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Significance of thyroid blood flow as a predictor of methimazole sensitivity in untreated hyperthyroid patients with Graves' disease
Biomedicine & Pharmacotherapy 61 (2007) 472e476 www.elsevier.com/locate/biopha
Dossier : Thyroid functions and diseases
Significance of thyroid blood flow as a predictor of methimazole sensitivity in untreated hyperthyroid patients with Graves’ disease Toshiki Nagasaki, Masaaki Inaba*, Yasuro Kumeda, Misako Fujiwara-Ueda, Yoshikazu Hiura, Yoshiki Nishizawa Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan Received 20 January 2007; accepted 6 February 2007 Available online 7 March 2007
Abstract Objective: The peak systolic velocity (PSV) of the inferior thyroid artery (ITA) is increased in untreated hyperthyroid patients with Graves’ disease (GD). We investigated the clinical significance of the ITA-PSV and its determinants in hyperthyroid GD patients. Patients and methods: ITA-PSV, together with thyroid volume, was measured by ultrasonography in untreated hyperthyroid GD patients (n ¼ 49) and healthy subjects (n ¼ 22). Established markers of GD activity such as TSH receptor antibody (TRAb), thyroid stimulating antibody (TSAb), vascular endothelial growth factor (VEGF) and immunoglobulin E (IgE) were simultaneously determined. Results: ITA-PSV, thyroid volume, VEGF and IgE were significantly higher in hyperthyroid GD patients than in normal subjects. ITA-PSV in hyperthyroid GD patients was correlated positively with serum levels of FT3, FT4 and IgE, smoking index and thyroid volume, and negatively with total, HDL- and LDL-cholesterols, but did not correlate significantly with age, triglyceride, TRAb, TSAb or VEGF. In stepwise regression analysis, ITA-PSV showed significant positive and negative associations with IgE and LDL-cholesterol, respectively, in hyperthyroid GD patients. In the pre-treatment hyperthyroid state, FT4 and ITA-PSV, but not IgE, were found to be significantly and positively associated with the maintenance dose of methimazole (MMI) required to keep serum TSH within normal range for at least 12 months. Conclusion: These results suggest that ITA-PSV in untreated hyperthyroid GD patients may reflect GD activity and thus MMI sensitivity. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Inferior thyroid artery; Color Doppler measurement; Hyperthyroidism; Graves’ disease; Immunoglobulin E; Methimazole
1. Introduction The recent sophistication of ultrasonographic instrumentation has made it possible to measure blood flow at the inferior thyroid artery (ITA), a major feeding artery of the thyroid gland, to differentiate Graves’ disease (GD) from other thyroid diseases [1,2]. Thyroid blood flow is measured in pulsed Doppler mode as the peak systolic velocity (PSV) at the ITA, and the ITA-PSV in hyperthyroid patients with GD is
* Corresponding author. Tel.: þ81 6 6645 3806; fax: þ81 6 6645 3808. E-mail address: [email protected] (M. Inaba). 0753-3322/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biopha.2007.02.002
higher than that of hypothyroid or euthyroid patients with other types of autoimmune thyroiditis [1]. However, the factors associated with increased ITA-PSV in hyperthyroid GD patients are yet to be determined. We recently reported that ITA-PSV in euthyroid GD patients provides a more precise marker for prediction of early relapse of GD after withdrawal of anti-thyroid drug (ATD), compared to established parameters, such as serum levels of TSH receptor antibody (TRAb) and vascular endothelial growth factor (VEGF) [2]. These studies were performed in euthyroid GD patients whose thyroid function had been controlled within normal range by ATD therapy, and thus whose ITA-PSV had not been measured in the untreated hyperthyroid state.
T. Nagasaki et al. / Biomedicine & Pharmacotherapy 61 (2007) 472e476
This background prompted us to examine: (i) whether ITAPSV is higher in untreated hyperthyroid GD patients; (ii) whether factors that are associated with GD activity, such as smoking index, TSH receptor autoantibody, VEGF, thyroid volume, and immunoglobulin E (IgE) [3e5], might be associated with an increase of ITA-PSV in hyperthyroid GD patients; and (iii) whether ITA-PSV measurement in the pre-treatment phase of GD patients can predict the maintenance dose of methimazole (MMI) to keep thyroid function normal for at least 12 months, as well as differentiating GD patients from those with other thyroid diseases.
2. Patients and methods 2.1. Patients Forty-seven consecutive hyperthyroid GD patients (6 males, 41 females), aged 13 to 70 years (mean SE: 35.2 3.7 years old), were studied over a period of 26 months from September 2001 to October 2003 (all were followed for more than 12 months). Normal controls consisted of 22 healthy subjects (4 males, 18 females), aged 19 to 75 years (mean SE: 40.8 3.9 years old), who were examined for their ITA-PSV over the same period. Potential subjects with allergic diseases such as bronchial asthma, allergic rhinitis, allergic pharyngitis, and atopic dermatitis were excluded from the present study. Thyroid blood flow at the ITA was measured in all subjects. Diagnosis of hyperthyroid GD was established based on symptoms and signs of hyperthyroidism, diffuse goiter, elevated FT3 and FT4 with TSH concentration suppressed below normal lower limit in serum, and increased thyroid uptake of iodine-123 before initiation of MMI treatment. Informed consent was obtained from all subjects, and the study was approved by the ethical committee of Osaka City University Hospital.
