Subacute Thyroiditis 

Updated: Mar 23, 2021
Author: Stephanie L Lee, MD, PhD; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

Practice Essentials

Subacute thyroiditis is a self-limited thyroid condition associated with a triphasic clinical course of hyperthyroidism, hypothyroidism, and return to normal thyroid function. Subacute thyroiditis may be responsible for 15-20% of patients presenting with thyrotoxicosis and 10% of patients presenting with hypothyroidism. Thyroid function testing will help to indicate the presence of subacute thyroiditis, as well as determine its phase. Recognizing this condition is important; because it is self-limiting, no specific treatment, such as antithyroid or thyroid hormone replacement therapy, is necessary in most patients. (See Presentation, Workup, and Treatment.)

In general, the following three forms of subacute thyroiditis are recognized:

  • Subacute granulomatous thyroiditis - Also known as subacute painful or de Quervain thyroiditis (see the image below)[1]

  • Subacute lymphocytic thyroiditis - Also known as subacute painless thyroiditis

  • Subacute postpartum thyroiditis

    Three multinucleated, giant cell granulomas observ Three multinucleated, giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid; from a patient with thyrotoxicosis resulting from subacute granulomatous thyroiditis.

Disease course

Although the etiology appears to be different for the three subtypes, the clinical courses are the same. High thyroid hormone levels result from the destruction of the thyroid follicle and the release of preformed thyroid hormone into the circulation, with thyrotoxicosis consequently developing. (The high thyroid hormone levels are not a function of new thyroid hormone synthesis and secretion.) This phase lasts 4-10 weeks. (See Pathophysiology and Etiology.)

The thyrotoxic phase undergoes spontaneous remission in 4-8 weeks. At this time, the thyroid is depleted of colloid and is now incapable of producing thyroid hormone, resulting in hypothyroidism. The hypothyroid phase may last up to 2 months. Often, the hypothyroidism is mild, and no thyroid hormone therapy is required unless the patient has signs or symptoms of hypothyroidism. As the follicles regenerate, the euthyroid state is restored. Depending on the etiology, 90-95% of patients return to normal thyroid function. (See Prognosis.)

Subacute granulomatous thyroiditis

Subacute granulomatous thyroiditis is the most common cause of a painful thyroid gland. This condition is also known as painful subacute thyroiditis, de Quervain thyroiditis, and migratory thyroiditis (this last because the pain can shift to different locations in the thyroid). It is a transient inflammation of the thyroid, the clinical course of which is highly variable. Most patients have pain in the region of the thyroid, which is usually diffusely tender, and some have systemic symptoms. Thyrotoxicosis often occurs initially, sometimes followed by transient hypothyroidism. Complete recovery in weeks to months is characteristic. Some patients will clinically note only one phase—thyrotoxic or hypothyroid—while others will note both. (See the Table, below.)

Table. Characteristic Course of Subacute Granulomatous Thyroiditis (Open Table in a new window)

Parameters

Stage 1

Stage 2

Stage 3

Stage 4

Symptoms

Thyrotoxicosis

Euthyroid

Hypothyroid

Euthyroid (recovery)

T4, T3

Elevated

Normal

Decreased

Normal

TSH

Decreased

Normal

Elevated

Normal

T4 = thyroxine

T3 = triiodothyronine

TSH = thyroid-stimulating hormone

Signs and symptoms of subacute thyroiditis

Local symptoms of subacute granulomatous thyroiditis include the following:

  • Dysphagia
  • Hoarseness (uncommon)
  • Pain over the thyroid area that is gradual or of sudden onset

Constitutional symptoms (often absent) of subacute granulomatous thyroiditis can include the following:

  • Fever
  • Malaise
  • Anorexia
  • Fatigue
  • Muscle aches

Signs and symptoms of hyperthyroidism occurring in the acute phase of subacute granulomatous thyroiditis include the following:

  • Tachycardia
  • Tremulousness
  • Heat intolerance
  • Sweating
  • Nervousness
  • Warm skin
  • Frequent bowel movements

Signs and symptoms of hypothyroidism occurring during the second phase of subacute granulomatous thyroiditis include the following:

  • Fatigue
  • Dry skin
  • Lethargy
  • Eyelid swelling
  • Cold intolerance
  • Constipation

Workup in subacute thyroiditis

Thyroid function testing will help to indicate the presence of subacute thyroiditis, as well as determine its phase. Laboratory examination may also reveal anemia, hyperglobulinemia, and leukocytosis. Tests include the following:

  • Thyroid-stimulating hormone - The most reliable measure of thyroid function
  • Triiodothyronine (T3) and thyroxine (T4)
  • Thyroglobulin
  • Erythrocyte sedimentation rate
  • Thyroid autoantibodies

Occasionally, patients with subacute thyroiditis may present with a solitary, hard nodule. A fine-needle aspiration (FNA) sample in subacute thyroiditis contains a mononuclear infiltrate composed mostly of lymphocytes and multinucleated giant cells.

In subacute thyroiditis, as in all types of thyroid inflammation, histologic samples from the thyroid contain inflammatory cells, primarily lymphocytes. The destructive nature of subacute thyroiditis is reflected in the disruption and disarray of the normal follicular unit, composed of a monolayered sheet of thyroid follicular cells surrounding the storage form of thyroid hormone, colloid.

Management of subacute thyroiditis

The treatment of subacute thyroiditis is generally supportive to reduce the symptoms of thyrotoxicosis and to control neck pain in the setting of subacute granulomatous thyroiditis. Because no new hormone is being made, antithyroid medications are not effective in these conditions. Although the abnormal thyroid levels are temporary, emotional support is often necessary.[2, 3]

Subacute granulomatous thyroiditis

Thyroid pain in this condition can be extreme (although some patients with mild pain require no treatment). Nonsteroidal anti-inflammatory drugs (NSAIDs)—such as such as ibuprofen (800-1200 mg/day in divided doses) and naproxen (1-1.5 g/day in divided doses)—are the first-line agents used for pain treatment, although large dosages are typically needed. Treatment can be tapered as allowed by the patient's pain.

In extreme cases, stronger pain medications, including narcotic analgesics, are indicated for a brief period of 2-3 weeks. In the most extreme cases, high-dose steroids (eg, prednisone 40-60 mg/day) must be administered.

Hypothyroidism

The hypothyroid phase in subacute thyroiditis is usually mild and transient, and typically it does not require treatment. However, if symptoms are present or the TSH level is elevated, the patient needs replacement therapy with levothyroxine.

Thyroid hormone levels in subacute thyroiditis

The release of preformed hormone cannot be stopped in the destructive phase. In patients with very high levels of thyroid hormone, ipodate may be administered to inhibit the conversion of T4 to the more active form of thyroid hormone, T3.

Patient education

For patient education information, see the Thyroid and Metabolism Center, as well as Thyroid Problems.

Pathophysiology

Destruction of follicular epithelium and loss of follicular integrity are the primary events in the pathophysiology of subacute granulomatous thyroiditis. Thyroglobulin (TG), thyroid hormones, and other iodinated compounds are released into the blood, often in quantities sufficient to elevate the serum thyroxine (T4) and triiodothyronine (T3) concentrations and suppress thyroid-stimulating hormone (TSH) secretion. This state lasts until the stores of TG are exhausted or until healing occurs. Thyroidal iodine uptake and new hormone synthesis temporarily ceases because of the low level of TSH.

As inflammation subsides, the thyroid follicles regenerate and thyroid hormone synthesis and secretion resume. In some patients, several months are required for thyroid hormone synthesis to return to a normal rate; during that period, clinical hypothyroidism may be evident.

Thyrotoxicosis

The hypermetabolic effect of thyrotoxicosis is the same, regardless of cause. Thyrotoxicosis affects every organ system, because thyroid hormones made in the thyroid travel via the circulation to reach every cell in the body. Thyroid hormone is necessary for normal growth and development, and it regulates cellular metabolism.

Excess thyroid hormone causes an increase in metabolic rate that is associated with increased total body heat production, increased cardiovascular activity (eg, increased heart contractility, heart rate, vasodilation) to remove heat to the periphery and remove metabolic wastes, and perspiration to cool the body.

