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Long-Term Changes in Nodular Goiter: A 5-Year Prospective Randomized Trial of Levothyroxine Suppressive Therapy for Benign Cold Thyroid Nodules

Department of Endocrine, Metabolic, and Digestive Diseases, and Diagnostic Imaging Department (R.F., C.M.P.), Ospedale Regina Apostolorum, Albano; Systematic Medical Therapy Institute, Umberto I Polyclinic (V.B.); and the Department of Experimental Medicine, La Sapienza University (F.N.), Rome, Italy

Address all correspondence and requests for reprints to: Dr. Enrico Papini, Department of Endocrine, Metabolic, and Digestive Diseases, Ospedale Regina Apostolorum, Via San Francesco 50, 00041 Albano, Rome, Italy.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We studied for 5 yr a homogeneous group of 83 patients randomly assigned to a levothyroxine (L-T₄) suppressive therapy or to a control group to evaluate changes in nodule or thyroid size, appearance of new nodules, and correlations with clinical parameters.

In the control group, mean nodule volume increased significantly after 5 yr (2.12 ± 1.46 vs. 1.46 ± 0.77 mL), whereas in the treatment group it decreased, although not significantly (1.45 ± 1.17 mL vs. 1.53 ± 0.61 mL). Baseline nodule volume was not different in the two groups, but a significant difference was observed at 5 yr. After 5 yr, sonograms detected 12 new nodules in the control group (28.5%) and 3 (7.5%) in the treatment group. Nodule shrinkage was more frequent in patients with complete TSH suppression, but no correlation was found with other parameters. A significant increase in thyroid size was observed in the control group.

In conclusion, long term TSH suppression induced volume reduction in only a subgroup of thyroid nodules, but effectively prevented the appearance of new lesions and increases in nodule and thyroid volume. As the changes in the natural history of nodular goiter are related to prolonged TSH suppression, which can induce unfavorable side-effects, L-T₄ suppressive therapy should be reserved for small nodules in younger patients.

	Introduction

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THERE ARE conflicting views on the efficacy of suppressive doses of L-T₄ on solitary benign thyroid nodules (1, 2, 3, 4, 5, 6), probably due to variations in iodine intake, to the histological heterogeneity of thyroid nodules, and to the slow and unpredictable pattern of nodule growth (7, 8, 9). The present study evaluated over a 5-yr period 1) changes in nodule size and thyroid volume in a homogeneous group of patients randomly assigned to L-T₄ suppressive therapy or to a control group; 2) enlargement of small concomitant lesions and appearance of new nodules; 3) correlations among baseline size, clinical and laboratory parameters, degree of TSH suppression, and observed thyroid changes; 4) rate of growth (or reduction) of thyroid nodules; and 5) reliability of cytological diagnosis.

	Subjects and Methods

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Study design

The study was a multicentric prospective randomized clinical trial. One hundred consecutive patients from the Rome metropolitan area, nonendemic for goiter, were randomly assigned to a L-T₄ treatment (2 µg/kg) group or to a nontreatment control group. Entry criteria included a single palpable thyroid nodule with greatest diameter between 10–30 mm; cytology consistent with a colloid nodule by fine needle aspiration (FNA); echographic (US) characteristics of a single solid nodule (patients harboring concomitant nonpalpable nodules >5 mm were excluded) (10); thyroid volume within normal limits (<14.3 mL) (11); ^99mTc thyroid scan consistent with a hypofunctioning or nonvisualized nodule; ¹³¹I uptake within normal limits; normal levels of serum TSH, free thyroid hormones (FT₄ and FT₃), and antithyroglobulin (TgAb) and antithyroid peroxidase (TPOAb) antibodies; no previous treatment with thyroid hormones, iodine compounds, or antithyroid drugs; and no history of neck irradiation or surgery.

The study was conducted according to the principles of the Helsinki declaration and was approved by the bioethics committee of the Ospedale Regina Apostolorum. Written informed consent was obtained from all subjects.

Protocol

Clinical and hormonal evaluations were unblinded, whereas US scans were blindly performed. Sonograms and hormone profiles were performed at 0, 12, 24, 36, 48, and 60 months. FNA (12, 13) and scintiscans were performed at enrollment and after 5 yr, after 2 months of L-T₄ withdrawal.