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2.3. Biochemical parameters for thyroid function, autoantibodies, VEGF and ICAM-1 Blood samples were drawn just before ultrasonographic measurement after an overnight fast. The blood was kept on ice for 1 h and then centrifuged at 1000 g for 10 min to obtain serum samples, which were stored in aliquots at 20 C until assayed. Immediately after thawing, FT4, FT3, and TSH were measured using commercially available kits (Ortho-Clinical Diagnostics, Amersham, UK) [6], TRAb was measured by radioreceptor assay using a commercial kit (Cosmic Corporation, Tokyo, Japan) [7], thyroid stimulating antibody (TSAb) was measured using a radioimmunoassay kit (Yamasa, Chiba, Japan) [8], and serum IgE and VEGF were assayed with a FEIA kit (Pharmacia Diagnostics AB, Uppsala, Sweden) [9] and an EIA kit (R&D System, Minneapolis, USA) [10,11], respectively. 2.4. Ultrasonographic measurements of thyroid volume and blood flow at the inferior thyroid artery Thyroid blood flow was measured at the ITA, as previously described [1,2]. Ultrasonographic examinations were performed using a duplex Doppler apparatus (Aloka SSD 2000, Aloka, Tokyo, Japan) with a 5-MHz convex array probe operating in both color Doppler and pulsed Doppler modes [2]. The angle-correction cursor was positioned parallel to the direction of flow. The PSV of the right ITA was automatically calculated by the ultrasound apparatus and used as an index of thyroid blood flow. All measurements were performed by the same examiner (M.F-U.), who was blinded to the characteristics of the subjects. Measurements were made at the ITA because this artery contributes strongly to the thyroid blood flow, and measurement at this position is straightforward and has a coefficient of variation (CV) of less than 5.0%. Thyroid volume was also determined by ultrasonography, based on a calculation using an ellipsoid model (width length thickness 0.7 for each lobe) [12].
2.2. Protocol for GD treatment with MMI
2.5. Statistical analysis
GD patients in an untreated hyperthyroid state were administered MMI at an initial daily dose of 30 mg and serum levels of FT4, FT3 and TSH were checked every 4 weeks during the observation period. When serum FT3 decreased to below the normal lower limit or serum TSH increased to above the normal upper limit, the dose of MMI was decreased serially to 20 mg/day, 15 mg/day, 10 mg/day and then finally to 5 mg/ day. The dose of MMI required to keep euthyroidism (maintenance of serum levels of FT4, FT3 and TSH within the respective normal range) for at least 12 months was defined as the maintenance dose. Recurrence, defined as an elevation of serum FT3 or FT4 above normal upper limit, or the suppression of serum TSH below normal lower limit after restoration of euthyroidism, was not seen during the observation period. None of the patients was obliged to quit MMI administration due to its side effect in this study.
Data are expressed as means SE unless otherwise indicated. Statistical analysis was performed with the Stat View V system (Abacus Concepts, Berkeley CA) for the Apple computer. Differences in basal values between untreated hyperthyroid patients with GD and normal controls were examined using a ManneWhitney U-test for assessment of medians. Differences in ITA-PSV values in the pre-treatment hyperthyroid phase among those who required different MMI maintenance dose were examined using a ManneWhitney U-test for assessment of medians. The Spearman rank correlation was used to examine correlation between parameters. Stepwise multiple regression analysis with forward elimination was performed to assess the independent influence of a variable on ITA-PSV or the maintenance dose of MMI, with the F value was set at 4.0 at each step. P values of less than 0.05 were considered to be statistically significant.
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Table 2 Correlation between ITA-PSV and other parameters in hyperthyroid GD patients and control subjects
3. Results 3.1. ITA-PSV and clinical variables in untreated hyperthyroid GD patients and normal subjects
Hyperthyroid patients with GD
The clinical characteristics of the hyperthyroid patients and normal controls are shown in Table 1. All hyperthyroid GD patients showed increased serum FT4 and FT3 levels above the normal upper limit, with suppression of serum TSH to undetectable levels. There were no significant differences between the two groups in age, gender ratio, smoking index (daily number of cigarettes multiplied by the number of years of smoking), and serum levels of HDL-cholesterol or triglyceride. ITA-PSV, thyroid volume and serum markers of GD activity such as VEGF, IgE, TRAb and TSAb were all significantly higher in hyperthyroid GD patients than in normal controls, and serum levels of total and LDL-cholesterol were significantly lower in hyperthyroid GD patients. ITA-PSV in normal controls ranged from 8.8 to 39.0 cm/s. 3.2. Correlation between ITA-PSV and other parameters in untreated hyperthyroid GD patients ITA-PSV in hyperthyroid GD patients was significantly correlated in a positive manner with smoking index, serum levels of FT4, FT3 and IgE, and thyroid volume, and in a negative manner with total, LDL- and HDL-cholesterols (Table 2). There was no significant correlation of ITA-PSV in hyperthyroid GD patients with age, or serum levels of triglyceride, TRAb, TSAb and VEGF. In normal controls, ITA-PSV did not show a significant correlation with any of the variables listed in Table 2. Table 1 Baseline characteristics of hyperthyroid GD patients and control subjects Hyperthyroid GD patients
Normal controls
Number of subjects 47 22 Gender (female/male) 41/6 19/3 Age (years) 35.2 3.7 40.8 3.9 Smoking index 142.9 34.4 128.7 28.9 T. Chol (mmol/l) 3.32 0.16 5.32 0.27 Triglyceride (mmol/l) 0.92 0.11 1.34 0.25 LDL-C (mmol/l) 1.56 0.13 2.93 0.40 HDL-C (mmol/l) 1.22 0.07 1.71 0.20 FT4 (pmol/l) [9.01e24.45] 88.4 11.5 15.9 0.50 FT3 (pmol/l) [4.00e7.70] 22.49 1.64 5.06 0.12 TSH (mIU/l) [0.4e4.7] <0.1 1.7 0.31 TRAb (%) [<15] 47.6 5.8 3.40 1.81 TSAb (%) [<179] 712.7 119.8 10.8 3.62 ITA-PSV (cm/s) 84.0 12.9 20.0 2.0 IgE (IU/ml) [<173] 641.6 277.0 132 45.4 VEGF (pg/ml) [<115] 27.2 4.56 13.2 2.36 Thyroid volume (mm3) 32,949.0 3732.0 1224.1 1022.6
P
ns ns ns <0.0001 ns 0.0013 ns <0.0001 <0.0001 <0.0001 0.0073 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
Data are expressed as means SE. Differences between the two groups were examined using a ManneWhitney U-test for assessment of medians. The difference in the male/female ratio between the two groups was analyzed by chisquare test. GD, Graves’ disease; ns, not significant; T. Chol, total cholesterol; LDL-C, LDL-cholesterol; HDL-C, HDL-cholesterol; ITA-PSV, peak systolic velocity at the inferior thyroid artery; IgE, immunoglobulin E; VEGF, vascular endothelial growth factor.
