Review of Systems for Graves’ Disease

Weight loss, despite normal eating habits
Enlargement of thyroid gland (goiter)
Change in menstrual cycles
Erectile dysfunction or reduced libido
Frequent bowel movements/diarrhea
Bulging eyes
Double vision
Thick, red skin, usually on shins or top of  feet
Anxiety and irritability
Difficulty sleeping
Rapid or irregular heartbeat
Fine tremor of hands or fingers
Increase in perspiration

NO SPECS: Werner Classification of Ocular Findings in Graves’ Disease9
 N    No signs or symptoms
 O    Only signs
 S    Soft tissue involvement (signs and   
 P    Proptosis
 E    Extraocular muscle involvement
 C    Corneal involvement
 S    Sight loss (due to optic nerve

Associated Factors That Modify GD/TED5,6

Other Autoimmune Disorders
People with other disorders of the immune system, such as type 1 diabetes or rheumatoid arthritis, have an increased risk. Optimal control of these other conditions is essential.

Emotional or Physical Stress
Stressful life events or illness may act as a trigger for the onset of GD/TED among people who are genetically susceptible.

Thyroid Function Status
Control of thyroid function could mitigate severity. Monitor thyroid function every 4-6 weeks during initial phase of TED.

Tobacco Use
Smoking has been identified as an important contributing environmental factor in the development of GD. Retrospective studies suggest that stopping tobacco use is associated with less severe TED, especially with regard to diplopia and proptosis.

The endocrine system operates like a physiological factory: hormones are produced and stored until the body needs them, then delivered through the bloodstream to specific targets, like organs, tissues or cells. The thyroid gland, which affects metabolism, growth and maturation, is one of the most valuable players in this process.

The state of normal thyroid function is called euthyroidism, but abnormalities of the thyroid gland are fairly common, affecting 1% to 5% of the population, mostly women.1 Disorders of the thyroid gland cause hormone imbalance, which can complicate personal health in many ways.

The Axis

The thyroid gland is attached to the lower part of the larynx and upper part of the trachea. It has two sides (or “lobes”), each about 4cm long and 1cm to 2cm wide, which are connected by a narrow isthmus.2 The thyroid gland is influenced by the pituitary gland, which produces thyroid-stimulating hormone (TSH), and the hypothalamus, a small part of the brain above the pituitary, which produces thyrotropin-releasing hormone (TRH).2

The hypothalamus and pituitary detect low levels of thyroid hormones in the blood. When TRH is released, it stimulates the pituitary to release TSH. In turn, increased levels of TSH stimulate the thyroid gland to produce more thyroid hormone, thereby returning the level of thyroid hormone in the blood back to normal.2,3 The three structures and the hormones they produce make up the hypothalamic-pituitary-thyroid axis.

Graves’ and TED

Thyrotropin is a glycoprotein that stimulates the thyroid gland to produce and secrete the hormone thyroxine. Graves’ disease (GD) is an autoimmune disorder characterized by hyperthyroidism—the overproduction of thyroid hormones—due to circulating autoantibodies. Thyroid-stimulating immunoglobulins (TSIs) bind to and activate thyrotropin receptors, causing the gland to grow and its follicles to increase synthesis of thyroid hormone.4 While several conditions may result in hyperthyroidism, GD is the most common. Because thyroid hormones affect multiple body systems, signs and symptoms associated with GD are wide ranging.

Thyroid eye disease (TED), which has also been referred to as Graves’ orbitopathy or ophthalmopathy, affects up to 60% of patients with GD. Despite our detailed understanding of the etiology of hyperthyroidism in GD, the pathogenesis of TED remains uncertain.4 This has limited the development of targeted therapies, particularly those that alter the course of TED.

Signs of TED

Evaluate the patient for upper eyelid abnormalities, such as retraction and von Graefe's sign.
TED usually begins with orbital/periorbital inflammation, which may be progressive and can last for six months to two years.5 Expansion of the extraocular muscles and orbital fat occurs during this period, and can result in proptosis, eyelid abnormalities, extraocular muscle motility deficits and compressive optic neuropathy.

In GD, the onset of hyperthyroidism and TED usually occur within 18 months of one another. A small minority of patients never develop thyroid dysfunction and are referred to as having “euthyroid GD.”4,5  The majority of patients with TED have mild, self-limiting disease. Nonetheless, even patients with mild disease experience a reduced quality of life.

