INTRODUCTION — Graves' orbitopathy is an autoimmune disease of the retroocular tissues occurring in patients with Graves' disease. Although it has often been referred to as Graves' ophthalmopathy, or simply thyroid eye disease (TED), it is primarily a disease of the orbit and is better termed Graves' orbitopathy. This topic review will provide an overview of the pathogenesis, clinical features, and diagnosis of Graves' orbitopathy. Treatment of this disorder is discussed separately. (See "Treatment of Graves' orbitopathy (ophthalmopathy)".)

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 and appears to be closely aligned with the insulin-like growth factor 1 (IGF-1) receptor. TSHR antibodies and activated T cells also play an important role in the pathogenesis of Graves' orbitopathy by activating retroocular fibroblast and adipocyte TSHR and IGF-1 receptors and initiating a retro-orbital inflammatory environment [1].

The volume of both the extraocular muscles and retroocular connective tissue is increased, due to fibroblast proliferation, inflammation, and the accumulation of hydrophilic glycosaminoglycans (GAG), mostly hyaluronic acid [2,3]. 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 retroocular adipogenesis, displace the eyeball forward, leading to extraocular muscle dysfunction and impaired venous drainage (figure 1 and image 1).

●Graves' orbitopathy antigen – The TSHR is the prime antigen for Graves' orbitopathy. Immunization of mice with the TSHR induces retroocular adipogenesis, an inflammatory infiltrate, and GAG accumulation [4]. TSHR mRNA and protein can be detected in orbital fibroblasts and adipocytes, and preadipocytes from patients with Graves' orbitopathy may express more TSHR mRNA and produce more cyclic adenosine monophosphate (cAMP) in response to TSH than do similar cells from normal individuals [5].

Although evidence for extrathyroidal TSHR expression is widespread [6], the evidence that TSHR expression is greater in the retroocular 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 enhanced by an external stimulus from the local inflammatory cells or directly by TSHR antibodies.

●Role of TSH receptor autoantibodies – High titers of thyrotropin receptor autoantibodies have long been known to correlate with the presence and severity of extrathyroidal manifestations (orbitopathy and dermopathy) of Graves' disease. As the measurement of these antibodies has become more precise, it appears that even in patients with milder disease, there is an independent correlation between these autoantibodies and the prevalence and course of orbitopathy [1].

There also appears to be significant crosstalk between the TSHR and the IGF-1 receptor in retroocular fibroblasts, such that activation of the TSH receptor by TSH receptor autoantibodies leads to IGF-1 signal transduction and a synergistic effect on GAG production occurs after activation of both receptors [7,8]. This crosstalk between the TSH receptor and the IGF-1 receptor forms the basis for the therapeutic use of teprotumumab, an IGF-1 receptor inhibitor, in the treatment of Graves' orbitopathy [9]. (See "Treatment of Graves' orbitopathy (ophthalmopathy)", section on 'Teprotumumab'.)

●Role of T-cells – The following observations suggest that not just TSHR antibodies but T cells also play a role in the development of orbitopathy [10-12]:

•In vitro studies of retroocular tissue from patients with Graves' orbitopathy have shown that the infiltrating T cells are activated by retroocular tissue fractions.

•Retroocular 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 perpetuate if not initiate the pathological process [10-12].

•T cells isolated from retroocular tissue (similar to those isolated from thyroid tissue) have limited V-region genotypes [13,14], and the same genotypes have been seen in the thyroid and retroocular tissues.

EPIDEMIOLOGY — The epidemiology of Graves' orbitopathy is not well described. In a large series from a single Italian center, approximately 20 to 25 percent of patients with Graves' hyperthyroidism had clinically obvious Graves' orbitopathy [15]. Most patients had mild disease, whereas approximately 5 percent had moderate to severe disease. In another report from Europe, the estimated prevalence of all cases of Graves' orbitopathy ranged from 9 to 15 per 10,000 persons [16].

Enlargement of retroocular muscles is evident in a larger proportion of patients on orbital imaging (eg, ultrasonography, computed tomography [CT], or magnetic resonance imaging [MRI]) [17,18]. In a study of MRI in 17 patients with no clinical findings of orbitopathy, 12 had extraocular muscle enlargement, which was bilateral in eight [18].

RISK FACTORS — Several factors may increase the risk of orbitopathy in patients with Graves' disease [19].

Genetics — The evidence for a genetic component to the pathogenesis of Graves' hyperthyroidism applies equally to the associated orbitopathy. 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 [20]. There is, however, no confirmed, reproducible evidence of a distinct genetic risk for eye disease itself.

Certain human leukocyte antigen (HLA) haplotypes have been associated with the presence of eye disease [21], but this has not been a common observation and appears more likely to be the same as for all patients with Graves' disease.

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

Smoking — Cigarette smoking is a confirmed risk factor for Graves' orbitopathy [19,23]. As an example, in a case-control study from Australia, the odds ratio for orbitopathy was 2.22 in current smokers compared with never smoking [19].

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 orbitopathy. In particular, radioiodine therapy may be more likely to lead to the development or worsening of orbitopathy than antithyroid drug therapy or subtotal thyroidectomy. (See "Treatment of Graves' orbitopathy (ophthalmopathy)", section on 'Reversal of hyperthyroidism, if present' and "Radioiodine in the treatment of hyperthyroidism", section on 'Moderate to severe orbitopathy'.)

Other risks — Other possible risk factors for Graves' orbitopathy include advancing age [19,22], stress [20,27], and poorly controlled thyroid function [28].

