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Endocrine Care |
Department of Nuclear Medicine (W.-A.N., F.S.-P., D.A.H.), Catharina Hospital, 5602 ZA Eindhoven, The Netherlands; and Departments of Endocrinology (W.-A.N., A.R.H.) and Nuclear Medicine (F.H.C.), University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands
Address all correspondence and requests for reprints to: Dr. D. Huysmans, Department of Nuclear Medicine, Catharina Hospital, P.O. Box 1350, 5602 ZA Eindhoven, The Netherlands.
Abstract
In a recent study, we demonstrated that pretreatment with a single, low dose of recombinant human TSH (rhTSH) doubles 24-h thyroid radioactive iodine uptake in patients with nodular goiter. The purpose of the present study was to investigate whether rhTSH pretreatment induces changes in the regional distribution of radioiodine as visualized on thyroid scintigrams in these patients.
Anterior planar thyroid 123I scintigrams were obtained in 26 patients with a nodular goiter (23 women and 3 men; age, 62 ± 9 yr, mean ± SD; thyroid weight, 165 ± 72 g) 24 h after administration of a diagnostic dose of radioiodine. All patients were studied twice: first, without rhTSH pretreatment (baseline study), and second, after an im injection of 0.01 mg (n = 10) or 0.03 mg rhTSH (n = 16), given 24 h before radioiodine administration (rhTSH study). For quantification of regional differences in radioiodine uptake, a region of interest method was used.
Upon visual inspection, baseline scintigrams showed a heterogeneous uptake of radioiodine. In general, rhTSH scintigrams also showed heterogeneous radioiodine uptake. In some patients, the distribution of radioiodine in the rhTSH scintigram was considerably more homogeneous than in the baseline scintigram. In a few patients, originally "cold" areas had changed into "hot" ones, whereas originally hot areas had changed into cold ones. Quantification of regional radioiodine uptake showed that pretreatment with rhTSH caused a larger increase in radioiodine uptake in relatively cold areas and a smaller increase in radioiodine uptake in relatively hot areas, compared with the increase in radioiodine uptake in the entire thyroid. In patients with a baseline serum TSH level of 0.5 mU/liter or lower, the increase in radioiodine uptake in relatively cold areas was significantly larger than in patients with a baseline serum TSH level higher than 0.5 mU/liter.
In conclusion, a single, low dose of rhTSH not only doubled 24-h radioactive iodine uptake but also caused a more homogeneous distribution of radioiodine within the thyroid gland in patients with a nodular goiter by stimulating radioiodine uptake in relatively cold areas more than in relatively hot areas. This was most marked in patients with a low baseline serum TSH level. Our data suggest that pretreatment with rhTSH may improve the efficacy of radioiodine treatment for volume reduction of nodular goiters, especially in patients with a low baseline serum TSH level.
RADIOIODINE TREATMENT IS effective in reducing thyroid volume in most patients with nontoxic, nodular goiter. In a number of reports in which ultrasonography, computed tomography, or magnetic resonance imaging for accurate measurements of thyroid volume were used, decreases in goiter size of approximately 40%, on average, after 1 yr, (1, 2, 3, 4, 5, 6) and of 50–60% after 3–5 yr have been described (2, 7, 8). In most patients, compressive symptoms improved as well (3). The improvement in compressive symptoms was accompanied by significant tracheal widening, as measured by magnetic resonance imaging (3), and improvement in respiratory function (3, 9).
In the reported studies, a single dose of approximately 100 µCi (3.7 MBq) of 131I per gram of thyroid tissue corrected for radioactive iodine uptake (RAIU) at 24 h was given. In patients with nontoxic, nodular goiter, RAIU is usually rather low. As a result, high doses of 131I are often needed, causing a relatively high radiation burden to extrathyroidal tissues (10). One of the causes of a low RAIU in these patients is a low-normal or below normal serum level of TSH.
In the last few years, recombinant human TSH (rhTSH) has become available for diagnostic use in patients with differentiated thyroid cancer (11, 12, 13). In these patients, rhTSH stimulates RAIU in thyroid remnants or thyroid cancer tissue. Recently, we reported that the administration of a single, low dose of rhTSH also considerably increases RAIU in patients with nodular goiter. A dose of 0.01 mg rhTSH given 24 h before 131I administration increased 24-h RAIU from 29 to 51%, on average, and 0.03 mg rhTSH given 24 h before 131I administration increased 24-h RAIU from 33 to 63%, on average (14). These observations suggest that administration of rhTSH before 131I therapy for nodular goiter might allow treatment with lower doses of 131I without diminishing the radiation-absorbed dose in the thyroid.
