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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4549-4553
Copyright © 1999 by The Endocrine Society

Original Studies

Levothyroxine Suppression of Thyroglobulin in Patients with Differentiated Thyroid Carcinoma1

Pei-Wen Wang, Shan-Tair Wang, Rue-Tsuan Liu, Wen-Yen Chien, Shih-Chen Tung, Yung-Chuan Lu, Hue-Yong Chen and Chiang-Hsuan Lee

Departments of Internal Medicine (P.W.W., R.T.L., W.Y.C., S.C.T., Y.C.L.) and Nuclear Medicine (H.Y.C., C.H.L.), Chang Gung Memorial Hospital, Kaohsiung; and Department of Public Health, National Cheng Kung University Medical Center (S.T.W.), Tainan, Taiwan, Republic of China

Address all correspondence and requests for reprints to: Dr. Pei-Wen Wang, Department of Internal Medicine, Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien 83305, Taiwan, Republic of China. E-mail: jhc1997{at}ms18.hinet.net


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
For patients with differentiated thyroid carcinoma, the appropriate degree of TSH suppression by levothyroxine (L-T4) is still unknown. To find the target level of TSH suppression, we analyzed the relationship between the degree of TSH suppression determined by third generation assay and thyroglobulin (Tg) response during the titration of the dosage of L-T4. Ninety-two patients with differentiated thyroid carcinoma (19 males and 73 females; age, 40.5 ± 13.5, mean ± SD) were included. All of the recruited patients had near-total thyroidectomy, 30–150 mCi 131I thyroid ablation, and negative Tg autoantibodies. They were classified into 3 groups. Group A was composed of 25 patients with local or distant relapse. Group B was composed of 12 patients without clinically detectable relapse, but Tg levels either above 2 ng/mL under L-T4 suppression or above 3 ng/mL off L-T4 therapy. Group C included 55 patients who had no active disease and Tg levels below 2 and 3 ng/mL during and off L-T4 suppression, respectively. Serum TSH and Tg were measured simultaneously at the end of 8–12 weeks of a certain dose of L-T4 therapy during dosage titration and also after withdrawal of L-T4 for 4–6 weeks for the total body scan. Wilcoxon signed ranks test was used to compare paired samples of Tg, and Spearman rank correlation was used to determine the correlation of relative changes in TSH to changes in Tg calculated by individual. The results showed that 1) Tg levels were significantly higher during the period off L-T4 therapy than on L-T4 therapy in all 3 groups (P < 0.01); 2) during L-T4 therapy, within the same treatment course, mean Tg levels were higher when TSH levels were normal than when TSH levels were suppressed, statistically significant in group A (P = 0.001), nonsignificant in group B (P = 0.09), and nonsignificant in group C (P = 0.30); and 3) when TSH was suppressed below normal, there was no correlation between the relative changes in TSH and Tg by individual in all 3 groups (P > 0.05). The data suggest a stratified postoperative thyroid hormone management of patients with differentiated thyroid carcinoma. TSH should be lowered to below normal in patients with active disease. If patients are clinically disease free with Tg levels below 2 ng/mL, TSH can be kept within the normal range. For the most controversial group B patients, it is recommended that the TSH be suppressed and be closely followed up.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THYROID HORMONE treatment has proven its therapeutic benefit in patients with differentiated thyroid cancers (DTC), lowering the recurrence and mortality rates (1, 2, 3). However, long term supraphysiological L-T4 therapy has many side-effects, including an increase in cardiac workload, a higher prevalence of arrhythmia (4, 5), and a reduced bone mass (6, 7). The consensus at present is that TSH suppression therapy should be given to all patients with DTC. However, the appropriate degree of TSH suppression is still a matter of debate (8, 9, 10, 11, 12, 13, 14).

