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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-0458
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2775-2780
Copyright © 2005 by The Endocrine Society

Recombinant Human Thyrotropin as Adjuvant in the Treatment of Multinodular Goiters with Radioiodine

C. C. Albino1, C. O. Mesa, Jr.1, M. Olandoski, C. E. Ueda, L. C. Woellner, C. A. Goedert, A. M. Souza and H. Graf

Instituto de Diabetes e Endocrinologia de Maringá (C.C.A.), Maringá 87013-010 Brazil; Serviço de Endocrinologia e Metabologia do Hopital de Clínicas da Universidade Federal do Paraná (C.O.M.J., H.G.), Brazil; Núcleo de Bioestatística da Pontifícia Universidade Católica do Paraná (M.O.), Centro de Medicina Nuclear (C.E.U., L.C.W.), Centro de Tomografia Computadorizada (C.A.G.), and Serviço de Ecocardiografia da Universidade Federal do Paraná (A.M.S.), Curitiba 80810-070, Brazil

Address all correspondence and requests for reprints to: Hans Graf, Federal University of Parana, Internal Medicine, Solimoes Street 1184 Curitiba PR, Brazil 80810-070. E-mail hansgraf{at}bsi.com.br.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The use of 131I in the treatment of multinodular goiters (MNG) is well established. We evaluated the effect of 30 µCi 131I (1.11 GBq) in 18 patients with MNG with the aid of two injections of 0.1 mg recombinant human TSH (rhTSH), given on d 1 and 2. A dose of 30 µCi 131I was given on d 3. TSH, T3, free T4, and thyroglobulin were measured on d 1, 2, 3, 5, 10, 30, 60, 90, and 180, and antithyroid antibodies were measured on d 1, 30, 90, and 180. Twenty-four-hour 131I uptake measured 1–3 months before rhTSH increased from 12.3 ± 6.2 to 53.5 ± 10.9% (P < 0.0001), free T4 from 1.3 ± 0.2 to peak 3.2 ± 1.1 ng/dl levels (P < 0.0001), T3 from 113.9 ± 35.0 to peak 332.2 ± 123.0 ng/dl levels (P < 0.0001), TSH from 0.76 ± 0.71 to peak 18.9 ± 5. 3 mU/liter levels (P < 0.0001), and thyroglobulin from 280.9 ± 370.0 to peak 1838.5 ± 1360.7 ng/dl levels (P = 0.001). Painful thyroiditis (33%) and mild thyrotoxicosis (39%) constituted minor side effects. There were no changes in echocardiographic parameters, done before and after rhTSH administration, on d 3. Hypothyroidism developed in 65%. Mean goiter size, measured by computed tomography, decreased from 97.9 ± 45.4 to 65.5 ± 47.3 ml (P < 0.0001; reduction: 39 ± 19%) after 6 months. We conclude that rhTSH is a safe and efficient therapeutic tool in the treatment of MNG allowing the use of outpatient therapeutic 131I doses.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE USE OF 131I for the treatment of multinodular goiter (MNG) patients has been described in several studies in the past 15 yr, leading to a decrease in goiter volume ranging from 33.9 (1) to 48% (2) in the first year of follow-up. An improvement in the compressive symptoms and respiratory function has also been described (1, 3). The administered 131I doses vary and depend on both the glandular volume and on the iodide uptake. Because iodide uptake is commonly low in MNG patients, high 131I activity may be necessary, requiring patient hospitalization and greater exposure to radiation. One cause of the reduced uptake in MNG is the low serum TSH level found in a large number of patients, which is a consequence of the autonomous areas in the gland (4). In iodine-sufficient areas, MNG have a lower radioiodine uptake, indicating that the amount of iodine in the patient’s diet affect this variable.

