Association of the Ultrasonographic Findings of Subacute Thyroiditis with Thyroid Pain and Laboratory Findings

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1 Endocrine Journal 2008, 55 (3), Association of the Ultrasonographic Findings of Subacute Thyroiditis with Thyroid Pain and Laboratory Findings NARIKO OMORI, KAZUE OMORI AND KAZUE TAKANO Department of Medicine II, Tokyo Women s Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, , Japan Abstract. We aimed to determine whether ultrasonography is a useful diagnostic tool by correlating its findings with biological data of patients with subacute thyroiditis (SAT). Thirty-two SAT patients were evaluated in a retrospective study. Thirty-one patients (96.9%) had tenderness, 14 (43.8%) had localized pain, and 11 patients (34.4%) had radiating pain during a state of SAT. With ultrasonography, we found 51 hypoechoic areas in 32 patients. The hypoechoic volume per unilateral thyroid gland (%) was significantly larger in areas accompanied with pain (P<0.001). Out of 27 patients measured, 18 (67%) were positive for thyroglobulin antibodies (TgAb), of whom all were females. TgAb levels ranged from 0.3 to 13.8 U/ml. During therapy, TgAb levels gradually increased in 2 of the 7 patients who were measured several times. Both thyroglobulin antigen (TgAg) and free thyroxine (FT4) correlated well with total hypoechoic volume (cm 3 ), and the TgAg level showed a strong correlation with the FT4 level (r = 0.7; P<0.0001). The area (%) that the hypoechoic volume occupied in the total thyroid gland, even if the area was over half, was not related to the need of L-T4 replacement therapy. Also, none of the other variables (age, days from onset until diagnosis, serum levels of FT4, TgAg, CRP, autoantibodies, therapies, treatment) differed between the patients with and without replacement therapy. In summary, we found that the hypoechoic area in patients with SAT reflected the degree of inflammation and thyroid hormone levels, though it was difficult to predict continuous hypothyroidism. Key words: Subacute thyroiditis, Thyroid ultrasonography (Endocrine Journal 55: , 2008) SUBACUTE thyroiditis (SAT) is generally caused by viruses, and is an inflammatory thyroid disease [1 3]. SAT is characterized by a clinical course of cervical pain with symptoms of hyperthyroidism, suppressed levels of TSH, elevated thyroid hormone levels, and positive inflammatory data. Thyroid autoimmunity is often present during the active phase of the disease [4]. This autoimmunity is usually transitory and mild, although some patients may retain thyroid autoimmunity for many years. A small number of patients eventually develop autoimmune thyroid disease [4, 5]. For this disease, it is necessary to differentiate SAT from Hashimoto s thyroiditis. Ultrasonography is an effective tool for diagnosis and determining prognosis [6 Received: December 19, 2007 Accepted: December 25, 2007 Correspondence to: Nariko OMORI, M.D., Department of Medicine II, Tokyo Women s Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, , Japan 9]. Clinical features and outcomes of the disease have been reported in several studies [8, 10 12], but few have made ultrasonographic and biological data comparisons in patients with SAT. Bennedbaek and Hegedüs evaluated thyroid function by ultrasonographically determined morphology [8]. The aim of our study is to determine whether a correlation exists between ultrasonographic findings and biological data, including thyroid hormone levels and the characteristics of hypothyroidism due to SAT. Study design and patients Patients and Methods Our study was a retrospective study involving 32 SAT patients (29 females and 3 males) with the mean age of 44.2 ± 9.4 years (range years) were studied. They were diagnosed with SAT at our hospital

