Overview of thyroiditis

INTRODUCTION — The term thyroiditis encompasses a diverse group of disorders characterized by some form of thyroid inflammation (table 1). They include conditions that cause acute illness with severe thyroid pain (eg, subacute thyroiditis and infectious thyroiditis) and conditions in which there is no clinically evident inflammation and the illness is manifested primarily by thyroid dysfunction or goiter (eg, painless thyroiditis and fibrous [Riedel's] thyroiditis) [1,2].

This topic review provides an overview of the different types of thyroiditis. These disorders can be categorized in several ways: according to their known or suspected etiology, their pathology, or their clinical features. The approach we use is to categorize thyroiditis according to whether it is associated with thyroid pain and tenderness because the presence or absence of those findings dominates the major diagnostic considerations (table 1). The clinical manifestations, diagnosis, and management of several of the individual disorders, ie, subacute thyroiditis (or subacute granulomatous thyroiditis), painless thyroiditis, and postpartum thyroiditis, are discussed in more detail elsewhere, as is chronic autoimmune thyroiditis (Hashimoto's thyroiditis).

●(See "Subacute thyroiditis".)

●(See "Painless thyroiditis".)

●(See "Postpartum thyroiditis".)

●(See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)".)

NOMENCLATURE — There is some controversy concerning the nomenclature used to categorize the different forms of thyroiditis. However, most thyroidologists use the following terms:

●Chronic autoimmune thyroiditis (Hashimoto's thyroiditis) – Hashimoto's thyroiditis is characterized by gradual thyroid failure, with or without goiter formation, due to lymphocytic infiltration and autoimmune-mediated destruction of the thyroid gland. Serum concentrations of thyroid peroxidase (TPO) autoantibodies are elevated in more than 90 percent of patients. (See "Disorders that cause hypothyroidism", section on 'Chronic autoimmune (Hashimoto's) thyroiditis'.)

●Painless thyroiditis – Painless thyroiditis is also known as silent thyroiditis and lymphocytic thyroiditis with spontaneously resolving hyperthyroidism. It is considered a variant from of chronic autoimmune thyroiditis (Hashimoto's thyroiditis). (See "Painless thyroiditis".)

●Postpartum thyroiditis – Postpartum thyroiditis is painless thyroiditis that occurs within one year after childbirth or a spontaneous or induced abortion. (See "Postpartum thyroiditis".)

●Subacute thyroiditis – The term subacute thyroiditis typically applies to a specific disease called subacute granulomatous thyroiditis. Other names for this disorder include subacute nonsuppurative thyroiditis, giant cell thyroiditis, painful thyroiditis, and de Quervain's thyroiditis. (See "Subacute thyroiditis".)

●Infectious thyroiditis – Infectious thyroiditis (also called suppurative thyroiditis), may be caused by gram-positive or gram-negative organisms, which reach the thyroid either via hematogenous spread, usually in an immunocompromised patient. (See 'Infectious thyroiditis' below.)

●Fibrous thyroiditis – Fibrous thyroiditis is also known as Riedel's thyroiditis or invasive thyroiditis. It is characterized by extensive fibrosis and macrophage and eosinophil infiltration of the thyroid gland that extends into adjacent tissues. (See "Infiltrative thyroid disease", section on 'Riedel's thyroiditis'.)

THYROIDITIS WITH THYROID PAIN AND TENDERNESS — Causes of this pattern of thyroiditis include subacute, infectious, traumatic, and radiation thyroiditis. Painful Hashimoto's thyroiditis is very rare and, in some circumstances, has been treated surgically [3].

Subacute thyroiditis — In the hyperthyroid phase, subacute thyroiditis (subacute granulomatous thyroiditis) is characterized by neck pain; a tender, diffuse goiter; and elevated thyroxine (T4) and/or triiodothyronine (T3). The classic pattern of changes in thyroid function in patients with subacute thyroiditis is hyperthyroidism, followed by hypothyroidism, and then recovery (figure 1). (See "Subacute thyroiditis".)