Recombinant human TSH (rhTSH) has become available for diagnostic purposes in thyroid cancer patients (5). rhTSH is also effective in increasing iodine uptake by thyroid remnants after total thyroidectomy and, therefore, may be used in preparation for thyroid remnant ablation (6). Huysmans et al. (4) demonstrated that a single 0.03-mg dose of rhTSH may double iodine uptake in MNG patients. Thus, the use of rhTSH increases iodine uptake in MNG patients, enabling the administration of lower therapeutic doses of 131I and avoiding the need for hospitalization. Using 0.01- and 0.03-mg doses of rhTSH, the same group was able to reduce the 131I dose used in treating MNG patients without negatively affecting the result (7).

The possibility of thyroid hormone elevations, painful thyroiditis, and an increase in thyroid volume are issues of concern after rhTSH administration in these patients. Our goal in this study was to evaluate goiter reduction up to 6 months after a fixed, small 131I dose with the aid of rhTSH. Furthermore we assessed the increase in thyroid 131I uptake, the acute changes in TSH, thyroid hormones, thyroglobulin (Tg), antithyroid antibodies, and TSH receptor antibodies (TRAbs) and whether the procedure affects the cardiovascular system.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
From September 2002 through May 2003, 18 MNG patients were evaluated. Diagnosis of MNG was done clinically and through ultrasound. None of the patients had previous surgical or 131I radioactive treatment. They either had contraindications for surgery or refused a surgical approach. Seven patients had a TSH level less than 0.1 mU/liter, with high normal or slightly elevated free T4 (fT4) values on initial presentation and were treated with 5–10 mg methimazole every day, during a mean time of 6 wk (4–12 wk). The thioamides were stopped 2 wk before receiving the 131I dose, with all patients presenting normal thyroid hormone values at this point. All these patients were receiving 80–120 mg propranolol every day. All patients underwent fine needle aspiration biopsy and were found to have colloid nodules on cytopathological analysis.

The subjects‘ mean age was 62 yr (range 45–77 yr), with 15 female (83%) and three male (17%) patients (Table 1Go). The thyroid volume was measured through helical computed tomography (Secura; Phillips Medical Systems, Eindhoven, The Netherlands) with 2.5-mm-wide axial sections, with posterior multiplane and three-dimensional reconstructions, performed before and 6 months after treatment. We used the Advantage Work ADW 4.0 workstation (GE Medical Systems, Milwaukee, WI) for volume measurement with the aid of the HISTO program.


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  		TABLE 1. Characteristics of 18 patients with MNG submitted to rhTSH and 30 mCi 131I

 
One to 3 months before the treatment with rhTSH, the patients underwent a 131I scintigraphy and 24-h 131I uptake using a rectilinear scanner with a 3-inch-thick NaI (Tl) crystal (Pho/Dot Scanner; Nuclear-Chicago, Chicago, IL) and an uptake measurement device (model 8725; Nuclear-Chicago). Previously published reference values for the 24-h radioactive iodine uptake in Brazilian individuals, which were 25 ± 5% (8), probably represent an overestimation because the iodine intake has increased because of the recent introduction of more iodized salt containing 40–100 ppm (9). At this moment, none of the patients was treated with methimazole. They were instructed to eat a low-iodine diet (removal of iodized salt and iodine-rich foods) for at least 15 d before administration of the therapeutic dose.

A 0.9-mg vial of rhTSH (Thyrogen; Genzyme Transgenics Corp., Cambridge, MA) was diluted in 9 ml sterile water for injection and 1 ml (0.1 mg) rhTSH was administered im on 2 consecutive days (d 1 and 2), and a tracer dose of 50 µCi 131I of was administered on d 2, immediately after the second rhTSH injection, followed by scintigraphy and 24-h uptake on d 3. On d 3, 24 h after the second rhTSH injection, a standard therapeutic dose of 30 µCi (1.11 GBq) of 131I was administered to all patients.

