Disorders that cause hyperthyroidism

INTRODUCTION — 

Several different disorders can cause hyperthyroidism. It is essential that the correct cause be identified because appropriate therapy depends upon the underlying mechanism of the hyperthyroidism. From a pathogenetic viewpoint, hyperthyroidism results from two different mechanisms that can be distinguished by the findings on the 24-hour radioiodine uptake or thyroid ultrasound with Doppler flow (table 1):

●Hyperthyroidism with a normal or high radioiodine uptake or thyroidal blood flow on ultrasound indicates de novo synthesis of hormone. These disorders can be treated with a thionamide, such as methimazole, which will interfere with hormone synthesis. (See "Thionamides in the treatment of Graves' disease".)

●Hyperthyroidism with a near absent radioiodine uptake or low thyroidal blood flow indicates either inflammation and destruction of thyroid tissue with release of preformed hormone into the circulation (destructive thyroiditis) or an extrathyroidal source of thyroid hormone. Thyroid hormone is not being actively synthesized when hyperthyroidism is due to thyroid inflammation; as a result, thionamide therapy is not useful in these disorders.

This topic will review the main causes of hyperthyroidism and outline the therapeutic approach to the less common conditions. The treatment of Graves' disease and toxic nodular goiter and the diagnostic approach to patients with hyperthyroidism are discussed separately. (See "Diagnosis of hyperthyroidism".)

EPIDEMIOLOGY — 

The global prevalence of hyperthyroidism is 0.2 to 1.4 percent [1,2]. In the United States, the overall prevalence of hyperthyroidism is approximately 1.3 percent, and it increases to 4 to 5 percent in older women [3]. Hyperthyroidism is more common in women than men (5:1 ratio), and in smokers [4-6]. Graves' disease is seen most often in younger women and in regions of iodine sufficiency, while toxic nodular goiter is more common in older women and in regions of mild to moderate iodine deficiency.

INCREASED THYROID HORMONE SYNTHESIS — 

When hyperthyroidism is due to increased new thyroid hormone synthesis, thyroid radioiodine uptake will be high (or inappropriately normal given a suppressed thyroid-stimulating hormone [TSH] level). Thyroidal blood flow on ultrasound will be high or normal. Common causes of hyperthyroidism due to increased thyroid hormone synthesis include Graves' disease and autonomous thyroid tissue (eg, toxic adenoma, toxic multinodular goiter) (table 1). In patients with increased thyroid activity (de novo synthesis of hormone) who are receiving a continuous exogenous iodine load (eg, kelp tablets containing high concentrations of iodine, or amiodarone), radioiodine uptake will be "artifactually" low due to dilution of the radioiodine tracer. (See 'Iodine-induced hyperthyroidism' below and "Iodine-induced thyroid dysfunction", section on 'Iodine-induced hyperthyroidism'.)

Graves' disease — Graves' disease is the most common cause of hyperthyroidism [7]. It is an autoimmune disorder resulting from TSH-receptor antibodies (also called thyroid-stimulating immunoglobulins), which stimulate thyroid gland growth and thyroid hormone synthesis and release [8]. Stressful life events may be a risk factor for the disease [9]. Another risk factor may be a relatively high iodine intake [10]. Several drugs have been implicated with the onset of Graves' disease including lithium [11], interferon alfa [12], and alemtuzumab [13]. The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a rare cause of Graves' disease, and it has been reported after SARS-CoV-2 vaccination [14,15]. However, analysis of a population-based medical record database of 2.3 million people who received either an inactivated or mRNA coronavirus disease 2019 (COVID-19) vaccine failed to demonstrate a subsequent increase in the diagnosis of Graves' hyperthyroidism [16]. Ophthalmopathy and pretibial myxedema are additional autoimmune manifestations of Graves' disease. (See "Pathogenesis of Graves' disease".)

"Hashitoxicosis" — "Hashitoxicosis" (a neologism that combines "Hashimoto" and "thyrotoxicosis") is a term used to describe rare patients with autoimmune thyroid disease who initially present with hyperthyroidism and a high radioiodine uptake caused by TSH-receptor antibodies similar to Graves' disease [17] (see "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)"). This is followed by the development of hypothyroidism due to infiltration of the gland with lymphocytes and resultant autoimmune-mediated destruction of thyroid tissue similar to chronic lymphocytic thyroiditis (Hashimoto's thyroiditis).