Age Smoking Index T. Chol Triglyceride LDL-C HDL-C FT4 FT3 TRAb TSAb IgE VEGF Thyroid volume Total MMI dose maintenance MMI dose Duration of therapy
Normal controls
Rho
P
Rho
P
0.178 0.533 0.488 0.034 0.479 0.443 0.563 0.641 0.259 0.123 0.507 0.078 0.334 0.030 0.520 0.217
ns 0.0017 0.0012 ns 0.0067 0.012 0.0001 <0.0001 ns ns 0.0098 ns 0.027 ns 0.0033 ns
0.488 0.313 0.273 0.139 0.190 0.048 0.004 0.033 0.500 0.306 0.012 0.024 0.134
ns ns ns ns ns ns ns ns ns ns ns ns ns
Data are expressed as means SE. Spearman correlation coefficients were used. ITA-PSV, peak systolic velocity of the inferior thyroid artery; GD, Graves’ disease; ns, not significant; T. Chol, total cholesterol; LDL-C, LDLcholesterol; HDL-C, HDL-cholesterol; TRAb, TSH receptor antibody; TSAb, thyroid stimulating antibody; IgE, immunoglobulin E; VEGF, vascular endothelial growth factor; MMI, methimazole.
3.3. Factors affecting ITA-PSV in untreated hyperthyroid GD patients The result of stepwise multiple regression analysis of the association of various clinical variables with ITA-PSV in untreated hyperthyroid GD patients is shown in Table 3. Parameters analyzed included smoking index, thyroid volume, and serum levels of FT4, FT3, IgE, and total, HDL- and LDL-cholesterols, which showed significant correlations with ITA-PSV (Table 2). Among these parameters, IgE and LDL-cholesterol emerged as significant factors associated with ITA-PSV in positive and negative manners, respectively. 3.4. Relationship between ITA-PSV in the pre-treatment phase and MMI therapy The total and maintenance doses of MMI and the duration of therapy until restoration of euthyroidism are 2578.5 390.5 (mean SE) mg/patient, 6.70 0.45 mg/day, and 13.6 1.43 months, respectively. ITA-PSV in the pre-treatment phase was significantly and positively correlated with the maintenance Table 3 Stepwise multiple regression analysis of the association of ITA-PSV with other parameters in hyperthyroid GD patients Dependent variables
Independent variables
b
F value
ITA-PSV
Immunoglobulin E LDL-cholesterol
0.499 0.406
8.884 5.860
Immunoglobulin E, LDL-cholesterol, smoking Index, total cholesterol, HDLcholesterol, FT4, FT3, and thyroid volume were included as parameters in the analysis. b, standard regression coefficient. R2 ¼ 0.624 ( p < 0.0005).
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dose of MMI, but not total dose or duration for MMI to restore normal thyroid function (Table 2).
Table 4 Stepwise multiple regression analysis of the association of the maintenance dose of MMI with other parameters in hyperthyroid GD patients
3.5. Comparison of individual values of ITA-PSV in the pre-treatment phase with the maintenance dose of MMI in untreated hyperthyroid GD patients
Dependent variables
Independent variables
b
F value
Maintenance dose of MMI
FT4 ITA-PSV
0.453 0.373
6.045 4.101
Fig. 1 shows the individual values of ITA-PSV in the pretreatment phase in comparison with the maintenance dose of MMI in untreated hyperthyroid GD patients. Of the 47 GD patients, 34 (72.3%) patients required 5 mg/day MMI, while 10 (21.3%) and 3 (6.4%) patients required 10 and 15 mg/day MMI, respectively. The mean ITA-PSV value of patients whose maintenance dose of MMI 10 mg/day or greater was significantly higher than that of patients who required MMI at 5 mg/day. Similarly, the mean ITA-PSV of patients who required 10 mg/day MMI was also significantly higher than that of patients who required 5 mg/day MMI. No difference was found between the mean ITA-PSVs of patients requiring 10 mg/day MMI and 15 mg/day MMI. The maintenance dose of MMI was significantly and positively correlated with thyroid volume, ITA-PSV, and serum levels of FT4, FT3, TRAb and IgE (data not shown), but not with age, VEGF or TSAb. 3.6. Factors affecting the maintenance dose of MMI in untreated hyperthyroid GD patients Table 4 shows the results of stepwise multiple regression analysis of the association of various clinical variables with p=0.0003
ns
350
p=0014
ITA-PSV (cm/s)
300 250 200 150 100 50 0 5
10
15
Maintenance dose of MMI (mg/day) Fig. 1. Individual values of ITA-PSV in the pre-treatment phase plotted against maintenance dose of MMI after restoration of euthyroidism. Data are expressed as means SE. The mean ITA-PSV of patients who required more than 10 mg MMI (closed cycle) was significantly higher than that of patients who required 5 mg MMI [132.79 18.72 vs. 65.11 5.18 (mean SE) cm/s; p ¼ 0.0003]. The mean ITA-PSV of patients who required 10 mg MMI (132.08 23.12 cm/s) was also significantly higher than that of patients who required 5 mg MMI ( p ¼ 0.014). No difference was found between the mean ITA-PSV of patients who required 10 mg MMI and that of patients who required 15 mg MMI (135.1 33.0 cm/s).
FT4, FT3, ITA-PSV, immunoglobulin E, and thyroid volume were included as parameters in the analysis. b, standard regression coefficient. R2 ¼ 0.585 ( p ¼ 0.0053).
the maintenance dose of MMI in untreated hyperthyroid GD patients. Parameters analyzed included thyroid volume, ITAPSV, and serum levels of FT4, TRAb and IgE, all of which showed a significant correlation with the maintenance dose of MMI. Among these parameters, FT4 and ITA-PSV emerged as significant factors that were positively associated with the maintenance dose of MMI, whereas thyroid volume and serum levels of FT3, TRAb and IgE did not show a significant association with the maintenance dose of MMI.