Blood samples were collected on d 1, 2, 3, 5, and 10 and 1, 2, 3, and 6 months for TSH analysis (chemiluminescence, reference values 0.4–4.0 mU/liter), total T3 (chemiluminescence, reference values 70–170 ng/dl), fT4 (chemiluminescence, reference values 0.8–1.9 ng/dl), and Tg (immunofluorometric assay with 0.01 ng/ml sensitivity). Serum was collected on d 1, 30, 90, and 180 for the determination of anti-Tg antibody levels (chemiluminescence, positive > 40 IU/ml), antithyroperoxidase antibody levels (chemiluminescence, positive > 35 IU/ml), and TRAb (TRAb, radioreceptor assay, normal range < 10 U/liter).

The patients underwent cardiovascular assessment with two-dimensional Doppler echocardiography, with analysis of parameters related to systolic function (shortening percentage and ejection fraction) and diastolic function (isovolumetric relaxation time and E/A ratio) as well as left ventricular (LV) mass. One patient presented with atrial fibrillation. Echocardiography was performed by a single operator, without significant intraobserver variation (<4%). The E/A ratio was determined in 17 of 18 patients, excluding the patient with atrial fibrillation, an arrhythmia that prevents to perform this evaluation. Basal echocardiography was done 1–2 wk before rhTSH and 131I administration, when all patients were in a euthyroid state and repeated again on d 3. The board of ethics of the Hospital de Clínicas of the Universidade Federal do Paraná approved the study, and all patients signed an informed consent form.

Statistical analysis

The results are expressed as mean ± SD or median (range). The Kolmogorov-Smirnov test was used to test normality of distributions. The time effect was analyzed by Student’s paired t test or Wilcoxon’s test, as appropriate. Pearson’s or Spearman’s correlation coefficient, as appropriate, evaluated the relation between variables. Two-sided tests were used, and P < 0.05 was considered significant. The calculations were performed using the SPSS software, version 10.0 (SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The basal thyroid volume by computed tomography scan was 97.9 ± 45.4 and decreased to 66 ± 47 ml 6 months after therapy, an average reduction of 39 ± 19% (P = 0.0004). One patient was excluded because she died secondary to sepsis 5 months after treatment, an event without any relation to her thyroid problem.

Using the pretreatment thyroid volume and the post-rhTSH 131I uptake, we calculated the effective µCi/g activity of 131I, which was given to each patient, and correlated this with the decrease in thyroid volume. This analysis revealed a significant positive correlation between the administered dose and the degree of volume reduction (r = 0.676, P = 0.002) (Fig. 1Go).



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  		FIG. 1. There was a significant positive correlation between the degree of goiter volume reduction and the effective µCi/g activity of administered 131I (r = 0.676, P = 0.002).

 
Administration of 0.1 mg rhTSH on 2 consecutive days increased 131I uptake in 24 h from 12.3 ± 6.2% to 53.5 ± 10.9% (P < 0.0001) (Table 1Go). The ratio between post- and pre-rhTSH 24-h 131I uptake (R uptake) indicates the fold increase in the 24-h 131I uptake in response to rhTSH. Median R uptake was 4.6 (1.5–36.3), and there was an inverse correlation between the R uptake and the pre rhTSH 131I 24-h uptake (r = –0.758, P < 0.0001).

We observed a change in the scintigraphic pattern between the pre- and post-rhTSH images; areas that had been previously cold showed a greater increase of iodine concentration on post-rhTSH images, which displayed a homogeneous uptake.

TSH, fT4, T3, and Tg values are summarized in Table 2Go. TSH levels increased from 0.76 ± 0.7 mU/liter to a peak of 18.9 ± 5.3 mU/liter on d 3 (P = 0.001). Whenever TSH levels began to rise (>5.0 mU/liter) after the 131I therapy, thyroxine therapy was initiated. The prevalence of hypothyroidism at the end of the study was 65%. fT4 levels increased from 1.3 ± 0.2 to 3.2 ± 1.1 ng/dl on d 3 (P = 0.0117), remaining at high levels until d 30 and then generally showed low levels after 3 months. Mean fT4 and TSH values after therapy (shown at each point in Table 2Go) do not include patients on T4 treatment. T3 levels increased from 113.9 ± 35.0 ng/dl (median, 100.3; range, 76.9–212.0) to a peak of 332.2 ± 123.0 ng/dl on d 3 (P = 0.001), remaining at levels above the normal range until d 10. Basal Tg levels were 280.9 ± 370.0 ng/ml (median, 112.1; range, 0.34–1150.0) and rose to 1838.5 ± 1360.6 on d 5 (P = 0.001). The Tg levels declined to values below the basal levels after month 6. Five patients had transient anti-TPO antibody titer elevation, and one patient had transient anti-Tg titer elevation. None of the patients developed positive TRAb levels.


