Role of the Underlying Thyroid Disease on the Phenotype of Graves' Orbitopathy in a Tertiary Referral Center

Abstract

Background:

Clinically overt Graves' orbitopathy (GO) is associated with Graves' disease (GD) in approximately 95% of cases, whereas the remaining 5% is observed in patients with hypothyroid autoimmune thyroiditis (AT) or without overt thyroid dysfunction (euthyroid GO). However, it is not known whether there is a difference in terms of GO phenotype between patients with GD and those with hypothyroid AT or without thyroid dysfunction, and hence this is investigated here.

Methods:

The study design was to evaluate retrospectively all consecutive patients with a recent manifestation of GO, seen at their first visit to a tertiary referral center over a period of 10 years. In total, 358 GO patients were studied, and all of them underwent GO assessment.

Results:

Of the 358 patients studied, 341 had hyperthyroid GD, 10 had AT with hypothyroidism, and seven had euthyroid GO. Age, sex, and smoking habits were similar in the three groups, as was the time since GO was first noticed (GO duration). The vast majority of patients had moderate to severe, active GO, as expected in a tertiary referral center. Exophthalmometry, eyelid width, clinical activity score (CAS), diplopia, and visual acuity did not differ between patients with GD and those with AT or euthyroid GO, suggesting that the GO phenotype was similar. Accordingly, the NOSPECS score did not differ between the three groups.

Conclusions:

The phenotype of GO is similar regardless of the underlying thyroid disease. Because this study was performed in a tertiary referral center, this conclusion can be restricted only to patients who develop moderate to severe GO.

Introduction

Clinically overt Graves' orbitopathy (GO) is reported to occur in about 25% of patients with Graves' disease (GD) (1,2), and to be severe enough to require major treatment in 2–3% of them (2 –4). The other extrathyroidal manifestations of GD, namely pretibial myxedema and Graves' acropachy, are less common, as they occur in 1.5% and 0.3% of patients with GD, respectively (1).

GO is associated with GD in approximately 95% of the cases, whereas in the remaining 5% it is observed in hypothyroid patients with autoimmune thyroiditis (AT), or in the absence of overt thyroid dysfunction, which is referred to as euthyroid GO (2,5). A discrete proportion of patients with euthyroid GO, however, develop thyroid dysfunction within one to two years from the first observation of GO (2).

In view of the substantial differences between GD and AT both at the pathogenetic and the clinical level, the involvement of orbital tissues may be different in the two entities, and they may therefore be characterized by a different clinical presentation. Recognition of differences among the entities would be quite useful to know in clinical practice. With the exception of some case reports (6,7), only a few studies have investigated this issue (8 –11), but these have led to conflicting findings.

Both myxedema and acropachy are almost invariably associated with the presence of GO (2,12), and all of the extrathyroidal manifestations of GD, including GO, are strongly associated with the presence of detectable antithyrotropin receptor autoantibodies (TRAb) in the serum (13,14). In patients with AT, either hypo- or euthyroid, TRAb are commonly detectable in the presence of GO, but they are rare in patients without GO (13). The prevalence of pretibial myxedema or Graves' acropachy in GO patients with AT or with euthyroid GO has not been estimated, although it is thought to be even rarer than in patients with GD (1,12).

The aim of the present study was to evaluate retrospectively whether the type of the underlying thyroid disease affects the features of GO at the first visit to a tertiary referral center, in a large series of consecutive patients seen over a period of 10 consecutive years. In addition, the prevalence of pretibial myxedema and Graves' acropachy were evaluated according to the thyroid diagnosis, in order to determine whether there is a difference between GO patients with GD and those with AT or euthyroid GO.

