Graves Ophthalmopathy a neglected comorbidity of Graves’ Disease; A Detailed investigation and management of Sixty Eight Patients in a tertiary healthcare center.

doi:10.21203/rs.3.rs-3896820/v1

Aim: To compare the measurements of macular thickness, intraocular pressure and retinal fiber nerve layer (RFNL) and hormone parameters before and after antithyroid therapy in patients with Graves’ Ophthalmopathy (GO).

Methods: A prospective observational study conducted at a tertiary care center. Patients with GO were included and scored (Clinical Activity Score, CAS) according to EUGOGO guideline. The participants underwent optical coherence tomography (OCT) and OCT angiography (OCT-A) of the peripapillary and macular areas. Baseline and follow-up hormone parameters including free T3, free T4, Thyroid stimulating hormone (TSH), Thyroid receptor autoantibodies and intravitreal measurements (RFNL, macular thickness, intraocular pressure) were performed and compared in the current study.

Results: During the 24 weeks, CAS was significantly decreased (0.5±0.8 vs 0.1±0.4, p=0.00). Although measurements of Intraocular pressure (14.9±2.8 vs 14.2±1.9), RFNL (100.2±9.05 vs 99.9±8.7) and macular thickness (274.7±42.9 vs 271.2±43.3) were between baseline and were similar after antithyroid therapy, baseline RFNL measurements were significantly correlated with serum TRAbs (p=0.008), fT3 (p=0.01), fT4 (p=0.003), negatively. Baseline intraocular pressure and macular thickness were also negatively correlated with serum TSH levels.

Conclusion: Serum fT3, fT4 and TRAbs levels were the main significant factor for the evaluation of intraocular structure, especially retinal nerve in patients with GO.

Graves’ Disease (GD) is an autoimmune condition which is related with increased thyroid hormone levels. Graves’ Disease is the commonest cause of hyperthyroidism, typically seen in patients between 40–60 years of age (1). Clinical and biochemical features of GD are characterized specifically with ophthalmopathy (and/or dermopathy). Elevated thyroid circulating hormone levels in GD arise because of stimulating thyroid stimulating hormone (TSH) Receptor Autoantibodies (TRAbs) which mimics the action of TSH (2, 3).

TSH receptor is also found in orbital fibroblasts where binding of TRAbs results in proliferative response that contributes to the extrathyroidal signs seen in GD called as Graves’ Orbitopathy (GO) (4, 5). For assessing orbitopathy activity, 7 point activity score (CAS) is frequently used, in which one point is shown for pain behind the eyes, point with eye movement, eyelid swelling, eyelid edema conjunctival redness, chemosis or caruncle swelling. An activity is described as score of 3 or greater for a patient with GD. For accurate diagnosis, there have been several classifications which are called European Group of Graves’ Orbitopathy’/ EUGOGO or VISA inflammatory system (6, 7). And both of them recommend that control of thyroid hormone levels is crucial in all patients with GO.

Nearly 50% of patients with GD report symptoms of ophthalmopathy which are generally mild. But if timely diagnosis is not performed, more cases could have severe sight-threatening form of the disease due to corneal exposure or compressive optic neuropathy (8, 9). Retinal nerve fiber layer, the innermost layer of retina, consists of unmyelinated fibers generated from ganglion cells and thickness of RFNL could be used to evaluate the axon loss (10). Optic nerve damage could be shown due to orbital mechanical compression by the extraocular muscles and soft tissue expansion. Sometimes it is difficult to evaluate involvement of optic nerve in patients with GO (11). Optic coherence tomography (OCT) is a valuable and noninvasive method to detect retinal diseases and optic disc pathologies. It has been commonly used to diagnose and monitor RFNL, macular ring thickness (12, 13). Previously mentioned measurements and those comparisons with thyroid function tests in patients with GO have been performed in limited studies and reported as prognostic value for these patients.

For this reason, we aim to find answer these 3 important questions.

