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甲状腺相关眼病眼表损伤的研究进展

Research progress of ocular surface injury in thyroid-associated ophthalmopathy

来源期刊： 眼科学报 | 2023年4月 第38卷 第4期： 344-349 发布时间：2023-04-18 收稿时间：2023/4/19 11:42:39 阅读量：4088
作者：
李智闻,
李蓓,
郑燕林,
关键词：
甲状腺相关眼病眼表损害临床表现病理改变研究进展
thyroid-associated ophthalmopathy Ocular surface damage clinical feature pathologic change research progress
DOI：
10.12419/j.issn.1000-4432.2023.04.06
甲状腺相关眼病是一种器官特异性自身免疫性疾病，其发病机制复杂，是成人最常见的眼眶疾病，且发病率逐年升高。该病不仅会导致眼球突出、眼睑退缩、睑裂扩大、眼球运动障碍等外观上的变化，且患者往往伴发眼红、眼痛、干涩、异物感、复视、视力下降等不适症状，其中眼表疾病的发病率较正常人明显增高，但其具体发病机制尚待进一步挖掘。目前研究表明甲状腺相关眼病患者的眼表损伤主要与眼表暴露增加、炎症侵犯、激素改变有关。角膜、结膜、泪膜、睑板腺等组织受累发生病理改变是患者表现出不同临床症状的直接原因。文章通过分析近年来国内外关于甲状腺相关眼病与眼表疾病等方面的相关研究，针对甲状腺相关眼病眼表损伤的病理改变及机制研究进展做一综述。
Tyroid-associated ophthalmopathy is an organ-specifc autoimmune disease with complex pathogenesis. It is the most common orbital disease in adults, and its incidence increases year by year. Tis disease can not only lead to appearance changes such as eyeball protrusion, eyelid retraction, eyelid cleat enlargement, eye movement disorders, and patients are ofen accompanied by red eyes, eye pain, dryness, foreign body sensation, diplopia, vision loss and other uncomfortable symptoms, among which the incidence of ocular surface diseases is signifcantly higher than that of normal people, but its specifc pathogenesis needs to be further explored. Current studies have shown that ocular surface injury in patients with thyroid-associated ophthalmopathy is mainly related to increased ocular surface exposure, infammatory invasion, and hormonal changes. Te pathological changes of cornea, conjunctiva, tear flm, meibomian gland and other tissues involved are the direct causes of different clinical symptoms of patients. In this paper, through the analysis of recent domestic and foreign studies on thyroid-associated ophthalmopathy and ocular surface diseases, the pathological changes and mechanism of ocular surface injury in thyroid-associated ophthalmopathy were reviewed.
甲状腺相关眼病(thyroid-associatedophthalmopathy , TAO)又称为格雷夫斯眼病(Graves’ophthalmopathy, GO)，是一种可导致眼外肌、眼眶脂肪和结缔组织炎症的器官特异性自身免疫性疾病[1]，其发病率居成人眼眶病之首[2]。本病可发生在不同甲状腺功能状态的患者中，包括甲状腺功能亢进(甲亢)、亚临床甲亢、甲状腺功能减退(甲减)、亚临床甲减，以及甲状腺功能正常者[3]。眼表是一个微妙而复杂的系统，除了角膜、结膜、睑板腺、泪腺和神经网络外，免疫细胞、激素甚至微生物群等其他成分也参与调节眼表的动态平衡，其中任何一种成分的改变都可以引起眼表的动态平衡失衡[4]。目前TAO患者眼表损害的具体机制尚不明确，本文将TAO的眼表损害临床表现及病理改变进行归纳如下。

1 临床表现

TAO所致眼表损害的临床表现多样，常见的症状包括：眼干涩、异物感和(或)磨砂样感、视疲劳、眼睑沉重感、黏性分泌物、刺痛、流泪、视物模糊和(或)视力波动、痒感、畏光、眼红、烧灼感、畏风，重者可致角膜炎、角膜溃疡等。常见体征包括：角膜上皮损伤、脱落、荧光素染色结果升高、神经敏感性降低、角膜浑浊；结膜充血、水肿；睑板腺开口堵塞或加重；泪液分泌试验下降；泪膜破裂时间缩短等。

