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Departments of Endocrinology and Metabolism (M.F.T.W., W.M.W.), Nuclear Medicine (M.M.C.T.-v.-B.), and Radiodiagnostics (N.J.S.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam; and Department of Endocrinology (P.L.), Academic Hospital of the Free University, 1007 MB Amsterdam, The Netherlands
Address correspondence and requests for reprints to: Prof. Dr. W. M. Wiersinga, Department of Endocrinology and Metabolism F5.171, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Because 131I treatment has never been compared directly with L-thyroxine treatment, we performed a randomized clinical trial comparing the efficacy, tolerability, and safety of L-thyroxine with 131I therapy in the treatment of sporadic nontoxic nodular goiter. The very study design—via the instantaneous induction of a suppressed TSH in the patients randomized to receive L-thyroxine—allowed us to evaluate prospectively the effect of thyroid hormone-suppressive therapy on bone density in a controlled manner. The main outcome measurements, as assessed after 2 yr, were goiter size, bone mineral density (BMD), and thyroid function.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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One hundred consecutive patients with SNG, referred because of
goiter, were included. The diagnosis of SNG was ascertained by
ultrasound (nodular goiter), 99mTc-pertechnetate thyroid
scintigraphy (inhomogenous uptake), and by fine-needle aspiration
cytology indicating the benign (dysplastic) nature of the goiter. None
had been treated for goiter in the preceding 2 yr, and all patients
lived in an iodine-sufficient region (the mean 24-h urinary iodine
excretion of healthy Dutch adults is 147 µg; Refs. 12
and 24). Exclusion criteria were severe obstructive
symptoms and signs (n = 2), cardiac disorders precluding
L-thyroxine treatment (n = 3), pregnancy (-wish) or
breastfeeding precluding radio-iodine treatment (n = 3), and
inability to complete follow-up (n = 2). Of the 90 eligible
patients, 64 gave informed consent to enter the trial (Fig. 1
), which was approved by the local
medical ethics committee. None of them used medication affecting bone
metabolism, except four premenopausal women who continued to use oral
contraceptives during the whole duration of the study. According to a
sample size calculation, at least 44 patients were required to have an
80% chance of detecting a difference of 50% (P <
0.05) in reduction of goiter size between both groups.
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In patients randomized to 131I, pretreatment thyroidal radioiodine uptake was measured with a tracer activity of 3.7 MBq Na 131I. The therapeutic 131I dose (aiming at 4.44 MBq/mL thyroid tissue) was calculated by the following formula: 131I dose (MBq) = [4.44 (MBq) x 100/24 h uptake (%)] x TV (thyroid volume; mL, measured by ultrasonography). Patients were hospitalized for 131I treatment for 2–6 days. After 131I therapy, L-thyroxine was given if TSH increased above 4.0 mU/L, aiming at TSH values in the normal range.
In patients randomized to L-thyroxine, the initial dose of L-thyroxine was 2.5 µg/kg body weight, aiming at TSH values between 0.01 and 0.1 mU/L. If pretreatment TSH was already suppressed, free T4 (FT4) values were aimed at 20–22 pmol/L. Dose adjustments of L-thyroxine (25 µg at a time) were performed on the basis of TSH values, or of clinical signs and symptoms of thyrotoxicosis. L-thyroxine tablets were taken late in the evening.
Patients were evaluated at 0, 1.5, 3, 6, 9, 12, 18, and 24 months; the main outcome measurements were obtained before treatment and after 1 and 2 yr.
Methods
At each visit at the outpatient clinic, complaints related to the goiter were noted, together with signs and symptoms of thyrotoxicosis or hypothyroidism. The daily calcium intake was determined by a dietician. Serum thyroid function tests were obtained at every visit. At baseline and at 1 and 2 yr of follow-up, markers of tissue thyrotoxicosis and bone turnover were determined in fasting blood samples and 2-h fasting urine samples, collected between 0800 and 1000 h.
Thyroid volume was measured by ultrasonography using a contact B-scanner (Searle Pho/Sonic-SM, Siemens AG, Munich, Germany) with a 5.0-MHz, 14-mm transducer (focal length, 4.5 cm). Transverse scans of the thyroid were obtained in supine position at 5-mm intervals from caudal to cranial with hyperextension of the neck. The sum of all partial volumes equals the total thyroid volume. All determinations were performed by one radiologist (N.J.S.), who was blinded to the given treatment. The accuracy and precision of the method has been reported earlier (24). A significant decrease in thyroid volume was defined as a decrease greater than 13% (i.e. the mean + 2 SD of the coefficient of variation).
