A prospective study on the role of Color Doppler Ultrasonography in differentiation of Grave’s disease from Thyroiditis
Key Words
Color Doppler ultrasonography, Thyroid blood flow, Graves’ disease, Destructive thyroiditis, Peak Systolic velocity, Superior thyroid artery
ABSTRACT
Background
Thyrotoxicosis due to Grave’s Disease(GD) and Thyroiditis(DT) needs differentiation, as management strategy differs. Factors which help in diagnosis are biochemical and nuclear imaging. Utility of High Resolution Ultrasonography & color doppler (HRUSG & CD) in differentiation, is not widely practiced. We undertook the prospective study in Department of Endocrine surgery at a tertiary care center, among South Indian Population in 1 year as cost effective model
MATERIALS AND METHODS
Out of 120 newly diagnosed thyrotoxicosis patients, 54 were GD(Group-A) and 66 were DT(Group-B) patients. 55 Euthyroid patients served as controls. Parameters analyzed were demography, Free TFT anti-TSH receptor antibody (TSHrAB), anti-TPO antibody (ATPO), anti-Thyroglobulin antibody (ATG) & Tc-99m Thyroid Scintigraphy. Parameters analyzed using HRUSG & CD were Peak systolic velocity (PSV), End diastolic volume (EDV), Pulsatility index (PI), Resistive Index (RI) of bilateral Superior thyroid artery (STA) and Inferior thyroid artery (ITA)
RESULTS
Both groups were age & sex matched. TFT, ATPO and ATG were comparable between both groups (p=0.609). TSHrAB(IU/ml) was significantly higher in group-A(36.11±0.82) than group-B(1.23±0.24) (p<0.001). Mean thyroid Volume(ml) was higher in group-A(28.9±14.9) than group-B(26.2±8.81) (p=0.022). Mean PSV-STA(cm/s) was Statistically higher in group-A(54.09±4.67) than group-B(28.92±4.39) (p=<0.001). Mean PSV-ITA(cm/s) was higher in group-A(32.11±2.45) than group-B(25.23±3.45) (p= 0.006). Other parameters measured in both arteries like mean EDV(cm/s), mean RI, mean PI were comparable between two groups
CONCLUSION
HRUSG with CD evaluation of PSV STA &ITA is a cost-effective alternative to TSHrAB and Thyroid scintigraphy in differentiating GD from DT patients. Additionally, we observed that PSV in STA was higher than ITA in patients with GD. To conclude, HRUSG & CD is a simple, cost effective and widely available tool in differentiation of GD from DT
Introduction
The management of hyperthyroidism depends upon the differentiation of two of its common etiology i.e., Graves’ disease (GD) and destructive thyroiditis (DT) and may cause a diagnostic dilemma in few cases. In GD, thyrotoxicosis is due to the hyperfunctioning of thyroid gland where as in DT, destruction of gland leads to excess release of the stored thyroid hormones. Thyroid Scintigraphy is a gold standard tool in differentiating the etiology of hyperthyroidism, but its not widely available and not cost effective. In GD, the modalities of treatment advocated include anti thyroid drugs, Radioactive iodine and Surgery, but in thyroiditis, symptomatic relief with anti-inflammatory agents and beta blockers constitute the first line of management. Elucidating the diagnosis is of paramount importance in categorizing hyperthyroidism with regard to GD and DT.
HRUSG with CD is a widely available, cost effective tool employed in all cases of hyperthyroidism. Various parameters can be analyzed by HRUSG with CD in addition to the routinely measured sonographic details of the thyroid. Blood flow in GD is usually so high, that the PSV in thyroid arteries can reach up to a mean of 100 cm/s more than the reported normal mean thyroid artery PSV which is 15-30 cm/s, and it would vary from thyroiditis.1 The major source of blood supply to the thyroid gland is by the STA and ITA. STA, being the first direct branch of external carotid artery has preponderance of blood supply to the thyroid parenchyma compared to the ITA, which is a branch of Thyrocervical trunk arising from the Subclavian artery. This increased vascularity in GD is exploited in our study to evaluate the dynamics of blood flow with regard to thyrotoxicosis. 1-3
HRUSG with CD is a technology used for quantitative and qualitative measurement of vascularity in Thyroid gland. It records the blood flow velocity, using color encoding images which is superimposed on grayscale image. The condition of parenchymal blood flow is an important indicator of thyroid status. For quantitative doppler evaluation, the peak systolic velocity (the doppler wave form recorded at the point with the highest frequency shift) was used, which permits the analysis of velocity and spectral parameters of the blood flow as well as the calculation of some indices.
