Endocrine Care 505
Authors
P. W. Rosario, J. B. N. Santos, N. S. Nunes, A. L. da Silva, M. R. Calsolari
Affiliation
Postgraduation Program, Endocrinology Service, Santa Casa de Belo Horizonte, Minas Gerais, Brazil
Key words ▶ color flow Doppler ● sonography ▶ thyrotoxicosis ● ▶ etiology ●
Abstract
▼
The objective of this prospective study was to compare the results of color flow Doppler sonography (CFDS) and radioiodine scintigraphy in patients with thyrotoxicosis. A total of 176 patients, 102 with clinical thyrotoxicosis and 74 with subclinical dysfunction, were included. Pregnant and breast-feeding women, patients using amiodarone or recently exposed to iodinated contrast, and patients treated with antithyroid drugs were excluded. Total T3, free T4, TSH, and anti-TSH receptor antibodies were measured before scintigraphy and CFDS. Excluding one patient whose etiology of thyrotoxicosis remained undefined, CFDS showed 100 % specificity. In fact, in all 10 cases in which scintigraphy and CFDS provided discordant results, the
diagnosis suggested by the latter was correct. In patients with clinical thyrotoxicosis, the sensitivity of CFDS was 96 % for diffuse toxic goiter, 95 % for the absence of hyperfunction, and 100 % for toxic nodular disease. In patients with subclinical dysfunction, the sensitivity of CFDS was 72.7 % for diffuse toxic goiter, 90 % for toxic adenoma, and 86.6 % for toxic multinodular disease. CFDS was inconclusive in patients with parenchymal blood flow with patchy uneven distribution or with macronodules in which nodule vascularity compared to the remaining parenchyma did not permit to establish the diagnosis with certainty. CFDS can be used instead of scintigraphy not only in situations in which the latter is contraindicated or of limited value to define the etiology of thyrotoxicosis.
received 20.08.2013 accepted 28.11.2013
Introduction Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1363282 Published online: January 20, 2014 Horm Metab Res 2014; 46: 505–509 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence P. W. Rosario, MD Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte Rua Domingos Vieira 590 Santa Efigênia CEP 30150-240 Belo Horizonte MG Brazil Tel.: + 55/31/32388 819 Fax: + 55/31/32388 980 [email protected]
▼
The laboratory diagnosis of thyrotoxicosis should be followed by the establishment of its etiology. Except for patients with ophthalmopathy and diffuse goiter, characteristics of Graves’ disease, this definition requires laboratory tests and imaging methods. Traditionally, scintigraphy with 131I, 123I, or 99mTc is the most recommended method [1]. However, this method is contraindicated in pregnant women and during breastfeeding, has a limited value in patients using amiodarone or those recently exposed to excessive iodine (e. g., iodinated contrasts), requires preparation and more than one visit to the nuclear medicine service (131I), exposes to radiation, and equivocal results are possible [1]. In addition, in some countries scintigraphy is not easily available and is expensive. Some studies have demonstrated the value of color flow Doppler sonography (CFDS) for defining the etiology of thyrotoxicosis [2–7]. In addition to its application in situations in which
scintigraphy is contraindicated or of limited value, CFDS is an interesting option since it is a noninvasive method that does not require preparation, does not use radiation, and provides immediate results. Furthermore, the method is less expensive and more easily available than scintigraphy in some countries. This prospective study compared the results of CFDS using easily applicable criteria with the results of scintigraphy in patients with a laboratory diagnosis of thyrotoxicosis (clinical or subclinical).
Materials and Methods
▼
Design This study was designed as a prospective study.
Patients Patients consecutively referred to our institution for scintigraphy of the thyroid were studied. Pregnant and breast-feeding women, patients
Rosario PW et al. Doppler Sonography in Thyrotoxicosis. … Horm Metab Res 2014; 46: 505–509
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Color Flow Doppler Sonography for the Etiologic Diagnosis of Thyrotoxicosis
506 Endocrine Care
The term DTG rather than Graves’ disease was used because other causes, although uncommon, can result in a similar feature in the imaging methods [1]. For the same reason, we prefer the term “absence of hyperfunction” instead of subacute thyroiditis [1]. In cases in which CFDS and scintigraphy provided discordant results, the final diagnosis was established based on clinical data (duration and progression of thyrotoxicosis, presence of ophthalmopathy), TRAb, comparison of the imaging findings and, when necessary, cytology and a new scintigraphy several weeks later.
Assays TSH, free T4, and total T3 were measured with a chemiluminescent assay (Immulite 2000, Diagnostic Products Corporation, Los Angeles, CA, USA), with reference values of 0.4–4 mIU/l, 0.8– 2.0 ng/dl, and 80–180 ng/dl, respectively. TRAb were determined by a radioimmunoassay (radioreceptor); inhibition > 10 % was defined as positive.