The major symptoms of thyrotoxicosis include palpitations, nervousness, sweating, hyperdefecation, and heat intolerance. Women often note a reduction in menstrual flow, or oligomenorrhea. Common signs of thyrotoxicosis include the following:

  • Weight loss despite increased appetite

  • Lid lag and stare

  • Sinus tachycardia

  • Atrial fibrillation or high-output failure (in elderly persons)

  • Fine tremor

  • Muscle weakness

Synergism occurs between thyrotoxicosis and the adrenergic system, with increases in nervousness, stare, tremor, and tachycardia.

The manifestations of thyrotoxicosis vary among patients. Younger patients tend to exhibit more sympathetic activations (eg, anxiety, hyperactivity, tremor), while older patients have more cardiovascular symptoms (eg, dyspnea, atrial fibrillation) and unexplained weight loss. The clinical manifestation of thyrotoxicosis does not always correlate with the extent of the biochemical abnormality.

Papillary thyroid carcinoma

A retrospective study by Gül et al suggested that papillary thyroid carcinoma is more prevalent in subacute thyroiditis than has previously been indicated. While one report found the rate of papillary thyroid carcinoma to be 0.4% in subacute thyroiditis, and another found no cases of such carcinomas in patients with the condition, the prevalence in this study was 4.4% (6 out of 137 patients).[4]

A study by Nishihara et al reported that under ultrasonographic evaluation, hypoechoic inflammatory regions in subacute thyroiditis can severely obscure coexisting papillary carcinoma. Consequently, the investigators advised that ultrasonographic reexamination be performed after a sufficient interval in patients with subacute thyroiditis.[5]

Etiology

The causes of subacute thyroiditis, other than those of subacute granulomatous thyroiditis, are not entirely clear.

Subacute granulomatous thyroiditis

The most accepted etiology for this condition is a viral illness.[6] Viral particles have never been identified within the thyroid, but episodes often follow upper respiratory infections and are associated with falling postconvalescent viral titers of various viruses, including influenza, adenovirus, mumps, and coxsackievirus. The occurrence of subacute granulomatous thyroiditis in the course of novel H1N1 influenza infection has been reported from Greece.[7]

De Quervain thyroiditis is not associated with autoimmune thyroiditis. The transient presence of autoantibodies (eg, inhibitory immunoglobulins that bind to TSH, antibodies that block thyroid stimulation, thyroid antimicrosomal antibodies, thyroglobulin [TG] antibodies) has been noted in the acute phase of the disease, but this has been attributed to a virally induced autoimmune response and has not been implicated in the pathologic process. (Viral inclusion bodies are not observed in thyroid tissue in subacute granulomatous thyroiditis.)

It is unclear, however, whether the destructive thyroiditis in De Quervain patients is caused by direct viral infection of the gland or by the host's response to the viral infection.

In contrast to autoimmune thyroid disease, the immune response in subacute granulomatous thyroiditis is not self-perpetuating; therefore, the process is limited.

HLA-B35

A genetic predisposition to the development subacute granulomatous thyroiditis clearly exists; risk for developing the disease in patients with human leukocyte antigen (HLA)–Bw35 is 6-fold that of the general population.[8] In one study, as many as 72% of patients with subacute thyroiditis manifested HLA-Bw35.

A proposed etiologic mechanism suggests that the disease results from a viral infection that provides an antigen, one that is either viral or that results from virus-induced host tissue damage, that uniquely binds to HLA-B35 molecules on macrophages. The antigen–HLA-B35 complex activates cytotoxic T lymphocytes that damage thyroid follicular cells, because these cells have some structural similarity to the infection-related antigen.

In Japanese patients, an association seems to exist between subacute granular thyroiditis and HLA-B67. In a study, 87% of Japanese patients with subacute thyroiditis had either HLA-B35 or HLA-B67. Research indicates that HLA-B67 is associated with a greater risk of developing a hypothyroid phase than is HLA-Bw35.

Growth factors

The role of growth factors in the development of subacute thyroiditis has received some attention. In the granulomatous stage of subacute thyroiditis, growth factor–rich monocytes and/or macrophages infiltrating follicular lumina are thought to trigger the granulomatous reaction, with this reaction probably being mediated by vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor beta 1 (TGF-β1) produced by the stromal cells.

In the regenerative phase, endothelial growth factor (EGF) mediates follicular regeneration through its mitogenic effect on thyrocytes, along with cofactors. In addition, the decreased expression of TGF-β1, a fibrogenic factor, contributes to thyroid tissue repair. VEGF and bFGF may be responsible for angiogenesis in both stages.

Subacute lymphocytic thyroiditis

This condition most likely is autoimmune in nature. Patients develop an autoimmune goiter and permanent hypothyroidism more often than they do with subacute granulomatous thyroiditis. An HLA association may be present, suggesting a genetic predisposition to subacute lymphocytic thyroiditis.

Certain drug exposures relating to excess iodine and cytokines may cause this form of silent thyroiditis. These drugs include amiodarone (iodine-rich), interferon alfa, interleukin 2, and lithium. Cases of thyroiditis resulting from these drugs are typically treated in a similar way.

Amiodarone

Amiodarone has multiple established effects on thyroid function. One of the 2 types of amiodarone-induced thyrotoxicosis is a destructive subacute lymphocytic thyroiditis. This form of thyroiditis is more common in men, likely due to the higher prevalence of amiodarone therapy in men. Subacute lymphocytic thyroiditis typically occurs after more than 2 years of amiodarone therapy.[9]

Interferon alfa

Up to 5% of patients taking interferon alfa may experience subacute lymphocytic thyroiditis. This condition is detected biochemically, after 3 months of therapy, more often than it is found clinically. Subacute lymphocytic thyroiditis in patients taking interferon alfa is associated with an increased antithyroid antibody concentration.

Interleukin 2

Although case reports exist that interleukin 2 is associated with subacute lymphocytic thyroiditis, its causative role is less established than that of interferon alfa.

Lithium

Lithium is a well-known cause of either subclinical or clinical hypothyroidism, as well as of goiter. Because of lithium’s ability to inhibit the release of thyroid hormone, it has been used as a treatment for thyrotoxicosis. However, reports exist of lithium-associated thyrotoxicosis due to a subacute lymphocytic thyroiditis, with the classic picture of hyperthyroidism, absent neck tenderness, and low radioactive iodine uptake.

Subacute lymphocytic thyroiditis can occur during lithium administration, as well as up to 5 months following discontinuation of lithium therapy. Increased thyroid antibodies in lithium users and a direct toxic effect of lithium have been proposed as possible mechanisms.

Subacute postpartum thyroiditis

This condition is likely autoimmune in nature.[10] Patients develop an autoimmune goiter and permanent hypothyroidism more often than they do with subacute granulomatous thyroiditis. In iodine-sufficient countries, such as the United States, postpartum thyroiditis occurs in approximately 5-8% of pregnant women. In Japan where the diet is rich in iodine, nearly 20% of pregnancies are associated with this condition.

Patients with positive test results for thyroid autoantibodies either before their pregnancy or during the third trimester are at much higher risk of developing postpartum thyroiditis.

Cigarette smoking is also associated with an increased incidence of postpartum thyroiditis. Once patients have an episode of subacute postpartum thyroiditis, they are likely to have additional episodes following each pregnancy.