Nodular goiters are characterized not only by a relatively low uptake of radioiodine but also by an irregular distribution of radioiodine on thyroid scintigrams. The regional distribution of radioiodine in nodular goiters is likely to be dependent on the level of TSH stimulation, with some parts of the goiter needing higher circulating TSH levels to reach sufficient radioiodine uptake than other parts. It is unknown whether giving rhTSH before radioiodine administration preferentially stimulates radioiodine uptake in areas with a relatively high baseline uptake (hot areas) or in those with a relatively low baseline uptake (cold areas) or that radioiodine uptake in hot and cold areas is equally stimulated. If radioiodine uptake in at least some of the cold areas of the goiter would be increased by pretreatment with rhTSH, thyroid volume reduction of nodular goiters by radioiodine therapy might be improved by pretreatment with rhTSH. Therefore, the purpose of this study was to investigate whether pretreatment with rhTSH causes changes in the regional distribution of radioiodine on thyroid scintigrams in patients with nodular goiter.
Patients and Methods
Patients
Twenty-six patients with nodular goiter (23 females and 3 males; age, 62 ± 9 yr, mean ± SD; range, 45–74 yr), who were referred for radioiodine therapy to reduce thyroid volume, participated in the study. All patients had a negative test result (<1 IU/liter) for serum levels of TSH receptor binding antibodies (DYNOtestTRAK human, Brahms Diagnostica GmbH, Hennigsdorf, Germany). The mean thyroid weight, as estimated from planar thyroid scintigraphy (15), was 165 ± 72 g (mean ± SD; range, 60–300 g). All patients had normal serum levels of free T4 (FT4; chemiluminescent immunoassay; ACS:180 FrT4, Chiron Corp., Fernwald, Germany) and total T3 (chemiluminescent immunoassay; ACS T3, Ciba Diagnostics Corp., Medfield MA), whereas the serum TSH level (two-site chemiluminometric immunoassay; ACS TSH-3, Ciba Diagnostics Corp.; normal range, 0.2–5.5 mU/liter) was either normal (22 patients) or below normal (4 patients). Based on the results of careful palpation of the thyroid, followed by fine needle aspiration biopsy of dominant nodules and of those that had a different consistency from other nodules within the gland, there was no suspicion of thyroid malignancy in any of the patients. None of the patients had a history of significant cardiopulmonary disease or a recent history of taking any medication known to affect thyroid function or RAIU. Patients had not received iodine-containing agents in the last 6 months. An electrocardiogram, complete blood count, liver enzyme determinations, plasma creatinine and glucose measurements, and screening urinalysis did not show abnormalities in any of the patients. The study was approved by the institutional human research committee, and written informed consent was obtained from all patients.
Baseline planar thyroid scintigraphy and RAIU measurements
For thyroid scintigraphy, all 26 patients received a dose of 1 mCi (40 MBq) sodium (123I) iodide as an oral solution. In 17 patients, administration of 123I was combined with administration of 20 µCi (0.8 MBq) sodium (131I) iodide for measurements of RAIU and effective half-time of radioiodine in the thyroid (results of effective half-time measurements not included in the present report). In the remaining nine patients, RAIU measurements were performed with 123I, and the effective half-time of radioiodine in the thyroid was not measured.
Twenty-four hours after radioiodine administration, the thyroid region was imaged in the anterior plane for a preset time of 10 min with a single-headed gammacamera (Philips Medical Systems, Eindhoven, The Netherlands), using a low-energy general purpose collimator. A 20% energy window around the 159 keV photon peak of 123I and a 256 x 256 matrix were used.
In the patients who had received both 123I and 131I, RAIU was measured as percentage of the administered dose of 131I, corrected for physical decay, at 3, 6, 24, 48, 72, and 168 h, using a 3-inch x 3-inch NaI(Tl) detector. Deadtime corrections were made using standard software. It was checked that the use of the net area under the 364 keV peak of 131I prohibited any interference of the low-energy photons of 123I with RAIU measurements. In the patients who had received 123I only, RAIU was measured as percentage of the administered dose of 123I, corrected for physical decay, at 3, 6, 24, and 48 h using the same 3-inch x 3-inch NaI(Tl) detector. The net area under the 159 keV peak of 123I was used.
