� ENDOCRINE PRACTICE Vol 15 No. 1 January/February 2009

Original Article

ROlE OF ThyROID DOPPlER IN DIFFERENTIAl DIAgNOsIs OF ThyROTOxICOsIs

K. V. S. Hari Kumar, MD1; Vamsikrishna Pasupuleti, MBBS, DMRB2; Muthukrishnan Jayaraman, MD1; Verma Abhyuday, MD1;

Ramasubba Rayudu B, MD2; Kirtikumar D. Modi, MD, DM1

Submitted for publication July 18, 2008Accepted for publication August 7, 2008Departments of 1Endocrinology and 2Radiology, Medwin Hospitals, Nampally, India.Address correspondence and reprint requests to Dr. K. V. S. Hari Kumar, Department of Endocrinology, Medwin Hospitals, Chirag Ali Lane, Nampally, Hyderabad-500001.AP. India. E-mail: hariendo@rediffmail.com. © 2009 AACE.

ABSTRACT

Objective: To evaluate the role of thyroid blood flow assessment by color-flow Doppler ultrasonography in the differential diagnosis of thyrotoxicosis. Methods: Consecutive patients with thyrotoxicosis presenting to our center between June 2007 and March 2008 were included in the study. Clinical data were col-lected, and thyroid function tests including measurements of thyrotropin, total thyroxine, and total triiodothyronine were performed. Thyroid glands of all patients were evalu-ated with color-flow Doppler ultrasonography for size, vas-cularity, and peak systolic velocity of the inferior thyroid artery. Technetium Tc 99m pertechnetate scan was done when the diagnosis was not clear on the basis of clinical findings. Patients were divided into 2 groups for analysis: patients with destructive thyrotoxicosis and patients with Graves disease. Paired t tests and Fisher exact tests were used for statistical analysis. Results: A total of 65 patients participated in the study; 31 had destructive thyrotoxicosis and 34 had Graves dis-ease. Thyroid blood flow, as assessed by peak systolic velocity of the inferior thyroid artery, was significantly higher in patients with Graves disease than in patients with destructive thyroiditis (57.6 ± 13.1 cm/s vs 22.4 ± 5.4 cm/s; P<.05). All patients with destructive thyroiditis had low peak systolic velocity of the inferior thyroid artery, and 32 of 34 patients with Graves disease had high peak

systolic velocity. Color-flow Doppler ultrasonography parameters correlated significantly with pertechnetate scan results, demonstrating a comparable sensitivity of 96% and specificity of 95%. Conclusions: Differentiating Graves thyrotoxico-sis from destructive thyrotoxicosis is essential for proper selection of therapy. Assessment of thyroid blood flow by color-flow Doppler ultrasonography is useful in this dif-ferentiation. (Endocr Pract. 2009;15:6-9)

Abbreviations: T3 = triiodothyronine; T4 = thyroxine; TSH = thyrotropin

INTRODUCTION

Thyrotoxicosis with diffuse thyroid disease is caused by Graves disease or destructive thyrotoxicosis. Destructive thyrotoxicosis includes various subsets like silent thyroiditis, subacute thyroiditis, and postpartum thy-roiditis. Because antithyroid drugs are indicated in Graves disease and not in destructive thyrotoxicosis, distinguish-ing between these 2 conditions is essential. Diagnosis of typical cases of Graves disease with ophthalmopathy and skin and nail changes is not difficult, but it is difficult to differentiate between destructive thyrotoxicosis and early Graves disease. This differentiation is essentially done by nuclear imaging using technetium Tc99m pertechnetate or iodine123 radioisotopes and measuring thyrotropin (TSH) receptor antibody levels (1). However these methods are not widely available in India. Contraindication of nuclear imaging during pregnancy and lactation prohibits the use of this modality for differential diagnosis of gestational toxicosis and postpartum thyroiditis. Color-flow Doppler ultrasonography is a useful, inexpensive, and noninvasive method for measuring tis-sue vascularization and blood flow. The evaluation can be both qualitative (visual assessment of thyroid vascularity) and quantitative (peak systolic velocity in inferior thyroid artery). Color-flow Doppler ultrasonography of the thyroid

Role of Doppler in Thyrotoxicosis, Endocr Pract. 2009;15(No. 1) �

gland can provide valuable information about underlying thyroid functional status and is useful in the differential diagnosis of thyrotoxicosis (2-4). We studied patients with untreated thyrotoxicosis using color-flow Doppler ultraso-nography and analyzed its role in the differential diagnosis of destructive thyrotoxicosis and Graves disease.