Patients and Methods

Study design and patients

The study aimed at retrospectively evaluating the features of a recent manifestation of GO and the presence of pretibial myxedema and/or Graves' acropachy in a large series of consecutive patients at their first visit to a GO clinic over a period of 10 consecutive years, and then to compare findings in patients with GD and those with AT or euthyroid GO. Inclusion criteria were as follows. First, appearance of GO signs or symptoms for no more than 24 months; this criterion was introduced because GO could have improved spontaneously over a longer period, as it is known to occur during its natural history (15,16). Second, no previous treatment for GO with the exception of local measures (eye lubricants); this criterion was introduced because treatment of GO with glucocorticoids, other immune suppressants, radiotherapy, and surgical procedures could have modified its phenotype (2 –4). Third, no previous treatment for Graves' hyperthyroidism except for antithyroid drugs; this criterion was introduced because treatment of hyperthyroidism with either radioiodine or thyroidectomy may to some extent affect the GO phenotype, possibly due to thyroid antigen removal, based on the hypothesis that GO pathogenesis is characterized by autoimmunity against antigens shared by the thyroid and by orbital tissues (17,18). Fourth, in patients with euthyroid GO, a follow-up period of at least two years since the first observation of thyroid autoimmunity, in order to reclassify those who would eventually have developed thyroid dysfunction.

From January 1, 2002, to December 31, 2011, 358 patients (112 males; age 47.1±12.8 years, range 10–91 years) with GO who fulfilled the above mentioned criteria were seen on their first clinic visit and were included in the study.

Patient evaluation

All patients underwent a physical examination, which included leg observation to determine the presence of pretibial myxedema, and GO assessment, which included: (a) exophthalmometry; (b) measurement of eyelid width; (c) evaluation of the Clinical Activity Score (CAS) according to Mourits et al. (19,20); (d) assessment of ocular motility and diplopia; (e) assessment of the corneal status; (f) examination of the fundi; and (g) measurement of visual acuity. All measurements were performed according to the recommendations of the European Group on Graves' Orbitopathy (EUGOGO) (20). Serum free triiodothyronine(fT3; Lysophase), thyrotropin (TSH; Delfia Wallac), antithyroglobulin (TgAb; Sorin Biomedica), antithyroperoxidase (TPOAb; Sorin Biomedica), and TRAb (Brahms) were measured in all patients. Thyroid ultrasound was performed in all patients. Thyroid volume was estimated according to the ellipsoid formula (21).

The diagnosis of GD was based on the presence of hyperthyroidism associated with detectable serum TRAb (14,22). The diagnosis of hypothyroid AT was based on the presence of hypothyroidism associated with detectable serum TgAb and/or TPOAb. The diagnosis of euthyroid GO was formulated in patients with clear-cut GO, but without overt thyroid dysfunction (either hyper- or hypothyroidism) for at least two years, in the presence of positive serum antithyroid autoantibodies.

Endpoints

The primary endpoint of the study was the difference in GO between patients with GD and those with AT or euthyroid GO in terms of (a) exophthalmometry, (b) eyelid width, (c) CAS, (d) diplopia, (e) visual acuity, and (f) overall degree, evaluated using the NOSPECS score, where NOSPECS stands for no GO signs (N), only eyelid sign (O), soft tissue involvement (S), proptosis (P), extraocular motility restriction (E), corneal involvement (C), and sight loss (S) (16).

The secondary endpoint was the difference in the frequency of the extrathyroidal manifestations of GD other than GO, namely pretibial myxedema and/or Graves' acropachy, between patients with GD and those with AT or euthyroid GO.

Data presentation and statistics

Descriptive data are presented as mean±standard deviation (SD) or median and interquartile range, as appropriate. When appropriate, analysis of variance, Fisher's exact test, or Kruskal–Wallis test were performed.

Results

General features of patients

As reported in Table 1, of the 358 patients included in the study, the vast majority had hyperthyroid GD, 10 had hypothyroid AT, and seven had euthyroid GO. Age, sex, and smoking habits were similar in the three groups, as was the time since GO was first noticed (GO duration). The majority of patients in the three groups were euthyroid at the time of our observation, although a discrete proportion of patients in the GD group were untreated hyperthyroid, and only a few were hypothyroid on antithyroid drugs. As expected, the thyroid volume was significantly greater in the GD group, whereas TgAb and TPOAb serum levels and prevalence were significantly greater in the remaining two groups. Also as expected, TRAb prevalence and serum levels were significantly higher in GD patients.

Table 1.