1) to evaluate the effect of thyroid hormone levels on retinal nerve layer and thickness of macula in patients with GD.

2) to determine whether there is a correlation between those parameters and severity of orbital disease,

3) to compare those patients’ measurements before and after antithyroid treatment.

We included patients between the ages of 18–70 aged who were referred to the endocrinology department in our university hospital. Patients with elevated free thyroxine (free T4) and/or free tri-iodothyronine (free T3) concentrations, a suppressed TSH, positive TRAbs and presence of diffuse goiter were diagnosed as Graves’ Disease. Written informed consent was obtained from all patients.

The exclusion criteria were as follows:

1) presence of thyroid nodules suspicious for malignancy,

2) injection of iodinated radiographic contrast media within the 4 weeks prior to radioiodine therapy, concurrent or previous amiodarone treatment,

3) cases with lymphoma, idiopathic orbital inflammation, cellulitis, orbital tumors, glaucoma, uveitis, retinal and corneal disease,

4) history of ocular trauma or surgery, and patients using eye drops and contact lenses

5) previous and concomitant treatment for hyperthyroidism by any means.

All patients were evaluated in detail for the GD and baseline biochemical and hormonal parameters including hemogram, liver function tests, TSH, free T4 (fT4), free T3 (fT3), thyroid peroxidase autoantibody (Anti TPO), TRAbs.

Eye Examination

The patients underwent a comprehensive ophthalmological examination, including best-corrected visual acuity, slit lamp biomicroscopy, intraocular pressure measurement with Goldmann applanation tonometry, fundoscopic examination and hertel exophthalmometry. Clinical activity scores were evaluated according to the European Group of Graves' Orbitopathy (EUGOGO) classification⁶. The activity was graded on clinical activity score. Thyroid eye diseases were deemed to be active if the score was more than 3 on 7 at the first examination or 4 on 10 on the follow-up examinations of a patient (6). EUGOGO classification was used for the severity of the disease. The disease was classified into mild moderate and severe as described by the EUGOGO classification. Central macular thickness and optic disc retinal nerve fiber layer values were recorded and evaluated by optic coherence tomography (Heidelberg Spectralis; Heidelberg Engineering Inc).

After the biochemical evaluation and the eye examination, antithyroid drugs (methimazole or propylthiouracil) were given in proper doses to all patients and they were followed-up for a year. All parameters including demographical (age, gender) biochemical (fT3, fT4, TSH, TRAbs, hemogram, liver function test), dosage of antithyroid treatment and eye examination were recorded at the beginning and during the follow-up period.

Statistical analyses

For the right and the left eye, to examine the correlation between TSH, TRABs, FT3 and FT4 measurements and the treatment difference (before-after), Pearson correlation was used if the assumptions were met, and Spearman correlation was used if the assumptions were not met.

Considering the correlation between both eyes, Generalized Linear Mixed Model (GLMM) was used to compare pre and post-treatment GİB, RNFL, Macular thickness and CAS measurements.

Categorical variables were expressed as numbers and percentages, whereas continuous variables were summarized as mean and standard deviation and as median and minimum-maximum where appropriate.

All analyses were performed using IBM SPSS Statistics Version 20.0 statistical software package. The statistical level of significance for all tests was considered to be 0.05.

SPSS reference: IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0 Armonk, NY: IBM Corp.

Demographic parameters, baseline hormone levels and eye measurements before anti thyroid therapy

We enrolled 68 patients (female to male, 66.2% vs 33.8%) with mean age of 45.4 ± 13.7 years. Mean TSH, fT3, fT4 and TRAbs values of all patients were 0.27 ± 1.2, 10.5 ± 7.4, 2.7 ± 2.05 and 12.1 ± 14.3, respectively. Mean TSH, fT3, fT4 and TRAbs values between two genders were similar (p = 0.25, 0.30, 0.51, 0.62) (Table 2).

