Are you sure the patient has Graves' disease?

Graves’ disease is the most common cause of hyperthyroidism. It is an autoimmune disease resulting from the activation of the thyrotropin receptor by serum thyroid stimulating immunoglobulins (TSI). This stimulation results in thyroid follicular hyperplasia and increased production of thyroid hormones. Although Graves’ disease can occur at any age, most patients present between the 4th to 6th decades of life. This disease has a female predominance with an incidence that is 5-10 fold higher in women than in men. In patients with Graves’ disease, the following symptoms and signs may be present:

  • weight loss

  • heat intolerance

    Continue Reading

  • fatigue

  • hair loss

  • irritability

  • restlessness

  • lack of concentration

  • insomnia

  • labile emotion

  • palpitations

  • exertional dyspnea

  • increased appetite

  • increased frequency of bowel movements

  • proximal muscle weakness

  • irregular menses

Signs of Graves' Disease
  • tremors

  • tachycardia

  • flow murmurs

  • warm and moist skin

  • hyperreflexia with rapid relaxation phases

  • goiter with a bruit

  • proptosis

  • diplopia

  • conjunctival injection

  • periorbital edema

Key laboratory findings
  • suppressed serum TSH concentrations

  • elevated serum total T4 and free T4 concentrations

  • elevated serum total T3 and free T3 concentrations

  • elevated thyroid stimulating immunoglobulin (TSI) titers

In patients suspected of thyroid hormone binding protein abnormalities, the T3 resin uptake can be obtained to calculate the free T4 index.

What else could the patient have?

The differential diagnoses for Graves’ disease are:

  • Solitary toxic adenoma and toxic multinodular goiter: In these conditions, serum laboratory results are consistent with hyperthyroidism. Thyroid nodules can be identified by physical examination, thyroid ultrasound, and a pattern of elevated radioactive iodine uptake (RAIU) showing areas of increased and decreased uptake in the thyroid.

  • Thyroiditis: Thyroiditis classically follows a triphasic pattern of hyperthyroidism, hypothyroidism, and euthyroidism. During the acute hyperthyroid phase, preformed thyroid hormone (predominantly T4, and to a lesser extent, T3) is released from the thyroid gland and may be confused with Graves’ disease. Key laboratory findings in the hyperthyroid phase are elevated serum total T3, free T3, total T4, and free T4 levels and a suppressed TSH level. Serum thyroid stimulating immunoglobulin (TSI) and thyrotrophin binding inhibiting immunoglobulin (TBII) will be negative and thyroid peroxidase (TPO) antibody may be positive in thyroiditis. The acute phase of thyroiditis is characterized by a low thyroidal RAIU. In addition, anterior neck pain is commonly seen in subacute thyroiditis or certain conditions caused by infection, trauma or radiation.

  • Medication-induced thyrotoxicosis: Certain medications, including interferon-α, amiodarone, and lithium, may induce a thyroiditis similar to the pattern described above.

  • Iodine-induced hyperthyroidism: Exposure to a large iodine load (such as from radiographic contrast dye, iodine supplements, or iodine-rich medications) may induce hyperthyroidism, especially in elderly patients with a nontoxic nodular goiter.

  • HCG-induced thyrotoxicosis: Thyrotoxicosis induced by high serum levels of β-HCG is most commonly associated with molar pregnancies and choriocarcinomas. However, it can also be found in 0.1-0.4% of normal pregnancies, termed physiologic gestational thyrotoxicosis, due to higher levels of β-HCG which are perhaps more potent. Physiologic gestational thyrotoxicosis is more pronounced in pregnancies with multiple fetuses.

  • Struma ovarii: This is a rare ovarian tumor (teratoma or desmoid) which produces thyroid hormones and results in the laboratory findings of thyrotoxicosis. The RAIU is low or absent in the thyroid and increased in the pelvis.

  • Thyrotoxicosis factitia: This entity refers to the thyrotoxicosis resulting from the ingestion of supraphysiologic doses of thyroid hormone (prescribed or non-prescribed). Key laboratory findings consist of a suppressed TSH level and elevated thyroid hormones levels (T3 and/or T4, depending on what is ingested). Thyroidal RAIU is low or absent. The distinguishing factor from thyroiditis are low serum thyroglobulin levels in thyrotoxicosis factitia.

