Improving Thyrotoxicosis Diagnosis: The Clinical Necessity of Refining Tc-99m Pertechnetate Uptake Reference Ranges

INTRODUCTION

Thyroid imaging plays a crucial role in diagnosing and managing various thyroid disorders, such as hyperthyroidism and thyroid nodules. Radioactive iodine isotopes, particularly iodine-131 (I-131) and iodine-123 (I-123), are considered the gold standard for thyroid uptake measurements due to their high specificity for thyroid tissue and their ability to provide functional insights into the activity of the thyroid gland.^[1] This technique evaluates the thyroid’s capacity to trap and incorporate iodine, which is essential for hormone synthesis, making it invaluable in diagnosing hyperthyroidism, assessing thyroid nodules, and guiding treatment decisions.^[2,3] The accuracy and reproducibility of radioactive iodine uptake (RAIU) tests have been extensively validated, reinforcing their vital role in evaluating thyroid function. Among other available radiopharmaceuticals, Technetium-99m pertechnetate (Tc-99m pertechnetate) has become a cornerstone in clinical practice due to its availability, cost-effectiveness, and favorable characteristics, such as high count rates, efficient collimation, and low radiation exposure, rendering it a suitable alternative for radioactive iodine.^[4] Similar to iodine, Tc-99m pertechnetate is taken up by the sodium-iodide symporter (NIS); however, it is not incorporated into thyroid hormones, allowing for efficient functional imaging without interference in the synthesis process.^[5] Since Tc-99m pertechnetate is not incorporated into thyroid hormones, its uptake indirectly measures thyroid function, leading to discrepancies between Tc-99m pertechnetate and I-131 uptake values, necessitating a nuanced approach to diagnosis, as Tc-99m pertechnetate uptake (TU) may not always align with the patient’s thyroid functional status.^[6]

Determining accurate reference ranges for typical TU is crucial for reliable interpretation. Globally, the reported reference ranges for TU exhibit substantial variation, reflecting differences in dietary iodine intake and population-specific characteristics. For instance, normal uptake values range from 0.2%–2.0% in the United Kingdom (UK),^[7] 0.26%–1.64% in Turkey,^[8] 0.54%–1.80% in Northern Iran,^[6] and 0.15%–1.69% in Namibia,^[9] 0.4%–2.80% in Southern Germany,^[10] all of which are lower than the previously internationally used range of 0.75%–4.5%^[1,11] [Table 1]. These discrepancies underscore the need for localized reference values to ensure diagnostic accuracy and relevance across diverse populations. In Kuwait, the commonly used regional range is 0.2%–2.0%; however, we have noted that many cases are misdiagnosed, highlighting the importance of re-evaluating these ranges in our population.

A variety of patient-specific characteristics, including age, sex, ethnicity, medications, and underlying thyroid disorders, can significantly influence TU measurements.^[7,9] Conditions associated with hyperthyroidism, such as Graves’ disease, toxic multinodular goiter, and Hashitoxicosis, commonly exhibit elevated TU. However, the etiology and stage of thyrotoxicosis, as well as iodine turnover and the thyroid’s functional reserve, can lead to uptake values that overlap with the normal range. In contrast, thyroiditis can also cause thyrotoxicosis in its early stage, but it typically presents with reduced or absent TU.^[3,10,12] Consequently, the diagnostic utility of TU necessitates careful integration with clinical, laboratory, and imaging assessments to prevent misinterpretation.

This study focuses on thyrotoxic patients since existing Tc-99m pertechnetate reference ranges are primarily based on euthyroid individuals with stable iodine metabolism and normal thyroid function. However, thyrotoxic patients exhibit altered iodine kinetics, increased NIS activity, and variable uptake patterns, which may lead to misclassification under current reference thresholds. Including euthyroid individuals could broaden the range unnecessarily, reducing sensitivity in detecting hyperfunctioning thyroid states. By refining the reference range specifically for thyrotoxicosis, this study aims to improve diagnostic accuracy and reduce missed cases, ensuring more precise clinical decision-making.

