Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1085
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 11 6123-6125
Copyright © 2005 by The Endocrine Society
Children with Differentiated Thyroid Cancer Achieve Adequate Hyperthyrotropinemia within 14 Days of Levothyroxine Withdrawal
Wichert J. Kuijt and
Stephen A. Huang
Division of Endocrinology, Children’s Hospital Boston, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. Stephen A. Huang, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Room 642, Boston, Massachusetts 02115. E-mail: stephen.huang{at}childrens.harvard.edu.
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Abstract
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Context: The preparation for radioiodine administration recommended by the current pediatric literature is a 6-wk withdrawal that typically includes the transient administration of T3. Compared with adults, T4 clearance rates and serum TSH to free T4 ratios are higher in children, implying that pediatric patients can achieve adequate hyperthyrotropinemia with shorter levothyroxine withdrawals.
Objective: The objective of this study was to determine whether children with differentiated thyroid cancer achieve adequate hyperthyrotropinemia using an abbreviated levothyroxine withdrawal protocol.
Design: The study design was a retrospective analysis of 15 consecutive levothyroxine withdrawals performed without T3 at Children’s Hospital Boston.
Patients: Eleven children with differentiated thyroid cancer were included. The average age at the time of withdrawal was 12.5 ± 0.8 yr.
Main Outcome Measurement: Serum TSH concentrations obtained after the discontinuation of levothyroxine were analyzed to determine the time interval required to achieve a serum TSH level greater than 25 µU/ml for each patient.
Results: Adequate hyperthyrotropinemia was documented in all children tested by d 14. The mean interval required to achieve a serum TSH level above 25 µU/ml from a suppressed serum TSH was 12.3 ± 0.7 d.
Conclusions: Shorter withdrawals minimize hypothyroid morbidity and the theoretical risk of decreased 131I residence time from excessive hyperthyrotropinemia. These benefits are amplified in children due to their high incidence of distant metastases. We propose an abbreviated 2-wk withdrawal protocol to facilitate the adjunctive therapy and surveillance of children with follicular cell-derived cancers.
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Introduction
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THE PREPARATION FOR radioiodine administration recommended by the current pediatric literature is a 6-wk withdrawal that includes the transient administration of T3 (1, 2, 3, 4, 5). Recent publications have demonstrated that 83–96% of adults with differentiated thyroid cancer achieve adequate hyperthyrotropinemia 3 wk after the discontinuation of levothyroxine (6, 7, 8, 9). Shorter withdrawals minimize hypothyroid morbidity and the theoretical risk of decreased 131I residence time (shortened 131I biological half-life) in avid cancers (7, 10). These benefits are amplified in children due to their high incidence of distant metastases, and in this study we show that the progression to hyperthyrotropinemia is accelerated in children, with serum TSH concentrations greater than 25 µU/ml in all patients by d 14 of withdrawal. We propose a 2-wk withdrawal protocol to simplify the adjunctive therapy and surveillance of children with follicular cell-derived cancers.
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Patients and Methods
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Fifteen consecutive withdrawals performed in 11 patients at Children’s Hospital Boston between May of 2000 and February of 2005 were retrospectively analyzed. Inclusion criteria were age under 18 yr at the time of withdrawal and documentation of a baseline serum TSH before the discontinuation of levothyroxine. Ten of the 11 patients had papillary thyroid carcinoma, and one had well-differentiated thyroid carcinoma not otherwise specified (positive vascular invasion). All patients were studied after near-total thyroidectomy. The mean age of diagnosis was 12.1 ± 1.0 yr (range, 7.4–16.6 yr), and the mean age at the time of withdrawal was 12.5 ± 0.8 yr (range, 7.8–17.0 yr). With the exception of one patient who presented 2 yr after thyroidectomy and radioiodine therapy at an outside institution, radioiodine whole-body scanning was performed in all patients before radioiodine therapy and again after 131I therapy. Two children presented at 7 and 8 yr of age with diffuse lung abnormalities by computerized tomography and underwent quantitative 131I dosimetry before treatment. One patient presented at 7 yr of age with a negative chest computerized tomography and a negative 123I diagnostic whole-body scan, but diffuse pulmonary uptake on posttherapy scanning, consistent with avid microscopic metastases. For the remaining seven patients, initial 123I whole-body scanning performed after abbreviated levothyroxine withdrawal showed thyroid remnant uptake with or without cervical uptake (no definitive evidence of distant metastases). Using the American Joint Committee on Cancer stage groupings for thyroid carcinoma, three patients were stage II, and the remainder were stage I (11).
Serum TSH was measured within 48 h of withdrawal for 10 of the 15 withdrawals. For the remaining five withdrawals, the baseline TSH was obtained 5, 11, 16, or 19 d before the discontinuation of levothyroxine. Serum TSH was measured serially beginning approximately 7 d into withdrawal. All withdrawals were directly supervised by the same physician. All serum TSH measurements were performed in Clinical Laboratory Improvement Amendments-approved laboratories, and hyperthyrotropinemia was defined as a serum TSH concentration greater than 25 µU/ml (7, 9). Studies were approved by the investigative review board of Children’s Hospital Boston.