Thyroid planar scintigraphy and RAIU measurements after administration of rhTSH
At least 2 wk after the baseline investigation, a second thyroid scintigraphy and RAIU measurement were performed as described before, but this time after pretreatment with rhTSH. Twenty-four hours before radioiodine administration, rhTSH was injected in the quadriceps muscle in a dose of either 0.01 mg (n = 10) or 0.03 mg (n = 16). Before injection, freeze-dried rhTSH (ampoules containing 0.9 mg rhTSH; Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) was reconstituted with 1.2 ml sterile water. Then, part of the obtained solution was diluted with saline to a final concentration of 0.05 mg/ml.
The 17 patients who had received the combination of 131I and 123I in the baseline investigation received again both 131I (20–40 µCi; 0.8–1.6 MBq) and 123I (1 mCi; 40 MBq). Ten of these patients were pretreated with 0.01 mg rhTSH, and 7 with 0.03 mg rhTSH. The nine patients who had received only 123I in the baseline investigation received again only 123I (1 mCi; 40 MBq) and were pretreated with 0.03 mg rhTSH.
Comparison of baseline planar thyroid scintigraphy and planar thyroid scintigraphy after administration of rhTSH
To compare the thyroid scintigram after rhTSH administration (rhTSH scintigram) of each patient with the baseline scintigram, all scintigrams were corrected for background activity using a region immediately below the thyroid as background. Then, rhTSH scintigrams were moved into exactly the same position in the field of view as the baseline scintigrams, using standard software.
In the baseline scintigrams, regions of interest (ROIs) of 1
cm2 were placed in the region corresponding with
the highest number of counts per square centimeter
(ROImax). Then, a ROI corresponding with 90% of
counts of ROImax was sought, thereafter a ROI
corresponding with 80% of counts of ROImax,
etc., until ROImin, the region with
the lowest number of counts per square centimeter, was reached. The
number of counts in each ROI was recorded. The ROIs were saved and then
placed in exactly the same position in the rhTSH scintigrams. Again,
the numbers of counts in the ROIs were recorded. For each ROI, the
ratio between the number of counts in the rhTSH scintigram and that in
the baseline scintigram was calculated. This ratio was corrected for
the difference in the total number of counts in the entire thyroid in
the rhTSH scintigram and that in the baseline scintigram, resulting in
a normalized count ratio in each ROI, according to the following
formula:
 |
cient of variation [CV =
(SD/mean) x 100%] was calculated for each thyroid
scintigram. Statistical analyses
The mean values ± SD are given. Statistical analyses were done using the Mann-Whitney U test for unpaired observations (P values denoted as P) and the Wilcoxon sign-rank test for paired observations (P values denoted as P*). The level of significance was 0.05.
Results
On visual inspection, baseline planar thyroid scintigrams showed
the typical scintigraphic appearance of a nodular goiter,
i.e. heterogeneous uptake of radioiodine with areas of
increased and decreased radioiodine uptake, in all patients. In
general, the rhTSH scintigrams also showed heterogeneous uptake of
radioiodine. In some patients (e.g. no. 15 and 20; Fig. 1
), the distribution of radioiodine in
the rhTSH scintigram was considerably more homogeneous than in the
baseline scintigram. Interestingly, in a few patients (e.g.
no. 11 and 15; Fig. 1) originally cold areas had changed into hot ones,
whereas originally hot areas had changed into cold ones.
|
shows the normalized count
ratios in the ROIs of all 26 patients. A normalized count ratio of more
than 1.00 in a ROI indicates an increase of radioiodine uptake in this
ROI relative to the uptake in the entire thyroid gland, and a
normalized count ratio of less than 1.00 indicates a decrease of
radioiodine uptake in the ROI relative to the uptake in the entire
thyroid gland. In most patients, pretreatment with rhTSH caused a
relatively larger increase in radioiodine uptake in cold areas,
compared with the increase in radioiodine uptake in the entire thyroid.
Furthermore, in most patients rhTSH pretreatment led to a relatively
smaller increase in radioiodine uptake in hot areas, compared with the
increase in radioiodine uptake in the entire thyroid.
|
shows that the ratio between 24-h
RAIU after rhTSH administration and the baseline 24-h RAIU (RAIU ratio)
was 2.12 ± 0.53 (range, 1.23–3.11). Table 1 also shows that the
normalized count ratio in the ROI with the lowest number of counts in
the baseline study (normalized count ratio
ROImin) was 1.30 ± 0.29 (range,
0.93–2.04), which is significantly different from 1.00 (P*
< 0.0001). The normalized count ratio in the ROI with the highest
number of counts in the baseline study (normalized count ratio
ROImax) was 0.87 ± 0.16 (range,
0.50–1.11), which is also significantly different from 1.00
(P* < 0.0005). The normalized count ratio in
ROImin was more than 1.00 in 81%, more than 1.10
in 69%, and more than 1.20 in 58% of the 26 patients, respectively.
