究[46]对15~34岁的1型和2型DM患者进行了为期10年的随访，发现身体质量指数(body mass index, BMI)较高的个体更容易发生DR。Hammes等[7]的研究也显示BMI>35 kg/m2 是DR 和DME的重要危险因素。可见，肥胖可能并非独立的危险因素，这些研究结论存在差异的原因，可能与肥胖所引起的血糖、血脂、血压异常程度及是否出现其他并发症有一定关系。

1.6 肾功能异常

       肾功能异常主要表现为蛋白尿和低肾小球滤过率。Hsieh 等[47-48]在中国台湾2个医疗中心纳入2 135例2型DM 患者，并进行8年随访，结果发现基线尿白蛋白/肌酐比值越高(>30 mg/g)，DME发生和发展的风险越高；而微量白蛋白尿的减少是DME的保护因素。另一项美国研究纳入725例1型非裔DM患者，也得到了相似的结果，大量蛋白尿(OR=11.83)和微量蛋白尿(OR=4.17)均为DME的重要危险因素[49]。另外，他们根据估算肾小球滤过率(estimated glomerular filtration rate, eGFR)对糖尿病慢性肾脏病患者进行分期并发现，在晚期慢性肾脏病患者中，囊样黄斑水肿最常见；椭圆体带缺损可能是这类患者的光学相干断层扫描(optical coherence tomography, OCT)生物标志物[50]。但是，在Temkar[51]及Man 等[52]的研究中，eGFR水平和DME的严重程度并无统计学意义。因此，蛋白尿与DME关系可能更密切；而GFR与DME关联度较小。
       也有部分文献提示，血液透析有助于改善DME[53-54]。顽固性DME或伴有硬性渗出的DME患者在接受血液透析后都获得了不同程度的改善[55]。Theodossiadis等[54]对36例终末期糖尿病肾病患者的72只患眼(伴或不伴DME)进行评估后发现，血液透析可减少DME患眼的CMT，但对不伴DME的患眼作用不明显。
       蛋白尿的出现降低血清渗透压，而血液透析能提高血清渗透压，这可能是它们影响DME的主要原因[54]。

1.7 妊娠状态

       妊娠期间，体内激素的剧烈变化会使孕妇出现受孕前不存在的DR，但这些病变往往在产后自然消退；在妊娠开始时存在的非增殖期DR(non-proliferative diabetic retinopathy, NPDR)或DME也较少进展为PDR；在妊娠开始时存在的PDR继续进展的风险非常高，应在早期进行激光或眼内注药等治疗[56]。根据最近丹麦学者一项研究可知，在1型DM患者中，5%的患者在妊娠早期已有DME，2%的患者在妊娠期间发生DME。在妊娠早期有DME而未接受治疗的 20只患眼中，50%患眼的DME自发消退；而在2型DM中，没有患者在妊娠早期发生DME，而且只有1%患者在妊娠期间新发DME[57]。另外，DM也会使妊娠期妇女的激素变化更加剧烈，从而促进DR和DME进展。DM妊娠女性的孕酮、胎盘催乳素水平比非DM妊娠女性显著增加，血清催乳素水平显著下降[58]。除了妊娠本身，DM持续时间、病程、血糖控制、血糖急速下降至正常水平、妊娠初期DR严重程度、高血压、高血脂、DR等因素也在DME的发生和发展中起重要作用[56,59]。虽然NPDR或DME在妊娠晚期或产后期的消退率较高，但关于妊娠与DME的关系尚无大样本的前瞻性证据，规律随访、密切监测患者的视功能和视网膜形态结构十分必要。

1.8 降糖药物使用

       格列酮类药物在治疗胰岛素抵抗的同时，会引起水钠潴留，可能会增加充血性心力衰竭和DME的风险[60-62]。格列酮类药物引起DME的可能机制：1)增加视网膜血管内皮细胞通透性；2)增加VEGF的浓度3)增加血浆容量；4)提高血压；5)改变肾脏排泄和肠道离子转运[62-64]。一项美国前瞻性研究对17 000例DM患者进行危险因素分析，发现使用格列酮类药物的DM患者发生DME的风险是不使用该类药物患者的2.6倍[63]。另一项小样本量的研究报道，在停止使用格列酮类药物后，DME大多有不同程度的消退，但速度因人而异[64]。然而，ACCORD研究的结论与上述研究不同，无论是从横断面还是纵向队列分析均显示，格列酮类药物与DME的发生和发展无关联[65- 66]。
       其他降糖药物也存在一些争议。Phu等[67]的研究显示，胰高血糖素样肽-1(glucagon-like peptide-1, GLP-1)受体激动剂和钠-葡萄糖协同转运蛋白2(sodium-dependent glucose transporters 2, SGLT2)抑制剂与DME的发生无明显关系。另一回顾性研究则指出，使用GLP-1受体激动剂的DM患者DME发生率较使用SGLT2抑制剂的明显升高[68]。但也有文献报道，GLP-1受体激动剂和SGLT2抑制剂均主要通过降低血糖来减少DME发生和发展的风险，GLP-1受体激动剂还有抗炎和保护血管的作用，可能也在一定程度上协同减少DME的风险[69-70]。
       因此，降糖药物的使用与DME风险的关系仍需更多基础和临床证据的支持。