Markova et al (2001) suggested the following values as normal blood flow parameters. Mean PSV in STA was 16.8 ± 0.94 cm/s and in the ITA it was 15.8 ± 0.77 cm/s. The mean EDV in STA is 7 ± 1.2 cm/s and in ITA is 6.36 ± 0.29 cm/s. The RI in STA is 0.56 ± 0.01 and in ITA is 0.58 ± 0.01. 4 Struchkova et al (2003) also suggested the following parameters as the nominal blood flow in thyroid arteries, PSV – 10.4 ± 28.1 cm/s, EDV – 3.1 ± 9.6 cm/s, RI – 0.5 ± 0.75 and PI – 0.72 ± 1.2. 5
PATIENTS AND METHODS
This prospective study was done in the department of Endocrine surgery, Madras Medical College Chennai, a tertiary care referral center in south India over a one year period from August 2015 to July 2016. Patient informed consent and Institutional Ethical Committee approval was obtained for this study.
Newly diagnosed hyperthyroid patients exhibiting features of thyrotoxicosis with biochemically elevated FT3 and FT4 and suppressed TSH values (normal range TSH – 0.5–5.0 μIU/mL, FT4 – 0.82–1.51ng/dl, FT3 – 1.95–5.4 pg/ml) were included as study cohorts. The study cohorts were classified into two groups based on the scintigraphic findings performed using (Tc 99m) technetium per technetate. Group A comprised Grave’s disease(GD) showing diffuse increased uptake and patients with low or no uptake were categorized as Destructive thyroiditis (DT) in group B. 120 patients were eligible and included in this study based on the above said criteria. Of these 120 patients, 54 patients were in Group A and the remaining 66 cohorts in group B. 55 age and sex matched euthyroid patients were included in the study to serve as controls.
The basic parameters analyzed include demography, Serum Anti-TSH receptor antibody levels (TSHrAB) measured using Electro chemiluminescence Immunoassay (normal range <1.8 IU/L), Anti-TPO antibody (normal value is < 2 IU/ml), Anti-Thyroglobulin antibody (normal value is < 7 IU/ml) both measured by Enzyme linked fluorescent assay. High resolution ultrasonography with Color Doppler (HRUSG with CD), (Siemens Acuson Antares Premium Edition) with a 15-MHz linear transducer was used to analyze various parameters.
Using HRUSG with CD, various parameters like mean peak systolic velocity (PSV), end diastolic volume (EDV) pulsatility index (PI), resistive index (RI), of superior and inferior thyroid arteries on both sides were evaluated by a single sonologist who was blinded to the biochemical and scintigraphic details. The thyroid volume was also calculated using the formula
length × width × depth × 0.479.
The HRUSG with CD evaluation of thyroid arteries, measurement was done in 1 mm sample volume adjustment, in vessel center with the insonation angle kept 0˚- 60˚ and correction angle adjusted parallel to the vessel wall 6. Transducer pressure over skin was minimum, with appropriate transducer and equipment adjustment, velocity scale was maintained with values ≤5.0 cm/s. The PSV and indices were measured in the inferior and the superior thyroid arteries.
Data were analyzed using SPSS software (IBM SPSS statistics 21.0; SPSS Inc, Chicago, IL). For comparison of continuous variables between different groups, student ‘t’ test was used. Categorical data analysis was done using Chi-square test. Data from each group were expressed as mean ± standard deviation. A ‘p’ value of <0.05 was considered significant statistically.
RESULTS
Of the 120 study cohorts in both the groups, predominantly 109 (91%) were females and 11(9%) were males and 85% of the control group were females. The cohorts in the study groups were age and sex matched. (p=0.205). The mean age in Group-A was 40.9 ± 12.5 years and in group-B it was 38.0 ± 10.1(p=0.806). The mean age of the control euthyroid patients were 36.7 ± 09.5 years.
