De Quervain thyroiditis was first reported in 1825, but de Quervain recorded its pathological description in 1904.
De Quervain (subacute granulomatous) thyroiditis is the most common cause of a painful thyroid gland. 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. Hyperthyroidism often occurs initially, sometimes followed by transient hypothyroidism. Complete recovery in weeks to months is characteristic.
Some authors use the term subacute thyroiditis for this disease. However, subacute thyroiditis is a generic term that may be used for all types of thyroiditis with a subacute course, including subacute granulomatous thyroiditis (de Quervain disease), subacute lymphocytic (painless) thyroiditis, and some forms of postpartum thyroiditis and drug-induced thyroiditis.
A viral infection or a postviral inflammatory response is presumed to cause de Quervain thyroiditis. Serial studies of viral antibody titers have implicated many viruses (including coxsackievirus, Ebstein-Barr, mumps, measles, adenovirus, echovirus, and influenza), but the changes could be attributed equally to nonspecific anamnestic responses. Occurrence of de Quervain thyroiditis in the course of novel H1N1 influenza infection was recently reported from Greece.[1] Viral inclusion bodies are not observed in thyroid tissue in de Quervain thyroiditis.
A strong association exists with human leukocyte antigen (HLA)-B35 in most ethnic groups. A proposed mechanism is that the disease results from a viral infection that provides an antigen, either viral or resulting 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 they have some structural similarity with the infection-related antigen. The transient presence of autoantibodies (eg, inhibitory immunoglobulins that bind to thyrotropin [TSH], antibodies that block thyroid stimulation, thyroid antimicrosomal antibodies, thyroglobulin [TGB] antibodies) has been noted in the acute phase of the disease, but their presence is attributed to a virally induced autoimmune response and is not implicated in the pathological process. In contrast with autoimmune thyroid disease, the immune response is not self-perpetuating; therefore, the process is limited.
Destruction of follicular epithelium and loss of follicular integrity are the primary events in the pathophysiology of de Quervain thyroiditis. TGB, 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 TSH secretion. This state lasts until the stores of TGB are exhausted or until healing occurs. New hormone synthesis temporarily ceases because of the low 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.
De Quervain thyroiditis occurs in less than 5% of all patients with thyroid pathology. It tends to have seasonal and geographical distribution and is most common during the summer and fall. It tends to follow viral epidemics.
A systematic review of all cases diagnosed between 1960 and 1997 in Olmsted County, Minnesota revealed an age- and sex-adjusted incidence of 4.9 cases per 1000,000 per year.[2]
International
International frequency is approximately the same as US frequency.
Mortality/Morbidity
De Quervain thyroiditis is a benign self-limited disease. Morbidity is caused during the initial phase by pain, which usually prompts the patient to consult a physician. Mild and transient hyperthyroidism occurs, and, in as many as 50% of patients, hypothyroidism may occur later. Recurrence of thyroiditis up to 21 years following the initial episode has been reported.
Sex
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.
Age
De Quervain thyroiditis has a peak incidence 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.[3] Occurrence during pregnancy has been reported as well.[4]
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 that usually unfold over a period of 3-6 months:
The acute phase, lasting 3-6 weeks, presents primarily with pain. Symptoms of hyperthyroidism also may be present.
The transient asymptomatic and euthyroid phase lasts 1-3 weeks.
The hypothyroid phase lasts from weeks to months, and it may become permanent in 5-15% of patients.
The recovery phase is characterized by normalization of thyroid structure and function.
Table. Characteristic Course of de Quervain Thyroiditis
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See Table
The diagnosis is made based on clinical findings. Prodromal flulike symptoms 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
Pain over the thyroid area that is gradual or of sudden onset; that usually involves both lobes (in 30% of cases, it starts on one side and then migrates contralaterally within a few days); that radiates to the neck, ear, jaw, throat, or occiput; and is aggravated by swallowing and head movement; pain is the presenting symptom in over 90% of cases
Dysphagia
Hoarseness (uncommon)
Constitutional symptoms (often absent)
Fever
Malaise
Anorexia
Fatigue
Muscle aches
Symptoms of hyperthyroidism (palpitations, tremulousness, heat intolerance, sweating, nervousness) occurring in the initial phase of the disease
Hyperthyroidism that usually is mild and rarely is severe
Transient symptoms, usually lasting 3-6 weeks
Symptoms of hypothyroidism, occurring in the late phase of the disease in as many as half the cases
Mostly mild or moderate
Transient hypothyroidism in 90-95% of cases
Hypothyroidism lasts weeks to months
Atypical presentations (extremely rare, documented as case reports)
Thyroid storm[5]
Fever of unknown origin
Painless subacute granulomatous thyroiditis
Occult de Quervain disease mimicking giant cell arteritis
Prominent prostration and confusion lasting several weeks
Thyroid tenderness is usually symmetrical, but, occasionally, it starts in one lobe and then involves the contralateral lobe. Often, the pain is so severe that the patient cannot tolerate palpation of the neck.
