Clinical features and diagnosis of thyroid eye disease

INTRODUCTION — Thyroid eye disease (also called Graves' orbitopathy or ophthalmopathy) is an autoimmune disease of the orbit and retro-ocular tissues occurring in patients with Graves' disease and rarely in patients with Hashimoto's thyroiditis. This topic review will provide an overview of the pathogenesis, clinical features, and diagnosis of thyroid eye disease. Treatment of this disorder is discussed separately. (See "Treatment of thyroid eye disease".)

PATHOGENESIS — In Graves' disease, the main autoantigen is the thyroid-stimulating hormone (TSH) receptor (TSHR), which is expressed primarily in the thyroid but is also expressed in adipocytes, fibroblasts, and a variety of additional sites [1]. The TSHR forms a functional complex with the insulin-like growth factor 1 (IGF-1) receptor [2]. TSHR antibodies, activated T cells, and macrophages play an important role in the pathogenesis of thyroid eye disease by activating orbital fibroblast and adipocyte TSHRs and IGF-1 receptors and initiating cellular expansion and orbital inflammation [3].

The volume of both the extraocular muscles and orbital connective tissue is increased, due to fibroblast proliferation, adipogenesis, inflammation, and the accumulation of hydrophilic glycosaminoglycans (GAG), mostly hyaluronic acid [4,5]. GAG secretion by fibroblasts is increased by thyroid-stimulating antibodies and activated T cells (via cytokine secretion), implying that both B and T cell activation are integral to this process. The accumulation of hydrophilic GAG in turn leads to fluid accumulation, muscle swelling (picture 1), and an increase in pressure within the orbit. These changes, together with the orbital adipogenesis, displace the eyeball forward, leading to extraocular muscle dysfunction and impaired venous drainage causing periorbital swelling (figure 1 and image 1).

●Thyroid eye disease antigen: TSHR – The main autoantigen is the TSHR, which is expressed in orbital fibroblasts and forms a functional complex with the IGF-1 receptor.

Immunization of mice with the TSHR induces orbital adipogenesis, an inflammatory infiltrate, and GAG accumulation [6,7]. TSHR messenger ribonucleic acid (mRNA) and protein can be detected in orbital fibroblasts and adipocytes, and preadipocytes from patients with thyroid eye disease may express more TSHR mRNA and produce more cyclic adenosine monophosphate (cAMP) in response to TSH than do similar cells from control individuals [8].

Although there is much evidence for extrathyroidal TSHR expression, the evidence that TSHR expression is greater in the orbital tissues of Graves' patients when compared with that found elsewhere is compelling. Hence, in addition to TSHR antigen directly activating the immune system, these observations suggest that TSHR expression in vivo is also enhanced by an external stimulus from the local inflammatory cells or directly by TSHR antibodies.

●Role of TSHR autoantibodies – TSHR antibodies play an important role in the pathogenesis of thyroid eye disease by activating orbital fibroblast and adipocyte TSHRs and the closely linked IGF-1 receptors and initiating an orbital inflammatory environment.

There is significant crosstalk between the TSHR and the IGF-1 receptor in orbital fibroblasts, such that activation of the TSHR by TSHR autoantibodies can lead to IGF-1 receptor signal transduction, and a synergistic effect on GAG production occurs after activation of both receptors [9]. This crosstalk between the TSHR and the IGF-1 receptor forms the basis for the therapeutic use of teprotumumab (an IGF-1 monoclonal blocking antibody) in the treatment of thyroid eye disease [10]. Inhibition of the IGF-1 receptor ultimately results in apoptosis of orbital fibroblasts and adipocytes, and a subsequent reduction in proptosis [11]. (See "Treatment of thyroid eye disease", section on 'Initial medical therapy'.)

●Role of T-cells – The following observations suggest that not just TSHR antibodies but T cells also play a role in the development of thyroid eye disease [12,13]:

•In vitro studies of orbital tissue from patients with thyroid eye disease have shown that the infiltrating T cells are activated by orbital tissue fractions.