Table 1

Comparison baseline and follow-up hormone parameters of all patients
N = 68	Baseline	Follow-up	p
TSH (mIU/L)	0.07 ± 1.2	3.4 ± 1.9	0.00
fT3 (ng/mL)	10.5 ± 7.4(3.2–32)	3.6 ± 1.35	0.00
fT4 (ng/mL)	2.7 ± 2.0 (0.6–11.9)	0.9 ± 0.4	0.00
TRAbs	12.1 ± 14.3 (0.17-50)	2.3 ± 4.5	0.00
AntiTPO	208.7 ± 320.6 (0-1100)	NA	NA
ALT (U/L)	29.6 ± 16.6	21.6 ± 11.8	0.00
WBC (10³/µL)	7229 ± 1977	7911 ± 2064	0.03
CAS (score)	0.5 ± 0.8	0.1 ± 0.4	0.00
Data is demonstrated as mean standard deviation.
CAS: Clinical Activity Score, TSH: Thyroid Stimulating Hormone, fT3: free T3, fT4:free T4 WBC: White Blood Cell counter

Table 2

Comparison of the hormone parameters between two gender
	Female (n = 45)	Male (n = 23)	p
Age (year)	47.4 ± 14.5	46.5 ± 13.7	0.34
TSH (mIU/L)	0.08 ± 0.36	0.43 ± 1.81	0.25
fT3 (ng/mL)	10.3 ± 6.06	11.3 ± 9.17	0.30
fT4 (ng/mL)	2.82 ± 1.32	3.06 ± 2.26	0.51
TRAbs	14.3 ± 14.72	10.56 ± 14.2	0.62
CAS	0.47 ± 0.72	0.77 ± 1.1	0.41
Data is demonstrated as mean standard deviation
CAS: Clinical Activity Score, TSH: Thyroid Stimulating Hormone, fT3: free T3, fT4:free T4

Mean CAS of all patients was evaluated as 0.5 ± 0.8 (range 0–3) and the other baseline measurements including intraocular pressure was 14.9 ± 2.8; RFNL 100.2 ± 9.05; central macular thickness 274.7 ± 42.9, respectively. There was no difference between the two genders in terms of all hormone parameters (Table 1–3).

Table 3

Comparison between before and after treatment of OCT parameters
	Before treatment		After treatment
	Male	Female	Male	Female
	Mean ± sd	Mean ± sd	Mean ± sd	Mean ± sd	p
IOP (mmHg)	15.11 ± 2.46	14.69 ± 2.79	14.41 ± 2.28	14.92 ± 2.58	0.890
RNFL (µm)	102.36 ± 8.85	101.54 ± 9.93	101.27 ± 7.93	99.86 ± 9.92	0.374
MT (µm)	272.91 ± 41.25	269.14 ± 43.29	271.30 ± 39.15	269.36 ± 43.65	0.614
Data is demonstrated as mean standard deviation.
IOP: Intraocular Pressure, RFNL: Retinal Nerve Fiber Layer, Macular Thickness

RFNL measurements were significantly correlated with serum baseline TRAbs, antiTPO, fT3, fT4, negatively (p < 0.05) (Table 4, Fig. 1).

Table 4

Correlation between OCT parameters and baseline hormone parameters and autoantibodies of all patients’
Before Treatment	IOP	RNFL	MT
Trab	0.037	-0.216^*	0.136
AntiTPO	-0.017	-0.255^*	0.144
TSH (mIU/L)	-0.046	0.054	-0.139
FT3 (ng/mL)	0.153	-0.290^*	0.060
FT4 (ng/mL)	0.125	-0.268^*	0.093
Data is demonstrated as mean standard deviation.
IOP: Intraocular Pressure, RFNL: Retinal Nerve Fiber Layer, Macular Thickness

Intraocular pressure of all patients was negatively correlated with serum baseline TSH levels but there was no relation to other hormone parameters.

