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How is Graves' Disease Diagnosed and Evaluated?
Author(s)
Moises Auron, MD, FAAP, FACP
Aaron C. Hamilton, MD, MBA, FACP

click for large version
Graves’ disease, the most common cause of hyperthyroidism, can also carry unique clinical features unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

Case

A 25-year-old, previously healthy woman presents with one month of anxiety, palpitations, intermittent loose non-dysenteriform stools, fine tremors, and hair loss. She has had a 20-pound weight loss in the previous four months, even though she reports an increased appetite. Her heart rate ranges from 115 to 130 beats per minute, and her temperature is 37.5oC. An exam is notable for mild bilateral proptosis, thin hair, and moist skin. A goiter is visible; it has increased consistency on palpation with an audible bruit over it. She has hyperreflexia and fine tremors. An EKG reveals sinus tachycardia. How should this patient be evaluated? What treatment should be initiated?

Overview

Graves’ disease, the most common cause of hyperthyroidism, is caused by autoimmune stimulation of the thyrotropin (TSH) receptor. It generally presents with a variety of signs and symptoms found with hyperthyroidism, but it can also carry unique clinical features unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

Graves’ disease diagnosis mainly is clinical, but also is supported by elevated free levels of thyroid hormones (mainly triiodothyronine [T3]) and suppressed TSH levels. Anti-thyrotropin receptor antibodies generally are present. Imaging in Graves’ disease is characterized by increased radioiodine uptake, as well as increased perfusion by Doppler ultrasonography.

Treatment can be pharmacologic, using anti-thyroid drugs, or ablative, with either radioiodine or thyroidectomy. Adjunctive therapy includes symptom control with beta-blocker agents, as well as steroid supplementation, especially in patients with orbitopathy undergoing radioablative treatment.

The Data

Epidemiology. Graves’ disease is the most common cause of hyperthyroidism, with a prevalence of ~0.5% of the population. Women are most commonly affected, with a prevalence five to 10 times higher than in male peers. The most common age of presentation is between the fifth and sixth decades of life.1-3

The fact that Graves’ disease occurs with higher incidence in patients with a family history of thyroid disease—and that concordance rates of up to 35% are seen with monozygotic twins—suggests that both genetic and environmental factors influence disease susceptibility.2,4

Pathophysiology. Graves’ disease occurs as a result of direct activation of the G-protein-coupled adenylate cyclase in the thyrotropin receptor by circulating IgG antibodies.2,3 Follicular hypertrophy and hyperplasia, and increased vascularity, cause goiter formation and an increased production of T3 and thyroxine (T4). The increase in T3 and T4 subsequently suppress TSH production.

Graves’ disease also is associated with unique clinical manifestations unrelated to the circulating levels of thyroid hormones, such as Graves’ ophthalmopathy and infiltrative dermopathy (localized or pretibial myxedema). Both of these occur as a result of local tissue infiltration by inflammatory cells and deposition of glycosaminglycanes.5

Clinical manifestations. Graves’ disease is characterized by a constellation of clinical findings and patient symptoms (see Table 1).1-3 The clinical presentation could differ in elderly patients, who present more commonly with weight loss or depression (also known as apathetic hyperthyroidism) and less commonly with tachycardia and tremor.2,3

click for large version
Table 1. Clinical Manifestations Of Hyperthyroidism

Although clinically apparent, exophtalmos is detected in 30% to 50% of patients; when using orbital imaging, it is identified in ≥80% of patients.5 Ophthalmopathy has a clinical course typically independent of the thyroid activity; its manifestations include proptosis, periorbital edema and inflammation, exposure keratitis, photophobia, extraocular muscle infiltration, and eyelid lag.5-8

Thyroid dermopathy (localized dermal myxedema) can occur in 0.5% to 4.3% of patients with Graves’ disease; it occurs most commonly among patients with Graves’ ophthalmopathy, in whom it occurs in up to 13% of cases. About 20% of patients with dermal myxedema have associated thyroid acropachy.3,9

 

 

click for large version
This CT image from a patient with Graves disease shows bilateral proptosis and orbital fat deposition.