The advent of a third generation TSH assay with greater sensitivity has provided a better tool for the evaluation of TSH suppression (15). Thyroglobulin (Tg), a thyroid tissue-specific tumor marker, bears a good correlation to the amount of DTC present (16, 17, 18, 19, 20, 21, 22). Therefore, studying the relationship between the degree of TSH suppression and the Tg response helps manage the postoperative hormone therapy for patients with DTC.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Ninety-two patients with thyroid carcinoma, 19 males and 73 females, were included. All of these patients met the following criteria: 1) they had undergone near-total thyroidectomy; 2) they had received 30–150 mCi 131I postoperatively to ablate residual functioning normal thyroid tissue; and 3) they had no serum Tg autoantibodies. The 92 patients were classified into 3 groups according to their disease activity and serum Tg levels. Group A consisted of 25 patients with local tumor or lymph node recurrence or distant metastasis. They usually had high Tg levels. Group B consisted of 12 patients who had either baseline Tg levels above 2 ng/mL or stimulated Tg levels after L-T4 withdrawal above 3 ng/mL. However, there was no clinically detectable disease, as evidenced by negative whole body radioiodine scans, chest x-ray, and bone scans. Group C consisted of 55 patients who had no active disease and Tg levels below 2 ng/mL under L-T4 suppression and below 3 ng/mL after L-T4 withdrawal. The cut-off values of baseline (2 ng/mL) and stimulated (3 ng/mL) levels of Tg were chosen with reference to the study by Ozato et al. (22). Clinical information of the patients is summarized in Table 1Go.


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  		Table 1. Demographic and clinical characteristics of the three groups of patients

 
Serum Tg and TSH assays were performed simultaneously once the patients were off L-T4 for 4–6 weeks bfore receiving a total body scan. During L-T4 therapy, the L-T4 was usually started at a dose of 2.0–2.2 µg/kg·day for young patients and 1.5–1.8 µg/kg·day for the elderly. The dose was adjusted at an increment/decrement of 12.5–25 µg/day according to the TSH value at 8- to 12-week intervals. An effort was made to suppress TSH to a value below 0.01 µIU/mL if possible. Serum Tg and TSH were determined after the patients had been treated with a certain dose of L-T4 for 8–12 weeks, excluding the time period within 6 months of a therapeutic dose of 131I. Serial paired Tg/TSH data were obtained for analysis.

Assays

Patients’ serum samples from Sepember 1994 to September 1997 were studied. For the TSH assay, the Nichols Institute Diagnostics (San Juan Capistrano, CA) chemiluminescent assay was used. The interassay coefficients of variation were 17.5%, 6.5%, and 8.2% at low (0.02 µIU/mL), median (1.24 µIU/mL), and high (20.63 µIU/mL) levels, respectively. The intraassay coefficients of variation were 9.3%, 5.4%, and 6.0% at low (0.02 µIU/mL), median (1.27 µIU/mL), and high (20.44 µIU/mL) levels, respectively. The functional sensitivity was 0.01 µIU/mL. The normal range was between 0.5–4.6 µIU/mL. Tg was measured by immunoradiometric assay (ELSA-HTG, CIS-Bio International, France). This assay has interassay coefficients of variation of 10.5%, 7.5%, and 6.8% at low (4.3 ng/mL), median (120.5 ng/mL), and high (450.8 ng/mL) levels of measurement, respectively. The intraassay coefficients of variation were 5.2%, 3.5%, and 4.6% at low (4.5 ng/mL), median (120.2 ng/mL), and high (451.6 ng/mL) levels of measurement, respectively. The functional sensitivity was 0.7 ng/mL. The detection limit was 0.5 ng/mL. The Tg autoantibodies were checked by a solid phase immunoradiometric assay (TGAb IRMA, Biocode, Belgium). The sensitivity was 3 IU/mL. Tg measurements performed within 1–6 months after a therapeutic dose of 131I or those showing Tg autoantibodies above 3 IU/mL were excluded.

Statistics

All continuous data were expressed as the mean ± SD unless indicated otherwise. The demographic and clinical characteristics of the three groups of patients were compared using one-way ANOVA for continuous data and generalized Fisher’s exact statistics (23) for categorical data. Wilcoxon signed ranks test was used to compare the difference between paired samples of Tg. The relation between the individual change in TSH level and that in Tg during follow-up was analyzed using Spearman’s rank correlation. The changes were expressed as ratios of follow-up values to baseline values to account for individual differences at baseline. P < 0.05 was considered statistically significant. StatXact 3 (24) was used for calculation in small samples.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Comparison of paired samples of Tg levels on and off L-T4 therapy

Tg levels were significantly higher during the period off L-T4 therapy than on L-T4 therapy in all three groups. Figure 1AGo displays the 25 paired measurements of Tg on and off L-T4 therapy in group A patients with metastasis or recurrence (39.8 ± 60.7 vs. 259.3 ± 207.4 ng/mL; P < 0.001). Figure 1BGo displays the 12 paired measurements of Tg in group B patients with elevated Tg levels, but without detectable metastasis or recurrence (7.7 ± 11.5 vs. 125.0 ± 203.1 ng/mL; P < 0.01). Figure 1CGo displays the 55 paired samples of Tg from group C patients with low Tg levels and undetectable active disease (0.52 ± 0.1 vs. 1.2 ± 0.9 ng/mL; P < 0.001).