Additional causes of subacute thyroiditis

Other causes of subacute thyroiditis, or at least conditions that have been associated with the disease, include the following:

  • Radioiodine therapy for Graves disease can result in transient thyroidal inflammation, causing thyroiditis

  • Subacute thyroiditis also has been described following external radiation to the neck

  • Subacute thyroiditis has presented as a paraneoplastic manifestation of renal cell carcinoma

  • An association between subacute thyroiditis and febrile neutrophilic dermatoses (Sweet syndrome) has been reported

  • Concurrence of giant cell arteritis has been reported in patients with classic de Quervain thyroiditis

  • Subacute thyroiditis has been described after bone marrow transplantation for chronic granulocytic leukemia

COVID-19

A case study by Brancatella et al suggested that in some patients, subacute thyroiditis may arise from coronavirus disease 2019 (COVID-19). The report involved a woman aged 18 years who was found to have no thyroid disease before then testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). About three weeks later, she tested negative for the virus, but, a few days after that, presented with symptoms of subacute thyroiditis, which was subsequently diagnosed. The timing of the thyroiditis, the investigators believe, points to a COVID-19 origin, particularly in light of the fact that subacute thyroiditis is commonly thought to develop in response to viral infection or a postviral inflammatory reaction in persons with a genetic predisposition.[11, 12]

Additional research has continued to point to the development of a condition resembling subacute thyroiditis in persons with COVID-19. This includes an Italian study that found that among 85 patients with COVID-19 admitted to high-intensity-care units (HICUs), up to 13 (15%) were thyrotoxic, compared with just 1% of HICU patients from pre-pandemic 2019 who were studied in the report.[13, 14]

Further investigation indicates that subacute thyroiditis may persist months later in patients in whom the thyroid gland becomes inflamed during acute COVID-19 illness, even after normalization of thyroid function. In addition, the effects of SARS-CoV-2 on thyroid function appear to be multifactorial, with the thyroiditis being atypical in that no neck pain seems to be involved and more men than women appear to be affected. In addition, patients who were examined exhibited low TSH and free T3 levels, while free T4 levels were normal or elevated.[15]

Epidemiology

Subacute granulomatous thyroiditis occurs in less than 5% of all patients with thyroid pathology, although estimates indicate that together, the 3 forms of subacute thyroiditis account for 20-25% of thyrotoxicosis cases. De Quervain thyroiditis tends to have a seasonal and geographic distribution and is most common during the summer and fall. It tends to follow viral epidemics.

A systematic review of all cases of subacute granulomatous thyroiditis diagnosed between 1960 and 1997 in Olmsted County, Minnesota, revealed an age- and sex-adjusted annual incidence of 4.9 cases per 100,000 population.[16]

Postpartum thyroiditis has an incidence of 5.4% in the general population. An isolated hypothyroid phase occurs in 48% of women with the condition, while isolated thyrotoxicosis is found in 30% patients, and a presentation of hyperthyroidism followed by hypothyroidism is seen in 22% of them.[2]

Sex-related demographics

As is the case for most thyroid diseases, de Quervain thyroiditis appears more frequently in females, with a female-to-male ratio of 3-5:1. Subacute lymphocytic thyroiditis occurs twice as often in women as it does in men.

Postpartum thyroiditis occurs 1-6 months after giving birth. If a woman has postpartum thyroiditis with one baby, all other pregnancies are likely to be associated with this condition.

Age-related demographics

Subacute lymphocytic thyroiditis can occur in any age group, while postpartum thyroiditis occurs in women of childbearing age.

Subacute granulomatous thyroiditis usually occurs in adults (ie, aged 20-60 y), with the incidence peaking in the fourth and fifth decades of life. It is rare in the first decade and relatively infrequent in people older than 50 years, although it has been reported in extreme age groups.[17] Occurrence during pregnancy has been reported as well.[18]

Prognosis

The prognosis is excellent in 90-95% of patients who experience subacute thyroiditis. Approximately 5-10% of patients have permanent thyroid dysfunction, usually hypothyroidism, after an episode of subacute thyroiditis. Permanent goiter and thyroid dysfunction occur most frequently after postpartum thyroiditis.

Thyrotoxicosis

Thyrotoxicosis from subacute thyroiditis is brief, usually lasting no longer than 6-8 weeks. Patients can be extremely thyrotoxic during this period and can appear extremely ill, but concerns regarding left ventricular hypertrophy and osteoporosis are not as great as those associated with conditions of permanent hyperthyroidism. However, sudden-onset thyrotoxicosis and severe thyrotoxicosis can be associated with atrial arrhythmia and congestive heart failure (CHF).

Subacute granulomatous thyroiditis

This condition generally resolves completely in more than 90-95% of patients. No special thyroidal follow-up is needed. Morbidity is caused during the initial phase by pain, which usually prompts the patient to consult a physician. Hyperthyroidism, usually a mild, transient form, occurs in approximately 50% of patients with subacute granulomatous thyroiditis; in up to half of all patients, hypothyroidism may later develop.

Acute complications

When acute complications do occur, they can include the following:

  • Severe hyperthyroidism - May be observed during the inflammatory phase

  • Severe anterior neck pain over the thyroid - Usual treatment is nonsteroidal therapy, but emerging studies suggest that prednisolone 15 mg/day with a taper of 5 mg every 2 weeks is safe and effective to quickly reduce pain; in a study of prednisolone use by Kubota et al, most patients had resolution of symptoms by 6-8 weeks, although the longest period of therapy was 40 weeks[19]

  • Multiple system organ failure - May complicate the course of the disease in exceptionally rare cases

  • Pancreatitis or splenomegaly - Associated with de Quervain thyroiditis in case reports only

  • Vocal cord paralysis - Occurs occasionally in cases with severe thyroid gland inflammation

  • Cerebral venous thrombosis - has been reported in some cases; in one case, the patient was a heterozygous carrier for the G20210A mutation of the prothrombin gene, which predisposed her to this complication

Long-term complications

Permanent hypothyroidism is the most frequent long-term complication of de Quervain thyroiditis. It is observed in less than 5-10% of the patients and requires thyroid replacement therapy.

Disease recurrence has been documented in occasional cases (up to 20% of cases in some series). Recurrence is more frequent in the first year but has been reported even 30 years after the initial diagnosis. The risk of recurrence cannot be correlated with initial thyroid function, inflammatory syndrome, or ultrasonographic aspect (ie, thyroid volume, echogenicity).

Subacute lymphocytic thyroiditis

Occasionally, patients have recurrent episodes of painless thyrotoxicosis.[20] No treatment exists to prevent the recurrences except subtotal thyroidectomy. However, this condition generally resolves completely in more than 90-95% of patients. Patients with goiters or permanent thyroid dysfunction should be monitored with a thyroid examination and thyroid function tests every 6 months.

Subacute postpartum thyroiditis

Usually, repeat episodes occur after each pregnancy; no known treatment exists to prevent these. Patients may have a residual goiter and thyroid hypofunction after postpartum thyroiditis, because this condition is associated with chronic autoimmune thyroiditis. Patients should be observed routinely for goiter enlargement and thyroid hypofunction every 6-12 months.

 

Presentation

History

Patient presentation depends on the etiology of the thyrotoxicosis. Subacute granulomatous thyroiditis is associated with an acute, viruslike illness with fevers and myalgias with a painful thyroid. A recent birth signals postpartum thyroiditis. Often, thyrotoxicosis caused by subacute lymphocytic thyroiditis, postpartum thyroiditis, or the surreptitious use of thyroid hormone is symptomatic because of persistent tachycardia, nervousness, and weight loss. Symptoms of thyrotoxicosis that persist for longer than 2 months are probably not caused by subacute thyroiditis.

Subacute granulomatous thyroiditis

Some patients experience a flulike prodromal episode 1-3 weeks prior to the onset of clinical disease. The natural course of the disease can be divided into the following 4 phases, which usually unfold over a period of 3-6 months:

  • Acute phase - Lasts 3-6 weeks and presents primarily with pain; symptoms of hyperthyroidism also may be present

  • Transient asymptomatic and euthyroid phase - Lasts 1-3 weeks

  • Hypothyroid phase - Lasts from weeks to months; it may become permanent in 5-15% of patients

  • Recovery phase - Characterized by normalization of thyroid structure and function

The diagnosis is made based on clinical findings. Prodromal flulike symptoms (fevers, myalgia, malaise) or known infectious disease, such as pharyngitis, measles, mumps, Q fever, or typhoid fever, may occur. In young patients, de Quervain thyroiditis may develop following an episode of Henoch-Schönlein purpura. However, a history of prodromal symptoms often cannot be obtained.

Local symptoms

Local symptoms can include the following:

  • Dysphagia

  • Hoarseness (uncommon)

  • Pain over the thyroid area that is gradual or of sudden onset

Pain is the presenting symptom in over 90% of cases. It usually involves both lobes of the thyroid; in 30% of cases, it starts on one side and then migrates contralaterally within a few days. While the pain may be limited to the region of the thyroid, it may also involve the upper neck, throat, jaw, or ears. Some patients may first consult an otolaryngologist.

The pain may be so severe that the patient cannot tolerate palpation of the neck. The pain is most commonly bilateral. Occasionally, it may be unilateral, beginning in one lobe and spreading to the opposite side (creeping thyroiditis). Coughing, swallowing, or even tightening a necktie aggravates pain.

