Hyperthyroidism refers to increased thyroid hormone synthesis and secretion from the thyroid gland, whereas thyrotoxicosis is characterized by the clinical manifestations of inappropriately high thyroid hormone action in tissues.1 These manifestations result from hormone excess at any level of the hypothalamic-pituitary-thyroid axis or from release or ingestion of thyroid hormones.1

Overt hyperthyroidism is defined as subnormal thyroid-stimulating hormone (TSH) levels and elevated serum levels of triiodothyronine (T3) and/or free thyroxine (fT4).2 Subclinical hyperthyroidism is defined as subnormal TSH levels and normal T3 and fT4 levels.2

In most cases of overt hyperthyroidism, patients present with a constellation of symptoms, including anxiety, tremor, palpitations, more frequent bowel movement, heat intolerance, increased perspiration, and weight loss with normal or increased appetite.2,3 Furthermore, women may present with menstrual irregularities and men with erectile dysfunction and gynecomastia.4 In older patients, symptoms may be more subtle or may include mainly tachycardia or atrial fibrillation and dyspnea on exertion.

Etiology

It is vital to determine the etiology of thyrotoxicosis, as the appropriate therapy depends on the underlying mechanism. In iodine-sufficient populations, the most common cause of endogenous thyrotoxicosis is Graves disease, followed by toxic multinodular goiter, toxic adenoma, and thyroiditis, whereas nodular thyroid disease causes approximately half of cases in iodine-deficient regions.1

Findings specific to Graves disease include ophthalmopathy with proptosis, chemosis, or conjunctival injection; pretibial myxedema; and thyroid acropachy.3,5 Physical examination can reveal findings consistent with or suspicious for nodular thyroid disease. Subacute thyroiditis is usually characterized by fever and neck pain, with a recent history of upper respiratory symptoms.6 Painless thyroiditis is frequently seen in the postpartum period in patients with a personal or family history of autoimmune or thyroid disease.2,7 New anticancer drugs, such as tyrosine kinase inhibitors and immune checkpoint inhibitors, may cause thyroiditis or induce autoimmune thyroid disease, and thyroid function monitoring should be considered in patients who receive these drugs.2

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Diagnosis

If the diagnosis is not apparent based on the clinical presentation and initial biochemical evaluation, the 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and thyrotoxicosis recommend diagnostic testing, including measurement of thyrotropin receptor antibodies (TRAb), determination of the radioactive iodine (RAI) uptake, or measurement of thyroidal blood flow on ultrasound.2 The 2018 European Thyroid Association guidelines for the management of Graves hyperthyroidism recommended ultrasonography with color-flow Doppler as the imaging procedure to support the diagnosis of Graves disease, while limiting the use of radioiodine imaging to patients with potential autonomous thyroid nodules or before RAI treatment.8

The presence of TRAb supports the diagnosis of Graves disease, as third-generation TRAb assays have a sensitivity of 97% and specificity of 99% for the diagnosis of Graves disease.1,2 Of note, biotin ingestion can cause spurious results in thyroid function tests, with a biochemical profile that is indistinguishable from Graves disease, including low TSH and increased levels of fT4, T3, and TRAb.1,2 However, discontinuation of biotin supplements for 2 to 3 days will result in resolution of the biochemical abnormalities.1,2

Radioiodine uptake can also be used as a diagnostic tool in nonpregnant patients who have not had a recent exposure to iodine.2 High or normal radioiodine uptake indicates de novo synthesis of thyroid hormone, thus supporting that the thyrotoxicosis is secondary to hyperthyroidism.2 In contrast, thyrotoxicosis with low or nearly absent RAI uptake over the neck can be seen in cases of thyroiditis, ingestion of thyroid hormone, struma ovarii, or recent exposure to iodine.2

Where expertise is available, use of ultrasonography with color-flow Doppler to measure the peak systolic velocity from intrathyroidal arteries or the inferior thyroidal artery can distinguish thyroid hyperactivity (increased flow) from destructive thyroiditis.2 Thyroid Doppler ultrasonography may assist in distinguishing between destructive thyroiditis and Graves disease. In addition, it can assist in distinguishing between different types of amiodarone-induced thyrotoxicosis.2