Imaging Scintigraphy was carried out 24 h after the administration of 100–300 μCi of 131I. All patients received a low-iodine diet 7 days before the exam. Diffuse, normal, or elevated uptake was compatible with diffuse toxic goiter (DTG); focal uptake with suppression or decreased uptake in the remaining parenchyma was compatible with toxic adenoma (TA); more than one focal area of radioiodine uptake accompanied by suppression or decreased uptake in the remaining parenchyma was diagnostic of toxic multinodular disease (TMD), and diffusely reduced or abolished uptake was indicative of the absence of thyroid hyperfunction [1]. CFDS was performed with a linear multifrequency 12–14 MHz transducer for morphological analysis (B-mode) and for power Doppler evaluation. A criterion that can be easily applied in clinical practice was used for the analysis of vascularity [2, 3]. The following possible CFDS patterns were considered: pattern 0: absent intraparenchymal (or nodular) vascularity or minimal spots; pattern I: presence of parenchymal (or nodular) blood flow with patchy uneven distribution; pattern II: mild increase in the color flow Doppler signal with patchy distribution (for nodules: mainly peripheral); pattern III: markedly increased color flow Doppler signal with diffuse homogeneous distribution (for nodules: intranodular and peripheral vascularity). A gland showing diffuse hypoechogenicity or normal echogenicity and type II or III pattern vascularity was considered to be compatible with DTG. The finding of micronodule(s) or nodule(s) > 1 cm with type 0 pattern vascularity did not change this impression. The finding of a nodule with a solid component measuring > 1 cm3 and type II or III pattern vascularity, accompanied by a type 0 pattern vascularity in the remaining parenchyma, was compatible with TA. The finding of two or more macronodules with type II or III pattern vascularity, accompanied by a type 0 pattern vascularity in the remaining parenchyma, was compatible with TMD. The remaining situations were classified as inconclusive. It should be noted that the radiologist was unaware of the diagnosis of thyrotoxicosis and of the scintigraphy and TRAb results. Although previous studies have shown good intra- and interobserver agreement of CFDS in diffuse and nodular thyroid disease [2, 10–12], we randomly selected 12 participants (6 with and 6 without nodular disease) to be evaluated on two occasions by the same examiner and also by two other examiners. Agreement in the type of vascularity (0–III) was obtained for these 12 patients in all evaluations.
Statistical analysis The sensitivity and specificity of the method (CFDS or scintigraphy) for a given etiology (DTG, TMD, TA or absence of hyperfunc▶ Table 1). tion) was determined as follows: (●
Results
▼
A total of 176 patients (142 women and 34 men), ranging in age from 16 to 78 years (mean 45 years), were included. Of these, 102 had clinical thyrotoxicosis and 74 had subclinical dysfunction. The clinical and biochemical features of the subjects are ▶ Table 2. shown in ●
Clinical thyrotoxicosis CFDS was suggestive of DTG in 50 patients. Scintigraphy confirmed this diagnosis in 48 of these patients (96 %), but was compatible with TMD in 2. The absence of thyroid hyperfunction was suggested by CFDS in 19 patients, showing 100 % agreement with scintigraphy. CFDS was compatible with TA in 16 patients. Scintigraphy confirmed this diagnosis in 15 cases (94 %), but suggested the absence of hyperfunction in one. TMD was diagnosed by CFDS in 14 patients. Scintigraphy confirmed this impression in 11 cases (78.6 %), but was compatible with DTG in two cases and with TA in one. In 5/6 of discordant cases, the final diagnosis was suggested by CFDS [based on clinical data (duration and progression of thyrotoxicosis, presence of ophthalmopathy), TRAb, repetition of scintigraphy, cytology] and one case remained doubtful (Marine-Lenhart syndrome?). On the basis of the criteria used in this study, CFDS did not permit a safe diagnosis in only 3/102 patients (3 %). These patients had a gland with type I pattern vascularity, in which scintigraphy distinguished between DTG (n = 2) and the absence of
Table 1
Calculation of sensitivity and specificity.
Method
Etiology analyzed
Other etiologies
Positive for the etiology analyzed Negative for the etiology analyzed Sensitivity = A/A + B Specificity = D/D + C
A (true positive) B (false negative)
C (false positive) D (true negative)
Rosario PW et al. Doppler Sonography in Thyrotoxicosis. … Horm Metab Res 2014; 46: 505–509
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using amiodarone or recently exposed to iodinated contrast (less than 3 months), and patients treated with antithyroid drugs (ATD) were excluded. Immediately before the administration of 131 I, the patients were submitted to clinical examination and blood collection for the measurement of TSH, free T4, total T3, and anti-TSH receptor antibodies (TRAb). Patients with TSH ≤ 0.1 mIU/l and elevated free T4 or total T3 (clinical thyrotoxicosis) and patients with TSH ≤ 0.3 mIU/l and normal free T4 and total T3 (subclinical dysfunction) were selected. In the latter situation, the following criteria also need to be met: (i) absence of acute illness or pituitary disease and no use of corticosteroids or drugs with dopaminergic action (non-thyroid causes of low TSH [1, 8, 9]); (ii) free T4 and total T3 should not be close to the lower limit of normal; and (iii) TSH ≤ 0.3 mIU/l measured 4–12 weeks prior to inclusion in the study to exclude transient changes in thyroid function [1, 8, 9]. The study was approved by the Ethics Committee of the institution and the subjects gave written informed consent.