Constitutional symptoms

Constitutional symptoms (often absent) can include the following:

  • Fever

  • Malaise

  • Anorexia

  • Fatigue

  • Muscle aches

Symptoms of hyperthyroidism

Hyperthyroidism is usually is mild, becoming severe only in rare cases. The symptoms are transient, typically lasting 3-6 weeks. Symptoms of hyperthyroidism occurring in the acute phase of subacute granulomatous thyroiditis include the following:

  • Tachycardia

  • Tremulousness

  • Heat intolerance

  • Sweating

  • Nervousness

  • Warm skin

  • Frequent bowel movements

Symptoms of hypothyroidism

Symptoms of hypothyroidism occur in the late phase of the disease in up to 50% of cases. The hypothyroidism is most often mild or moderate. It is also transient, lasting weeks to months in 90-95% of cases. Symptoms of hypothyroidism occurring during the second phase of subacute granulomatous thyroiditis include the following:

  • Fatigue

  • Dry skin

  • Lethargy

  • Eyelid swelling

  • Cold intolerance

  • Constipation

Atypical symptoms

Atypical presentations of subacute granulomatous thyroiditis—that is, extremely rare symptoms that have been documented as case reports—can include the following:

  • Thyroid storm[21]

  • Fever of unknown origin

  • Painless subacute granulomatous thyroiditis

  • Occult de Quervain disease mimicking giant cell arteritis

  • Prominent prostration and confusion lasting several weeks

  • Solitary painless nodule

Subacute lymphocytic thyroiditis

This form of subacute thyroiditis is associated with a painless, firm enlargement of the thyroid gland and high thyroid hormone levels. Only suspicion by the clinician and use of radioactive iodine uptake measurement can distinguish Graves hyperthyroidism from subacute lymphocytic thyroiditis.

Subacute postpartum thyroiditis

This condition is associated with a painless, firm enlargement of the thyroid gland and high thyroid hormone levels. The identifying feature is its occurrence 1-6 months after childbirth. Patients may report lack of sleep, nervousness, fatigue, and easy weight loss.[3, 2]

Autoimmune hyperthyroidism from Graves disease can also occur for the first time postpartum and must be distinguished from postpartum thyroiditis. Both conditions are associated with high antithyroid antibody titers.

Physical Examination

All conditions described are associated with thyrotoxicosis and the signs and symptoms of hypermetabolism. None of the forms of subacute thyroiditis is associated with the thyroid eye disease observed primarily with Graves hyperthyroidism. The presence of bilateral proptosis and chemosis with high thyroid hormone levels and goiter is highly suggestive of Graves disease.

Subacute granulomatous thyroiditis

Patients often present with an acute, viruslike illness characterized by high, spiking fever; malaise; myalgia; fatigue; and prostration.

Thyroid pain is usually symmetrical. In 30% of cases, however, it starts on one side and then migrates contralaterally within a few days. While the pain may be limited to the region of the thyroid, it may also involve the upper neck, throat, jaw, or ears. In many patients, the pain is so severe that he or she cannot tolerate palpation of the neck. The pain may be intense enough to prevent the swallowing of saliva, liquids, and food.

Thyroid enlargement, however, is usually symmetrical and mild, occasionally with areas of localized firmness. Erythema and hyperesthesia of the overlying skin may be present at the onset of severe cases. Cervical lymphadenopathy is uncommon. Lid retraction is rare, and exophthalmos does not occur.

Thyroid hormone levels are often extremely elevated, resulting in marked signs and symptoms of thyrotoxicosis. Cases of lesser severity also exist, and the etiology may be confusing.

Symptoms of hyperthyroidism occurring in the acute phase of subacute granulomatous thyroiditis include the following:

  • Tachycardia

  • Tremulousness

  • Heat intolerance

  • Sweating

  • Nervousness

  • Warm skin

  • A rapid relaxation phase of tendon reflexes

Subacute lymphocytic thyroiditis

Patients present with a nonpainful thyroid enlargement and elevated thyroid hormone levels. This condition must be distinguished from Graves thyrotoxicosis because antithyroid medication is not indicated in this temporary condition.

Subacute postpartum thyroiditis

Patients present 1-6 months postpartum with painless thyroid enlargement and elevated thyroid hormone levels. Sometimes, distinguishing between the usual postpartum changes in physiology and additional thyroid pathology is difficult.[3, 2]

 

DDx

Diagnostic Considerations

It is important to determine whether elevated thyroid hormone levels are from the causes listed in this article rather than from excess synthesis of thyroid hormone. Generally, the conditions described here are temporary and therefore do not require definitive therapy, such as thyroid surgery, radioactive iodine treatment, or antithyroid therapy. Radioactive iodine treatment and antithyroid therapy are never appropriate for these forms of subacute thyroiditis.

Conditions to consider in the differential diagnosis of subacute thyroiditis include the following:

  • Acute hemorrhage into a thyroid cyst, nodule, or neoplasm

  • Infectious thyroiditis

  • Radiation-induced thyroiditis

  • Trauma- or palpation-induced thyroiditis

  • Riedel or fibroid thyroiditis

  • Graves thyrotoxicosis

  • Toxic thyroid adenoma

  • Toxic multinodular goiter

  • Acute suppurative thyroiditis

The last disorder in the above list, acute suppurative thyroiditis, is most commonly caused by a bacterial infection of the thyroid via the conduit of a congenital pyriform sinus fistula. This pain and swelling in the early stages can be confused with subacute thyroiditis. A study by Masuoka et al of 60 patients with acute suppurative thyroiditis found that careful imaging can provide clues to an early diagnosis of this condition, which can develop into a life-threatening endocrine emergency.[22]

Differential Diagnoses

 

Workup

Approach Considerations

Thyroid function testing will help to indicate the presence of subacute thyroiditis, as well as determine its phase. Laboratory examination may also reveal anemia, hyperglobulinemia, and leukocytosis.

Thyroid-stimulating hormone

The most reliable measure of thyroid function is thyroid-stimulating hormone (TSH). In hyperthyroidism, the TSH is typically suppressed to levels that are not measurable (< 0.05 μIU/mL). The degree of thyrotoxicosis, however, cannot be estimated with a TSH level and must instead be measured by the thyroid hormone (T3 and T4) levels in the plasma.

T3 and T4

The active hormones in the circulation are represented by triiodothyronine (T3) and thyroxine (T4). During the initial phase of the illness, serum thyroxine and free T4 concentrations are elevated in almost all patients. Due to the concomitant release of nonhydrolyzed iodoproteins from the inflamed tissue, the serum T3 level is also high. The total T3:T4 ratio usually is less than 20, in contrast to patients with Graves disease.

T3 is 20-100 times more biologically active than T4; 5% of patients with thyrotoxicosis have elevations only in T3. Therefore, estimated measurements of free T4 and free T3 are recommended.

Most laboratories use a calculation to estimate free T4 levels; ie, total T4 x correction for thyroid hormone binding = free thyroxin index.

As the subacute thyroiditis evolves into the second phase, the serum T3 and T4 levels decline, and the serum TSH level remains suppressed.

Thyroglobulin

Serum thyroglobulin (TG) levels are elevated. The elevation may persist for well over a year after the initial diagnosis, indicating that disordered follicular architecture, low-grade inflammation, or both can persist for a relatively long period. TG in patients with subacute thyroiditis is heterogeneous with respect to sedimentation properties and structural integrity. The presence of serum TG with hormone residue is a common and distinctive feature of subacute thyroiditis.

Erythrocyte sedimentation rate

The erythrocyte sedimentation rate (ESR) is elevated only with subacute granulomatous thyroiditis and is usually greater than 50 mm/h, often exceeding 100 mm/h. An elevated ESR is diagnostic in this setting. The C-reactive protein (CRP) level may also be elevated.

Thyroid autoantibodies

The most specific autoantibody for autoimmune thyroiditis is antithyroperoxidase (anti-TPO) antibody. Positive antithyroglobulin antibodies are less often associated with autoimmune thyroid disease.

Antithyroid antibody titers can be elevated temporarily in all causes of subacute thyroiditis. The highest elevation in subacute thyroiditis is associated with subacute postpartum thyroiditis.

The antithyroid titers are usually elevated significantly in the most common type of hyperthyroidism, Graves thyrotoxicosis.

