Subacute thyroiditis

INTRODUCTION — Most thyroidologists use the term subacute thyroiditis to apply specifically to subacute granulomatous thyroiditis. Other names for this disorder are subacute nonsuppurative thyroiditis, giant cell thyroiditis, painful thyroiditis, and de Quervain's thyroiditis. It is a relatively uncommon cause of hyperthyroidism and affects women more often than men (3 to 5:1) [1].

Subacute thyroiditis (subacute granulomatous thyroiditis) is characterized by neck pain or discomfort, a tender diffuse goiter, and a predictable course of thyroid function evolution. Hyperthyroidism is typically the presentation followed by euthyroidism, hypothyroidism, and ultimately restoration of normal thyroid function (figure 1).

The diagnosis and management of subacute thyroiditis will be provided here. Other types of thyroiditis are discussed separately. (See "Overview of thyroiditis".)

EPIDEMIOLOGY — The best available incidence data for subacute thyroiditis come from the Rochester Epidemiology Project in Olmsted county, Minnesota [2,3]. Between 1970 and 1997, 94 patients with subacute thyroiditis were identified. They report an incidence of 12.1 cases per 100,000/year with a higher incidence in females than in males (19.1 and 4.1 per 100,000/year, respectively). It is most common in young adulthood (24 per 100,000/year) and middle age (35 per 100,000/year), and it decreases in frequency with increasing age.

PATHOGENESIS — Subacute thyroiditis is presumed to be caused by a viral infection or a postviral inflammatory process. Many patients have a history of an upper respiratory infection prior to the onset of thyroiditis (typically two to eight weeks beforehand). The disease was thought to have a seasonal incidence (higher in summer) [4], and clusters of cases have been reported in association with Coxsackievirus, mumps, measles, adenovirus, SARS-CoV-2, and other viral infections [1,5-9]. However, in other series, there was a relatively comparable distribution of presentation throughout the year [2,10]. Serial studies of viral antibody titers have implicated many of the same viruses, but the changes could equally be attributed to nonspecific anamnestic responses [11]. Viral inclusion bodies are not seen in thyroid tissue.

Thyroid autoimmunity does not appear to play a primary role in the disorder, but it is strongly associated with human leukocyte antigen (HLA)-B35 in many ethnic groups [12]. A unifying hypothesis might be that the disorder results from a subclinical viral infection that provides an antigen, either of viral origin or resulting from virus-induced host tissue damage, that uniquely binds to HLA-B35 molecules on macrophages. The resulting antigen-HLA-B35 complex activates cytotoxic T lymphocytes that then damage thyroid follicular cells because the cells have partial structural similarity with the infection-related antigen. Unlike autoimmune thyroid disease, however, the immune reaction is not self-perpetuating, so the process is limited.

Whatever factors initiate subacute thyroiditis, the resulting thyroid inflammation damages thyroid follicles and activates proteolysis of the thyroglobulin stored within the follicles. The result is unregulated release of large amounts of thyroxine (T4) and triiodothyronine (T3) into the circulation resulting in clinical and biochemical hyperthyroidism. This state lasts only until the stores of thyroglobulin are exhausted because new hormone synthesis also ceases, not only because of damage to the thyroid follicular cells but also because of inhibition of thyroid-stimulating hormone (TSH) secretion by the increased serum T4 and T3 concentrations.

As the inflammation subsides, the thyroid follicles regenerate and thyroid hormone synthesis and secretion resume (figure 1). There is usually a period of rapid evolution through euthyroidism and then into hypothyroidism. The hypothyroidism lasts until the thyroid gland can generate sufficient thyroid hormone synthesis and secretion so that the patient regains normal homeostasis. Each phase typically lasts two to eight weeks with the possible exception of the initial transition through euthyroidism, which may be shorter. Recovery is nearly always complete. (See 'Clinical manifestations' below.)

PATHOLOGY — The thyroid is usually moderately enlarged in subacute thyroiditis. Large-needle thyroid biopsies reveal widespread infiltration with neutrophils, lymphocytes, histiocytes and giant cells, disruption and collapse of thyroid follicles, and necrosis of thyroid follicular cells. Later there may be some fibrosis, but eventually the gland histology returns to normal. Fine-needle aspiration biopsies reveal the same inflammatory cells, plus clusters of follicular cells and masses of colloid.