Endocrine Care 507
Table 2 Clinical and biochemical features of the subjects. Clinical thyrotoxicosisa
Clinical and bio-
Subclinical thyrotoxicosis
chemical features Sex (M/F) Age [years (range)] Ophthalmopathy Goiter (palpable) Positive TRAb TSH [mIU/l (range)] FT4 [ng/dl (range)]b
DTG (n = 51)
TMD (n = 14)
TA (n = 16)
AH (n = 20)
DTG (n = 22)
TMD (n = 30)
TA (n = 20)
AH (n = 2)
10/41 16–63 25 (49 %) 33 (65 %) 45 (88 %) 0.02–0.05 1.85–12
4/10 42–76 0 12 (86 %) 0 0.02–0.06 1.65–7.1
6/10 50–78 0 10 (62 %) 0 0.02–0.07 1.63–5.3
1/19 21–48 0 10 (50 %) 0 0.02–0.09 2.3–4.1
4/18 18–60 10 (45 %) 11 (50 %) 20 (91 %) 0.06–0.22 1.3–1.9
5/25 40–71 0 21 (70 %) 0 0.04–0.29 1.2–1.95
4/16 40–77 0 12 (60 %) 0 0.05–0.25 1.05–1.96
0/2 22–28 0 1 0 0.1–0.22 1.08–1.6
DTG: Diffuse toxic goiter; TMD: Toxic multinodular disease; TA: Toxic adenoma; AH: Absence of hyperfunction; M: Male; F: Female; TRAb: Anti-TSH receptor antibodies; No defined etiologic diagnosis could be obtained for one patient
b
Patients with normal free T4 ( < 2 ng/dl) had elevated total T3
Table 3 Sensitivity and specificity of color flow Doppler sonography and scintigraphy. Clinical thyrotoxicosisa
Etiology Sensitivity DTG TMD TA AH
Subclinical thyrotoxicosis Specificity
Sensitivity
Specificity
CFDS
Scintigraphy
CFDS
Scintigraphy
CFDS
Scintigraphy
CFDS
Scintigraphy
96 % 100 % 100 % 95 %
98 % 78.6 % 93.7 % 100 %
100 % 100 % 100 % 100 %
96 % 98.9 % 98.8 % 98.7 %
72.7 % 86.6 % 90 % 0/2
95.4 % 90 % 100 % 2/2
100 % 100 % 100 % 100 %
94.2 % 97.7 % 100 % 100 %
DTG: Diffuse toxic goiter; TMD: Toxic multinodular disease; TA: Toxic adenoma; AH: Absence of hyperfunction; CFDS: Color flow Doppler sonography a
No defined etiologic diagnosis could be obtained for one patient
hyperfunction (n = 1). Interestingly, the clinical and TRAb data also permitted the correct diagnosis in these patients.
Subclinical thyrotoxicosis CFDS was suggestive of DTG in 16 patients. Scintigraphy confirmed this impression in 15 patients (94 %), but suggested TMD in one. CFDS was compatible with TA in 18 patients and agreement was obtained by scintigraphy in all cases. TMD was diagnosed by CFDS in 26 patients. Scintigraphy confirmed this diagnosis in 23 cases (88.5 %), but was compatible with DTG in 3. In 4 discordant cases, the final diagnosis was suggested by CFDS. Considering the criteria of this study, CFDS did not permit a safe diagnosis in 14/74 patients (19 %). Seven of these cases exhibited echogenicity of the normal gland (n = 2) or hypoechogenicity (n = 5) with type I pattern vascularity, in which scintigraphy permitted the distinction between DTG (n = 5) and the absence of hyperfunction (n = 2). Interestingly, the clinical and TRAb data permitted the correct diagnosis in 6 of these 7 patients. The addition of scintigraphy was more useful in the 7 cases with macronodules in which analysis of nodule vascularity in relation to the remaining parenchyma did not permit to establish a diagnosis with certainty, and scintigraphy suggested DTG with a cold nodule in one case, TA in 2, and TMD in 4.
Sensitivity and specificity of CFDS and scintigraphy The sensitivity and specificity of CFDS and scintigraphy are ▶ Table 3. Of note, excluding one case whose etiology shown in ● remained undefined despite extensive workup, CFDS using the criteria established in this study showed 100 % specificity (in all 10 discordant cases between scintigraphy and CFDS, the diagnosis suggested by the latter was correct).
