Ocular Surface Changes And Diagnostic Model Of Disease Activity In Patients With Thyroid Associated Ophthalmopathy

Objectives:The purpose of this study was to investigate the prevalence and risk factors of dry eye in patients with thyroid associated ophthalmopathy（TAO）,observe the morphological and functional changes of conjunctival goblet cell（GC）and Meibomian gland（MG）in patients with TAO based on tear film compositions,and establish a diagnostic model to assist in evaluating the activity of TAO.Methods:1.Ocular signs and dry eye indicators were assessed in 210 patients（420 eyes）with TAO and 156 healthy controls（312 eyes）.The prevalence of dry eye in TAO patients was analyzed,and risk factors of dry eye in TAO patients were explored using univariate and multifactorial analyses.2.Ocular signs,ocular surface parameters,GC morphology and mucin expression of 60 patients（120 eyes）with TAO and 40 healthy controls（80 eyes）were analyzed.Confocal microscopy was used to detect goblet cell density（GCD）of the temporal bulbar conjunctiva in vivo.The impression cytology sample of the temporal bulbar conjunctiva was immunolabeled with cytokeratin-7（CK7）and mucin 5AC（MUC5AC）antibodies to determine CK7⁺GCD,MUC5AC⁺GCD and GC area.Expression levels of mucin 16（MUC16）and MUC5AC m RNA in nasal bulbar conjunctiva impression cytology sample were detected by RT-q PCR.Normalized tear MUC5AC protein was determined by ELISA.The correlation between the morphology and function of GC and clinical parameters in patients with TAO was analyzed.3.Ocular signs,ocular surface parameters,lid margin abnormalities,and the structure and function of MG were analyzed in 45 patients（90 eyes）with TAO and 38 healthy controls（76 eyes）.The structure and function of MG were observed by apparent method and in vivo confocal microscopy,and its correlation with clinical parameters was analyzed.The diagnostic model of TAO activity was established based on MG microcosmic indexes.Results:1.The prevalence of dry eye in TAO patients was 74.29%.Smoking,¹³¹I treatment,being in active stage and moderate to severe severity were independent risk factors for dry eye in TAO.Compared with the controls,the intraocular pressure,exophthalmos,palpebral fissure height,partial blinking rate,ocular surface disease index（OSDI）and corneal fluorescein staining（CFS）scores were increased in TAO patients,while breakup time,tear secretion and tear meniscus height were decreased.2.The scores of conjunctival lisamine green staining and ocular redness in TAO group were higher than those in control group.GCD,GC area,m RNA expression of MUC16 and MUC5AC,and tear MUC5AC protein were decreased in TAO,and other indicators except MUC16m RNA were more significantly decreased in active TAO.GCD was positively correlated with tear MUC5AC protein and negatively correlated with partial blinking rate.GCD,GC area and tear MUC5AC protein were negatively correlated with ocular redness,clinical activity score（CAS）,OSDI and lisamine green staining scores,but positively correlated with breakup time.3.Compared with controls,TAO patients had higher lid margin congestion,plugging of MG orifices and MG dropout,as well as worse MG expressibility and thinner lipid layer thickness.In MG of TAO patients,the orifice area was reduced,the acinar showed dilated fusion with irregularity and decreased density,acinar wall and periglandular interstices inhomogeneity was increased,and meibum reflex and MG fibrosis were more obvious.The MG dropout,meibum quality and MG expressibility scores of TAO patients were positively correlated with OSDI,CFS,CAS,exposure and lid margin abnormalities.MG acinar irregularity and acinar wall inhomogeneity were positively correlated with OSDI,CFS,CAS,lid margin abnormalities,MG dropout,meibum quality and MG expressibility scores.Acinar periglandular interstices inhomogeneity（API）was positively correlated with CFS,CAS,lid margin abnormalities,MG dropout,meibum quality and MG expressibility scores.Severity of meibomian gland fibrosis（MF）was positively correlated with lid margin congestion,lid margin thickening,plugging of MG orifices and MG expressibility scores,but negatively correlated with CAS.Meibum secretion reflectivity（MSR）was positively correlated with plugging of MG orifices while negatively correlated with CAS.Meibomian gland acinar density was negatively correlated with CAS.The diagnostic model of TAO disease activity based on MG microscopic indexes was log[P/（1-P）]=0.42+2.66×MSR-3.72×API+1.92×MF,when P>0.57 can judge TAO in the activity.The area under the ROC curve was 0.92（95%CI:0.87～0.98）,the sensitivity was 80.00%,and the specificity was 94.00%.The nomogram visualization regression model can be used to predict the probability of active TAO.Conclusions:The exposure and damage of ocular surface and dry eye symptom were aggravated in TAO patients,with reduced tear production and tear film stability.The prevalence of dry eye in TAO patients was 74.29%.Smoking,¹³¹I treatment,being in active period and moderate to severe severity were independent risk factors for dry eye in TAO patients.The expression of mucin on the ocular surface of TAO patients was decreased,and the decrease of tear MUC5AC protein was associated with the decrease of conjunctival GCD,in which inflammation may play an important role.Structural disorders and functional abnormalities of MG may be caused by obstruction and inflammation.Abnormal morphology and function of GC and MG can aggravate ocular surface damage and dry eye symptoms in TAO patients.The diagnostic model based on MSR,API and MF has good clinical application value for evaluating the activity of TAO.