The initial therapeutic considerations are similar to those for Graves' disease. However, hypothyroidism may intervene, making further antithyroid therapy unnecessary.

Toxic adenoma and toxic multinodular goiter — Toxic adenoma and toxic multinodular goiter are the result of focal and/or diffuse hyperplasia of thyroid follicular cells whose functional capacity is independent of regulation by TSH. Activating somatic mutations of the genes for the TSH receptor have been identified in both toxic adenomas and nodules of toxic multinodular goiters [18-20]. Similarly, activating mutations of the Gs-alpha protein have been identified in toxic adenomas [18,20], but it is uncertain whether they occur in toxic multinodular goiters [20]. Other mutations must also play a role because, in one study, mutations in neither of these genes were found in 15 toxic adenomas [21].

Mutations of the TSH-receptor gene are most common; they were found in 15 of 31 toxic adenomas in one study [22]. The mutations are usually in the transmembrane domain of the receptor but can be in the extracellular domain [22,23]. The mutant receptors activate adenylyl cyclase in the absence of TSH.

Toxic multinodular goiter tends to be more common in areas where iodine intake is relatively low [10]. In comparison, the frequency of thyroid adenomas is not related to iodine intake. (See "Treatment of toxic adenoma and toxic multinodular goiter".)

Iodine-induced hyperthyroidism — Iodine-induced hyperthyroidism can develop after an iodine load, as an example, after administration of contrast agents used for angiography or computed tomography (CT) or iodine-rich drugs such as amiodarone. However, this is uncommon. In a meta-analysis, the overall estimated prevalence of overt hyperthyroidism after iodine containing contrast was 0.1 percent [24].

In iodine-induced hyperthyroidism, the radioiodine uptake will be high only if sufficient time has passed for most of the administered iodine to be excreted. By comparison, the uptake will be low if iodine continues to be given or if the original preparation has a long biologic life because, despite the increase in thyroid activity, a recent exogenous iodine load will dilute the radioiodine tracer used to determine the uptake. These disorders are reviewed in detail elsewhere. (See "Iodine-induced thyroid dysfunction" and "Amiodarone and thyroid dysfunction".)

Trophoblastic disease and germ cell tumors — Hyperthyroidism can occur in women with a hydatidiform mole or choriocarcinoma or in men with testicular germ cell tumors via direct stimulation of the TSH receptor. High levels of isoforms of human chorionic gonadotropin (hCG) with more thyrotropic activity are responsible for the hyperthyroidism [25]. Therapy is directed against the tumor. Thionamides are useful adjunctive therapy since hormone synthesis is occurring within the thyroid. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'hCG-mediated hyperthyroidism' and "Serum tumor markers in testicular germ cell tumors", section on 'Hyperthyroidism and hCG'.)

TSH-mediated hyperthyroidism — Hyperthyroidism caused by increased thyroid-stimulating hormone (TSH) production is rare. Two forms, neoplastic and non-neoplastic, are recognized.

TSH-producing pituitary adenomas are usually macroadenomas by the time of diagnosis, and some are locally invasive [26,27]. Almost all of these patients have a goiter, 40 percent have a visual field defect, and one-third of women have galactorrhea. All patients have high serum thyroid hormone concentrations.

Therapy is directed at the pituitary tumor. Although not perfect, surgery is reasonably successful (two-thirds are improved or cured), particularly when the serum TSH concentration falls to a low level (<0.2 mU/L) one week after surgery [28]. Radioiodine or thyroid surgery are used only when transsphenoidal surgery, external beam radiotherapy, or somatostatin analogues do not control the hyperthyroidism.

Octreotide and the longer-acting somatostatin analogue lanreotide have been useful for suppressing TSH production in patients with these adenomas [27,29] and, given preoperatively, may permit more effective surgery of locally invasive tumors [30].

Further information about the clinical manifestations and treatment of these tumors can be found elsewhere. (See "TSH-secreting pituitary adenomas".)