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Results
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Children with differentiated thyroid cancer achieve adequate hyperthyrotropinemia within 14 d of levothyroxine withdrawal
The baseline serum TSH was 0.1 µU/ml or less for 10 of the 15 withdrawals, and the average baseline TSH was 0.26 ± 0.10 µU/ml (range, 0.01–1.37 µU/ml). Discontinuation of levothyroxine was followed by a rapid rise in serum TSH (Fig. 1
). Using the first day that a serum TSH level above 25 µU/ml was documented for each individual patient, the mean interval required to achieve a serum TSH concentration greater than 25 µU/ml was 12.3 ± 0.7 d. The mean interval required to achieve a serum TSH concentration greater than 30 µU/ml was 12.4 ± 0.8 d. Two patients (indicated by the asterisks in Fig. 1) had their first TSH measurements (54.49 and 204.6 µU/ml) 17 d after stopping levothyroxine. On subsequent withdrawals, these same two patients achieved a serum TSH concentration greater than 25 µU/ml by d 14. A serum TSH level greater than 25 (mean, 55.5 µU/ml; range, 29.1–123.0 µU/ml) was documented in all other patients by d 14 of withdrawal.
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FIG. 1. TSH rise after levothyroxine withdrawal. Each point represents a serum TSH measurement, with values in the same patient connected by a line. •, Withdrawals performed after the measurement of baseline serum TSH within 48 h of discontinuing levothyroxine;  , withdrawals performed after the measurement of baseline serum TSH 5–19 d before withdrawal. For two withdrawals, TSH measurements were first obtained 17 d after stopping levothyroxine.
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Discussion
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Pediatric thyroid cancer is characterized by high rates of regional lymph node involvement (74%), distant metastasis (25%), and recurrence (34%) (4, 12, 13). Consistent with this, three of the 11 patients in this cohort have pulmonary metastases. Because radioiodine response depends in part on metastasis size, surveillance of high-risk children should include radionuclide imaging to facilitate the early detection of avid metastases (14). The preparation for radioiodine administration recommended by the current pediatric literature is a 6-wk withdrawal that includes the transient administration of T3 (1, 2, 3, 4, 5). However, we show here that TSH elevation after levothyroxine withdrawal is accelerated in children. The mean interval required to achieve a serum TSH level above 30 µU/ml was 12 d (compared with 17 d in adults), and all children tested achieved adequate hyperthyrotropinemia by 14 d (compared with 42% in adults) (8, 9). These differences can be explained by the more rapid T4 clearance (T4 half-life, 4.95 ± 0.13 d in 3- to 9-yr-olds, 6 ± 0.35 d in 10- to 16-yr-olds, and 6.7 ± 0.3 d in 23- to 26- yr-olds) and higher serum TSH to free T4 ratio (1.66 in 5-yr-olds, 1.71 in 14-yr-olds, and 0.97 in 21- to 54-yr-olds) in children (15, 16).
The ability of malignant thyroidal tissue to concentrate and organify radioiodine is considerably less than that of normal thyroid tissue, but it can be stimulated by TSH elevation (14). A serum TSH concentration above 25–30 µU/ml is recommended for radioiodine administration, but despite a continued rise in serum TSH, additional prolongation of thyroid hormone withdrawal does not appear to increase the iodine-concentrating ability (7, 9, 10). In fact, one study of 33 thyroid cancer patients comparing serial uptake and whole-body retention data obtained at 2 wk and then again at 4 wk after T3 withdrawal documented that patients with the highest cervical radioiodine uptake (19.9–52.0%) experienced a paradoxical greater than 50% decrease in uptake when withdrawal was extended by 2 wk (10). It is postulated that this is due to increased iodine turnover from prolonged activation of the TSH receptor, and this is another reason to favor abbreviated withdrawals.
For the above reasons and to simplify management, we recommend 2-wk withdrawals for radioiodine administration (Fig. 2). Levothyroxine is discontinued 14 d before planned radionuclide administration, and a low-iodine diet is started 7 d later. Serum is obtained the morning before administration to confirm adequate hyperthyrotropinemia, measure thyroglobulin, and, for postmenarchal females, document negative pregnancy. We favor 123I for diagnostic imaging because its 
emission is optimally suited to modern scintillation cameras and its lack of ß emission minimizes pediatric radiation exposure and stunning (17, 18). The morning after 123I administration, a diagnostic whole-body scan is performed, which, together with the patient’s postoperative staging and stimulated thyroglobulin, is used to determine whether additional imaging or 131I treatment is indicated. If radioiodine therapy is not recommended, levothyroxine and a normal diet are immediately resumed. If radioiodine therapy is recommended, 131I is administered the following day with the resumption of levothyroxine and a normal diet 48 h after treatment. Prepubertal children are prescribed antiemetics as needed, and a posttherapy scan is performed in all patients 4–7 d after 131I. We do not administer T3 for withdrawal, but do offer a 10-d course of T3 coincident with the resumption of levothyroxine to speed the restoration of euthyroidism.
This protocol requires coordination among endocrinology, nuclear medicine, radiation safety, and laboratory control, but in our experience, it shortens withdrawals to an interval that is not associated with hypothyroid symptoms. For most children, the absence of distant uptake on 123I diagnostic whole-body scan combined with a low stimulated thyroglobulin level will obviate the need for formal dosimetry (17, 18). Given the rapid hyperthyrotropinemia observed after serum TSH has normalized (Fig. 1
), TSH should be measured 7 d after the discontinuation of levothyroxine if the baseline TSH level is not suppressed. We routinely offer a 6-wk course of levothyroxine following thyroidectomy to avoid the confounder of hyperthyroglobulinemia from surgery itself (19). In conclusion, assuming the adequate resection of thyroid tissue, abbreviated withdrawals are an effective alternative to the traditional 6-wk withdrawal currently recommended for children, resulting in shorter periods of hypothyroidism and avoiding the theoretical decrease in residence time associated with prolonged hyperthyrotropinemia.
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Acknowledgments
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We thank Dr. P. Reed Larsen for helpful insights and comments on this manuscript.
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Footnotes
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First Published Online August 9, 2005
Received May 16, 2005.
Accepted August 1, 2005.
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Abstract
Introduction
