Original article
Assessment of normal reference values for thyroid uptake of
technetium-99m pertechnetate in a single centre UK
population
Mavin Macauleya, Mohamed Shawgid, Tamir Alib, Andrew Curryb, Kim Howeb,
Elizabeth Howellb,c, Elizabeth Jeffersonb, Andrew Jamesa, Petros Perrosa and
George S. Petridesb
Objective This study aims to explore the normal reference
values for thyroid uptake of technetium-99m (99mTc)
pertechnetate in a UK population.
Patients and methods A retrospective review of 60
euthyroid patients who underwent thyroid imaging with
99m
Tc pertechnetate between January 2012 to April 2014 as
part of dual-tracer subtraction parathyroid scintigraphy.
99m
Tc pertechnetate thyroid uptake values were determined
for each patient. Medical records and biochemical thyroid
function tests were reviewed to ensure that all patients were
not on medication that could affect thyroid function and they
were both clinically and biochemically euthyroid 6 months
before and following the scan.
Results Median and interquartile uptake range of 99mTc
pertechnetate in euthyroid patients were 0.9 and 0.5–1.4%,
respectively. The normal reference range in the study
population was 0.2–2.0%. Thyroid uptake inversely
correlated with age in females (r = − 0.40, P = 0.04), males
(r = − 0.50, P = 0.04), and whole group (r = − 0.40, P = 0.002).
Introduction
Radionuclide imaging plays an important role in the
investigation of patients with thyroid disorders. In Europe,
technetium-99m (99mTc) pertechnetate has become the
most commonly used radiopharmaceutical in thyroid scin-
tigraphy owing to its low cost, ready availability, a short
duration for imaging, lower radiation burden to the patient
and preferable energy (140 KeV) for radionuclide imaging
[1]. Although iodine-123 (123I) provides better image
quality than 99mTc pertechnetate because of lower back-
ground activity, the diagnostic information provided by
both isotopes is broadly equivalent [2]. 99mTc pertechne-
tate uptake differs from 123I uptake in that the former does
not undergo organification [3].
Management of thyroid disorders depends on accurate
clinical assessment, appropriate investigations, ther-
apeutic interventions and subsequent careful monitoring.
Observed patterns of radionuclide scintigraphy and cal-
culation of uptake provide useful information on the
Data were presented previously at the Society for Endocrinology BES 2017 and
published as an abstract Endocrine Abstracts 2017; 50: P402.
0143-3636 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Conclusion The calculated normal reference range in this
study was found to be less than that used in our own and
many other UK institutions. The results demonstrate the
importance of periodic evaluation of normal uptake values
and provide support for prospective studies defining the
normal reference range to be performed. Nucl Med
Commun 00:000–000 Copyright © 2018 Wolters Kluwer
Health, Inc. All rights reserved.
Nuclear Medicine Communications 2018, 00:000–000
Keywords: endocrinology, euthyroid, pertechnetate, thyroid, thyrotoxicosis,
uptake
Departments of aEndocrinology, bRadiology and Nuclear Medicine, Newcastle
Upon Tyne Hospitals NHS Foundation Trust, cPET centre, Newcastle University,
Newcastle Upon Tyne and dDepartment of Radiology and Nuclear Medicine,
James Cook University Hospital, Middlesbrough, UK
Correspondence to George S. Petrides, MBBS, BSC, Nuclear Medicine,
Freeman Hospital, Freeman Road, Newcastle Upon Tyne NE7 7DN, UK
Tel: + 44 191 213 8203; fax: + 44 191 223 1230;
e-mail: george.petrides@nuth.nhs.uk
Received 14 February 2018 Revised 17 May 2018 Accepted 18 May 2018
aetiology of thyroid disease and thyroid dysfunction.
These patterns include diffuse increased uptake, diffuse
decreased uptake as well as focal and multifocal uptake.
Graves’ disease is usually associated with diffuse homo-
genously increased uptake on scintigraphy but occa-
sionally the gland may appear normal. Measurement of
thyroid uptake helps differentiate hyperthyroidism from
other causes of thyrotoxicosis. For instance, reduced
uptake with very low or absent uptake in a diffuse pat-
tern is often associated with subacute thyroiditis whereas
elevated uptake is often seen in patients with Graves’
disease or toxic nodular goitre [4].
The normal values for thyroid uptake in euthyroid
patients are dependent on the geographical location and
dietary iodine intake of a given population [5]. Thyroid
uptake may also be influenced by other factors including
hormones, medications and other conditions such as
pregnancy [6–8]. Thyroid uptake within a given popu-
lation may fluctuate over time. Blum and Chandra [9]
reported that normal thyroid uptake had changed twice
over a period of 20 years. Periodic validation of the
DOI: 10.1097/MNM.0000000000000876
 2 Nuclear Medicine Communications 2018, Vol 00 No 00
normal range is therefore strongly advocated [10,11]. To
date published location-specific normal reference ranges