Demographical Features, Smoking Habits, Thyroid Features, and Serological Findings in 358 Consecutive Patients with Recently Diagnosed Graves' Orbitopathy

Feature	GD	AT	Euthyroid GO	p
N	341	10	7	NA
Age	47.1 ± 12.9 years (range 10–91 years)	52.1 ± 7.4 years (range 39–42 years)	44.5 ± 13 years (range 18–58 years)	0.41
Sex	110 males; 231 females	2 males; 8 females	2 males; 5 females	0.70
Smoking habits	170 nonsmokers; 58 ex-smokers; 113 current smokers	5 nonsmokers; 2 ex-smokers; 3 current smokers	3 nonsmokers; 1 ex-smoker; 3 current smokers	0.98
GO duration (time since GO appearance)	8 months (IQR: 4–12)	4 months (IQR: 7–9)	10 months (IQR: 7.2–18.7)	0.10
Thyroid treatment	None: 29; MMI: 312	LT4: 10	None: 7	NA
Thyroid status	Hyperthyroid: 96 (28.1%); untreated: 29; on MMI: 67 Euthyroid: 208 (60.9%); on MMI: 208 Hypothyroid: 37 (10.8%); on MMI: 37	Euthyroid: 9 (90%); hypothyroid: 1 (10%)	Euthyroid: 7 (100%)	NA
Thyroid volume	20 mL (IQR: 13–30)	8 mL (IQR: 4.5–17.2)	6.5 mL (IQR: 4–12)	<0.0001
	14 IU/mL (IQR: 0–89)	143 IU/mL (IQR: 14–552)	395 IU/mL (IQR: 81–1206)	0.0006
TgAb	Positive: 129	Positive: 7	Positive: 7	0.0006
	Negative: 212	Negative: 3	Negative: 0
TPOAb	30 IU/mL (IQR: 0–186.5)	419 IU/mL (IQR: 105–1000)	306 IU/mL (IQR: 38–717)	0.0005
	Positive: 203	Positive: 10	Positive: 7	0.0037
	Negative: 138	Negative: 0	Negative: 0
TRAb	10 IU/L (IQR: 3.1–26)	12 IU/L (IQR: 4.5–30)	1.4 IU/L (IQR: 0–2.3)	0.0028
	Positive: 315	Positive: 9	Positive: 4	0.0038
	Negative: 26	Negative: 1	Negative: 3

Numerical values are reported as median, with the exception of age (mean ± standard deviation).

Statistical tests: analysis of variance (age); Fisher's exact test (gender, smoking, prevalence of TgAb, TPOAb, and TRAb); Kruskal–Wallis (GO duration, thyroid volume, levels of TgAb, TPOAb and TRAb).

GD, Graves' disease; GO, Graves' orbitopathy; AT, autoimmune thyroiditis; MMI, methimazole; LT4, L-thyroxine; TgAb, antithyroglobulin autoantibodies; TPOAb, antithyroperoxidase autoantibodies; TRAb, anti-TSH receptor autoantibodies.

GO phenotype and other extrathyroidal manifestations of GD

As shown in Table 2, the vast majority of patients had moderate to severe, active GO, as expected in a tertiary referral center. Exophthalmometry, eyelid width, CAS, diplopia, and visual acuity did not differ between patients with GD and those with AT or euthyroid GO (Table 2), suggesting that the GO phenotype was similar. Accordingly, the NOSPECS score did not differ between the three groups (Table 2).

Table 2.

Features of GO According to the Underlying Thyroid Disease in 358 Consecutive Patients with Recently Diagnosed GO

Feature	GD	AT	Euthyroid GO	p
Exophthalmometry (most prominent eye)	22 mm (IQR: 19.5–24)	20.5 mm (IQR: 18.5–21)	21 mm (IQR: 19.1–21.7)	0.20
Eyelid width (most affected eye)	13 mm (IQR: 11–15)	13 mm (IQR: 11–13)	12 mm (IQR: 11–14.5)	0.81
CAS	3 (IQR: 2–4)	4 (IQR: 3–4)	3 (IQR: 2–4)	0.25
Diplopia	Absent: 142Intermittent: 33Inconstant: 98Constant: 68	Absent: 6Intermittent: 0Inconstant: 1Constant: 3	Absent: 4Intermittent: 0Inconstant: 2Constant: 1	0.59
Visual acuity (most affected eye)	10/10 (IQR: 10–10)	10/10 (IQR: 10–10)	10/10 (IQR: 10–10)	0.76
NOSPECS score	4 (IQR: 2–4)	3 (IQR: 2–4)	3 (IQR: 2–4)	0.67

NO SPECS classes were converted into numerical values from 0 to 6.

Numerical values are reported as median.