Diagnostic Work-up

Diagnostic testing of free T4 (thyroxine) and TSH or serum TSH (thyrotropin) are highly sensitive and specific. Serum TSH is useful to establish a diagnosis of hyperthyroidism or hypothyroidism. Usually, the TSH is low in hyperthyroidism and high in hypothyroidism. Radiologic testing using a small amount of radioactive iodine may be implemented. A high uptake of radioactive iodine indicates that the thyroid gland is overproducing hormones.

Neuroimaging may be necessary if a diagnosis of TED cannot be established clinically. MRI is more sensitive than CT in showing compressive optic neuropathy. CT scanning usually reveals thick extraocular muscles with tendon sparing. The inferior rectus and medial rectus muscles are usually involved.

Treatment and Management

• Graves’ Disease. Treatment of GD centers on correction of the thyrotoxic state. Normalization of thyroid hormone levels can be achieved with agents that block the synthesis of thyroid hormones or by treatment with radioactive iodine.  Systemic beta-adrenergic blockers are prescribed to reduce the effect of hormones on the body.4,5  

• Mild/Moderate TED. Most patients with TED can be observed, with the follow-up interval depending on disease status. Evaluation for corneal exposure, optic neuropathy and diplopia should be performed at these visits. Visual field and color vision testing may help in early detection of visual loss.4,5

The use of prism may be beneficial to patients with diplopia, if the deviation is small-angle and relatively comitant. If large-angle and/or incomitant, tape occlusion of one lens or segment of the glasses may be helpful. If this doesn’t work, an occluder or vaulted eye patch (with care not to touch the cornea or compress the orbit) may be indicated. If a patient has dry eye symptoms, prescribe preservative-free artificial tears during the day and lubricating ointment at night, and consider punctal plugs.

• Severe TED. Systemic steroids represent the primary treatment for patients with moderate to severe, active TED. An IV steroid of 250mg of methylprednisolone given weekly over six weeks can be effective and have fewer side effects compared to oral steroids.8 Surgical decompression of the orbit may be considered when vision is threatened by compressive optic neuropathy. Orbital radiotherapy remains an adjunctive strategy. Targeted immunotherapies have the potential to alter disease progression, but further evidence is needed to establish safety and efficacy.5,7

Some of the immunosuppressive agents are azathioprine, cyclosporine and methotrexate. In severe cases of TED, treatment should be customized for each patient in close collaboration with the endocrinologist.8

Patient education

Patients living with TED should be advised that the condition usually runs a self-limited, but prolonged, course over one or more years, and no immediate cure is available. In addition, we must encourage patients to stop smoking, to decrease the risk of congestive orbitopathy. Sleeping with the head of the bed elevated may decrease morning lid edema.

TED likely involves both genetic and environmental factors. Until ongoing research establishes a target antigen, clinicians must focus on early signs and symptoms, along with timely treatment and management.

1. Furszyfer J, Kurland LT, McConahey WM, Elveback LR. Graves’ disease in Olmsted County, Minnesota, 1935 through 1967. Mayo Clin Proc. 1970 Sep;45(9):636-44.
2. Cummings CW, Frederickson JM, Harker LA, et al. Thyroid anatomy. In: Otolaryngology - Head and Neck Surgery. 3rd ed. St. Louis, Mo: Mosby;1998:2445-9.
3. Thyroid gland. In: Williams PL, Bannister LH, Berry MM, et al., eds. Gray’s Anatomy. 38th ed. New York: Churchill Livingstone;1995:1891-6.    
4. Ing E, Abuhaleeqa K. Graves’ ophthalmopathy (thyroid-associated orbitopathy). Clin Surg Ophthalmol. 2007;25:386-92.
5. Bartalena L, Pinchera A, Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev. 2000 Apr;21(2):168-99.
6. Brix TH, Kyvik KO, Christensen K, Hegedus L. Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts. J Clin Endocrinol Metab. 2001 Feb;86(2):930-4.
7. Genovese BM, Noureldine SI, Gleeson EM, Tufano RP, Kandil E. What is the best definitive treatment for graves’ disease? A systematic review of the existing literature. Ann Surg Oncol. 2013 Feb;20(2):660-7.
8. Smith D, Cockerham KP, Douglas RS. Thyroid eye disease: Current and Emerging Therapies. EyeNet. 2011 Nov/Dec;31-3.
9. NJ Friedman, PK Kaiser. Orbit. In: Essentials in Ophthalmology. 1st ed. Philadelphia:Saunders Elsevier;2007:113 -24.