Macular thickness of all patients was also correlated with serum TSH levels.

When comparing the gender differences, we also did not see a significant difference between the genders and measurements of RFNL, central macular thickness and intraocular pressure. Detailed results are indicated in Tables 3–4.

Hormone levels and eye measurements after the antithyroid therapy

During the 24 weeks, the patients were under the antithyroid therapy and all hormone parameters (TSH, fT3, fT4), TRAbs levels were decreased significantly (detailed results are shown in Table 1). In addition, CAS was significantly decreased after the treatment (0.1 ± 0.4, p = 0.00). (Table 1)

Intraocular pressure (14.2 ± 1.9), RFNL (99.9 ± 8.7) and macular thickness (271.2 ± 43.3) after the antithyroid therapy did not significantly change in all patients during the management (Table 3).

There was no significant difference between before and after treatment of the intraocular pressure, RFNL and central macular thickness in patients with GO.

Our study showed that measurements of RFNL were significantly related with plasma fT3 and fT4, TRAbs and antiTPO levels in patients with GO but not TSH levels. Baseline intraocular pressure and macular thickness were also correlated with serum baseline TSH levels. This study suggested fT3, fT4 and TRAbs levels were the main significant factor for the evaluation of intraocular structure especially optic nerve. RFNL, macular thickness and intraocular pressure measurements were similar before and after the treatment and this result could be related with the baseline mild orbitopathy of all patients. By providing those objective measures of retinal damage, early and effective antithyroid therapy is necessary for all patients with GO.

GO is an uncommon, disfiguring and disabling autoimmune condition and more than 90% of cases occur in patients presenting with hyperthyroidism due to Graves’ Disease (14). Thyroid eye diseases and Graves’ hyperthyroidism have been commonly seen in female patients who are 30–50 years old. In addition, some studies (15, 16) reported severity of the disease tends to be worse in men and in patients over the 50 years old. Our study showed that mean age values were similar. Although mean serum fT3, fT4 values and CAS were more increased in male patients than the female patients but we did not find any significance between the two genders. This may be related with the small sample size of our study.

Graves orbitopathy is related with involvement of the orbital fibroblast as a result of the autoimmune processes that collectively induce proliferation excess adipogenesis and overproduction of the extracellular matrix (17, 18). Extracellular matrix including glycosaminoglycans is able to absorb up to 1000 times its weight in water. This results in an increase in the orbital volume and therefore an increase in intraorbital pressure (19). This is evaluated clinically as the disease activity by using clinical activity score. In general, optic nerve involvement is expected in patients with severe thyroid eye disease (20). Tehrani et al. (21) showed that macular and peripapillary vessel density were significantly lower in patients with active GO compared to nonactive noncompressive which reported CAS as equal to or less than 3. They also reported mean intraocular pressure for active GO and nonactive noncompressive GO were similar (18.7 ± 5.4 vs 16.4 ± 3.3). In their cohort, TRAbs was present in 90% of patients and anti-thyroid peroxidase was positive in 12.7% patients. Dave et al. (22) showed that peripapillary and macular vascularity indexes were lower in patients with active GO. They also presented that RFNL thickness was increased in active GO versus the inactive eyes and healthy controls. Sayın et al. (23) demonstrated that intraocular pressure (14.3 ± 2.7 vs 12.9 ± 1.9, p = 0.00) was higher in patients with GO (NOSPECS score; 2.4 ± 0.9) than the healthy controls. But they did not show any significant difference of RFNL (98.3 ± 29.4 vs 101.7 ± 30.7) among the patients with GO and healthy controls. In the above mentioned study, we did not know baseline and follow-up hormone levels or autoantibodies between the patient groups. In our study we did not find any correlation of RFNL, intraocular pressure and macular thickness measurements between pre and after antithyroid therapy. Different from these results, we found a robust correlation between serum fT3, fT4, TRAbs, anti TPO levels and RFNL measurements. Before the ATDs intraocular pressure and macular thickness were negatively correlated with TSH levels. Although mean baseline intraocular pressure (14.8 ± 2.6 vs 14.6 ± 2.5) and macular thickness (270.53 ± 42.42 vs 270.07 ± 42.07) measurements were similar during the following period, we found serum TSH levels were a significant factor that affected macular thickness and intraocular pressure. We believe that this can be related with maintaining long term TSH suppression even normalized fT3, fT4 levels.