  • Secondary hyperthyroidism (TSH-secreting pituitary tumor): This is a rare thyrotroph pituitary adenoma in which TSH is produced and secreted independently of the negative feedback from the circulating thyroid hormones. Key laboratory findings include a normal or elevated TSH level and simultaneously elevated circulating thyroid hormones. The α-subunit to TSH ratio is increased, and pituitary MRI will usually identify a mass. The TSH that is produced is also more bioactive.

  • Generalized resistance to thyroid hormone: This is characterized by a widespread mutation of central and peripheral thyroid hormone receptors that results in the loss of feedback inhibition from circulating thyroid hormones. Similar to the laboratory findings of TSH-secreting pituitary tumors, serum TSH and circulating thyroid hormones are all elevated. However, no pituitary tumor will be found on imaging.

Key laboratory and imaging tests

In patients with hyperthyroid Graves’ disease, serum total T3, free T3, total T4 and free T4 levels are elevated and serum TSH is suppressed. The free T4 index (useful in the presence of a thyroid hormone binding protein abnormality) is also increased and can be calculated by measuring total T4 and T3 uptake. The serum T3 is significantly elevated compared to serum T4, and a T3/T4 ratio of more than 20 is commonly observed. A thyroid radioactive iodine uptake (RAIU) can be used to differentiate Graves’ disease (in which the result will be diffusely elevated) from other types of thyrotoxicosis.

Other tests that may prove helpful diagnostically

Antibodies against the thyroid receptor (thyroid stimulating immunoglobulin [TSI] and thyrotrophin binding inhibiting immunoglobulin [TBII]) are not recommended routinely but are useful when the diagnosis or etiology of thyrotoxicosis is not obvious. They may also be useful for assessing pregnant patients for the etiology of thyroid dysfunction and fetal risk of passively transferred antibody-mediated thyroid dysfunction. With the use of second generation assays using antibodies against the human TSH receptor, TRab positivity confers a diagnosis of Graves’ disease with sensitivity ranging from 95.3-98.8% and specificity of 99-99.6%.

Management and treatment of the disease

Management of Graves’ disease is directed toward decreasing thyroid hyperfunction, supportive treatment, and in the rare case of thyroid storm, emergency therapies. Long term therapy is defined by three options: antithyroid drugs (ATD), radioactive iodine ablation (RAI), and thyroid surgery. ATD and RAI have been the preferred therapies for the majority of patients. The treatment option should be based on clinical judgment and the patent’s personal preference.

Anti-thyroid drugs (ATD)

ATD therapy is preferable in the following:

  • Pregnant or lactating women

  • Mild hyperthyroidism

  • Previous history of neck surgery or irradiation

  • Patients with significant comorbidities

  • When pretreatment for RAI or surgery is indicated

The two FDA-approved ATDs are methimazole (MMI) and propylthiouracil (PTU). The starting dose of either drug should be chosen based on the severity of disease and gradually titrated down to a maintenance dose. MMI can be given, usually 10-40 mg once a day, depending on the size of the goiter and the severity of the hyperthyroidism. PTU can be given at a maximum of 200 mg three times a day. MMI is generally preferred due to the concerns of hepatotoxicity associated with PTU.

However, PTU is the treatment of choice in the first trimester of pregnancy, due to the concerns of a rare gastrointestinal embryopathy with methimazole, and MMI in the second and third trimesters of pregnancy to avoid the unusual complication of PTU-induced hepatotoxicity. A complete blood count (CBC) profile and hepatic function tests may be obtained before beginning an ATD. However, periodic monitoring of the CBC and hepatic function during ATD use has not shown to be helpful in predicting potential serious side effects. Patients should be counseled to report symptoms suggestive of agranulocytosis (high fever and/or severe sore throat) or liver abnormalities (abdominal pain or jaundice) promptly. ATD use is generally continued for approximately 12-18 months, after which the medication may be discontinued and the patient observed for the potential recurrence of hyperthyroidism.