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 retroocular discomfort or pain

●Blurring of vision

●Diplopia

●Color vision desaturation

●Loss of vision in severe cases

The characteristic signs of Graves' orbitopathy are proptosis (exophthalmos), tearing, and periorbital edema (picture 2). The degree of proptosis is dependent on the depth of the orbit and the degree of enlargement of the retroocular muscles and retroocular 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 more severe disease, there may be severe conjunctival inflammation and ulceration from over exposure [29].

Laboratory findings — In most patients, orbitopathy 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, Graves' hyperthyroidism is absent [2,30]. Such patients are labeled as having "euthyroid" Graves' disease, but they may still have high serum thyroid autoantibody concentrations or circulating thyroid-specific T cells [31,32]. While some of these patients go on to develop typical Graves’ hyperthyroidism over a period of years, some become hypothyroid, and others remain euthyroid [32]. Sometimes orbitopathy 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 [33].

There is usually a temporal relationship between the orbitopathy and the onset of hyperthyroidism. The orbitopathy 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 [34]. In the remainder, the eye disease first becomes apparent after treatment of the hyperthyroidism, more often in patients treated with radioiodine. (See "Treatment of Graves' orbitopathy (ophthalmopathy)", section on 'Reversal of hyperthyroidism, if present'.)

DIAGNOSIS — In most patients, the diagnosis of Graves' orbitopathy 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 Graves' orbitopathy 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 orbitopathy and subside when the hyperthyroidism is treated.

Unilateral Graves' orbitopathy 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 computed tomography (CT) or magnetic resonance imaging (MRI) of the orbits. Imaging is also performed in patients with moderate to severe Graves' orbitopathy to assess the risk of complications (see 'Imaging' below) and is sometimes helpful in the differential diagnosis.

DIFFERENTIAL DIAGNOSIS — Eye signs simulating Graves' orbitopathy can also be present in patients with:

●Orbital cellulitis (see "Orbital cellulitis")

●Severe obesity

●Cushing's 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")

●Statin-induced extraocular muscle myopathy (see "Statin muscle-related adverse events", section on 'Clinical features')

EVALUATION — The evaluation of a patient with Graves' orbitopathy 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 diagnosis but also in assessing the severity of the condition and monitoring the patient's response to treatment [1,35].

Eye examination — Physical examination of the eyes of a patient with Graves' orbitopathy 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 21 mm in White and 24 mm in Black males (19 and 23 mm in White and Black females, respectively) (table 1). 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. If any evidence of impairment is obtained, the patient should be evaluated by an ophthalmologist.

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 anomalies 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 [36].

Assessment of disease activity and severity — Disease activity is commonly assessed using a seven-point clinical activity score (CAS) (table 2) [37]. Patients with a score of 3 or more are classified as having active disease and are therefore more likely to respond to immunomodulatory therapy, such as corticosteroids. The CAS is also used to monitor response to therapy and is 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)

Disease severity can be assessed using a different scale, based on the degree of threat to vision and the severity of proptosis and soft tissue involvement (table 1) [37]. It is important to recognize that patients may have severe disease, such as advanced longstanding proptosis, which is no longer active based on the CAS, 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 [29].

Another classification system is the European Group of Graves' Orbitopathy (EUGOGO) classification [38]. The older classification system, NO SPECS, with initials representing various features of Graves' orbitopathy, is no longer used but still included in some clinical trials.

Imaging — In moderate to severe disease, baseline imaging of the orbits, commonly with noncontrast computed tomography (CT), 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 retroocular fat accumulation, and is sometimes helpful in the differential diagnosis. (See 'Differential diagnosis' above.)

We prefer CT scanning because of the extensive normative data available on intraorbital volumes and the better bone visualization compared with magnetic resonance imaging (MRI) (table 1 and image 1) [39]. It is important not to inject iodinated contrast material in patients with Graves' disease, since the iodine can worsen the hyperthyroidism and can interfere with planned radioiodine therapy for 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

●Graves' orbitopathy, an autoimmune disease of the retroocular tissues, occurs in 20 to 25 percent of patients with Graves' disease. (See 'Introduction' above and 'Epidemiology' above.)

●The main autoantigen is the thyroid-stimulating hormone (TSH) receptor (TSHR), which is expressed primarily in the thyroid but also in adipocytes, fibroblasts, and a variety of additional sites. TSHR antibody and activated T cells play an important role in pathogenesis of Graves' orbitopathy by activating retroocular fibroblasts and adipocytes. The volume of both the extraocular muscles and retroocular connective and adipose tissue is increased, due to inflammation 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 insulin-like growth factor-1 (IGF-1). (See 'Pathogenesis' above.)

●Risk factors for the development of Graves' orbitopathy include genetics, female sex, smoking, and prior radioiodine therapy. (See 'Risk factors' above.)

●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 retroocular discomfort or pain; blurring of vision; diplopia; and occasionally, loss of vision. The characteristic signs of Graves' orbitopathy are proptosis and periorbital edema. (See 'Symptoms and signs' above.)

●In the majority of patients, orbitopathy 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, Graves' thyroid disease is absent. Orbitopathy appears before the onset of hyperthyroidism in approximately 20 percent of patients, concurrently in approximately 40 percent, in the six months after diagnosis in approximately 20 percent, and after treatment for Graves' hyperthyroidism in the remainder (most commonly after radioiodine therapy). (See 'Laboratory findings' above.)

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

●In moderate to severe disease, noncontrast computed tomography (CT) scanning 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.)

●Activity of disease, assessed using the clinical activity score (CAS) (table 2), is useful for determining therapy and gauging response to that therapy. Severity of disease is an independent measure that assesses threat to vision and the degree of proptosis and soft tissue involvement (table 1). (See 'Assessment of disease activity and severity' above.)