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  		Figure 1. A, Comparison of 25 paired samples of Tg levels on and off L-T4 therapy in group A patients. The paired samples were from the same patient, and the interval between two samples was 6 weeks. The TSH level off L-T4 therapy was usually above 30 µIU/mL. Tg levels were significantly higher when off L-T4 therapy (by Wilcoxon signed ranks test, P < 0.001). B, Comparison of 12 paired samples of Tg levels on and off L-T4 therapy in group B patients. Tg levels were significantly higher when off L-T4 therapy (P < 0.01). C, Comparison of 55 paired samples of Tg levels in group C patients. Tg levels were significantly higher when off L-T4 therapy (P < 0.001).

 
During L-T4 therapy, comparison of mean Tg levels when TSH was normal with those when TSH was suppressed

Within a treatment course, for each patient who had Tg data with corresponding TSH measurements in both the normal and the suppressed range, the mean Tg value obtained at normal TSH levels was compared with the mean Tg value when TSH was suppressed. Figure 2AGo shows a comparison of 14 paired observations of mean Tg levels in the patients of group A. When TSH levels were normal (2.2 ± 2.0 µIU/mL), mean Tg levels were higher than when TSH levels were suppressed (0.08 ± 0.01 µIU/mL); this difference was statistically significant (70.7 ± 83.9 vs. 43.9 ± 49.7 ng/mL; P = 0.001). Figure 2BGo shows the results of nine paired observations of mean Tg values in patients in group B. The mean Tg levels tended to be higher when TSH levels were normal (1.83 ± 1.08 µIU/mL) than when TSH was suppressed (0.16 ± 0.01 µIU/mL), but without statistical significance (4.9 ± 11.3 vs. 2.8 ± 6.4 ng/mL; P = 0.09). Figure 2CGo shows the results of 49 paired observations of mean Tg levels in patients of group C. There was no significant difference between Tg levels (0.53 ± 0.08 vs. 0.52 ± 0.04 ng/mL; P = 0.30) when TSH was normal (1.68 ± 0.64 µIU/mL) and when it was suppressed (0.11 ± 0.01 µIU/mL).



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  		Figure 2. A, Comparison of 14 paired observations of mean Tg levels under normal or suppressed TSH status in group A patients. The paired data were from the same patient within the same treatment course. The Tg level was defined as the mean value of all assessments in the treatment course. Tg levels were significantly higher when TSH levels were normal than when TSH levels were suppressed (by Wilcoxon signed ranks test, P = 0.001). B, Comparison of 9 paired observations of mean Tg levels under normal or suppressed TSH status in group B patients. Tg levels were higher when TSH levels were normal than when TSH levels were suppressed but statistically nonsignificant (P = 0.09). C, Comparison of 49 paired observations in group C patients. There was no significant difference (P = 0.30).

 
Interrelationship between serial Tg and TSH values when TSH levels were below normal

Figure 3Go, A–C, displays the relationship between the within-subject relative changes in TSH and Tg within a treatment course for 21 patients in group A, 11 patients in group B, and 50 patients in group C, respectively. The relative changes were expressed as ratios of follow-up values to baseline value by individual. The display by the relative change within each individual was aimed to minimize patient to patient variability related to tumor mass. There was no correlation between the relative changes in TSH and Tg in group A (Spearman rank correlation, rs = -0.17; P = 0.26), group B (rs = 0.19; P = 0.39), or group C (rs = 0.06; P = 0.60).



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  		Figure 3. Scatterplot of individual relative changes in TSH vs. those in Tg in 21 patients in group A, 11 patients in group B, and 50 patients in group C. The relative changes were expressed as ratios of follow-up values to baseline value by individual. No correlation was observed in group A (rs = -0.17; P = 0.26), group B (rs = 0.19; P = 0.39), and group C (rs = 0.06; P = 0.60).