To achieve this, we evaluate the diagnostic utility of TU in thyrotoxic patients in Kuwait. Specifically, the study investigates the applicability of the commonly used regional reference range of 0.2%–2.0%, considering regional variations in dietary iodine intake and Kuwait’s unique demographic and clinical characteristics. Given the limitations of current reference values, this research seeks to refine the normal reference range by employing statistical analyses, including receiver operating characteristic (ROC) curve assessment and quartile distribution analysis, to determine a more clinically relevant threshold for distinguishing hyperfunctioning from nonhyperfunctioning thyroid conditions.

MATERIAL AND METHODS

RESULTS

The data of two hundred fifty-five patients who underwent a thyroid uptake study for the workup of thyrotoxicosis from January 2018 to September 2024 were reviewed. This study analyzed data of two hundred eighteen thyrotoxicosis patients with Tc-99m pertechnetate and I-131 thyroid uptake studies. The mean age of this group was 40.1 ± 12.9 years, with a mean thyroid-stimulating hormone (TSH) value of 0.042 ± 0.047 and a mean Free Thyroxine (FT4) value of 42.3 ± 24.0. There were 148 females with a mean age of 38.8 ± 13.5 years, a mean TSH value of 0.041 ± 0.052, and a mean FT4 value of 43.4 ± 24.8, and 70 males with a mean age of 42.8 ± 11.2 years, a mean TSH value of 0.043 ± 0.037, and a mean FT4 value of 40.0 ± 22.1 [Table 2].

Among these patients, 47 had subacute thyroiditis, 6 had Hashimoto’s thyroiditis, 124 had Graves’ disease, 28 had Plummer’s disease, 5 had multinodular goiter, and 8 had toxic solitary nodules (TSNs). Their 24-h I-131 uptake and TU mean values, along with the uptake range, are listed in Table 3.

After stratifying patients based on TU values, only those with uptake ≤2% were included in the analysis, narrowing the study population to 89 patients (41%) [Figure 1]. Within this group, 56 patients had uptake values within the currently accepted normal range of 0.2%–2.0%, with a mean uptake of 1.0 ± 0.5% [Table 4]. The TU values were compared with their I-131 uptake values, as illustrated in Figure 2. Of these 56 patients, there were 34 (61%) with normal 99mTcO4− and I-131 uptake values, 15 (27%) with normal Tc-99m pertechnetate and high I-131 uptake, and only 7 (13%) with normal Tc-99m pertechnetate and low I-131 uptake. The patients’ diagnosis of each group is shown in Table 5.

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Figure 1:

This flowchart illustrates the selection and stratification of patients based on Tc-99m pertechnetate and I-131 uptake. Of 255 patients who underwent thyroid uptake studies, 218 had Tc-99m pertechnetate and I-131 uptake measurements and were included in the analysis. Patients were categorized into those with Tc-99m pertechnetate uptake >2.0% (n = 129) and those with uptake ≤2.0% (n = 89). Within the latter group, 56 patients fell within the commonly accepted normal uptake range (0.2%–2.0%), while further refinement using the proposed 0.5%–1.5% range reduced the number of patients classified as normal to 31. (99mTcO4−: Tc-99m pertechnetate, 131I−: I-131)

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Figure 2:

This scatter plot illustrates the relationship between Tc-99m pertechnetate uptake (y-axis) and 24-h I-131 uptake (x-axis) for patients with uptake values within the normal range of 0.2%–2.0%. Each dot represents an individual patient, color-coded by diagnosis: Graves’ disease, Hashimoto’s thyroiditis, multinodular goiter, Plummer’s disease, subacute thyroiditis, and toxic solitary nodule. The green-shaded area represents the normal reference range for 24-h I-131 uptake (8%–35%). (99mTcO4−: Tc-99m pertechnetate, 131I−: I-131)

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To further evaluate the functional significance of the uptake values, Pearson correlation analysis was conducted between TU and Free T4 levels. A statistically significant moderate positive correlation was observed (r = 0.43, P < 0.001), indicating that higher uptake values generally reflected higher circulating thyroid hormone levels. This supports the clinical applicability of the revised reference range and underscores its relevance in identifying biochemically hyperthyroid states.

