Keywords
normal - pertechnetate - reference - thyroid - uptake
Introduction
Thyroid gland function can be evaluated in two ways. Laboratory assessment by measurement
of serum-free triiodothyronine (T3), free tetraiodothyroxine (fT4), and thyroid-stimulating
hormone (TSH) is an indirect way of assessing thyroid gland function. Thyroid uptake
and scintigraphy performed in the Department of Nuclear Medicine is a direct way of
assessing thyroid function. It has the advantage of evaluating the gland structure
in addition to its function.
Radioiodine (I-131 Iodide) was first introduced in 1946. Its potential for the diagnosis
and management of thyroid diseases and thyroid cancer was soon appreciated. It was
the first radioisotope used for measuring thyroid uptake, and for several years it
has remained the primary imaging agent for evaluating thyroid function.[1] Despite the high sensitivity and specificity of the currently used in vitro tests
for the evaluation of thyroid function, thyroid uptake and scintigraphy play an important
role in various clinical settings, such as differential diagnosis of thyrotoxicosis.
When there is a strong clinical suspicion in a biochemically confirmed thyrotoxic
patient, increased uptake in the thyroid gland is indicative of hyperthyroidism while
decreased uptake suggests other clinical conditions such as subacute thyroiditis,
Hashimoto's thyroiditis, extrathyroidal cause of thyrotoxicosis, thyrotoxicosis factitia,
and drug interference. Thyroid uptake and scintigraphy also play an important role
for therapeutic decision making in various clinical settings, such as functional assessment
and characterization of nodule(s), identification of other causes of thyrotoxicosis,
detection and localization of ectopic thyroid tissue, and calculation of therapeutic
doses of I-131 iodide.[2]
In a normal euthyroid healthy individual, technetium-99m (Tc-99m) pertechnetate or
radioactive iodine uptake (RAIU) values depend upon iodine reserves in the thyroid
gland that in turn varies primarily based on the long-term dietary intake of iodine.[3]
[4] Pertechnetate and iodine are both transported into the thyroid gland by the same
sodium iodide symporter present in the thyroid follicular cells. The normal thyroid
uptake reference values for Tc-99m pertechnetate and radioactive iodine in euthyroid
person vary with the geographical location, and may change from one decade to the
next because of change in dietary intake and supplementation of iodine fortified foods.
Since there are geographical variations in the dietary iodine content, Tc-99m pertechnetate
or RAIU values may also vary accordingly.[5] Hence, there is a need for re-defining the local Tc-99m pertechnetate or RAIU reference
values periodically for accurate diagnosis of thyroid diseases as well as verification
of laboratory reports.
Thyroid uptake values that are currently used in various nuclear medicine departments
across the globe were established since the 1960s when there was widespread iodine
deficiency across various geographic regions. With the introduction of Universal Salt
Iodination Program from Nepal government since 1973, the prevalence of iodine deficiency
has decreased significantly. In the current setting of iodine sufficiency in Nepal,
the normal pertechnetate or RAIU values are expected to be lower than those international
references established earlier. With the current pertechnetate or RAIU reference values,
many patients with upper normal uptake values may be misdiagnosed as being normal.
Therefore, there is a need to re-establish the pertechnetate or RAIU local reference
range in the iodine sufficiency era.
A number of radioisotopes have been used for thyroid uptake studies. I-131 iodide
has the disadvantage of high radiation doses delivered to the gland (1–3 rad/mCi)
because of its long half-life of 8.2 days and 606 keV beta-particle emission. Its high principal gamma photon energy of 364 keV is inadequately
collimated by the commonly used scintillation gamma cameras, and therefore they produce
poor quality images. Thus, I-131 iodide for thyroid imaging has been restricted only
to staging and follow-up of patients with differentiated thyroid cancer.[2]
[6] Even in developing countries like Nepal, it is not used for imaging of thyroid gland.
I-123 is preferable to I-131 and is the imaging agent of choice as of 2023 because
it has a shorter half-life of 13 hours and 159 keV gamma photon suitable for imaging
with current scintillation cameras. It is devoid of beta-radiation; thus, it has a favorable radiation dosimetry. However, it is not available
in developing countries like Nepal because it is cyclotron produced and is expensive.
