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慢性肝病患者眼底表现及眼底检查的临床应用进展

Ocular fundus manifestations and the clinical application of fundal examinations in patients with chronic liver disease: a systematic review

来源期刊: 眼科学报 | 2024年12月 第39卷 第12期 640-647 发布时间:2024-12-28 收稿时间:2024/12/30 9:31:56 阅读量:201
作者:
关键词:
慢性肝病眼底检查视网膜结构与血流
chronic liver disease fundal examination retinal structure and blood flow
DOI:
10.12419/24073101
收稿时间:
2024-07-30 
修订日期:
2024-08-20 
接收日期:
2024-10-30 
慢性肝病(chronic liver disease, CLD)是一种或多种损伤因素长期作用于肝脏导致的疾病总称,其影响范围广、患者人群基数大。病毒性肝炎、非酒精性脂肪性肝病和终末期肝病等慢性肝病会累及眼底,造成视网膜渗出、出血等病变;同时眼底结构改变,如脉络膜和视网膜不同层次厚度,也与慢性肝病严重程度相关。对慢性肝病患者进行眼底检查不仅用于防治相关的眼底并发症,也对肝病临床评估及监测具有潜在应用价值。文章综述不同病因、严重程度和药物治疗下的慢性肝病患者可能出现的眼底病变,以及眼底结构功能检查在慢性肝病患者中的临床应用进展,以比较不同眼底检查方法在慢性肝病患者临床实施过程中的特点及适用场景,并提示未来在慢性肝病患者中应用眼底检查的潜在新方向。
Chronic Liver Disease (CLD) is a collective term for diseases resulting from the long-term effects of one or more damaging factors on the liver. It has a broad impact and affects a large patient population. Viral hepatitis, non-alcoholic fatty liver disease, and end-stage liver disease can involve the ocular fundus, leading to retinal exudates and hemorrhages. Additionally, structural changes in the fundus, such as the thickness of the choroid and different retinal layers, are associated with the severity of chronic liver disease. Through fundus examinations in patients with chronic liver disease, not only can ocular complications related to liver disease be prevented and treated, but these examinations may also offer potential value in the clinical assessment and monitoring of liver disease. This article reviews the potential ocular fundus abnormalities in patients with chronic liver disease under different etiologies, severities, and drug treatments. It discusses the progress in the clinical application of fundus structure and function examinations in patients with chronic liver disease. It compares the characteristics and appropriate clinical scenarios of various fundus examination methods in these patients and suggests potential new directions for the future use of fundus examinations in chronic liver disease management.

文章亮点

1. 关键发现

通过总结慢性肝病与眼底检查的国内外研究现状,发现在特定病因、分期或治疗阶段的慢性肝病患者易发生眼底出血、渗出等病变。

2. 已知与发现

病毒性肝炎和非酒精性脂肪性肝病患者在肝病早期即可发生眼底出血和渗出病变。
不同病因慢性肝病进展为终末期肝病后均可导致患者发生眼底出血、渗出和视网膜厚度改变,这些眼底改变可随肝病严重程度改善而部分缓解。

3. 意义与改变

检眼镜和眼底照相可简便观察眼底,在病毒性肝炎、非酒精性脂肪性肝病、终末期肝病和干扰素治疗患者中使用这两种检查,可以及时发现这部分患者的眼底病变。
光学相干断层扫描检查可定量测量与肝病严重程度相关的视网膜厚度,为无创定量评估肝病严重程度提供了研究方向。

全球范围内慢性肝脏疾病影响范围广、患者人群基数大,据估计全球约有15亿人患有慢性肝病[1]。已有研究表明慢性肝病和眼底改变之间存在广泛联系,例如病毒性肝炎、非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)患者可出现眼底渗出、出血等病理改变;随着病程迁移肝病严重程度增加,各种病因慢性肝病可能会发展为终末期肝病,终末期肝病除了造成棉绒斑和眼底出血等病理改变外,也被发现其严重程度与脉络膜和视网膜神经节细胞复合体(ganglion cell complex,GCC)层厚度相关[2-3]。在慢性肝病患者中实施眼底照相、光学相干断层成像(optical coherence tomography, OCT)、视网膜电图(electroretinogram, ERG)和视觉诱发电位(visual evoked potential, VEP)等非侵入性眼底检查技术不仅有利于眼底病变的及时诊断治疗,还可能对慢性肝病本身的严重程度评估具有应用价值。为此本文通过在PubMed、EmBase、SinoMed三个中英文数据库使用肝病、眼等主题词结合自由词检索并纳入中英文文章,针对慢性肝病患者在病因诊断、疾病分期和药物治疗的疾病诊疗全程的眼底病变情况进行综述,并总结在慢性肝病患者中实施眼底检查的价值。