for uptake of 99mTc pertechnetate are scarce and vary
significantly [12,13]. The most recently published ranges
by Ramos et al. [13] (0.4–1.7%) and Hamunyela et al. [14]
(0.15–1.69%) were from Brazil and Namibia respectively.
To our knowledge, there have been no published reports
of experiences in determining normal reference values
for 99mTc pertechnetate uptake from institutions in the
UK or Europe in the last 10 years.
The issue is highlighted in a recent UK audit of quan-
titative thyroid uptake imaging that identified a range of
normal reference ranges across the country with 43.8% of
centres unsure of their references for the normal range
[15]. This uncertainty was presumably because of the age
of the most recent published UK data. In Newcastle, a
normal reference range of 1–3.5% is employed and was
due for re-evaluation. The aim of this study was to
evaluate the normal reference range for uptake of 99mTc
pertechnetate in the Newcastle population using thyroid
uptake scans performed as part of dual subtraction para-
thyroid scintigraphy.
Patients and methods
Study design
A retrospective design was considered appropriate for the
study. It was also safe, considering that a prospective
design would raise concerns about radiation exposure to
healthy volunteers.
Patients
We identified 67 consecutive patients between January
2012 and April 2014 who met the following criteria:
(1) Had thyroid imaging with 99mTc pertechnetate as
part of dual-tracer subtraction parathyroid scintigra-
phy for primary hyperparathyroidism.
(2) Underwent thyroid scintigraphy 15–25 min post-99mTc
pertechnetate injection.
(3) Were biochemically euthyroid for 6 months before
and after scanning.
All studies were performed at the Nuclear Medicine
departments, Newcastle Upon Tyne Hospitals. An elec-
tronic review of medical records for individual patients was
then undertaken to ensure that the patients were not on
any medication or supplements that could affect thyroid
function, they had not received iodinated contrast or
radionuclide administration within 6 months of thyroid
scanning and they had not undergone previous thyroid
surgery or radioiodine treatment. This led to a further
seven patients being excluded from the analysis: five had
primary hypothyroidism treated with levothyroxine and
two had Graves’ disease treated with thionamide drugs.
Biochemical measurement of thyroid function was per-
formed locally at our Newcastle upon Tyne Hospital NHS
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Table 1 Euthyroid patient characteristics
TSH (0.3–4.7) FT4 (11–27)
Patients Age (years) (mU/l) (pmol/l)
Male (n = 16) 56.3 ± 17.3 1.5 ± 0.6 14.6 ± 2.2
Female (n = 44) 60.1 ± 13.3 2.0 ± 0.9 15.0 ± 2.9
All patients (n = 60) 59.4 ± 14.4 1.8 ± 0.9 14.9 ± 2.8
Data are expressed as mean ± SD.
FT4, free T4; TSH, thyroid stimulating hormone.
Foundation Trust laboratory (Roche platform). The char-
acteristics of the study group are summarized in Table 1.
Imaging protocol
All patients were scanned using a standard thyroid scin-
tigraphy protocol. Images were acquired 20 ± 5 min fol-
lowing intravenous administration of 80 MBq 99mTc
pertechnetate. Patients were imaged with a gamma
camera equipped with a low-energy, high-resolution,
parallel-hole collimator. Images were acquired as a
dynamic series on a 128 × 128 matrix and summed over
time without further processing. The system sensitivity
was measured using a thyroid uptake neck phantom.
99m
Tc pertechnetate imaging was performed before the
sestamibi imaging component of the dual-tracer para-
thyroid subtraction investigation. The subsequent sesta-
mibi imaging was not reviewed in the present work.
Calculation of thyroid uptake
The number of counts in the thyroid was determined by
drawing a region of interest around the borders of the
gland. Another region of interest was drawn below the
neck for background subtraction. All the counts obtained
were corrected for the decay of 99mTc pertechnetate and
acquisition time. Residual activity from pertechnetate
injection was not routinely measured as part of the
parathyroid subtraction scintigraphy protocol. It was
therefore not available for correction of injected activity,
which has been taken to be the measured activity in the
syringe before injection. Thyroid uptake at 20 min was
automatically calculated using the following equation:
Thyroid uptake %
Thyroid countbackground count
¼ 100:
Injected activitysystem sensitivityimage duration
Data analysis
Statistical analysis was performed using Graphpad Prism
7.0d software (GraphPad Software, La Jolla, California,
USA). Data were expressed as median (interquartile
range). Shapiro–Wilk normality test was used to analyse
the distribution of the data. Mann–Whitney test was used
to compare groups as appropriate. Spearman’s correlation
was used to assess relationship between variables.
Statistical significance was defined as P less than 0.05.
 99m
Tc thyroid uptake reference values Macauley et al. 3

Fig. 1 Fig. 2

Distribution of 99mTc pertechnetate uptake in the study group. The

unbroken lines represent the current normal range in our institution and
the broken lines represent the normal range in our study group.

A cumulative frequency curve was used to estimate a

normal reference range at the 5th and 95th percentile.

Results
Median uptake of 99mTc pertechnetate in the thyroid was
0.9%, and the interquartile range was 0.5–1.4%. The
observed range in the study group was 0.1–6.3% (Fig. 1).
Median (interquartile range) uptake observed in the male
group was 1.2% (0.6–1.6%), and in the female group 0.8%
(0.5–1.1%). There was a negative correlation between
age and per cent uptake of 99mTc pertechnetate in the
female (r = − 0.40; P = 0.04), male (r = − 0.50; P = 0.05)
and entire groups (r = − 0.40; P = 0.002) (Fig. 2).
99m
Tc pertechnetate uptake in the euthyroid group was
not normally distributed (Shapiro–Wilk normality test;
P < 0.0001). Therefore, the mean ± SD and 95% con-
fidence interval cannot directly reflect the normal reference Relationship between 99mTc pertechnetate uptake and age in females (a),
males (b) and whole group (c).
range. Figure 3 shows a cumulative frequency curve which
demonstrates a normal reference range of 0.2–2.0%.
Only 47 patients had an ultrasound of the thyroid. Fig. 3
Normal thyroid sonography was reported in 49% and
benign nodules were reported in 51%. There were no
statistically significant differences in 99mTc pertechnetate
uptake between patients with or without benign thyroid
nodularity (1.3 ± 1.3 vs. 0.9 ± 0.6%; P = 0.26).

Discussion
The normal 99mTc pertechnetate uptake reference range
calculated by this study was found to be 0.2–2.0%. Both
the upper and the lower limits of this range are lower than
those used in our centre and in many other UK institu-
tions. A recent national audit that addressed normal The cumulative frequency of 99mTc pertechnetate uptake with proposed
reference range (5th and 95th percentiles).
ranges in use across the UK demonstrated the mean
99m
Tc pertechnetate uptake value at 20 min (± 5 min)
used by institutions in their normal range was 0.6% for limit of the reference range are less than all of those
the lower limit and 3.3% for the upper limit (n = 15) [15]. employed by the audited UK institutions with one
In addition, both the calculated lower limit and the upper exception [15].