•Orbital fibroblasts secrete GAG in response to cytokines such as interferon gamma and tumor necrosis factor (TNF)-alpha secreted by helper (CD4+) T cells of the Th1 type.

•Some of the muscle cells and fibroblasts express human leukocyte antigen (HLA) class II antigens, as seen on thyroid cells in patients with autoimmune thyroid disease, which suggests they can present antigen to T cells and resident dendritic cells, thereby serving to initiate or perpetuate the pathological process [12-14].

•T cells isolated from orbital tissue (similar to those isolated from thyroid tissue) have limited V-region genotypes [1], and the same genotypes have been seen in the thyroid and orbital tissues.

●Role of genetics – The evidence for a genetic component to the pathogenesis of Graves' hyperthyroidism applies equally to the associated eye disease. A family history of Graves' disease or Hashimoto's disease, the presence of other autoimmune diseases in the patients and their relatives, and a high percentage of concordance in identical twins (depending on their age), all point toward a major genetic component in these disorders [15]. There are, however, no data confirming a distinct genetic risk that can be ascribed to thyroid eye disease.

Certain HLA haplotypes have been associated with the presence of eye disease [16], but this has not been a common observation and appears more likely to be the same as for all patients with Graves' disease. The HLA gene region contains the genes most associated with Graves' disease itself.

EPIDEMIOLOGY — The epidemiology of thyroid eye disease in most studies of Graves' disease is not well defined. In a large series from a single Italian center, approximately 25 percent of patients with Graves' hyperthyroidism had clinically obvious eye involvement [17]. Most patients (20 percent) had mild disease, whereas 5.8 percent had moderate to severe disease. In another report from Europe, the estimated prevalence of all cases of thyroid eye disease ranged from 9 to 15 per 10,000 persons [18].

Enlargement of orbital muscles is evident in a larger proportion of patients on orbital imaging (eg, ultrasonography, computed tomography [CT], or magnetic resonance imaging [MRI]) [19,20]. In a study of MRI in 17 patients with no clinical findings of thyroid eye disease, 12 had extraocular muscle enlargement, which was bilateral in eight [20]. This type of study suggests that the majority of patients with Graves' disease have eye involvement; however, only a small percentage of individuals progress to clinically apparent eye disease. Preventing such progress may be a result of treating the hyperthyroidism early in the natural course of the disease.

RISK FACTORS — Several factors may increase the risk of thyroid eye disease in patients with Graves' disease [21].

●Sex – Graves' eye disease, like hyperthyroidism, is more common in females than males. However, males who have eye involvement are more likely to have an increase in severity during follow-up [22]. The explanation for this may be that males often have more severe Graves' disease for unclear reasons.

●Smoking – Cigarette smoking is a confirmed risk factor for thyroid eye disease [21,23]. As an example, in a case-control study from Australia, the odds ratio for eye disease was 2.22 in current smokers compared with never smoking [21].

Smoking is associated with an increase in the connective tissue volume of the orbit but not the extraocular muscle volumes [24]. How this might occur is not known, but direct toxic effects of smoke on the inflamed eyes are likely, and immunologic changes have been described in smokers that could affect the autoimmune process [25]. In addition, in vitro data suggest that cigarette smoke stimulates glycosaminoglycan (GAG) production and adipogenesis in a dose-dependent manner [26]. (See 'Pathogenesis' above.)

●Radioiodine therapy – The type of treatment given for Graves' thyroid disease may be a risk factor for thyroid eye disease. In particular, radioiodine therapy is more likely to lead to the development or worsening of eye disease than antithyroid drug therapy or subtotal thyroidectomy. (See "Treatment of thyroid eye disease", section on 'Reversal of hyperthyroidism, if present' and "Radioiodine in the treatment of hyperthyroidism", section on 'Thyroid eye disease'.)

●Thyrotropin receptor antibodies, high levels – High titers of TSH receptor (TSHR) autoantibodies correlate with the presence and severity of extrathyroidal manifestations (thyroid eye disease and dermopathy) of Graves' disease. Even in patients with milder disease, there is an independent correlation between these autoantibodies and the prevalence and course of thyroid eye disease [27].