Statistical tests: Kruskal–Wallis (exophthalmometry, eyelid width, CAS, visual acuity, NOSPECS score) and Fisher's exact test (diplopia).

CAS, clinical activity score.

Pretibial myxedema was observed in eight patients with GD (2.3%), in one patient with AT (10%), and in none of the patients with euthyroid GO, but the difference was not statistically significant (p=0.28). Graves' acropachy was observed in only one patient with GD (0.29%). The overall prevalence rates of pretibial myxedema and Graves' acropachy, regardless of the thyroid diagnosis, were 2.5% and 0.27% respectively.

Discussion

GO is known to occur in association with GD and more rarely in association with AT or in the absence of an overt thyroid dysfunction (euthyroid GO). However, it is not established with certainty whether the features of the eye syndrome differ depending on the underlying thyroid disease. In order to address this, the eye features were retrospectively analyzed of a large number of consecutive patients with a recent manifestation of GO seen at a tertiary referral center on their first visit.

As expected, the majority of patients had GD and only a minority had an AT, the proportions of which (∼3%) were similar to those reported in the literature (1). The prevalence of AT patients without thyroid dysfunction (euthyroid GO) was 1.9% of the total number of GO patients, which is similar to the prevalence reported previously (∼1%) (2). The three groups of patients (GD, AT, and euthyroid GO) were similar in terms of demographical features, smoking habits, and GO duration. In contrast, and as expected, the thyroid volume was greater in patients with GD, whereas TgAb and TPOAb were observed more commonly and at higher levels in the other two groups (23). As mentioned above, serum TRAb are almost invariably associated with GO (13). Here, they were found to be more frequently positive and at higher levels in patients with GD than in the remaining two groups. A small proportion of GO patients did not have detectable TRAb at first observation. It is, however, possible that TRAb had been positive before the first observation and had become undetectable after treatment of the thyroid dysfunction, a quite well-known phenomenon (23).

Exophthalmometry, eyelid width, CAS, diplopia, and visual acuity did not differ between GO patients with GD and those with AT or euthyroid GO. Consistent with these findings, the NOSPECS score, a measure of the overall degree of GO, was similar in the three groups. These results seem to indicate that the phenotype of GO is similar, regardless of the underlying thyroid disease. This suggests that GO is a unique syndrome, possibly TSH receptor-mediated (24), in which, however, the type of autoimmunity against the TSH receptor (stimulating vs. blocking) or the remaining thyroid autoantigens possibly shared by orbital tissues, as for example Tg (25), do not affect the phenotype. In agreement with this hypothesis, the presence and or the levels of TRAb, TPOAb, and TgAb did not correlate with any of the features of GO or with the NOSPECS score (not shown).

These findings are in agreement with those of Kashokouli et al. (10), who found no difference in terms of GO severity and activity between patients with GD and those with hypothyroid AT. In contrast, Eckstein et al. reported less severe GO in patients with hypothyroid AT compared with those with GD (8). The different selection of patients may explain these apparent discrepancies. Thus, in the study of Eckstein et al., GD patients had untreated hyperthyroidism (8), whereas in the present study, the majority of GD patients where euthyroid on methimazole. Hyperthyroidism per se is known to affect the severity and activity of GO (26), as also shown by a recent study from Termote et al. (11). In addition, in the study by Eckstein et al., patients with a history of GO for >12 months were excluded (8), whereas in the present study patients who had GO for up to 24 months were included, which could also have affected the results. In another study, Jang et al. found more severe and active GO in patients with Graves' hyperthyroidism compared with euthyroid patients with orbitopathy (9). However, in that study, patients with AT where excluded, and euthyroid patients actually had an undefined orbitopathy. Because of that, the findings are rather difficult to compare with the remaining literature on the subject, even taking into account that some patients commonly classified as having euthyroid GO and some GO patients with AT may actually have an unrelated orbitopathy, such as IgG4-related ophthalmic disease, for example, as suggested recently (27). Moreover, Jang et al. included patients treated with thyroidectomy or radioiodine in the GD group (9), which could also have affected the findings (17,18).