Thyroid enlargement is usually symmetric 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.
Hyperthyroidism
Hyperthyroidism is present in approximately half the patients.
Signs of hyperthyroidism consist of tremor, tachycardia, warm skin, and a rapid relaxation phase of tendon reflexes
Lid retraction is rare; exophthalmos does not occur.
A viral infection or a postviral inflammatory response in genetically predisposed individuals is presumed to cause de Quervain thyroiditis. Serial studies of viral antibody titers have implicated many viruses (including coxsackievirus, Ebstein-Barr, mumps, measles, adenovirus, echovirus, and influenza), but the changes could be attributed equally to nonspecific anamnestic responses. Recent studies failed to demonstrate significant changes in serum antiviral antibody titers, or to detect viral DNA in the thyroid specimens.
Usually, the diagnosis is made on clinical grounds, and the only laboratory studies needed initially are those to determine whether hyperthyroidism is present, including TSH and free T4.
If any doubt exists as to whether de Quervain thyroiditis is the correct diagnosis, 2 other tests may be helpful.
Serum thyroglobulin is almost always markedly elevated.
Erythrocyte sedimentation rate (ESR) is usually higher than 50 mm/h in the initial phase. A normal or slightly elevated ESR makes the diagnosis of de Quervain thyroiditis relatively unlikely. ESR falls as the inflammatory process resolves, but following the ESR provides no useful information beyond what clinical observation yields.
After the initial inflammatory phase subsides, TSH should be monitored at intervals of 4-6 weeks for a few months to determine whether hypothyroidism occurs.
Antibodies to TGB, thyroid peroxidase, and TSH receptor are usually absent in de Quervain thyroiditis and need not be sought unless the clinical differential diagnosis includes immune thyroid disease (Graves disease, chronic lymphocytic [Hashimoto] thyroiditis).
In rare cases with systemic multiorgan involvement, elevation of serum alkaline phosphatase, gamma-glutamyl transpeptidase, aminotransferases, and pancreatic enzymes may occur. Glucose intolerance has been reported.
Ultrasonography of the thyroid gland[6, 7, 8, 9, 10, 11]
Ultrasonography provides no additional information and is rarely indicated for diagnostic purposes.
In the first 3 phases of the disease, the thyroid gland is enlarged, shows unclear contour, and is diffusely or focally hypoechogenic.
In the recovery phase, the thyroid structure and dimensions return to normal.
Fibrosis is observed in some patients as hyperechogenicity and may occur as a form of healing. Extensive fibrosis is a predictor of hypothyroid state.
Doppler ultrasonography shows a near absence of vascularization in 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.[12]
Ultrasonographic abnormalities are not correlated with the intensity of the inflammatory syndrome and/or thyroid function status. Recurrence can be seen as a 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.
One study noted that thyroid volume is much smaller during the acute phase of the disease, and end-stage mean thyroid volume is significantly lower in patients who develop persistent hypothyroidism compared to patients with final normal thyroid function.
CT scanning of the neck[11]
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.
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.
Magnetic resonance imaging: MRI is not indicated for the diagnosis or evaluation of subacute granulomatous thyroiditis. If one is performed during the acute phase, the thyroid gland shows irregular margins and a higher than normal T1-weighted signal intensity and a much higher than normal T2-weighted signal intensity.[13, 14]
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 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 in 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 ESR, TGB, or CRP levels for active disease or relapse.
Genetic studies show a high incidence of HLA-B35 antigen in patients with subacute granulomatous thyroiditis in selected populations.[15]
Neither radioiodine uptake (RAIU) nor thyroid scanning is indicated unless pain is mild or absent, in which case Graves disease might be considered in the differential diagnosis.
RAIU is very low in the initial phase of subacute thyroiditis (< 1-2% at 24 h) but usually is elevated in Graves disease.
Technetium-99m-pertechnetate scintigraphy typically demonstrates markedly reduced uptake in the thyroid gland during the acute stage, but this finding is not present in all patients.
Technetium-99m-tetrafosmin 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.
Technetium-99m-sestamibi scanning may show diffuse increased uptake in the region of the thyroid gland, suggesting increased perfusion. The clearance rate of Technetium-99m-sestamibi during the early phase (ie, from 10 min to 1 h) is decreased in the acute stage of subacute granulomatous thyroiditis.[16]
Fine-needle aspiration of the thyroid[17, 18, 19, 20]
Fine-needle aspiration (FNA) is rarely needed; most of the time, the diagnosis of de Quervain thyroiditis can be made solely on clinical grounds. Some authors advocate that FNA should be performed in all patients with a tender thyroid to avoid misdiagnosis and inappropriate management.
FNA is useful for diagnosis when atypical presentations of thyroid carcinoma and thyroid abscess are considered in the differential diagnoses.
It usually shows the specific histological features of de Quervain thyroiditis (see Histologic Findings).
FNA may provide unclear results in the acute stage when atypical follicular cells may appear in the aspirate, mimicking thyroid carcinoma.