The normalized count ratio in ROImax was lower
than 1.00 in 77%, lower than 0.90 in 54%, and lower than 0.80 in 27%
of the 26 patients, respectively. The combination of a normalized count
ratio in ROImin of more than 1.00 and a
normalized count ratio in ROImax of less than
1.00 was found in 73% of patients. Using cut-off levels of 1.10/0.90
and 1.20/0.80, respectively, this percentage was 50 and 23%. There
were no significant differences in normalized count ratios in
ROImin or ROImax among the
patients who had received 0.01 mg rhTSH and the combination of
123I and 131I, those who
had received 0.03 mg rhTSH and the combination of
123I and 131I, and those
who had received 0.03 mg rhTSH and only 123I
(P > 0.1 for all comparisons).
|
The coefficient of variation of the numbers of counts per pixel in the thyroid scintigram was 60 ± 11% in the baseline study and 55 ± 11% in the rhTSH study (P < 0.001), indicating a significantly more homogeneous uptake of radioiodine throughout the thyroid gland after rhTSH administration.
Discussion
The present study demonstrates that administration of a single, low dose of rhTSH before a diagnostic dose of radioiodine not only doubles 24-h thyroid RAIU but also induces significant changes in the regional distribution of radioiodine on thyroid scintigrams in patients with nodular goiter. In most patients, pretreatment with rhTSH caused a larger increase in radioiodine uptake in relatively cold areas and a smaller increase in radioiodine uptake in relatively hot areas, compared with the increase in radioiodine uptake in the entire thyroid. As a result, the distribution of radioiodine on the rhTSH scintigram was significantly more homogeneous than that on the baseline scintigram, as demonstrated by a significantly lower mean coefficient of variation of the numbers of counts per pixel in the thyroid scintigram after rhTSH administration. In patients with a baseline serum TSH level of 0.5 mU/liter or lower, the increase in radioiodine uptake in relatively cold areas was significantly larger than in patients with a baseline serum TSH level higher than 0.5 mU/liter. This suggests that especially in patients with a low baseline serum TSH level, a more homogeneous distribution of radioiodine on the thyroid scintigram can be reached by pretreatment with rhTSH.
Our observations have important consequences when rhTSH pretreatment is considered as an adjunct to radioiodine therapy for volume reduction of nodular goiters. From our study, one may derive that the effects of rhTSH pretreatment for this purpose will depend on the decision whether or not the therapeutic dose of radioiodine is lowered according to the rhTSH-induced increase in 24-h RAIU. When the therapeutic dose of radioiodine is lowered according to the rhTSH-induced increase in 24-h RAIU, in a number of areas with relatively low baseline radioiodine uptake the 24-h retained amount of radioiodine per gram of thyroid tissue will nevertheless increase, which might improve the efficacy of radioiodine therapy for volume reduction of the goiter. In contrast, in a number of areas with relatively high baseline radioiodine uptake, the 24-h retained amount of radioiodine per gram of thyroid tissue will decrease. However, it is not likely that this will negatively influence the efficacy of radioiodine therapy; without rhTSH pretreatment, the 24-h retained amount of radioiodine per gram in these hot areas would have been considerably higher than the average retained amount per gram in the entire thyroid, and with rhTSH pretreatment, in most of these areas at least the average amount of radioiodine per gram in the entire thyroid will be retained at 24 h.
When the therapeutic dose of radioiodine is not lowered according to
the rhTSH-induced increase in 24-h RAIU, but based on the baseline 24-h
RAIU, most areas in the goiter, cold as well as hot ones, will retain a
higher amount of radioiodine per gram of thyroid tissue with
pretreatment with rhTSH than without pretreatment with rhTSH. This
conclusion can be drawn from multiplying the normalized count ratio
with the RAIU ratio (see Table 1
). This multiplication indicates the
difference in uptake in a ROI between the rhTSH study and the baseline
study when the dose of radioiodine in both studies is the same. From
the calculation "normalized count ratio x RAIU ratio" in
ROImin and ROImax in the
individual patients, one may derive that 24-h radioiodine uptake in the
area with the lowest baseline radioiodine uptake
(ROImin) will increase by a factor of three
(normalized count ratio ROImin x RAIU ratio,
2.81 ± 1.08, mean ± SD; range, 1.21–5.23) and
that 24-h radioiodine uptake in the area with the highest baseline
radioiodine uptake (ROImax) will increase 2-fold
(normalized count ratio ROImax x RAIU ratio,
1.84 ± 0.55, mean ± SD; range, 1.03–2.96). Not
lowering the therapeutic dose of radioiodine according to the
rhTSH-induced increase in 24-h RAIU may be advantageous for the
efficacy of the therapy. However, this dosage regimen carries a higher
risk of inducing radiation thyroiditis.