Hyperthyroidism, when it occurs, is due to damage to thyroid follicular cells and breakdown of stored thyroglobulin, leading to unregulated release of T4 and T3. Since ongoing synthesis of the thyroid hormones is inhibited due to thyroid-stimulating hormone (TSH) suppression and thyroid radioiodine uptake is low during the hyperthyroid phase (in contrast to Graves' hyperthyroidism), the hyperthyroidism lasts only until the stores of T4 and T3 are depleted, usually two to six weeks. Hypothyroidism is also usually transient but can occasionally be permanent.

Subacute thyroiditis is presumed to be caused by a viral infection or postviral inflammatory process because many patients have a history of an upper respiratory infection preceding the onset of thyroiditis, and clusters of cases have occurred in association with epidemics of Coxsackievirus or other viral infections. There is a strong association with human leukocyte antigen (HLA)-B35. (See "Subacute thyroiditis".)

Infectious thyroiditis

●Clinical manifestations – Infectious thyroiditis may be either acute or chronic. Acute infectious thyroiditis is characterized by the sudden onset of neck pain and tenderness that is usually unilateral and accompanied by fever, chills, and other symptoms and signs of infection. Most patients have a unilateral neck mass, which may be fluctuant. Thyroid function in patients with acute infectious thyroiditis is usually normal, but thyrotoxicosis may be present [4].

Patients with more chronic thyroid infections often have bilateral disease. Thyroid pain and tenderness are less prominent than with acute infections, and some patients have hypothyroidism.

●Pathogens – The organisms most commonly reported to cause acute infectious thyroiditis are Staphylococcus and Streptococcus, but many other pathogens have also been reported [4,5]. Acute infectious thyroiditis with abscess formation may be caused by gram-positive or gram-negative organisms, which reach the thyroid either via hematogenous spread, usually in an immunocompromised patient or via a fistula from the piriform sinus adjacent to the larynx [4]. The latter is probably the most common cause of suppurative thyroiditis, and it usually occurs in children.

Other infections of the thyroid (including mycobacterial, fungal, and Pneumocystis infections) are more chronic, and these infections occur most frequently in immunocompromised patients [6-8].

●Evaluation – Acute neck pain and tenderness and a thyroid mass may be caused by infectious thyroiditis, hemorrhage into a thyroid nodule, or subacute thyroiditis. Fever and thyroid pain may occur with both subacute thyroiditis and a thyroid abscess. (See "Subacute thyroiditis", section on 'Clinical features'.)

If thyroid abscess is suspected, rapid evaluation, diagnosis, and treatment is required. Evaluation includes clinical examination, ultrasonography, and fine-needle aspiration (FNA) of the mass. Thyroid ultrasound can differentiate between subacute thyroiditis (diffuse heterogeneity and low intensity vascular flow) and infectious thyroiditis (abscess). A thyroid FNA may be indicated to help differentiate subacute thyroiditis and thyroid cyst from a thyroid abscess. In subacute thyroiditis, cytology shows multinucleated giant cell granulomas. In infectious thyroiditis, an FNA would show neutrophils. Appropriate staining and culture of the thyroid fluid obtained will help determine if there is an abscess present.

For patients with chronic thyroid infection, additional radiologic studies to identify fistulae or tracts contributing to the disease process may be warranted. Otolaryngology consult and relevant head and neck examination may also be helpful in this regard.

●Treatment – If abscess is present on ultrasound, it should be drained and antibiotic therapy initiated according to the results of studies of the fluid obtained from the neck mass or of blood or other cultures. Intravenous antibiotics are generally preferred over oral antibiotics as initial treatment for acute bacterial thyroiditis [4]. Infrequently, surgical drainage or removal is required in patients who do not respond to percutaneous drainage and systemic antibiotic therapy.

Radiation thyroiditis — An occasional patient with hyperthyroidism caused by Graves' disease, who is treated with radioiodine, develops thyroid pain and tenderness 5 to 10 days later, due to radiation-induced injury and necrosis of thyroid follicular cells and associated inflammation. The neck pain and tenderness are usually mild and subside spontaneously in a few days to one week. There also may be transient exacerbation of the hyperthyroidism. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Adverse effects'.)

Palpation or trauma-induced thyroiditis — Vigorous palpation of the thyroid gland during physical examination, manipulation of the gland during thyroid biopsy or neck surgery, especially parathyroid surgery, or even trauma (ie, from an automobile seat belt) can cause thyroiditis, manifested by transient neck pain and tenderness and transient hyperthyroidism [9-13].