Radioactive iodine (RAI)

RAI is suitable for:

  • Most adult patients without overt eye disease

  • Women of child-bearing age with Graves’ disease planning a pregnancy more than 6 months after RAI

  • Patients with contraindications to or a history of side effects from ATD

RAI (as 131I) is considered to be definitive treatment for Graves’ disease and is intentionally dosed to achieve LT4-dependent hypothyroidism. RAI is contraindicated in patients with Graves’ ophthalmopathy, especially in those who smoke, as any coexisting Graves’ eye disease may worsen. Methimazole may be used as pretreatment and should be stopped 4-5 days prior to RAI dosing. Methimazole is then restarted and tapered off as the RAI dose takes effect. In most patients, the serum TSH returns to normal (or may already even be elevated) approximately 3-6 months following RAI therapy. A second RAI dose (within 6-12 months of the initial dose) may be considered for patients not controlled after 12 months.


Thyroidectomy is preferred in:

  • Patients with large goiters associated with symptoms of compression; these patients would usually require more than one dose of RAI and rarely go into remission with ATD therapy alone

  • Patients in whom there is a clinical suspicion of thyroid cancer

  • Women planning a pregnancy within 4-6 months of diagnosis

  • Pregnant women, during the second trimester, with severe Graves’ disease uncontrolled by antithyroid drug therapy

  • Patients with significant Graves’ ophthalmopathy and/or those who smoke and in whom ATD therapy is ineffective

  • Patients who fail or have severe side effects from ATD therapy and are unwilling to receive radioactive iodine ablation

Supportive therapy

Beta-blockers are indicated to treat symptomatic hyperthyroidism. Propranolol is the drug of choice for severe disease, since it can also mildly inhibit peripheral T4 to T3 conversion. Esmolol is the drug of choice in the intensive care unit or emergency room, since it can be administered intravenously. However, hypotension may be a severe side effect.

Thyroid storm: This is an endocrine emergency that results when a severe intercurrent illness or stress precipitates worsening or uncontrolled Graves’ disease. The topic is discussed separately in another chapter.

What’s the Evidence?/References

Bahn, RS, Burch, HB, Cooper, DS, Garber, JR, Greenlee, MC, Klein, I, Laurberg, P, McDougall, IR, Montori, VM, Rivkees, SA, Ross, DS, Sosa, JA, Stan, MN. ” Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists”. Endocr Pract. vol. 17. 2011. pp. 456-520. (A panel of thyroid experts, appointed by American Thyroid Association (ATA)/American Association of Clinical Endocrinologist (AACE) performed systematic Pubmed search on relevant literatures on thyrotoxicosis. This task force thus provided 100 evidence-based uptodate recommendations on the care of thyrotoxicosis that serves as the clinical guideline.)

Stagnaro-Green, A, Abalovich, M, Alexander, E, Azizi, F, Mestman, J, Negro, R, Nixon, A, Pearce, EN, Soldin, OP, Sullivan, S, Wiersinga, W. ” Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum”. Thyroid. vol. 21. 2011. pp. 1081-125. (A task force appointed by American thyroid Association (ATA) performed systematic literature search on thyroid disease during pregnancy and formulated 76 evidence-based recommendations. These guidelines comment on the multiple unique physiological and pathological changes of thyroid function during pregnancy and postpartum periods.)

Brent, GA. “Clinical practice. Graves' disease”. New Engl J Med. vol. 358. 2008. pp. 2594-605. (The author presented a case of Graves’ disease and discussed the pathophysiology, diagnosis, and management of patients with Graves’ disease. The author also reviewed the pertinent literatures on this subject, thus provided a comprehensive review on this most common cause of hyperthyroidism.)

Cooper, DS. “Antithyroid drugs”. New Engl J Med. vol. 352. 2005. pp. 905-17. (The article reviewed the classification, mechanisms of action, and pharmacology of antithyroid medications. Emphasis was placed on the clinical applications of these medications, their potential side effects, and contraindications.)

Ross, DS. “Radioiodine therapy for hyperthyroidism”. New Engl J Med. vol. 364. 2011. pp. 542-50. (This is a comprehensive review on using radioactive iodine as the definitive treatment of hyperthyroidism. It covers several important topics including when and how to use this treatment modality, potential side effects, and contraindications.)