Subacute Thyroiditis Workup

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 ^[24]

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. ^[25]

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. ^[26]

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 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.

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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

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. ^[23]

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. ^{[27, 28]}

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 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.

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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 of^99m Tc -sestamibi during the early phase (ie, from 10 min to 1 h) is decreased in the acute stage of subacute granulomatous thyroiditis. ^[29]

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. ^{[23, 30, 31, 32, 33, 34, 35]}

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. ^{[36, 37, 38]}

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. ^[39] In the recovery phase, the thyroid structure and dimensions return to normal. (See the image below.)

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.

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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.” ^[40]

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. ^[41]

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. ^{[42, 43, 44, 45]}

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.

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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.

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.