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Authors: Roberto Toni, M.D.,Ph.D., Anastassios G. Pittas, M.D.
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1. Goal

To learn the causes, symptoms and management of hyperthyroidism.

2. Learning Objectives

  • To learn the differential diagnosis of hyperthyroidism (primary vs. secondary vs. exogenous)
  • To understand the pathophysiology of the common causes of hyperthyroidism, such as Graves' disease, toxic multinodular goiter, thyrotoxic phase of subacute thyroiditis, and toxic adenoma
  • To learn the symptoms of hyperthyroidism as well as additional symptoms specific for each cause of hyperthyroidism that help in making the diagnosis
  • To learn the biochemical evaluation of hyperthyroidism
  • To be able to differentiate between the common causes of hyperthyroidism based on radioactive iodine uptake
  • To learn the management of hyperthyroidism (general concepts only, including classes and mechanisms of medications)

3. Etiology of Hyperthyroidism

Thyrotoxicosis refers to the presence of excess thyroid hormone from any cause that may or may not result in symptoms. Hyperthyroidism refers to excess thyroid hormone from hyperactivity of the thyroid gland (excess production or release). In clinical practice, these terms are used interchangeably. The causes of hyperthyroidism based on TSH measurement are shown in Table 1. Specific causes are described in detail below.

Table 1. Causes of Thyrotoxicosis
Low TSH
  • Primary
  • Graves' disease
    • Graves' disease, ~ 60% of all cases of thyrotoxicosis
    • Toxic multinodular goiter
    • Hyperthyroid phase of thyroiditis
      • Painful subacute thyroiditis (pseudogranulomatous De Quervain's)
      • Painless lymphocytic thyroiditis
      • Post-partum thyroiditis
    • Toxic adenoma
    • Iodine-induced
    • Metastatic thyroid carcinoma, rare
    • Excess beta-HCG from a molar pregnancy or choriocarcinoma
  • Ectopic/Exogenous, rare
    • Thyrotoxicosis Factitia (excessive ingestion of thyroid hormone, usually T3), rare
    • Struma ovarii (thyroid hormone producing), rare
Elevated or inappropriately normal TSH
  • TSH producing pituitary adenoma, rare
  • Thyroid hormone resistance (symptoms may not be present), rare

3.1. Graves' Disease (Diffuse Toxic Goiter)

3.1.1. Epidemiology/Pathophysiology

Graves' disease is the most common form of hyperthyroidism accounting for 60-70% of all cases. It occurs in up to 3% of the population. There is a strong familial component and the disease is more common in women (F:M ratio 5:1) in the third and fourth decade.

Graves' disease is an autoimmune disorder of unknown cause, characterized by circulating antibodies against various thyroid antigens. The most important antibody is the TSH receptor antibody (TSH-R Ab) which is directed against the TSH receptor on the thyroid follicular cell membrane. TSH-R Ab most often act as TSH receptor agonists increasing the activity of adenylate cyclase, increasing intracellular cyclic AMP levels which result in cellular overactivity (increased iodine uptake and thyroid hormone synthesis and release). TSH-R Ab are present in the majority of patients with active Graves' disease. TSH-R Ab that bind to the TSH receptor but act as antagonists may be found in some patients with autoimmune hypothyroidism. Similar to other autoimmune diseases, Graves' may be cyclic with exacerbations and remissions. In most patients, there is ongoing destructive inflammation of the thyroid gland that eventually results in a "burn out" form of the disease leading to hypothyroidism over a period of many years.

The autoimmune and hereditary nature of Graves' disease is highlighted by its familial predisposition, clinical overlap with autoimmune Hashimoto's thyroiditis, and its association with other autoimmune diseases such as pernicious anemia, myasthenia gravis, vitiligo, Addison's disease (autoimmune adrenalitis leading to adrenal insufficiency), and type 1 diabetes mellitus. The basic defect in Graves’ disease is an HLA-related organ specific defect in suppressor T-lymphocyte function. Precipitating factors from the environment (e.g.. stress, infection, drugs, trauma) may cause further dysfunction in suppressor T-lymphocyte which together with the genetic abnormality result in the activation of thyroid directed helper T-lymphocytes. The activated helper T-lymphocytes become sensitized to thyroid antigens and stimulate specific B-lymphocytes to produce TSH-R Ab. Antibodies against other thyroid antigens such as thyroid peroxidase (TPO) and thyroglobulin (TG) are also present in patients with Graves' disease.