Contaminants such as I-124 iodide and I-125 iodide are frequently encountered increasing
the radiation dosimetry and degrading the image quality.[7]
[8] Currently Tc-99m in the form of pertechnetate (99mTcO4-) is the most commonly used agent for thyroid scintigraphy and uptake measurement
using scintillation gamma cameras in developing countries. The similarity of volume
and charge between the iodide and pertechnetate ions explains that Tc-99m pertechnetate
is taken up by the thyroid gland by the same sodium iodine symporter that uptakes
iodine.[9]
[10] It is trapped by the thyroid follicular cells by the same mechanism as iodine but
unlike iodine it is neither organified nor incorporated into thyroid hormones.
Tc-99m pertechnetate is extensively used across the globe because of a number of advantages:
(1) short half-life of 6 hours, (2) short retention in the gland, (3) devoid of beta-radiation, (4) favorable radiation dosimetry to the thyroid gland (10,000 times less
than that of I-131) and to the whole body, (5) its principal gamma photon of 140 keV
is ideal for collimation using scintillation cameras, and (6) it is generator produced
thus inexpensive, and (7) readily available form Molybdenum-Technetium generator.[11] Although Tc-99m pertechnetate is only trapped but not organified by the thyroid
gland, in the majority of cases the uptake and imaging data provide all necessary
information for accurate clinical diagnosis.[12] In rare instances, where available, I-123 can subsequently be used for the assessment
of organification defects.
In Nepal, there are mixed ethnic population with universal access to dietary iodine
in the form of iodized salt since 1973. Despite historical reports on deviating normal
thyroid uptake values in different geographical location (thus highlighting the importance
of establishing local standard normal reference values), the concerned Nepalese authorities
have neither revised nor established these reference values. The reason for this is
that only a few centers are available for nuclear thyroid scintigraphy and uptake
studies in Nepal as of 2023. Since Chitwan Medical College (CMC) lies in the central
region of Nepal and given the setting of only a few nuclear medicine centers in the
entire country, patients visiting CMC are ideal representatives of all ethnic groups
including Brahmins, Newars, Janajatis, and Chhetris and all geographical location
including terai, hills, mountains, and Himalayas all over Nepal. The aim of this study
was to standardize and establish the normal reference values for thyroid uptake of
Tc-99m pertechnetate in the Nepalese population.
Materials and Methods
We prospectively evaluated 52 normal euthyroid individuals comprising 46 females and
6 males (female-to-male ratio 7.6:1 and mean age of 38.6 ± 12.0 years within age range
of 20 to 71 years) in the Department of Nuclear Medicine, CMC, Bharatpur, Nepal during
the period from December 2020 to November 2023.
Prior laboratory assessment of recent thyroid function tests was obtained via serum
measurements of free tetraiodothyroxine (fT4) and TSH that were all within normal
limits of the institution's laboratory range. Quantitative determination of the serum
TSH was assessed in vitro using ADVIA Centaur, ADVIA Centaur XP, and ADVIA Centaur
XPT systems TSH assay using two-site sandwich immunoassay with direct chemiluminometric
technology, which uses constant amounts of two antibodies. The first antibody, in
the Lite Reagent, is a monoclonal mouse anti-TSH antibody labeled with acridinium
ester. The second antibody, in the Solid Phase, is a polyclonal sheep anti-TSH antibody
that is covalently coupled to paramagnetic particles. Quantitative determination of
free thyroxine (FT4) in serum or plasma (heparinized or ethylenamineintetraacetic
acid) was also performed using the ADVIA Centaur, ADVIA Centaur XP, and ADVIA Centaur
XPT systems that are competitive immunoassay using direct chemiluminescent technology.
The study protocol was approved by the Ethics Committee of CMC, Tribhuvan University.
All individuals were on a low iodine diet 2 weeks prior to the thyroid uptake and
scintigraphy study. Clinically euthyroid individuals aged more than 18 years with
no evidence of nodules or enlarged gland on palpation along with normal scan and background
findings confirmed by scintigraphic images were selected for the study.