Quartile analysis of Tc-99m pertechnetate values within the normal range (0.2%–2.0%) demonstrated a 25th percentile (Q1) of 0.575%, median (Q2/50th percentile) of 0.900% and a 75th percentile (Q3) of 1.500% [Figure 3].

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Figure 3:

The box plot illustrates the quartile distribution of Tc-99m pertechnetate uptake within the normal range (0.2%–2.0%). The blue box represents the interquartile range between the first quartile (Q1) (0.575%) and third quartile (Q3) (1.500%), with the whiskers extending to the minimum and maximum non-outlier values. A grey line marks the median (0.900%). The recommended revised uptake thresholds are indicated by the solid orange line (lower limit: 0.5%) and the solid purple line (upper limit: 1.5%). These findings support refining the normal range to 0.5%–1.5% for improved diagnostic accuracy in thyrotoxicosis. (99mTcO4−: Tc-99m pertechnetate, 131I−: I-131)

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The ROC curve analysis identified 0.5% as the threshold with the highest sensitivity (95.1%), meaning nearly all hyperfunctioning cases were correctly classified [Figure 4]. However, the low specificity (24.9%) indicated that many nonhyperfunctioning cases were also classified as hyperfunctioning. A higher threshold of 1.5% was associated with a more balanced sensitivity (75.6%) and specificity (35.0%), making it a potential upper limit for the refined reference range. The currently used threshold of 2.0% showed lower sensitivity (58.5%), indicating that it may fail to detect some hyperfunctioning cases [Figure 5].

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Figure 4:

The receiver operating characteristic (ROC) curve illustrates the diagnostic performance of Tc-99m pertechnetate uptake in detecting thyrotoxicosis. The red line represents the calculated ROC curve, while the grey dashed line indicates the reference line for random classification. The area under the curve =0.75 suggests moderate diagnostic accuracy of Tc-99m pertechnetate uptake in distinguishing thyrotoxic patients from non-thyrotoxic individuals. Higher true positive rates with lower false positive rates indicate better diagnostic performance

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Figure 5:

This bar chart shows the sensitivity (blue) and specificity (orange) at different Tc-99m pertechnetate uptake thresholds for diagnosing thyrotoxicosis. Lower thresholds (e.g., 0.5%) yield higher sensitivity but lower specificity, while higher thresholds (e.g., 2.0%) improve specificity at the cost of sensitivity. The 1.5% threshold offers a balanced diagnostic cutoff . (99mTcO4−: Tc-99m pertechnetate)

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The calculation of Youden’s Index demonstrated that the threshold of 0.5% yielded the highest index value, confirming its effectiveness in distinguishing hyperfunctioning from non-hyperfunctioning conditions. However, the threshold of 1.5% represented a practical balance between sensitivity and specificity, making it an appropriate upper limit for the revised reference range [Table 6].

The interquartile range, 0.5%–1.5%, decreased the number of patients from 56 to 31 out of the 89 patients, as illustrated in Figures 6 and 7. Within this range, 22 of the 31 (70%) patients had normal I-131 uptake values compared to 34 of the 52 (61%) patients in the earlier group. Details of the uptake with the diagnosis are listed in Table 7, and the comparison of numbers between the two reference ranges with correlation with the I-131 uptake is in Table 8.

