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Division of Clinical and Molecular Endocrinology, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio 44106
Address all correspondence and requests for reprints to: Baha M. Arafah, M.D., Division of Clinical and Molecular Endocrinology, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: bxa{at}po.cwru.edu.
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Abstract |
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Two groups of patients requiring RAI therapy were investigated. One group included patients studied immediately after thyroidectomy, whereas the other included those withdrawn from chronic suppressive T4 therapy that followed thyroidectomy and postoperative RAI ablation. Serum TSH concentrations were serially measured two to three times weekly until they reached more than 30 mU/liter, after which RAI therapy was administered.
Serum TSH concentrations reached more than 30 mU/liter 8–26 d (mean ± SD, 14.2 ± 4.8) after thyroidectomy or 9–29 (18.1 ± 4.1) d after T4 withdrawal. That level of TSH elevation was achieved 18 d after thyroidectomy and 22 d after T4 withdrawal in more than 95% of patients. Minimal symptoms of hypothyroidism were noted in either group when RAI was administered.
Serum TSH concentrations increased rapidly without transient therapy with T3. To minimize symptoms of hypothyroidism, serum TSH levels should be measured twice weekly, starting 10 d after thyroidectomy or T4 withdrawal. The data cast doubt about the value and benefits from using T3 in preparing patients for RAI therapy.
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Introduction |
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Standard monitoring of patients with DTC after thyroidectomy and RAI ablation includes measurements of serum thyroglobulin levels and 131I whole-body scans (1, 2). A high serum TSH concentration is required to stimulate the release of thyroglobulin and optimize 131I uptake by cancer cells. High serum TSH concentrations were traditionally achieved in patients who had thyroidectomies by withdrawing suppressive thyroid hormone therapy and more recently (3, 4) by the use of recombinant human TSH (rhTSH). Although rhTSH has been widely used in the diagnostic follow-up scanning of patients with DTC, it has not been approved for use alone in preparation for RAI therapy. Thyroid hormone withdrawal is currently required with or without rhTSH before RAI therapy.
The interval between discontinuation of T4 therapy and the subsequent rise in serum TSH to appropriate levels (25–30 mU/liter) for RAI administration has not been well studied, although intervals of up to 4–6 wk have been established in many centers (5, 6, 7, 8, 9). Because T3 has a shorter half-life than T4, most endocrinologists switch patients from T4 to T3 for several weeks in preparation for RAI therapy. Subsequently, T3 is withdrawn and RAI therapy is administered whenever the serum TSH concentration reaches the desired value of more than 25–30 mU/liter. It has been found that the average T3 withdrawal time is approximately 2 wk (10, 11). Thus, patients would experience shorter periods of hypothyroidism after T3 withdrawal than they would after discontinuing T4 therapy. However, a persistent symptomatic period of hypothyroidism despite the above preparation continues to be reported (12). A study by Tamai et al. (13) evaluated thyroid function immediately after thyroidectomy and found that serum TSH concentrations reached 30–40 mU/liter in 9–10 d. A very recent study involving a small number of patients suggested that after thyroid hormone withdrawal serum TSH concentrations might reach the desired elevation in a shorter period of time than originally thought (14).
In the current investigation, we examined the changes in serum TSH levels in two groups of patients requiring ablative doses of RAI. One group included patients studied immediately after total thyroidectomy, whereas the other included those withdrawn from suppressive T4 therapy after having had a thyroidectomy and one or more ablative doses of RAI. We postulated that serum TSH concentrations increase rapidly after total thyroidectomy and also after withdrawal of suppressive T4 therapy such that RAI can be administered to patients before they develop significant symptoms of hypothyroidism.
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Patients and Methods |
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Consequently, patients recruited for the current investigation were included in either the thyroidectomy group or the T4 withdrawal group.