2 584 OMORI et al. during the period from August 2000 to December Diagnosis of SAT was according to the diagnostic criteria of the Japan Thyroid Association: (1) a swelling with pain and tenderness in the thyroid gland; (2) elevation of C-reactive protein and/or erythrocyte sedimentation rate; (3) elevation of serum free thyroxine (FT4) and suppression of serum thyroid stimulating hormone (TSH) less than 0.1 µu/ml; and (4) hypoechoic lesion at a painful portion of the thyroid gland confirmed by ultrasonography. Thirty-one patients satisfied all four criteria. One patient satisfied (1), (2) and (3), but lacked pain. This patient s condition was diagnosed SAT by aspiration biopsy cytology. We identified pain and tenderness of the thyroid or neck radiating to the jaw and ears which were worsened by swallowing, coughing and movement of the neck. We also evaluated serum FT4, TSH and C-reactive protein (CRP) levels in the acute phase. We conducted ultrasonography of the thyroid to assess hypoechoic areas that accompanied tenderness. Drugs used for treatment were non-steroidal anti-inflammatory drug (NSAID; ibuprofen or loxoprofen sodium), prednisolone (PSL) and thyroid hormone (L-T4: levothyroxine sodium). Laboratory measurement Serum FT4 was measured using the commercial kits by Roche Diagnostic Co., Ltd., Tokyo, Japan. The normal range of FT4 is ng/dl. Serum thyroglobulin antigen (TgAg) was measured using the commercial kits by Eiken Chemical, CO., Ltd., Japan. TgAg is normally below 30 ng/ml. Serum thyroglobulin antibodies (TgAb) were measured using the commercial kit by RSR Ltd., Pentwyn Cardiff, UK Normal TgAb is below 0.3 U/ml. CRP was measured using the commercial kits by Daiichi Pure Chemical CO., Ltd., Tokyo, Japan. The normal range of CRP is below 0.03 mg/dl. Ultrasonography evaluation Ultrasonography was performed using a 7.5 MHz linear probe (LOGIQ 500, GE Yokokawa Medical Systems, Japan). The long-axis and short axis diameters, and depth were estimated and the volume (cm 3 ) of the hypoechoic area was calculated using the approximate formula for an ellipsoid: π/6 (length) (width) (depth) [13]. Thyroid hypoechoic areas represented pseudocystic tumors. Thyroid hypoechogenicity was defined as an echo density clearly lower than that of healthy thyroid glands as described elsewhere [14]. We calculated the mean ratio of hypoechogenicity (area of hypoechogenicity/total area) based on each of a minimum of three transsectional scans of each lobe as an estimate of the extension of hypoechogenicity. Statistical analysis All data are expressed as means ± standard deviation. Statistical analyses were performed using the chisquare test or Student s non-paired t-test for the comparison of groups between the patients with and those without replacement therapy. The differences were considered significant when P<0.05. Thyroid pain Results Pain was studied retrospectively from the patients medical record. We categorized thyroid pain into (1) localized pain, (2) tenderness, and (3) radiating pain. Thirty-one patients (96.9%) had tenderness, 14 (43.8%) had localized pain, and 11 (34.4%) had radiating pain during a state of SAT. One patient had painless SAT. Hypoechoic areas were found at 51 areas of 32 patients. Fig. 1 shows the hypoechoic volume of the SAT areas. The hypoechoic volume per unilateral thyroid gland (%) was significantly larger in the areas accompanied by pain (Fig. 1) (P<0.001). Laboratory findings The distribution of the laboratory variables and ultrasonographic findings are shown in Fig. 2. FT4 and CRP were elevated in all patients (Fig. 2). Serum TgAb was measured in 27 patients. Out of these patients, 18 patients (67%) were positive and all were female. TgAb levels ranged from 0.3 to 13.8 U/ ml (Fig. 3). Seven patients were measured for TgAb for several times (patient No. 1, 2, 4, 5, 8, 11, and 14). Five patients (patient No. 1, 2, 4, 5, and 11) who showed weak positive TgAb (range: U/ml), ex-

3 ULTRASONOGRAPHY OF SUBACUTE THYROIDITIS 585 Fig. 1. Total hypoechoic volume distribution of subacute thyroiditis patients with or without pain. The figure demonstrates that more subacute thyroiditis patients with hypoevhoic volume per unilateral thyroid gland has pain. perienced a drop of serum TgAb to within the normal or almost normal range after the treatment with PSL (total dosage used was 515 mg, 575 mg, 945 mg, 1365 mg and 1505 mg, respectively). However, in the other two patients (patient No. 8 and 14), these levels gradually increased despite the treatment with PSL; one increased from 0.7 U/ml to 12.4 U/ml (total dosage 180 mg), and the other from 2.5 U/ml to 17 U/ml (total dosage 745 mg). The former patient became euthyroid afterwards, but the latter patients required permanent L-T4 replacement therapy. Ultrasonographic findings Fig. 4 (A, B) shows the correlation between FT4, TgAg and total hypoechoic volume (cm 3 ). Both FT4 and TgAg positively correlated with total hypoechoic volume (cm 3 ) (r = 0.4; P<0.05). Moreover, TgAg level showed a strong correlation with FT4 levels (Fig. 4C) (r = 