CLINICAL FEATURES

Clinical manifestations — In an analysis of 94 patients with subacute thyroiditis, pain was the presenting symptom in 96 percent [2]. The onset may be sudden or gradual and may be preceded by an upper respiratory infection. The pain may be limited to the region of the thyroid or radiate to the upper neck, jaw, throat, upper chest, or ears. Pain can be exacerbated by coughing or turning the head. As a result, some patients first consult an otolaryngologist. Fever, fatigue, malaise, anorexia, and myalgia are common [1].

The thyroid gland is typically slightly or moderately diffusely or asymmetrically enlarged, and it is nearly always tender. In some cases, the pain is so severe that the patient cannot tolerate palpation of the neck. Both thyroid lobes are involved from the beginning in most patients, but the pain, tenderness, and enlargement can be unilateral or start on one side and later spread to the other side days or even weeks (so called "creeping thyroiditis") later [1]. Approximately one-half of patients have symptoms and signs of hyperthyroidism, but the neck pain and tenderness usually dominate the illness, and the diagnosis should not routinely be made in their absence. Temperature elevations also can occur [13].

The thyroid inflammation and hyperthyroidism are transient, usually subsiding in two to eight weeks, even if the patient is not treated. It may be followed by a period of transient, usually asymptomatic hypothyroidism lasting from two to eight weeks or longer, but recovery is most frequently complete in the short term. In a follow-up study of 160 patients with subacute thyroiditis seen at the Mayo Clinic, 15 percent of patients eventually developed permanent hypothyroidism requiring levothyroxine therapy [2]. Only 4 percent of the patients had a recurrence (6 to 21 years after the initial episode). In another study, recurrence occurred in 1.6 percent of patients after 13.6±5.6 years [13].

Although the hyperthyroidism is usually mild and transient, it may rarely be associated with serious side effects such as ventricular tachycardia and thyroid storm [14,15].

Laboratory findings

●Thyroid tests – In addition to thyroid tenderness, nearly all patients have biochemical evidence of hyperthyroidism (high serum free T4 and T3 and low serum TSH concentrations) during the early stages of the illness, even though many have few, if any, symptoms of thyroid excess. The serum free T4 and T3 concentrations are usually only mildly elevated, and serum T3 is not typically disproportionately increased, as it is in some patients with Graves’ hyperthyroidism [16]. Hyperthyroidism is transient, lasting from two to eight weeks, and may be followed by a period of transient, usually asymptomatic, overt or subclinical hypothyroidism (high TSH and low, low-normal, or normal serum free T4 and T3).

●Inflammatory markers – The erythrocyte sedimentation rate is usually greater than 50 mm/hour and may exceed 100 mm/hour. C-reactive protein (CRP) may also be elevated [17].

●Other findings – Other characteristic laboratory findings (although not routinely needed to confirm diagnosis) include high serum thyroglobulin concentrations due to release from the thyroid gland, mild anemia, and leukocytosis. Liver function tests are also frequently abnormal during the initial hyperthyroid phase and then typically return to normal over the next one to two months as the disease improves [18]. The specific cause of the elevated liver function tests is unknown but could be related to the viral infection or less likely the hyperthyroidism. Serum antithyroid peroxidase or antithyroglobulin antibodies are usually undetectable or present at low titer. Some patients have increases in serum antithyroid antibody concentrations during the period of transient subclinical or overt hypothyroidism, probably caused by the response to release of thyroid antigens during the preceding period of inflammation [11].

Imaging studies — In patients with subacute thyroiditis and hyperthyroidism, a radioiodine or technetium imaging study will show low uptake (usually less than 1 to 3 percent) or a faint heterogeneous pattern of radionuclide uptake during the hyperthyroid phase (in the absence of previous recent exposure to high iodine-containing radiocontrast agents). On ultrasonography, the thyroid appears to be normal or enlarged but is diffusely or focally hypoechogenic regardless of its size [16,19]. Color Doppler sonography shows low flow during the hyperthyroid phase, whereas Graves' hyperthyroidism usually shows enhanced flow [20,21]. After recovery, thyroid ultrasonography appearance normalizes [20,22,23].