Hospitalists should be aware of thyroid storm. Although rare, occurring in only 1% to 2% of patients with hyperthyroidism, it can be a medical emergency. It is generally manifested by fever (due to severe thermogenesis), atrial tachyarrhythmias (due to hyperadrenergic response), mental status changes, and liver dysfunction.

In addition, patients with thyroid storm might present with hyperglycemia, hypercalcemia, hypocortisolism, and hypokalemia.10 Thyroid storm requires prompt treatment of both the clinical manifestations and the underlying condition.

Differential Diagnosis from Other Causes of Thyroiditis

Laboratory. The classic presentation of Graves’ disease is a suppressed TSH and elevated serum T3 and T4 levels.1-3 Generally, T3 is higher than T4, which also occurs in toxic multinodular goiter, solitary hyperfunctioning nodule, and iodine-induced hyperthyroidism.2,6 The free T3 and T4 levels should be obtained, as these are useful for monitoring response to therapy.1-3

click for large version
Table 2. Differential diagnosis of thyroiditis

Most patients with Graves’ disease also have anti-thyroid antibodies (see Table 2), although these are not required for the diagnosis.1-3,11

Following initiation of treatment, TSH levels remain suppressed for approximately two to three months, even after free T3 and T4 levels return to normal or below normal. After this period of suppression is over, TSH levels can be used to adjust therapy.1-3

Imaging. A thyroid radioiodine-uptake study provides a measure of iodine uptake, as well as an image of functioning thyroid tissue; the imaging is done 24 hours after the intake of iodine-123 or iodine-131. Generalized increased uptake is characteristic of Graves’ disease.1-3,12 In comparison, patients with thyroiditis have decreased radioiodine uptake as well as low blood flow in Doppler ultrasonography.13

In patients with large goiters, when there are signs or symptoms of upper airway or thoracic outlet obstruction, imaging with a neck and upper-chest CT scan is recommended.2 In patients with unilateral proptosis, asymmetric ophthalmopathy, or visual loss, orbital imaging is advised (CT scan or MRI).2,5 In patients with tachyarrhythmias, an electrocardiogram should evaluate for the presence of atrial fibrillation.2 Table 2 illustrates how Graves’ disease can be distinguished from other causes of thyroiditis.1-3

Initial Treatment

Treatment of Graves’ disease has two main tenets: treating the underlying thyroid disorder and quickly controlling symptoms. The underlying thyroid disorder can be treated with such anti-thyroid drugs as thionamides (methimazole or propylthiouracil), ablative radioiodine, or surgical excision of the thyroid. Adjunct symptom therapy can include beta-blockers, organic iodide, and glucocorticoids.11,14 Thionamides are preferred in young patients, pregnant women, and cases with orbital involvement.14

In pregnancy, treatment with propylthiouracil is preferred, especially during the first two trimesters due to the risk of teratogenicity with methimazole (there have been associated case reports of choanal atresia, aplasia cutis, and facial malformations).15

Steroid prophylaxis is used in patients with prominent ocular symptoms who undergo radioiodine ablation to minimize risk of worsening of ophthalmopathy.16

Back to the Case

The patient was admitted; free T3 and T4 levels were elevated, TSH was suppressed, and anti-thyroid antibodies (anti-TPO, anti-TG, and anti-TRAb) were positive. An I-123 radioiodine uptake scan showed diffuse thyroid gland uptake. Beta-blockers were initiated for heart-rate control (atenolol 25 mg) with adequate response.

Given the patient’s young age, it was decided to initiate thionamides. A pregnancy test was negative, so methimazole was initiated at a dose of 10 mg orally once daily.