Research-oriented tests

Tests of research interest but seldom of clinical value include the following:

  • Sex hormone–binding globulin (SHBG) levels usually are within the reference range because of the short time of exposure to increased thyroid hormone levels; SHBG is usually elevated in chronic hyperthyroid conditions

  • Acute phase reactants, including serum C-reactive protein (CRP), are elevated in the initial phase

  • Test results for viral nucleic acid fragments by polymerase chain reaction (PCR) assay in the thyroid tissue are negative

  • Soluble interleukin-2 receptor concentrations, CD4+ cell count, cytotoxic T cell count, and gamma interferon–positive lymphocytes have been used to assess the role of the immune system in de Quervain thyroiditis; increased levels of these markers support a viral etiology of the disease

  • Intercellular adhesion molecules have been found to be increased in de Quervain thyroiditis and other thyroid disorders (eg, Graves disease, Hashimoto thyroiditis), independent of the hypothyroid or hyperthyroid state, reflecting the degree of inflammatory activity in the thyroid gland

  • Sialic acid level was studied as a marker of disease activity and was found to be a better indicator than erythrocyte sedimentation rate (ESR) or thyroglobulin (TG) or CRP levels for active disease or relapse

  • In selected populations, genetic studies show a high incidence of HLA-B35 antigen in patients with subacute granulomatous thyroiditis[23]

Additional findings

Serum alkaline phosphatase levels may be elevated in as many as 60% of patients; less commonly, other liver function test results may be elevated. Mild increases in pancreatic enzymes have also been reported.[24]

Serum IL-6 levels are increased, probably reflecting ongoing inflammation. While other parameters, such as ESR and CRP, decrease during corticosteroid therapy, IL-6 levels continue to increase (up to 17 days in some patients). This probably reflects dissociation between persistent release of IL-6 from the damaged thyroid cells and immediate inhibition of secondary inflammatory reactions by corticosteroids.

A Japanese study derived from a medical records review of 852 patients with subacute thyroiditis found that most of the laboratory test–based indications for thyrotoxicosis and thyroiditis-associated inflammation peaked within a week after the onset of subacute thyroiditis.[25]

Laboratory Studies

Subacute granulomatous thyroiditis

Thyroid hormone levels are very elevated in this disease. The 6- to 8-week destructive phase of thyroiditis causes the release of preformed hormone stores from the thyroid. This form of thyroid hormone is highly iodinated, such that the levels of released hormones have a lower ratio of total T3 to total T4 than does Graves disease. A ratio of T3 to T4 of less than 15 usually increases suspicion of subacute thyroiditis. (See the image below.)

Example of laboratory values as they vary over the Example of laboratory values as they vary over the course of subacute granulomatous thyroiditis. The entire episode may evolve through all 3 phases of the disorder over a period of as long as 6 months.

Episodes are associated with high fever, severe myalgia, thyroid pain that often radiates to the ear, and very high levels of thyroid hormone.

The hallmarks of subacute granulomatous thyroiditis are a very high ESR, often as high as 60-100, and a radioiodine uptake of less than 1% at 24 hours.

After the thyroid is depleted of thyroid hormone, patients' serum levels of T4 and T3 decrease into the hypothyroid range. The hypothyroidism is usually mild but persists for 2-4 months. Supplementation with thyroid hormone is necessary only if the patients become symptomatic from the hypothyroidism. Ninety to 95% of patients spontaneously return to normal thyroid function.

Subacute lymphocytic thyroiditis

The time course for subacute lymphocytic thyroiditis is identical to that for subacute granulomatous thyroiditis. Thyroid hormone levels are very elevated in subacute lymphocytic thyroiditis. The destructive phase of thyroiditis causes the release of preformed hormone stores in the thyroid. This form of thyroid hormone is highly iodinated, such that the release of hormone has a lower ratio of total T3 to total T4 than does Graves disease. A ratio of T3 to T4 of less than 15 usually increases suspicion of subacute thyroiditis.

As with subacute granulomatous thyroiditis, radioiodine uptake is less than 1% at 24 hours. However, the ESR is within the reference range and the thyroid is not painful in subacute lymphocytic thyroiditis, which distinguishes this condition from the other disease.

After the thyroid is depleted of thyroid hormone, patients' serum levels of T4 and T3 decrease into the hypothyroid range. The hypothyroidism is usually mild but persists for 2-4 months. Supplementation with thyroid hormone is necessary only if the patient becomes symptomatic.

Subacute postpartum thyroiditis

An isolated hypothyroid phase occurs in 48% of women with postpartum thyroiditis, while isolated thyrotoxicosis is found in 30% patients, and a presentation of hyperthyroidism followed by hypothyroidism is seen in 22% of them.[2]

As with subacute lymphocytic thyroiditis, the time course for thyroid dysfunction in subacute postpartum thyroiditis is the same as that for subacute granulomatous thyroiditis. The ESR is within the reference range and the thyroid is not painful, which distinguishes this condition from subacute granulomatous thyroiditis.[3, 2]

Thyroid hormone levels can be moderately or extremely elevated, with (as in the other 2 diseases) a radioiodine uptake of less than 1% at 24 hours.

After the thyroid is depleted of thyroid hormone, patients' serum levels of T4 and T3 decrease into the hypothyroid range. The hypothyroidism is usually mild but persists for 2-4 months. Supplementation with thyroid hormone is necessary only if patients become symptomatic. Antithyroid antibody levels can transiently become very elevated.

CT Scanning and MRI

CT scanning

Computed tomography (CT) scanning of the neck is not indicated for the diagnosis of thyroiditis. Consider that the administration of iodinated contrast material before measuring radioiodine uptake may result in a falsely decreased iodine uptake. If CT scanning is planned, it should be performed after any radioiodine uptake studies are completed.[22]

The normal thyroid gland has a high attenuation (80-100 HU), because the normal thyroid gland concentrates iodine almost 100 times more than does the serum. In subacute thyroiditis, a diffusely swollen thyroid gland is observed, with a low attenuation corresponding to 45 HU. There is also moderate enhancement of the thyroid gland on contrast-enhanced scanning, suggesting the diffuse, inflammatory nature of the disease process.

MRI

Magnetic resonance imaging (MRI) is not indicated for the diagnosis or evaluation of subacute granulomatous thyroiditis. If an MRI scan is performed during the acute phase, the thyroid gland shows irregular margins, a higher than normal T1-weighted signal intensity, and a much higher than normal T2-weighted signal intensity.[26, 27]

Nuclear Scintigraphy

Radioiodine

Neither radioiodine uptake nor thyroid scanning is indicated unless pain is mild or absent, in which case Graves disease might be considered in the differential diagnosis.

In subacute thyroiditis, radioiodine uptake is low (< 1-2% at 24 h), reflecting thyrotoxicosis due to a discharge of preformed stores of thyroid hormone and resulting from an increase in synthesis (see the image below). Administration of TSH usually fails to produce normal increase in uptake, probably because thyroid cell damage reduces the ability of the cell to respond to TSH.

Absence of iodine-123 (123I) radioactive iodine up Absence of iodine-123 (123I) radioactive iodine uptake in a patient with thyrotoxicosis and lymphocytic (subacute painless) thyroiditis. Laboratory studies at the time of the scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/h. The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the diagnosis of lymphocytic thyroiditis.

In the later phases of subacute thyroiditis, scintigraphy reveals virtually no uptake of isotope in the thyroid. Less dramatic presentations may demonstrate patchy uptake. If only one part of the thyroid gland is involved, the radioactive iodine uptake may be within the reference range.

Technetium-99m

Technetium-99m (99m Tc)-pertechnetate scintigraphy typically demonstrates markedly reduced uptake in the thyroid gland during the acute stage, but this finding is not present in all patients.

99m Tc-tetrofosmin uptake correlates with the stage of disease, particularly with inflammation, and shows increased uptake in the damaged area during the acute phase. However, this procedure is rarely used in the United States.