1.9 贫血

       贫血引起的缺血、缺氧会进一步损伤视网膜血管内皮，增加BRB的损伤及血管通透性，从而更容易引起DME[71]。在一项纳入69 982例NPDR患者的回顾性研究中，10 322例患者为DME，贫血严重程度与DME发生和发展的危险性呈正比(轻度贫血OR为1.06；中重度贫血OR为1.14)[72]。在印度，另一项为期2年的前瞻性研究[71]纳入306例2型DM患者，也得到了相似的结论。既往也有研究使用促红细胞生成素(Erythropoietin, EPO)治疗DME，但效果并不一致。Friedman等[73]使用EPO治疗3例氮质血症的贫血患者，3例患者的血细胞比容有所改善，视力及DME均比之前有所好转。然而，在另一项治疗顽固性DME的随机双盲试验[74]中，贝伐珠单抗联合EPO与单独贝伐单抗治疗在6个月随访时间内疗效相似。在DM患者中，贫血也会和肾脏疾病、高血压等多种疾病共存，共同促进DME的发生和进展[75]。

1.10 阻塞性睡眠呼吸暂停低通气综合征

       阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea-hypopnea syndrome, OSAHS)与DME存在密切关系。Vié等[76]和Chiang等[77]的临床研究指出，重度OSAHS是DME的危险因素。除此以外，氧分压低于90%的累积时间越长，DME发生和发展风险越高；而且，重度OSAHS 的患者发生难治性DME的比例较高。Yang等的研究[78]提示：有OSAHS 的DME患者的血清表皮生长因子、细胞间黏附分子和白介素-6(interleukin-6, IL-6)等炎性因子水平比不伴OSAHS 的DME患者明显升高。尽管上述研究均显示OSAHS 与DME存在相关性，但确切的机制尚未阐明。OSAHS 引起的低氧血症、高血压和高碳酸血症可能是引起和加重DME的主要原因[79]。

1.11 遗传

       遗传因素在DME的发生和发展中也可能发挥重要作用。目前，相关基因包括VEGF-A、VEGFC、ApoE、一氧化氮合酶(nitric oxide synthase, NOS)、超氧化物歧化酶(superoxide dismutase, SOD)等。
       VEGF由VEGF-A、VEGF-B、VEGF-C、VEGF-D和胎盘生长因子(placental growth factor, PlGF)组成。VEGF-A主要作用为血管发育和血管生成，与DR或DME关系密切。VEGFA具有多态性。Awata等[80]和Shazly等[81]均发现DME患者中-634C>G CC基因型和C等位基因频率显著增加。但是，Tetikoğlu等[82]的研究仅发现-634C>G[rs2010963]与DR的严重程度有明显的关联，却尚未发现其与抗VEGF治疗DME效果存在关系。VEGF-C主要与VEGF-D一起通过与VEGF受体(VEGFR)结合，促进淋巴管形成，这可能在DME中有重要作用[83-84]。VEGF-C的rs17697515在2型DM 患者中与 DME 发生风险呈负相关(OR=0.53，95%CI 0.35~0.82)[85]。
       ApoE主要作用是运输脂质，近年来发现可能与DME相关。它具有三个等位基因ε2、ε3和ε4，并且在视网膜中高度表达。一项墨西哥学者的研究显示：Apoε4基因的携带者黄斑硬性渗出发生的比例较高[86]。而另一项研究则发现Apoε2和Apoε3在PDR和DME患者的玻璃体液中的表达增加，并且ε2和ε3可能参与视网膜新生血管的形成和发展[87]。
       NOS协助产生一氧化氮，一氧化氮可损伤血管内皮细胞。NOS主要分为三型，分别为神经元型NOS(NOS-1)、诱导型NOS(NOS-2)和内皮型NOS(NOS-3)[88]。NOS-3被认为是与DME关系最密切的基因。一项日本学者的研究分析了2型DM患者NOS-3的基因多态性，结果发现DME患者的-786T>C多态性和DME发生风险显著相关；而894G>T多态性与DME发生风险无关[89]。
       SOD2编码锰超氧化物歧化酶(manganese superoxide dismutase, MnSOD)，MnSOD可以减轻超氧自由基的破坏作用[90]。SOD2中的Ala等位基因多态性与DME发生风险相关。一项韩国研究[91]显示：DME组Ala等位基因频率显著降低。
       除此以外，EPO、色素上皮衍生因子、醛糖还原酶、微小RNA等也在相关文献中有所报道[92-95]。但是，总的来说，遗传因素在DME中的研究相对较少，需要进行大规模的研究，以获得更高质量的证据。