Discussion
▼
In agreement with previous series [2–7], CFDS was useful for the differential diagnosis of thyrotoxicosis. At the time of CFDS, the patients studied here had active thyrotoxicosis and had not yet received any treatment, factors contributing to the results obtained. In fact, normal or slightly increased blood flow, instead of the decreased vascularity seen in the initial thyrotoxic phase, is observed during recovery of subacute thyroiditis [13]. In Graves’ disease compensated with ATD, particularly after TSH normalization, hyperflow characteristic of the decompensated phase may not be seen. In addition, a clear difference in vascularity between the nodule(s) and the remaining parenchyma may not be visible in toxic nodular disease after TSH normalization. The importance of imaging methods during active thyrotoxicosis also applies to scintigraphy, which may detect normal or slightly elevated uptake during recovery of subacute thyroiditis, normal uptake in treated Graves’ disease, or diffuse uptake in toxic nodular disease after TSH normalization. We found a higher frequency of doubtful CFDS results (absence of typical vascularity) in patients with subclinical thyrotoxicosis (19 vs. 3 % in clinical dysfunction). The addition of scintigraphy was useful in these cases, although this method also did not reveal characteristic findings in many patients. In a patient with thyrotoxicosis without macronodules on ultrasound and type I pattern vascularity on Doppler, normal diffuse uptake detected by scintigraphy is sufficient for the diagnosis of DTG, whereas absent uptake favors the absence of hyperfunction. In contrast, in a patient with macronodule(s) and vascularity similar to the remaining parenchyma, the detection of focal uptake by scintigraphy corresponding to this (these) nodule(s) and decreased
Rosario PW et al. Doppler Sonography in Thyrotoxicosis. … Horm Metab Res 2014; 46: 505–509
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FT4: Free T4 a
508 Endocrine Care
Laboratory diagnosis of thyrotoxicosisa CFDSb,c
Diagnosis
Doubtful No macronodule
With macronodule(s)
Clinical data and TRAb
Scintigraphyb,c No diagnosis
uptake (even without suppression) in the remaining gland is highly suggestive of toxic nodular disease. The exclusive use of CFDS may not permit an etiologic diagnosis. For example, diffuse hyperfunction of the thyroid due to Graves’ disease, stimulation by human chorionic gonadotropin, TSHproducing adenoma and resistance to thyroid hormone can exhibit a similar pattern of vascularity [2, 14, 15]. Similarly, subacute thyroiditis and factitious thyrotoxicosis can present reduced vascularity on CFDS [2]. Again, scintigraphy is also unable to establish the etiologic diagnosis of DTG or low homogenous uptake [1]. In cases of disagreement between CFDS and scintigraphy, the final diagnosis was suggested in all but one case. In fact, there are situations in which scintigraphy can lead to an equivocal diagnosis, such as the absence of uptake in patients with Graves’ disease; TA or TMD exposed to excessive iodine which cannot always be suspected without the measurement of urinary iodine; unilateral uptake (simulating TA) in patients with unilateral Graves’ disease or associated agenesis of one of the thyroid lobes (rare); multinodular Graves’ disease; and TMD simulating DTG or DTG with atoxic nodules simulating TMD [3]. One limitation of the present study was the fact that vascularity was only analyzed quantitatively (score 0–III) and that no quantitative measures (e. g., peak systolic velocity, thyroid blood flow area, thyroid blood flow, flow velocity in the superior thyroid artery) were obtained. However, these measures are also influenced by the examiner, are time consuming, and are therefore less applicable to routine clinical practice. In contrast, the strengths of the study include its prospective design; the number of patients, including those with subclinical thyrotoxicosis who were rarely included in previous series, and the fact that scintigraphy and CFDS were performed on all patients for comparison. Although not evaluated in the present study, CFDS has also been investigated as a predictor of sensitivity to ATD [16], recurrence after ATD withdrawal [10, 17], need for radioiodine therapy [18] in patients with Graves’ disease, and as a parameter of the response to percutaneous ethanol injection in toxic nodular disease [19]. In addition, ultrasonography can identify atoxic nodules associated with Graves’ disease that are not palpable or detected by scintigraphy and that correspond to thyroid carcinoma [20]. CFDS is clearly recommended in cases in which an imaging method is required for the differential diagnosis of thyrotoxicosis and scintigraphy is contraindicated (pregnancy and breastfeeding), has a limited value (use of amiodarone or recent
exposure to iodinated contrasts), or is not available. The present results suggest that, even if these special situations do not apply, especially in countries where scintigraphy is not easily available and expensive, and if scintigraphy is not necessary for the definition of the therapeutic 131I activity, CFDS can be used as a first ▶ Fig. 1. option instead of scintigraphy, as suggested in ●
Conflict of Interest
▼
The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.
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Rosario PW et al. Doppler Sonography in Thyrotoxicosis. … Horm Metab Res 2014; 46: 505–509
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Diagnosisc
Fig. 1 Suggestion for the evaluation of the etiology of thyrotoxicosis by color flow Doppler sonography. CFDS: Color flow Doppler sonography; TRAb: Anti-TSH receptor antibodies. a The laboratory diagnosis of thyrotoxicosis should precede imaging methods. b Imaging methods better define the etiology of thyrotoxicosis when performed during active disease. c Imaging methods do not define the etiology of thyroiditis or the distinction between this condition and factitious thyrotoxicosis or ectopic hormone production. Similarly, imaging methods alone may not be able to distinguish between Graves’ disease and other causes of diffuse thyroid hyperfunction.