●Other risks – High serum cholesterol levels correlate with the development of thyroid eye disease [28], and statins have been shown to have a protective effect [29,30]. (See "Treatment of thyroid eye disease", section on 'Other medical therapies'.)

Other possible risk factors for thyroid eye disease include advancing age [21,22], stress [31], and poorly controlled thyroid function [32]. There are case reports of reactivation (or new-onset) thyroid eye disease occurring after coronavirus 2019 (COVID-19) vaccination [33].

CLINICAL FEATURES

Symptoms and signs — Patients may have no ocular symptoms, may be distressed by the appearance of their eyes, or may be symptomatic. The major ocular symptoms include one or more of the following:

●A gritty or foreign object sensation in the eyes

●Excessive tearing that is often made worse by exposure to cold air, wind, or bright lights

●Eye or retro-ocular discomfort or pain

●Blurring of vision

●Diplopia

●Color vision desaturation

●Loss of vision in severe cases

●Periorbital swelling

The characteristic signs of thyroid eye disease are proptosis (exophthalmos), conjunctival inflammation, and periorbital edema (picture 2). The degree of proptosis is dependent on the depth of the orbit and the degree of enlargement of the orbital muscles and orbital fibrous and fatty tissue. The proptosis may be symmetric, but is often asymmetric, and may be accompanied by a sensation of pressure behind the eyeballs. The proptosis may be partially masked by periorbital edema, which is a common accompaniment. In rare cases of very severe disease, there may be corneal ulceration from over exposure [34].

Laboratory findings — There is no disease marker for thyroid eye disease. In most patients, eye involvement occurs in the setting of current or past Graves' hyperthyroidism (low TSH, high free thyroxine [T4] and/or triiodothyronine [T3]), but in approximately 10 percent of patients, hyperthyroidism is absent [4,35]. Such patients are labeled as having "euthyroid" Graves' disease, but they may still have high serum thyroid autoantibody concentrations [36,37]. While some of these patients go on to develop typical Graves' hyperthyroidism over a period of years, some become hypothyroid, and others remain euthyroid [37]. Sometimes thyroid eye disease occurs in patients with hypothyroidism (high TSH, low free T4) due to classical chronic autoimmune thyroiditis (Hashimoto's disease), and these patients may have stimulating TSH receptor (TSHR) antibodies but inadequate thyroid reserve [38].

There is usually a temporal relationship between the thyroid eye disease and the onset of hyperthyroidism. The eye involvement appears before the onset of hyperthyroidism in approximately 20 percent of patients, concurrently in approximately 40 percent, and in the six months after diagnosis in approximately 20 percent [39]. In the remainder, the eye disease first becomes apparent after treatment of the hyperthyroidism, more often in patients treated with radioiodine. (See "Treatment of thyroid eye disease", section on 'Reversal of hyperthyroidism, if present'.)

DIAGNOSIS — In most patients, the diagnosis of thyroid eye disease is obvious because of the combination of the characteristic ocular abnormalities (proptosis, periorbital edema) (picture 2) and hyperthyroidism. It is, however, important to differentiate the eye signs of thyroid eye disease from the nonspecific eye signs of thyroid hormone excess, including lid lag and stare (due to enhanced contraction of the levator palpebrae muscles of the eyelids) without proptosis. The stare may give the appearance of proptosis, when none in fact exists. These signs alone do not indicate the presence of thyroid eye disease and may subside when the hyperthyroidism is treated.

Unilateral thyroid eye disease may be considerably more difficult to diagnose in the absence of thyroid dysfunction and must be differentiated from space-occupying lesions of the orbit, typically with CT (without contrast) or MRI of the orbits. Imaging is also performed in patients with moderate to severe thyroid eye disease to assess the risk of complications (eg, crowding of the optic nerve at the orbital apex), and it is sometimes helpful in the differential diagnosis or in planning for surgery. (See 'Imaging' below.)