0.7; P<0.0001). Treatment for SAT and hypothyroidism Three patients (9.4%) took non-steroidal antiinflammatory drug (NSAID) and one patient took propranolol hydrochloride only. The remaining patients received PSL therapy. There was no significant differences in PSL dosage between the two groups of patients with (n = 3) or without (n = 24) L-T4 therapy (778 ± 281 mg and 879 ± 398 mg, respectively). Table1 shows the clinical and laboratory data of five patients (patient No. 12, 14 and patients with negative TgAb) who had L-T4 replacement therapy. Two patients, one treated with PSL (patient No. 14) and the other treated with NSAID, needed L-T4 replacement therapy continuously while the other three patients required temporary replacement that lasted 25 days to 84 days. With patient No. 14, TgAb levels gradually increased, and the dose of L-T4 was increased from 25 µg to 50 µg per day. Three patients with the hypoechoic volume (%) occupying over half of the total thyroid gland needed a replacement therapy, but these patients did not need the therapy continuously. The area of the hypoechoic volume (%) occupied in the total thyroid gland was not related to the need of L-T4 replacement therapy. None of the other variables (age, days from onset until diagnosis, serum levels of FT4, TgAg, CRP, autoantibodies, therapies; treatment) also differed between the patients with and those without replacement therapy, too (data not shown). Discussion The characteristic symptom of SAT is pain in the region of the thyroid. In our study, thyroid pain was observed in all cases except one. The symptom was characterized by tenderness rather than pain. Pain coincided with hypoechoic area on ultrasonography in all cases. The larger the hypoechoic area, the more pain experienced. Rarely, SAT may present as a nontender solitary nodule. In such cases, the diagnosis is made by using fine-needle aspiration biopsy, which differentiates SAT from Hashimoto s thyroiditis [11]. One of our patients did not have pain, but the patient s clinical course, inflammation data and ultrasonographic changes were consistent with SAT. Alterations in the morphology and topography of SAT are observed during the course of the illness. Some reports indicate that color Doppler sonography was effective for differentiating SAT from Graves dis-

4 586 OMORI et al. Fig. 2. The distribution of FT4, TgAg, CRP, total hypoechoic volume (cm 3 ), and total hypoechoic volume (%). The bar indicates the mean value. FT4 ranged from 2.0 to 9.7 ng/dl with a mean (±SD) of 4.0 ± 1.7 ng/dl,tgag ranged from 11 to 4400 ng/ml with a mean (±SD) of ± ng/ml, CRP ranged from 0.11 to 10.7 mg/dl with a mean (±SD) of 4.0 ± 3.0 mg/dl, total hypoechoic volume (cm 3 ) ranged from 0.6 to 14.3 cm 3 with a mean (±SD) of 5.0 ± 3.8 cm 3 and total hypoechoic volume (%) ranged from 5.3 to 80.5 % with a mean (±SD) of 29.1 ± 20.0%. Fig. 3. The distribution of the serum TgAb in 18 patients. The shaded areas indicate the normal range. ease in the active phase [15, 16]. Ultrasonography has been regarded as a useful supporting tool in the diagnosis of SAT by showing an extension of hypoechogenicity. The thyroid structure is nonhomogeneous under ultrasonography, as with Hashimoto s thyroiditis and carcinogenic tumors. The hypoechoic to nonechoic area corresponds to the inflamed area. No correlation between thyroid function and the extent of hypoechogenicity has been reported [8]. However, in our study, the hypoechoic area correlated well with thyroid

5 ULTRASONOGRAPHY OF SUBACUTE THYROIDITIS 587 Fig. 4. The correlation among TgAg, FT4, and total hypoechoic volume (cm 3 ). These figures demonstrate a positive correlation between FT4 or TgAg with total hypoechoic volume (cm 3 ), and FT4 and FT4 with TgAg. Five solid circles (patient No. 12, 14 and three patients with negative TgAb) indicate patients who developed hypothyroidism and they were treated with L-T4 replacement therapy. Table 1. Clinical and laboratory data of 5 patients who had subacute hypothyroiditis and L-T4replacement therapy Time before start of therapy (days) FT4 (ng/dl) TgAg (ng/dl) TgAb (U/mL) CRP (mg/dl) Hypoechoic volume in cm 3 (%) Drug used; dose (mg) Thyroid hormone and replacement therapy No. a) age L-T4 treatment Days b) < (62.2) PSL (730) TSH, 65.2; FT4, 0.4; 30 replacement, 25 µg < (80.5) PSL (1158) TSH, 2.5; FT4, 0.8; 84 replacement, 25 µg (80.4) PSL (480) TSH, 8.8; FT4, 0.9; 25 replacement, 25 µg (11.4) PSL (745) TSH, 7.9; FT4, 0.8; Continuous replacement, 50 µg < (21.2) NSAID TSH, 41.9; FT4, 0.4; Continuous Loxonin replacement, 25 µg (2460) a) Patients who had l-t4 replacement therapy. b) Period of L-T4 treatment (days). pain, FT4 and TgAg in patients with SAT. The hypoechoic area reflected the increase in FT4 and TgAg due to the destruction of the thyroid gland. Papi and Ezzat speculated that the trigger for a progression of SAT into Hashimoto s thyroiditis, during the inflammatory phase of SAT, facilitated an immune response [17]. In