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Figure 6:

This scatter plot shows the relationship between Tc-99m pertechnetate uptake (y-axis) and 24-h I-131 uptake (x-axis) within the refined Tc-99m pertechnetate uptake range of 0.5%–1.5%. Each dot represents a patient, color-coded by diagnosis. The green-shaded area marks the normal reference range for 24-h I-131 uptake. (99mTcO4−: Tc-99m pertechnetate, 131I−: I-131)

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Figure 7:

This bar chart compares the number of cases per diagnosis using two Tc-99m pertechnetate uptake ranges: 0.2%–2.0% (blue) and the refined 0.5%–1.5% range (orange). The refined range reduces the number of cases classified within the normal uptake category, particularly in Graves’ disease, Plummer’s disease, and subacute thyroiditis. (99mTcO4−: Tc-99m pertechnetate)

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For patients on Carbimazole, antithyroid medication, who stopped taking their dosage 7 days before the study, there were five patients with Graves’ disease and one patient with Plummer’s disease in the whole studied population. Of the five Graves patients, three were within the normal range of TU values (0.2%–2%), and two had TU values >2%. The Plummer patient was also within the normal range of TU values. While using the smaller, more restricted range of TU values (0.5%–1.5%), only one patient with Graves was excluded as the value was above 1.5%.

DISCUSSION

Both I-131 and Tc-99m pertechnetate are transported by the NIS, utilizing the exact mechanism to enter thyroid cells. However, Tc-99m pertechnetate has a significantly lower affinity for NIS than I-131, reducing uptake and transport efficiency. While I-131 is retained in the thyroid due to organification and its role in hormone synthesis, Tc-99m pertechnetate is not organified and is rapidly cleared.^[13] Kinetic studies further demonstrate that I-131 has a higher transport capacity (Vmax) and more significant steady-state accumulation than 99mTcO4−, emphasizing their functional differences in thyroid physiology and diagnostic applications.^[13]

The internationally accepted reference range for Tc-99m pertechnetate thyroid uptake is 0.75%–4.5%.^[1,11] This range has been widely used in nuclear medicine to assess thyroid function; however, it includes populations with dietary iodine content ranging from inadequate to optimum. The dietary iodine intake in Kuwait is generally adequate, with a content commonly consumed in Kuwaiti dishes ranging from 7.4 μg/100g to 61.2 μg/100g.^[14] The urinary iodine excretion (UIE) levels in Kuwait (UIE of 148 μg/L) align with the World Health Organization recommendations and fall in the adequate iodine nutrition category-median UIE levels between 100 and 199 μg/L-for the general population, including school-age children.^[15-17] Individual UIE levels were not available in this retrospective cohort, but population-wide data were considered sufficient for contextual interpretation of uptake thresholds. Since there is an inverse relation between dietary iodine intake and thyroid TU,^[18] this data supports the idea of a lower uptake value than the internationally applied one, especially in Kuwait. It is important to note that this has led to more recent studies re-evaluating this range, which have reported lower normal ranges in various populations. Thus, it reinforces the notion of a reduced uptake value compared to the internationally accepted standard. Notably, this has prompted recent studies to reassess this range, revealing lower normal ranges across different populations. As the Saudi and UK papers suggested, the regionally accepted range for pertechnetate uptake is 0.2%–2%^.[7,19] This range is established for euthyroid patients, and when applied to the cohort in this paper, 56 out of the 218 patients (26%) were diagnosed with thyrotoxicosis but had normal TU.

Furthermore, the papers published to determine the normal range for TU were performed on either euthyroid patients with neither thyroid nor parathyroid disease or those referred to the nuclear medicine department to investigate parathyroid problems. Since the aim was to determine the normal range, none of the studies were conducted on patients with thyrotoxicosis. Interestingly, the studies on the Saudi Arabian population (Alshahrani et al., 2021)^[19] and Turkey (Gungor, 2021)^[8] were conducted on patients undergoing parathyroid scintigraphy for suspected primary hyperparathyroidism. However, a crucial inclusion criterion was that these individuals were biochemically and clinically euthyroid for 12 months before the thyroid uptake scan. Including patients with parathyroid adenomas can impact the determination of the upper limit of the normal range since some adenomas have been reported to show TU.^[20-22] The other studies (Paudel and Bhattarai, 2024)^[1], (Gholami et al., 2024)^[6], (Macauley et al., 2018)^[7], (Hamunyela et al., 2014)^[9], and (Ramos et al., 2002)^[23] focused on establishing normal thyroid uptake ranges and specifically selected euthyroid individuals without known parathyroid issues. This method is standard practice for defining normal reference intervals, as the presence of other conditions could confound the results. Therefore, finding the proper population sample with normal thyroid glands, including function and structure, is challenging, especially if dietary iodine intake and prior episodes of thyroiditis are all considered. Not forgetting the effect of gender and age on iodine uptake.^[24-27]