2 病理改变与机制

2.1 角膜

2.1.1 角膜上皮
Mohsen等[5]发现中重度TAO患者超过2/3的眼睛角膜荧光素染色强度明显高于正常人。这与TAO患者角膜的暴露时间过长有密切关系。由于角膜长时间暴露在空气中引起干燥、上皮脱落，或继发感染，严重者甚至出现暴露性角膜炎和溃疡[6]，由于角膜上皮的持续性缺损，角膜基质成纤维细胞通过调节细胞因子、趋化因子，使局部发生以多核白细胞为中心的炎症细胞浸润，并且分泌基质金属蛋白酶，引起以Ⅰ型胶原为中心的细胞外基质破坏，角膜基质融解，形成溃疡。
2.1.2 角膜神经与敏感性
在生理情况下，角膜传入神经的刺激会引起眼睑闭合和泪液分泌，角膜神经释放的营养因子有助于调节伤口修复、维持角膜的健康[7]。角膜神经功能障碍会破坏眼表的稳态，引起各种眼表不适症状[8]。Wu[9]等通过体内共聚焦显微镜发现，TAO患者的中央角膜基底神经丛参数值均低于正常人，包括角膜神经纤维密度、角膜神经分支密度、角膜神经纤维长度、角膜神经纤维总分支密度、角膜神经纤维面积、角膜神经纤维宽度和角膜神经纤维分形维数(均P<0.001)。Villani等[10]研究发现TAO患者角膜神经数量减少，神经纤维的弯曲度和珠状结构的数量增加，推测这是全身性疾病相关的神经丛的代谢激活有关的一种表现，这可能是神经退化或损伤的后续反馈机制[11]。角膜上皮含有丰富的感觉神经，角膜神经的受损使角膜敏感性下降。角膜感觉功能使角膜能够对各种热、机械和化学刺激迅速反应，对眼表的结构和功能完整性至关重要。Vasilis等[12]用新型Chochet-Bonnet触觉计测量角膜中央的角膜敏感度，结果显示TAO患者双眼角膜敏感度明显低于正常人(P<0.05)。TAO患者角膜敏感性的下降可能会导致短暂或长期的眼部并发症。Villani等[10]揭示了TAO患者角膜敏感性与眼球突出呈负相关(P<0.001)。
2.1.3 角膜内皮
角膜内皮是面向前房的最内层角膜，通过“泵漏”功能保持角膜透明度。角膜内皮的严重损伤会导致角膜浑浊、水肿，影响角膜结构稳定性。Zhou[13]等研究表明，TAO患者角膜内皮细胞的形态变化更多并且体积更大，细胞面积变异系数显著更高，并且与临床活动评分(clinical activity score,CAS)呈正相关(P<0.001)。这些结果推测TAO患者的角膜内皮可能承受了更大的压力，需通过改变内皮细胞的体积来补偿丢失的细胞所占面积。
2.1.4 角膜生物力学特点
角膜生物力学特性是角膜在压力下可逆变形的能力，其降低反映的是角膜组织承受压力的能力下降[14]。Karabulut等[15]利用眼反应分析仪研究了TAO患者的角膜迟滞(corneal hysteresis,CH)测量角膜黏弹性，反应角膜组织吸收和耗散能量的能力，结果显示TAO患者的CH较正常人明显降低。Pandey等[16]、Moghimi等[17]也得出了类似的结论。推测TAO患者可能在引起角膜生物力学参数变化的微观结构中发生了变化，导致角膜抗压能力的下降。