Non-neoplastic, TSH-mediated hyperthyroidism is due to resistance to the feedback effect of thyroid hormone on pituitary TSH production. This condition is usually due to mutations in the nuclear triiodothyronine (T3) receptor [26,31]. Treatment is rarely satisfactory. T3 [31] and 3,5,3'-triiodothyroacetic acid (a derivative of T3) [32] have been effective in a few patients.

Another rare form of "TSH-induced" hyperthyroidism results from an activating mutation in the TSH receptor [33,34]. This disorder is transmitted as an autosomal dominant trait, and affected patients are hyperthyroid with appropriate suppression of TSH release.

Mild TSH-mediated hyperthyroidism after surgery for Cushing syndrome during periods of inadequate corticosteroid replacement has been reported [35].

Epoprostenol — Patients taking epoprostenol (prostaglandin I2) for pulmonary arterial hypertension may develop hyperthyroidism with an elevated radioiodine uptake and negative thyroid-stimulating immunoglobulin levels [36,37]. In one report, 3 of 45 patients developed hyperthyroidism after more than 1.5 years of therapy [36].

RELEASE OF PREFORMED THYROID HORMONE — 

Inflammation and destruction of thyroid tissue (thyroiditis) causes release of preformed hormone into the circulation, resulting in thyrotoxicosis. Patients with thyroiditis usually have low thyroidal blood flow on ultrasound and a radioiodine uptake of less than 1 percent (table 1).

Thyroiditis — The term destructive thyroiditis has been applied to a group of heterogeneous disorders that result in inflammation of thyroid tissue with transient thyrotoxicosis due to release of preformed hormone from the colloid space. This initial presentation is followed by a hypothyroid phase and then recovery of thyroid function. The definitions and clinical features of this disorder are reviewed elsewhere. (See "Overview of thyroiditis".)

When the term subacute thyroiditis is used without modification, it usually refers to subacute granulomatous thyroiditis (de Quervain's thyroiditis), which is a viral or postviral syndrome characterized by fever, malaise, and an exquisitely painful and tender goiter [38] (see "Subacute thyroiditis", section on 'Clinical features'). In comparison, painless thyroiditis (silent thyroiditis or subacute lymphocytic thyroiditis) is part of the spectrum of autoimmune thyroid disease [39] and has a particular proclivity to occur in the postpartum period (postpartum thyroiditis) [40]. (See "Painless thyroiditis" and "Postpartum thyroiditis".)

Other causes of thyroiditis include:

●Direct chemical toxicity with inflammation, which is one mechanism by which amiodarone can cause hyperthyroidism [41] (see "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring"). Sunitinib, pazopanib, axitinib, and other tyrosine kinase inhibitors may also be associated with a destructive thyroiditis [42,43]. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Sunitinib'.)

●Radiation thyroiditis, from external radiation or after radioiodine therapy.

●Drugs that interfere with the immune system, such as interferon alfa and the checkpoint inhibitors. The programmed death 1 (PD-1) inhibitors (eg, nivolumab and pembrolizumab) and the combination of a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; eg, ipilimumab) with a PD-1 inhibitor cause a destructive thyroiditis in which hyperthyroidism may more rapidly transition to hypothyroidism than with other causes of destructive thyroiditis [44]. (See "Overview of thyroiditis", section on 'Drug-induced thyroiditis' and "Overview of toxicities associated with immune checkpoint inhibitors", section on 'Endocrinopathies'.)

●A painful destructive thyroiditis possibly due to an autoimmune/inflammatory syndrome induced by adjuvants (ASIA) has been described after inactivated SARS-CoV-2 vaccine [45].

●Lithium. (See "Lithium and the thyroid".)

●Palpation thyroiditis occurring, as an example, during parathyroid surgery.

There is no role for antithyroid drugs or radioiodine in the treatment of thyrotoxicosis due to thyroiditis, because it is not caused by excess thyroid hormone synthesis and because uptake of radioiodine is very low. Therapy consists of beta blockers for symptomatic control and antiinflammatory drugs such as aspirin, nonsteroidal antiinflammatory drugs, or, in severe cases, prednisone. Therapy is discussed in more detail separately. (See "Overview of thyroiditis" and "Subacute thyroiditis" and "Painless thyroiditis" and "Postpartum thyroiditis".)