Dr. Auron is a hospitalist in the Department of Hospital Medicine and the Center for Pediatric Hospital Medicine at Cleveland Clinic. Dr. Hamilton is a hospitalist in the Department of Hospital Medicine at Cleveland Clinic.

 

 

Key Points

  • Graves’ disease is an autoimmune disease and the most common etiology of hyperthyroidism.

  • A biochemical profile of hyperthyroidism should include measurement of free T3, free T4, and TSH levels.

  • Anti-thyroid antibodies can confirm the disease but are not required for diagnosis if both clinical and biochemical features are present.

  • Patients with Graves’ disease can have extrathyroid manifestations unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

  • The initial treatment of Graves’ disease is with anti-thyroid medications, such as thionamides, especially in young patients, during pregnancy, and in cases with ocular involvement. Beta-blockers can also be used to reduce adrenergically mediated symptoms. Steroids can be initiated in patients with orbital disease who undergo radioiodine ablative therapy.

References

  1. Baskin HJ, Cobin RH, Duick DS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. (2006 Amended version). Endocr Pract. 2002;8:457-469.

  2. Brent GA. Clinical practice. Graves’ disease. N Engl J Med. 2008;358:2594-2605.

  3. Nayak B, Hodak SP. Hyperthyroidism. Endocrinol Metab Clin North Am. 2007;36:617-656.

  4. Manji N, Carr-Smith JD, Boelaert K, et al. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J Clin Endocrinol Metab. 2006;91:4873-4880.

  5. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362:726-738.

  6. Woeber KA. Triiodothyronine production in Graves’ hyperthyroidism. Thyroid. 2006;16:687-690.

  7. Osman F, Franklyn JA, Holder RL, Sheppard MC, Gammage MD. Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study. J Am Coll Cardiol. 2007;49:71-81.

  8. Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid. 2002;12:855-860.

  9. Fatourechi V. Pretibial myxedema: pathophysiology and treatment options. Am J Clin Dermatol. 2005;6:295-309.

  10. Chong HW, See KC, Phua J. Thyroid storm with multiorgan failure. Thyroid. 2010;20:333-336.

  11. De Groot L. Diagnosis and treatment of Graves’ disease. Thyroid Disease Manager website. Available at: http://www.thyroidmanager.org/chapter/diagnosis-and-treatment-of-graves-disease/. Accessed Jan. 20, 2012.

  12. Cappelli C, Pirola I, De Martino E, et al. The role of imaging in Graves’ disease: a cost-effectiveness analysis. Eur J Radiol. 2008;65:99-103.

  13. Ota H, Amino N, Morita S, et al. Quantitative measurement of thyroid blood flow for differentiation of painless thyroiditis from Graves’ disease. Clin Endocrinol (Oxf). 2007;67:41-45.

  14. Fumarola A, Di Fiore A, Dainelli M, Grani G, Calvanese A. Medical treatment of hyperthyroidism: state of the art. Exp Clin Endocrinol Diabetes. 2010;118:678-684.

  15. Fitzpatrick DL, Russell MA. Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin North Am. 2010;37:173-193.

  16. Bartalena L. The dilemma of how to manage Graves’ hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab. 2011;96:592-599.

Issue
The Hospitalist - 2012(07)
Publications
The Hospitalist
Sections
All Content
Author(s)
Moises Auron, MD, FAAP, FACP
Aaron C. Hamilton, MD, MBA, FACP
Author(s)
Moises Auron, MD, FAAP, FACP
Aaron C. Hamilton, MD, MBA, FACP

click for large version
Graves’ disease, the most common cause of hyperthyroidism, can also carry unique clinical features unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

Case

A 25-year-old, previously healthy woman presents with one month of anxiety, palpitations, intermittent loose non-dysenteriform stools, fine tremors, and hair loss. She has had a 20-pound weight loss in the previous four months, even though she reports an increased appetite. Her heart rate ranges from 115 to 130 beats per minute, and her temperature is 37.5oC. An exam is notable for mild bilateral proptosis, thin hair, and moist skin. A goiter is visible; it has increased consistency on palpation with an audible bruit over it. She has hyperreflexia and fine tremors. An EKG reveals sinus tachycardia. How should this patient be evaluated? What treatment should be initiated?