99m Tc -sestamibi scanning may show diffuse increased uptake in the region of the thyroid gland, suggesting increased perfusion. The clearance rate of99m Tc -sestamibi during the early phase (ie, from 10 min to 1 h) is decreased in the acute stage of subacute granulomatous thyroiditis.[28]

Ultrasonography

Thyroid ultrasonography alone is not helpful in distinguishing between abnormalities resulting from subacute thyroiditis and those from other causes of high thyroid hormone levels, including Graves thyroiditis. It is rarely indicated for diagnostic purposes.[22, 29, 30, 31, 32, 33, 34]

Graves hyperthyroidism can often be distinguished from the thyrotoxicosis of subacute thyroiditis by ultrasonography. A sonogram of Graves disease typically shows a hypoechoic thyroid, with diffuse, increased vascular flow shown by Doppler ultrasonography, while subacute thyroiditis shows hypoechoic heterogeneity and indistinct margins on sonogram, with a lack of internal vascular flow revealed by Doppler ultrasonography.[35, 36, 37]

Doppler ultrasonography shows a near absence of vascularization in affected areas of the thyroid gland during the acute phase and slightly increased vascularization in the recovery phase. During the acute phase, the more affected areas in the thyroid gland show the greatest decrease in vascularization, with the echogenically healthy-appearing regions of the thyroid showing normal or slightly increased vascularization.[38] In the recovery phase, the thyroid structure and dimensions return to normal. (See the image below.)

Ultrasonogram of subacute granulomatous thyroiditi Ultrasonogram of subacute granulomatous thyroiditis. A. Transverse image. B. Sagittal image with Doppler analysis. The echotexture is very heterogeneous and hypoechoic. The vascular flow is absent in much of the affected hypoechoic regions of the lobe and much less than would be expected if this were Graves disease hyperthyroidism.

Ultrasonographic abnormalities are not correlated with the intensity of the inflammatory syndrome and/or thyroid function status.

Recurrence can be seen as new thyroid enlargement and an extension of hypoechoic regions. Risk of recurrence is not correlated with the initial ultrasonographic aspect, and there are no significant differences between patients with and without recurrence concerning the initial thyroid volume or echogenicity.

Fibrosis is observed in some patients as hyperechogenicity and may occur as a form of healing. Extensive fibrosis is a predictor of hypothyroid state.

One study noted that thyroid volume is much smaller during the acute phase of subacute thyroiditis and that end-stage mean thyroid volume is significantly lower in patients who develop persistent hypothyroidism than it is in patients with final normal thyroid function.

A study by Lee and Kim on the ultrasonographic characteristics and interval changes of subacute thyroiditis found a high prevalence of nodular subacute lesions, as well variable interval changes. Out of 64 patients with subacute thyroiditis, 39 had nodular lesions, with 10 patients having both nodular and nonnodular lesions. Common interval changes were classified as “disappeared,” “decreased,” and “eventually smaller.”[39]

Sonoelastography

A study by Ruchala et al indicated that sonoelastography may be useful in the diagnosis and differentiation of subacute, acute, and chronic autoimmune thyroiditis, and may be an effective means of monitoring treatment success in these disorders. The investigators compared thyroid tissue stiffness in 40 healthy control subjects with stiffness in 2 patients with acute thyroiditis, 18 patients with subacute thyroiditis, and 18 patients with chronic autoimmune thyroiditis.

Findings included higher thyroid tissue stiffness in patients with the subacute disorder than in the control subjects at baseline and when the disease was in remission. The thyroid tissue was also stiffer at baseline in the subacute subjects than it was in patients with chronic autoimmune thyroiditis but was less stiff during remission than it was in the chronic patients.[40]

Fine-Needle Aspiration Biopsy

Occasionally, patients with subacute thyroiditis may present with a solitary, hard nodule. A fine-needle aspiration (FNA) sample in subacute thyroiditis contains a mononuclear infiltrate composed mostly of lymphocytes and multinucleated giant cells (see the image below). Some authors advocate that FNA be performed in all patients with a tender thyroid to avoid misdiagnosis and inappropriate management.[41, 42, 43, 44]

Three multinucleated, giant cell granulomas observ Three multinucleated, giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid; from a patient with thyrotoxicosis resulting from subacute granulomatous thyroiditis.

FNA is useful for diagnosis when atypical presentations of thyroid carcinoma and thyroid abscess are considered in the differential diagnoses.

FNA may provide unclear results in the acute stage, when atypical follicular cells may appear in the aspirate, mimicking thyroid carcinoma.

Histology

In subacute thyroiditis, as in all types of thyroid inflammation, histologic samples from the thyroid contain inflammatory cells, primarily lymphocytes. The destructive nature of subacute thyroiditis is reflected in the disruption and disarray of the normal follicular unit, composed of a monolayered sheet of thyroid follicular cells surrounding the storage form of thyroid hormone, colloid. Specific to subacute granulomatous thyroiditis, a plethora of multinucleated giant cells (which have angulated shapes; dense, foamy cytoplasm; and a high number of nuclei) is present in the inflammatory cell mix.

Histologic findings in subacute granulomatous thyroiditis

Macroscopic

The thyroid gland is moderately enlarged (unilaterally or bilaterally) and edematous in de Quervain thyroiditis, and the gland’s capsule is intact. Affected areas are firm and yellow-white; they stand out from the normal thyroid substance, which is brown and has a more rubbery consistency.

Microscopic

The changes are patchy and vary with the stage of the disease. The early phase is the active inflammatory phase and is characterized by areas of entirely disrupted follicles, which are replaced by neutrophils, forming microabscesses.

In a later phase, the classic changes of granulomatous thyroiditis develop. This is characterized by aggregations of lymphocytes, large histiocytes, and plasma cells among damaged thyroid follicles. Multinucleated giant cells enclose pools or fragments of colloid, from which stems the designation giant cell thyroiditis. Colloid is also found within the giant cells, following a process called colloidophagy.

In the final stages, the areas of injury are replaced by a chronic, inflammatory infiltrate and fibrosis. Different histologic stages sometimes are found in the same gland, suggesting waves of destruction over a period of time.

Under a scanning electron microscope, the cytomorphology of subacute granulomatous thyroiditis shows loss of a uniform honeycomb cellular arrangement, variation in size and decreased or shortened microvilli in follicular cells, and the appearance of round or ovoid giant cells.

The giant cells are closely associated with the granulomas; the small lymphocytes in the granulomas are CD3+, CD8+, and CD45RO+ cytotoxic T cells.

In the nongranulomatous lesions, the follicles are infiltrated by CD8+ T lymphocytes, plasmacytoid monocytes, and histiocytes, resulting in disrupted basement membrane and rupture of the follicles. These findings suggest that cellular immune response may play an important role in the pathogenesis of subacute thyroiditis.

 

Treatment

Approach Considerations

The treatment of subacute thyroiditis is generally supportive to reduce the symptoms of thyrotoxicosis and to control neck pain in the setting of subacute granulomatous thyroiditis. Because no new hormone is being made, antithyroid medications are not effective in these conditions. Although the abnormal thyroid levels are temporary, emotional support is often necessary.[2, 3]

Patients are often dehydrated from thyrotoxicosis; encourage all patients to drink 6-8 cups per day of noncaffeinated fluids.

Surgical care is almost never recommended for subacute thyroiditis. In rare cases, surgery is recommended for patients who have frequent recurrences of thyrotoxicosis from subacute lymphocytic thyroiditis or recurrent pain from subacute granulomatous thyroiditis.[45]

Inpatient care

Inpatient care is only recommended in the rare cases in which severe symptomatic hyperthyroidism is present.

Diet

Avoiding high-dose iodine supplements, such as those found in seaweed tablets, during and after an episode of subacute thyroiditis is important. Inflammation appears to prevent the thyroid from escaping the iodine-induced Wolff-Chaikoff suppression of thyroid hormone synthesis. Consequently, patients are likely to become hypothyroid when ingesting large amounts of iodine.

Activity

No limitation in activity is necessary, but patients may experience tachycardia with exercise. Good hydration and beta-blocker therapy should allow patients with subacute thyroiditis–caused thyrotoxicosis to exercise normally.

Consultations

Generally, all patients with thyrotoxicosis should be referred to an endocrinology specialist. Distinguishing between the causes of thyrotoxicosis is important, because the therapies are very different.

Prevention

No medical intervention is known to prevent any form of subacute thyroiditis. Recurrent episodes in patients with recurrent subacute thyroiditis with severe symptoms can be prevented with thyroidectomy.