All US evaluations were performed in the same center (Ospedale Regina Apostolorum) by three blinded examiners with a real-time instrument (Ansaldo Idea, Genua, Italy) using a high resolution 10-megahertz linear probe. Volumes were calculated according to the ellipsoid formula (14). The coefficient of variation for repeated measurements in the same patient was 11.7%. We, therefore, considered volume changes exceeding this value to be clinically significant. During follow-up, concomitant lesions with a diameter exceeding 10 mm were considered to be new nodules (15).

Laboratory evaluation

Serum TSH (TSH immunoradiometric assay, Radim, Pomezia, Italy; sensitivity, 0.05 IU/L), FT₄, FT₃, thyroglobulin (Tg), TgAb, and TPOAb [commercially available kits: Sorin (Saluggia, Italy) and Radim] were determined. Normal values are: TSH, 0.20–4.0 mIU/L; FT₄, 6.53–15.30 ng/L; FT₃, 2.60–5.80 ng/L; Tg, 0.20–50 µg/L; and TgAb and TPOAb, less than 10⁵ U/L.

A thyroid scan with ^99mTc pertechnetate and ¹³¹I uptake (normal values, 10–40% at 6 h and 15–60% at 24 h) were performed with a -camera (Philips, The Netherlands).

Statistical analysis

Nonparametric statistical methods (Mann-Whitney, Wilcoxon, and Spearman rank correlation tests) were used to analyze nodule and thyroid size changes. The frequency distribution of volume changes and of new nodule development in the two groups was compared by ² and Fisher exact tests. Statistical comparisons of clinical and hormonal patterns were performed using t tests for paired data. The significance level was set at P < 0.05.

	Results

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Eighty-three of 100 patients (42 in the treatment group and 41 in the control group) completed the study. Clinical and laboratory characteristics of the 2 groups are compared in Table 1. Three patients (2 in the control group and 1 in the L-T₄ group) were operated upon because of progressive nodule growth. In all cases the histological diagnosis was micro-/macrofollicular goiter. There were 14 drop-outs (8 in the L-T₄ group and 6 in the control group). In the L-T₄ group, 7 patients experienced side-effects (nervousness, tachycardia, and headache), and 3 of them abandoned the study.

Hormonal changes (Table 2)

In the L-T₄ group, constant and complete TSH suppression was achieved in 20 patients, whereas in 22 patients the values were occasionally above the lower normal limits. Average FT₄ remained within the upper limits of normal; FT₃ did not change significantly. Tg showed a decrease at 1 yr (-30%) and remained stable thereafter. In the control group, TSH and peripheral thyroid hormones did not show any significant change during the follow-up period. No changes were observed in thyroid ^99mTc scans at the 5-yr examination.

In the control group, mean nodule size increased significantly at 5 yr (2.12 ± 1.46 vs. 1.46 ± 0.77 mL; P = 0.001). In the L-T₄ group, mean nodule size decreased nonsignificantly (1.45 ± 1.17 vs. 1.53 ± 0.61 mL; P = 0.61). At baseline, no mean nodule volume differences were observed between the groups (P = 0.36), but a significant difference (P = 0.041) was observed at 5 yr (Fig. 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. Nodule volume changes in the L-T4 treatment group and in the control group (median and range).

After 5 yr, US showed 12 new nodules in the control group (28.5%) and 3 (7.5%) in the L-T₄ group (P = 0.02). The distribution of nodule volume changes and that of new nodule development are summarized in Tables 2 and 3.

View larger version (9K): [in this window] [in a new window]   Figure 2. Thyroid volume changes in the L-T4 treatment group and in the control group (median and range).

View larger version (13K): [in this window] [in a new window]   Figure 3. Nodule volume changes in the treatment group: differences between patients with TSH levels greater than 0.1 mU/L and patients with TSH levels less than 0.1 mU/L.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Several controlled studies failed to demonstrate a significant reduction in thyroid nodule size after L-T₄ suppressive therapy (16, 17, 18). On the other hand, recent prospective studies have found significant nodule volume reduction (19, 20) or higher frequency of regression (21) after 1 yr of TSH suppression. These relatively short trials, focused on nodule size reduction, were inadequate to evaluate the efficacy of L-T₄ in decreasing the spontaneous growth, usually slow and irregular (9), of benign nodular disease. Our trial was therefore designed to evaluate both the efficacy of various degrees of TSH suppression in nodule volume reduction and the natural history of untreated nodular goiter.