Overview

Graves’ disease, the most common cause of hyperthyroidism, is caused by autoimmune stimulation of the thyrotropin (TSH) receptor. It generally presents with a variety of signs and symptoms found with hyperthyroidism, but it can also carry unique clinical features unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

Graves’ disease diagnosis mainly is clinical, but also is supported by elevated free levels of thyroid hormones (mainly triiodothyronine [T3]) and suppressed TSH levels. Anti-thyrotropin receptor antibodies generally are present. Imaging in Graves’ disease is characterized by increased radioiodine uptake, as well as increased perfusion by Doppler ultrasonography.

Treatment can be pharmacologic, using anti-thyroid drugs, or ablative, with either radioiodine or thyroidectomy. Adjunctive therapy includes symptom control with beta-blocker agents, as well as steroid supplementation, especially in patients with orbitopathy undergoing radioablative treatment.

The Data

Epidemiology. Graves’ disease is the most common cause of hyperthyroidism, with a prevalence of ~0.5% of the population. Women are most commonly affected, with a prevalence five to 10 times higher than in male peers. The most common age of presentation is between the fifth and sixth decades of life.1-3

The fact that Graves’ disease occurs with higher incidence in patients with a family history of thyroid disease—and that concordance rates of up to 35% are seen with monozygotic twins—suggests that both genetic and environmental factors influence disease susceptibility.2,4

Pathophysiology. Graves’ disease occurs as a result of direct activation of the G-protein-coupled adenylate cyclase in the thyrotropin receptor by circulating IgG antibodies.2,3 Follicular hypertrophy and hyperplasia, and increased vascularity, cause goiter formation and an increased production of T3 and thyroxine (T4). The increase in T3 and T4 subsequently suppress TSH production.

Graves’ disease also is associated with unique clinical manifestations unrelated to the circulating levels of thyroid hormones, such as Graves’ ophthalmopathy and infiltrative dermopathy (localized or pretibial myxedema). Both of these occur as a result of local tissue infiltration by inflammatory cells and deposition of glycosaminglycanes.5

Clinical manifestations. Graves’ disease is characterized by a constellation of clinical findings and patient symptoms (see Table 1).1-3 The clinical presentation could differ in elderly patients, who present more commonly with weight loss or depression (also known as apathetic hyperthyroidism) and less commonly with tachycardia and tremor.2,3

click for large version
Table 1. Clinical Manifestations Of Hyperthyroidism

Although clinically apparent, exophtalmos is detected in 30% to 50% of patients; when using orbital imaging, it is identified in ≥80% of patients.5 Ophthalmopathy has a clinical course typically independent of the thyroid activity; its manifestations include proptosis, periorbital edema and inflammation, exposure keratitis, photophobia, extraocular muscle infiltration, and eyelid lag.5-8

Thyroid dermopathy (localized dermal myxedema) can occur in 0.5% to 4.3% of patients with Graves’ disease; it occurs most commonly among patients with Graves’ ophthalmopathy, in whom it occurs in up to 13% of cases. About 20% of patients with dermal myxedema have associated thyroid acropachy.3,9

 

 

click for large version
This CT image from a patient with Graves disease shows bilateral proptosis and orbital fat deposition.

Hospitalists should be aware of thyroid storm. Although rare, occurring in only 1% to 2% of patients with hyperthyroidism, it can be a medical emergency. It is generally manifested by fever (due to severe thermogenesis), atrial tachyarrhythmias (due to hyperadrenergic response), mental status changes, and liver dysfunction.

