Painless Subacute Thyroiditis Presenting as Fever of Unknown Origin: Detected by Gallium-67 Scan

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1 Painless Subacute Thyroiditis Presenting as Fever of Unknown Origin: Detected by Gallium-67 Scan Pei-Yung Liao 1, Chen Pi-Yu 2, Guang-Uei Hung 3 1 Division of Endocrinology and Metabolism, Changhua Christian Hospital, Changhua, Taiwan 2 Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan 3 Department of Nuclear Medicine, Chang-Bing Show Chwan Hospital, Changhua, Taiwan Gallium-67 ( 67 Ga) scan is a useful tool in the evaluation of fever of unknown origin (FUO). Here we present a case of 77-year-old man with prolonged fever for more than 2 weeks without definitely infectious origin. The whole body 67 Ga scan showed intense and diffuse tracer uptake in the bilateral thyroid glands. Then the patient was further assessed with other diagnostic tests, including 99m Tc thyroid scintigraphy, laboratory tests, ultrasonography and fine needle aspiration cytology. Finally, an atypical subacute thyroiditis with painless neck was diagnosed. Key words: subacute thyroiditis, fever of unknown origin, 67 Ga scan Ann Nucl Med Sci 2009;22:53-58 Introduction Fever of unknown origin (FUO) is not an accurate medical term and usually refers to a prolonged febrile illness without an established etiology despite intensive evaluation and diagnostic testing. The definition derived by Petersdorf and Beesnon has become the clinical standard, which include the following criteria: (1) fever higher than 38.3 C on several occasions; (2) duration of fever for at least three weeks; (3) uncertain diagnosis after one week of study in the hospital [1]. Refinements to the definition have been proposed including eliminating the in-hospital evaluation requirement because of the increased sophistication of outpatient evaluation [2]. Expansion of the definition has also been suggested to include nosocomial, neutropenic, and HIV-associated fevers that may not be prolonged [3]. Gallium-67-gallium citrate ( 67 Ga) can be avidly accumulated in various kinds of inflammatory/infectious and malignant diseases. In addition, 67 Ga scan has the advantage of scanning the whole body. Therefore, 67 Ga scan has been playing an important role in the evaluation of FUO. In one study of 145 cases of FUO, 29% of the 67 Ga scans were helpful in establishing a diagnosis, versus 6% and 14% of ultrasound examinations and CT scans, respectively [4]. The diagnosis of subacute thyroiditis is usually made clinically with the typical manifestations of neck pain, thyroid tenderness and/or diffuse goiters [5]. In an analysis of 94 patients, pain was the presenting symptom in 96% [6]. However, the diagnosis would become very difficult in the absence of neck pain or tenderness. Here we presented an atypical case of subacute thyroiditis initially presenting as FUO, but no neck pain or thyroid tenderness. The 67 Ga whole body scanning helped localize the abnormality in the anterior neck, and the following serial work-ups made the diagnosis of subacute thyroiditis finally. Received 6/26/2008; revised 7/22/2008; accepted 7/24/2008. For correspondence and reprints contact: Guang-Uei Hung, M.D., Department of Nuclear Medicine, Chang-Bing Show Chwan Hospital. 6 Lugong Road, Lukang Zhen, Changhua 500, Taiwan. Tel: (886) ext , @gmail.com Case Report A 77-year-old male was admitted for further evaluation due to prolonged fever and chillness for more than 2 weeks.

2 Liao PY et al The associated symptoms included mild cough with whitish sputum, mild diarrhea, poor appetite, and abdominal fullness. There was no headache, neck pain, dysuria, frequency, arthralgia or other significant discomfort. Physical examination revealed no palpable mass, no goiter, no abnormal breathing sound or any other significant abnormality except for fever and body weight loss of 5 kg in a period of 2 weeks. Tracing back his medical history, he has been a case of hypertension, chronic obstructive pulmonary disease (COPD) and eczema for more than 10 years. He received chest radiograph, upper gastrointestinal endoscopy and abdominal ultrasonography as initial examinations, but no significant abnormality of suggesting an infectious focus can be found. Urine analysis revealed no significant abnormality. Blood and sputum cultures also showed negative finding. Empiric antibiotics with minocin 100 mg every 12 h in intravenous route was tried but fever still persisted. He then was referred for 67 Ga whole body scanning as a result of FUO. He received an intravenous injection of 3 mci of 67 Ga-gallium citrate and images were obtained 48 h later. The whole body images (Figure 1A) revealed intense tracer accumulation in the anterior neck, and the static high-count images (Figure 1B) revealed thyroidlike lesions in its uptake pattern. Based on the findings of 67 Ga scanning, the patient then received serial work-ups focusing on the thyroid disorders. The 99m Tc thyroid scintigraphy showed almost no tracer uptake in bilateral thyroid glands (Figure 1C). The uptake ratio was 0.3% of injected dose (reference normal range: 2.34% 1.63%). The thyroid stimulating hormone (TSH) level was significantly suppressed (<0.0025, reference range: µiu/ml), and free thyroxine (T4) was elevated (3.11, reference range: ng/dl). The erythrocyte sedimentation rate (ESR) was as high as 101 mm/h (reference range: <10 mm/h for male). Thyroid ultrasonography revealed multiple hypoechoic and heterogenous patches involving bilateral thyroid glands (Figure 2). Fine needle aspiration and cytological examination (FANC) were performed. Microscopically, the smear is hypocellular. Some multinucleated giant cells with engulfing colloid are seen (Figure 3). Lymphocytes, neutrophils and cellular debris and degenerated follicular cells are also present (Figure 4). These Figure 1. (A) The whole body 67 Ga image obtained at 48th hour reveals intense tracer accumulation in the anterior neck. (B) The static high-count image of head and neck reveals thyroid-like uptake with diffuse involvement of bilateral thyroid glands. (C) The 99m Tc thyroid scintigraphy shows almost absent uptake in bilateral thyroid glands. A A B C B Figure 2. Thyroid ultrasonography reveals multiple hypoechoic and heterogenous patches in bilateral thyroid glands. Ann Nucl Med Sci 2009;22:53-58 Vol. 22 No. 1 March