The mean Free T4 (ng/dl) values in group-A was 8.86 ± 1.14 which was non-statistically higher than the mean values in Group B 6.42 ± 1.65. (p=0.061). The mean Sr.TSH (μIU/ml) in group-A was 0.02 ± 0.04 and it was 0.04 ± 0.32 in Group B. (p=0.120). The TSHrAB(IU/l) levels were elevated in 52/54 (96.3%) of group A cohorts measuring 36.11± 0.82 whereas only 5/66 (7.57%) patients in group-B had higher TSHrABlevels, with a mean value of 1.23 ± 0.24. (p<0.001) The Anti-TPO antibody(IU/ml) levels were elevated in 44/54 (81.8%) of group A patients measuring 428.2 ± 100.86 and 59/66 (89.39%) patients in group-B with a mean value of 510.9 ± 200.72. (p=0.095). The Anti-Thyroglobulin antibody(IU/ml) levels were elevated in 41/54 (75.92%) patients in group A with a mean value of 654.7 ±102.98 and 53/66 (80.30%) in group-B with a mean measurement of 550.3 ± 104.27. (p=0.083).
The Mean thyroid Volume(ml) in Group A was (28.9±14.9) comparable to Group B patients (26.2±8.81) (p=1.324). The Mean Thyroid volume in the control group was 8.97± 5.27 ml.
The mean PSV-STA (cm/s) in group-A was 54.09 ± 4.67 and in group-B it was 28.92± 4.39. The PSV-STA in group-A (Figure:1) was statistically significant than in group-B. (Figure:2) (p=<0.001). The PSV-STA in control group was 14.3 ± 0.92 cm/s. The mean PSV-ITA (cm/s) in group-A (Figure:3) was 32.11 ± 2.45 cm/s and in group-B (Figure:4) it was 25.23 ± 3.45 cm/s. (p=0.006) The PSV-ITA in control group was 11.2 ± 0.68 cm/s. The bilateral mean EDV-STA(cm/s) in group A (22.15 ± 2.45) and in group B (18.12 ± 3.55) (p= 0.098). The EDV-STA was non-significantly higher in group A than group B. The EDV-STA in control group was 07.72 ± 4.68 cm/s.
The bilateral mean EDV-ITA(cm/s) in group A (17.11 ± 2.05) and group B (15.13 ± 1.49) (P=0.067) The EDV-ITA was non-significantly higher in group A than group B. The EDV-ITA in control group was 06.372 ±2.38 cm/s. The bilateral mean RI-STA in group A (0.79±0.18) was not statistically higher than in group B (0.67±0.12) (p=0.863). The RI-STA in control group was 0.52 ± 1.08. The bilateral mean RI-ITA in group A (0.69±0.15) was not statistically higher than in group B (0.60±0.08). (p=0.091). The RI-ITA in control group was 0.49 ±04.68.
The bilateral mean PI-STA in group A(1.95±0.33) was not statistically higher than in group B (1.87±0.43) (p=0.576). The PI-STA in control group was 0.89 ±0.18. The bilateral mean PI-ITA in group A (1.01±0.18) was not statistically higher than in group B (0.96±0.0.5). (p=0.565). The PI-ITA in control group was 0.79 ±0.25.
The comparison of various parameters between the two study groups were documented in Table 1.
Table 1. Comparison of parameters between study groups
Parameters GROUP-A
(Graves’ disease)
(n=54) GROUP-B
(Destructive Thyroiditis)
(n=66) ‘P’ VALUE
AGE(years) 40.89 ± 12.45 38.00 ± 10.11 0.086
SEX(M:F) 5:49 6:60 0.205
FT4 (ng/dl) 8.86 ± 1.14 6.42 ± 1.65 0.061
TSH (μIU/ml) 0.02 ± 0.04 0.04 ± 0.32 0.120
Anti-TPO (IU/ml) 428.2 ± 100.86 510.9 ± 200.72 0.095
ATG (IU/ml) 654.7 ±102.98
550.3 ± 104.27 0.083
TSHrAB(IU/ml) 36.11± 0.82
1.23 ± 0.24 <0.001
PSV-STA (cm/s) 54.09 ± 4.67
28.92± 4.39 <0.001
PSV-ITA (cm/s) 32.11 ± 2.45
25.23 ± 3.45 0.006
EDV-STA (cm/s) 22.15 ± 2.45 18.12 ± 3.55 0.098
EDV- ITA (cm/s) 17.11 ± 2.05 15.13 ± 1.49 0.067
RI-STA 0.59±0.18 0.57±0.12 0.863
RI-ITA 0.60±0.08 0.69±0.15 0.091
PI- STA 1.95±0.33
1.87±0.43 0.576
PI-ITA 1.01±0.18
0.96±0.0.5 0.565
Values = mean ± Standard deviation
DISCUSSION
Our study has demonstrated the utility of HRUSG combined with CD, in the evaluation of the most common forms of hyperthyroidism in a simpler and cost effective way, negating the use of the Scintigraphy in selected patients. The major concern for the clinician in the out-patient setting would be to distinguish Grave’s disease from Destructive thyroiditis in a thyrotoxic patient. Grave’s Disease though has its unique features of ophthalmopathy and other skin changes, there are certain overlapping signs and symptoms in both the entities. HRUSG with CD is widely available and being increasingly used by Thyroid Specialists in their out-patient setting. This Surgeon performed USG examination will be an extension of clinical evaluation in the out-patient department with the results available immediately for choosing the management strategy. 7-8
Ralls et al., in 1987 used CD in Grave’s patient to show the increased blood flow in the thyroid gland. He coined the term as “thyroid inferno”, indicating diffuse increase in thyroid parenchyma vascularization. Since then CD has been used to investigate the pathogenesis of thyrotoxicosis.9 Increased Thyroid parenchyma vascularization can also occur in thyroiditis, but to a lesser level. The thyroid parenchyma vascularization correlates with the underlying functional status, it decreases when the disease is under control and can rise again in cases of relapse.