In addition, patients with thyroid storm might present with hyperglycemia, hypercalcemia, hypocortisolism, and hypokalemia.10 Thyroid storm requires prompt treatment of both the clinical manifestations and the underlying condition.

Differential Diagnosis from Other Causes of Thyroiditis

Laboratory. The classic presentation of Graves’ disease is a suppressed TSH and elevated serum T3 and T4 levels.1-3 Generally, T3 is higher than T4, which also occurs in toxic multinodular goiter, solitary hyperfunctioning nodule, and iodine-induced hyperthyroidism.2,6 The free T3 and T4 levels should be obtained, as these are useful for monitoring response to therapy.1-3

click for large version
Table 2. Differential diagnosis of thyroiditis

Most patients with Graves’ disease also have anti-thyroid antibodies (see Table 2), although these are not required for the diagnosis.1-3,11

Following initiation of treatment, TSH levels remain suppressed for approximately two to three months, even after free T3 and T4 levels return to normal or below normal. After this period of suppression is over, TSH levels can be used to adjust therapy.1-3

Imaging. A thyroid radioiodine-uptake study provides a measure of iodine uptake, as well as an image of functioning thyroid tissue; the imaging is done 24 hours after the intake of iodine-123 or iodine-131. Generalized increased uptake is characteristic of Graves’ disease.1-3,12 In comparison, patients with thyroiditis have decreased radioiodine uptake as well as low blood flow in Doppler ultrasonography.13

In patients with large goiters, when there are signs or symptoms of upper airway or thoracic outlet obstruction, imaging with a neck and upper-chest CT scan is recommended.2 In patients with unilateral proptosis, asymmetric ophthalmopathy, or visual loss, orbital imaging is advised (CT scan or MRI).2,5 In patients with tachyarrhythmias, an electrocardiogram should evaluate for the presence of atrial fibrillation.2 Table 2 illustrates how Graves’ disease can be distinguished from other causes of thyroiditis.1-3

Initial Treatment

Treatment of Graves’ disease has two main tenets: treating the underlying thyroid disorder and quickly controlling symptoms. The underlying thyroid disorder can be treated with such anti-thyroid drugs as thionamides (methimazole or propylthiouracil), ablative radioiodine, or surgical excision of the thyroid. Adjunct symptom therapy can include beta-blockers, organic iodide, and glucocorticoids.11,14 Thionamides are preferred in young patients, pregnant women, and cases with orbital involvement.14

In pregnancy, treatment with propylthiouracil is preferred, especially during the first two trimesters due to the risk of teratogenicity with methimazole (there have been associated case reports of choanal atresia, aplasia cutis, and facial malformations).15

Steroid prophylaxis is used in patients with prominent ocular symptoms who undergo radioiodine ablation to minimize risk of worsening of ophthalmopathy.16

Back to the Case

The patient was admitted; free T3 and T4 levels were elevated, TSH was suppressed, and anti-thyroid antibodies (anti-TPO, anti-TG, and anti-TRAb) were positive. An I-123 radioiodine uptake scan showed diffuse thyroid gland uptake. Beta-blockers were initiated for heart-rate control (atenolol 25 mg) with adequate response.

Given the patient’s young age, it was decided to initiate thionamides. A pregnancy test was negative, so methimazole was initiated at a dose of 10 mg orally once daily.

Dr. Auron is a hospitalist in the Department of Hospital Medicine and the Center for Pediatric Hospital Medicine at Cleveland Clinic. Dr. Hamilton is a hospitalist in the Department of Hospital Medicine at Cleveland Clinic.

 

 

Key Points

  • Graves’ disease is an autoimmune disease and the most common etiology of hyperthyroidism.

  • A biochemical profile of hyperthyroidism should include measurement of free T3, free T4, and TSH levels.

  • Anti-thyroid antibodies can confirm the disease but are not required for diagnosis if both clinical and biochemical features are present.