1 慢性肝病患者诊疗全程眼底表现的研究现状

1.1 慢性肝病不同病因与眼底病变的关系

       既往研究提示,病毒性肝炎、NAFLD会造成患者眼底病变患病率改变,例如视网膜缺血性病变、黄斑病变和糖尿病性视网膜病变(diabetic retinopathy, DR)。根据病因分类,这三种慢性肝病与眼底异常表现的关系(表1、图1)简述如下。
图 1 慢性肝病常见眼底表现
Figure 1 Common fundus manifestations in chronic liver disease 
图片显示慢性肝病常见眼底改变,即(a)棉绒斑;(b)视网膜出血[27]
The image illustrates common fundus changes in chronic liver disease, including (a) cotton-wool spots and (b) retinal hemorrhages [27].

表 1 慢性肝病诊疗全过程中眼底改变研究现状总结
Table 1 Fundus changes observed during the diagnosis and treatment of chronic liver disease

项 目

慢性肝病类型

表现

病理机制

病因诊断

乙型病毒性肝炎

黄斑变性

病毒直接作用

丙型病毒性肝炎

视网膜缺血、年龄相关性黄斑变性

病毒直接作用、免疫复合物、炎症

非酒精性脂肪性肝病

糖尿病性视网膜病变(争议)

全身代谢

疾病分期

终末期肝病

视网膜缺血病变与功能异常

全身代谢与血流动力学

治疗药物

抗病毒药物(干扰素)

视网膜缺血病变、视神经病变

药物作用

免疫抑制药物

视神经病变、脉络膜视网膜炎

药物作用、免疫重建综合征

1.1.1 乙型病毒性肝炎

       乙型病毒性肝炎是感染乙型肝炎病毒(hepatitis B virus, HBV)造成肝脏损伤的疾病,病理机制主要是由于HBV的直接作用和诱导的免疫炎症反应对肝脏造成损伤。同样地,其在眼底造成的损伤也主要经由这两种途径。研究者发现,相对于未感染HBV的正常人,乙型肝炎患者中年龄相关性黄斑变性等的患病率会升高[4-5]

1.1.2  丙型病毒性肝炎

       丙型病毒性肝炎患者发生眼底病变较为常见,由于丙型肝炎病毒(hepatitis C virus, HCV)的感染和免疫炎症反应,丙型肝炎患者在眼底更易发生视网膜缺血性病变,主要表现为棉绒斑和后极部视网膜出血[6],同时有研究者发现HCV感染与年龄相关性黄斑变性患病风险增加相关[7]

1.1.3  非酒精性脂肪性肝病

       NAFLD作为全身代谢性疾病在肝部的表现,常与另一种全身代谢性疾病糖尿病伴发, 而在此类患者中NAFLD常影响DR的患病率。相关研究表明,在不同类型的糖尿病患者中,NAFLD与DR的相关性有所差异:例如在1型糖尿病患者中,NAFLD作为DR的危险因素存在[8];在2型糖尿病患者中,NAFLD与DR的相关性存在争议,造成这种结论差异可能与人种差异有关:意大利2型糖尿病患者中进行的研究提示,NAFLD的诊断与DR之间呈正相关[9],而在韩国、中国和伊朗的2型糖尿病患者中进行的研究则显示NAFLD与DR之间呈负相关[10–12]

1.2 慢性肝病严重程度与眼底改变的关系

       各种病因导致的慢性肝病随着病程的增加,慢性肝病可能会发展为终末期肝病,主要表现为肝衰竭、肝硬化失代偿和肝癌。肝衰竭和肝硬化可通过全身代谢和血流动力学改变造成视网膜结构和功能异常(表1)。
       肝衰竭往往会导致血氨升高,显微镜下观察发现视网膜Müller细胞出现核肿大等一系列形态学改变直至细胞坏死[13]。在功能方面,Uhlmann等[14]通过电生理检查发现严重肝衰竭的患者(Child C级)ERG可呈现多项指标异常,并在肝移植术后得到缓解。肝硬化失代偿作为终末期肝病的另一表现,会导致门静脉高压和肝脏合成功能受损,进而影响渗透压造成眼底改变。例如Dittmer等[15]研究发现肝硬化患者经颈静脉肝内门体分流术(transjugular intrahepatic portosystemic shunt, TIPS)术前视网膜会出现棉绒斑(5例)、散在血管异常(3例),视网膜内少量出血(2例)和视盘水肿(1例)等眼底改变,在肝硬化治疗后以上眼底症状会消失,更加证明了以上眼底症状与肝硬化的关联。