THYROIDITIS WITHOUT PAIN AND TENDERNESS — Causes of this pattern of thyroiditis include painless, postpartum, drug-induced, and fibrous thyroiditis.

Painless thyroiditis — Painless thyroiditis is characterized primarily by transient hyperthyroidism, followed sometimes by hypothyroidism, and then recovery (figure 1). Painless thyroiditis should be considered as the cause of hyperthyroidism in any patient who has had symptoms for less than two months and has a small diffuse goiter or no thyroid enlargement. The key clinical findings are mild hyperthyroidism of short duration, little or no thyroid enlargement, and no Graves' ophthalmopathy or pretibial myxedema. (See "Painless thyroiditis".)

Painless thyroiditis accounts for 1 to 5 percent of cases of hyperthyroidism, although the frequency has increased due to the use of tyrosine kinase inhibitors and immune checkpoint inhibitor therapy. It is considered a variant form of chronic autoimmune thyroiditis (Hashimoto's thyroiditis), suggesting that it is part of the spectrum of thyroid autoimmune disease. It can also be caused by administration of interferon alfa, interleukin 2, or lithium administration, although the pathogenesis of these disorders may be different. (See 'Drug-induced thyroiditis' below.)

Postpartum thyroiditis — Postpartum thyroiditis is similar clinically and pathogenetically to painless thyroiditis except that, by definition, it occurs in women within one year after parturition (or after spontaneous or induced abortion). Based upon biochemical studies, it occurs after approximately 8 to 10 percent of pregnancies, although the number of women with clinically evident thyroid disease is lower. In clinically hyperthyroid women, it must be distinguished from postpartum exacerbations of Graves' disease. (See "Postpartum thyroiditis".)

Postpartum thyroiditis differs from painless thyroiditis in that more patients have elevated levels of serum antithyroid antibody (ie, antithyroglobulin or antithyroid peroxidase antibodies) concentrations, the concentrations are higher, and the likelihood of permanent thyroid disease later is greater. This apparent difference may reflect the greater ease of studying postpartum women prospectively than women in the general population. (See "Painless thyroiditis".)

Drug-induced thyroiditis — Patients receiving interferon alfa, interleukin 2, amiodarone, lithium, a tyrosine kinase inhibitor, or checkpoint inhibitor immunotherapy may develop painless thyroiditis. Its occurrence in patients receiving these drugs does not seem coincidental, and the evidence of a causal association is best for interferon alfa and tyrosine kinase inhibitors.

Interferon alfa — The most common interferon alfa-associated thyroid abnormality is the development of de novo antithyroid antibodies without clinical disease (5 to 15 percent). Approximately 5 to 10 percent of patients develop clinical thyroid disease, including painless thyroiditis, Hashimoto's thyroiditis, or Graves' disease [14]. These changes usually appear after three months of therapy but can occur as long as interferon alfa is given. The risk of any form of thyroid dysfunction is greater in those patients who have increased serum antithyroid antibody concentrations before initiation of interferon alfa, a finding that suggests that it in some way exacerbates underlying thyroid autoimmune disease.

Interleukin 2 — Patients with metastatic cancer and leukemia are sometimes treated with interleukin 2, usually in combination with other cytokines or anticancer drugs. In several studies, a syndrome mimicking painless thyroiditis occurred in approximately 2 percent of the patients [15,16].

Amiodarone — Amiodarone is an anti-arrhythmic drug that contains 37 percent iodine. As a result, it can cause hyperthyroidism or hypothyroidism. There are two types of amiodarone-induced thyrotoxicosis (AIT). In type 1, there is increased synthesis of thyroid hormone (usually in patients with a preexisting nodular goiter), whereas in type 2, there is excess release of T4 and T3 due to a destructive thyroiditis. These types differ in their pathogenesis, management, and outcome. (See "Amiodarone and thyroid dysfunction", section on 'Differentiating the two types'.)