2.2 结膜

2.2.1 细胞改变
有研究发现，相比正常人，TAO患者上方球结膜浅表上皮细胞和杯状细胞密度明显降低，朗格汉斯细胞密度和结膜上皮鳞状化生程度明显更高(均P<0.05)[18]。然而，TAO组颞球结膜浅表上皮细胞密度未有下降。据此猜测可能上方球结膜的浅表上皮在眨眼时受到较高的机械压力，这种机械损伤会产生炎症刺激，促使结膜上皮细胞和淋巴细胞产生和分泌各种细胞因子，包括白介素-1α (IL-1α)、IL-1β、IL-6、IL-8、转化生长因子-β1(TGF-β1)和肿瘤坏死因子-α(TNF-α)进入泪膜[19]。泪膜内细胞因子水平升高会反过来损害眼表上皮的终末分化，导致眼表上皮表达保护分子的能力受损，眼表保护机制恶化，影响结膜上皮细胞的更新[20]。其次，理论上TAO患者的上方球结膜由于眼球突出和上眼睑回缩而受到的泪膜保护少于颞部。结膜杯状细胞密度降低的确切机制仍然未知，但结膜杯状细胞的减少可能会改变黏蛋白的表达，导致泪膜不稳定，至于鳞状化生的升高推测可能与眼睑边缘反射距离有关，具体机制尚待探究[18]。
2.2.2 血管改变
TAO患者的活动等级是根据Mourits在1983年提出的CAS系统进行分类的。其中，结膜症状如充血和水肿也被列入评分之一，结膜高度充血水肿表明疾病可能处于炎症活动期。此时观察到TAO患者血管密度更大，微血管形态更复杂，血流速度、血流量与正常人之间也有明显差异[21]。血流速度的改变是由于血管壁剪切应力的变化而引起人结膜毛细血管中血管直径的改变[22]。此时活动期结膜上皮人白细胞抗原- DR(HLA-DR)和细胞间黏附分子-1(ICAM-1)的表达增加[23]，ICAM-1升高提示结膜炎症细胞、免疫细胞(尤其白细胞、T淋巴细胞)的募集增强，HLA-DR的表达可以促使结膜上皮传递抗原，激活不同免疫通路，扩大炎症反应。提示微血管形态学、血流动力学测量、HLA-DR、ICAM-1检测在诊断活动性TAO方面表现良好。

2.3 睑板腺

睑板腺(meibomian gland,MG)是眼睑特殊的皮脂腺，其在睑板上呈垂直于睑缘、互相平行的栅栏状排列，其腺泡内睑板细胞分泌的脂质由眨眼动作泵送至眼睑边缘，稳定泪膜，降低表面张力，从而防止泪液蒸发[24-25]。TAO可引起睑板腺的腺周炎症，改变患者的MG数量、面积、分泌功能，引起眼表组织损害。
2.3.1 腺体脱落及堵塞
Vannarut等[26]研究发现TAO组睑板腺缺失的平均面积高于正常组，但TAO组平均睑脂质量及睑板腺可表达性均高于对照组(均P<0.05)，且脂质层厚度(lipid layer thickness,LLT)与正常组相差不大。推测TAO患者的睑板腺缺失较多，但剩余的睑板腺可能会产生正常或增强水平的脂质，配合强力眨眼促进脂质从腺管分泌，从而维持正常的LLT。这与Finis[27]的研究结果一致。此外还有研究者提出[28-29]，与非活动性TAO患者相比，活动性TAO患者的睑板腺脱落率明显更高，进一步研究显示了CAS评分与活动性和非活动性TAO患者睑板腺脱落程度之间的正相关关系，当然这一结果尚需要更多研究进一步证实。程胜男等[30]研究发现，TAO组睑缘血管扩张评分与睑板腺开口堵塞评分均高于正常组(P<0.01)，这可能是TAO对睑缘的炎症反应促使局部毛细血管扩张，眼表炎症引起的泪膜蒸发率升高导致热量损失，眼表温度降低，增加了睑脂的黏度；这种黏度变化会导致腺体功能恶化，增加脂质排出的难度，从而引起睑板腺开口堵塞[31]。
2.3.2 腺体结构变化
Shengnan[32]等发现，与正常组对照，TAO组结果显示出更低的MG孔面积(MG orifice area,MOA)和MG腺泡密度(MG acinar density,MAD)(P= 0.000)，更大的MG最长和最短直径(MG longest and shortest diameters,MALD and MASD)(P= 0.000)，更高程度的MG腺泡不规则性(MG acinar irregularity,MAI)、睑脂分泌反射率(meibum secretion reflectivity,MSR)和MG纤维化(MG fibrosis,MF)(均P<0.05)，推测可能TAO患者眼表炎症介导的纤维化和导管萎缩使得孔口面积减少，睑脂分泌困难并阻塞孔口。腺体生产力继续，但睑脂分泌减少，脂质池储存增加，这导致腺泡单位扩张和MALD和MASD的值增加。并随着TAO的自然病程，炎症从活跃期转至不活跃的纤维化期，引起睑板腺纤维化增高，脂质在腺泡中积存，出现更高的MSR。该研究认为阻塞性和炎症性致病机制促进了TAO患者MG的形态学变化，可能导致腺周炎症和随后的MGD。此外还有学者观察到，TAO患者的不完全眨眼和上眼睑MG结构的变化比单纯干眼症患者更为突出，认为不完全眨眼可能也是MG变化的致病机制之一[28]。Sachiko等[33-34]进一步研究发现，铜锌超氧化物歧化酶-1(Superoxide Dismutase-1,SOD1)的缺失导致氧化应激相关脂质和DNA损伤增加、炎症状态增加，引起MG的明显形态改变。腺体周围炎症细胞浸润与MG腺泡密度下降和腺体周围纤维化增加有关。推测TAO的炎症相关反应和氧化应激会引起MG的形态改变。