PATIENTS AND METHODS

Patients The study population consisted of consecutive patients presenting to our center with thyrotoxicosis between June 2007 and March 2008. Patients with multinodular goiter, toxic nodule, and history of thyroid surgery or radioiodine therapy and radiation exposure to neck were excluded from the study. Demographic information including sex and age was collected. A detailed history was taken with special emphasis on palpitations, weight loss, ophthalmic com-plaints, and history of similar illness or family history of thyroid illness. Investigators assessed radial pulse, blood pressure, and pulse pressure and looked for ophthalmo-pathic problems, skin and nail changes related to hyperthy-roidism, goiter, and thyroid bruit. Thyroid function assess-ment by measurement of TSH, total triiodothyronine (T3), and total thyroxine (T4) was performed in all participants. The study was approved by an institutional ethical commit-tee, and all participants provided informed consent. Patients were subdivided into 2 groups for analysis: patients with destructive thyrotoxicosis and patients with Graves disease. Destructive thyrotoxicosis was diagnosed on the basis of the presence of insignificant symptoms (no weight loss, occasional palpitations, absent eye signs with or without goiter); T3 to T4 ratio less than 20; increased T3 and T4 concentrations and low TSH concentration last-ing for fewer than 3 months and/or later development of hypothyroidism; and/or low uptake on pertechnetate thy-roid scan. Graves disease was diagnosed on the basis of clinical parameters (marked weight loss, adrenergic symp-toms, goiter, skin and nail changes), eye signs (lid-lag, exophthalmos, and congestive ophthalmopathy), T3 to T4 ratio greater than 20, and increased uptake on pertechnetate thyroid scan.

Imaging Color-flow Doppler ultrasonography of the thyroid gland was done in all patients by the same radiologist using digital ultrasonography equipment (Envisor; Philips Medical Systems, Andover, Massachusetts) in connection with a 7.5-MHz linear transducer provided by the manu-facturer. Parameters such as size, gland vascularity, and peak systolic velocity of the inferior thyroid artery were assessed. Gland vascularity was categorized into 4 grades according to the following patterns: grade 1, absent intra-parenchymal vascularity or minimal spots; grade 2, pres-ence of parenchymal blood flow with patchy uneven dis-

tribution; grade 3, mild increase of color-flow Doppler signal with patchy distribution; and grade 4, markedly increased color-flow Doppler signal with diffuse homoge-neous distribution—the so-called “thyroid inferno” (5,6). Grades 1 and 2 were considered to represent low or nor-mal vascularity, and grades 3 and 4 were considered to represent increased vascularity of the gland. Peak systolic velocity of both the right and left inferior thyroid arteries was assessed; for the purposes of this study, mean inferior thyroid artery flow was considered. Inferior thyroid artery peak systolic velocity of more than 40 cm/s is considered significantly increased and is suggestive of Graves disease (7,8). Technetium Tc 99m pertechnetate scan was done in patients when the diagnosis was not clear on the basis of clinical findings.

Statistical Analysis Summary data are expressed as mean ± standard devi-ation, and comparison of means between groups was done by paired t test. Fisher exact test was used to compare the frequency distribution, and a P value less than .05 was con-sidered to be significant.

RESULTS A total of 65 consecutive patients participated in this study. Thirty-one patients had destructive thyrotoxicosis, and 34 patients had Graves disease. The demographic and biochemical characteristics of the patients are sum-marized in Table 1. TSH was undetectable in 12 of 31 patients (39%) with destructive thyrotoxicosis and in 26 of 34 patients (76%) with Graves disease. A T3 to T4 ratio greater than 20 was seen in 6 patients (19%) with destruc-tive thyrotoxicosis and in 25 patients (74%) with Graves disease. Patients with Graves disease had higher thyroid volume than patients with destructive thyrotoxicosis (28.3 ± 11.1 cc vs 13.6 ± 4.9 cc; P<.001). Intraparenchymal vascularity of thyroid gland was greater in patients with Graves disease than in patients with destructive thyroiditis (Fig. 1). Thyroid blood flow, as assessed by peak systolic velocity of the inferior thyroid artery, was significantly higher in patients with Graves disease than in patients with destructive thyroiditis (57.6 ± 13.1 cm/s vs 22.4 ± 5.4 cm/s; P<.05) (Fig. 2). Of the patients with Graves disease, all but 2 had inferior thyroid artery flow velocity greater than 40 cm/s. Diagnosis of Graves disease was established in these 2 patients by increased uptake on pertechnetate scan and a T3 to T4 ratio greater than 20. None of the patients in the destructive thyroiditis group had inferior thyroid artery flow faster than 40 cm/sec. Pertechnetate scan was per-formed in 9 patients (29%) with destructive thyrotoxicosis, and 8 of these 9 showed low uptake. The increased uptake in 1 patient was considered to be due to destructive thyro-toxicosis on the basis of insignificant clinical features, tran-sient thyrotoxicosis, and a T3 to T4 ratio less than 20. Of

� Role of Doppler in Thyrotoxicosis, Endocr Pract. 2009;15(No. 1)

the 34 patients with Graves disease, 14 (41%) underwent pertechnetate scan, and all showed increased uptake.