6 588 OMORI et al. our study, weak positive TgAb reflected the thyroid damage caused by SAT as previously reported [18]. Symptomatic hypothyroidism is less common in SAT [4], because the duration and degree of hypothyroxinemia are not severely prolonged, and it is reported that less than 5% of patients developed permanent hypothyroxynemia [19]. In our study, 2 of 32 (6.2%) patients received permanent L-T4 replacement therapy. The patients who had hypoechoic volume of over 50% required L-T4 replacement therapy, but it was temporary. We suggested hypoechoic volume (%) represented cell destruction associated with active inflammation, but not the prediction of L-T4 replacement therapy. In summary, we found that hypoechoic area in patients with SAT reflected the degree of inflammation and thyroid hormone levels, though it was difficult to predict continuous hypothyroidism. References 1. Volpe R (1979) Subacute (de Quervain s) thyroiditis. Clin Endocrinol Metab 8: Walfish PG (1997) Thyroiditis. Curr Ther Endocrinol Metab 6: Ross DS (1998) Syndromes of thyrotoxicosis with low radioactive iodine uptake. Endocrinol Metab Clin North Am 27: Wall JR, Fang SI, Ingbar SH, Braverman LE (1976) Lymphocyte transformation in response to human thyroid extract in patients with subacute thyroiditis. J Clin Endocrin Metab 43: Weetman AP, Smallridge RC, Nutman TB, Burnman KD (1987) Persistent thyroid autoimmunity after subacute thyroiditis. J Clin Lab Immunol 23: Vulpoi C, Zbranca E, Preda C, Ungureanu MC (2001) Contribution of ultrasonography in the evaluation of subacute thyroiditis. Rev Med Chir Soc Med Nat Iasi 105: Tokuda Y, Kasagi K, Iida Y, Yamamoto K, Hatabu H, Hidaka A, Konishi J, Ishii Y (1990) Sonography of subacute thyroiditis: Changes in the findings during the course of the disease. J Clin Ultrasound 18: Bennedbaek FN, Hegedüs L (1997) The value of ultrasonography in the diagnosis and follow-up subacute thyroiditis. Thyroid 7: Mizukoshi T, Noguchi S, Murakami T, Futaba T, Yamashita H (2001) Evaluation of recurrence in 36 subacute thyroiditis patients managed with prednisolone. Intern Med 40: Kitchener MI, Chapman IM (1989) Subacute thyroiditis: a review of 105 cases. Clin Nucl Med 14: Fatourechi V, Aniszewski JP, Fatourechi GZE, Atkinson EJ, Jacobsen SJ (2003) Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab 88: García Solano J, Giménez Bascuñana A, Sola Pérez J, Campos Fernández J, Martínez Parra D, Sánchez Sánchez C, Montalbán Romero S, Pérez-Guillermo M (1997) Fine-needle aspiration of subacute granulomatous thyroiditis (De Quervain s thyroiditis): a clinicocytologic review of 36 cases. Diag Cytopathol 16: Miyakawa M, Onoda N, Etoh M, Fukuda I, Takano K, Okamoto T, Obara T (2005) Diagnosis of thyroid follicular carcinoma by the vascular pattern and velocimetric parameters using high resolution piled and power ultrasonography. Endocrin J 52: Marcocci C, Vitti P, Cetani F, Catalano F, Concetti R, Pinchera A (1991) Thyroid ultrasonography helps to identify patients with diffuse lymphocytic thyroiditis who are prone to develop hypothyroidism. J Clin Endocrin Metab 72: Kunz A, Blank W, Braun B (2005) De Quervain s subacute thyroiditis-color Doppler sonography findings. Ultraschall Med 26: Hiromatsu Y, Ishibashi M, Miyake I, Soyejima E, Yamashita K, Koike N, Nonaka K (1999) Color Doppler ultrasonography in patients with subacute thyroiditis. Thyroid 9: Papi G, Ezzat S (2004) Progression of subacute (de Quervain) thyroiditis into Hashimoto s thyroiditis. Thyroid 14: Iitaka M, Momotani N, Hisaoka T, Noh JY, Ishikawa N, Ishii J, Katayama S, Ito K (1998) TSH receptor antibody-associated thyroid dysfunction following subacute thyroiditis. Clin Endocrinol (Oxf) 48: Lio S, Pontecori A, Caruso M, Monaco F, D Armiento M (1984) Transitory subclinical and permanent hypothyroidism in the course of subacute thyroiditis (de Quervain). Acta Endocrinologica 103: