Is 99mTechnetium Pertechnetate Thyroid Uptake accurate in Thyrotoxicosis Evaluation?

This study aimed to evaluate the 99mTc thyroid uptake (TcTU) in terms of (1) normal mean and range, (2) level of uncertainty in thyrotoxic patients and (3) effectiveness of adding radioiodine uptake in patients with uncertain TcTU values. groups: normal, Graves’ disease, toxic nodular goiter (single or multiple) and subacute thyroiditis. Mean and range of 99mTc thyroid uptake were obtained separately in the following groups: euthyroid patients, Graves’ disease patients, Toxic nodular patients and subacute thyroiditis patients. As far as patients who underwent second thyroid uptake test utilizing radioiodine 131I; mean and range of radioiodine 131I thyroid uptake were also obtained for same groups.


Abstract Background
This study aimed to evaluate the 99mTc thyroid uptake (TcTU) in terms of (1) normal mean and range, (2) level of uncertainty in thyrotoxic patients and (3) effectiveness of adding radioiodine uptake in patients with uncertain TcTU values.

Methods
Patients referred for TcTU test were included and categorized into groups: euthyroid, Graves' disease, toxic nodular goiter and subacute thyroiditis. Mean and range of TcTU were obtained separately for each group. Second radioiodine uptake test was performed in patients who had uncertain TcTU (overlap with normal range).
Results 209 patients were included (54 euthyroid, 112 Graves' disease, 29 toxic nodules and 17 subacute thyroiditis patients). Normal mean and range of TcTU were 1.5 +/-1.1% and 0.17-4.8%, respectively. Mean TcTU was high in hyperthyroid patients and was extremely low in subacute thyroiditis patients, however, uncertain values was noted in about 30% of the patients. TcTU was uncertain in 39 hyperthyroid patients and in 10 subacute thyroiditis patients, while second radioiodine uptake was high in the former and extremely low in the latter.

Conclusion
TcTU major disadvantage is the uncertainty seen in third of patients degrading test sensitivity and accuracy. We managed to overcome this uncertainty by adding second radioiodine thyroid uptake test.
Accordingly, single visit TcTU was accurate and su cient in about two thirds of patients while the remainder required second radioiodine uptake to reach accurate diagnosis.

Background
Thyrotoxicosis is a common endocrine medical problem manifested clinically by several non-speci c symptoms (including but not limited to tremor, palpitation, excessive sweating, weight loss, diarrhea, nervousness... etc.) and con rmed biochemically by thyroid function text (TFT). Biochemically, thyrotoxic patient has suppressed thyroid stimulating hormone (TSH) with elevated thyroid hormones (T3 and T4).
Thyroid scan and uptake is the test of choice for thyroid function evaluation that could discriminate between causes of thyrotoxicosis. Causes of thyrotoxicosis include subacute thyroiditis, Graves' disease and toxic nodular goiter (1, 2). Technetium-99m (99mTc) pertechnetate is becoming radiotracer of choice in thyroid uptake evaluation owing to its low cost, ready availability, rapid single visit imaging, lower radiation burden to the patient and good image quality (1). Iodine-123 (123I) is expensive and requires a return visit by the patient next day (1). Iodine-131 (131I) has high radiation burden on the patients so it is abandoned in developed countries (2).
However, reported major disadvantages of 99mTc thyroid uptake are narrow normal uptake range of 0.5-4% and overlap between normal range and ranges of thyrotoxic patients (3,4). Accordingly, some endocrinologists and some nuclear physicians agree on conducting 99mTc thyroid uptake but with some level of uncertainty about the results.
This study aimed to evaluate the 99mTc thyroid uptake in terms of (1) normal mean and range in our euthyroid patients, (2) level of uncertainty in thyrotoxic patients and (3) effectiveness of adding radioiodine uptake in patients with uncertain 99mTc uptake values.

Methods
Patients included in this study were those referred to our nuclear medicine department for thyroid scan and uptake. The study started in March 2016 and ended in April 2018. The study was approved by Jordan University of Science and Technology institutional review board (IRB). Consents were waived according to hospital policy. Patients were referred for investigation of thyrotoxicosis con rmed biochemically by TFT test. However, some euthyroid patients (normal TFT) were also referred and included in the study. Main reasons for euthyroid patient referral were thyroid nodule evaluation and thyrotoxic symptoms as well as borderline TFT (low normal TSH). All patients underwent 99mTc thyroid scan and uptake. Normal 99mTc uptake reference range in our department is 0.4-4% according to data published by Atkin (3). Second thyroid uptake test utilizing radioiodine was performed in thyrotoxic patients who had uncertain 99mTc uptake that was within the normal reference range. Our local mean reference range of radioiodine 131I thyroid uptake is 15% +/-7% according to our previously published data (2). Based on image ndings and uptake value, patients were categorized into the following groups: normal, Graves' disease, toxic nodular goiter (single or multiple) and subacute thyroiditis. Mean and range of 99mTc thyroid uptake were obtained separately in the following groups: euthyroid patients, Graves' disease patients, Toxic nodular patients and subacute thyroiditis patients. As far as patients who underwent second thyroid uptake test utilizing radioiodine 131I; mean and range of radioiodine 131I thyroid uptake were also obtained for same groups.
Clinically, all thyrotoxic patients included in this study were followed up by endocrinology clinics and treated according to diagnosis. We looked up the type of treatment and range of follow up for each group to validate the diagnosis obtained by thyroid scan and uptake.

Statistics:
Sensitivity, speci city, positive predicative valve (PPV) and negative predicative value (NPV) for 99mTc thyroid uptake in thyrotoxicosis were calculated. Moreover; accuracy of 99mTc thyroid uptake in Page 4/19 thyrotoxicosis was calculated. Technique: 99mTc Scintiscan: 30 minutes after intravenous administration of 18.5-MBq (5 mCi) 99mTc pertechnetate, 5 minutes static thyroid images were obtained in anterior, right anterior oblique and left anterior oblique views while the patient is supine with extended neck. Images were obtained by a large-eld-of-view gamma camera (Mediso, Anyscan, Budapest, Hungary) tted with low energy all-purpose parallel hole collimator. Image data were recorded on a 128 × 128 computer matrix.

Results
Patient group characteristics are summarized in Table 1. Two-hundred and nine patients were included in our study. About 72% of the patients were females and 28% were males. Most patients were middle aged with average (± SD) of 43 (± 15) y and range of 7-81 y. Thyrotoxic patients had suppressed TSH and elevated T3 and T4 hormones as shown in Table 2. All patients underwent 99mTc thyroid scan and uptake, whereas only 60 patients had combined 99mTc /radioiodine thyroid uptake because of uncertain 99mTc uptake values. 19 +/-13 10 +/-5 9 +/-4 3.1-6.8 Figure 1 shows mean and range of 99mTc thyroid uptake for euthyroid and thyrotoxic patient groups. Normal mean and range of 99mTc uptake were 1.5 +/-1.1% and 0.17-4.8%, respectively. Mean 99mTc uptake is markedly high in hyperthyroid patients and extremely low in subacute thyroiditis patients, but there is an overlap between ranges of thyrotoxic patient groups and normal individuals (euthyroid) as noted in Fig. 1. Table 3 and Figs. 2-3 show that 99mTc uptake was uncertain (overlap with normal range) in 39 hyperthyroid patients while radioiodine uptake was high in all of them. Eleven euthyroid patients underwent both Tc99m and radioiodine uptake which was normal in both radiotracers (Fig. 4).  Figure 1 shows that mean 99mTc thyroid uptake was extremely low (< 1%) in subacute thyroiditis patients. However, 10 out of 17 subacute thyroiditis patients had uncertain 99mTc thyroid uptake as uptake (overlap with normal range). Accordingly, those 10 patients underwent radioiodine thyroid uptake which was low (Table 3 and Fig. 5).
Hyperthyroid patients (Graves' disease and toxic nodules) were followed-up clinically for at least 6 months while subacute thyroiditis patients were followed-up clinically for at least 2 months (Table 4). Graves' disease patients and toxic nodules' patients were treated successfully by anti-thyroid medications and/or by radioiodine ablation. Most patients with subacute thyroiditis recovered within 2-3 months (Table 4). Table 4 showing follow up duration range, type of treatment and treatment outcome in each patient group. Sensitivity, speci city, PPV, NPV and accuracy of 99mTc thyroid uptake in thyrotoxicosis were as follow: sensitivity was 68%, speci city was 100%, PPV was 100%, NPV was 52% and accuracy was 76%.

Discussion
Thyroid uptake value along with thyroid scintigraphic features provides useful information on the etiology of thyrotoxicosis. Reduced uptake value with poor visualization of thyroid gland is often associated with subacute thyroiditis whereas elevated uptake value with diffusely enlarged thyroid or focal nodules is often seen in patients with Graves' disease or toxic nodular goiter (1,2).
99mTc pertechnetate is becoming the radiotracer of choice in thyroid uptake evaluation owing to its low cost, ready availability, rapid single visit imaging, lower radiation burden to the patient and good image quality (1).
Although 99mTc does not undergo organi cation by follicular cells like iodine; thyroid uptake of 99mTcpertechnetate is closely correlated with radioiodine uptake in thyrotoxic patients (5). Iodine-123 (123I) provides good image quality and low radiation burden to the patient. However, 123I is expensive and not readily available as well as test is requiring a return visit by the patient next day (1). Iodine-131(131I) is abandoned in Europe and North America because of its high radiation burden on patients secondary to long half-life and beta radiation (2).
In the present study, normal range of 99mTc thyroid uptake was 0.17-4.8% and normal mean was 1.5 +/-1.1%. Our results are very close to previously published results. In 1971, Atkin reported normal mean of 1.73 +/-0.85% and normal range of 0.5-4% (3). A normal range of 0.4-2.5% was reported in another study (6). One more study reported normal mean of 0.9% and normal range of 0.1-6.3% (1). In contrary, one study reported a narrower normal range of 0.4-1.7% (7).
Despite all advantages of 99mTc thyroid uptake, overlap between normal uptake range in euthyroid patients and uptake range of thyrotoxic patients is considered a major disadvantage. This disadvantage is even exaggerated because the normal range of 99mTc thyroid uptake is generally low and narrow as well as neck background activity is relatively high (8)(9). In concordance with that; our data showed that 28% (39/138) of our hyperthyroid patients had uncertain values of 99mTc thyroid uptake (overlap with normal range). Moreover, 59% (10/17) of subacute thyroiditis patients in our study had uncertain 99mTc thyroid uptake values (overlap with lower end of normal range). It has been reported that 8 out of 26 (31%) thyrotoxic patients had normal 99mTc thyroid uptake (4). In another study, 24 out of 201 (12%) Graves' disease patients had normal 99mTc uptake (6). In addition, it was found that 99mTc thyroid uptake in 57 Graves' disease patients ranged from 0.97%-40.1% (10).
In order to overcome disadvantages of 99mTc thyroid uptake; we added second thyroid uptake test utilizing radioiodine for thyrotoxic patients who had uncertain 99mTc uptake values (overlap with normal range). Radioiodine uptake was high in all 28% of hyperthyroid patients with uncertain 99mTc uptake value. As well; radioiodine uptake was low in 11 subacute thyroiditis patients with uncertain 99mTc uptake value.
To con rm the results of thyroid uptake test in our patients we reviewed the medical records of our patients. All patients diagnosed with Graves' disease or toxic nodules by 99mTc alone or by 99mTc/radioiodine were treated by anti-thyroid medications and/or radioiodine ablation. Outcome in those patients was good (recovery or hypothyroidism) re ecting that our approach succeeded in overcoming the uncertainty of 99mTc in thyrotoxicosis evaluation. Similarly, we noted good outcome in patients diagnosed to have subacute thyroiditis by this approach. Most of them recovered spontaneously and few of them became hypothyroid.
Statistically, 99mTc thyroid scan is found to be speci c in thyrotoxicosis evaluation. However, uncertain values of this test degraded sensitivity and accuracy of the test which were found to be 68% and 76% respectively. Adding second radioiodine uptake test to uncertain cases managed to overcome this disadvantage. In another word, third of thyrotoxic patients are expected to have uncertain 99mTc thyroid uptake values overlapping with normal range. By combining radioiodine thyroid uptake to 99mTc uptake in this circumstance, we could reach accurate diagnosis in those patients. Two thirds of thyrotoxic patients will gain advantages of 99mTc thyroid uptake i.e single visit test, good image quality and low radiation burden (1). This approach is found very helpful in our department as radioiodine 131I is available for imaging not radioiodine 123I which is expensive and of relative short half-life. By this approach, we managed to abandon radioiodine 131I from 2 thirds of our patients and at the same time we continued to have accurate diagnosis in all patients. We believe that this approach is helpful in most developing countries where radioiodine 123I is not readily available.
We admit that third of our patients who underwent combined 99mTc/131I thyroid uptake received higher radiation dose. The dose to the thyroid from 131I is about 100 times greater than that from 123I for the same administered activity (≈ 1 rad/µCi [10 mGy/0.037 MBq] versus 1 rad/100 µCi [10 mGy/3.7 MBq]). The absorbed thyroid dose from 99mTc-pertechnetate is about 1 rad/5000 µCi (10 mGy/185 MBq) (11). The average administered dose is 5 mCi (185 MBq) 99mTc which results in 1 rad radiation absorption to thyroid. This is a negligible radiation absorbed dose as compared to that resulting from radioiodine.

Conclusion
This study showed that 99mTc thyroid uptake is the test of choice for evaluation of thyrotoxic patients for several reasons; the most important is being performed in single visit. Second important reason is that we managed to abandon 131I radioiodine from thyroid imaging as 123I radioiodine is not available in our country which is true for most developing countries. However, its major disadvantage is the uncertainty as third of our patients had uncertain thyroid uptake values overlapping with normal range. This uncertainty degraded test sensitivity and accuracy. We managed to overcome this uncertainty by adding second radioiodine thyroid uptake test in patients with uncertain 99mTc thyroid uptake. According to this approach, single visit 99mTc thyroid uptake was accurate and su cient in about two thirds of our thyrotoxic patients while the remainder third of our patients with uncertain 99mTc thyroid uptake values required additional 2-day visit radioiodine thyroid uptake to reach accurate diagnosis.  Mean and range of 99mTc thyroid uptake in euthyroid (normal) group and thyrotoxic groups including