The pathogenesis of the ophthalmopathy (see clinical findings below) associated with Graves' disease is not clear. Cytotoxic lymphocytes and antibodies sensitized to a common antigen between the thyroid and orbital fibroblasts and muscle tissue are implicated. Infiltration of the fibrous tissue and extraocular muscles and edema give rise to the ophthalmopathy.

3.1.2. Clinical Findings

Graves' disease is often characterized by very high circulating levels of thyroid hormone which give rise to many of the symptoms and signs shown in Table 1. Other symptoms and signs of hyperthyroidism specific to Graves' include: diffuse symmetrical goiter (enlarged thyroid), ophthalmopathy, and dermopathy. The latter two conditions are not common, but they are highly specific for Graves' disease.

Graves' ophthalmopathy is characterized chiefly by periorbital edema and proptosis (forward displacement of the globe due to swelling of extraocular muscles in the bony orbit). Other manifestations include: chemosis (swelling of the conjunctiva), extraocular muscle dysfunction (most commonly the inferior rectus limiting upward gaze), keratitis (inflammation of the cornea) and loss of vision from optic nerve involvement. Graves' ophthalmopathy follows a course that is often independent of the thyrotoxicosis and is unaffected by the treatment for the excessive thyroid hormone. It is usual bilateral but can be unilateral. This infiltrative ophthalmopathy is seen only in Graves' disease and should be differentiated from the common ocular clinical findings of thyrotoxicosis from any cause (lid retraction, stare and lid lag). The latter changes arise from hyperactivity of the sympathetically innervated Mueller's fibers in the upper palpebral muscle and resolve when the thyrotoxicosis in treated.

Grave's dermopathy is an uncommon clinical finding of Graves' disease, characterized by thickening of the skin especially in the anterior tibial area and it is due to deposition of glycosaminoglycans which cause local fluid retention.

3.1.3. Laboratory & Imaging Evaluation

Increased thyroxine (T4) and triiodothyronine (T3) levels in the setting of suppressed serum TSH confirm the diagnosis of hyperthyroidism (see below for an algorithm for the differential diagnosis of hyperthyroidism). Because of the rapid turnover and synthesis of new thyroid hormone and the immunologic damage to the follicular cell, T3 is usually secreted in excess of T4 in Graves' disease. The ratio of T3 (ng/dL) to T4 (mcg/dL) is usually > 20. Occasionally, T4 levels are normal and T3 may be the only hormone that is elevated. If ophthalmopathy is present, then the diagnosis of Graves' may be made without any further diagnostic tests. If eye signs are not present, then functional imaging of the thyroid should be done with radioactive iodine (I-123) or 99m-Technicium scan. An elevated, diffuse and symmetric I-123 thyroid uptake is highly suggestive of Graves' disease (see Functional Imaging below). Thyroid autoantibodies are frequently present. TSH-R Ab are specific but anti-TPO and anti-TG may also be present. In clinical practice, anti-TPO is often measured, as measurement of TSH-R Ab is not readily available. Orbital CT or MRI may be used to look for retro-orbital inflammation, especially in the setting of unilateral ophthalmopathy.

3.2. Toxic Multinodular Goiter (MNG)

3.2.1. Epidemiology/Pathophysiology

Toxic MNG accounts for approximately 20-30% of all patients with hyperthyroidism. Multinodular goiters occur 5 times more frequently in women than men. Thyrotoxicosis in MNG occurs when follicles with some degree of autonomy become large enough such that the overall hormone production is elevated. Large doses of iodide may precipitate thyrotoxicosis in patients with non-toxic multinodular goiters.

3.2.2. Clinical Findings

The presence of a non-toxic MNG for many years (>10) often antedates the development of the thyrotoxicosis. The extent of circulating thyroid hormones is mild compared to Graves' disease. Symptoms and signs are those of thyrotoxicosis (Table 2) but cardiovascular and muscular abnormalities predominate. Symptoms may be less evident due to the moderate increase in thyroid hormones and gradual onset, and they may be blunted in elderly or chronically ill patients (apathetic thyrotoxicosis, see below). Although generally mild, the thyrotoxicosis is unremitting without treatment.