The method used in Thyroid HRUSG and CD evaluation, is a semi-quantitative measurement of the blood-flow pattern in the thyroid gland parenchyma, thyroid blood-flow pixels per thyroid cross-sectional area and blood-flow velocity in the thyroid artery.10 Thyroid CD is a cost effective, viable alternative available widely which is non-invasive and radiation free. HRUSG with CD can be used initially in the differential diagnosis of thyrotoxicosis., 11-13
In a study by Donkol et al., the mean PSV of 40.0 cm/s in ITA was higher and suggestive of GD, while most other studies proposed a PSV of above 50.0 cm/s. Values above 100cm/s can be reached in newly diagnosed patients or patients not responsive to treatment. 11 In our study group, the mean PSV in STA in untreated Graves’ disease patients was 54.09 ± 4.67.cm/s.
In a study it was demonstrated that, PSV of ITA was significantly higher in GD than DT patients. HRUSG with CD demonstrated sensitivity of 88.9% and specificity of 87.5%, and a positive predictive value of 94.1%, negative predictive value of 77.8% and diagnostic accuracy of 88.5%, in the differential diagnosis of thyrotoxicosis compared to 99mTc scintigraphy.11
Kumar et al., in his study reported a mean PSV-ITA values of 22.4 ± 5.4 cm/s in DT and 57.6 ± 13.1 cm/ s in untreated GD patients. In our study the PSV-ITA in GD was 32.11±2.45 cm/s whereas PSV-ITA in DT patients were 25.23±3.45 cm/s. The reported values were slightly lower than the values in our study subjects, probably due to operator dependent sites of thyroid artery sampling and racial differences between studies.13
In Most literatures, it has been observed that, vascularity in GD decreased in parallel to the biochemical remission and clinical control, and that HRUSG with CD has the potential to monitor therapy response in patients, as well as distinguish GD patients from DT, with B-mode pattern, without the need for expensive laboratory assays in their studies. 9,14-15
Vitti et al., in his study demonstrated that the thyroid parenchymal blood flow can be correlated with the functional state of GD patients, being significantly increased in 17/18 patients with newly diagnosed active hyperthyroidism patients.15 In patients with DT, the thyroid blood flow did not correlate to the functional state of the gland.16
In a study by Macedo et al., using HRUSG with CD, in 84 healthy iodine sufficient subjects, the following parameters was proposed as normal, PSV of 24.80 cm/s to 25.85 cm/s in the STA and 20.92 cm/s to 21.50 cm/s in ITA.16 In this study the mean PSV in euthyroid control subjects (n=52) were 14.3 ± 0.92 cm/s in STA and 11.2 ± 0.68 cm/s in ITA.
The 2011 American Thyroid Association (ATA) guidelines, as mentioned HRUSG with CD, as a reliable indicator of thyroid blood flow, and that it may have a practical value in the differentiation of cause of thyrotoxicosis, especially in pregnant patients or patients with recent Iodine exposure. It’s use as also been recommended in special Circumstances like Amiodarone induced thyrotoxicosis (AIT). In differentiation of type 1 AIT from type 2 AIT. 17
To conclude, measurement of PSV in thyroid arteries using HRUSG with CD is a practical and reliable method in differentiating GD from DT. Although PSV in both STA and ITA are significantly higher, technically measurement of PSV in STA is easier than ITA as it is a direct branch from External carotid artery. Thus, our study suggests that PSV measurement using HRUSG with CD can be used in daily routine, especially in places where thyroid scintigraphy is not feasible or when scintigraphy is contraindicated.