DIAGNOSIS — Subacute thyroiditis is fundamentally a clinical diagnosis. In most patients, clinical manifestations (the presence of neck pain, often radiating upward to the jaw; marked thyroid tenderness; and a diffuse goiter) are sufficient to establish the diagnosis. Symptoms and signs of hyperthyroidism may or may not be present, but the serum TSH is usually suppressed (typically <0.1 mU/L) and free T4 and total T3 concentrations elevated, particularly in the early stages of the illness.

Serum TSH, free T4, and total T3 should be measured in all patients in whom there is a clinical suspicion of subacute thyroiditis. We also typically measure an erythrocyte sedimentation rate or C-reactive protein (CRP) level and obtain a radioiodine or technetium imaging study. A high erythrocyte sedimentation rate and/or CRP measurement and a low radioiodine uptake (usually less than 1 to 3 percent) during the hyperthyroid phase help confirm the diagnosis. In patients with thyroid pain and mild hyperthyroidism, radioiodine or technetium imaging may be deferred and thyroid function monitored. If thyroid function normalizes and pain resolves within several weeks, the diagnosis of subacute thyroiditis is confirmed.

For patients in whom the clinical presentation is less obvious (eg, thyroid tenderness less prominent), thyroid ultrasonography may be useful to assess for cystic and/or solid masses. In addition, Doppler sonography may be used to distinguish subacute thyroiditis (decreased flow during hyperthyroid phase) from Graves' disease (enhanced flow). Rarely, fine-needle aspiration biopsy, typically under ultrasound guidance, is necessary to distinguish infection (eg, abscess), hemorrhage, thyroid cancer, or lymphoma from subacute thyroiditis. However, considering the possibility of the presence of a thyroid abscess is important in all cases of subacute thyroiditis.

DIFFERENTIAL DIAGNOSIS

●Acute infectious thyroiditis – The differential diagnosis of thyroid pain and goiter includes acute infectious (also called "suppurative") thyroiditis and hemorrhage into a thyroid nodule (table 1). Both infection and hemorrhage can cause severe thyroid pain and tenderness, but the thyroid abnormalities are predominantly unilateral. It is most important to differentiate acute infectious thyroiditis from subacute thyroiditis. The diagnosis of infection should be suspected if the patient has a leukocytosis and confirmed by ultrasonography and fine-needle aspiration biopsy. Patients with acute infectious thyroiditis usually have a cystic or mixed cystic/solid mass on ultrasound that may represent an abscess. A fine-needle aspiration would show neutrophils and should be analyzed with stains and cultures for bacteria, fungi, and parasites, as appropriate. Although thyroid function is usually normal, on rare occasions patients with infectious thyroiditis may present with hyperthyroidism. (See "Overview of thyroiditis", section on 'Infectious thyroiditis'.)

●Other causes of hyperthyroidism with low radioiodine uptake – When a low radioiodine uptake is noted, but the more classic clinical (or laboratory) manifestations of subacute thyroiditis such as neck discomfort and elevated sedimentation rate are lacking, the diagnosis of subacute thyroiditis may be more difficult. In this setting, a random urine iodine measurement may be helpful to distinguish subacute thyroiditis from other causes of a low radioiodine uptake (table 2). Urine iodine values are below approximately 500 mcg/L in patients with subacute thyroiditis. In contrast, in patients with low radioiodine uptake due to exposure to excess exogenous iodine (eg, radiocontrast materials, amiodarone), random urine iodine measurements are usually markedly elevated (>1000 mcg/L) for several weeks following the exposure. (See "Disorders that cause hyperthyroidism" and "Iodine-induced thyroid dysfunction", section on 'Iodine-induced hyperthyroidism'.)

●Autoimmune thyroid disease – Occasional patients with either chronic autoimmune thyroiditis (Hashimoto's thyroiditis) or Graves' hyperthyroidism have neck pain and tenderness. However, the pain in both conditions is much less severe than in subacute thyroiditis, while thyroid dysfunction should be much more severe. In Graves' hyperthyroidism, radioiodine uptake is high, not low. Painless (silent) and postpartum thyroiditis may cause similar changes in thyroid function and are associated with low radioiodine uptake, but thyroid gland or neck tenderness is not present (table 1) [24]. (See "Painless thyroiditis" and "Postpartum thyroiditis".)