  • Patients with Graves’ disease can have extrathyroid manifestations unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

  • The initial treatment of Graves’ disease is with anti-thyroid medications, such as thionamides, especially in young patients, during pregnancy, and in cases with ocular involvement. Beta-blockers can also be used to reduce adrenergically mediated symptoms. Steroids can be initiated in patients with orbital disease who undergo radioiodine ablative therapy.

References

  1. Baskin HJ, Cobin RH, Duick DS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. (2006 Amended version). Endocr Pract. 2002;8:457-469.

  2. Brent GA. Clinical practice. Graves’ disease. N Engl J Med. 2008;358:2594-2605.

  3. Nayak B, Hodak SP. Hyperthyroidism. Endocrinol Metab Clin North Am. 2007;36:617-656.

  4. Manji N, Carr-Smith JD, Boelaert K, et al. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J Clin Endocrinol Metab. 2006;91:4873-4880.

  5. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362:726-738.

  6. Woeber KA. Triiodothyronine production in Graves’ hyperthyroidism. Thyroid. 2006;16:687-690.

  7. Osman F, Franklyn JA, Holder RL, Sheppard MC, Gammage MD. Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study. J Am Coll Cardiol. 2007;49:71-81.

  8. Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid. 2002;12:855-860.

  9. Fatourechi V. Pretibial myxedema: pathophysiology and treatment options. Am J Clin Dermatol. 2005;6:295-309.

  10. Chong HW, See KC, Phua J. Thyroid storm with multiorgan failure. Thyroid. 2010;20:333-336.

  11. De Groot L. Diagnosis and treatment of Graves’ disease. Thyroid Disease Manager website. Available at: http://www.thyroidmanager.org/chapter/diagnosis-and-treatment-of-graves-disease/. Accessed Jan. 20, 2012.

  12. Cappelli C, Pirola I, De Martino E, et al. The role of imaging in Graves’ disease: a cost-effectiveness analysis. Eur J Radiol. 2008;65:99-103.

  13. Ota H, Amino N, Morita S, et al. Quantitative measurement of thyroid blood flow for differentiation of painless thyroiditis from Graves’ disease. Clin Endocrinol (Oxf). 2007;67:41-45.

  14. Fumarola A, Di Fiore A, Dainelli M, Grani G, Calvanese A. Medical treatment of hyperthyroidism: state of the art. Exp Clin Endocrinol Diabetes. 2010;118:678-684.

  15. Fitzpatrick DL, Russell MA. Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin North Am. 2010;37:173-193.

  16. Bartalena L. The dilemma of how to manage Graves’ hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab. 2011;96:592-599.

click for large version
Graves’ disease, the most common cause of hyperthyroidism, can also carry unique clinical features unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

Case

A 25-year-old, previously healthy woman presents with one month of anxiety, palpitations, intermittent loose non-dysenteriform stools, fine tremors, and hair loss. She has had a 20-pound weight loss in the previous four months, even though she reports an increased appetite. Her heart rate ranges from 115 to 130 beats per minute, and her temperature is 37.5oC. An exam is notable for mild bilateral proptosis, thin hair, and moist skin. A goiter is visible; it has increased consistency on palpation with an audible bruit over it. She has hyperreflexia and fine tremors. An EKG reveals sinus tachycardia. How should this patient be evaluated? What treatment should be initiated?

Overview

Graves’ disease, the most common cause of hyperthyroidism, is caused by autoimmune stimulation of the thyrotropin (TSH) receptor. It generally presents with a variety of signs and symptoms found with hyperthyroidism, but it can also carry unique clinical features unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

Graves’ disease diagnosis mainly is clinical, but also is supported by elevated free levels of thyroid hormones (mainly triiodothyronine [T3]) and suppressed TSH levels. Anti-thyrotropin receptor antibodies generally are present. Imaging in Graves’ disease is characterized by increased radioiodine uptake, as well as increased perfusion by Doppler ultrasonography.