1.3 慢性肝病治疗药物与眼底改变的关系

       病毒性肝炎在治疗过程中使用的抗病毒药物和终末期肝病在肝移植治疗术后使用的免疫抑制药物会造成眼底结构和功能改变,已被既往多项研究所证实(表1)。
       1.3.1 抗病毒药物
       抗病毒药物作为病毒性肝炎治疗过程中的常用药物,其中最常被报道造成眼底改变的药物类型是干扰素,已有许多研究表明其在眼底主要会引起棉绒斑和视网膜出血,功能上导致视觉诱发电位延长。而其他抗病毒药物,例如:索非布韦、达拉他韦和利巴韦林经研究证实在眼部并发症方面具有一定的安全性[16]。Ikebe等[17]在1990年首次报道了干扰素造成的视网膜损伤,此后陆续有研究者发现在干扰素治疗前无明显视网膜异常的患者,在干扰素治疗前期(2~4个月)即出现棉绒斑或视网膜出血病变,并在干扰素治疗停止后消失[18–22]。在功能上,干扰素会诱发视神经功能异常,例如在使用低剂量干扰素治疗的慢性乙型肝炎、丙型肝炎患者的前瞻队列中,11例(20.3%)治疗前视觉诱发电位正常的患者,在干扰素治疗中出现了P100潜伏期延长,并有7例患者在停药后恢复正常[23]
       1.3.2  免疫抑制药物
       肝移植术后为了延长移植物的存活率,患者常会服用免疫抑制药物以降低宿主抗移植物免疫排斥反应。免疫抑制药物糖皮质激素可通过诱发眼压升高导致视神经病变[24],他克莫司也可通过药物毒性作用导致视神经病变[25],同时免疫抑制后的免疫重建综合征可引发巨细胞病毒相关性脉络膜视网膜炎[26]

2  眼底检查在慢性肝病患者中的应用

       视网膜是全身唯一可以直视下观察神经和血管的结构,借助于眼底检查不仅可以诊断慢性肝病患者眼底疾病本身,也通过观察视网膜形态结构与微循环改变反映慢性肝病对全身神经系统和微循环的影响,进而评价慢性肝病的严重程度。既往研究在慢性肝病患者中应用眼底相关的检查,诊断眼底病变并发现与肝病严重程度相关的生物学标志物。

2.1 检眼镜与眼底照相

       眼底照相通过光学原理对患者眼底情况进行观察,可以直观地反映眼底基本病变并提供真实的色彩图像。直接检眼镜具有体积小便携、操作简单、价格低廉的优点,各种科室和临床场景的一线医生经过简单培训即可进行使用[28]。但直接检眼镜受检查者主观影响较大,且观察视野较小。这两点问题可通过眼底照相对眼底病变的客观记录和超广角检眼镜或广域眼底照相的广视角检查得到解决[29](表2)。

表 2 在慢性肝病患者中使用的眼底检查及其特点
Table 2 Fundus examination methods used in patients with chronic liver disease: advantages, limitations, and characteristics

检查类型

检查项目

优点

缺点

检眼镜与眼底照相

检眼镜

便携:体积小,适合各场景使用

直观:直观真实地体现眼底基本病变(软硬性渗出、出血等)

简便:操作简单各学科医生经短期培训即可使用

 

无法反映早期病变的细微改变;

平面图像无法反映病变层次结构;

受到屈光介质浑浊的影响

眼底照相

标准:步骤简单,采集流程标准化

光学相干断层扫描

OCT

分辨率高,精确显示视网膜各层微细改变。

多模态:保留有图像数据和参数数据

 

无法直观反映病变原始形态改变和色彩情况;

受到屈光介质浑浊的影响

OCTA

显示视网膜各层毛细血管血流改变

电生理检查

视网膜电图

 