11 Wienke JR, Chong WK, Fielding JR, Zou KH, Mittelstaedt CA. Sonographic features of benign thyroid nodules: interobserver reliability and overlap with malignancy. J Ultrasound Med 2003; 22: 1027–1031 12 Choi SH, Kim EK, Kwak JY, Kim MJ, Son EJ. Interobserver and intraobserver variations in ultrasound assessment of thyroid nodules. Thyroid 2010; 20: 167–172 13 Hiromatsu Y, Ishibashi M, Miyake I, Soyejima E, Yamashita K, Koike N, Nonaka K. Color Doppler ultrasonography in patients with subacute thyroiditis. Thyroid 1999; 9: 1189–1193 14 Bogazzi F, Manetti L, Tomisti L, Rossi G, Cosci C, Sardella C, Bartalena L, Gasperi M, Macchia E, Vitti P, Martino E. Thyroid color flow Doppler sonography: an adjunctive tool for differentiating patients with inappropriate thyrotropin (TSH) secretion due to TSH-secreting pituitary adenoma or resistance to thyroid hormone. Thyroid 2006; 16: 989–995 15 Zuhur SS, Ozel A, Velet S, Buğdacı MS, Cil E, Altuntas Y. Is the measurement of inferior thyroid artery blood flow velocity by color-flow Doppler ultrasonography useful for differential diagnosis between gestational transient thyrotoxicosis and Graves’ disease? A prospective study. Clinics (Sao Paulo) 2012; 67: 125–129
16 Nagasaki T, Inaba M, Kumeda Y, Fujiwara-Ueda M, Hiura Y, Nishizawa Y. Significance of thyroid blood flow as a predictor of methimazole sensitivity in untreated hyperthyroid patients with Graves’ disease. Biomed Pharmacother 2007; 61: 472–476 17 Baldini M, Castagnone D, Rivolta R, Meroni L, Pappalettera M, Cantalamessa L. Thyroid vascularization by color doppler ultrasonography in Graves’ disease. Changes related to different phases and to the longterm outcome of the disease. Thyroid 1997; 7: 823–828 18 Wang CY, Chang TC. Thyroid Doppler ultrasonography and resistive index in the evaluation of the need for ablative or antithyroid drug therapy in Graves’ hyperthyroidism. J Formos Med Assoc 2001; 100: 753–757 19 Cerbone G, Spiezia S, Colao A, Marzullo P, Assanti AP, Lucci R, Zarrilli S, Siciliani M, Fenzi G, Lombardi G. Percutaneous ethanol injection under Power Doppler ultrasound assistance in the treatment of autonomously functioning thyroid nodules. J Endocrinol Invest 1999; 22: 752–759 20 Cappelli C, Pirola I, De Martino E, Agosti B, Delbarba A, Castellano M, Rosei EA. The role of imaging in Graves’ disease: a cost-effectiveness analysis. Eur J Radiol 2008; 65: 99–103
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Endocrine Care 509
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Authors
P. W. Rosario, J. B. N. Santos, N. S. Nunes, A. L. da Silva, M. R. Calsolari
Affiliation
Postgraduation Program, Endocrinology Service, Santa Casa de Belo Horizonte, Minas Gerais, Brazil
Key words ▶ color flow Doppler ● sonography ▶ thyrotoxicosis ● ▶ etiology ●
Abstract
▼
The objective of this prospective study was to compare the results of color flow Doppler sonography (CFDS) and radioiodine scintigraphy in patients with thyrotoxicosis. A total of 176 patients, 102 with clinical thyrotoxicosis and 74 with subclinical dysfunction, were included. Pregnant and breast-feeding women, patients using amiodarone or recently exposed to iodinated contrast, and patients treated with antithyroid drugs were excluded. Total T3, free T4, TSH, and anti-TSH receptor antibodies were measured before scintigraphy and CFDS. Excluding one patient whose etiology of thyrotoxicosis remained undefined, CFDS showed 100 % specificity. In fact, in all 10 cases in which scintigraphy and CFDS provided discordant results, the
diagnosis suggested by the latter was correct. In patients with clinical thyrotoxicosis, the sensitivity of CFDS was 96 % for diffuse toxic goiter, 95 % for the absence of hyperfunction, and 100 % for toxic nodular disease. In patients with subclinical dysfunction, the sensitivity of CFDS was 72.7 % for diffuse toxic goiter, 90 % for toxic adenoma, and 86.6 % for toxic multinodular disease. CFDS was inconclusive in patients with parenchymal blood flow with patchy uneven distribution or with macronodules in which nodule vascularity compared to the remaining parenchyma did not permit to establish the diagnosis with certainty. CFDS can be used instead of scintigraphy not only in situations in which the latter is contraindicated or of limited value to define the etiology of thyrotoxicosis.
received 20.08.2013 accepted 28.11.2013
Introduction Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1363282 Published online: January 20, 2014 Horm Metab Res 2014; 46: 505–509 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence P. W. Rosario, MD Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte Rua Domingos Vieira 590 Santa Efigênia CEP 30150-240 Belo Horizonte MG Brazil Tel.: + 55/31/32388 819 Fax: + 55/31/32388 980 [email protected]
▼
The laboratory diagnosis of thyrotoxicosis should be followed by the establishment of its etiology. Except for patients with ophthalmopathy and diffuse goiter, characteristics of Graves’ disease, this definition requires laboratory tests and imaging methods. Traditionally, scintigraphy with 131I, 123I, or 99mTc is the most recommended method [1]. However, this method is contraindicated in pregnant women and during breastfeeding, has a limited value in patients using amiodarone or those recently exposed to excessive iodine (e. g., iodinated contrasts), requires preparation and more than one visit to the nuclear medicine service (131I), exposes to radiation, and equivocal results are possible [1]. In addition, in some countries scintigraphy is not easily available and is expensive. Some studies have demonstrated the value of color flow Doppler sonography (CFDS) for defining the etiology of thyrotoxicosis [2–7]. In addition to its application in situations in which
scintigraphy is contraindicated or of limited value, CFDS is an interesting option since it is a noninvasive method that does not require preparation, does not use radiation, and provides immediate results. Furthermore, the method is less expensive and more easily available than scintigraphy in some countries. This prospective study compared the results of CFDS using easily applicable criteria with the results of scintigraphy in patients with a laboratory diagnosis of thyrotoxicosis (clinical or subclinical).
Materials and Methods
▼
Design This study was designed as a prospective study.
