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Scintigraphic Features of Autoimmune Thyroiditis1 ONLINE-ONLY CME See www.rsna.org /education/rg _cme.html.

LEARNING OBJECTIVES After reading this article and taking the test, the reader will be able to: Identify the causes 䡲 and scintigraphic appearances of silent and postpartum thyroiditis. 䡲 Identify the causes and scintigraphic appearances of various stages of Hashimoto thyroiditis.

Charles M. Intenzo, MD ● David M. Capuzzi, MD, PhD ● Serge Jabbour, MD ● Sung M. Kim, MD ● Ann E. dePapp, MD The term autoimmune thyroiditis encompasses multiple inflammatory conditions of the thyroid gland, each with variable clinical manifestations. The more acute forms, silent (painless) thyroiditis and postpartum thyroiditis, are associated with transient hyperthyroidism and are sometimes mistaken for Graves disease. The chronic form, Hashimoto thyroiditis (chronic autoimmune thyroiditis), results in goiter and eventual hypothyroidism unless it is recognized and treated promptly. Thyroid uptake measurements and scintigraphic findings (usually obtained with technetium-99m or iodine-123) play a complementary role along with thyroid function testing in differentiating autoimmune thyroiditis from other thyroid diseases, thereby influencing treatment. In some cases, histologic evaluation of biopsy specimens is required to yield the definitive diagnosis. Knowledge of the entire spectrum of these disorders is essential for appropriate case management.

䡲 Discuss less common autoimmune thyroid disorders such as Hashitoxicosis and amiodaroneassociated thyroid disease.

Abbreviations: H-E ⫽ hematoxylin-eosin, RAIU ⫽ radioactive iodine uptake, TPO ⫽ thyroid peroxidase, TSH ⫽ thyroid-stimulating hormone, T4 ⫽ thyroxine, T3 ⫽ triiodothyronine Index terms: Thyroid, hyperthyroidism, 273.522 ● Thyroid, hypothyroidism, 273.521, 273.64 ● Thyroid, radionuclide studies, 273.12171, 273.12172 ● Thyroiditis, 273.292 RadioGraphics 2001; 21:957–964 1From the Departments of Radiology (C.M.I., S.M.K.) and Medicine (D.M.C., S.J., A.E.D.), Thomas Jefferson University Hospital, 132 S 10th St, Rm 861 Main Bldg, Philadelphia, PA 19107. From the 1999 RSNA scientific assembly. Received August 28, 2000; revision requested November 6 and received December 22; accepted December 28. Address correspondence to C.M.I. ©

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Introduction Autoimmune inflammatory disorders of the thyroid gland are very common and have variable clinical manifestations. Signs and symptoms can range from hyperthyroidism to hypothyroidism. Scintigraphy is useful in demonstrating the functional state of the thyroid at the time of clinical presentation. In this article, we review the clinical, scintigraphic, and histopathologic features of both acute and chronic forms of autoimmune thyroiditis. More specifically, we discuss silent and postpartum thyroiditis, Hashimoto thyroiditis and its multiple manifestations, Hashitoxicosis, and amiodarone-associated thyroid disease. The Table shows the normal values for thyroid function tests performed at our institution.

Scintigraphic Technique At our institution, the vast majority of thyroid scintigraphic scans are acquired with technetium (Tc)–99m pertechnetate. All but one of the thyroid scans shown in this article were obtained in this way. Imaging was performed approximately 15 minutes after intravenous administration of 10 mCi (370 MBq) of Tc-99m pertechnetate using a pinhole collimator with a 3.5-mm aperture and an energy setting of 140 keV photopeak for Tc-99m. The images consisted of anterior and right and left anterior oblique projections (100,000 counts each) with the collimator positioned as close to the patient’s extended neck as possible. A “distant” anterior view was subsequently obtained with the collimator positioned 10 cm above the patient’s neck and a 2-cm “cold” lead marker placed at the sternal notch. The field of view for this image was set to include the sternal notch and the salivary glands so that the size of the thyroid or any intraglandular abnormalities could be assessed. With pinhole collimators, the magnification changes depending on the distance of the thyroid from the detector; thus, good imaging practice includes placement of a marker of a known size to facilitate internal measurements. I–131 uptake was determined with a thyroid uptake probe 24 hours after oral administration of 5 ␮ci (⬃0.19 MBq) of this radiotracer. If specifically requested by the referring physician, I-123 is used for both thyroid uptake measurements and imaging. Images (100,000 counts