One study suggests that there is an unusual entity of painful Hashimoto's thyroiditis characterized by chronic neck discomfort or pain [25]. Patients who have elevated thyroid antibodies and fine-needle aspiration and surgical pathology show Hashimoto's thyroiditis. This variant, painful Hashimoto's thyroiditis, does not respond well to corticosteroid therapy, in contrast to subacute thyroiditis.

●Thyroid cancer or lymphoma – Rarely, patients with thyroid nodules harboring thyroid cancer or patients with primary thyroid lymphoma may demonstrate thyroid gland discomfort or pain (so called "malignant pseudothyroiditis") [26]. Although not every patient suspected of having subacute thyroiditis requires a thyroid ultrasound, this test can be extremely helpful in ensuring that the patient does not have one of these conditions that can mimic many of the clinical findings of subacute thyroiditis. (See "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Criteria for identifying cancer'.)

●Temporal arteritis – Subacute thyroiditis is an uncommon cause of fever of unknown origin, and because it may cause pain in the upper neck and jaw area, it has rarely been mistaken for temporal arteritis [27]. (See "Diagnosis of giant cell arteritis".)

TREATMENT — Treatment of patients with subacute thyroiditis should be directed at providing relief for thyroid pain and tenderness and ameliorating symptoms of hyperthyroidism, if present. Thyroid function tests should be monitored every two to eight weeks to confirm resolution of hyperthyroidism, detection of hypothyroidism, and subsequent normalization of thyroid function.

There are limited data assessing optimal treatment of subacute thyroiditis [28]. Treatment recommendations are based upon observational data and clinical experience.

Pain management — Some patients need no treatment because their symptoms are mild or are subsiding by the time they seek medical attention and the diagnosis is established. In many patients, however, antiinflammatory therapy with either a nonsteroidal antiinflammatory drug (NSAID) or prednisone is indicated [28,29].

●If the neck discomfort and systemic symptoms are mild or moderate, either monitoring or starting acetylsalicylic acid (aspirin, 2600 mg daily in four divided doses) or an NSAID (eg, naproxen [500 to 1000 mg daily in two divided doses] or ibuprofen [1200 to 3200 mg daily in three or four divided doses]) is reasonable. If there is no improvement with aspirin or NSAID in two or three days, aspirin or NSAID should be discontinued and prednisone (40 mg daily) initiated.

●If the neck discomfort is more severe in the context of significant systemic symptoms, starting prednisone (40 mg daily) as initial therapy is reasonable. Prednisone therapy should result in pain relief in one to two days; if not, the diagnosis should be questioned. The clinical response will determine the duration of steroid therapy. Once the pain is relieved by prednisone, an attempt should be made to find the lowest possible dose that provides adequate pain relief by reducing the dose by 5 to 10 mg every five to seven days. Should pain reoccur, increase to the prior dose and maintain that dose for approximately two weeks, then attempt to taper again. Typically, a two- to eight-week course of prednisone is required, and occasionally, the course may be even more prolonged

NSAIDs and prednisone can cause a variety of systemic symptoms, and the prescribing health care provider and patient should be familiar with its relative contraindications, medication interactions, and adverse effects. (See "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs: Therapeutic use and variability of response in adults" and "Major adverse effects of systemic glucocorticoids".)

Although symptomatic relief is achieved with prednisone, it does not prevent early- and late-onset thyroid dysfunction. As an example, in one retrospective community study, during long-term monitoring, patients who had received prednisone had a greater likelihood of developing transient hypothyroidism (25 percent) as compared with those who did not receive prednisone (10 percent) [2]. Glucocorticoids may be associated with shorter overall disease duration [10].

Management of symptomatic hyperthyroidism — Therapy for hyperthyroidism is not often needed because symptoms, if present, are mild and short-lived. Those few patients who have bothersome symptoms of hyperthyroidism, such as palpitations, anxiety, or tremor, may benefit from treatment with a beta blocker such as 40 to 120 mg propranolol, propranolol LA 80 mg daily, or 25 to 50 mg atenolol daily for a few weeks while they are thyrotoxic.

Thionamides should not be used, because hyperthyroidism is not caused by excess thyroid hormone synthesis. Radioiodine therapy is neither effective nor indicated, because the uptake of radioiodine is very low, and the disease is usually self-limiting.

