Pathogenesis and clinical features of Graves' ophthalmopathy (orbitopathy)

INTRODUCTION The eye disease often associated with Graves' thyroid disease is referred to as Graves' ophthalmopathy. However, it is primarily a disease of the orbit and has also been called Graves' orbitopathy. This topic review will provide an overview of the pathogenesis and clinical features of Graves' ophthalmopathy, which is an autoimmune disease of the retroorbital tissues. Treatment of this disorder is discussed separately.

PATHOGENESIS The pathogenesis of Graves' ophthalmopathy is becoming more clearly understood. The volume of both the extraocular muscles and retroorbital 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 such as tumor necrosis factor (TNF) alpha and interferon gamma, implying that T-cell activation is an important part of this immunopathology. The accumulation of GAG causes a change in osmotic pressure, which in turn leads to a fluid accumulation and an increase in pressure within the orbit. These changes displace the eyeball forward and can also interfere with the function of the extraocular muscles and the venous drainage of the orbits.

On histologic examination, the extraocular muscles are swollen, and some muscle fibers show loss of striation, fragmentation, and infiltration with lymphocytes, most of which are T lymphocytes. The following observations suggest that these T cells may play a central role in the development of ophthalmopathy

  • In vitro studies of retroorbital tissue from patients with Graves' ophthalmopathy have shown that the infiltrating T cells are activated by retro-orbital tissue fractions.
  • Retroorbital fibroblasts secrete GAG in response to cytokines such as interferon gamma and TNF alpha secreted by helper (CD4+) T cells of the Th1 type.
  • Some of the muscle cells and fibroblasts express 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
  • T cells isolated from retroorbital tissue (similar to those isolated from thyroid tissue) have limited V-region genotypes  and the same genotypes have been seen in the thyroid and retro-orbital tissues

Autoantibodies to various components of retroorbital tissues, particularly components of extraocular muscle cells, have been detected in the serum of patients with Graves' ophthalmopathy. However, these are secondary markers of the inflammatory process and not unique to Graves' disease

Antigen The initial activation of T cells in Graves' ophthalmopathy is now thought to be initiated by thyrotropin (TSH) receptor antigen. Mechanistic observations, plus the fact that Graves' hyperthyroidism and Graves' ophthalmopathy often occur concomitantly, have led to the suggestion that activation of the immune system must be secondary to an antigen shared by both tissues. The presence of TSH receptor mRNA and protein in orbital fibroblasts and adipocytes has provoked speculation that this receptor may be the antigen involved in the pathogenesis of ophthalmopathy

Not only can TSH receptor mRNA and protein be detected in orbital fibroblasts and adipocytes but pre-adipocytes from patients with Graves' ophthalmopathy may also express more TSH receptor mRNA and produce more cyclic AMP in response to TSH than do similar cells from normal subjects. These cells are thought to be derived from a subset of fibroblasts and differentiate ultimately into adipocytes.

Although evidence for extra-thyroidal TSH receptor expression is widespread the evidence that TSHR expression is greater in the retro-orbital tissues of Graves' patients when compared to that found elsewhere is compelling. In fact, only small amounts of TSH receptor protein are found in orbital fibroblasts from normal subjects  and it disappears when the fibroblasts are cultured in vitro for prolonged periods. Hence, in addition to TSHR antigen directly activating specific T cells, these observations suggest that TSHR expression in vivo is dependent upon a stimulus external to the eye such as TSH receptor antibodies.

The role of TSH receptor antibodies in the pathogenesis of Graves' hyperthyroidism is no longer in doubt.  The observation of a correlation between the severity of ophthalmopathy and serum TSH receptor antibody concentrations is also compatible with the hypothesis that these antibodies, and not just T cells, may play an important role in the eye disease by activating fibroblast and adipocyte TSH receptors  Low levels of TSHR stimulation have a positive effect on TSHR mRNA and expression

Other autoantigens may be involved in the pathogenesis of ophthalmopathy  but they are most likely to be secondary in importance. As an example, thyroglobulin (of thyroid origin) was identified in extracts of orbital tissue from three patients with Graves' ophthalmopathy but not in two patients with no thyroid or eye disease

RISK FACTORS Several factors may increase the risk of ophthalmopathy in patients with Graves' disease.