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Normal Thyroid Function Test Values at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Test

Symbol

Normal Range

Thyroxine Tri-iodothyronine Thyroid-stimulating hormone Free T4 Iodine-131 uptake

T4 T3

4.5–12.0 ␮g/dL 50–150 ␮g/dL

TSH FT4 RAIU*

0.4–4.5 ␮IU/mL 0.7–1.6 ng/dL 8%–35% at 24 h

*Radioactive iodine uptake.

each) are obtained with the same pinhole collimator with an energy setting of 159 keV photopeak for I-123. We prefer thyroid imaging with Tc99m pertechnetate mainly because acquisition of 100,000-count images is much faster with Tc99m than with I-123. This is because the allowable dose of Tc-99m (5–10 mCi [⬃185–370 MBq]) is much higher than that of I-123 (200 – 300 ␮ci [⬃7.27–11.11 MBq]); thus, a much greater amount of Tc-99m can be administered, and acquisition is considerably faster. This is particularly important in elderly patients because extending the neck for long periods of time can result in considerable discomfort. In addition, Tc-99m is readily available either from molybdenum generators or in bulk unit doses that are delivered daily to hospital radiopharmacies. In contrast, I-123 capsules are produced with a cyclotron and must be requested from outside facilities. For these reasons, some nuclear medicine laboratories prefer using Tc-99m.

Silent Thyroiditis Silent thyroiditis, also known as “painless” or atypical thyroiditis, is a clinical syndrome that manifests as transient thyrotoxicosis followed by transient hypothyroidism. It was initially described as a painless form of subacute thyroiditis, a disorder characterized by thyrotoxicosis associated with thyroid pain and tenderness. Silent thyroiditis is an autoimmune disease that is characterized by elevated levels of thyroid peroxidase (TPO) antibodies and thyroglobulin antibodies (1). At histopathologic analysis, silent thyroiditis manifests as an lymphocytic infiltration of the thyroid follicles, resulting in follicular cell damage. Consequently, excess T4 and T3 are released

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Figure 1. Silent thyroiditis in a 28-year-old woman with hyperthyroidism. Laboratory values were as follows: T4 ⫽ 21 ␮g/dL, T3 ⫽ 289 ␮g/dL, and TSH ⬍ 0.02 ␮IU/mL. RAIU was less than 1% at 24 hours. (a) On a distant anterior scintigram, the thyroid is barely visible (broad arrow at left). The round photopenic area (thick arrow) represents a 2-cm lead marker placed at the suprasternal notch. The dark structures (thin arrow) represent the salivary glands. Because of associated thyromegaly and the patient’s morbid fear of thyroid cancer (as diagnosed in a sibling), large-core needle biopsy was performed. (b) Photomicrograph (original magnification, ⫻150; hematoxylin-eosin [H-E] stain) demonstrates mild lymphocytic infiltration within the thyroid parenchyma.

into the circulation, resulting in thyrotoxicosis (2,3) and making the clinical manifestation of silent thyroiditis very similar to that of Graves disease. The thyrotoxicosis is usually mild to moderate and lasts for 1– 4 weeks, followed by euthyroidism and transient hypothyroidism (4). The thyroid is enlarged in 50%– 60% of affected patients. Thyroid function testing reveals elevated serum T3 and T4 levels, with very low levels of TSH. RAIU determinations of the thyroid are very low, reflecting the inability of the inflamed gland to organify iodine. Thyroid scintigraphy reveals markedly decreased glandular activity (Fig 1). RAIU and thyroid scintigraphic findings help differentiate silent thyroiditis from Graves disease. Such a distinction is crucial because the management of these thyroid disorders differs significantly. In general, the thyrotoxicosis from silent thyroiditis will resolve spontaneously, and no treatment is usually warranted, except for possible palliation of an elevated pulse rate with the use of

␤-blockers. Thyroid hormone therapy is sometimes needed in the recovery phase of silent thyroiditis, which is characterized by transient hypothyroidism (4).

Postpartum Thyroiditis In general, thyrotoxicosis during the postpartum period is caused by either Graves disease or, more commonly, thyroiditis. Postpartum thyroiditis is a subtype of silent thyroiditis that appears during the 1st postpartum year and occurs in 5% of all pregnancies. Thyrotoxicosis usually occurs 2– 6 months after delivery and lasts for 2– 6 weeks. This is followed by a period of hypothyroidism that also usually lasts 2– 6 weeks. Approximately 23% of patients develop permanent hypothyroidism. The thyrotoxicosis and hypothyroidism are both mild to moderate, and this disorder tends to recur with multiple pregnancies (5). During the thyrotoxic phase, serum thyroid hormone levels are elevated, whereas TSH levels are suppressed

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as in silent thyroiditis. At histologic analysis, postpartum thyroiditis closely resembles silent thyroiditis with marked lymphocytic infiltration (6). Similarly, radioiodine uptake is below normal, and thyroid scintigraphy demonstrates markedly reduced uptake within the gland (Fig 2). These findings help differentiate postpartum thyroiditis from Graves disease.

Hashimoto Thyroiditis Hashimoto thyroiditis, also known as chronic autoimmune thyroiditis, is autoimmune destruction of the thyroid characterized by goiter, autoimmunity to thyroid antigens, and lymphocyte infiltration. This condition is the most common of all thyroid disorders (7) and affects people of all ages, especially those who are 30 –50 years old. Hashimoto thyroiditis has a strong genetic component because there is a high prevalence of thyroid antibodies among first-degree relatives (8). The pathogenesis of Hashimoto thyroiditis can be summarized as an autoimmune reaction against the thyroid, with both cellular and humoral features. Antithyroglobulin antibodies are present in 55%–90% of patients, whereas TPO antibodies are present in 90%–95% (8). The autoimmune reaction results in lymphocytic and plasma cell infiltration with formation of lymphoid follicles, which in turn leads to thyroid follicle deterioration. Fibrosis develops over time, resulting in glandular enlargement. As a result of the ongoing replacement of the normal thyroid follicles by lymphocytes and fibrous tissue, there is eventual reduction in thyroid function because thyroid hormone production by the gland is impaired. Therefore, goiter and hypothyroidism are the main clinical features of this disease (9). In the early (preclinical) stage of Hashimoto thyroiditis, thyroid function is normal. This is because initially a mild decline in circulating thyroid hormones is sensed by the pituitary gland,

Figure 2. Postpartum thyroiditis in a 27-year-old woman who was experiencing palpitations, nervousness, and insomnia 2 months after giving birth. At physical examination, the patient’s thyroid felt enlarged and nodular. Laboratory values were as follows: T4 ⫽ 17.3 ␮g/dL, FT4 ⫽ 2.4 ng/dL, and TSH ⬍ 0.02 ␮IU/ mL. The 24-hour RAIU was 2%. Anterior image shows an enlarged thyroid with poor radiotracer concentration (thin arrow) (cf Fig 1). Thick arrow indicates the salivary glands.

and a compensatory rise in TSH secretion stimulates the gland to synthesize more thyroid hormone so that T3 and T4 levels return to normal. Such thyroid stimulation results in elevated radioiodine uptake values as well as diffusely increased radionuclide activity throughout the thyroid (Fig 3). In some instances, thyroid follicles demonstrate a variable response to the chronic TSH stimulation, leading to patchy proliferation of these follicles. On a thyroid scan, this phenomenon manifests as areas of increased activity (follicles that respond to TSH) and of decreased activity (those that do not respond). Consequently, a multinodular goiter develops (Fig 4). RAIU may remain elevated due to TSH

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Figure 3. Early-stage Hashimoto thyroiditis in a 42-year-old woman who presented with goiter as well as firmness of the right thyroid lobe. Laboratory values were as follows: T4 ⫽ 7.6 ␮g/dL, T3 ⫽ 121 ng/dL, and TSH ⫽ 5.5 ␮IU/mL. The 24-hour RAIU was mildly elevated at 39%. (a) Anterior scintigram demonstrates an enlarged thyroid with diffusely increased radiotracer uptake (high target-to-background activity), findings that are similar to those in a diffuse toxic goiter. Note the decreased background activity as shown by the low radiotracer concentration in the salivary glands (thin arrow). The photopenic area (thick arrow) represents the cold sternal marker. (b) Photomicrograph (original magnification, ⫻150; H-E stain) of a histologic specimen obtained during open biopsy of the right lobe reveals dense lymphocytic infiltration with reactive germinal centers (arrow).

Figure 4. Hashimoto thyroiditis manifesting as a multinodular goiter in a 51-year-old man who presented with multiple palpable thyroid nodules. Laboratory values were as follows: FT4 ⫽ 0.7 ng/dL, T3 ⫽ 95 ng/dL, and TSH ⫽ 6.1 ␮IU/mL. The 24-hour RAIU was 40%. (a) Anterior image demonstrates an enlarged thyroid with both cold (thin arrows) and “hot” (thick arrows) nodules. (b) Photomicrograph (original magnification, ⫻100; H-E stain) of a histologic specimen of the large, cold nodule in the left lower pole reveals lymphocytes surrounded by large islands of colloid (arrow).

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Figure 5. Late-stage Hashimoto thyroiditis in a 59year-old woman who complained of weight gain, diffuse muscle weakness, and somnolence. At physical examination, the patient’s thyroid felt very firm. Laboratory values were as follows: T4 ⫽ 2.8 ␮g/dL and TSH ⫽ 98 ␮IU/mL. The 24-hour RAIU was 7%. (a) Distant (left) and close-up (right) anterior images reveal nonuniform and relatively low thyroid activity compared with background activity. (b) Photomicrograph (original magnification, ⫻200; H-E stain) of a histologic specimen obtained at open biopsy shows the thyroid architecture distorted by fibrosis with lymphoid follicles containing reactive germinal centers (arrow).

stimulation. Eventually, however, as more thyroid parenchyma is replaced by fibrous tissue, serum thyroid hormone levels decrease as the gland fails to respond to the elevated TSH level (10), and overt hypothyroidism ensues, with nonuniform decreased uptake in varying degrees throughout the thyroid (Fig 5). Figure 6 demonstrates a solitary cold nodule. The nodule proved to be Hashimoto thyroiditis at histologic analysis. To our knowledge, Hashimoto thyroiditis manifesting as a solitary cold nodule has not been reported previously.

Hashitoxicosis Hashimoto thyroiditis can also manifest as acute, firm, painless thyroid enlargement with mild to moderate hyperthyroidism. The hyperthyroidism is typically self-limiting and resolves spontaneously over a period of weeks or several months. The thyrotoxicosis is caused by the antigen-antibody reaction leading to relatively rapid follicular cell damage, thereby releasing excess thyroid hormone into the circulation (Fig 7) (11).

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Figure 6. Hashimoto thyroiditis manifesting as a solitary cold nodule in a 34-year-old woman who complained of a palpable right-sided neck mass of 5 months duration. At physical examination, the nodule felt very firm. Thyroid function parameters were all in the normal range, and the 24-hour RAIU was 22%. (a) Anterior image reveals a large, cold nodule in the right lower pole (arrow). A partial right lobectomy was performed to remove the nodule because of its firmness. (b) Photomicrograph (original magnification, ⫻150; H-E stain) demonstrates Hashimoto thyroiditis.

Figure 7. Hashitoxicosis in a 52-year-old woman who had presented 1 month earlier with symptoms of hyperthyroidism. At that time, laboratory values were as follows: T4 ⫽ 13.2 ␮g/dL, T3 ⫽ 192 ng/dL, and TSH ⫽ 0.01 ␮IU/mL. Over the next few weeks, the patient’s symptoms spontaneously resolved. A close-up anterior image was obtained 6 hours following oral administration of 300 ␮ci (⬃11.1 MBq) of I-123. At the time of the scan, T3 and total T4 values had normalized, and TSH was 0.2 ␮IU/mL. The 6-hour RAIU was 19%. A TPO antibody titer was elevated at 1:160. The image reveals nonuniformly increased activity throughout the thyroid.

Amiodaroneassociated Thyroid Disease Amiodarone is an antiarrhythmic cardiac drug rich in iodine (75 mg iodine per 200-mg tablet) that is used in certain arrhythmias that prove re-

fractory to standard medical therapy. Amiodarone therapy is sometimes associated with iodineinduced thyroid dysfunction (thyrotoxicosis or hypothyroidism). Thyrotoxicosis occurs either as a result of iodine-induced hyperthyroidism itself or secondary to acute destructive thyroiditis (12). Hypothyroidism associated with amiodarone therapy is more common, occurring in about 20% of patients in the United States who undergo amiodarone therapy (Fig 8) (13). In these patients, the level of TPO antibodies is elevated, and the

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mechanism of hypothyroidism is autoimmune thyroiditis. The prevalence of amiodarone-associated thyroid disease has been reported as high as 23%–25% (14).

Conclusions Autoimmune thyroiditis, with its various manifestations, often mimics other thyroid disorders such as Graves disease and multinodular goiter. Thyroid uptake measurements and scintigraphic findings play a complementary role along with thyroid function testing in differentiating autoimmune thyroiditis from other thyroid diseases, thereby influencing treatment. In some cases, histologic evaluation of biopsy specimens is required to yield the definitive diagnosis. Nevertheless, familiarity with the spectrum of scintigraphic findings in these disorders will enable the radiologist to provide the clinician with a meaningful differential diagnosis.

References 1. McDougall LR. Thyroiditis. In: McDougall LR. Thyroid disease in clinical practice. New York, NY: Oxford University Press, 1992; 257–281. 2. Hamburger JI. The various presentations of thyroiditis: diagnostic considerations. Ann Intern Med 1986; 104:219 –224. 3. Weetman AP. Autoimmune thyroiditis: predisposition and pathogenesis. Clin Endocrinol 1992; 36:307–323. 4. Lazarus JH. Silent thyroiditis and subacute thyroiditis. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the thyroid. 7th ed. Philadelphia, Pa: Lippincott-Raven, 1996; 577–591. 5. Roti E, Emerson C. Postpartum thyroiditis. J Clin Endocrinol Metab 1992; 74:3–5. 6. Jansson R, Dahlberg PA, Karlson FA. Postpartum thyroiditis. Thyroidology 1989; 1:143–147. 7. Levine SN. Current concepts of thyroiditis. Arch Intern Med 1983; 143:1952–1956. 8. McGregor AM, Hall R. Thyroiditis. In: DeGroot LJ, Besser GM, Cahill GF, eds. Endocrinology. 2nd ed. Vol 1. Philadelphia, Pa: Saunders, 1989; 683–701.

Figure 8. Amiodarone-associated thyroid disease in a 60-year-old man who complained of extreme fatigue, weight gain, and depression. Several weeks earlier during hospitalization for arrhythmias, the patient had been placed on amiodarone and was now clinically hypothyroid. At the time of imaging, total T4 was 3.3 ␮g/dL, T3 was 119 ng/dL, and TSH was 96 ␮IU/mL. The 24-hour RAIU was 4%. Anterior image shows an enlarged, nonuniform thyroid with overall decreased radiotracer concentration (arrow). Because of the high iodine content of amiodarone, patients taking the drug will have low RAIU. 9. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996; 335:99 –107. 10. Hayashi Y, Tamai H, Fukata S, et al. A long-term clinical, immunological, and histological follow-up study of patients with goitrous chronic lymphatic thyroiditis. J Clin Endocrinol Metab 1985; 61: 1172–1178. 11. Falk SA, Birken EA, Ronquillo AH. Graves’ disease associated with histologic Hashimoto’s thyroiditis. Otolaryngol Head Neck Surg 1985; 93: 86 –92. 12. Seminara MD, Daniels GH. Amiodarone and the thyroid. Endocr Pract 1998; 4:48 –54. 13. Martino E, Aghini-Lombardi F, Mariotti S, et al. Amiodarone iodine-induced hypothyroidism: risk factors and follow-up in 28 cases. Clin Endocrinol 1987; 26:227–235. 14. Harjai K. Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126:63–73.

This article meets the criteria for 1.0 credit hour in category 1 of the AMA Physician’s Recognition Award. To obtain credit, see www.rsna.org/education/rg_cme.html.