反映功能:实现视网膜生理功能评估

灵敏:可能在结构改变早期甚至之前发现异常

 

检查结果不够稳定,易检查环境和患者的配合程度的影响;

结果解读受检查者主观性影响,具体情况需结合临床信息

视觉诱发电位

反映功能:实现视神经生理功能评估

       慢性肝病通过各种机制影响全身,在眼底造成黄斑变性、棉绒斑、视网膜出血等眼底改变。既往在慢性肝病患者中使用检眼镜和眼底照相检查的相关研究也提示了这类检查在慢性肝病患者中识别经典眼底病变的优势。例如,Roh等[5]通过眼底照相发现乙型肝炎患者中年龄相关性黄斑变性患病率更高;在丙型肝炎患者中使用检眼镜可发现后极部视网膜出血(24.7%)、棉绒斑(10.6%)和周边部视网膜出血(8.2%)[6],同时丙型肝炎患者治疗过程中常会使用干扰素治疗,进一步提高了眼底病变的发病率[18–22],这提示丙型肝炎患者应在疾病全程定期进行眼底检查。在NAFLD患者中通过对眼底照片中眼底血管分析,有望实现全身代谢和肝纤维化的分级,Liccardo等[30]通过眼底照相探究了全身代谢参数和肝纤维化程度与视网膜微血管的相关关系;在终末期肝病患者中,Dittmer在肝移植术前患者的眼底照片中发现了5例棉绒斑、3例散在血管异常、2例视网膜内少量出血和1例视盘水肿,并均在TIPS术后的眼底照片中消失[15],提示了肝病严重程度与眼底病变的关联,并且随着肝病严重程度的改善这种眼底病变存在可逆的趋势。 

2.2  光学相干断层扫描

       基于光学干涉原理的OCT和光学相干断层血管成像检查(optical coherence tomography angiography, OCTA)提供了视网膜的高分辨率切面图像与各层厚度和毛细血管丛密度的参数数据(表2)。已有相关研究在慢性肝病尤其是终末期肝病和肝移植患者中使用OCT和OCTA检查,并发现视网膜各层的厚度和黄斑区深浅层的毛细血管密度相应改变[3,31-32],这提示OCT和OCTA检查在终末期肝病患者中评估神经和微循环情况的潜在价值。
       2.2.1  光学相干断层成像检查
       OCT检查通过提供视网膜切面的图像,并划分层次,同时为医生提供了更加精细和高分辨率的视网膜图像。例如Gkotsi等[33]报道,通过检眼镜发现酒精性肝病患者眼底大小不一、微黄、半透明、隆起浆液性的视网膜病变,并最终经OCT确诊为多个病灶的视网膜神经上皮层脱离。此外OCT还可以实现对视网膜各层厚度和区域体积的测量并提供参数,例如视神经纤维层厚度、脉络膜厚度、黄斑体积等,实现视网膜结构的精确性评估。借助于视网膜结构的精确测量,为慢性肝病患者肝纤维化和肝病病情评估提供了新思路。已有研究者在HCV感染患者和肝硬化患者中使用OCT检查发现,脉络膜厚度和视网膜GCC层厚度与肝纤维化严重程度相关[2-3];Gifford等[31]在严重的终末期肝病患者中发现脉络膜厚度、视网膜厚度和黄斑体积与终末期肝病相关,并且视网膜厚度和黄斑体积在肝移植术后缓解,这提示了肝病严重程度与视网膜结构变化的关系。该研究还发现,鼻侧至中央凹2 mm处脉络膜可以预测术后急性肾损伤,这可能作为对肝移植术后并发症的预测指标。
       2.2.2  光学相干断层血管成像检查
       OCTA是OCT技术的扩展,提供了视网膜微血管的非侵入性检查手段,可以计算并显示各层毛细血管密度,既往研究发现视网膜和脉络膜微血管改变与全身循环功能障碍相关,例如系统性高血压和糖尿病(未发生DR)患者浅层毛细血管丛(superficial capillary plexus, SCP)和深层毛细血管丛(deep capillary plexus, DCP)的血管密度下降。SCP和DCP有望作为全身微循环的一种评价指标。既往已有在儿科肝移植术后患者中使用OCTA检查技术发现肝移植组的浅层全区、黄斑中心凹周围和深层黄斑中心凹区毛细血管丛血管密度降低,中心凹无血管区面积增大[32]
       2.2.3  电生理检查
       电生理检查更多反映视网膜和视神经的功能改变。常见的电生理检查有ERG和VEP,在Wilson’s病(Wilson's Disease, WD)、肝衰竭和肝移植患者中已经发现ERG或VEP指标异常[14,34-35],且这部分神经功能异常可发生在结构改变之前[36],提示了ERG和 VEP检查的高敏感性。但这两项检查结果受检查者和检查环境影响较大,在临床和科研中需结合其他资料综合分析(表2)。
       2.2.3.1  视网膜电图和视觉诱发电位
       ERG和VEP通过神经电生理原理,反映视网膜和视神经的功能。有研究者发现,在严重慢性肝病患者中ERG的a波、b波和振荡电位(oscillatory potentials, OPs)振幅减小、潜伏期延长,且患者的肝衰竭严重程度和视网膜振幅降低程度相关,其中OPs的降低最为敏感[34]。另一项在肝移植患者中的研究发现肝移植前ERG明视和暗视条件下a波潜伏期延长,暗视条件下b波潜伏期和达峰时间(阻抗时间)延长且这些改变与肝病严重程度相关,并在肝移植后均得到缓解[14]。在 WD患者中,通过MRI是否有形态学改变进行分组并与正常人对照,研究发现在图形视觉诱发电位检查中,与MRI-组相比,MRI+组测量的所有图形视觉诱发电位潜伏期均延长;与对照组相比,MRI -组仅N135潜伏期延长,这提示图形视觉诱发电位改变能在形态学MRI检查异常之前被发现,但N135有不稳定的特点可能影响其应用价值[35]