Patients Patients consecutively referred to our institution for scintigraphy of the thyroid were studied. Pregnant and breast-feeding women, patients
Rosario PW et al. Doppler Sonography in Thyrotoxicosis. … Horm Metab Res 2014; 46: 505–509
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Color Flow Doppler Sonography for the Etiologic Diagnosis of Thyrotoxicosis
506 Endocrine Care
The term DTG rather than Graves’ disease was used because other causes, although uncommon, can result in a similar feature in the imaging methods [1]. For the same reason, we prefer the term “absence of hyperfunction” instead of subacute thyroiditis [1]. In cases in which CFDS and scintigraphy provided discordant results, the final diagnosis was established based on clinical data (duration and progression of thyrotoxicosis, presence of ophthalmopathy), TRAb, comparison of the imaging findings and, when necessary, cytology and a new scintigraphy several weeks later.
Assays TSH, free T4, and total T3 were measured with a chemiluminescent assay (Immulite 2000, Diagnostic Products Corporation, Los Angeles, CA, USA), with reference values of 0.4–4 mIU/l, 0.8– 2.0 ng/dl, and 80–180 ng/dl, respectively. TRAb were determined by a radioimmunoassay (radioreceptor); inhibition > 10 % was defined as positive.
Imaging Scintigraphy was carried out 24 h after the administration of 100–300 μCi of 131I. All patients received a low-iodine diet 7 days before the exam. Diffuse, normal, or elevated uptake was compatible with diffuse toxic goiter (DTG); focal uptake with suppression or decreased uptake in the remaining parenchyma was compatible with toxic adenoma (TA); more than one focal area of radioiodine uptake accompanied by suppression or decreased uptake in the remaining parenchyma was diagnostic of toxic multinodular disease (TMD), and diffusely reduced or abolished uptake was indicative of the absence of thyroid hyperfunction [1]. CFDS was performed with a linear multifrequency 12–14 MHz transducer for morphological analysis (B-mode) and for power Doppler evaluation. A criterion that can be easily applied in clinical practice was used for the analysis of vascularity [2, 3]. The following possible CFDS patterns were considered: pattern 0: absent intraparenchymal (or nodular) vascularity or minimal spots; pattern I: presence of parenchymal (or nodular) blood flow with patchy uneven distribution; pattern II: mild increase in the color flow Doppler signal with patchy distribution (for nodules: mainly peripheral); pattern III: markedly increased color flow Doppler signal with diffuse homogeneous distribution (for nodules: intranodular and peripheral vascularity). A gland showing diffuse hypoechogenicity or normal echogenicity and type II or III pattern vascularity was considered to be compatible with DTG. The finding of micronodule(s) or nodule(s) > 1 cm with type 0 pattern vascularity did not change this impression. The finding of a nodule with a solid component measuring > 1 cm3 and type II or III pattern vascularity, accompanied by a type 0 pattern vascularity in the remaining parenchyma, was compatible with TA. The finding of two or more macronodules with type II or III pattern vascularity, accompanied by a type 0 pattern vascularity in the remaining parenchyma, was compatible with TMD. The remaining situations were classified as inconclusive. It should be noted that the radiologist was unaware of the diagnosis of thyrotoxicosis and of the scintigraphy and TRAb results. Although previous studies have shown good intra- and interobserver agreement of CFDS in diffuse and nodular thyroid disease [2, 10–12], we randomly selected 12 participants (6 with and 6 without nodular disease) to be evaluated on two occasions by the same examiner and also by two other examiners. Agreement in the type of vascularity (0–III) was obtained for these 12 patients in all evaluations.
Statistical analysis The sensitivity and specificity of the method (CFDS or scintigraphy) for a given etiology (DTG, TMD, TA or absence of hyperfunc▶ Table 1). tion) was determined as follows: (●
Results
▼
A total of 176 patients (142 women and 34 men), ranging in age from 16 to 78 years (mean 45 years), were included. Of these, 102 had clinical thyrotoxicosis and 74 had subclinical dysfunction. The clinical and biochemical features of the subjects are ▶ Table 2. shown in ●
Clinical thyrotoxicosis CFDS was suggestive of DTG in 50 patients. Scintigraphy confirmed this diagnosis in 48 of these patients (96 %), but was compatible with TMD in 2. The absence of thyroid hyperfunction was suggested by CFDS in 19 patients, showing 100 % agreement with scintigraphy. CFDS was compatible with TA in 16 patients. Scintigraphy confirmed this diagnosis in 15 cases (94 %), but suggested the absence of hyperfunction in one. TMD was diagnosed by CFDS in 14 patients. Scintigraphy confirmed this impression in 11 cases (78.6 %), but was compatible with DTG in two cases and with TA in one. In 5/6 of discordant cases, the final diagnosis was suggested by CFDS [based on clinical data (duration and progression of thyrotoxicosis, presence of ophthalmopathy), TRAb, repetition of scintigraphy, cytology] and one case remained doubtful (Marine-Lenhart syndrome?). On the basis of the criteria used in this study, CFDS did not permit a safe diagnosis in only 3/102 patients (3 %). These patients had a gland with type I pattern vascularity, in which scintigraphy distinguished between DTG (n = 2) and the absence of
Table 1
Calculation of sensitivity and specificity.