3.2.3. Imaging Evaluation

Serum TSH is suppressed and T4 and T3 may be high normal or only marginally elevated. Radioiodine (I-123) or 99m Technetium scan typically shows areas of increased (“hot” or “warm”) and decreased (“cold” or “cool”) uptake corresponding to the multiple thyroid nodules. The glands have nodules that may vary in size from a few mm to several cm. The nodules consist of solid follicular adenomas (hyperplasia), colloid-rich nodules or degenerative cystic structures. The nodules filled with colloid, or cystic fluid will appear as an area of low isotope uptake or a "cold/cool” nodule on a thyroid scan. High isotope uptake in "hot/warm" nodules is due to relatively autonomous hyperplastic follicular cells.

3.3. Subacute Thyroiditis

Subacute thyroiditis is due to destruction of the thyroid gland often seen in the setting of an upper respiratory illness. Destruction leads to release of thyroid hormone in the circulation (rather than from an increase in synthesis of hormone). Symptoms/signs are those of hyperthyroidism (Table 2). Subacute thyroiditis is diagnosed based on a very low radioiodine I-123 uptake. Following the thyrotoxic phase, subacute thyroiditis may progresses to hypothyroidism, which is almost always transient. In the majority of patients, thyroid function recovers and euthyroidism ensues but it may take 6-12 months for full recovery. Treatment is supportive. No inhibitors of thyroid hormone synthesis are required.

3.4. Toxic Adenoma

Toxic adenomas account for 3-5% of thyrotoxicosis and occur in a younger age group compared to Graves or toxic MNG. Thyrotoxicosis is caused by a single hyperfunctioning follicular thyroid adenoma. More than half of toxic adenomas contain a somatic activating mutation in the TSH receptor resulting in overproduction of thyroid hormone in the monoclonal tumor. The excess thyroid hormone secreted by the adenoma, , inhibits pituitary TSH secretion resulting in the remainder of the thyroid gland becoming quiescent (suppressed). Radioiodine I-123 scan shows a "hot" nodule while the remainder of the gland is suppressed. The treatment of choice is ablation with radioiodine 1-131.

3.5. Iodine-Induced Thyrotoxicosis

The administration of iodides may induce thyrotoxicosis (Jod Basedow's syndrome) in patients with an iodine deficient (endemic) goiter, a multinodular goiter with areas of autonomy or an autonomous nodule. The pathogenesis is not clear, but reflects the loss of the normal adaptation of the thyroid to iodine excess. Iodine-induced hyperthyroidism is usually mild and will ultimately remit after stopping the source of the iodine.

3.6. Metastatic Thyroid Carcinoma

Thyrotoxicosis due to autonomous metastatic thyroid carcinoma occurs rarely and should be suspected if hyperthyroidism appears in a patient with a previous history of follicular thyroid carcinoma.

3.7. Molar Hydatiform Pregnancy and Choriocarcinoma

Many patients with these disorders have hyperthyroidism due to the thyroid stimulatory effects of excess human chorionic gonadotropin (hCG). hCG has weak thyrotropic activity as it shares a common subunit (alpha) with TSH. The excessive levels of beta-HCG results in "cross-over" stimulation of TSH receptors and results in oversecretion of thyroid hormone. Symptoms/signs are those of hyperthyroidism. Treatment of the thyrotoxicosis consists of removing the abnormal trophoblastic tissue.

3.8. Thyrotoxicosis Factitia

Surreptitious ingestion of thyroid hormone, most often seen in psychiatric patients, medical professionals and some individuals who wish to lose weight. Thyrotoxicosis Factitia must be distinguished from subacute thyroiditis and struma ovarii. Patients taking excessive doses of either T4 (L-thyroxine) or T3 (triiodothyronine) will suppress TSH levels. The low TSH levels result in decreased radioiodide I-123 uptake and decreased secretion of thyroglobulin.