 
Individual paired mean Tg levels when TSH was above 0.1 µIU/mL and when it was below 0.05 µIU/mL were also compared. There was no significant difference between Tg levels in group A (n = 9; P = 0.91), group B (n = 5; P = 0.88), and group C (n = 35; P = 0.58).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Due to its thyroid tissue-specific origin, serum Tg is the most widely used index of a tumor’s sensitivity to TSH (16, 17, 18, 19, 20, 21, 22). To observe the serum Tg/TSH relationship, our series using a longitudinal study with serial Tg follow-up is better than a cross-sectional study with a single serum Tg value. As the presence of residual normal thyroid tissue decreases the diagnostic value of Tg (19), all of the patients included in this study underwent near-total thyroidectomy followed by 131I ablation of normal remnant tissue. Interference from Tg autoantibodies and radiation damage was avoided by excluding the Tg determinations with Tg autoantibodies and those checked within 6 months after a therapeutic dose of 131I.

In the first part of the study, Tg levels off L-T4 treatment were significantly higher than those on L-T4 therapy in all three groups of patients. The results agreed with the consensus of treating all patients postoperatively with L-T4 (1, 2, 8, 9). However, during L-T4 therapy there was a difference among the groups of patients. When metastasis or recurrence was present (group A), the mean Tg levels obtained at normal TSH levels were higher than those when TSH levels were suppressed (P = 0.001). If active disease persists, the data suggest that growth of the tumor is not maximally inhibited when TSH is in the euthyroid range. However, if patients are clinically disease free and Tg levels are below 2 ng/mL (group C), the TSH level probably can be kept within normal range. Dr. DeGroot’s group (22) also suggested that suppression of TSH below the normal level was not necessary when patients were thought to be free of disease. This concept is again supported by a recent report of data from the National Thyroid Cancer Treatment Cooperative Study Registry (14), which states that a greater degree of TSH suppression is not required to prevent disease progression in low risk patients. Actually, about half (25 of 55) of the group C patients had undetectable Tg levels both during and off L-T4 suppression. Undetectable Tg levels off L-T4-suppressive therapy indicate a complete remission. There are no further beneficial effects obtained by increasing dosage of L-T4. Furthermore, the side-effects of such long term supraphysiological doses of L-T4 therapy are to be avoided. For the most controversial group (group B), patients without clinically detectable recurrence but with elevated Tg levels, there was a trend toward lower Tg levels when TSH was suppressed (P = 0.09). As elevated Tg levels in group B patients may indicate the presence of neoplastic tissue or its recurrence some years later (25, 26), it is recommended that we keep the TSH levels suppressed and perform periodic check-ups. The researchers suggest a stratified management of postoperative hormone therapy for patients with different risk factors. Older patients and those who have more advanced stages of disease, such as the cases in group A in our study, should receive more aggressive TSH suppression.

The last part of this study observed the relationship between Tg values and subnormal levels of TSH to find the optimal target of TSH suppression. However, for all patients, we found no correlation between the relative changes in Tg and in TSH when TSH levels were suppressed below normal, even in group A with active disease. Furthermore, when analyzed in a clinically relevant way, the mean Tg levels were not lower when TSH was below 0.05 µIU/mL compared to when TSH was above 0.1 µIU/mL. This probably means that TSH suppression below the normal range is important, but lowering the cut-off to an undetectable value is less crucial. As Pujol et al. reported (13), relapse-free survival was longer in a constantly suppressed TSH group than in a nonsuppressed TSH group, but the difference between the groups was statistically significant whatever the cut-off used for defining TSH suppression. Furthermore, the possibility of non-TSH-dependent Tg secretion (27, 28, 29) or the persistence of basal constitutional TSH release not suppressed by L-T4 (30, 31) should be considered. It is obvious that the overall data do not suggest the lower the TSH level the lesser the Tg response.

Therefore, we conclude that TSH should be suppressed to below normal in patients with active disease or more risk factors. However, extreme suppression is not advised for all patients. Probably just below the lower limit of normal range suppression is adequate. For patients who are thought to be disease free and have Tg levels below 2 ng/mL, TSH can be kept within the normal range.


   Acknowledgments
 
We thank Ms. Yun-Hsuan Hsu, Ms. Yin-Ling Yang, and Mr. Chung-Dar Chen for their technical assistance, and Ms. Shu-Hsuan Kung and Ms. Bih-Ru Hsueh for careful preparation of the manuscript.


   Footnotes
 
1 This work was supported by National Science Council (Republic of China) Research Grant NSC-85–2331-B-182A-040. Back

Received May 21, 1999.

Revised July 29, 1999.

Accepted August 20, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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