Furthermore, thyroid TU exhibits an inconsistent reference range pattern in the presence of thyroid nodularity. Some individuals with thyrotoxicosis may demonstrate lower TU, potentially leading to diagnostic challenges.^[28,29] In such cases, I-131 uptake measurements are essential to accurately assess the thyroid gland’s functional state.^[26,30] Within the patient cohort of this study, 41 individuals exhibited thyroid nodularity on their scans. Twenty-four of these 41 patients had an elevated TU, while 17 were in the normal range. Further analysis revealed that 11 of the 17 patients with normal TU had a normal I-131 uptake. The remaining 6 patients, however, exhibited elevated RAIU. These findings highlight the importance of comprehensively utilizing Tc-99m pertechnetate and I-131 uptake measurements to evaluate thyroid function, especially in thyroid nodularity.^[31,32]

Among the 124 patients with Graves’ disease, 18 exhibited a normal TU. Further investigation revealed that 8 of these patients demonstrated elevated 4-h (early) I-131 uptake but normal 24-h (delayed) uptake, suggesting a state of rapid thyroid hormone turnover in Graves’ disease. Other cases of normal pertechnetate uptake in Graves’ disease patients may occur in the initial stage of the condition; therefore, complementing the TU findings with an assessment of TSH-binding inhibitor immunoglobulins is recommended to aid in the diagnostic process.^[33]

Follow-up thyroid function results were available for 29 patients, mostly those with subacute thyroiditis or recovering from Graves’ disease. In 27 of these, repeat testing at around 3 to 6 months showed patterns that matched what was initially seen on imaging, either normalization or progression to hypothyroidism. While this represents a smaller portion of the cohort, it offers some reassurance that the refined uptake range corresponds with the expected clinical course. That said, we acknowledge the limitations of retrospective data and incomplete follow-up across all cases.

Our analysis focused on thyrotoxic patients within the normal range; we examined data from 56 out of 218 patients, accounting for 26%. We established a 0.5% to 1.5% range by isolating the first and fourth quartiles. Consequently, only 31 out of the 218 patients (14%) had normal TU. This revised range aligns closely with findings from Turkey and Brazil, which reported ranges of 0.3%–1.64% and 0.4%–1.70%, respectively.^[8,34] Increasing the lower limit from 0.2% to 0.5% removes 13 patients from the normal uptake category, including 9 diagnosed with recovery-phase thyroiditis, 3 with Hashimoto’s thyroiditis, and one with Plummer’s disease. Importantly, this change will not significantly impact their clinical management since continued follow-up laboratory investigations are still planned for most of them to exclude future onset of hypothyroidism.^[34-36]

In addition, reducing the upper limit from 2% to 1.5% moves 12 patients from the normal range to the high pertechnetate uptake category, reflecting their hyperthyroid condition more accurately. This change will impact many thyrotoxic patients labeled with normal uptake if the 2% upper limit is to be clinically used. This refined reference range of 0.5%–1.5% will effectively exclude as many hyperfunctioning and hypofunctioning patients as possible, ensuring a more accurate and clinically useful classification of thyroid function.