The thyroidectomy group (n = 42) included patients who were studied immediately after total thyroidectomy and did not receive any form of thyroid hormone therapy until the therapeutic dose of RAI was administered. Nine of the 42 patients had a hemi-thyroidectomy first followed, within a few days, by total thyroidectomy. Once the serum TSH level reached the desired value (>30 mU/liter), these patients received approximately 100 mCi of RAI and were subsequently started on suppressive T4 therapy. Serum TSH levels were measured before thyroidectomy in 25 of these 42 patients and were normal. The remaining 17 patients in this group were clinically euthyroid, but their serum TSH levels were not measured before thyroidectomy.
The T4 withdrawal group (n = 31) included patients who had already had a total thyroidectomy followed by RAI ablation and more than 1 yr of suppressive T4 therapy to maintain serum concentrations less than 0.5 mU/liter. All patients included in this group had documentation of suppressed serum TSH concentrations (<0.5 mU/liter) at the time of thyroid hormone withdrawal.
Methods
Patients were started on a low-iodine diet immediately after thyroidectomy (thyroidectomy group) or at the time T4 therapy was discontinued (T4 withdrawal group). The study design consisted of measuring serum concentrations of TSH and free T4 in all patients every 2–3 d, starting 6–8 d after thyroidectomy or withdrawal of T4 therapy. This is followed by the administration of therapeutic doses of RAI once serum TSH concentrations reach the desired values of more than 30mU/liter. Data on all patients were included in the analysis until RAI was administered, which is usually 1–5 d after the last measured concentration.
Patients were examined on the day they received RAI therapy and assessed for clinical hypothyroidism as well as any potential tumor growth. Evaluation of clinical hypothyroidism was based on patients’ reported symptoms, heart rate, blood pressure measurements, and assessment of their deep tendon reflexes. Clinical evaluation of hypothyroid symptoms in patients was not quantified in detail but was clinically characterized as nonexistent (no signs or symptoms), minimal (some fatigue without any sign), moderate (moderate fatigue, cold intolerance, and some physical findings), or severe (severe symptoms and signs). Generally, patients treated immediately after thyroidectomy were given 100 mCi of 131I, whereas those treated for metastatic or recurrent disease were given 100–150 mCi. A scan was obtained 7–10 d after RAI therapy was administered to identify the areas of uptake. The study was approved by the Institutional Review Board.
Serum TSH concentration was measured using the Centaur TSH assay, which is a two-site, ultrasensitive, chemiluminometric sandwich immunoassay. Results were available within 24 h of obtaining the blood sample. The assay has intraassay CV of 7.32, 2.48, and 2.41% and interassay CV of 10.03, 4.12, and 2.05% at three different ranges (0.021, 0.74, and 19.00 mU/liter) within the assay, respectively. Serum free T4 concentration was measured using Advia Centaur competitive chemiluminescent immunoassay with a sensitivity range 0.1 ng/dl, intraassay CV of 4.69, 2.31, and 2.22%, and interassay CV of 4.59, 1.95, and 1.58% at three different ranges (0.47, 1.08, and 3.09 ng/dl) within the assay, respectively.
Statistical analysis
Data are presented as mean ± SD unless stated otherwise. 
2 was used to compare ordinal variables, and Kruskal-Wallis followed by the Mann-Whitney test was used for continuous variables.
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Results |
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. Among the patients who were studied immediately after thyroidectomy, those who had known baseline serum TSH levels before surgery (n = 25) had identical clinical characteristics to those who did not have their levels measured before surgery (n = 17). This included similarity in age, gender, tumor type, and stage as well as in the serial measurements of TSH and free T4 concentrations obtained serially after thyroidectomy. Thus, the data on both subgroups were included together to represent patients studied immediately after thyroidectomy (n = 42). Other than the expected differences in serum TSH and free T4 concentrations, the two groups of patients had similar clinical characteristics (Table 1).
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, serum TSH and free T4 levels were normal before thyroidectomy. The mean (±SD) serum TSH concentration increased to 34.2 ± 13.3 (mU/liter), 9–11 d after thyroidectomy and continued to rise thereafter (Table 2 and Fig. 1). Serum free T4 decreased gradually after thyroidectomy reaching a mean (±SD) of 0.54 ± 0.08 ng/dl at 9–11 d (Table 2 and Fig. 1).