DISCUSSION Thyrotoxic features in destructive thyroiditis and early Graves disease may be mild, and differentiating between these 2 conditions is often difficult. Although patients with Graves disease show persistent hyperthyroidism with high levels of T3 and T4, as seen in our study participants, these findings may not be the same in persons with early Graves disease. TSH receptor antibody and nuclear uptake scan are definitive modalities to diagnose Graves disease. However, limited availability, expense, and contraindica-tion for radioisotope scan during pregnancy restrict their widespread application. In this study, we evaluated thyroid blood flow as a marker to differentiate types of thyrotoxi-cosis. The clinical characteristics established the diagno-sis in only 14 of 65 patients who presented with classic features of Graves disease including ophthalmopathy. Various biochemical parameters using thyroid hormone levels are proposed in the differentiation of thyrotoxicosis (9). Amino et al suggested a T3 to T4 ratio less than 20 as a marker of destructive thyrotoxicosis (10). In our study, 81% of patients with destructive thyrotoxicosis had a T3 to T4 ratio less than 20, but this was also true in 26% of patients with Graves disease. This indicates marked over-lap between the conditions when using the T3 to T4 ratio as a criterion, as also observed by others (11). The free T3 to free T4 ratio was also proposed to be useful for this dif-ferentiation, albeit there is overlap of values (12).

In our study, mean inferior thyroid artery flow in patients with Graves disease was significantly higher than in patients with destructive thyrotoxicosis. Bogazzi et al reported a similar observation; intraparenchymal peak sys-tolic velocity was increased in Graves disease but not in destructive thyrotoxicosis (5). Color-flow Doppler ultraso-nography in our study showed a sensitivity of 96% with specificity of 95%. In a study of 75 patients with thyrotoxi-cosis, Kurita et al demonstrated that color-flow Doppler ultrasonography had a sensitivity of 84% and specificity of 90% in the differential diagnosis of thyrotoxicosis (13). In our study, pertechnetate scan findings correlated signifi-cantly with color-flow Doppler ultrasonography parameters, giving comparable sensitivity and specificity. One patient was considered to have destructive thyrotoxicosis despite increased uptake on nuclear imaging because of transient thyrotoxicosis and minimal clinical features. Resolving thyroiditis can occasionally produce increased uptake on nuclear imaging similar to that observed in Graves disease, which may cause confusion (14). Other forms of thyroid blood flow assessment like thyroid blood flow area, vascu-larization index, and high-resolution power Doppler have been used by investigators to provide better differentiation (3,15). On the basis of various studies, color-flow Doppler ultrasonography of the thyroid gland is proposed as an ini-tial investigation of choice in the differential diagnosis of thyrotoxicosis and also in the differentiation of type 1 and type 2 amiodarone-induced thyrotoxicosis (16,17). The limitations of this study include the fact that nuclear imaging results were not available for all patients, and diagnosis of Graves disease lacked confirmation by

Table 1 Demographic and Biochemical Parameters in 65 Patients With Thyrotoxicosis

ParameterDestructive thyrotoxicosis

(n = 31)Graves disease

(n = 34) P valued

Sex, No. (%) .83 Male 4 (13) 10 (29) Female 27 (87) 24 (71)Age, mean (SD), y 29.1 (9.2) 37.1 (12.7) .012Total T3, mean (SD), ng/dLa 203.7 (81.8) 405.9 (218.8) <.001Total T4, mean (SD), µg/dLb 13.9 (2.8) 18.2 (5.2) <.001TSH, mean (SD), mIU/Lc 0.08 (0.1) 0.07 (0.1) .126T3 to T4 ratio >20, No. (%) 6 (19) 25 (74) .004T3 to T4 ratio <20, (No. %) 25 (81) 9 (26) .004

Abbreviations: T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.a Reference range, 45.5-155.8 ng/dL.b Reference range, 5.5-12.4 µg/dL.c Reference range, 0.34-4.3 mIU/L.d P values are for the paired t test and Fisher exact test.

Role of Doppler in Thyrotoxicosis, Endocr Pract. 2009;15(No. 1) 9

thyroid receptor antibody assessment. Thyroid ultrasonog-raphy examination is operator dependent. To address this, we assigned a single radiologist to perform ultrasonogra-phy on all patients.