4. Discussion ITA-PSV showed a positive correlation with smoking index, FT4, FT3, IgE and thyroid volume, and a negative correlation with total, HDL- and LDL-cholesterols in untreated hyperthyroid GD patients (Table 2). Among these variables, IgE and LDL-cholesterol were found to be significant factors that were independently associated with increased ITA-PSV in these patients in positive and negative manners, respectively, while smoking index, thyroid volume, serum levels of FT4, FT3, and total and HDL-cholesterol failed to show such an association (Table 3). Of great interest, ITA-PSV, together with FT4, in the pre-treatment phase was independently and positively associated with the dose of MMI required to maintain euthyroidism for at least 12 months in GD patients (Table 4). This result may suggest that an increase in ITA-PSV in the pre-treatment hyperthyroid phase partly reflects GD severity, and thus greater maintenance dose MMI to restore euthyroidism. Elevation of IgE in the untreated hyperthyroid GD state is reported to be associated with the severity of GD [3,4]. A recent study of a Japanese population of GD patients showed that a significant increase in serum IgE correlates with the recurrence rate of hyperthyroidism after withdrawal of ATD treatment [5]. Therefore, it is of interest that ITA-PSV in the hyperthyroid GD state associated with IgE, the representative marker of a type I allergic reaction, but not with either serum levels of thyroid hormones or anti-thyroid autoimmune antibodies. Since ITA-PSV did not associate with established parameters for GD severity, such as thyroid volume in the untreated hyperthyroid state, early measurement of ITA-PSV might offer a new approach for prediction of GD severity before initiation of MMI treatment. We recently reported that ITA-PSV in the euthyroid state is a more sensitive marker for prediction of GD relapse after ATD withdrawal, compared to serum parameters such as TSH receptor autoantibody and VEGF [2]. Considering these
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data and previous reports of the validity of serum IgE in prediction of GD remission after ATD withdrawal [5], ITA-PSV and serum IgE may be the sensitive parameters for estimation of GD activity independently of thyroid function. Serum IgE was also found to be independently associated with ITAPSV, suggesting that ITA-PSV might also reflect GD activity, even in the pre-treatment hyperthyroid phase. Stepwise multiple regression analysis showed that ITA-PSV, contrary to IgE, in the pre-treatment phase is an independent factor positively associated with the maintenance dose of MMI, suggesting that high ITA-PSV in the pre-treatment phase may indicate a reduced MMI sensitivity. Since FT4 was also found to be an independent factor associated with the maintenance dose of MMI, patients who show higher levels of serum FT4 and ITA-PSV may require a higher dose of MMI to maintain euthyroidism. Interestingly, serum IgE failed to emerge as an independent factor associated with the maintenance MMI dose, suggesting that it might not be a good marker for MMI sensitivity. The exact reason for the significant and negative association of LDL-cholesterol with ITA-PSV is unclear; however, metabolism of LDL-cholesterol is more heavily affected by hyperthyroidism than that of HDL-cholesterol [13]. Alternatively, thyroid blood flow may reflect metabolism and degradation of LDL-cholesterol more directly than that of serum thyroid hormones. The lack of significant association of smoking index and thyroid volume with ITA-PSV suggests that smoking habit and an increase in thyroid volume might not be responsible for the increase of ITA-PSV in hyperthyroid GD patients, although smoking index is known as a traditional a risk factor of GD and a predictor of Graves’ hyperthyroidism [14]. Similarly, TRAb, TSAb and VEGF are known as markers of thyroid activity [15,16], and serum VEGF, which increases in GD patients [16], is thought to increase intrathyroidal vascularity in Graves’ thyroid by stimulating proliferation of endothelial cells; however, the lack of correlation of ITA-PSV with these factors suggests that the autoimmune antibody titer and intrathyroidal vascularity may have no direct effects on ITA-PSV. We have previously shown that ITA-PSV is positively correlated with TRAb and VEGF and negatively correlated with FT4 in euthyroid GD patients by antithyroid therapy [2], suggesting that regulation of blood flow at ITA in euthyroid GD patients may differ from that in the hyperthyroid state. The reason for this difference is unclear, but ATD might act directly on the thyroid gland to decrease thyroid blood flow, in addition to its inhibitory effect on thyroid hormone synthesis; this possibility is supported by the lack of correlation in euthyroid GD patients between ITA-PSV and smoking index, which is a traditional indicator of GD activity [2]. None of the factors that correlated with ITA-PSV in hyperthyroid GD patients showed a significant correlation with ITAPSV in normal subjects (Table 2). This finding suggests that increased thyroid blood flow may be an important characteristic of GD patients. Overall, ITA-PSV may be a relevant parameter for prediction of GD autoimmune activity, as reflected by its significant association with serum IgE in the pre-treatment phase of GD patients. Furthermore, ITA-PSV is a positive and
independent factor associated with the maintenance dose of MMI, suggesting that high ITA-PSV in the pre-treatment phase may indicate a reduced MMI sensitivity.
References [1] Bogazzi F, Bartalena L, Brogioni S, Burelli A, Manetti L, Tanda ML, et al. Thyroid vascularity and blood flow are not dependent on serum thyroid hormone levels: studies in vivo by color flow Doppler sonography. European Journal of Endocrinology 1999;140:452. [2] Ueda M, Inaba M, Kumeda Y, Nagasaki T, Hiura Y, Tahara H, et al. The significance of thyroid blood flow at the inferior thyroid artery as a predictor for early Graves’ diseases relapse. Clinical Endocrinology 2005; 63:657. [3] Sato A, Takemura Y, Yamada T, Ohtsuka H, Sakai H, Miyahara Y, et al. A possible role of immunoglobulin E in patients with hyperthyroid Graves’ disease. The Journal of Clinical Endocrinology and Metabolism 1999;84:3602. [4] Yamada T, Sato A, Komiya I, Nishimori T, Ito Y, Terao A, et al. An elevation of serum immunoglobulin E provides a new aspect of hyperthyroid Graves’ disease. The Journal of Clinical Endocrinology and Metabolism 2000;85:2775. [5] Komiya I, Yamada T, Sato A, Kouki T, Nishimori T, Takasu N. Remission and recurrence of hyperthyroid Graves’ disease during and after methimazole treatment when assessed by IgE and interleukin 13. The Journal of Clinical Endocrinology and Metabolism 2001;86:3540. [6] Christofides ND, Sheehan CP. Enhanced chemiluminescence labeledantibody immunoassay (Amerlite-MAB) for free thyroxine: design, development, and technical validation. Clinical Chemistry 1995;41:17. [7] Smith BR, Hall R. Thyroid-stimulating immunoglobulins in Graves’ disease. Lancet 1974;2:427. [8] Yoshikawa N, Nishikawa M, Horimoto M, Uno C, Taniguchi N, Inada M. Activity of thyroid stimulating antibody and thyroid stimulation blocking antibody determined by radioiodine uptake into FRTL-5 cells. Endocrinologia Japonica 1989;36:55. [9] Paganelli R, Ansotegui IJ, Sastre J, Lange CE, Roovers MH, de Groot H, et al. Specific IgE antibodies in the diagnosis of atopic disease. Clinical evaluation of a new in vitro test system, UniCAP, in six European allergy clinics. Allergy 1998;53:763. [10] Cooper BC, Ritchie JM, Broghammer CL, Coffin J, Sorosky JI, Buller RE, et al. Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clinical Cancer Research 2002;8:3193. [11] Lacy MJ, Wang R, Brookshire V, Floyd K. Adaptation of commercial immunoassays to analysis of complex biological substances. Journal of Immunoassay and Immunochemistry 2002;23:1. [12] Murakami Y, Takamatsu J, Sakane S, Kuma K, Ohsawa N. Changes in thyroid volume in response to radioactive iodine for Graves’ hyperthyroidism correlated with activity of thyroid-stimulating antibody and treatment outcome. The Journal of Clinical Endocrinology and Metabolism 1996;81:3257. [13] Kung AW, Pang RW, Lauder I, Lam KS, Janus ED. Changes in serum lipoprotein (a) and lipids during treatment of hyperthyroidism. Clinical Chemistry 1995;41:226. [14] Holm IA, Manson JE, Michels KB, Alexander EK, Willett WC, Utiger RD. Smoking and other lifestyle factors and the risk of Graves’ hyperthyroidism. Archives of internal medicine 2005;165:1606. [15] Massart C, Orgiazzi J, Maugendre D. Clinical validity of a new commercial method for detection of TSH-receptor binding antibodies in sera from patients with Graves’ disease treated with antithyroid drugs. Clinica Chimica Acta 2001;304:39. [16] Iitaka M, Miura S, Yamanaka K, Kawasaki S, Kitahama S, Kawakami Y, et al. Increased serum vascular endothelial growth factor levels and intrathyroidal vascular area in patients with Graves’ disease and Hashimoto’s thyroiditis. The Journal of Clinical Endocrinology and Metabolism 1998;83:3908.
Dossier : Thyroid functions and diseases
Significance of thyroid blood flow as a predictor of methimazole sensitivity in untreated hyperthyroid patients with Graves’ disease Toshiki Nagasaki, Masaaki Inaba*, Yasuro Kumeda, Misako Fujiwara-Ueda, Yoshikazu Hiura, Yoshiki Nishizawa Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan Received 20 January 2007; accepted 6 February 2007 Available online 7 March 2007
Abstract Objective: The peak systolic velocity (PSV) of the inferior thyroid artery (ITA) is increased in untreated hyperthyroid patients with Graves’ disease (GD). We investigated the clinical significance of the ITA-PSV and its determinants in hyperthyroid GD patients. Patients and methods: ITA-PSV, together with thyroid volume, was measured by ultrasonography in untreated hyperthyroid GD patients (n ¼ 49) and healthy subjects (n ¼ 22). Established markers of GD activity such as TSH receptor antibody (TRAb), thyroid stimulating antibody (TSAb), vascular endothelial growth factor (VEGF) and immunoglobulin E (IgE) were simultaneously determined. Results: ITA-PSV, thyroid volume, VEGF and IgE were significantly higher in hyperthyroid GD patients than in normal subjects. ITA-PSV in hyperthyroid GD patients was correlated positively with serum levels of FT3, FT4 and IgE, smoking index and thyroid volume, and negatively with total, HDL- and LDL-cholesterols, but did not correlate significantly with age, triglyceride, TRAb, TSAb or VEGF. In stepwise regression analysis, ITA-PSV showed significant positive and negative associations with IgE and LDL-cholesterol, respectively, in hyperthyroid GD patients. In the pre-treatment hyperthyroid state, FT4 and ITA-PSV, but not IgE, were found to be significantly and positively associated with the maintenance dose of methimazole (MMI) required to keep serum TSH within normal range for at least 12 months. Conclusion: These results suggest that ITA-PSV in untreated hyperthyroid GD patients may reflect GD activity and thus MMI sensitivity. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Inferior thyroid artery; Color Doppler measurement; Hyperthyroidism; Graves’ disease; Immunoglobulin E; Methimazole
1. Introduction The recent sophistication of ultrasonographic instrumentation has made it possible to measure blood flow at the inferior thyroid artery (ITA), a major feeding artery of the thyroid gland, to differentiate Graves’ disease (GD) from other thyroid diseases [1,2]. Thyroid blood flow is measured in pulsed Doppler mode as the peak systolic velocity (PSV) at the ITA, and the ITA-PSV in hyperthyroid patients with GD is
* Corresponding author. Tel.: þ81 6 6645 3806; fax: þ81 6 6645 3808. E-mail address: [email protected] (M. Inaba). 0753-3322/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biopha.2007.02.002
higher than that of hypothyroid or euthyroid patients with other types of autoimmune thyroiditis [1]. However, the factors associated with increased ITA-PSV in hyperthyroid GD patients are yet to be determined. We recently reported that ITA-PSV in euthyroid GD patients provides a more precise marker for prediction of early relapse of GD after withdrawal of anti-thyroid drug (ATD), compared to established parameters, such as serum levels of TSH receptor antibody (TRAb) and vascular endothelial growth factor (VEGF) [2]. These studies were performed in euthyroid GD patients whose thyroid function had been controlled within normal range by ATD therapy, and thus whose ITA-PSV had not been measured in the untreated hyperthyroid state.
T. Nagasaki et al. / Biomedicine & Pharmacotherapy 61 (2007) 472e476
This background prompted us to examine: (i) whether ITAPSV is higher in untreated hyperthyroid GD patients; (ii) whether factors that are associated with GD activity, such as smoking index, TSH receptor autoantibody, VEGF, thyroid volume, and immunoglobulin E (IgE) [3e5], might be associated with an increase of ITA-PSV in hyperthyroid GD patients; and (iii) whether ITA-PSV measurement in the pre-treatment phase of GD patients can predict the maintenance dose of methimazole (MMI) to keep thyroid function normal for at least 12 months, as well as differentiating GD patients from those with other thyroid diseases.