Genetics The evidence for a genetic component to the pathogenesis of Graves' hyperthyroidism applies equally to the ophthalmopathy. 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 all point toward a major genetic component in these disorders There is, however, no confirmed evidence of a distinct genetic risk for eye disease. While families have been described with a number of individuals affected with ophthalmopathy  in practice it is unusual to obtain such a history

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

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

Smoking Cigarette smoking is a confirmed risk factor for Graves' ophthalmopathy. As an example, in a large study from the Netherlands, the odds ratio for ophthalmopathy was 7.7 in smokers compared with nonsmokers. Furthermore, among patients with ophthalmopathy, smokers were more likely to have severe disease than nonsmokers. Smoking is associated with an increase in the connective tissue volume of the orbit, but not the extraocular muscle volumes. 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

Type of treatment for Graves' disease The type of treatment given for Graves' disease may be a risk factor for ophthalmopathy. In particular, radioiodine therapy may be more likely to lead to the development or worsening of ophthalmopathy than antithyroid drug therapy or subtotal thyroidectomy.

Others Other possible risk factors for Graves' ophthalmopathy include advancing age (>60 years)  and stress

EPIDEMIOLOGY Approximately 20 to 25 percent of patients with Graves' hyperthyroidism have clinically obvious Graves' ophthalmopathy, not just the eye signs of thyroid hormone excess (lid retraction and stare), at the time of diagnosis of the hyperthyroidism. However, many more patients with Graves' hyperthyroidism have evidence of ophthalmopathy, primarily enlargement of retroocular muscles, on ultrasonography, computed tomography (CT), or magnetic resonance (MR) imaging of the orbits. In a study of MR imaging in 17 patients with no clinical findings of ophthalmopathy: 12 had extraocular muscle enlargement, which was bilateral in 8. The estimated incidence of Graves' ophthalmopathy in the general population is 16 women and 3 men per 100,000 population per year

Similarly, most patients with ophthalmopathy have evidence of thyroid disease, but in approximately 10 percent of patients it is not obvious. Such patients are labeled as having "euthyroid" Graves' disease, but they often have high serum antithyroid autoantibody concentrations or circulating thyroid-specific T cells. Rarely, ophthalmopathy occurs in patients with chronic autoimmune thyroiditis (Hashimoto's disease).

There is usually a temporal relationship between the ophthalmopathy and the onset of hyperthyroidism. The ophthalmopathy appears before the onset of hyperthyroidism in approximately 20 percent of patients, concurrently in about 40 percent, and in the six months after diagnosis in about 20 percent. In the remainder, the eye disease first becomes apparent after treatment of the hyperthyroidism, more often in patients treated with radioiodine

CLINICAL MANIFESTATIONS The characteristic signs of Graves' ophthalmopathy are proptosis and periorbital edema.  The patient may have no ocular symptoms, may be distressed by the appearance of his or her eyes, or may be symptomatic. The major 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 retroorbital discomfort or pain; blurring of vision; diplopia; and occasionally loss of vision.

The degree of proptosis (exophthalmos) is dependent on the depth of the orbit and the degree of enlargement of the retroocular muscles and retroorbital fibrous and fatty tissue. The proptosis is usually symmetric, but can be asymmetric, and may be accompanied by a sensation of pressure behind the eyeballs. The proptosis may be masked by periorbital edema, which is a common accompaniment.

Physical examination Many patients with hyperthyroidism have lid retraction secondary to thyroid hormone excess, leading to stare and lid lag (due to contraction of the levator palpabrae muscles of the eyelids). The stare may give the appearance of proptosis, when none in fact exists ("apparent proptosis"). These signs alone do not indicate the presence of ophthalmopathy, and subside when the hyperthyroidism is treated.

Physical examination of the eyes of a patient with Graves' ophthalmopathy 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 an inability to achieve or maintain convergence. Limitation of upward gaze may be present, leading to a characteristic head-back position in order to see ahead. Muscle dysfunction also leads to double vision, initially on extremes of gaze, and eventually in almost all directions, necessitating use of appropriate lenses or an eye patch.
  • 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 20 mm in whites and 22 mm in blacks. 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 extreme forms of ophthalmopathy, 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.