1.12 其他

       还有研究显示，吸烟、饮酒、高血钙、低血镁等也有可能是DME的危险因素[96-98]。

2 眼部因素

2.1 白内障、青光眼及玻璃体切割手术

       无论DM患者术前是否存在DR，在进行白内障手术后DME发生和发展风险增加。原有的PDR患者术后DME发病率可达12%[99]，而目前存在DME或既往曾发生DME的患者术后发病率可高达50%[100]。一项多中心、前瞻性研究纳入了293 例DR患者，这项研究指出，对于无CI-DME的DR患者而言，术前出现未累及中心凹的DME或有 DME 治疗史可能会增加白内障术后16周内发生CI-DME的风险[101]。Bek 等[102]的研究还表明，DME的风险在白内障手术后的前5年最高，随后风险降低，并在20年后达到稳定。此外，在术后不同时间、不同的因素会增加DME的风险：术后0.5~5年以HbA1c和收缩压为主；术后5~20年以HbA1c为主；术后20年以舒张压为主。与非DM患者相比，DM患者在接受白内障手术后，由于手术创伤使一系列促炎因子和促新生血管生成因子升高，进一步损伤视网膜血管内皮，使DM患者已受损的BRB屏障损伤加重，DME随之发生和发展[103-104]。因此，在DM患者中，尤其是DME患者在白内障手术围术期进行眼内抗炎和抗新生血管治疗，可以有效降低DME进展的风险[105-107]。在一项澳大利亚学者的研究中，DME患者被分为两组，在白内障手术时分别接受玻璃体腔贝伐珠单抗及曲安奈德注射，两组患者在术后6个月均获得了显著的视力改善[105]。一项意大利学者的研究显示，在DME患者白内障手术结束时进行玻璃体腔地塞米松缓释剂注射可延缓DME进展和复发[106]。
       据此类推：在DM患者中，与白内障手术相似，青光眼、玻璃体切割等手术操作也有可能会在一定程度上造成眼内损伤、破坏BRB屏障，引起眼内炎症，从而促进DME的发生和发展。但是目前缺少相关的文献证据。相反，Behera等[108]发现，使用玻璃体切割术治疗PDR后，对新发DME的治疗可以延迟1年，因为这种DME可能会随着时间自发消退，这可能与减少玻璃体对视网膜的牵拉、炎症因子的清除有一定关系。

2.2 全视网膜激光光凝术

        全视网膜激光光凝术(pan-retinal photocoagulation, PRP)是治疗重度NPDR和PDR的最佳手段之一[109]。激光治疗通过损伤周边视网膜细胞和血管，从而减少视网膜的耗氧量，增加对中心视网膜的氧灌注，同时下调VEGF，从而减少新生血管生成[110-111]。但是，激光治疗一方面通过热效应引起炎性因子的变化，另一方面破坏了血眼屏障，从而使DME发生和发展[112]。与抗VEGF治疗相比，PRP似乎更容易引起和促进DME。美国学者一项前瞻性随机对照研究纳入了55个医疗中心305例PDR患者，一组行PRP，另一组行雷珠单抗玻璃体腔注射，经过2年随访；在基线无DME的患者中，雷珠单抗组DME发生率为9%，而PRP组为28%；雷珠单抗组CMT减少(18±37) µ m，PRP组增加(10±54) µ m[113-114]。而在基线DME的患者中，雷珠单抗组CMT减少(153±129) µ m，PRP组减少(48±124) µ m。当随访到达第5年时，在基线无DME的患者中，雷珠单抗组DME发生率为22%，而PRP组为38%；而在基线DME的患者中，雷珠单抗组CMT减少(139±157) µ m，PRP组减少(59±102) µ m。根据Bressler等[115]的研究，单纯使用 PRP 治疗PDR时，高水平的HbA1c及严重程度更高的DR与CI-DME发生风险增加有关；但单纯使用雷珠单抗治疗PDR 时，并无与增加CI-DME发生风险相关的基线特征。因此，单独使用PRP治疗PDR时需更关注血糖控制和密切监测DR的进展。