Lithium — Patients with mood disorders who are treated with lithium have an increased incidence of hyperthyroidism. In a retrospective study of patients with Graves' hyperthyroidism and painless thyroiditis, the odds of lithium exposure were higher in patients with painless thyroiditis as compared with those with Graves' disease (odds of exposure 4.7, 95% CI 1.3-17.1) [17]. (See "Lithium and the thyroid", section on 'Hyperthyroidism'.)

Kinase inhibitors — Tyrosine kinase inhibitors are used to treat a variety of disorders (eg, gastrointestinal stromal tumors, renal cell carcinoma, and differentiated and medullary thyroid cancer). In euthyroid patients with intact thyroid glands, these agents have been associated with the development of hypothyroidism and an elevated TSH in approximately 50 to 70 percent of patients [18]. Hypothyroidism has been most frequently reported with sunitinib, but it appears to be a class effect and probably can occur with any tyrosine kinase inhibitor. Hyperthyroidism, possibly from a destructive thyroiditis, has also been reported. This topic is reviewed in detail separately. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Thyroid dysfunction'.)

Checkpoint inhibitor immunotherapy — Immunologic checkpoint inhibition agents targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) receptor are used to treat patients with advanced melanoma and are rapidly being explored as therapy for other malignancies. They are associated with clinically significant endocrinopathies, the most common of which are hypophysitis and hypothyroidism (secondary to a destructive thyroiditis) [19]. This topic is reviewed in detail separately. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Endocrinopathies'.)

Fibrous thyroiditis — Fibrous thyroiditis, also known as Riedel's thyroiditis or invasive thyroiditis, is characterized by extensive fibrosis and macrophage and eosinophil infiltration of the thyroid gland that extends into adjacent tissues [20]. It is probably a primary fibrosing disorder and has been reported in patients who also had mediastinal and retroperitoneal fibrosis. This disease complex is thought to be part of the immunoglobulin G 4 (IgG4)-related systemic disease system [21,22].

Affected patients have neck discomfort or tightness, sometimes dysphagia or hoarseness, and a diffuse, although occasionally asymmetric, goiter that is very hard, fixed, and often not clearly separable from the adjacent tissues. Most patients are euthyroid, but a few are hypothyroid, and serum antithyroid antibody concentrations are often high. The diagnosis is established by thyroid biopsy. Patients should be evaluated for evidence of systemic fibrosis in other areas, such as mediastinum and retroperitoneal areas. The clinical manifestations and treatment of Riedel's thyroiditis is reviewed in more detail separately. (See "Infiltrative thyroid disease", section on 'Riedel's thyroiditis'.)

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 topic (see "Patient education: Thyroiditis after pregnancy (The Basics)")

SUMMARY

●Nomenclature – The term thyroiditis encompasses a diverse group of disorders characterized by some form of thyroid inflammation (table 1). (See 'Nomenclature' above.)

●Thyroiditis with thyroid pain and tenderness – Thyroiditis that presents with thyroid pain and tenderness is typically caused by subacute thyroiditis and, less frequently, by infectious or traumatic etiologies. It may also occur after radioiodine therapy. (See 'Thyroiditis with thyroid pain and tenderness' above.)

●Thyroiditis without pain and tenderness – Causes of this pattern of thyroiditis include painless, postpartum, drug-induced, and fibrous thyroiditis. Painless thyroiditis is often autoimmune mediated and can also occur after exposure to certain drugs, such as interferon alfa, interleukin 2, lithium, tyrosine kinase inhibitors, and checkpoint inhibitor immunotherapy. (See 'Thyroiditis without pain and tenderness' above and 'Drug-induced thyroiditis' above and "Toxicities associated with immune checkpoint inhibitors", section on 'Autoimmune thyroid disease'.)

●Thyroid function in subacute and painless thyroiditis – The classic pattern of changes in thyroid function in patients with subacute and painless thyroiditis is hyperthyroidism, followed by hypothyroidism and then recovery (figure 1). Hyperthyroidism, when it occurs, is due to damage to thyroid follicular cells and breakdown of stored thyroglobulin, leading to unregulated release of thyroxine (T4) and triiodothyronine (T3). Hyperthyroidism lasts only until the stores of T4 and T3 are depleted, usually two to six weeks. Hypothyroidism is also usually transient but can rarely be permanent. (See 'Subacute thyroiditis' above and 'Painless thyroiditis' above.)