2. Patients and methods 2.1. Patients Forty-seven consecutive hyperthyroid GD patients (6 males, 41 females), aged 13 to 70 years (mean SE: 35.2 3.7 years old), were studied over a period of 26 months from September 2001 to October 2003 (all were followed for more than 12 months). Normal controls consisted of 22 healthy subjects (4 males, 18 females), aged 19 to 75 years (mean SE: 40.8 3.9 years old), who were examined for their ITA-PSV over the same period. Potential subjects with allergic diseases such as bronchial asthma, allergic rhinitis, allergic pharyngitis, and atopic dermatitis were excluded from the present study. Thyroid blood flow at the ITA was measured in all subjects. Diagnosis of hyperthyroid GD was established based on symptoms and signs of hyperthyroidism, diffuse goiter, elevated FT3 and FT4 with TSH concentration suppressed below normal lower limit in serum, and increased thyroid uptake of iodine-123 before initiation of MMI treatment. Informed consent was obtained from all subjects, and the study was approved by the ethical committee of Osaka City University Hospital.
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2.3. Biochemical parameters for thyroid function, autoantibodies, VEGF and ICAM-1 Blood samples were drawn just before ultrasonographic measurement after an overnight fast. The blood was kept on ice for 1 h and then centrifuged at 1000 g for 10 min to obtain serum samples, which were stored in aliquots at 20 C until assayed. Immediately after thawing, FT4, FT3, and TSH were measured using commercially available kits (Ortho-Clinical Diagnostics, Amersham, UK) [6], TRAb was measured by radioreceptor assay using a commercial kit (Cosmic Corporation, Tokyo, Japan) [7], thyroid stimulating antibody (TSAb) was measured using a radioimmunoassay kit (Yamasa, Chiba, Japan) [8], and serum IgE and VEGF were assayed with a FEIA kit (Pharmacia Diagnostics AB, Uppsala, Sweden) [9] and an EIA kit (R&D System, Minneapolis, USA) [10,11], respectively. 2.4. Ultrasonographic measurements of thyroid volume and blood flow at the inferior thyroid artery Thyroid blood flow was measured at the ITA, as previously described [1,2]. Ultrasonographic examinations were performed using a duplex Doppler apparatus (Aloka SSD 2000, Aloka, Tokyo, Japan) with a 5-MHz convex array probe operating in both color Doppler and pulsed Doppler modes [2]. The angle-correction cursor was positioned parallel to the direction of flow. The PSV of the right ITA was automatically calculated by the ultrasound apparatus and used as an index of thyroid blood flow. All measurements were performed by the same examiner (M.F-U.), who was blinded to the characteristics of the subjects. Measurements were made at the ITA because this artery contributes strongly to the thyroid blood flow, and measurement at this position is straightforward and has a coefficient of variation (CV) of less than 5.0%. Thyroid volume was also determined by ultrasonography, based on a calculation using an ellipsoid model (width length thickness 0.7 for each lobe) [12].
2.2. Protocol for GD treatment with MMI
2.5. Statistical analysis
GD patients in an untreated hyperthyroid state were administered MMI at an initial daily dose of 30 mg and serum levels of FT4, FT3 and TSH were checked every 4 weeks during the observation period. When serum FT3 decreased to below the normal lower limit or serum TSH increased to above the normal upper limit, the dose of MMI was decreased serially to 20 mg/day, 15 mg/day, 10 mg/day and then finally to 5 mg/ day. The dose of MMI required to keep euthyroidism (maintenance of serum levels of FT4, FT3 and TSH within the respective normal range) for at least 12 months was defined as the maintenance dose. Recurrence, defined as an elevation of serum FT3 or FT4 above normal upper limit, or the suppression of serum TSH below normal lower limit after restoration of euthyroidism, was not seen during the observation period. None of the patients was obliged to quit MMI administration due to its side effect in this study.
Data are expressed as means SE unless otherwise indicated. Statistical analysis was performed with the Stat View V system (Abacus Concepts, Berkeley CA) for the Apple computer. Differences in basal values between untreated hyperthyroid patients with GD and normal controls were examined using a ManneWhitney U-test for assessment of medians. Differences in ITA-PSV values in the pre-treatment hyperthyroid phase among those who required different MMI maintenance dose were examined using a ManneWhitney U-test for assessment of medians. The Spearman rank correlation was used to examine correlation between parameters. Stepwise multiple regression analysis with forward elimination was performed to assess the independent influence of a variable on ITA-PSV or the maintenance dose of MMI, with the F value was set at 4.0 at each step. P values of less than 0.05 were considered to be statistically significant.
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Table 2 Correlation between ITA-PSV and other parameters in hyperthyroid GD patients and control subjects
3. Results 3.1. ITA-PSV and clinical variables in untreated hyperthyroid GD patients and normal subjects
Hyperthyroid patients with GD
The clinical characteristics of the hyperthyroid patients and normal controls are shown in Table 1. All hyperthyroid GD patients showed increased serum FT4 and FT3 levels above the normal upper limit, with suppression of serum TSH to undetectable levels. There were no significant differences between the two groups in age, gender ratio, smoking index (daily number of cigarettes multiplied by the number of years of smoking), and serum levels of HDL-cholesterol or triglyceride. ITA-PSV, thyroid volume and serum markers of GD activity such as VEGF, IgE, TRAb and TSAb were all significantly higher in hyperthyroid GD patients than in normal controls, and serum levels of total and LDL-cholesterol were significantly lower in hyperthyroid GD patients. ITA-PSV in normal controls ranged from 8.8 to 39.0 cm/s. 3.2. Correlation between ITA-PSV and other parameters in untreated hyperthyroid GD patients ITA-PSV in hyperthyroid GD patients was significantly correlated in a positive manner with smoking index, serum levels of FT4, FT3 and IgE, and thyroid volume, and in a negative manner with total, LDL- and HDL-cholesterols (Table 2). There was no significant correlation of ITA-PSV in hyperthyroid GD patients with age, or serum levels of triglyceride, TRAb, TSAb and VEGF. In normal controls, ITA-PSV did not show a significant correlation with any of the variables listed in Table 2. Table 1 Baseline characteristics of hyperthyroid GD patients and control subjects Hyperthyroid GD patients
Normal controls
Number of subjects 47 22 Gender (female/male) 41/6 19/3 Age (years) 35.2 3.7 40.8 3.9 Smoking index 142.9 34.4 128.7 28.9 T. Chol (mmol/l) 3.32 0.16 5.32 0.27 Triglyceride (mmol/l) 0.92 0.11 1.34 0.25 LDL-C (mmol/l) 1.56 0.13 2.93 0.40 HDL-C (mmol/l) 1.22 0.07 1.71 0.20 FT4 (pmol/l) [9.01e24.45] 88.4 11.5 15.9 0.50 FT3 (pmol/l) [4.00e7.70] 22.49 1.64 5.06 0.12 TSH (mIU/l) [0.4e4.7] <0.1 1.7 0.31 TRAb (%) [<15] 47.6 5.8 3.40 1.81 TSAb (%) [<179] 712.7 119.8 10.8 3.62 ITA-PSV (cm/s) 84.0 12.9 20.0 2.0 IgE (IU/ml) [<173] 641.6 277.0 132 45.4 VEGF (pg/ml) [<115] 27.2 4.56 13.2 2.36 Thyroid volume (mm3) 32,949.0 3732.0 1224.1 1022.6
P
ns ns ns <0.0001 ns 0.0013 ns <0.0001 <0.0001 <0.0001 0.0073 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
Data are expressed as means SE. Differences between the two groups were examined using a ManneWhitney U-test for assessment of medians. The difference in the male/female ratio between the two groups was analyzed by chisquare test. GD, Graves’ disease; ns, not significant; T. Chol, total cholesterol; LDL-C, LDL-cholesterol; HDL-C, HDL-cholesterol; ITA-PSV, peak systolic velocity at the inferior thyroid artery; IgE, immunoglobulin E; VEGF, vascular endothelial growth factor.