One possible limitation of the present study is that patients were seen in a tertiary referral center, and therefore they had moderate to severe rather than mild GO. Thus, it is possible that patients with milder forms of GO who are usually taken care of by primary and/or secondary referral specialists/centers would have eventually changed these findings if included in the series. Because of this, the conclusions should be restricted only to patients with moderate to severe GO and from a tertiary referral center, whereas further studies are needed to investigate whether the phenotype of mild GO differ if associated with GD, AT, or euthyroid GO.

Another possible weakness of the present study is that the patients were not necessarily seen at their Rundle's curve peak, namely the highest individual level of GO severity and activity (15,16), a time point that varies from subject to subject and that is virtually impossible to predict. Another relative limitation is that three groups of patients quite different in size were compared (341 with GD, 10 with hypothyroid TA, and seven with euthyroid GO), which was, however, inevitable due to the relatively low frequency of AT and euthyroidism in GO patients (2).

Overall, in the GO series, a prevalence of pretibial myxedema of 2.5% and of thyroid acropachy of ∼0.3% was observed. In line with the phenotype of GO, there was no difference between patients with GD and patients with AT or euthyroid GO. In patients with GD, the prevalence of pretibial myxedema was 2.3% and that of thyroid acropachy was of 0.27%. Considering that the GD patients represented only those with GO, which is present in 25% of GD patients (1), and that pretibial myxedema and Graves' acropachy are virtually not seen in the absence of GO (1,12), a reasonable projection is that the overall prevalence rates of pretibial myxedema and of Graves' acropachy in our GD patients were 0.5% and 0.07% respectively, which are lower than those reported previously (1), and for which difference there is currently not an explanation. In contrast and as mentioned above, the proportions of patients in whom GO was associated with GD (∼95%) and AT (∼3%) were similar to those reported previously (2).

Footnotes

Acknowledgment

Supported by a grant from MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca Scientifica; 2004068078 to M.M.).

Author Disclosure Statement

Marenza Leo, Francesca Menconi, Roberto Rocchi, Francesco Latrofa, Eleonora Sisti, Maria Antonietta Profilo, Barbara Mazzi, Eleonora Albano, Marco Nardi, Paolo Vitti, Claudio Marcocci and Michele Marinò declare that they do not have any commercial association that might create a conflict of interest in connection with this manuscript.

References

Bartalena

, Fatourechi

. 2014. Extrathyroidal manifestations of Graves' disease: a 2014 update. J Endocrinol Invest, 37:691–700.

Bartalena

, Tanda

. 2009. Clinical practice. Graves' ophthalmopathy. N Engl J Med, 360:994–1001.

Marcocci

, Marinò

. 2012. Treatment of mild, moderate-to-severe and very severe Graves' orbitopathy. Best Pract Res Clin Endocrinol Metab, 26:325–337.

Marcocci

, Pinchera

, Marinò

. 2007. A treatment strategy for Graves' orbitopathy. Nat Clin Pract Endocrinol Metab, 3:430–436.

Marinò

, Barbesino

, Pinchera

, Manetti

, Ricciardi

, Rossi

, Muratorio

, Braverman

, Mariotti

, Chiovato

. 2000. Increased frequency of euthyroid ophthalmopathy in patients with Graves' disease associated with myasthenia gravis. Thyroid, 10:799–802.

Gleeson

, Kelly

, Toft

, Dickinson

, Kendall-Taylor

, Fleck

, Perros

. 1999. Severe thyroid eye disease associated with primary hypothyroidism and thyroid-associated dermopathy. Thyroid, 9:1115–1118.

Rocchi

, Altea

, Marinò

, Menconi

, Leo

, Sisti

, Profilo

, Lepri

, Nardi

, Vitti

, Marcocci

, Latrofa

. 2014. Development of optic neuropathy in two thyroidectomized patients with moderate to severe Graves' ophthalmopathy following L-thyroxine withdrawal in preparation for radioactive iodine treatment for thyroid carcinoma. Endoc Pract; in press, DOI:10.4158/EP14276.CR.

Eckstein

, Lösch

, Glowacka

, Schott

, Mann

, Esser

, Morgenthaler

. 2009. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves' ophthalmopathy. Br J Ophthalmol, 93:1052–1056.

Jang

, Lee

, Yoon

. 2012. Clinical features of thyroid-associated ophthalmopathy in clinically euthyroid Korean patients. Eye (Lond), 26:1263–1269.

10.