Each subject was selected by using a questionnaire that evaluated the clinical history,
history of iodinated-contrast radiographic procedures, and a physical examination
to exclude those with thyroid, cardiac, or renal diseases. Individuals with iodine
contamination such as use of iodex for local application were also excluded. Participants
taking medications known to affect thyroid function such as thyroid hormones, antithyroid
medications like methimazole, carbimazole, or propylthiouracil, amiodarone, Lithium,
cough syrups, multivitamins, any ayurvedic, homeopathic and desi medicines or patients
with recent ingestion of sea foods were excluded from the study. Patients with a history
of radionuclide administration within 6 months of thyroid scanning, previous thyroid
surgery or radioiodine treatment and pregnant and lactating women were also excluded
in the study.
Each participant received 3.5 to 4.5 mCi of Tc-99m pertechnetate intravenously. The
percentage of Tc-99m pertechnetate taken up by the thyroid gland was determined at
20 minutes, using scintigraphic imaging techniques with the Siemens Intevo Bold Hybrid
single-photon emission tomography/computed tomography with a dual head digital gamma
camera equipped with a low energy, high-resolution parallel hole collimator. First
Tc-99m pertechnetate dose was measured in the Cap-In-Tec dose calibrator. Then radioactivity
counts in the syringe before and immediately after injection were obtained for 15 seconds
each for uptake calculation and the exact time of injection was noted in all cases.
A 20% energy window was centered at 140 keV. All patients were asked to drink water
10 minutes before imaging to clear any Tc-99m pertechnetate labelled salivary activity
from the esophagus. Anterior spot view mages of the neck were obtained at 20 minutes
of injection at a preset data of 750k counts for studying the structure and shape
of the thyroid gland ([Fig. 1]). The neck was slightly extended with a support at the back during the scanning
time and the camera head placed close over the neck with a matrix size of 128 × 128
and at zoom of 2. A control image of the radiopharmaceutical injection site was also
obtained to confirm that there was no subcutaneous extravasation of the injected dose
that would otherwise invalidate the uptake percentage calculation. The method for
calculation of thyroid uptake, based on images of the gland obtained and syringe counts
before and after radiopharmaceutical injection, was previously described by Maisey
et al[13] and simplified for routine use.[14] The number of counts present in the thyroid (T) was determined by manually drawing
the region of interest (ROI) along the borders of the right and left lobes of the
gland ([Fig. 1]). Other two ROIs were again drawn manually adjoining to the right and left lobes
for background subtraction (BG) ([Fig. 1]). The counts in the syringe before (B, i.e., presyringe counts) and after (A, i.e.,
postsyringe counts) radioisotope injection were obtained directly from the images.
All counts were corrected for the acquisition time and decay of Tc-99m by the computer.
The thyroid uptake (TU) was calculated from the equation: TU = (T–BG)/(B–A).
Fig. 1 Normal uptake of technetium-99m pertechnetate (0.7%: right—0.3%; left—0.4%).
Results
Thyroid uptake of Tc-99m pertechnetate in the study population ranged from 0.3 to
3.6%. Mean uptake was 1.26%, median uptake was 0.85%, and interquartile range was
0.7 to 1.7%. The mean (± standard deviation) Tc-99m pertechnetate uptake for males
and females were 1.1 ± 0.7 and 1.28 ± 0.79%, respectively, and overall mean pertechnetate
uptake in the population was 1.26 ± 0.78% ([Tables 1] and [2]).
Table 1
TSH values and Tc-99m pertechnetate uptake in normal population
|
Age
Median (IQR)
|
TSH
Median (IQR)
|
Uptake
Median (IQR)
|
|
Overall
|
37.5 (28.0–47.0)
|
2.28 (1.19–4.20)
|
0.85 (0.7–1.7)
|
|
Gender
|
Male
|
39.0 (38.0–56.5)
|
2.0 (0.92–2.05)
|
0.75 (0.57–2.00)
|
|
Female
|
35.5 (27.75–47.0)
|
2.4 (1.19–4.31)
|
1.0 (0.7–1.7)
|
Abbreviations: IQR, interquartile range; Tc-99m, technetium-99m; TSH, thyroid-stimulating
hormone.