DIFFERENTIAL DIAGNOSIS — Eye signs simulating thyroid eye disease can also be present in patients with:

●Orbital cellulitis. (See "Orbital cellulitis".)

●Severe obesity.

●Cushing syndrome.

●Orbital myositis. (See "Overview of diplopia", section on 'Orbital myositis'.)

●Histiocytosis. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

●Myasthenia gravis. (See "Ocular myasthenia gravis".)

●Orbital tumors, including metastatic tumors to the orbit. (See "Optic pathway glioma".)

●Drug-induced ocular muscle myopathy. (See "Drug-induced myopathies".)

EVALUATION — The evaluation of a patient with thyroid eye disease includes laboratory assessment (if not already available), examination of the eyes, and assessment of disease activity and severity.

Laboratory — Thyroid function tests will have already been obtained in most patients. If not available, we measure:

●TSH

●Free T4

●Total T3

●TSH receptor (TSHR) antibodies

Measurement of serum TSHR antibodies can be helpful in confirming an obvious or less than obvious diagnosis and helps assess the severity of the condition and monitoring the patient's response to treatment [27,40].

Eye examination — The classification of disease severity (mild, moderate, severe, sight threatening) (table 1) and activity (table 2) is based on elements of the eye examination (see 'Assessment of disease severity and activity' below). A multidisciplinary approach is recommended with early consultation and comanagement with ophthalmology in all patients with moderate-severe disease.

Physical examination of the eyes of a patient with thyroid eye disease should include:

●Inspection of the conjunctivae and periorbital tissue, looking for conjunctival injection and edema (chemosis) and periorbital edema.

●Determination of the extent to which the upper and lower lids can be closed, because failure of apposition promotes drying and ulceration of the cornea.

●Assessment of the range of motion of the eyes. Impairment of extraocular muscle function is often evident by the finding of dysconjugate gaze during extraocular muscle movement testing. Dysconjugate gaze may lead to double vision, initially on extremes of gaze, and eventually in almost all directions, necessitating use of prism lenses or an eye patch, while awaiting stable fibrosis of the eye muscles before attempting corrective eye muscle (strabismus) surgery.

●Objective measurements of the degree of proptosis, using an exophthalmometer. These instruments permit measurement of the distance between the lateral angle of the bony orbit and an imaginary line tangent to the most anterior part of the cornea. The upper limit of normal is approximately 21 mm in White, 24 mm in Black, and 19 mm in Chinese males (19, 23, and 18 mm in White, Black, and Chinese females, respectively) (table 1) [41]. The values may be as high as 30 mm in patients with severe proptosis.

●Visual acuity and color vision should be assessed by simple reading tests and color charts, and visual fields should be evaluated by confrontation.

Rare patients have extremely severe forms of orbitopathy, which can threaten vision. The forms include subluxation of the globe due to severe proptosis, ulceration or infection of the cornea secondary to an inability to close the lids, and optic neuropathy caused by compression of the optic nerve at the apex of the orbit. (See "Congenital and acquired abnormalities of the optic nerve", section on 'Compression'.)

The correlation between the symptoms and signs of orbitopathy is often poor. While attention to the physical findings is important in considering prognosis and therapy, it is equally important to listen to what the patient says about his or her symptoms and changes in the symptoms. A simple orbitopathy quality-of-life questionnaire has been validated to address this concern [42].

Assessment of disease severity and activity

●Disease severity – The classification of disease severity (mild, moderate, severe, sight threatening) is based on the degree of threat to vision and the severity of proptosis and soft tissue involvement (table 1) [42-44]. It is important to recognize that patients may have severe disease, such as advanced longstanding proptosis, which is no longer active based on a clinical activity score, and therefore unlikely to respond to immunomodulatory therapy. A photographic atlas of eye findings has also been developed, which may be helpful for ophthalmologic assessment [34].

The older classification system, NO SPECS, with initials representing various features of thyroid eye disease, is no longer used but still included in some clinical trials.

