Graves' Disease

Hyperactive
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Diagnosis and reasoning

This 48-year-old woman complains of a constellation of symptoms which form an almost textbook presentation of thyrotoxicosis; examination reinforces this impression, while also revealing a diffuse, non-tender goiter and ophthalmic signs. Biochemistry confirms the presence of hyperthyroidism by revealing decreased levels of serum thyroid stimulating hormone (TSH), along with elevated total T3 and free T4 fractions. The key causes of hyperthyroidism include Graves’ disease (GD), toxic multinodular goiter, toxic adenoma, and thyroiditis; in this specific case though, the first of these appears to be the overwhelming possibility. For thoroughness, a thyroid ultrasound should be ordered, to both confirm the absence of nodules, and also establish a baseline, as individuals with GD have a higher risk of thyroid cancer vis-a-vis the general population. Sonography in turn reveals a diffusely enlarged and hypoechogenic gland, with increased vascularity and no nodules; when considered along with the biochemical evidence of hyperthyroidism and clinical findings suggestive of Graves ophthalmopathy (GO), the diagnosis of GD can be established. Measurement of TSH receptor antibody (TRAb) levels, and radioisotope imaging of the thyroid are of little additional value here; in fact, the latter would merely result in unnecessary exposure to radiation. The activity and severity of the GO should also be determined, as this will direct key therapeutic decisions; this patient has active moderate ophthalmopathy, as per the standardized assessment criteria. Thus, high-dose intravenous (IV) glucocorticoids are essential; quick restoration and maintenance of euthyroidism is also crucial to prevent further progression of the orbitopathy. In this regard, note that radioactive iodine is contraindicated in active moderate GO; while both thyroidectomy and antithyroid drugs are therapeutic possibilities, the latter is probably a better first option, given that she is a professional singer. Surgery would run the risk of injury to the recurrent or superior laryngeal nerve, with the potential for deleterious effects on her voice.


Discussion

Graves' disease (GD) is both the most common autoimmune disorder of the thyroid gland, as well as the most common overall cause of hyperthyroidism, accounting for 50-80% of all cases. In the United States, around 1.2% of the population is affected by the condition; the peak incidence is between 40 and 60 years, with women being at higher risk. GD is autoimmune in origin, with both genetic and environmental factors, including smoking, stress, pregnancy, sex hormones, infections, and iodine consumption being involved in its genesis. In affected patients, autoantibodies bind to and stimulate TSH receptors on the surface of thyroid cells, resulting in excessive synthesis and secretion of thyroid hormones, and subsequently, hyperthyroidism. The characteristic ocular signs of the condition are believed to be secondary to overstimulation of thyrotropin receptors located in orbital fibroblasts and adipocytes. Most patients present with features of overt thyrotoxicosis: excessive sweating, heat intolerance, palpitations, anxiety, insomnia, fatigue, weight loss, muscle weakness, and in women, irregular menses. Classical signs include a low BMI, low-grade fever, tachycardia, tremors and warm moist skin. A smaller population presents with mild or subclinical thyrotoxicosis, where the symptoms and signs are similar but less prominent. Clinical findings which help differentiate GD from other causes of thyrotoxicosis include the presence of a goiter, which is classically diffuse and non-tender, and Graves' ophthalmopathy (GO). The latter affects approximately one-third of patients, and presents with proptosis, lid retraction, and periorbital soft tissue and extraocular muscle inflammation; diplopia may occur, and in very advanced cases, continuous corneal exposure may result in loss of sight. Standardized criteria have been formulated to categorized GO as either active or inactive, and as mild, moderate to severe, or sight threatening, based on clinical findings; this is important in determining the eventual management of the patient. Where GD is suspected, estimation of serum TSH, T3 and T4 levels is a good first step; in overt hyperthyroidism, total T3 and/or free T4 levels are elevated, while TSH is subnormal. In mild hyperthyroidism T3 alone be elevated ("T3-toxicosis"), while in subclinical hyperthyroidism, both total T3 and free T4 will be within the normal ranges, while TSH is subnormal. In individuals with clinical findings suggestive of hyperthyroidism, recent onset orbitopathy, and a compatible thyroid profile, GD is likely and further diagnostic measures are unnecessary. Where the above are equivocal, further investigations such as measurement of TSH receptor antibodies (TRAb), determination of radioactive iodine uptake, and ultrasonic measurement of thyroidal blood flow may be employed, depending on the available expertise and resources. Spontaneous remission has been reported in up to 30% of patients with mild GD; however, most will require therapy. Overall, the management can be classified into two key areas: treatment of the hyperthyroidism, and management of GO. Overt hyperthyroidism can be treated via antithyroid drugs, radioactive iodine (RAI) therapy, or surgery (i.e. near-total or total thyroidectomy); the choice between the above depends on the individual clinical situation and patient's preference. The presence of GO confers numerous complexities. As RAI therapy has a small but important risk of worsening or causing the de novo development of orbitopathy, these patients should receive prophylaxis with oral prednisone, while RAI should be completely avoided in moderate to sight threatening cases. Furthermore, in all patients with GO, quick restoration and maintenance of euthyroidism is crucial, as both hyper- and hypothyroidism will have a negative impact on disease progression. Overall, mild ophthalmopathy is best managed with watchful waiting along with selenium supplementation; high-dose intravenous glucocorticoids are the first-line treatment in more severe cases. Patients with sight-threatening GO may eventually require orbital decompression; corneal breakdown, recent-onset choroidal folds, and eyeball subluxation should be immediately addressed surgically. Note also that local measures such as artificial tears, ointments, and dark glasses, and control of risk factors for progression (e.g. thyroid dysfunction and smoking) are recommended in all of these patients.


Take home messages

  1. Graves’ disease (GD) is the most common cause of hyperthyroidism, accounting for 50-80% of all such cases.
  2. Affected individuals classically present with the triad of thyrotoxicosis, a diffuse non-tender goiter, and orbitopathy.
  3. In patients with the above clinical findings and a compatible thyroid profile, further diagnostic studies are unnecessary.
  4. Treatment of the hyperthyroidism and management of the orbitopathy are the two key principles of therapy.

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