Pharmacologic Therapy

Pain in subacute granulomatous thyroiditis

Management of subacute granulomatous thyroiditis is directed towards 2 problems: pain and thyroid dysfunction.

Thyroid pain in this condition can be extreme (although some patients with mild pain require no treatment). Nonsteroidal anti-inflammatory drugs (NSAIDs)—such as such as ibuprofen (800-1200 mg/day in divided doses) and naproxen (1-1.5 g/day in divided doses)—are the first-line agents used for pain treatment, although large dosages are typically needed. Treatment can be tapered as allowed by the patient's pain.

Most NSAIDs provide comparable efficacy in pain relief. Avoid high-dose aspirin because, in some circumstances, aspirin can competitively displace thyroid hormone from its binding protein and increase the free, or bioactive, fraction of thyroid hormone, which can make patients feel more thyrotoxic. Analgesic therapy can usually be stopped after 2-6 weeks.

In extreme cases, stronger pain medications, including narcotic analgesics, are indicated for a brief period of 2-3 weeks. In the most extreme cases, high-dose steroids (eg, prednisone 40-60 mg/day) must be administered. Corticosteroids are highly effective, and relief of pain is quick and dramatic. If pain and tenderness do not disappear within 72 hours after the start of therapy, the diagnosis of subacute thyroiditis should be questioned. Symptoms of thyrotoxicosis are also alleviated with glucocorticoids.

Research indicates that prednisolone 15 mg/day with a taper of 5 mg every 2 weeks is a safe and effective means of quickly reducing pain. In a study of prednisolone use by Kubota et al, most patients had resolution of symptoms by 6-8 weeks, although the longest period of therapy was 40 weeks.[19]  A study by Sato et al found that prednisolone (mean dose 15 mg/day) more quickly resolved symptoms of subacute thyroiditis than did the nonsteroidal anti-inflammatory drug loxoprofen (mean dose 180 mg/day) (7 vs 21 days to resolution, respectively). However, in the report, of 42 patients treated with either medication, the two drugs were comparable with regard to time to normalization of thyroid function.[46]

Hypothyroidism

The hypothyroid phase in subacute thyroiditis is usually mild and transient, and typically it does not require treatment. However, if symptoms are present or the TSH level is elevated, the patient needs replacement therapy with levothyroxine. Depending on the level of TSH, the starting dose can be 25-100 mcg/day; it is adjusted for normalization of TSH. Usually, the hypothyroid stage lasts 2-3 months, but some authors recommend treatment for as long as 6 months, followed by discontinuation of the drug and monitoring of TSH levels.

In rare cases, the hypothyroidism becomes permanent, with the patient requiring lifelong replacement therapy.

Thyroid hormone levels in subacute thyroiditis

The release of preformed hormone cannot be stopped in the destructive phase. In patients with very high levels of thyroid hormone, ipodate may be administered to inhibit the conversion of T4 to the more active form of thyroid hormone, T3. An ipodate dose of 1000 mg in 2 divided doses daily usually provides a rapid reduction in T3 and in thyrotoxic symptoms.

Peripheral manifestations of thyrotoxicosis

Patients often find great relief from tachycardia, palpitations, anxiety, and tremor with beta-blocker therapy. Beta-blockers may be used if symptoms of adrenergic stimulation are troublesome. Propranolol is generally recommended because of its central nervous system (CNS) effects; it also has the theoretical advantage of inhibiting conversion of T4 to T3 at higher doses. Beta blockade can usually be withdrawn in 2-6 weeks.

Exercise caution with the initial dose of propranolol; patients may become hypotensive, because they are often dehydrated from a decrease in the oral intake of fluids and increased perspiration from thyrotoxicosis. Beta-1 selective agents (metoprolol or atenolol) have more convenient dosing and are better tolerated.

Monitoring

All forms of subacute thyroiditis

Patients should be seen every 4 weeks for reassurance and for measurement of thyroid hormone levels. Occasionally, patients have relapses of the thyrotoxic phase and experience persistent symptoms. Monitor for the subsequent hypothyroid phase and treat with levothyroxine if patients are symptomatic.[47]

Subacute granulomatous thyroiditis

Patients usually recover completely from subacute granulomatous thyroiditis. The episodes rarely recur. Generally, patients are not prone to other thyroid disease and do not need long-term follow-up.

Subacute lymphocytic and subacute postpartum thyroiditis

These conditions are sometimes associated with chronic thyroiditis. Postpartum thyroiditis usually recurs after each pregnancy. Patients should be observed routinely every 6-12 months for the development of goiter or hypothyroidism from chronic thyroiditis.

 

Medication

Medication Summary

Medical treatment for subacute thyroiditis is supportive in general. Thyrotoxicosis can be extreme but temporary (eg, 6-8 wk). The subsequent hypothyroid phase is usually mild and lasts 2-4 months. Therapy is directed toward reducing the signs and symptoms of the hyperthyroidism with beta blockers or iodine agents. Pain is treated with nonsteroidal anti-inflammatory agents (NSAIDs). Rarely, high-dose steroids and narcotic analgesic agents are used for extremely painful or recurrent life-threatening hyperthyroidism.

Salicylates

Class Summary

Salicylates are used for symptomatic treatment. They aid in the relief of mild to moderate pain by inhibiting inflammatory reactions and pain. Patients should avoid high-dose aspirin because it can increase free thyroid hormone levels by displacing thyroid hormone from its protein-binding sites.

Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered)

Aspirin treats mild to moderate pain. It inhibits prostaglandin synthesis, which prevents the formation of platelet-aggregating thromboxane A2.

Nonsteroidal Anti-Inflammatory Drugs

Class Summary

Anti-inflammatory agents are administered to patients with subacute granulomatous thyroiditis. Narcotic analgesics can be administered if the pain is extreme and prevents oral hydration. In rare cases, high-dose steroids (eg, prednisone 40-60 mg/day PO for 4-6 wk) may be used to decrease the pain.

Ibuprofen (Advil, Motrin)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen (Aleve, Naprosyn, Naprelan)

Naproxen is used for the relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which results in a decrease of prostaglandin synthesis.

Indomethacin (Indocin)

Indomethacin, which is rapidly absorbed, inhibits prostaglandin synthesis. The drug is metabolized in the liver by demethylation, deacetylation, and glucuronide conjugation.

Iodinated Contrast Agents

Class Summary

High iodine levels inhibit the peripheral conversion of T4 to T3. The most effective agents are the iodinated contrast agents, but high levels of iodine provided by saturated solution of potassium iodide (SSKI; 2 drops in full glass of water PO tid) can be substituted.

Iopanoic acid (Telepaque)

This is an oral contrast agent used for the rapid and significant inhibition of the peripheral conversion of T4 to T3. Inorganic iodide also blocks the release of thyroid hormones. Reduction in the conversion of T4 to T3 can greatly reduce T3 levels and thyrotoxic symptoms.

Ipodate (Oragrafin)

Ipodate is one of the most effective inhibitors of deiodinase, which converts T4 to the more biologically active T3. Reduction in the conversion of T4 to T3 can greatly reduce T3 levels and thyrotoxic symptoms.

Thyroid Products

Class Summary

Most patients with subacute thyroiditis experience a hypothyroid phase following thyrotoxicosis. Asymptomatic patients do not need to be treated if the TSH level is mildly elevated (< 15 µIU/mL), but they should be tested every 4 weeks to confirm that hypothyroidism is not worsening or becoming permanent.

Thyroid hormone is generally administered (usually 50 mcg/day) to normalize TSH. After 6 months, when 90-95% of patients have returned to normal thyroid function, thyroid hormone is discontinued; the TSH level is checked 4 weeks after discontinuation of therapy. If the TSH level is within the reference range, no further treatment is necessary. If the level is elevated, however, the patient has permanent hypothyroidism, and therapy should be continued indefinitely.

Levothyroxine (Levoxyl, Synthroid, Tirosint)

Levothyroxine is used for supplementation during the hypothyroid phase of subacute thyroiditis. The goal of levothyroxine therapy is to keep the TSH level within the reference range for 6 months; therapy is then discontinued. The TSH level should be checked 4 weeks later; if the level is elevated, levothyroxine therapy must be reinstituted and continued indefinitely.