3  结语

       慢性肝病患者人群基数大,眼底病变患病率相对正常人更高,在慢性肝病患者中进行眼底检查是必要的。其中,病毒性肝炎和NAFLD患者在发展为终末期肝病前就可出现眼底改变,因此针对这类病因的患者要及早进行眼底检查;终末期肝病患者无论何种病因诊断均可引起眼底病变,但由于这种眼底病变常常可以在终末期肝病得到有效治疗后消失,因此针对有短期治疗计划的患者建议在终末期肝病治疗后复查眼底;在慢性肝病的治疗过程中,干扰素和免疫抑制药物常会引起视网膜病变,因此针对服用此类药物的患者需要定期复查眼底、及时干预治疗。在临床应用中,针对以上慢性肝病的眼底改变易感人群眼底照相和OCT有助于发现眼底改变并及时治疗。随着人工智能技术发展及医疗场景应用,深度学习在数据特征提取及决策输出上发挥了一定优势,Xiao等[37]利用人工智能技术基于眼底照片等眼部检查进行多种肝病筛查,其诊断受试者工作特征曲线下面积(area under receiver operating characteristic curve, AUROC)可达0.74,而OCT/OCTA提供的精细化测量参数与高分辨率图像丰富了数据模态,为人工智能模型性能的提升提供了坚实的基础,未来有望在肝病严重程度评估和肝病预后等方面实现创新与突破。但如何将智能模型应用于真实世界慢性肝病临床诊治,仍需要医工协同攻关:一方面需紧密结合临床需求及医学知识选取应用目标场景,另一方面需要结合工科知识选取合理的特征提取与融合手段,优化智能模型效果。本综述主要在医学常用的Pubmed、Embase、Sinomed三个中英文数据库进行检索并主要纳入中英文文章进行综述,可能对其他语言、未发表和发表在其他范围的文章存在遗漏。目前所纳入的文章中慢性肝病患者在眼底的表现一定程度上证实了肝眼之间存在的联系,但尚有许多问题未得到充分解决,例如,人种差异为何使NAFLD作为的DR患病的保护或危险因素、如何基于当前发现的视网膜厚度与肝病严重程度的相关性进一步建立评估模型。未来随着基础研究和大规模、多中心临床研究的推进与人工智能技术的发展,有望进一步明确肝-眼生物轴的复杂机制,并为精准临床评估与管理提供帮助。

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1、国家自然科学基金重大研究计划重点支持项目(92368205),广州市卫生健康科技项目 (2024A031004)。
This work was supported by National Natural Science Foundation of China(92368205); Science and Technology Planning Project of Guangzhou Municipal Health Commission(2024A031004).()
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