Management of hypothyroidism — Therapy for hypothyroidism is not often needed, because symptoms, if present, are usually mild and short lived. However, if the hypothyroidism is more pronounced (TSH >10 mU/L) or associated with more than mild symptoms, the patient should be treated with 50 to 100 mcg of T4 (levothyroxine) for six to eight weeks (with a goal TSH in the normal range). The T4 should then be discontinued, and the patient reevaluated in four to six weeks to be sure that the hypothyroidism is not permanent.

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 (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical features – Subacute thyroiditis (subacute granulomatous thyroiditis) is characterized by neck pain, a tender diffuse goiter, and a predictable course of thyroid function evolution. Hyperthyroidism is typically the presentation, followed by euthyroidism, hypothyroidism, and ultimately restoration of normal thyroid function (figure 1). It is presumed to be caused by a viral infection or a postviral inflammatory process. (See 'Clinical features' above and 'Pathogenesis' above.)

●Diagnosis – The diagnosis of subacute thyroiditis is based primarily upon clinical manifestations (the presence of neck pain, often radiating upward to the jaw; marked thyroid tenderness; and a diffuse goiter). In patients with suspected subacute thyroiditis, thyroid function tests (thyroid-stimulating hormone [TSH], free thyroxine [T4], total triiodothyronine [T3]) should be obtained. Although symptoms and signs of hyperthyroidism may or may not be present, the serum TSH is usually suppressed (typically <0.1 mU/L) and free T4 and total T3 concentrations elevated. Low radioiodine uptake during the hyperthyroid phase and a high erythrocyte sedimentation rate or C-reactive protein (CRP) help confirm the diagnosis. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of thyroid pain and goiter includes acute infectious (also called "suppurative") thyroiditis and hemorrhage into a thyroid nodule. Occasional patients with either chronic autoimmune thyroiditis (Hashimoto's thyroiditis) or Graves' hyperthyroidism have neck pain and tenderness, and rarely, patients with thyroid nodules harboring thyroid cancer or patients with primary thyroid lymphoma may demonstrate thyroid gland discomfort or pain. It is most important to differentiate acute infectious thyroiditis from subacute thyroiditis (table 1). The diagnosis of infection should be suspected if the patient has a leukocytosis and a cystic or mixed cystic/solid mass on ultrasound that may represent an abscess. Infectious thyroiditis is confirmed with fine-needle aspiration biopsy. (See 'Differential diagnosis' above and "Overview of thyroiditis", section on 'Infectious thyroiditis'.)

●Treatment – Treatment of patients with subacute thyroiditis should be directed at providing relief for thyroid pain and tenderness. Some patients need no treatment because their symptoms are mild or are subsiding by the time they seek medical attention and the diagnosis is established. Thyroid function tests should be monitored every two to eight weeks to confirm resolution of hyperthyroidism, detection of hypothyroidism, and subsequent normalization of function. (See 'Treatment' above.)

•Pain management – For pain relief, antiinflammatory therapy with either aspirin (2600 mg daily) or a nonsteroidal antiinflammatory drug (NSAID) (eg, naproxen [500 to 1000 mg daily in two divided doses] or ibuprofen [1200 to 3200 mg daily in three or four divided doses]) is usually effective. If there is no improvement in pain in two or three days, the NSAID should be discontinued and prednisone (40 mg daily) initiated. Prednisone can be used as initial therapy for patients with severe pain. Effective therapy should be continued until pain and tenderness have subsided and then gradually tapered. (See 'Pain management' above.)

•Hyperthyroidism – Therapy for hyperthyroidism is not often needed, because symptoms, if present, are mild and short lived. Beta blockers may be useful to relieve bothersome palpitations or tremulousness in symptomatic hyperthyroid patients. There is no role for thionamides or radioiodine in the treatment of hyperthyroidism in subacute thyroiditis. (See 'Management of symptomatic hyperthyroidism' above.)

•Hypothyroidism – Therapy for hypothyroidism is often not needed, because symptoms, if present, are mild and short lived. However, patients with symptomatic hypothyroidism require treatment with T4 (levothyroxine), typically 50 or 100 mcg daily. For asymptomatic patients with a TSH level ≥10 mU/L, we also suggest T4 replacement (Grade 2C). We continue T4 for six to eight weeks (with a goal TSH in the normal range). The T4 should then be discontinued, and the patient reevaluated in four to six weeks to be sure that the hypothyroidism is not permanent. (See 'Management of hypothyroidism' above.)