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  		TABLE 2. TSH, fT4, T3, and TG values on d 1 and after rhTSH and 30 mCI 131I on d 2, 3, 5, and 10 and on months 1, 2, 3, and 6 in 18 patients with MNG

 
There was a positive correlation between post-rhTSH 131I uptake and peak TSH (r = 0.676, P = 0.002) and fT4 values (r = 0.557, P = 0.016), with no correlation with Tg values (r = 0.13, P = 0.6479). We did not correlate the area under the curve of serum TSH levels and the thyroid hormone stimulation.

The Doppler echocardiogram did not show significant differences in the LV mass or in the systolic or diastolic function when the post- and pre-rhTSH tests were compared (Table 3Go). There were no significant differences in the comparisons between pre- and post-rhTSH echocardiograms among patients who used ß-blocking drugs compared with those who did not use them, in any of the parameters tested.


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  		TABLE 3. Pre- and post-rhTSH Doppler-echocardiographic parameters

 
Seven patients (39%) developed a few signs or symptoms of thyrotoxicosis such as palpitation, anxiety, and asthenia, which started 5–10 d after rhTSH treatment. Our protocol did not include thyroid hormone measurements between d 10 and 30, when some of the patients reported thyrotoxic symptoms. These patients were started on propranolol, with doses ranging between 80 and 120 mg daily, with prompt improvement in response to therapy. Six patients (33%) showed symptoms of radiation-related thyroiditis, starting at least 1 wk after the 131I dose, characterized by moderate cervical pain that responded to treatment with nonsteroidal anti-inflammatory drugs (Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
rhTSH has been safely used for several years in the follow-up of thyroid cancer patients (5, 10). In normal subjects, rhTSH leads to an increase in thyroid size and thyroid hormone values (11). The first study to show that it is possible to administer rhTSH to MNG patients to increase iodine uptake was carried out by Huysmans et al. (4). These authors have shown that it was possible to double the radioiodine uptake with as little as 0.03 mg rhTSH administered 24 h before the 131I dose. Other studies using higher rhTSH doses in MNG patients showed the same 131I uptake rise (9, 12).

Because the goiter size was highly variable in our study and we used a fixed 131I activity (30 µCi; 1.11 GBq), we calculated the retained thyroid 131I activity and determined correlations with the volume reduction of the goiter. We were able to show a positive correlation between the radiation dose to the thyroid and the decrease in thyroid volume at 6 months (Fig. 1Go). This is in fact the first observation that higher radiation doses to the thyroid obtained by pretreatment with rhTSH may improve the efficacy of radioiodine with respect to thyroid volume reduction. Although no great effect on goiter reduction from L-T4 therapy is expected in patients who developed hypothyroidism, this might be taken in consideration. In contrast, a fixed 30 µCi 131I dose without rhTSH results in a more modest decrease in goiter volume with an average decrease of 24.5% at 14 months (13). The 30-µCi 131I dose is the maximum outpatient dose allowed by Brazilian Nuclear Medicine Regulations.

In the current study, two doses of 0.1 mg rhTSH given on consecutive days before the uptake studies increased the mean 131I uptake by 4.6-fold. The effect of rhTSH on radioactive uptake is modest when 131I is given within the first hours after rhTSH administration, and the observed rise in radioactive uptake is perhaps mainly due to the stimulation obtained through the first of the two consecutive rhTSH injections. Also, because the time delay from rhTSH injection and 131I administration is of great importance (4, 14), the therapeutic dose of 131I given at d 3 may not completely correspond to the measured 24-h 131I uptake.