Treatment can be pharmacologic, using anti-thyroid drugs, or ablative, with either radioiodine or thyroidectomy. Adjunctive therapy includes symptom control with beta-blocker agents, as well as steroid supplementation, especially in patients with orbitopathy undergoing radioablative treatment.

The Data

Epidemiology. Graves’ disease is the most common cause of hyperthyroidism, with a prevalence of ~0.5% of the population. Women are most commonly affected, with a prevalence five to 10 times higher than in male peers. The most common age of presentation is between the fifth and sixth decades of life.1-3

The fact that Graves’ disease occurs with higher incidence in patients with a family history of thyroid disease—and that concordance rates of up to 35% are seen with monozygotic twins—suggests that both genetic and environmental factors influence disease susceptibility.2,4

Pathophysiology. Graves’ disease occurs as a result of direct activation of the G-protein-coupled adenylate cyclase in the thyrotropin receptor by circulating IgG antibodies.2,3 Follicular hypertrophy and hyperplasia, and increased vascularity, cause goiter formation and an increased production of T3 and thyroxine (T4). The increase in T3 and T4 subsequently suppress TSH production.

Graves’ disease also is associated with unique clinical manifestations unrelated to the circulating levels of thyroid hormones, such as Graves’ ophthalmopathy and infiltrative dermopathy (localized or pretibial myxedema). Both of these occur as a result of local tissue infiltration by inflammatory cells and deposition of glycosaminglycanes.5

Clinical manifestations. Graves’ disease is characterized by a constellation of clinical findings and patient symptoms (see Table 1).1-3 The clinical presentation could differ in elderly patients, who present more commonly with weight loss or depression (also known as apathetic hyperthyroidism) and less commonly with tachycardia and tremor.2,3

click for large version
Table 1. Clinical Manifestations Of Hyperthyroidism

Although clinically apparent, exophtalmos is detected in 30% to 50% of patients; when using orbital imaging, it is identified in ≥80% of patients.5 Ophthalmopathy has a clinical course typically independent of the thyroid activity; its manifestations include proptosis, periorbital edema and inflammation, exposure keratitis, photophobia, extraocular muscle infiltration, and eyelid lag.5-8

Thyroid dermopathy (localized dermal myxedema) can occur in 0.5% to 4.3% of patients with Graves’ disease; it occurs most commonly among patients with Graves’ ophthalmopathy, in whom it occurs in up to 13% of cases. About 20% of patients with dermal myxedema have associated thyroid acropachy.3,9

 

 

click for large version
This CT image from a patient with Graves disease shows bilateral proptosis and orbital fat deposition.

Hospitalists should be aware of thyroid storm. Although rare, occurring in only 1% to 2% of patients with hyperthyroidism, it can be a medical emergency. It is generally manifested by fever (due to severe thermogenesis), atrial tachyarrhythmias (due to hyperadrenergic response), mental status changes, and liver dysfunction.

In addition, patients with thyroid storm might present with hyperglycemia, hypercalcemia, hypocortisolism, and hypokalemia.10 Thyroid storm requires prompt treatment of both the clinical manifestations and the underlying condition.

Differential Diagnosis from Other Causes of Thyroiditis

Laboratory. The classic presentation of Graves’ disease is a suppressed TSH and elevated serum T3 and T4 levels.1-3 Generally, T3 is higher than T4, which also occurs in toxic multinodular goiter, solitary hyperfunctioning nodule, and iodine-induced hyperthyroidism.2,6 The free T3 and T4 levels should be obtained, as these are useful for monitoring response to therapy.1-3

click for large version
Table 2. Differential diagnosis of thyroiditis

Most patients with Graves’ disease also have anti-thyroid antibodies (see Table 2), although these are not required for the diagnosis.1-3,11

Following initiation of treatment, TSH levels remain suppressed for approximately two to three months, even after free T3 and T4 levels return to normal or below normal. After this period of suppression is over, TSH levels can be used to adjust therapy.1-3