Kashkouli

, Pakdel

, Kiavash

, Heidari

, Heirati

, Jam

. 2011. Hyperthyroid vs hypothyroid eye disease: the same severity and activity. Eye (Lond), 25:1442–1446.

11.

Termote

, Decallonne

, Mombaerts

. 2014. The influence of prior hyperthyroidism on euthyroid Graves' ophthalmopathy. J Ophthalmol, 2014:426898.

12.

Fatourechi

. 2012. Thyroid dermopathy and acropachy. Best Pract Res Clin Endocrinol Metab, 26:553–565.

13.

Barbesino

, Tomer

. 2013. Clinical review: clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab, 98:2247–2255.

14.

Menconi

, Marcocci

, Marinò

. 2014. Diagnosis and classification of Graves' disease. Autoimmun Rev, 13:398–402.

15.

Bartley

. 2011. Rundle and his curve. Arch Ophthalmol, 129:356–358.

16.

Menconi

, Profilo

, Leo

, Sisti

, Altea

, Rocchi

, Latrofa

, Nardi

, Vitti

, Marcocci

, Marinò

. 2014. Spontaneous improvement of untreated mild Graves' ophthalmopathy: Rundle's curve revisited. Thyroid, 24:60–66.

17.

Menconi

, Marinò

, Pinchera

, Rocchi

, Mazzi

, Nardi

, Bartalena

, Marcocci

. 2007. Effects of total thyroid ablation versus near-total thyroidectomy alone on mild to moderate Graves' orbitopathy treated with intravenous glucocorticoids. J Clin Endocrinol Metab, 92:1653–1658.

18.

Leo

, Marcocci

, Pinchera

, Nardi

, Megna

, Rocchi

, Latrofa

, Altea

, Mazzi

, Sisti

, Profilo

, Marinò

. 2012. Outcome of Graves' orbitopathy after total thyroid ablation and glucocorticoid treatment: follow-up of a randomized clinical trial. J Clin Endocrinol Metab, 97:E44–48.

19.

Mourits

, Prummel

, Wiersinga

, Koornneef

. 1997. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf), 47:9–14.

20.

Bartalena

, Baldeschi

, Dickinson

, Eckstein

, Kendall-Taylor

, Marcocci

, Mourits

, Perros

, Boboridis

, Boschi

, Currò

, Daumerie

, Kahaly

, Krassas

, Lane

, Lazarus

, Marinò

, Nardi

, Neoh

, Orgiazzi

, Pearce

, Pinchera

, Pitz

, Salvi

, Sivelli

, Stahl

, von Arx

, Wiersinga

. 2008. Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Thyroid, 18:333–346.

21.

Profilo

, Sisti

, Marcocci

, Vitti

, Pinchera

, Nardi

, Rocchi

, Latrofa

, Menconi

, Altea

, Leo

, Rago

, Marinò

. 2013. Thyroid volume and severity of Graves' orbitopathy. Thyroid, 23:97–102.

22.

Marinò

, Latrofa

, Menconi

, Chiovato

, Vitti

. 2014. An update on the medical treatment of Graves' hyperthyroidism. J Endocrinol Invest [Epub ahead of print].

23.

Marcocci

, Marinò

. 2005. Thyroid directed antibodies. In: Braverman

, Utiger

(eds) Werner and Ingbar's the Thyroid: A Fundamental and Clinical Text. Ninth edition. Lippincott, Williams & Wilkins, Philadelphia, PA, pp 360–372.

24.

Iyer

, Bahn

. 2012. Immunopathogenesis of Graves' ophthalmopathy: the role of the TSH receptor. Best Pract Res Clin Endocrinol Metab, 26:281–289.

25.

Marinò

, Chiovato

, Lisi

, Altea

, Marcocci

, Pinchera

. 2004. Role of thyroglobulin in the pathogenesis of Graves' ophthalmopathy: the hypothesis of Kriss revisited. J Endocrinol Invest, 27:230–236.

26.

Prummel

, Wiersinga

, Mourits

, Koornneef

, Berghout

, van der Gaag

. 1990. Effect of abnormal thyroid function on the severity of Graves' ophthalmopathy. Arch Intern Med, 150:1098–1101.

27.

Bartalena

, Chiovato

. 2014. Graves'-like orbitopathy: do not forget IgG4-related disease. J Endocrinol Invest, 37:1233–1235.