EXOGENOUS AND ECTOPIC HYPERTHYROIDISM — 

Exogenous or ectopic hyperthyroidism (hyperthyroidism resulting from excess thyroid hormone originating from outside the thyroid gland) can arise from external or internal sources of excess thyroid hormone. Thyroidal blood flow on ultrasound and thyroid radioiodine uptake will be low (table 1).

Examples of exogenous hyperthyroidism include:

●Factitious ingestion of thyroid hormone. (See "Exogenous hyperthyroidism".)

●Acute hyperthyroidism from a levothyroxine overdose. This disorder can be ameliorated with beta blockers, drugs that block the 5'-monodeiodinase (such as ipodate) and, in severe cases, plasmapheresis or dialysis. (See "Exogenous hyperthyroidism".)

Examples of ectopic hyperthyroidism include:

●Struma ovarii, in which functioning thyroid tissue is present in an ovarian neoplasm. Treatment consists of ovarian surgery. (See "Struma ovarii".)

●Functional thyroid cancer metastases, in which large, bony metastases from widely metastatic follicular thyroid cancer cause symptomatic hyperthyroidism. Treatment may require a variety of approaches including thionamides, radioiodine, surgery, or external radiotherapy. (See "Follicular thyroid cancer (including oncocytic carcinoma of the thyroid)", section on 'Metastases'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (The Basics)")

●Beyond the Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient education: Antithyroid drugs (Beyond the Basics)")

SUMMARY

●Epidemiology – The global prevalence of overt hyperthyroidism is 0.2 to 1.4 percent. Hyperthyroidism is more common in females and smokers. Graves' disease is seen most often in younger women and in regions of iodine sufficiency, while toxic nodular goiter is more common in older women and in regions of mild to moderate iodine deficiency. (See 'Epidemiology' above.)

●General principles – Several different disorders can cause hyperthyroidism. It is essential that the correct cause be identified because appropriate therapy depends upon the underlying mechanism of the hyperthyroidism. From a pathogenetic viewpoint, hyperthyroidism results from two different mechanisms that can be distinguished by the findings on the 24-hour radioiodine uptake or thyroidal blood flow on ultrasound (table 1). (See 'Introduction' above.)

●Increased thyroid hormone synthesis – When hyperthyroidism is due to increased new thyroid hormone synthesis, thyroid radioiodine uptake will be high (or inappropriately normal for the suppressed TSH level). Thyroidal blood flow on ultrasound will also be high or normal. Common causes of hyperthyroidism due to increased thyroid hormone synthesis include Graves' disease and autonomous thyroid tissue (eg, toxic adenoma, toxic multinodular goiter). (See 'Increased thyroid hormone synthesis' above.)

●Release of preformed thyroid hormone – Inflammation and destruction of thyroid tissue (destructive thyroiditis) causes release of preformed hormone into the circulation, resulting in thyrotoxicosis. Patients with destructive thyroiditis usually have low thyroidal blood flow on ultrasound and a radioiodine uptake of less than 1 percent. (See 'Release of preformed thyroid hormone' above.)

●Exogenous or ectopic hyperthyroidism – Exogenous or ectopic hyperthyroidism is caused by excess thyroid hormone originating from outside the thyroid gland. It can arise from external or internal sources of excess thyroid hormone. Thyroidal blood flow on ultrasound and thyroid radioiodine uptake will be low. (See 'Exogenous and ectopic hyperthyroidism' above.)

●Iodine-induced hyperthyroidism – Iodine-induced hyperthyroidism can occur after an iodine load in a patient with underlying autonomy in a nodule or nodular goiter. The radioiodine uptake will be high only if sufficient time has passed for the administered iodine to be excreted; iodine uptake is frequently low in patients with iodine-induced hyperthyroidism but is usually not under 1 percent unless the source of iodine is continuous (eg, a daily amiodarone tablet). (See 'Iodine-induced hyperthyroidism' above and "Iodine-induced thyroid dysfunction".)