Table 2
Mean and ranges of uptake in normal individuals
|
Group
|
Total
|
%
|
Mean age (y)
|
Age range (y)
|
% uptake range
|
% uptake mean ± SD
|
% uptake 95% CI
|
|
Male
|
6
|
11.5
|
44.67
|
38–58
|
0.5–2.0
|
1.1 ± 0.70
|
0.36–1.84
|
|
Female
|
46
|
88.5
|
37.87
|
20–71
|
0.3–3.6
|
1.28 ± 0.79
|
1.04–1.52
|
|
Population
|
52
|
52
|
38.65
|
20–71
|
0.3–3.6
|
1.26 ± 0.78
|
1.04–1.48
|
Abbreviations: CI, confidence interval; SD, standard deviation.
On comparing the gender-specific data, gender did not seem to play a significant role
in euthyroid pertechnetate uptake, but normal values appeared to be marginally lower
in men (1.1 ± 0.7%) than in women (1.3 ± 0.8%) ([Table 2]).
To determine if the uptake was distributed normally in the Nepalese population, uptake
values were grouped over intervals of 0.25% (0–0.25, > 0.25–0.50, > 0.50–0.75, and
so on) and a histogram of the mean uptake for the intervals generated ([Fig. 6]). These data clearly showed that pertechnetate uptake was skewed and not normally
distributed. Eight percent of the participants (n = 4) showed extremely low pertechnetate uptake (≤ 0.5%). Thirty-five percent of the
participants (n = 18) had uptake values below the departmental lower limit of 0.75%. The remaining
57% of participants had uptake values less than or equal to 3.6% (within the international
and departmental reference range of 0.75–4.5%). Because of skewness in uptake distribution,
we determined the reference range for Tc-99m pertechnetate by first plotting a cumulative
frequency curve and determined 5th and 95th percentiles to represent the normal reference
range for the euthyroid Nepalese population. The 5th and 95th percentiles were in
the range of 0.5 to 2.9% ([Fig. 7]).
Fig. 6 Frequency histogram of mean uptake of technetium-99m pertechnetate in Nepalese population.
Fig. 7 Cumulative frequency polygon with percentile of mean technetium-99m pertechnetate
uptake in Nepalese population.
Discussion
The existing literature on thyroid scintigraphy and uptake shows a number of radiotracers
currently used across the globe depending on the availability and indications of the
scan and uptake. Tc-99m pertechnetate is increasingly used as the radiotracer of choice
in patients with thyrotoxicosis because the result of the uptake is obtained in one
visit[15]
[16] in less than an hour time. Currently I-131 is not used for routine thyroid scintigraphy
because of its high radiation dosimetry and poor image quality. Its use is thus restricted
to extremely low doses (< 30 μCi) for obtaining uptake values for high-dose therapies
for differentiated thyroid cancer and hyperthyroidism from various causes. Currently
used radioisotopes for thyroid scintigraphy and uptake are I-123 iodide and Tc-99m
pertechnetate. However, I-123 iodide, being cyclotron produced, is expensive and not
available in developing countries like Nepal. Therefore, Tc-99m pertechnetate has
become the tracer of choice because it is readily available from Mo-Tc generator that
can be easily shipped to regional radiopharmacies. The use of I-123 iodide is restricted
to studies that require iodide organification such as organification defects in autoimmune
chronic thyroiditis and congenital dyshormonogenetic hypothyroidism.[9]
[10]
The maximum thyroid uptake of Tc-99m pertechnetate takes place at approximately 20 minutes
after intravenous injection of radioisotope, in contrast to I-131 iodide, which requires
a 24-hour uptake measurement period. Tc-99m pertechnetate uptake by the thyroid gland
is low and the currently used reference range by most of the laboratories in the world
is 0.75 to 4.5%.[17]
[18] But lower normal reference values have been described in different populations in
various literature. Studies have shown that normal values of Tc-99m pertechnetate
uptake depend on the technique used and on the dietary intake of iodide. Thus, each
laboratory should establish its own normal reference values for its local population.