The flowchart [Figure 8] outlines a diagnostic algorithm for evaluating thyroid disorders using Tc-99m pertechnetate scintigraphy and radiotracer uptake measurements. The diagnostic process begins with a Tc-99m pertechnetate scan and subsequent quantification of radiotracer uptake. The initial branching point distinguishes four primary patterns of radiotracer distribution: diffuse, reduced, TSN, and nodular. The diffused uptake is characterized by a homogeneous distribution of the radiotracer throughout the thyroid gland, and it is further stratified based on the magnitude of uptake. If the TU exceeds 1.5%, it strongly suggests a Graves’ disease diagnosis. Conversely, suppose the diffused uptake is <1.5%. In that case, it may represent either normal thyroid function or the early stages of Graves’ disease, warranting further clinical correlation and potentially serial testing.^[32,37,38] Reduced uptake signifies diminished overall radiotracer accumulation in the thyroid, a pattern typically observed in thyroiditis, encompassing various inflammatory thyroid conditions, such as postpartum, silent, or subacute thyroiditis.^[27,39,40] A TSN, identified by intensely increased radiotracer uptake concentrated within a single, well-defined nodule with suppression of uptake in the remaining thyroid tissue, is considered diagnostic of a hyperfunctioning nodule that autonomously produces thyroid hormones and suppresses TSH. In cases of nodular uptake, where multiple areas of increased or decreased radiotracer activity are observed within the thyroid gland, the algorithm again considers the overall uptake value. If the uptake is >1.5%, it suggests Plummer’s disease, also known as toxic multinodular goiter, characterized by multiple autonomously functioning nodules leading to hyperthyroidism. When nodular uptake is accompanied by an uptake value <1.5%, a RAIU test is indicated for further functional assessment of the nodules.

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Figure 8:

This flowchart outlines the diagnostic approach using Tc-99m pertechnetate uptake patterns. Diffuse uptake is classified based on the 1.5% threshold, distinguishing Graves’ disease from early or normal Graves’ cases. Reduced uptake suggests thyroiditis. Toxic solitary nodules lead to further evaluation. Nodular uptake is assessed using the 1.5% threshold; values above this suggest Plummer’s disease, while lower values require radioactive iodine uptake testing to differentiate between multinodular Goitre and Plummer’s disease. (99mTcO4−: Tc-99m pertechnetate, RAIU: Radioactive iodine uptake)

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A high RAIU in this context reinforces the diagnosis of Plummer’s disease, indicating increased iodine avidity by the hyperfunctioning nodules. This study has some important limitations. As a single-center retrospective analysis, it lacked long-term follow-up for many patients, and subgroup sizes– particularly for multinodular goiter and Hashimoto’s thyroiditis–were too small to support etiology-specific conclusions. These subgroup comparisons should therefore be interpreted as exploratory. While these factors may limit generalizability, the diagnostic trends observed remain consistent and clinically meaningful. Future studies should aim to prospectively validate the proposed 0.5%–1.5% range, ideally incorporating serial follow-up and thyroid antibody profiles to improve correlation between uptake and disease trajectory. Larger, multi-institutional cohorts may also help clarify whether tailored thresholds by etiology are warranted. If validated, the revised reference range could contribute to greater standardization in nuclear medicine reporting and enable more accurate functional assessment of thyrotoxic states, thereby informing timely and appropriate therapeutic decisions.

CONCLUSION

This study underscores the complexities of interpreting Tc-99m pertechnetate thyroid uptake, particularly in thyroid dysfunction. Our findings indicate that the widely accepted regional reference range of 0.2%–2% may not be universally applicable, with emerging evidence supporting a refined range of 0.5%–1.5%. This adjustment significantly enhances the accuracy of thyrotoxicosis diagnosis by minimizing missed cases and improving patient classification. Careful consideration of additional factors, such as thyroid nodularity and rapid turnover in Graves’ disease, is crucial for accurately assessing thyroid function using this diagnostic modality. While the revised range offers greater diagnostic clarity, its application should be tailored to specific populations, considering regional dietary iodine intake and clinical variability. Implementing this refined threshold in nuclear medicine practice could lead to more accurate diagnoses, optimized treatment decisions, and improved patient outcomes.