Method
Etiology analyzed
Other etiologies
Positive for the etiology analyzed Negative for the etiology analyzed Sensitivity = A/A + B Specificity = D/D + C
A (true positive) B (false negative)
C (false positive) D (true negative)
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using amiodarone or recently exposed to iodinated contrast (less than 3 months), and patients treated with antithyroid drugs (ATD) were excluded. Immediately before the administration of 131 I, the patients were submitted to clinical examination and blood collection for the measurement of TSH, free T4, total T3, and anti-TSH receptor antibodies (TRAb). Patients with TSH ≤ 0.1 mIU/l and elevated free T4 or total T3 (clinical thyrotoxicosis) and patients with TSH ≤ 0.3 mIU/l and normal free T4 and total T3 (subclinical dysfunction) were selected. In the latter situation, the following criteria also need to be met: (i) absence of acute illness or pituitary disease and no use of corticosteroids or drugs with dopaminergic action (non-thyroid causes of low TSH [1, 8, 9]); (ii) free T4 and total T3 should not be close to the lower limit of normal; and (iii) TSH ≤ 0.3 mIU/l measured 4–12 weeks prior to inclusion in the study to exclude transient changes in thyroid function [1, 8, 9]. The study was approved by the Ethics Committee of the institution and the subjects gave written informed consent.
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Table 2 Clinical and biochemical features of the subjects. Clinical thyrotoxicosisa
Clinical and bio-
Subclinical thyrotoxicosis
chemical features Sex (M/F) Age [years (range)] Ophthalmopathy Goiter (palpable) Positive TRAb TSH [mIU/l (range)] FT4 [ng/dl (range)]b
DTG (n = 51)
TMD (n = 14)
TA (n = 16)
AH (n = 20)
DTG (n = 22)
TMD (n = 30)
TA (n = 20)
AH (n = 2)
10/41 16–63 25 (49 %) 33 (65 %) 45 (88 %) 0.02–0.05 1.85–12
4/10 42–76 0 12 (86 %) 0 0.02–0.06 1.65–7.1
6/10 50–78 0 10 (62 %) 0 0.02–0.07 1.63–5.3
1/19 21–48 0 10 (50 %) 0 0.02–0.09 2.3–4.1
4/18 18–60 10 (45 %) 11 (50 %) 20 (91 %) 0.06–0.22 1.3–1.9
5/25 40–71 0 21 (70 %) 0 0.04–0.29 1.2–1.95
4/16 40–77 0 12 (60 %) 0 0.05–0.25 1.05–1.96
0/2 22–28 0 1 0 0.1–0.22 1.08–1.6
DTG: Diffuse toxic goiter; TMD: Toxic multinodular disease; TA: Toxic adenoma; AH: Absence of hyperfunction; M: Male; F: Female; TRAb: Anti-TSH receptor antibodies; No defined etiologic diagnosis could be obtained for one patient
b
Patients with normal free T4 ( < 2 ng/dl) had elevated total T3
Table 3 Sensitivity and specificity of color flow Doppler sonography and scintigraphy. Clinical thyrotoxicosisa
Etiology Sensitivity DTG TMD TA AH
Subclinical thyrotoxicosis Specificity
Sensitivity
Specificity
CFDS
Scintigraphy
CFDS
Scintigraphy
CFDS
Scintigraphy
CFDS
Scintigraphy
96 % 100 % 100 % 95 %
98 % 78.6 % 93.7 % 100 %
100 % 100 % 100 % 100 %
96 % 98.9 % 98.8 % 98.7 %
72.7 % 86.6 % 90 % 0/2
95.4 % 90 % 100 % 2/2
100 % 100 % 100 % 100 %
94.2 % 97.7 % 100 % 100 %
DTG: Diffuse toxic goiter; TMD: Toxic multinodular disease; TA: Toxic adenoma; AH: Absence of hyperfunction; CFDS: Color flow Doppler sonography a
No defined etiologic diagnosis could be obtained for one patient
hyperfunction (n = 1). Interestingly, the clinical and TRAb data also permitted the correct diagnosis in these patients.
Subclinical thyrotoxicosis CFDS was suggestive of DTG in 16 patients. Scintigraphy confirmed this impression in 15 patients (94 %), but suggested TMD in one. CFDS was compatible with TA in 18 patients and agreement was obtained by scintigraphy in all cases. TMD was diagnosed by CFDS in 26 patients. Scintigraphy confirmed this diagnosis in 23 cases (88.5 %), but was compatible with DTG in 3. In 4 discordant cases, the final diagnosis was suggested by CFDS. Considering the criteria of this study, CFDS did not permit a safe diagnosis in 14/74 patients (19 %). Seven of these cases exhibited echogenicity of the normal gland (n = 2) or hypoechogenicity (n = 5) with type I pattern vascularity, in which scintigraphy permitted the distinction between DTG (n = 5) and the absence of hyperfunction (n = 2). Interestingly, the clinical and TRAb data permitted the correct diagnosis in 6 of these 7 patients. The addition of scintigraphy was more useful in the 7 cases with macronodules in which analysis of nodule vascularity in relation to the remaining parenchyma did not permit to establish a diagnosis with certainty, and scintigraphy suggested DTG with a cold nodule in one case, TA in 2, and TMD in 4.
Sensitivity and specificity of CFDS and scintigraphy The sensitivity and specificity of CFDS and scintigraphy are ▶ Table 3. Of note, excluding one case whose etiology shown in ● remained undefined despite extensive workup, CFDS using the criteria established in this study showed 100 % specificity (in all 10 discordant cases between scintigraphy and CFDS, the diagnosis suggested by the latter was correct).
