Ocular Surface Changes in Graves' Ophthalmopathy
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Dry eye syndrome in Graves’ ophthalmopathy ·Review Article· Ocular surface changes in Graves’ ophthalmopathy Rou Sun1,2, Hui-Fang Zhou1,2, Xian-Qun Fan1,2 1Department of Ophthalmology, Ninth People’s Hospital, outbreak of GO[3-8]. Furthermore, the incidence of GO was Shanghai Jiao Tong University School of Medicine, Shanghai the highest of orbital diseases[9], leading to symptoms such 200011, China as proptosis, eyelid swelling, eyelid retraction, diplopia, 2Shanghai Key Laboratory of Orbital Diseases and Ocular photophobia, excessive tearing, vision loss, strabismus and eye Oncology, Shanghai 200011, China movement disorder[10-11]. Correspondence to: Hui-Fang Zhou and Xian-Qun Fan. GO is devided into active GO and inactive GO according Department of Ophthalmology, Ninth People’s Hospital, to the clinical activity scores (CAS)[12]. The presentation of Shanghai Jiao Tong University School of Medicine, No.639, each symptom mentioned below is considered as one point: Zhizaoju Road, Huangpu District, Shanghai 200011, China. moderate to severe eyelid erythema, moderate to severe eyelid [email protected]; [email protected] swelling, conjunctival redness, chemosis, redness and swelling Received: 2020-05-20 Accepted: 2020-10-19 of lacrimal caruncle, spontaneous orbital pain and orbital pain evoked by gaze. Inactive GO is defined as those scoring Abstract 0-2 and active as scoring of 3-7[13]. Dry eye syndrome (DES) ● Many patients with Graves’ ophthalmopathy (GO) suffer can prevail in any state or stage during the occurrence and from dry eye syndrome (DES), and this is one of the most development of GO. common reasons of eye discomfort in patients with GO. The DES was defined a multifactorial disease associated with tears prevalence of DES in patients with GO is significantly higher and ocular surface by the Tear Film and Ocular Surface Society than normal subjects. The ocular surface changes involving (TFOS) Dry Eye Workshop (DEWS) II. It causes discomfort, changes in tears, cornea, conjunctiva and glands occur in visual impairment as well as tear film instability, leading to GO patients. However, the mechanism of how DES occurs damage of the ocular surface[14]. These symptoms also bother in GO still remains unclear. In this review, the ocular surface GO patients with DES and some of them might even progress changes were illustrated and analyzed the reasons for high to corneal injury and exposed keratitis[15-16]. prevalence of DES in GO patients. For GO patients, proptosis and eyelid retraction might cause ● KEYWORDS: Graves’ ophthalmopathy; dry eye extra ocular exposure, increasing the evaporation of tears. syndrome; ocular surface The autoimmune and inflammatory responses might influence DOI:10.18240/ijo.2021.04.20 the composition of tears, leading to injury of the cornea and conjunctiva. GO also involves lacrimal glands and meibomian Citation: Sun R, Zhou HF, Fan XQ. Ocular surface changes in Graves’ ophthalmopathy. Int J Ophthalmol 2021;14(4):616-621 glands (MG). Therefore, the changes in tears, cornea, conjunctiva and glands in GO patients are considered as risk [17] INTRODUCTION factors for DES . raves’ ophthalmopathy (GO) usually occurs in EPIDEMIOLOGY G patients suffering from Graves disease (GD) with According to TFOS DEWS II, DES is one of the most hyperthyroidism or a history of hyperthyroidism[1]. In common eye diseases, and the prevalence is about 5 to 50 addition, it can also occur in patients with euthyroidism or percent. Based on the worldwide studies, the prevalence hypothyroidism due to autoimmune thyroiditis. The ocular of DES in women is 1.33-1.74 times than that of men. In abnormalities are referred to GO, and its pathogenesisis still addition, age seems to be associated with positive symptoms remains unknown. The orbital tissue has cross-reactivity of DES. The studies showed that the total prevalence of DES antigens with thyroid. They express the stimulating receptors is about 14.4-24.4 percent in Asia, 14.5 percent in America, targeting thyroid-stimulating hormone receptor (TSHR), and 18.4 percent in Spain, 20 percent in United Kingdom and 39.2 cause inflammatory reaction in the orbit[2]. Other antibodies percent in France. Many studies indicated that the prevalence that are targeted insulin-like growth factor-I receptor (IGF-1R) and changes slightly in people under 49 (about 15-25) percent, interleukin (IL)-17 might also play important roles in the which increases with age (about 25-45 percent)[18]. 616 Int J Ophthalmol, Vol. 14, No. 4, Apr.18, 2021 www.ijo.cn Tel: 8629-82245172 8629-82210956 Email: [email protected] The annual incidence of GO in women is about 16 cases per Other cytokines, in spite of no direct evidence in proving their 100 000 people and 3 cases per 100 000 in men[17]. Middle- relation with CAS, such as IL-17, IL-2, IL-10, tumor necrosis aged women are the main victims of GO. However, there is factor-α (TNF-α), interferon-γ (INF-γ), IL-7, IL-15, IL-17, no clear data with regard to prevalence in patients of different IL-12p70, IL-21 and RANTES showed higher expression in ages and genders with GO suffering from DES. Some studies GO patients[29-31]. have estimated that 65 to 85 percent of GO patients suffer from The spectrum of proteins has altered in the tears of GO patients. DES[19-20]. For middle-aged women, the prevalence of DES is In the study conducted by Matheis et al[32], some proteins undoubtedly higher in GO patients than normal subjects (<20 were downregulated when compared with normal subjects percent). by antibody microarray: proline-rich protein 1 (PROL1, OCULAR SURFACE CHANGES P<0.05), proline-rich protein 4 (PRP4, P<0.05), calgranulin A Objective Changes (S10A8, P=0.004) and transcription activator BRG1 (SMCA4, Tears P=0.002), while some were upregulated: Midasin and POTE- Tear breakup time and Schirmer’s test The changes in ankyrin-domain family-member I (P<0.05). Aass et al[33] tears play a significant role in the occurrence of DES in GO have reported a significant increase of lysozyme C (LYZ), patients. There are two basic indexes to estimate the condition lacritin (LACRT) and zinc-alpha-2 glycoprotein 1 (AZGP1) of tears: the tear breakup time (BUT) and the Schirmer’s I test by enzyme-linked immunosorbent assay (ELISA). Song (SIt). BUT is a test that assesses the stability of the tear film, et al[31] have reported overexpression of CD40, CD40 ligand, while SIt levels are the amount of basic secretion of tears. glucocorticoid-induced tumor necrosis factor receptor (GITR), Wei et al[15] have reported that the BUT (8.40±2.80s) and SIt IL-12p70, IL-1β, IL-2, IL-21, IL-6, macrophage inflammatory (8.53±3.54 mm) in a GO group showed statistically significant protein-3α (MIP-3α) and TRANCE in the tears of GO using differences from that of the control group (13.47±3.62s, high-throughput microarray technology. In addition, the P=0.002; 14.87±7.12 mm, P=0.009). This illustrated damage downregulation of granulocyte-macrophage colony stimulating to both quality as well as quantity of tears in GO. Many other factor (GM-CSF), IL-1 sRI, and IL-13 was also reported. reports have shown similar conclusions[21-23]. Furthermore, Choi et al[34] have reported increased levels of The tear film osmolarity The past studies have suggested oxidative stress markers, 8-hydroxy-2’-deoxyquanosine that the osmolarity of the tear film is often higher in GO (8-OHdG; r=0.676, P<0.001) and malondialdehyde (MDA; patients[17,24]. For example, Iskeleli et al’s[25] work mentioned r=0.506, P=0.002) in GO patients, especially active GO, and that the tear film osmolarity that is measured by an auto- are determined by ELISA. Also, CAS showed significant osmometer (OM-6030 AUTO STAT; Daiichi, Kyoto, Japan) correlation with the concentrations of these. in GO patients (340.38±18.74 mOsm) is significantly different Cornea from that of healthy subjects (290.80±13.58 mOsm/L, Staining Because of extra ocular exposure and abnormal state P=0.0001). The increased tear film osmolarity might be of tears in GO, patients might undergo corneal epithelial injury caused by proptosis and higher palpebral fissure. However, a and even exposed to keratitis. recent study conducted by Kashkouli et al[26] have provided Corneal fluorescein staining assesses the area and density of an inconsistent conclusion that even though 16.2% eyes of damage. It is often graded from 1-4 in every quadrant and the moderate-severe GO patients showed abnormal osmolarity, higher the total score is, the more severe the injury caused. the mean osmolarity measured by TearLab device was Li et al[35] have reported that almost 1/3 of GO patients suffer 295.9 mOsm/L, which might be due to the differences in the from epithelial injury and the results demonstrated statistical detection methods. differences between active GO and inactive GO. Similar Composition of tears For autoimmune and inflammatory conclusion has been drawn by many other studies[23,26,36-37]. reactions that take place in the orbit of GO patients, many In vivo confocal microscopy In vivo confocal microscopy is studies have tested the amount of proteins and cytokines in the a device that is used to scan and collect images of each layer tears and found several differences in active GO, inactive GO of cornea and conjunctiva. After examining the density and and healthy controls. morphology of Langerhans cells (LCs) of the cornea in 40 GO The studies conducted by Kishazi et al[27] and Ujhelyi et al[28] patients and 20 normal controls (NC), Wu et al[21] have found have revealed that some cytokines in tears such as IL-1β, IL-6, that both active and inactive GO patients have significantly IL-8, IL-13 are higher in GO patients than healthy subjects.