Nodule volume changes

According to previous observations (16, 17, 18), TSH suppression failed to induce significant volume reduction in the treatment group as a whole. However, L-T₄ treatment did affect the natural history of thyroid nodules, because it prevented the significant 5-yr volume increase observed in the control group, and it reduced the number of growing nodules (22). These findings suggest that the suppression of serum TSH removes the major growth stimulator for the large proportion of thyroid nodules (50%) still responsive to physiological stimuli. A smaller subgroup of lesions (30%) remains unaffected by L-T₄ and continues to grow, probably under the influence of local growth factors or growth-promoting mutations (23, 24, 25, 26). Some nodules decreased spontaneously in size in the control group, although much less frequently than in the treatment group. The incidence of this phenomenon was lower than that in previous trials (4, 27), probably in relation to the selection criteria requiring solid nodules and therefore avoiding spontaneous changes due to reabsorption of fluid.

As a whole, these observations confirm the clinical usefulness of long term L-T₄ treatment as more important in preventing thyroid nodule growth than in reducing their size.

Thyroid volume and the appearance of new lesions

L-T₄ did not induce any significant reduction in thyroid size, but a significant increase in thyroid dimensions was observed in the control group. Moreover, US demonstration of new nodule development after 5 yr was strikingly more frequent in the untreated patients. These findings, despite the conflicting results of previous studies on prevention of thyroid nodule recurrence after operation (28, 29, 30), seem to confirm the tendency of benign nodular disease toward progression and the efficacy of TSH suppression in improving its long term evolution (21, 22).

Pretreatment variables

The age and sex of patients, the nodule size, the baseline serum TSH and Tg levels, and the degree of Tg reduction did not predict nodule response. Thus, we could not delineate criteria for identifying nodules with a higher probability of decreasing in size in response to L-T₄. However, as our entry criteria included only relatively small nodules, the differences related to nodule size (31) could have been blunted.

It is noteworthy that nodule shrinkage was observed much more frequently in patients with TSH levels constantly suppressed below 0.1 mU/L than in subjects with incomplete serum TSH suppression.

In the treatment group, the lack of nodule growth after 1 yr was predictive of the absence of growth during the following 4 yr. In the untreated group, the absence of growth after 1 yr did not exclude the possibility of volume increase during the subsequent follow-up. Therefore, the nodule behavior during a 1-yr observation period seems to be useful in evaluating the efficacy of TSH suppression, but it cannot give information about the natural history of untreated nodules (32).

Reaspiration, performed after 1 yr, was always consistent with the previous cytological diagnosis. The routine performance of repeated FNA in the follow-up of benign thyroid nodules seems to be of limited value in the absence of suspicious clinical changes (33).

In conclusion, long term TSH suppression induces significant volume reduction in only a subgroup of thyroid nodules, which is not identifiable on the basis of pretreatment variables, but effectively prevents the development of new lesions and increases in nodule and thyroid size. Therefore, in patients not at risk for osteoporosis (34) or cardiovascular complications (35), we recommend L-T₄-suppressive treatment. L-T₄ treatment should be continued for 1 yr, and nodule size and thyroid gland characteristics should then reevaluated by ultrasonography. If the nodule has enlarged, the thyroid size has increased, or new nodules have developed, repeated aspiration and possibly surgery should be considered. If the nodule remains unchanged or decreases in size, as in most cases, therapy should be continued on a long term basis unless contraindications appear. Due to the slow, but progressive, growth of thyroid nodular disease, L-T₄ treatment seems to be especially useful in the younger age group. The longer life expectancy of these patients increases the risk of reaching a nodule size requiring surgery, and the side-effects of suppressive therapy are less bothersome. As the chances of achieving significant changes in the natural history of nodular goiter are related to a prolonged and near-complete suppression of TSH secretion, which can induce potentially unfavorable side-effects in older age groups, L-T₄ suppressive therapy does not seem to be suitable for postmenopausal women (36) or for men with cardiovascular problems (37).

	Acknowledgments

 
We are indebted to Susan Levenstein, M.D., for her technical assistance.

Received July 28, 1997.

Revised October 9, 1997.

Accepted November 12, 1997.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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