The correlation between the symptoms and signs of ophthalmopathy 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. As an example, a physician may be tempted to intervene in some way because the patient has rather marked proptosis, even though there are no severe symptoms.

Assessment of severity The type of examination described above provides the basis for the routine evaluation of most patients. However, for improved objectivity, a classification of the eye changes of Graves' disease developed by the American Thyroid Association has become widely used  The first letters of each category constitute the mnemonic NO SPECS NO connotes absence or mild degree of involvement; SPECS the more serious degrees of involvement.

The severity therefore ranges from 0 to 7.

  • Class 0 No symptoms or signs
  • Class I Only signs, no symptoms (eg, lid retraction, stare, lid lag)
  • Class II Soft tissue involvement
  • Class III Proptosis
  • Class IV Extraocular muscle involvement
  • Class V Corneal involvement
  • Class VI Sight loss (optic nerve involvement)

However, NO SPECS is not always satisfactory for prospective objective assessment of orbital changes, and determining an overall activity score is sometimes more helpful. This is done by assigning 1 point for the presence of each of the following findings:

  • Spontaneous retrobulbar pain
  • Pain on eye movement
  • Eyelid erythema
  • Conjunctival injection
  • Chemosis
  • Swelling of the carbuncle
  • Eyelid edema

A photographic atlas of eye findings has also been developed which may be helpful for ophthalmologic assessment

Some reports suggest that urinary glycosaminoglycan concentrations and somatostatin-receptor imaging with 111-indium-labeled pentetreotide correlate well with the clinical activity of Graves' ophthalmopathy. The uptake of this radionuclide has also been suggested to have value in predicting responsiveness to anti-inflammatory therapy in patients with ophthalmopathy

DIFFERENTIAL DIAGNOSIS The diagnosis of Graves' ophthalmopathy in most patients is obvious, because of the combination of the characteristic ocular abnormalities described above and hyperthyroidism. It is, however, important to differentiate the eye signs of Graves' ophthalmopathy from the eye signs of thyroid hormone excess (stare and lid lag), which can also occur in other forms of hyperthyroidism such as toxic multinodular goiter. Bilateral eye signs simulating Graves' ophthalmopathy can also be present in patients with severe obesity, Cushing's syndrome, orbital myositis, histiocytosis, myasthenia gravis, and very rarely orbital tumors

Unilateral Graves' ophthalmopathy may be considerably more difficult to diagnose in the absence of thyroid dysfunction, and must be differentiated from space-occupying lesions of the orbit.

When necessary, the diagnosis can be confirmed by ultrasonography, CT or MRI of the orbits, which show swelling of the extraocular muscles and increased retroorbital fat in virtually all patients with Graves' ophthalmopathy We prefer CT because of the extensive normative data available on intraorbital volumes, the better bone visualization, and the lower cost compared with MRI. It is important not to inject iodinated contrast material in patients with Graves' disease especially if radioiodine therapy is contemplated.

In patients in whom the diagnosis is not in doubt, the only testing that is necessary is measurement of serum TSH, free thyroxine, and TSHR antibodies. Measurements of serum TSH receptor 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

SUMMARY AND RECOMMENDATIONS Graves' ophthalmopathy, an autoimmune disease of the retroorbital tissues, occurs in 20 to 25 percent of patients with Graves' disease (more commonly in women than men). Important features include:

  • The initial activation of T cells in Graves' ophthalmopathy is thought to be initiated by thyrotropin (TSH) receptor antigen.
  • TSH receptor antibodies, and not just T cells, may play an important role in the eye disease by activating fibroblast and adipocyte TSH receptors.
  • The volume of both the extraocular muscles and retroorbital 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.
  • Risk factors for the development of Graves' ophthalmopathy include genetics, female sex, smoking, and possibly radioiodine therapy.
  • Ophthalmopathy appears before the onset of hyperthyroidism in approximately 20 percent of patients, concurrently in about 40 percent, in the six months after diagnosis in about 20 percent, and after treatment for Graves' hyperthyroidism in the remainder (most commonly after radioiodine therapy).
  • Severity of disease can be assessed using the NO SPECS classification or with an overall activity score.