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, serum TSH increased, whereas the free T4 concentrations decreased gradually after T4 withdrawal. In these patients, the mean serum TSH concentration, measured 9–11 d after T4 withdrawal, was 10.9 ± 5.6 mU/liter and rose steadily thereafter. Serum free concentrations declined gradually after withdrawal of T4 therapy, reaching a mean of 0.77 ± 0.14 ng/dl at 9–11 d. Serum TSH concentrations were consistently higher in group 1 until 18–20 d, when the differences between the two groups became statistically insignificant (Fig. 1 and Table 2). Measured serum free T4 concentrations were higher in the T4 withdrawal group at all times until d 15–17 when they were similar to those in the thyroidectomy group.
The cumulative percentages of patients in both groups who had achieved the desired elevation in serum TSH concentrations (>30 mU/liter) over time are shown in Table 3. Whereas 74% of patients had serum TSH concentrations of more than 30 mU/liter when measured 9–11 d after thyroidectomy, only 16% of the patients who were on thyroid hormone therapy had similarly elevated serum TSH values 9–11 d after hormone withdrawal (P < 0.001). However, the percentage of patients with serum TSH levels of more than 30 mU/liter increased quickly over time such that no significant differences were noted after 18 d. Over 95% of patients achieved the desired elevation in serum TSH concentrations 18 d after thyroidectomy or 22 d after withdrawal of suppressive T4 therapy.
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, the mean number of days was 14.2 ± 4.8 after thyroidectomy and was 18.1 ± 4.1 after withdrawal of T4 therapy (P < 0.001). Therapeutic doses of RAI were administered within 1–5 d of the last TSH measurement. By the time they received the therapeutic dose of 131I, most patients had minimal or no symptoms of hypothyroidism, and none had moderate or severe hypothyroidism. Similarly, none of the patients had measurable changes in evaluable neck disease during that time. Residual uptake in the thyroid bed was noted in 40 of 42 patients given RAI after thyroidectomy, and no uptake was noted in the remaining two. In the latter two patients, serum thyroglobulin levels measured just before RAI therapy were undetectable (<0.5 ng/ml). Variable uptake was noted in patients given RAI therapy to treat residual or recurrent disease (T4 withdrawal group) more than a year after total thyroidectomy and an initial ablative dose of iodine. |
Discussion |
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It is common practice to follow a 6-wk protocol in preparing patients for RAI administration (1, 2, 3, 5, 6, 7, 8, 9). Whereas cessation of T4 therapy represents one method, the most commonly used approach consists of substituting the more rapidly metabolized T3 for T4 for 3–4 wk followed by withdrawal of the former for 2–3 wk. This was based on some studies that demonstrated T3 withdrawal time to be 2 wk (9, 10, 11, 12) compared with the 4–6 wk for T4 withdrawal (5, 6, 7). Several reports have provided alternative approaches, aimed at minimizing the symptoms of hypothyroidism, in preparing patients for RAI therapy (7, 8, 9, 10, 11, 12, 13, 14, 15). Although some replace T4 with T3 for several weeks, others lower the dose of T4 by 50% or use rhTSH in addition. Although each of these approaches has been reported to be successful, we believe that our approach is very practical and effective.
Our data show that RAI ablation in patients with DTC can be effectively done 2–3 wk after thyroidectomy. It would, therefore, be unnecessary to use T4 or T3 transiently in this setting. We noted that serum TSH levels increased rapidly after thyroidectomy such that they were more than 30 mIU/liter in approximately 2 wk. This would be very similar to the reported time required for the rise in serum TSH levels to the same degree after several weeks of T3 use (7, 10, 11, 12). By the time they were ready for RAI therapy, patients had minimal symptoms of hypothyroidism. They tolerated RAI therapy very well and were started on suppressive T4 therapy immediately thereafter. The scans done 7–10 d after the ablative doses of RAI were administered showed minimal uptake in the thyroid bed in the majority of patients in our study. Being negligible, the latter uptake in the thyroid bed is consistent with the rapid increase in serum TSH levels immediately after thyroidectomy noted in our patients.