2.4 泪腺

泪腺由主腺和副腺组成。主泪腺被提肌腱膜肌的外侧角进一步分为眶叶和睑叶。除了泪液分泌外，主泪腺也是眼表免疫系统的重要组织[35]。目前多项基于CT和MRI影像学参数的研究[36-38]表明TAO患者泪腺组织体积增大，并且与CAS呈正相关，表明体积测量更能准确反映泪腺炎症程度。泪腺的炎症反应过程可能与球后组织过程类似，早期活动期多为淋巴细胞等浸润、间质水肿为主，后期以组织纤维化为主。有文献报道，在TAO泪腺中发现细胞因子和趋化因子的表达增加，伴有多种免疫细胞浸润，主要涉及T淋巴细胞、B淋巴细胞和单核细胞[39]。Eckstein等[40]首次报道了正常人泪腺腺泡细胞表达促甲状腺激素受体，这使其成为TAO自身抗体的潜在靶标，自身抗体结合在泪腺的受体上，引起异常的信号传导，导致泪腺功能障碍，泪液生成减少，引起眼表缺乏滋润。另有研究者发现，自身免疫性甲状腺疾病患者泪液中甲状腺素水平增高，影响角膜曲率，发生圆锥角膜，导致泪膜稳定性下降，而进一步研究证实这与甲状腺功能无关，而是泪腺直接合成了甲状腺素参与了这一发病过程[41]。

2.5 泪膜

泪膜是覆盖在眼球前表面的一层液体，主要起折射光线、保护和滋润角膜结膜的作用。TAO患者眼睑回缩、睑裂扩大、眼球突出、眼睑闭合不全等引起眼表组织暴露时间及暴露面积增加，泪液蒸发过多，导致泪膜渗透压明显升高[42]。这种高渗性可能会进一步刺激局部促炎细胞因子，加重眼表组织的炎症。研究发现，TAO患者泪液中眼表组织保护蛋白及抗炎蛋白下调、炎性蛋白上调，其中主要变化为保护性胱抑素(cystatin)、抗炎蛋白膜联蛋白A1(annexin A1,ANXA1)的下降，促凋亡POTE-锚蛋白(POTE-ankyrin–domain family-member I ,POTEI)、IL-1β、TNF-α和基质金属蛋白酶-9(matrix metalloproteinase 9 ,MMP-9)的升高[43]。MMP-9可以裂解角膜上皮基底膜和维持角膜上皮屏障功能的紧密连接蛋白，破坏角膜上皮的完整性。以上这些改变使泪液成分发生变化，直接或间接参与TAO致病过程，导致眼表损害[44]。此外TAO患者眼睑迟落、瞬目减少，不完全眨眼会引起泪液在眼表的分布不均匀，泪膜不稳定，引起眼表损害[44]。泪膜破裂时间明显降低，泪膜稳定性下降，这可能与泪液减少、泪膜成分变化、泪膜渗透压升高等多方面因素有关。

3 小结

本文对TAO的眼表组织的损害进行综述，阐释了TAO患者角膜、结膜、睑板腺、泪腺、泪膜均有不同程度的受累，但完整的发病机制尚待进一步揭示。炎症细胞及因子、多种激素对眼表组织损害的具体机制还需进一步研究发现。而临床医师在诊疗过程中要提高对TAO患者眼表损害的重视，制定有效的个体化方案，防止进一步的并发症。

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