The thyroid gland is moderately enlarged and edematous in de Quervain thyroiditis. It may be unilaterally or bilaterally enlarged and has an intact capsule. Affected areas are firm and yellow-white and stand out from the more rubbery, normal, brown thyroid substance.
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, and are CD68+, thyroglobulin negative, and cytokeratin negative. The small lymphocytes in the granulomas are CD3+, CD8+, 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.
Management is directed towards 2 problems—pain and thyroid dysfunction.
Pain
Some patients with mild pain require no treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (800-1200 mg/d in divided doses) or naproxen (1-1.5 g/d in divided doses), or aspirin (2-4 g/d in divided doses) are used. Treatment can be tapered as allowed by the patient's pain. Analgesic therapy can usually be stopped after 2-6 weeks.
Steroids have no proven superiority to NSAIDs in de Quervain thyroiditis and should be avoided. If NSAIDs provide insufficient relief of pain within 3 days, then prednisone may be tried at 30-40 mg/d initially. The response to prednisone is usually prompt (within 2-3 d), and, if a prompt response does not occur, prednisone should be stopped. The dose of prednisone should be tapered slowly; symptoms often recur upon withdrawal.
If pain does not respond within 3 days, the diagnosis should be reconsidered.
Management of thyroid dysfunction
In the initial phase of de Quervain thyroiditis, symptomatic hyperthyroidism can be treated with beta-blockade (propranolol 10-20 mg qid or atenolol 25-50 mg/d), although mild symptoms may not require treatment. Beta-blockade, if needed, can usually be withdrawn in 2-6 weeks. Antithyroid drugs are of no value because the excess T4 and T3 results from release of preexisting thyroid hormone by follicular damage rather than from active synthesis.
If hypothyroidism occurs during the late phase, it is usually mild and transient. If symptoms are present or TSH is elevated, the patient needs replacement therapy with levothyroxine. Depending on the level of TSH, the starting dose can be 25-100 mcg/d and 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 and monitoring of TSH.
Rare cases with permanent hypothyroidism require lifelong replacement therapy.
The goals of pharmacotherapy are to reduce disease-associated morbidity and prevent complications due to abnormal thyroid function. No treatment has been shown to impact the occurrence of permanent hypothyroidism.
Clinical Context:
For relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.
Although most NSAIDs are used primarily for their anti-inflammatory effects, they are effective analgesics and are useful for the relief of mild to moderate pain.
Clinical Context:
Symptomatic treatment used in NSAID-refractory cases. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Used for symptomatic relief of hyperthyroidism. Propranolol is used as an example, but any noncardioselective beta-blocker can be used. Use only in moderate to severe cases of hyperthyroidism, and many times it is not needed.
Required during the recovery phase if transient hypothyroidism occurs. Required indefinitely in the occasional patient who develops permanent hypothyroidism.
The authors recommend monitoring thyroid function every 2-4 months for 1 year or until thyroid function normalizes (whichever occurs later).[21] Yearly monitoring of thyroid function should be performed thereafter for several years, since permanent hypothyroidism may occur several years following the initial diagnosis.
Severe hyperthyroidism may be observed during the inflammatory phase (see History).
Multiple system organ failure may complicate the course of the disease in exceptionally rare cases.
Pancreatitis or splenomegaly has been associated with de Quervain thyroiditis in case reports only.
Vocal cord paralysis occurs occasionally in cases with severe thyroid gland inflammation.
Cerebral venous thrombosis was 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).
Prognosis is excellent. More than 90% of the patients with de Quervain thyroiditis recover completely, with or without treatment. Even in the 5-10% of patients who develop hypothyroidism, treatment with thyroid hormone is effective.
Ildiko Lingvay, MD, MPH, Assistant Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Texas Southwestern Medical Center at Dallas
Disclosure: Nothing to disclose.
Coauthor(s)
Daniel Matei Brailita, MD, Chief of Infectious Diseases, Mary Lanning Memorial Hospital
Disclosure: Nothing to disclose.
James Burks, MD, FACP, FACE, Professor of Medicine, Program Director, Department of Medicine, Texas Tech University Health Sciences Center
Disclosure: Nothing to disclose.
Joseph E Loewenstein, MD, Retired
Disclosure: Nothing to disclose.
KoKo Aung, MD, MPH, FACP, Associate Professor, Department of Medicine, University of Texas Health Science Center at San Antonio; Adjunct Associate Professor of Public Health, University of Texas School of Public Health
Disclosure: Nothing to disclose.
Specialty Editors
Amir E Harari, MD, Staff Physician, Endocrinology Division, Instructor, Department of Clinical Medicine, Naval Medical Center at San Diego
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics
Disclosure: Nothing to disclose.
Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.
Chief Editor
George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
Lazarus, JH. Silent thyroiditis and subacute thyroiditis. In: Braverman LE, Utiger R, eds. Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text. 7th ed. New York, NY: JB Lippincott; 1996:577.