2.3 合并视网膜静脉阻塞

       日本一项纳入17 403例患者的研究[116]对39个全身性危险因素和16个眼部危险因素进行Logistic回归分析，发现合并视网膜静脉阻塞(retinal vessel occlusion, RVO)为与DME最相关的眼部危险因素之一。RVO、DR和DME等眼部疾病代表视网膜血液循环出现障碍，这些疾病可能会相互促进，互为危险因素。另外，DM患者通常合并高血压、高血脂等全身病，全身代谢和循环障碍也促进了上述眼病的相伴发生[117-118]。

2.4 细胞因子

       上述DME眼内危险因素，归根结底，大多是通过提高眼内VEGF和炎性因子水平来促进DME的发生和发展。因此，高水平的眼内VEGF和炎性因子可能是DME发生的核心危险因素。
       VEGF主要通过增加血管通透性和促进炎症诱发DME。VEGF与VEGFR结合发挥作用。VEGFR主要分为VEGFR-1和VEGFR-2。VEGFR-1主要由单核及巨噬细胞表达，协助募集白细胞至炎症部位[119]。VEGF(如PlGF等)与VEGFR-1结合并促进单核细胞产生促炎因子[120]。另一方面，VEGFR-2存在于内皮细胞中。VEGF与VEGFR-2结合可通过核转录因子κB(nuclear factor-κB, NF-κB)等信号通路上调炎症因子，同时增加血管通透性[119, 121]。一项荟萃分析纳入了128项研究，其中包括4 163只DME患眼和1 281只对照眼[122]。DME患眼前房及玻璃体中的VEGF水平高于对照组。研究同时发现，房水中IL-6、IL-8和单核细胞趋化蛋白-1(monocytechemotactic protein-1, MCP-1)水平在DME患眼中也显著升高。IMAGINE DME研究和另一项研究均指出，对抗VEGF治疗反应较好的DME患眼，基线房水VEGF水平较高；而抗VEGF治疗反应较差的患眼，基线房水VEGF水平较低[123-124]。所以，在DME的治疗中，治疗反应差异性与眼内细胞因子密切相关。对于抗VEGF治疗不敏感的患眼，专门的抗炎治疗也很必要。一项西班牙学者的研究[125]纳入16只DME患眼，给予玻璃体腔地塞米松植入治疗，2月后发现干扰素诱导蛋白-10(interferon-inducible protein-10, IP-10)和MCP-1水平急剧下降；然而到DME复发时，IP-10、MCP-1、IL-6和IL-8的水平均显著上升。由此可见，炎性因子在DME的发展中具有重要作用。

2.5 其他

       最近，还有研究者指出，房水中高水平的尿酸有可能是DME的危险因素之一[126]。

3 结语

       综上，DME病理机制复杂，包括血-视网膜屏障和色素上皮屏障受损、VEGF过度表达等。它严重影响患者的视力和生活质量。随着社会发展和科技进步，DME危险因素相关研究也越来越深入。其全身危险因素主要包括血糖控制欠佳、糖尿病病程长、高血压、血脂代谢紊乱、肥胖、肾功能异常、妊娠状态、降糖药物使用、贫血、阻塞性睡眠呼吸暂停低通气综合征、遗传因素、吸烟、饮酒、高血钙、低血镁等；而其眼部危险因素主要包括白内障、青光眼及玻璃体切割术、PRP、合并RVO和相关细胞因子等。深入认识和理解这些危险因素，有助于更好地预防和早期治疗DME，同时为治疗DR过程中控制DME进展提供指引和参考。但是，其中一部分因素还存在一定争议，更多的DME危险因素仍有待进一步探索，期望在不久的将来，更多基础和前瞻性临床研究为DME危险因素及治疗提供高质量的证据。

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1、广东省医学科研基金(A2024187)。
This work was supported by Guangdong Medical Research Fund(A202418).()
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