Age Smoking Index T. Chol Triglyceride LDL-C HDL-C FT4 FT3 TRAb TSAb IgE VEGF Thyroid volume Total MMI dose maintenance MMI dose Duration of therapy
Normal controls
Rho
P
Rho
P
0.178 0.533 0.488 0.034 0.479 0.443 0.563 0.641 0.259 0.123 0.507 0.078 0.334 0.030 0.520 0.217
ns 0.0017 0.0012 ns 0.0067 0.012 0.0001 <0.0001 ns ns 0.0098 ns 0.027 ns 0.0033 ns
0.488 0.313 0.273 0.139 0.190 0.048 0.004 0.033 0.500 0.306 0.012 0.024 0.134
ns ns ns ns ns ns ns ns ns ns ns ns ns
Data are expressed as means SE. Spearman correlation coefficients were used. ITA-PSV, peak systolic velocity of the inferior thyroid artery; GD, Graves’ disease; ns, not significant; T. Chol, total cholesterol; LDL-C, LDLcholesterol; HDL-C, HDL-cholesterol; TRAb, TSH receptor antibody; TSAb, thyroid stimulating antibody; IgE, immunoglobulin E; VEGF, vascular endothelial growth factor; MMI, methimazole.
3.3. Factors affecting ITA-PSV in untreated hyperthyroid GD patients The result of stepwise multiple regression analysis of the association of various clinical variables with ITA-PSV in untreated hyperthyroid GD patients is shown in Table 3. Parameters analyzed included smoking index, thyroid volume, and serum levels of FT4, FT3, IgE, and total, HDL- and LDL-cholesterols, which showed significant correlations with ITA-PSV (Table 2). Among these parameters, IgE and LDL-cholesterol emerged as significant factors associated with ITA-PSV in positive and negative manners, respectively. 3.4. Relationship between ITA-PSV in the pre-treatment phase and MMI therapy The total and maintenance doses of MMI and the duration of therapy until restoration of euthyroidism are 2578.5 390.5 (mean SE) mg/patient, 6.70 0.45 mg/day, and 13.6 1.43 months, respectively. ITA-PSV in the pre-treatment phase was significantly and positively correlated with the maintenance Table 3 Stepwise multiple regression analysis of the association of ITA-PSV with other parameters in hyperthyroid GD patients Dependent variables
Independent variables
b
F value
ITA-PSV
Immunoglobulin E LDL-cholesterol
0.499 0.406
8.884 5.860
Immunoglobulin E, LDL-cholesterol, smoking Index, total cholesterol, HDLcholesterol, FT4, FT3, and thyroid volume were included as parameters in the analysis. b, standard regression coefficient. R2 ¼ 0.624 ( p < 0.0005).
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dose of MMI, but not total dose or duration for MMI to restore normal thyroid function (Table 2).
Table 4 Stepwise multiple regression analysis of the association of the maintenance dose of MMI with other parameters in hyperthyroid GD patients
3.5. Comparison of individual values of ITA-PSV in the pre-treatment phase with the maintenance dose of MMI in untreated hyperthyroid GD patients
Dependent variables
Independent variables
b
F value
Maintenance dose of MMI
FT4 ITA-PSV
0.453 0.373
6.045 4.101
Fig. 1 shows the individual values of ITA-PSV in the pretreatment phase in comparison with the maintenance dose of MMI in untreated hyperthyroid GD patients. Of the 47 GD patients, 34 (72.3%) patients required 5 mg/day MMI, while 10 (21.3%) and 3 (6.4%) patients required 10 and 15 mg/day MMI, respectively. The mean ITA-PSV value of patients whose maintenance dose of MMI 10 mg/day or greater was significantly higher than that of patients who required MMI at 5 mg/day. Similarly, the mean ITA-PSV of patients who required 10 mg/day MMI was also significantly higher than that of patients who required 5 mg/day MMI. No difference was found between the mean ITA-PSVs of patients requiring 10 mg/day MMI and 15 mg/day MMI. The maintenance dose of MMI was significantly and positively correlated with thyroid volume, ITA-PSV, and serum levels of FT4, FT3, TRAb and IgE (data not shown), but not with age, VEGF or TSAb. 3.6. Factors affecting the maintenance dose of MMI in untreated hyperthyroid GD patients Table 4 shows the results of stepwise multiple regression analysis of the association of various clinical variables with p=0.0003
ns
350
p=0014
ITA-PSV (cm/s)
300 250 200 150 100 50 0 5
10
15
Maintenance dose of MMI (mg/day) Fig. 1. Individual values of ITA-PSV in the pre-treatment phase plotted against maintenance dose of MMI after restoration of euthyroidism. Data are expressed as means SE. The mean ITA-PSV of patients who required more than 10 mg MMI (closed cycle) was significantly higher than that of patients who required 5 mg MMI [132.79 18.72 vs. 65.11 5.18 (mean SE) cm/s; p ¼ 0.0003]. The mean ITA-PSV of patients who required 10 mg MMI (132.08 23.12 cm/s) was also significantly higher than that of patients who required 5 mg MMI ( p ¼ 0.014). No difference was found between the mean ITA-PSV of patients who required 10 mg MMI and that of patients who required 15 mg MMI (135.1 33.0 cm/s).