Tirosint is a preparation of T4 in a liquid form in a gelatin capsule. This form of thyroid hormone contains only T4, glycerol, and gelatin, with no other additives. This form may be preferred in patients on long-term proton pump inhibitors, a history of erratic T4 absorption, and reactions to the nonhormone content of other pills (eg, gluten, dyes).

T3, liothyronine (Cytomel, Triostat)

Liothyronine is a synthetic form of natural thyroid hormone T3 converted from T4. Its duration of activity is short, which allows for quick dosage adjustments in the event of overdosage. Liothyronine may need to be administered as often as 4 times daily. In its active form, the drug influences the growth and maturation of tissues.

Thyroid hormone replacement with T3 alone is not recommended because of the need for dosing at 2-3 times daily. The short half-life means there is significant fluctuation between too low and too high levels during the course of the day.

Beta-Adrenergic Blocking Agents

Class Summary

Beta-blockers reduce many of the symptoms of thyrotoxicosis, including tachycardia, tremor, and anxiety. Propranolol is usually recommended because of its CNS penetration, but some patients prefer the longer-acting beta-blockers.

Propranolol (Inderal LA, InnoPran XL)

Propranolol is the drug of choice for treating cardiac arrhythmia resulting from hyperthyroidism. The drug effects cardiac and psychomotor manifestations within minutes.

Atenolol (Tenormin)

Atenolol selectively blocks beta1 receptors, with little or no effect on beta2 types. This agent is useful for treating cardiac arrhythmias resulting from hyperthyroidism. It effects cardiac and psychomotor manifestations within minutes.

Metoprolol (Lopressor, Toprol XL)

Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. It aids in the treatment of cardiac arrhythmias resulting from hyperthyroidism. The drug effects cardiac and psychomotor manifestations within minutes.

Corticosteroids

Class Summary

If thyroid pain is extreme, high-dose steroids rapidly reduce thyroid hormone levels and swelling. Generally, therapy must be continued for 4-6 weeks before tapering.

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects, modifying the body's immune response to diverse stimuli.

Prednisone

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) cell activity.

Prednisolone (Millipred, Orapred, Orapred ODT, Prelone)

Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosages.

Research indicates that prednisolone 15 mg/day with a taper of 5 mg every 2 weeks is a safe and effective means of quickly reducing pain.

 

Questions & Answers

Overview

What is subacute thyroiditis?

What are forms of subacute thyroiditis?

What is the clinical course of subacute thyroiditis?

What is subacute granulomatous thyroiditis?

What is the pathophysiology of subacute thyroiditis?

What is the role of thyrotoxicosis in the pathophysiology of subacute thyroiditis?

What are the signs and symptoms of thyrotoxicosis in subacute thyroiditis?

What is the prevalence of papillary thyroid carcinoma (PTC) in subacute thyroiditis?

What is the role of amiodarone in the etiology of subacute thyroiditis?

What is the role of lithium in the etiology of subacute thyroiditis?

What causes subacute thyroiditis?

What causes subacute granulomatous thyroiditis?

What is the role of human leukocyte antigen (HLA-B35) in the etiology subacute thyroiditis?

What is the role of growth factors in the etiology of subacute thyroiditis?

What causes subacute lymphocytic thyroiditis?

What is the role of interferon alfa in the etiology of subacute thyroiditis?

What is the role of interleukin 2 in the etiology of subacute thyroiditis?

What causes subacute postpartum thyroiditis?

Which conditions are associated with subacute thyroiditis?

What is the prevalence of subacute thyroiditis?

What are the sexual predilections of subacute thyroiditis?

Which age groups have the highest prevalence of subacute thyroiditis?

What is the prognosis of subacute thyroiditis?

What is the prognosis of thyrotoxicosis from subacute thyroiditis?

What is the prognosis of subacute granulomatous thyroiditis?

What are the acute complications of subacute thyroiditis?

What are the long-term complications of subacute thyroiditis?

What is the prognosis of subacute lymphocytic thyroiditis?

What is the prognosis of subacute postpartum thyroiditis?

Presentation

Which clinical history findings are characteristic of subacute thyroiditis?

What are the phases of subacute granulomatous thyroiditis?

How is subacute granulomatous thyroiditis diagnosed?

What are the signs and symptoms of subacute granulomatous thyroiditis?

What are the signs and symptoms of hyperthyroidism during the acute phase of subacute granulomatous thyroiditis?

What are the signs and symptoms of hyperthyroidism during the second phase of subacute granulomatous thyroiditis?

What uncommon signs and symptoms of subacute granulomatous thyroiditis?

Which clinical history findings are characteristic of subacute lymphocytic thyroiditis?

Which clinical history findings are characteristic of subacute postpartum thyroiditis?

Which physical findings are characteristic of subacute thyroiditis?

Which physical findings are characteristic of subacute granulomatous thyroiditis?

Which physical findings are characteristic of hyperthyroidism during the acute phase of subacute granulomatous thyroiditis?

Which physical findings are characteristic of subacute lymphocytic thyroiditis?

Which physical findings are characteristic of subacute postpartum thyroiditis?

DDX

Which conditions should be considered in the differential diagnosis of subacute thyroiditis?

What are the differential diagnoses for Subacute Thyroiditis?

Workup

What is the role of lab testing in the diagnosis of subacute thyroiditis?

What is the role of thyroid-stimulating hormone (TSH) measurement in the diagnosis of subacute thyroiditis?

What is the role of triiodothyronine (T3) and thyroxine (T4) measurement in the workup of subacute thyroiditis?

What is the role of serum thyroglobulin measurement in the workup of subacute thyroiditis?

What is the role of the erythrocyte sedimentation rate in the workup of subacute thyroiditis?

What is the role of thyroid autoantibody testing in the workup of subacute thyroiditis?

Which research-oriented tests are not beneficial in the diagnosis of subacute thyroiditis?

What is the role of liver function tests in the diagnosis of subacute thyroiditis?

What is the role of IL-6 testing in the diagnosis of subacute thyroiditis?

What is the role of lab testing in the diagnosis of subacute granulomatous thyroiditis?

What is the role of lab testing in the diagnosis of subacute lymphocytic thyroiditis?

What is the role of lab testing in the diagnosis of subacute postpartum thyroiditis?

What is the role of CT scanning in the diagnosis of subacute thyroiditis?

What is the role of MRI in the diagnosis of subacute thyroiditis?

What is the role of technetium-99m (99m Tc)-pertechnetate scintigraphy in the workup of subacute thyroiditis?

What is the role of radioiodine uptake in the workup of subacute thyroiditis?

What is the role of ultrasonography in the workup of subacute thyroiditis?

What is the role of sonoelastography in the workup of subacute thyroiditis?

What is the role of fine-needle aspiration (FNA) biopsy in the workup of subacute thyroiditis?

Which histologic findings are characteristic of subacute thyroiditis?

Which histologic findings are characteristic of subacute granulomatous thyroiditis?

Treatment

How is subacute thyroiditis treated?

When is inpatient care indicated for the treatment of subacute thyroiditis?

Which dietary modifications are used in the treatment of subacute thyroiditis?

What activities are restricted in patients with subacute thyroiditis?

Which specialist consultations are beneficial to patients with subacute thyroiditis?

How is subacute thyroiditis prevented?

How is subacute granulomatous thyroiditis treated?

How is hypothyroidism treated in subacute thyroiditis?

What is the role of ipodate in the treatment of subacute thyroiditis?

What is the role of propranolol in the treatment of subacute thyroiditis?

What is included in the long-term monitoring of patients with subacute thyroiditis?

What is included in the long-term monitoring of patients with subacute granulomatous thyroiditis?

What is included in the long-term monitoring of patients with subacute lymphocytic and subacute postpartum thyroiditis?

Medications

Which medications are used in the treatment of subacute thyroiditis?

Which medications in the drug class Corticosteroids are used in the treatment of Subacute Thyroiditis?

Which medications in the drug class Beta-Adrenergic Blocking Agents are used in the treatment of Subacute Thyroiditis?

Which medications in the drug class Thyroid Products are used in the treatment of Subacute Thyroiditis?

Which medications in the drug class Iodinated Contrast Agents are used in the treatment of Subacute Thyroiditis?

Which medications in the drug class Nonsteroidal Anti-Inflammatory Drugs are used in the treatment of Subacute Thyroiditis?

Which medications in the drug class Salicylates are used in the treatment of Subacute Thyroiditis?