●Disease activity – Activity of disease, assessed using the clinical activity score (CAS) (table 2), is useful for determining therapy and gauging response to that therapy [43]. Patients with a score of 3 or more are classified as having active disease and may be more likely to respond to immunomodulatory therapy, such as glucocorticoids. The CAS is also included in most clinical trials.

The CAS can also be extended to include change over time by adding the following three criteria:

•Increase in proptosis (≥2 mm)

•Decreased eye movements (≥5 degrees)

•Decreased visual acuity (≥1 line on the Snellen eye chart)

Imaging — In moderate to severe disease, baseline imaging of the orbits, with noncontrast CT or MRI, gives an assessment of the risk of future optic nerve compression by enlarged extraocular muscle at the orbit apex, provides an independent measurement of proptosis and orbital fat accumulation, and is sometimes helpful in the differential diagnosis. (See 'Differential diagnosis' above.)

We prefer CT (without contrast) scanning because of the extensive normative data available on intraorbital volumes and the better bone visualization compared with MRI (table 1 and image 1) [45], although MRI is being increasingly utilized in patients with thyroid eye disease. Iodinated contrast should be used with caution in patients with hyperthyroidism who are not receiving methimazole, since the iodine can worsen the hyperthyroidism. (See "Iodine-induced thyroid dysfunction", section on 'Iodine-induced hyperthyroidism'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (The Basics)")

●Beyond the Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient education: Antithyroid drugs (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – The main autoantigen in thyroid eye disease is the thyroid-stimulating hormone (TSH) receptor (TSHR), which is expressed in orbital fibroblasts and forms a functional complex with the insulin-like growth factor 1 (IGF-1) receptor. Stimulating TSHR antibodies and activated T cells play an important role in pathogenesis of thyroid eye disease by activating orbital fibroblasts and adipocytes. The volume of both the extraocular muscles and orbital connective and adipose tissue is increased, due to inflammation, adipogenesis, and the accumulation of hydrophilic glycosaminoglycans (GAG; principally hyaluronic acid) in these tissues. GAG secretion by fibroblasts is increased by activated T cell cytokines and by the activation of the receptors for TSH and IGF-1. (See 'Pathogenesis' above.)

●Epidemiology – Thyroid eye disease occurs in 20 to 25 percent of patients with Graves' disease. (See 'Introduction' above and 'Epidemiology' above.)

●Risk factors – Thyroid eye disease, like hyperthyroidism, is more common in females than males. Risk factors for the development of thyroid eye disease include smoking, prior radioiodine therapy, and possibly high serum cholesterol. (See 'Risk factors' above.)

●Clinical features – The major ocular symptoms include one or more of the following: a sense of irritation in the eyes; excessive tearing that is often made worse by exposure to cold air, wind, or bright lights; eye or retro-ocular discomfort or pain; blurring of vision; diplopia; and occasionally, loss of vision. The characteristic signs of thyroid eye disease are proptosis and periorbital edema. These findings typically occur in the setting of current or past Graves' hyperthyroidism (low TSH, high free thyroxine [T4] and/or triiodothyronine [T3]). (See 'Clinical features' above.)

●Diagnosis – In most patients, the diagnosis of thyroid eye disease is obvious because of the combination of the characteristic ocular abnormalities (proptosis, periorbital edema) (picture 2) and hyperthyroidism. (See 'Diagnosis' above.)

●Evaluation

•Thyroid function tests – Review prior thyroid tests. If thyroid tests are not available, measure (see 'Laboratory' above):

-TSH

-Free T4

-Total T3

-TSHR antibodies

•Eye examination – The classification of disease severity (mild, moderate, severe, sight threatening) (table 1) and activity (table 2) is based on elements of the eye examination. A multidisciplinary approach is recommended with early consultation and comanagement with ophthalmology in all patients with moderate-severe disease. (See 'Eye examination' above and 'Assessment of disease severity and activity' above.)

•Imaging – In moderate to severe disease, noncontrast CT or MRI imaging may give an assessment of the risk of future optic nerve compression by enlarged extraocular muscle at the orbital apex and is sometimes helpful in the differential diagnosis. (See 'Imaging' above.)