One limitation to our study is that the assessment of symptoms of hypothyroidism was not blinded and therefore somewhat subjective. However, none of our patients had clinically significant symptoms or signs of hypothyroidism. Furthermore, the study showed that the time required for the serum TSH concentrations to reach the desired value of more than 30 mU/liter was very similar to that reported with the transient use of T3. Over 95% of patients had achieved that degree of elevation in serum TSH concentrations at 18 d after thyroidectomy or 22 d after withdrawal of suppressive T4 therapy. Even though our study did not include a comparative group of patients given T3, it is important to emphasize the fact that the number of days required to raise serum TSH concentrations as reported in our study and by others (13) were very similar to those reported using T3 transiently.
Our data are remarkably similar to those of Tamai et al. (13), who found that serum TSH concentrations reached 30–40 mU/liter 9–10 days after thyroidectomy. In contrast, an earlier report by Edmonds et al. (16) showed that at 2–3 wk after presumed total thyroidectomy, only 20 of 48 patients had elevated serum TSH concentrations, whereas the rest had normal or minimally elevated levels associated with normal or near normal serum T4 concentrations. It is more than likely that the latter group of patients had significant residual thyroid tissue to account for the difference.
Similarly, serum TSH levels increased to more than 30 mU/liter approximately 18 d after discontinuing suppressive T4 therapy, with nearly 95% of the patients achieving such levels in less than 3 wk. This is remarkably similar to the data reported by Liel (14) who studied eight patients after discontinuing T4 suppressive therapy and found that the mean interval for serum TSH to be more than 30 mIU/liter was 17 d. Considering potential side effects from T3 use, particularly in elderly patients, the data cast doubt about the necessity for and benefit from the transient use of T3 before RAI administration.
As expected, patients who were withdrawn from T4 therapy had a slower rise in serum TSH compared with those who had total thyroidectomy. The slower rise in serum TSH after T4 withdrawal may reflect the delayed recovery of the pituitary-thyroid axis that has been suppressed by exogenous thyroid hormone (17, 18). Thus, the time required to raise serum TSH concentrations to more than 30 mIU/liter was longer (18.1 ± 3.9 d) in the patients who were discontinued T4 suppressive therapy than in those who had only thyroidectomy (14.1 ± 4.4 d).
In conclusion, our study shows that serum TSH levels increase rapidly after thyroidectomy or thyroid hormone withdrawal. Most patients reached the high serum TSH concentrations required for diagnostic or therapeutic administration of RAI at 2–3 wk after thyroidectomy or withdrawal of suppressive thyroid hormone treatment. To be effective in minimizing symptoms of hypothyroidism, we advocate that serum TSH levels should be measured twice weekly, starting 10 d after elimination of the endogenous (thyroidectomy) or exogenous source of thyroid hormone. Alternatively, serum TSH concentrations can be measured at 10–14 d after either thyroidectomy or withdrawal of T4 therapy and once or twice weekly thereafter. If a prolonged period of advanced notice is required before the administration of RAI, therapy can be tentatively planned 3 wk after thyroidectomy or T4 withdrawal, because by that time approximately 95% of patients would have achieved the desired elevation in serum TSH concentrations. The schedule can be adjusted to fit the needs and circumstances of individual patients. This will minimize potential tumor growth that might rarely occur during hypothyroxinemia, particularly in patients with aggressive cancer. We also recommend that a low-iodine diet should be instituted at the time of removal of the thyroid hormone source, in preparation for RAI therapy. Even though our study did not include a group of patients given T3, the data cast doubt about the value and benefits from the transient use of T3 before RAI administration.
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Acknowledgments |
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Footnotes |
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Abbreviations: DTC, Differentiated thyroid cancer; RAI, radioactive iodine; rh, recombinant human.
Received July 3, 2003.
Accepted March 19, 2004.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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