Treatment

Beta-adrenergic blocking agents are generally recommended in all patients with symptomatic thyrotoxicosis.2

The treatment options for overt hyperthyroidism secondary to Graves disease include 1 of 3 modalities: antithyroid drugs (ATDs), RAI therapy, or thyroidectomy.2

Thyroidectomy or RAI are the preferred treatment options for overt hyperthyroidism secondary to toxic multinodular goiter or toxic adenoma, whereas low-dose treatment with ATDs may be appropriate for some patients.2

ATDs can be combined with beta-adrenergic blocking agents to treat iodine-induced hyperthyroidism.2

ATDs are also recommended for treatment of overt thyrotoxicosis secondary to amiodarone treatment in patients with autonomous thyroid nodules or Graves disease, whereas corticosteroids are recommended for cases of amiodarone-induced thyroiditis.2

Corticosteroids may be used in patients with subacute thyroiditis who do not respond to nonsteroidal anti-inflammatory drugs or who present with moderate to severe symptoms.2

Treatment for subclinical hyperthyroidism is recommended when TSH is persistently <0.1 mU/L in all patients ≥65 years of age; patients with cardiac risk factors, heart disease, or osteoporosis; and in symptomatic patients. Treatment should be considered in younger patients (aged <65 years) when TSH is persistently <0.1 mU/L. The treatment should be based on the etiology of the hyperthyroidism.2

Antithyroid Drugs

In most cases, ATD therapy should include methimazole, except during the first trimester of pregnancy (when propylthiouracil is preferred), in cases of thyroid storm, or in patients with minor reactions to methimazole who decline other treatment options.2 If ATD therapy is chosen to treat Graves disease, it should be given for 12 to 18 months. TRAb level should be measured before discontinuation of ATD, as it can aid in predicting the chance for remission.2

Radioiodine Therapy

For Graves disease, RAI therapy should be administered at sufficient activity (usually 10-15 mCi) to render the patient hypothyroid.2 In patients with toxic multinodular goiter, the goal is to alleviate hyperthyroidism. Medical therapy of any comorbid conditions should be optimized before RAI therapy. When hyperthyroidism persists 6 months after RAI therapy, retreatment with RAI is suggested.2

Surgical Treatment

When surgery is chosen, it is recommended to complete near-total or total thyroidectomy for treatment of toxic multinodular goiter or Graves disease.2 For patients with toxic adenoma, an ipsilateral thyroid lobectomy or isthmusectomy should be performed.2 Thyroidectomy is recommended for patients with amiodarone-induced thyrotoxicosis who are unresponsive to medical treatment with ATDs and corticosteroids.2 Pituitary surgery is recommended for TSH-secreting pituitary tumors, and surgical intervention is also recommended for struma ovarii.2

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References

1. Sharma A, Stan MN. Thyrotoxicosis: diagnosis and management. Mayo Clin Proc. 2019;94(6):1048-1064.

2. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.

3. Mayo Clinic. Hyperthyroidism (overactive thyroid): symptoms & causes. https://www.mayoclinic.org/diseases-conditions/hyperthyroidism/symptoms-causes/syc-20373659. Accessed December 10, 2019.

4. Gabrielson AT, Sartor RA, Hellstrom WJG. The impact of thyroid disease on sexual dysfunction in men and women. Sex Med Rev. 2019;7:57-70.

5. Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med. 2016;375:1552-1565.

6. Hennessey Jv. Subacute thyroiditis. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. MDText.com, Inc.; 2000-. https://www.ncbi.nlm.nih.gov/books/NBK279084/. Updated June 12, 2018.

7. Keely EJ. Postpartum thyroiditis: an autoimmune thyroid disorder which predicts future thyroid health. Obstet Med. 2011;4(1):7-11.

8. Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid Association guideline for the management of Graves’ hyperthyroidism. Eur Thyroid J. 2018;7(4):167-186.