Discussion
▼
In agreement with previous series [2–7], CFDS was useful for the differential diagnosis of thyrotoxicosis. At the time of CFDS, the patients studied here had active thyrotoxicosis and had not yet received any treatment, factors contributing to the results obtained. In fact, normal or slightly increased blood flow, instead of the decreased vascularity seen in the initial thyrotoxic phase, is observed during recovery of subacute thyroiditis [13]. In Graves’ disease compensated with ATD, particularly after TSH normalization, hyperflow characteristic of the decompensated phase may not be seen. In addition, a clear difference in vascularity between the nodule(s) and the remaining parenchyma may not be visible in toxic nodular disease after TSH normalization. The importance of imaging methods during active thyrotoxicosis also applies to scintigraphy, which may detect normal or slightly elevated uptake during recovery of subacute thyroiditis, normal uptake in treated Graves’ disease, or diffuse uptake in toxic nodular disease after TSH normalization. We found a higher frequency of doubtful CFDS results (absence of typical vascularity) in patients with subclinical thyrotoxicosis (19 vs. 3 % in clinical dysfunction). The addition of scintigraphy was useful in these cases, although this method also did not reveal characteristic findings in many patients. In a patient with thyrotoxicosis without macronodules on ultrasound and type I pattern vascularity on Doppler, normal diffuse uptake detected by scintigraphy is sufficient for the diagnosis of DTG, whereas absent uptake favors the absence of hyperfunction. In contrast, in a patient with macronodule(s) and vascularity similar to the remaining parenchyma, the detection of focal uptake by scintigraphy corresponding to this (these) nodule(s) and decreased
Rosario PW et al. Doppler Sonography in Thyrotoxicosis. … Horm Metab Res 2014; 46: 505–509
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FT4: Free T4 a
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Laboratory diagnosis of thyrotoxicosisa CFDSb,c
Diagnosis
Doubtful No macronodule
With macronodule(s)
Clinical data and TRAb
Scintigraphyb,c No diagnosis
uptake (even without suppression) in the remaining gland is highly suggestive of toxic nodular disease. The exclusive use of CFDS may not permit an etiologic diagnosis. For example, diffuse hyperfunction of the thyroid due to Graves’ disease, stimulation by human chorionic gonadotropin, TSHproducing adenoma and resistance to thyroid hormone can exhibit a similar pattern of vascularity [2, 14, 15]. Similarly, subacute thyroiditis and factitious thyrotoxicosis can present reduced vascularity on CFDS [2]. Again, scintigraphy is also unable to establish the etiologic diagnosis of DTG or low homogenous uptake [1]. In cases of disagreement between CFDS and scintigraphy, the final diagnosis was suggested in all but one case. In fact, there are situations in which scintigraphy can lead to an equivocal diagnosis, such as the absence of uptake in patients with Graves’ disease; TA or TMD exposed to excessive iodine which cannot always be suspected without the measurement of urinary iodine; unilateral uptake (simulating TA) in patients with unilateral Graves’ disease or associated agenesis of one of the thyroid lobes (rare); multinodular Graves’ disease; and TMD simulating DTG or DTG with atoxic nodules simulating TMD [3]. One limitation of the present study was the fact that vascularity was only analyzed quantitatively (score 0–III) and that no quantitative measures (e. g., peak systolic velocity, thyroid blood flow area, thyroid blood flow, flow velocity in the superior thyroid artery) were obtained. However, these measures are also influenced by the examiner, are time consuming, and are therefore less applicable to routine clinical practice. In contrast, the strengths of the study include its prospective design; the number of patients, including those with subclinical thyrotoxicosis who were rarely included in previous series, and the fact that scintigraphy and CFDS were performed on all patients for comparison. Although not evaluated in the present study, CFDS has also been investigated as a predictor of sensitivity to ATD [16], recurrence after ATD withdrawal [10, 17], need for radioiodine therapy [18] in patients with Graves’ disease, and as a parameter of the response to percutaneous ethanol injection in toxic nodular disease [19]. In addition, ultrasonography can identify atoxic nodules associated with Graves’ disease that are not palpable or detected by scintigraphy and that correspond to thyroid carcinoma [20]. CFDS is clearly recommended in cases in which an imaging method is required for the differential diagnosis of thyrotoxicosis and scintigraphy is contraindicated (pregnancy and breastfeeding), has a limited value (use of amiodarone or recent
exposure to iodinated contrasts), or is not available. The present results suggest that, even if these special situations do not apply, especially in countries where scintigraphy is not easily available and expensive, and if scintigraphy is not necessary for the definition of the therapeutic 131I activity, CFDS can be used as a first ▶ Fig. 1. option instead of scintigraphy, as suggested in ●
Conflict of Interest
▼
The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.
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Rosario PW et al. Doppler Sonography in Thyrotoxicosis. … Horm Metab Res 2014; 46: 505–509
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Diagnosisc
Fig. 1 Suggestion for the evaluation of the etiology of thyrotoxicosis by color flow Doppler sonography. CFDS: Color flow Doppler sonography; TRAb: Anti-TSH receptor antibodies. a The laboratory diagnosis of thyrotoxicosis should precede imaging methods. b Imaging methods better define the etiology of thyrotoxicosis when performed during active disease. c Imaging methods do not define the etiology of thyroiditis or the distinction between this condition and factitious thyrotoxicosis or ectopic hormone production. Similarly, imaging methods alone may not be able to distinguish between Graves’ disease and other causes of diffuse thyroid hyperfunction.
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