3 67 Ga 67 Ga scan on painless subacute thyroiditis response to treatment, a final diagnosis of atypical subacute thyroiditis with painless neck was made. Table 1. The differential diagnosis of thyroid gallium uptake Diffuse uptake Focal uptake Figure 3. A multinucleated giant cell with ingested colloid and lymphocytes (Giemsa stain, original magnification 400) Amiodarone-induced hyperthyroidism Leiomyosarcoma Sarcoidosis Lymphoma Thyroiditis -- subacute and chronic Metastases Parathyroid adenoma Thyroid carcinoma Thyroiditis Figure 4. Some neutrophils, lymphocytes, cellular debris and degenerated follicular cells are noted. (Giemsa stain, original magnification 400) features are consistent with granulomatous thyroiditis, also named as subacute thyroiditis. All of the aforementioned findings were compatible with subacute thyroiditis. Steroid with prednisolone and antithyroid drug with propylthiouracil were given; and fever then subsided quickly. The thyroid functions were rechecked one month later and the level of TSH and free T4 both returned to normal ranges (TSH: 0.5 µiu/ml; free T4: 0.7 ng/dl). Based on the findings of serial work-ups and Discussion The differential diagnosis of thyroid gallium uptake is summarized on Table 1. Diffuse thyroid uptake in 67 Ga scanning was ever reported to be secondary to amiodaroneinduced hyperthyroidism [7], sarcoidosis [8] and subacute/chronic thyroiditis [9,10]. Amiodarone is an iodinerich drug and has been associated with a relatively high incidence (about 10%) of iodine-induced hyperthyroidism [11]. The thyroid radioactive iodine uptake (RAIU) in iodineinduced hyperthyroidism, including amiodarone-induced, is usually undetectable or low [12]. This means that amiodarone-induced hyperthyroidism and subacute thyroiditis share similar pictures in both 67 Ga and thyroid scintigraphy, and thus careful medical history taking would be important to discriminate these two diseases. Sarcoidosis is a multisystem granulomatous disorder and mostly frequently involves the lung, but also the skin, eyes, reticuloendothelial system, musculoskeletal system, exocrine glands, heart, kidney, and central nervous system [13]. It has still not been reported that sarcoidosis involve only the thyroid glands. Positive gallium uptake in thyroid glands has also been reported in other kinds of diseases, including leiomyosarcoma, lymphoma, metastases, parathyroid adenoma and thyroid carcinomas [9,14-17]. However, all of the aforementioned diseases usually showed focal uptake rather than diffuse pattern as in the presented case. Of course, histopathologic examination, like sonography-guided FNAC, would be necessary for confirmatory diagnosis. The exact mechanism of 67 Ga uptake inflammatory 2009;22:

4 Liao PY et al lesions is still not well known. According to Tsan s review, the increased blood supply and capillary hyperpermeability of the endothelium in areas of inflammation may contribute to the accumulation and retention of 67 Ga in the extracellular fluid spaces of an inflammatory lesion [18]. Leukocytes, especially the neutrophils, also take up 67 Ga, but they are not essential for the 67 Ga uptake in inflammation lesions. If bacteria are present, siderophores produced by bacteria, which can bind and transport ferric iron, may also play some roles in the uptake of 67 Ga. Subacute thyroiditis, also named as subacute granulomatous thyroiditis, subacute nonsuppurative thyroiditis, giant cell thyroiditis, and de Quervain s thyroiditis, is a self-limited thyroid inflammatory disease and typically characterized by neck pain, a tender diffuse goiter, and a predictable course of thyroid function evolution [5]. It is initially presented with hyperthyroidism, followed by euthyroidism, hypothyroidism and ultimately restoration of normal thyroid function. The thyroid inflammatory processes damage thyroid follicles and result in unregulated release of thyroid hormone into the circulation, causing a transient hyperthyroid state. In addition to neck pain and thyroid tenderness, fever, fatigue, malaise, anorexia, myalgia and body weight loss are also common. In addition to biochemically hyperthyroid state (high serum T4 and T3 and low TSH concentrations), other characteristic laboratory findings are low RAIU, mild anemia and leukocytosis, elevated thyroglobulin, ESR and C-reactive protein. On ultrasnonography, the thyroid appears to be diffusely or focally hypoechogenic regardless of its size [19].The FNAC may reveal enlarged, degenerated follicular cells with prominent nucleoli, lymphocytes, colloid substance, multinucleated giant cells and neutrophils [20]. In conclusion, it was rare that subacute thyroiditis was atypically presented as FUO without neck pain or thyroid tenderness. Our report showed that the gallium was highly avid to the inflammatory processes in subacute thyroiditis and 67 Ga scan would be very useful to help establish a correct diagnosis in such a rare clinical entity. References 1. Petersdorf RG, Beeson PB. Fever of unexplained origin: Report on 100 cases. Medicine (Baltimore) 1961;40: Petersdorf RG. Fever of unknown origin: an old friend revisited. Arch Intern Med 1992;152: Durack DT, Street AC. Fever of unknown origin: Reexamined and redefined. In: Remington JS, Swartz MN, eds. Current Clinical Topics in Infectious Diseases. Boston: Blackwell Science; 1991: Knockaert DC, Mortelmans LA, De Roo MC, Bobbaers HJ. Clinical value of gallium-67 scintigraphy in evaluation of fever of unknown origin. Clin Infect Dis 1994;18: Lazarus JH. Silent thyroiditis and subacute thyroiditis. In: Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text, 7th ed. Philadelphia: Lippincott-Raven; 1996: Fatourechi V, Aniszewski, JP, Fatourechi, GZ, Atkinson EJ, Jacobsen SJ. Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab 2003;88: Ling MC, Dake MD, Okerlund MD. Gallium uptake in the thyroid gland in amiodarone-induced hyperthyroidism. Clin Nucl Med. 1988;13: Moreno AJ, Brown JM, Salinas JA, Feaster BL 3rd, Brown TJ. Ga-67 positivity in sarcoidosis of the skin with coincident thyroid uptake of uncertain etiology. Clin Nucl Med 1984;9: Moreno AJ, Brown JM, Spicer MJ, Yedinak MA, Brown TJ. Thyroid localization of Ga-67 citrate. Semin Nucl Med 1985;15: Matsui Y, Sugawara Y, Tsukada K, Kishi Y, Shibahara J, Makuuchi M. Aspergillus thyroiditis in a living donor liver transplant recipient. J Infect 2006;53:e231-e Martino E, Safran M, Aghini-Lombardi F, et al. Environ mental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Ira Med 1984;101: Martino E, Aghini-Lombardi F, Lippi F, et al. Twentyfour hour radioactive iodine uptake in 35 patients with amiodarone associated thyrotoxicosis. J Nucl Med 1985;26: Baughman RP, Teirstein AS, Judson MA, et al. Clinical Ann Nucl Med Sci 2009;22:53-58 Vol. 22 No. 1 March

5 67 Ga 67 Ga scan on painless subacute thyroiditis characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001;164: White WB, Spencer RP, Sziklas JJ, Rosenberg RJ. Incidental finding of intense thyroid radiogallium activity during febrile illness. Clin Nucl Med 1985;10: Yoshimura M, Kawamoto A, Nakasone K, et al. Gallium-67 accumulation to the tumor thrombus in anaplastic thyroid cancer. Ann Nucl Med 2003;17: Ohta H. Gallium-67 imaging in a patient with malignant thyroid lymphoma that spontaneously regressed after subtotal gastrectomy. Clin Nucl Med 2003;28: Usui K, Shuke N, Yamamoto W, et al. Ga-67 and TI-201 accumulation in squamous cell carcinoma of the thyroid. Clin Nucl Med 2000;25: Tsan MF. Mechanism of gallium-67 accumulation in inflammatory lesions. J Nucl Med 1985;26: Park SY, Kim EK, Kim MJ, et al. Ultrasonographic characteristics of subacute granulomatous thyroiditis. Korean J Radiol 2006;7: Lu CP, Chang TC, Wang CY, Hsiao YL. Serial changes in ultrasound-guided fine needle aspiration cytology in subacute thyroiditis. Acta Cytol 1997;41: ;22:

6 Liao PY et al m ;22: (04) @gmail.com Ann Nucl Med Sci 2009;22:53-58 Vol. 22 No. 1 March