3.9. Struma Ovarii

Ectopic thyroid tissue associated with dermoid tumors or ovarian teratoma may secrete excessive thyroid hormone and produce symptoms and signs of thyrotoxicosis. Diagnosis is established by radioiodide scanning of the pelvic area (routine radioiodine scan over the neck shows decreased or absent uptake). This test should be performed in all female patients with thyrotoxicosis with ovarian masses or ascites and low thyroidal radioiodide uptake. The thyrotoxicosis responds to the removal of the ovarian tumor.

3.10. TSH Producing Pituitary Tumors

This is an extremely rare condition. Thyrotoxicosis is due to oversecretion of TSH from a pituitary tumor.

3.11. Resistance to Thyroid Hormone

A rare syndrome in which the pituitary is resistant to the suppressive effects of T4 and T3 resulting in excess TSH release, stimulation of the thyroid and subsequent clinical hyperthyroidism.

4. Clinical Presentation of Hyperthyroidism

Hyperthyroidism manifests in a variety of clinical and biochemical findings produced by excessive amounts of thyroid hormone. The symptoms and signs of hyperthyroidism, shown in Table 2, are shared among all etiologies and their severity correlates with the level of circulating thyroid hormone. Many symptoms are due to increased sensitivity of the body to catecholamines. Many of the symptoms are, at least partially, relieved by adrenergic antagonists (see treatment, below).

Table 2. Symptoms and Physical Signs of Thyrotoxicosis
General Weight loss, heat intolerance, insomnia
Skin Sweating, palmar erythema, onycholysis (nail separation from nail bed)
Nervous System Tremor, Nervousness, anxiety, hyperkinesis
Cardiovascular Dyspnea on exertion
Palpitations, arrhythmia (atrial fibrillation)
Increased systolic BP, decreased diastolic BP, Increased cardiac output
Reproductive Irregular menses, amenorrhea, infertility
Gastrointestinal Increased frequency of bowel movements
Musculoskeletal Myalgia, proximal muscle weakness, hypokalemic periodic paralysis
Osteopathy (subperiosteal bone formation and swelling)
Head and Neck Lid lag, stare, lid retraction
Goiter
Specific for Graves ophthalmopathy (proptosis, chemosis, conjuctival injection)

4.1. Uncommon Presentations of Hyperthyroidism

Apathetic thyrotoxicosis. In some elderly patients, thyrotoxicosis may exist without the adrenergic- peripheral manifestations. These patients may be depressed, appear apathetic and may even be diagnosed as having myxedema (hypothyroidism). The most common cause of thyrotoxicosis in this population is a toxic multinodular goiter with mild thyrotoxicosis. Most patients will have weight loss, evidence of cardiomyopathy, myopathy and may have atrial fibrillation, congestive heart failure, cardiomegaly and muscle weakness.

Thyroid storm. This is a decompensated form of severe thyrotoxicosis that is an uncommon, but life-threatening condition. Precipitating factors are infections, trauma, surgical emergencies or operations, eclampsia, parturition, and diabetic ketoacidosis. Clinically presentation occurs with high fever, tachycardia, delirium, psychosis, restlessness, prostration, nausea, vomiting, and abdominal pain. Apathy, stupor and coma may occur.

5. Clinical and Imaging Evaluation of Hyperthyroidism

Laboratory evaluation of thyrotoxicosis begins with a measurement of TSH. If TSH is suppressed (<0.03), then the levels of T4 and T3 need to be measured. The work-up then proceeds as shown in the figure. Often both thyroxine (T4) and triiodothyronine (T3) are elevated. A small number of hyperthyroid patients (<5%) will have only a T3 increase (termed T3 thyrotoxicosis). It is therefore important that when hyperthyroidism is suspected, T3 levels are checked (see Figure 1 below).

Figure 1. Diagnostic Algorithm for Thyrotoxicosis
Figure. Diagnostic Algorithm for Thyrotoxicosis

Following biochemical testing to confirm the thyrotoxicosis, the most useful test is the radioiodide (I-123) uptake and scan (see below).

The appearance of the thyroid uptake and scan for the most common causes of thyrotoxicosis is shown in Table 3 below.