CONCLUSION

We have demonstrated that inferior thyroid artery flow is a useful marker in the differential diagnosis of thyrotoxi-cosis. The high correlation between findings from radioiso-tope scan and inferior thyroid artery flow establishes this modality as an acceptable alternative. The role of assessing thyroid blood flow by color-flow Doppler ultrasonogra-phy in the setting of pregnancy or lactation, where nuclear imaging is contraindicated, must be emphasized. We rec-ommend measurement of thyroid blood flow as an essen-tial part of evaluation of thyrotoxicosis.

DISCLOSURE The authors have no conflicts of interest to disclose.

REFERENCES 1. Amino N, Yabu Y, Miyai K, et al. Differentiation of thy-

rotoxicosis induced by thyroid destruction from Graves’ disease. Lancet. 1978;2:344-346.

2. Vitti P, Rago T, Mazzeo S, et al. Thyroid blood flow evaluation by color-flow Doppler sonography distinguishes Graves’ disease from Hashimoto’s thyroiditis. J Endocrinol Invest. 1995;18:857-861.

3. Ota H, Amino N, Morita S, et al. Quantitative measure-ment of thyroid blood flow for differentiation of painless thyroiditis from Graves’ disease. Clin Endocrinol (Oxf). 2007;67:41-45.

4. Erdoğan MF, Anil C, Cesur M, Başkal N, Erdoğan G. Color flow Doppler sonography for the etiologic diagnosis of hyperthyroidism. Thyroid. 2007;17:223-228.

5. Bogazzi F, Bartalena L, Brogioni S, et al. Thyroid vas-cularity and blood flow are not dependent on serum thy-roid hormone levels: studies in vivo by color flow doppler sonography. Eur J Endocrinol. 1999;140:452-456.

6. Ralls PW, Mayekawa DS, Lee KP, et al. Color-flow Doppler sonography in Graves disease: “thyroid inferno.” AJR Am J Roentgenol. 1988;150:781-784.

7. Macedo TA, Chammas MC, Jorge PT, et al. Reference values for Doppler ultrasound parameters of the thyroid in a healthy iodine-non-deficient population. Br J Radiol. 2007;80:625-630.

8. Sponza M, Fabris B, Bertolotto M, Ricci C, Armini L. Role of Doppler color ultrasonography and of flowmetric analysis in the diagnosis and follow-up of Grave’s disease [article in Italian]. Radiol Med. 1997;93:405-409.

9. Yanagisawa T, Sato K, Kato Y, Shimizu S, Takano K. Rapid differential diagnosis of Graves’ disease and painless thyroiditis using total T3/T4 ratio, TSH, and total alkaline phosphatase activity. Endocr J. 2005;52:29-36.

10. Amino N, Yabu Y, Miki T, et al. Serum ratio of triiodothy-ronine to thyroxine and thyroxine-binding globulin and cal-citonin concentrations in Graves’ disease and destruction-induced thyrotoxicosis. J Clin Endocrinol Metab. 1981;53: 113-116.

11. Izumi Y, Hidaka Y, Tada H, et al. Simple and practical parameters for differentiation between destruction-induced thyrotoxicosis and Graves’ thyrotoxicosis. Clin Endocrinol (Oxf). 2002;57:51-58.

12. Yoshimura Noh J, Momotani N, Fukada S, Ito K, Miyauchi A, Amino N. Ratio of serum free triiodothy-ronine to free thyroxine in Graves’ hyperthyroidism and thyrotoxicosis caused by painless thyroiditis. Endocr J. 2005;52:537-542.

13. Kurita S, Sakurai M, Kita Y, et al. Measurement of thy-roid blood flow area is useful for diagnosing the cause of thyrotoxicosis. Thyroid. 2005;11:1249-1252.

14. Smith JR, Oates E. Radionuclide imaging of the thy-roid gland: patterns, pearls and pitfalls. Clin Nucl Med. 2004;29:181-193.

15. Arslan H, Unal O, Algün E, Harman M, Sakarya ME. Power Doppler sonography in the diagnosis of Graves’ dis-ease. Eur J Ultrasound. 2000;11:117-122.

16. Bogazzi F, Vitti P. Could improved ultrasound and power Doppler replace thyroidal radioiodine uptake to assess thyroid disease? Nat Clin Pract Endocrinol Metab. 2008;4:70-71.

17. Loy M, Perra E, Melis A, et al. Color-flow Doppler sonography in the differential diagnosis and manage-ment of amiodarone-induced thyrotoxicosis. Acta Radiol. 2007;48:628-634.

Fig. 1. Intraparenchymal vascularity of the thyroid gland in 31 patients with destructive thyrotoxicosis and in 34 patients with Graves disease.

Fig. 2. Mean peak systolic velocity of the inferior thyroid artery (ITA) in 31 patients with destructive thyrotoxicosis and in 34 patients with Graves disease. Each dot represents a patient. The horizontal lines represent the means.