This study assessed the normal values for thyroid Tc-99m pertechnetate uptake in Nepalese
population who were clinically and biochemically euthyroid. The normal reference range
for Tc-99m pertechnetate uptake used by our institute, a few other centers in Nepal
and many others across the globe (0.75–4.5%), is relatively wide. In our study, the
normal Tc-99m pertechnetate uptake reference range was 0.5 to 2.9%. This range of
thyroid uptake of Tc-99m pertechnetate in our study differed significantly from the
currently used international accepted reference range. Both the upper and the lower
range limits are lower than the international accepted standard range. These values
are similar to other literature data from other regions outside Nepal. Normal reference
ranges for thyroid uptake of Tc-99m pertechnetate vary significantly in different
geographic regions.[19]
[20] Recently published geographic specific literature data are as follows: Macauleya
et al (0.5–1.4%) from the UK, Ramos et al (0.4–1.7%) from Brazil, and Hamunyela et
al (0.15–1.69%) from Namibia.[19]
[21]
[22] All of these studies show normal reference values significantly lower than those
currently used in most of the nuclear medicine laboratories. Our study also closely
matches these lower limits of normal reference values proposed by different investigators
in different countries across the globe. However, upper limit of normal was slightly
higher in our study, that is, 2.9%. This variation is likely attributed to geographic
variation and dietary content of iodine in iodine fortified foods in this part of
the world. To our knowledge, there are no published reports of normal reference values
for thyroid Tc-99m pertechnetate uptake from institutions in Nepal or South Asian
countries. This study aimed to evaluate the normal values of Tc-99m pertechnetate
in the Nepalese population that will likely represent south Asian population too.
However, in contrast to study by Hamunyela et al that revealed decreased uptake with
increasing age, our study showed Tc-99m pertechnetate uptake increases with increasing
age of the individuals and the increased uptake with age was statistically significant
(p = 0.04; [Fig. 4]).[21]
Fig. 4 Relationship between technetium-99m pertechnetate and age (total euthyroid population).
The uptake values for 52 individuals revealed a non-Gaussian distribution, as previously
observed by Maisey et al.[13] In this study, the range of euthyroid uptake derived from Tc-99m pertechnetate was
significantly lower (0.5–2.9%) than the internationally accepted normal reference
values (0.75–4.5%) that are currently used by our institute (Department of Nuclear
Medicine, CMC, Nepal). The data in [Fig. 6] demonstrate that more than 50% of participants had very low uptake values below
1.0%. On the basis of the departmental reference values, 35% (n = 18) of these participants would have been diagnosed as abnormal. There is considerable
overlapping and significant differences between these data with those reported by
other investigators.
Thyroid uptake of radioiodine has shown persistent decline in the past decades. Lowering
of normal uptake values has been reported in Indian population that has ethnic and
geographic similarities with Nepalese population.[23] Some investigators have suggested that medication that contains supplements may
be responsible for the lowering of normal values of iodine. Anderson and Powsner demonstrated
that an increase in iodine ingestion in iodine fortified food was a major cause of
decreased reference values.[24]
Our study suggested that gender did not appear to significantly affect uptake of Tc-99m
pertechnetate ([Table 2]). The reasons for the low pertechnetate uptake values in our study may be attributed
to diet and dietary supplementation of iodine in the form of successful universal
salt iodination program by Nepal government since 1973. The continuous intake of iodized
salt could have reduced thyroid uptake of Tc-99m pertechnetate because thyroid uptake
of iodine directly correlates with Tc-99m pertechnetate uptake since the mechanism
of uptake of the two radioisotopes by the thyroid is similar. Reinhardt et al demonstrated
that thyroid uptake of pertechnetate inversely correlated with iodine intake.[25] Thus, thyroid uptake of pertechnetate tends to be low in iodine sufficient population
as in our study.