Table 3. Functional (Nuclear) Imaging for Thyrotoxicosis
Table 3. Functional (Nuclear) Imaging for Thyrotoxicosis

6. Therapy of Hyperthyroidism

6.1. Beta Adrenergic Blockers

Beta blockers relieve many of the peripheral manifestations of thyrotoxicosis and they are the first-line in the treatment of a thyrotoxic patient's severe symptoms (tremor, tachycardia, atrial fibrillation, palpitations or nervousness). Their role is adjunctive rather than primary in the treatment of hyperthyroidism. Propranolol inhibits extrathyroidal conversion of T4 to T3 and it is therefore the preferred beta-blocker. Side effects of beta-blockers should be considered.

6.2. Thionamides

Thionamides (propylthiouracil [PTU] and methimazole) inhibit thyroid hormone synthesis through inhibition of thyroidal peroxidase, prevention of oxidation of trapped iodine, inhibition of coupling of iodotyrosines, inhibition of conversion of T4 to T3 (PTU only). There is no effect on release of preformed hormone stores. Therefore, hormone is continually released until gland is depleted (in weeks) and serum thyroid hormones remain elevated until depletion. Thionamides are very effective medications. However, patients need to take them continuously for best results. Side effects (skin rash with pruritus or urticaria) occur in up to 15% of patients. The most serious complication is agranulocytosis that occurs with an incidence of approximately 0.5%. It may occur unpredictably during therapy and is reversible if the medication is stopped early. Patients on anti-thyroid medications should be advised to stop the drug and call their health care provider if they experience severe sore throat or high fever. Other rare reactions include neuritis, myalgia, arthralgia, hepatitis, thrombocytopenia, loss of taste, lymphadenopathy, edema, salivary gland enlargement and toxic psychosis.

6.3. Radioactive Iodine Ablation (I-131)

Radioactive iodine (I-131) acts by destroying the thyroid tissue through local radiation resulting from disintegration of the isotope. It is used to ablate hyperactive thyroid glands. The destructive radiation from radioactive iodine disintegration are beta rays that can travel only 2 mm and, therefore, does not damage surround structures. The major complication of I-131 therapy is hypothyroidism which occurs in most patients after such therapy is given. Radioiodide therapy can be administered as an outpatient, without discomfort or ill effects.

6.4. Iodine

Cold iodine is an adjunct therapy. Its main action is the rapid blocking of hormone release. It transiently will block iodine uptake (Wolff-Chaikoff effect) but most normal and autoimmune hyperfunctioning thyroid glands escape this inhibition. Therefore, even when T4 and T3 levels drop due to the decrease in thyroid secretion, thyroid hormone synthesis continues at an elevated rate. When the iodine is stopped, thyrotoxicosis will often become more severe due to the rapid release of stored hormone. It is the most effective drug in thyrotoxicosis crisis and in preparation for surgical removal of the hyperthyroid gland. One exception is thyroid autonomy from a toxic adenoma or toxic multinodular goiter do not escape and therefore can become severely thyrotoxic in the presence of high iodine levels.

6.5. Glucocorticoids

These are used in severe cases of thyrotoxicosis (e.g. thyroid storm) and subacute thyroiditis. High doses of glucocorticoids decrease thyroid hormone binding proteins and decrease peripheral conversion of T4 to T3. In severe subacute thyroiditis, glucocorticoids will lessen the inflammatory process.

6.6. Surgery

Subtotal or near total thyroidectomy may be done to remove the thyroid gland. The major complication is permanent hypothyroidism (less than 2%) and recurrent laryngeal nerve damage (less than 1%). Transient hypocalcemia may develop perioperatively. Permanent hypothyroidism occurs in the majority of patients. Given the availability of medications and I-131, few patients undergo surgery for thyrotoxicosis.

7. References

  • Pittas AG and Lee SL. Evaluation of thyroid disease in Hall JE, Nieman L, and Nieman L (editors), Handbook of Diagnostic Endocrinology . Humana Press, 2003
  • McIver, B, and Morris, J., "The Pathogenesis of Graves’ Disease" in Endocrinology and Metabolism Clinics of North America, M. Kaplan (ed), 27(1998) 73 - 90.
  • Siegel, R. And Lee, SL, "Toxic Nodular Goiter: Toxic Adenoma and Toxic Multinodular Goiter" in Endocrinology and Metabolism Clinics of North America, M. Kaplan (ed), 27(1998)151-168.