Imaging. A thyroid radioiodine-uptake study provides a measure of iodine uptake, as well as an image of functioning thyroid tissue; the imaging is done 24 hours after the intake of iodine-123 or iodine-131. Generalized increased uptake is characteristic of Graves’ disease.1-3,12 In comparison, patients with thyroiditis have decreased radioiodine uptake as well as low blood flow in Doppler ultrasonography.13

In patients with large goiters, when there are signs or symptoms of upper airway or thoracic outlet obstruction, imaging with a neck and upper-chest CT scan is recommended.2 In patients with unilateral proptosis, asymmetric ophthalmopathy, or visual loss, orbital imaging is advised (CT scan or MRI).2,5 In patients with tachyarrhythmias, an electrocardiogram should evaluate for the presence of atrial fibrillation.2 Table 2 illustrates how Graves’ disease can be distinguished from other causes of thyroiditis.1-3

Initial Treatment

Treatment of Graves’ disease has two main tenets: treating the underlying thyroid disorder and quickly controlling symptoms. The underlying thyroid disorder can be treated with such anti-thyroid drugs as thionamides (methimazole or propylthiouracil), ablative radioiodine, or surgical excision of the thyroid. Adjunct symptom therapy can include beta-blockers, organic iodide, and glucocorticoids.11,14 Thionamides are preferred in young patients, pregnant women, and cases with orbital involvement.14

In pregnancy, treatment with propylthiouracil is preferred, especially during the first two trimesters due to the risk of teratogenicity with methimazole (there have been associated case reports of choanal atresia, aplasia cutis, and facial malformations).15

Steroid prophylaxis is used in patients with prominent ocular symptoms who undergo radioiodine ablation to minimize risk of worsening of ophthalmopathy.16

Back to the Case

The patient was admitted; free T3 and T4 levels were elevated, TSH was suppressed, and anti-thyroid antibodies (anti-TPO, anti-TG, and anti-TRAb) were positive. An I-123 radioiodine uptake scan showed diffuse thyroid gland uptake. Beta-blockers were initiated for heart-rate control (atenolol 25 mg) with adequate response.

Given the patient’s young age, it was decided to initiate thionamides. A pregnancy test was negative, so methimazole was initiated at a dose of 10 mg orally once daily.

Dr. Auron is a hospitalist in the Department of Hospital Medicine and the Center for Pediatric Hospital Medicine at Cleveland Clinic. Dr. Hamilton is a hospitalist in the Department of Hospital Medicine at Cleveland Clinic.

 

 

Key Points

  • Graves’ disease is an autoimmune disease and the most common etiology of hyperthyroidism.

  • A biochemical profile of hyperthyroidism should include measurement of free T3, free T4, and TSH levels.

  • Anti-thyroid antibodies can confirm the disease but are not required for diagnosis if both clinical and biochemical features are present.

  • Patients with Graves’ disease can have extrathyroid manifestations unrelated to thyrotoxicosis, such as ophthalmopathy and dermopathy.

  • The initial treatment of Graves’ disease is with anti-thyroid medications, such as thionamides, especially in young patients, during pregnancy, and in cases with ocular involvement. Beta-blockers can also be used to reduce adrenergically mediated symptoms. Steroids can be initiated in patients with orbital disease who undergo radioiodine ablative therapy.

References

  1. Baskin HJ, Cobin RH, Duick DS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. (2006 Amended version). Endocr Pract. 2002;8:457-469.

  2. Brent GA. Clinical practice. Graves’ disease. N Engl J Med. 2008;358:2594-2605.

  3. Nayak B, Hodak SP. Hyperthyroidism. Endocrinol Metab Clin North Am. 2007;36:617-656.

  4. Manji N, Carr-Smith JD, Boelaert K, et al. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J Clin Endocrinol Metab. 2006;91:4873-4880.

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How is Graves' Disease Diagnosed and Evaluated?
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