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 4 Nuclear Medicine Communications 2018, Vol 00 No 00
The reference range calculated in our study is however
similar to that reported in the recent literature from
geographically distant locations suggesting the lower
values are not an anomaly [13,14]. The range does vary
from the most recent but older UK-based and US-based
studies in the 1960s and 1970s that are summarized in
Table 2 [1,16–18]. This may explain the higher reference
ranges employed in many UK institutions. In the late
1960s and early 1970s, a decreasing trend in normal
thyroid uptake was observed with increased dietary
iodine felt to be the main causative factor [19–21]. Since
this time, dietary iodine intake has increased with peak
activity in the 1970s and 1980s [22]. This was likely in
part because of iodine-rich dairy products and seafood
being more widely available. More recently, there has
been concern regarding iodine deficiency in certain UK
populations. A UK-based study from 2011 demonstrated
that two-thirds of teenage girls had iodine defi-
ciency [23].
The variation in iodine intake over the decades is likely
to be the main contributing factor to differing thyroid
uptake calculations over this time period but the exact
relationship is difficult to demonstrate. The fact that our
new derived normal reference range shows a reduction to
that seen in the majority of studies in Europe and the
USA in the 1960s/1970s, despite iodine deficiency being
described in some UK populations is felt more likely to
be because of an absence of data from the intervening
period when iodine intake was at its highest, as well as
the varying age of our study group. In addition, our stu-
died population may be significantly different from that
included in studies from which the adopted reference
ranges were derived.
Another factor that may play a role in the differing
thyroid uptake calculations is the absence of routine
measurement of residual activity as part of the para-
thyroid subtraction scintigraphy protocol. It was therefore
not available for correction of injected activity, which has
been taken to be the measured activity in the syringe
before injection. This will lead to a small systematic
overestimation of the injected activity and commensurate
underestimation of uptake. However, we believe this
effect to be small. To quantify the expected impact of
missing residual data, we reviewed residue information
from 100 consecutive pertechnetate thyroid scans.
Table 2 Normal values for uptake of
99m
Tc pertechnetate in the
literature
References (country of origin) Range (%)
Atkins and Richards [16] (USA) 0.5–4.0
De Garreta et al. [17] (UK) 0.4–3.0
Hurley et al. [18] (USA) 0.24–3.4
Van’t Hoff et al. [1] (UK) 0.7–2.9
Ramos et al. [13] (Brazil) 0.4–1.7
Hamunyela et al. [14] (Namibia) 0.15–1.69
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Dispensing and injection of these activities were per-
formed to exactly the same protocols as in the study group,
except that postinjection residual was routinely measured
and recorded. These thyroid scan injection data showed
mean residuals of 1.5 ± 1.0 MBq (0.1–5.5 MBq) or mean
dispensed activity of mean 1.8 ± 1.8% (0.1–5.7%).
Acknowledging unaccounted residuals in this range are
likely to be present in our data does not significantly alter
our results. Even assuming all the unmeasured residuals
were at the level of the highest seen amongst thyroid scan
injections, the adjusted reference range suggested would
be in the order of 0.2–2.1%.
Of interest, the data also showed that in-vivo 99mTc
pertechnetate uptake within the thyroid decreases with
age (Fig. 2). This may be secondary to the physiological
decrease in iodine uptake secondary to a reduction in
colloid content and follicular volume in the elderly [24].
Although 99mTc pertechnetate uptake was lower in
males, there was no significant difference in 99mTc per-
technetate uptake between the male and female groups.
This suggests that the age-related decline in 99mTc per-
technetate uptake should be taken into account when
interpreting scans of patients of different ages, but the
study group is too small to separate the data further.
The study had several limitations. The study was retro-
spective and the sample size was small. Data available
were limited to that collected during routine care and did
not include injection residual activities. Only electronic
notes from Newcastle Upon Tyne Hospitals NHS
Foundation Trust were available for review. Only 78% of
patients had an ultrasound. Although 99mTc pertechne-
tate uptake could be influenced by the presence of
benign nodules, we found no significant difference in
uptake between patients with normal glands and those
with benign thyroid nodules. Urine iodine levels were
not routinely measured to confirm the adequacy of iodine
intake. Although iodine is not routinely measured as part
of the biochemical assessment for parathyroid gland
pathologies, we did not expect the study population with
a mean age of 59.4 ± 14.4 years to be iodine deficient.
Conclusion
The study suggests the current reference range used in
our institution may not be accurate and a new, lower
normal reference range for thyroid uptake of 99mTc per-
technetate is likely to be needed in the Newcastle
population. This study provides support for prospective
studies to be carried out to properly determine a new
thyroid uptake reference range for a UK population.
Future work should ideally look at establishing an ‘age
corrected’ normal range given the statistically significant
age variation demonstrated. Periodic revalidation of nor-
mal reference values is advocated, but the authors
acknowledge the inherent difficulties associated with
conducting studies to establish reference ranges for
techniques involving radioactivity in healthy individuals.

Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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