FT4, FT3, ITA-PSV, immunoglobulin E, and thyroid volume were included as parameters in the analysis. b, standard regression coefficient. R2 ¼ 0.585 ( p ¼ 0.0053).
the maintenance dose of MMI in untreated hyperthyroid GD patients. Parameters analyzed included thyroid volume, ITAPSV, and serum levels of FT4, TRAb and IgE, all of which showed a significant correlation with the maintenance dose of MMI. Among these parameters, FT4 and ITA-PSV emerged as significant factors that were positively associated with the maintenance dose of MMI, whereas thyroid volume and serum levels of FT3, TRAb and IgE did not show a significant association with the maintenance dose of MMI.
4. Discussion ITA-PSV showed a positive correlation with smoking index, FT4, FT3, IgE and thyroid volume, and a negative correlation with total, HDL- and LDL-cholesterols in untreated hyperthyroid GD patients (Table 2). Among these variables, IgE and LDL-cholesterol were found to be significant factors that were independently associated with increased ITA-PSV in these patients in positive and negative manners, respectively, while smoking index, thyroid volume, serum levels of FT4, FT3, and total and HDL-cholesterol failed to show such an association (Table 3). Of great interest, ITA-PSV, together with FT4, in the pre-treatment phase was independently and positively associated with the dose of MMI required to maintain euthyroidism for at least 12 months in GD patients (Table 4). This result may suggest that an increase in ITA-PSV in the pre-treatment hyperthyroid phase partly reflects GD severity, and thus greater maintenance dose MMI to restore euthyroidism. Elevation of IgE in the untreated hyperthyroid GD state is reported to be associated with the severity of GD [3,4]. A recent study of a Japanese population of GD patients showed that a significant increase in serum IgE correlates with the recurrence rate of hyperthyroidism after withdrawal of ATD treatment [5]. Therefore, it is of interest that ITA-PSV in the hyperthyroid GD state associated with IgE, the representative marker of a type I allergic reaction, but not with either serum levels of thyroid hormones or anti-thyroid autoimmune antibodies. Since ITA-PSV did not associate with established parameters for GD severity, such as thyroid volume in the untreated hyperthyroid state, early measurement of ITA-PSV might offer a new approach for prediction of GD severity before initiation of MMI treatment. We recently reported that ITA-PSV in the euthyroid state is a more sensitive marker for prediction of GD relapse after ATD withdrawal, compared to serum parameters such as TSH receptor autoantibody and VEGF [2]. Considering these
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data and previous reports of the validity of serum IgE in prediction of GD remission after ATD withdrawal [5], ITA-PSV and serum IgE may be the sensitive parameters for estimation of GD activity independently of thyroid function. Serum IgE was also found to be independently associated with ITAPSV, suggesting that ITA-PSV might also reflect GD activity, even in the pre-treatment hyperthyroid phase. Stepwise multiple regression analysis showed that ITA-PSV, contrary to IgE, in the pre-treatment phase is an independent factor positively associated with the maintenance dose of MMI, suggesting that high ITA-PSV in the pre-treatment phase may indicate a reduced MMI sensitivity. Since FT4 was also found to be an independent factor associated with the maintenance dose of MMI, patients who show higher levels of serum FT4 and ITA-PSV may require a higher dose of MMI to maintain euthyroidism. Interestingly, serum IgE failed to emerge as an independent factor associated with the maintenance MMI dose, suggesting that it might not be a good marker for MMI sensitivity. The exact reason for the significant and negative association of LDL-cholesterol with ITA-PSV is unclear; however, metabolism of LDL-cholesterol is more heavily affected by hyperthyroidism than that of HDL-cholesterol [13]. Alternatively, thyroid blood flow may reflect metabolism and degradation of LDL-cholesterol more directly than that of serum thyroid hormones. The lack of significant association of smoking index and thyroid volume with ITA-PSV suggests that smoking habit and an increase in thyroid volume might not be responsible for the increase of ITA-PSV in hyperthyroid GD patients, although smoking index is known as a traditional a risk factor of GD and a predictor of Graves’ hyperthyroidism [14]. Similarly, TRAb, TSAb and VEGF are known as markers of thyroid activity [15,16], and serum VEGF, which increases in GD patients [16], is thought to increase intrathyroidal vascularity in Graves’ thyroid by stimulating proliferation of endothelial cells; however, the lack of correlation of ITA-PSV with these factors suggests that the autoimmune antibody titer and intrathyroidal vascularity may have no direct effects on ITA-PSV. We have previously shown that ITA-PSV is positively correlated with TRAb and VEGF and negatively correlated with FT4 in euthyroid GD patients by antithyroid therapy [2], suggesting that regulation of blood flow at ITA in euthyroid GD patients may differ from that in the hyperthyroid state. The reason for this difference is unclear, but ATD might act directly on the thyroid gland to decrease thyroid blood flow, in addition to its inhibitory effect on thyroid hormone synthesis; this possibility is supported by the lack of correlation in euthyroid GD patients between ITA-PSV and smoking index, which is a traditional indicator of GD activity [2]. None of the factors that correlated with ITA-PSV in hyperthyroid GD patients showed a significant correlation with ITAPSV in normal subjects (Table 2). This finding suggests that increased thyroid blood flow may be an important characteristic of GD patients. Overall, ITA-PSV may be a relevant parameter for prediction of GD autoimmune activity, as reflected by its significant association with serum IgE in the pre-treatment phase of GD patients. Furthermore, ITA-PSV is a positive and
independent factor associated with the maintenance dose of MMI, suggesting that high ITA-PSV in the pre-treatment phase may indicate a reduced MMI sensitivity.
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