Optic nerve pathology in thyroid ophthalmopathy is compressive neuropathy. Some studies (24–27) reported RFNL thickness was decreased in patients with GO versus the inactive eyes and healthy controls. The reduction in the RFNL may be hypothesized to be due to hypoxia and resultant ischemia caused by edema in the orbital soft tissue. But some of the other studies (28–30) reported the opposite argument related with RFNL thickness. They suggested that increase in RFNL thickness may be related with initial edema caused by optic nerve compression. But it has been known that RFNL measurements vary according to age, ethnicity and duration of the diseases. To find more accurate results of these measurements, they should be evaluated in the same patient population during the treatment or matched with similar age healthy controls. During the follow-up time, we observed similar thickness of RFNL in patients with GO. This can be explained as all of the patients having lower initial CAS. But we found a negative correlation between initial fT4, fT3 and TRAbs titer and RFNL thickness. Although patients with GO had similar measurements of RFNL; initial fT3, fT4 have been independent risk factors that influence the thickness of RFNL.

It has been known that TSH receptor antibodies are a major risk factor for the occurrence of GO. TSH receptor activation enhances the differentiation of orbital preadipocytes into adipocytes, favoring the expansion orbital adipose tissue (31–33). A multicenter prospective study (34) from 2018 proposed a predictive value of developing GO with baseline ocular inflammation, smoking, duration of thyroid disfunction and especially the TRAbs titer as the four key risk factors. Even though patients received euthyroid status during the follow-up, ophthalmopathy could progresses in patients with high titer of TRAbs. We found a significant negative correlation between serum TRAbs and before-after RFNL thickness. This may be related with long-term positivity of TRAbs titers .

There were several limitations in our study. This was an observational prospective study with a small sample size. Long-term follow-up studies need to evaluate the changes in the intraocular structure. In addition, all measurements including intraocular pressure, RFNL and macular thickness of patients could be compared with the age and sex of healthy controls.

The strength of our study is that we detailed evaluated intraocular structure before and after antithyroid therapy. All patients had lower CAS at baseline namely nonactive GO, but we found serum TRAbs, fT3 and fT4 had a significant factor for the RFNL. Up to date there have not been any studies which showed the correlation between macular thickness, RFNL and serum fT3, FT4 and TRAbs titers in patients with GO.

In conclusion, serum fT3, fT4 and TSH levels were independent and important parameters for the retinal nerve thickness in patients even with non-active orbitopathy. We postulate that these results could reflect early retinal effects by the thyroid hormone and autoantibody levels should be evaluated in all patients with GO.

Compliance with ethical standards:

Conflict of Interest: In our study there is no conflict of interests.

Ethical Approval: Ethical approval document was obtained from our university hospital.

Informed Consent: We obtained informed consent of all patients.

Author Contribution

Writing; GA, BU, MSEditing; MS, AÖData listed; FO, RSS

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No competing interests reported.

Graves Ophthalmopathy a neglected comorbidity of Graves’ Disease; A Detailed investigation and management of Sixty Eight Patients in a tertiary healthcare center.

Status:

Version 1

Abstract

Figures

Introduction

Material and Methods

Eye Examination

Statistical analyses

Results

Demographic parameters, baseline hormone levels and eye measurements before anti thyroid therapy

Hormone levels and eye measurements after the antithyroid therapy

Discussion

Declarations

References

Additional Declarations

Status:

Version 1