We cannot rule out that in some patients the change in iodide intake before the rhTSH administration has influenced the increase in the 131I thyroid uptake after rhTSH stimulation in a subset of patients. Ideally, the low-iodine diet should have been initiated before the initial 131I uptake and remain unchanged during the study period.

In subjects with no thyroid disease, 0.1 mg rhTSH significantly raised the TSH, T3, and T4 levels, without symptoms of thyrotoxicosis (15). In MNG patients, using 0.03 mg rhTSH, a 69% increase of T3 and a 42% increase of fT4 was noticed (4). In our study, the T3 and the fT4 levels were higher (191 and 146%, respectively), most likely due to the higher rhTSH dose administered in our protocol. Silva et al. (9) used a single 0.45-mg dose of rhTSH and 131I doses ranging from 50–150 µCi to treat MNG patients, who developed similar T3 and fT4 elevations (200 and of 136%, respectively).

About one third of our patients developed mild thyrotoxic symptoms that could be controlled easily by the administration of a ß-blocking agent. Perhaps ß-blockers should be given routinely as a prophylactic measure to reduce thyrotoxic symptoms, provided there are no contraindications. About one third of our patients developed a clinically significant radiation-induced thyroiditis, a higher incidence than that reported in MNG patients treated with conventional 131I therapy (4%) (16).

One of the major concerns of an acute increase of thyroid hormones is the impact on the cardiovascular system (17). To analyze such effects in our patients, we performed a basal two-dimensional Doppler echocardiography and repeated it on the day on which the thyroid hormone levels peaked (d 3). We found no significant differences between the two evaluations. We did not expect a change in the echocardiographic parameters concerning LV mass, a well-known consequence of chronic hyperthyroidism (17, 18). Hyperthyroidism, both acute and chronic, may also alter cardiac dynamics and increase preatrial heartbeats detected by a 24-h Holter (17, 18, 19), a parameter that was not assessed in the present study.

In our study, seven patients were taking a ß-blocker drug at the time of echocardiography. However, even after excluding this group, we found no significant differences in the parameters tested before and after rhTSH. We did not repeat the echocardiogram after d 10, when some patients presented with signs of thyrotoxicosis and may have had even higher thyroid hormone levels. It may be of interest to further evaluate this aspect in a future study.

In summary, this is a short-term observational study that focused on the safety and efficacy of rhTSH in euthyroid and marginally hyperthyroid patients with MNG. It is not a randomized trial, comparing the safety and efficacy of 131I therapy after treatment with various doses of rhTSH with that of standard 131I therapy, i.e. without pretreatment with rhTSH. Clinical trials in iodine sufficient and insufficient areas in symptomatic, toxic, and nontoxic MNG patients are needed to further determine the optimal doses of rhTSH for the treatment of these patients. We conclude that 0.1 mg rhTSH administered on 2 consecutive days is an efficient therapeutic tool in the treatment of MNG with low radioiodine uptake allowing the use of ambulatory therapeutic 131I doses. This is the first study demonstrating that radioiodine, using a standard ambulatory dose of 30 µCi (1.11 GBq), is effective in reducing thyroid volume in patients with MNG with low baseline radioactive iodine uptake when pretreatment with rhTSH is given.


   Acknowledgments
 
We thank David Cooper, Peter Kopp, and Shez-Basaria for continuous assistance and support during the preparation of this manuscript.


   Footnotes
 
First Published Online February 15, 2005

1 C.C.A. and C.O.M.J. contributed equally to this work. Back

Abbreviations: fT4, Free T4; LV, left ventricular; MNG, multinodular goiter; rhTSH, recombinant human TSH; Tg, thyroglobulin; TRAb, TSH receptor antibodies.

Received March 8, 2004.

Accepted January 6, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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123I Thyroid Uptake and Thyroid Size at 24, 48, and 72 Hours after the Administration of Recombinant Human Thyroid-Stimulating Hormone to Normal Volunteers
J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 506 - 510.
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