It should be noted that in a significant number of patients, rhTSH-induced increases in radioiodine uptake in areas with a relatively low baseline radioiodine uptake were small or even absent. This is not surprising, because part of these cold areas represent mainly cystic or fibrotic tissue or thyroid follicular cells that have (partially) lost their ability to express the Na+/I- symporter protein (16, 17). Such parts of the goiter cannot take up radioiodine, not even after heavy TSH stimulation. Furthermore, a relative increase in radioiodine uptake in cold areas on a planar scintigram should be cautiously interpreted because planar scintigraphy is a two-dimensional method. It cannot be excluded that an increase in radioiodine uptake in a relatively cold area by pretreatment with rhTSH is caused by an increase in radioiodine uptake in thyroid tissue lying anteriorly or posteriorly of a cold area that itself does not increase in uptake. In a small number of the patients described in the present study, single photon emission computed tomography (SPECT), a three-dimensional imaging method, was performed (our unpublished observations). Transaxial SPECT slices showed that in some cold areas rhTSH administration increased radioiodine uptake only in a rim of thyroid tissue, whereas the central part of the area showed no change in uptake. However, in other cold areas, SPECT images showed an increase in radioiodine uptake in the entire area, from anterior to posterior.
Seventeen of the 26 patients in our study received the combination of 123I and 131I. The high energy photons of 131I will have caused some scatter in the 123I thyroid scintigrams. However, the dose of 131I was only a small fraction of the dose of 123I, and the regional distribution of 131I within the thyroid is the same as that of 123I. Therefore, the effect of scatter of 131I on normalized count ratios will have been negligible. This was confirmed by the results in the patients who received only 123I, which were not different from those in the patients who received both 123I and 131I.
Our results do not allow the conclusion that 0.01 mg is the minimally effective dose of rhTSH in stimulating 24-h RAIU. However, the peak serum TSH level reached after administration of 0.01 mg rhTSH was only 4.64 mU/liter, on average. It is not likely that administration of a lower dose of rhTSH, resulting in peak serum TSH levels significantly lower than 4 mU/liter, will effectively elevate 24-h RAIU in these patients. Our data also do not demonstrate that the 0.03 mg dose is the maximally effective dose of rhTSH in stimulating 24-h RAIU. In fact, it is likely that a higher dose will increase 24-h RAIU even more. However, even when a higher dose of rhTSH is more effective in stimulating 24-h RAIU, it is doubtful whether this is clinically relevant, because with the 0.01 and 0.03 mg doses already a doubling of 24-h RAIU can be reached. Furthermore, larger amounts of thyroid hormones may be released after administration of higher doses of rhTSH.
In conclusion, a single, low dose of rhTSH not only doubled 24-h RAIU in patients with nodular goiter but also caused a more homogeneous distribution of radioiodine within the thyroid gland in the majority of these patients by stimulating radioiodine uptake in relatively cold areas more than in relatively hot areas. This was most marked in patients with a low baseline serum TSH level. Our data suggest that pretreatment with rhTSH might allow treatment with lower doses of 131I. Furthermore, they suggest that despite lowering of the dose of 131I, pretreatment with rhTSH might improve the efficacy of radioiodine treatment for volume reduction of nodular goiters, especially in patients with a low baseline serum TSH level. However, randomized studies comparing the efficacy of radioiodine therapy with and without rhTSH pretreatment have to be awaited before its use can be advised.
Acknowledgments
We thank Bernie Gitmans and Chris Jansen for their help in performing this study.
Footnotes
This work was supported by Genzyme BV (Naarden, The Netherlands).
Abbreviations: FT4, Free T4; RAIU, radioactive iodine uptake; rhTSH, recombinant human TSH; ROI, region of interest; ROImax, ROI with the highest number of counts; ROImin, ROI with the lowest number of counts; SPECT, single photon emission computed tomography.
Received November 11, 2000.
Accepted July 23, 2001.
References
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