BMD of the lumbar spine, femoral neck, and trochanter was measured by dual-energy x-ray absorptiometry, using a Norland XR26 (Norland Corp., Fort Atkinson, WI; coefficients of variation: 2.4% for the lumbar spine, 2.3% for the femoral neck, and 2.4% in the trochanteric region, as measured in 51 volunteers). Z-scores were calculated for comparison with a reference population. During the study, the Norland densitometer was replaced by a Hologic 2000 (Hologic, Inc., Waltham, MA); BMD was, thus, measured on two different densitometers in 20 patients. In 14 of them we measured BMD on both densitometers on the same day at 1-yr follow-up and found a correlation coefficient of 0.99 at the lumbar spine. We calculated Norland values from Hologic values with the formula y (Norland value) = -0.04 + 1.06x (Hologic value), obtained by regression analysis. The same procedure was applied to the femoral neck (r = 0.90, y = 0.07 + 0.99x) and trochanter (r = 0.85, y = 0.10 + 0.88x).
Plasma T4 and T3 were measured by in-house RIAs, FT4 by fluoroimmunoassay using the Delfia technique (Ultra; Wallac Oy, Turku, Finland), and TSH by an immunochemiluminometric assay (Behring, Amsterdam, The Netherlands; functional sensitivity, 0.01 mU/L). The reference values were: T4, 60–160 nmol/L; T3, 1.3–2.7 nmol/L; FT4, 10–22 pmol/L; and TSH, 0.4–4.0 mU/L. Autoantibodies against thyroid peroxidase (TPO) and thyroglobulin were measured by chemiluminescence immunoassays (LUMI-test; Brahms, Berlin, Germany). Serum TSH-binding inhibiting immunoglobulins were measured by TRAK assay (Brahms) in patients who developed a suppressed TSH after 131I treatment. Serum osteocalcin was measured by RIA (INCSTAR Corp., Stillwater, MN), bone alkaline phosphatase (BAP) by Alkphase-B (Metra Biosystems, Mountain View, CA), insulin-like growth factor I (IGF-I) by immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX), sex hormone-binding globulin (SHBG) also by immunoradiometric assay (Farmos Diagnostica, Turku, Finland), and 25-hydroxyvitamin D by competitive protein binding assay (TNO, Zeist, The Netherlands).
Statistical analysis
Differences in (baseline) values between groups were analyzed by
Student’s t test, Mann-Whitney U test, or
2 test (to compare percentages between
groups), where appropriate. Changes in (outcome-) variables were
analyzed by ANOVA using repeated measurements (and applying log
transformation, where appropriate). To compare the series of changes
between the two treatment groups, multivariate ANOVA was performed.
Correlation tests were performed by single linear regression analysis,
using a PC software program (SPSS, Inc., Chicago, IL). For
calculations, undetectable serum concentrations were considered as
corresponding to one half the functional sensitivity (i.e.
0.005 mU/L for TSH). The level of significance was taken as 
=
0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Initial clinical and laboratory data of the eligible but not
randomized patients and the two randomization groups are given in Table 1. No differences were found between the
three groups. Patients were accrued in the period 1993–1996. We
included one patient below the age of 30 yr, a woman of 29 yr old, who
was operated on before (subtotal thyroidectomy) and had complaints of a
goiter of 139 mL at study entry. Fourteen patients older than 60 yr
were included, of whom six were randomized to receive
L-thyroxine and eight to receive
131I; slightly low baseline TSH values
(>0.1–0.39 mU/L) were observed in three and two of these subjects,
respectively; none had a TSH value of 0.1 mU/L or less.
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Efficacy
In group A, a median decrease in goiter size of 38% at 1 yr and
of 44% at 2 yr was found (Table 2).
Twenty-eight patients (97%) were responders to treatment (defined as a
decrease in thyroid volume >13%) with a median decrease in thyroid
volume of 39% after 1 yr and 46% after 2 yr (Fig. 2). In group B, goiter size decreased
with 7% at 1 yr and 1% at 2 yr. Twelve patients (43%) were
responders to treatment with a median decrease in thyroid volume of
23% after 1 yr and 22% after 2 yr. There were 16 nonresponders with a
median decrease in thyroid volume of 1% after 1 yr and a median
increase in thyroid volume of 16% after 2 yr (Fig. 2).
Intention-to-treat analysis resulted in comparable results: in group A,
a median decrease in goiter size of 41% at 2 yr was found, whereas in
group B goiter size decreased with 5% at 2 yr of treatment
(P < 0.0001). Compliance with
L-thyroxine treatment was good as judged by
laboratory evaluation (Fig. 3). Taking
together all time points, TSH values were below 0.01 mU/L in 38%,
between 0.01 and 0.1 mU/L in 46%, and between 0.1 and 1.0 mU/L in
16%. No significant differences in TSH values were observed between
responders and nonresponders to L-thyroxine
treatment.
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In both treatment groups at 2 yr of follow-up, fewer patients had complaints of their goiter than at baseline; after 2 yr of treatment only 2 of 20 patients in group A and 9 of 19 patients in group B still had complaints of discomfort in the neck, 1 of 8 patients in group A and 5 of 10 patients in group B still had cosmetic complaints, whereas dyspnea disappeared in 4 of 4 patients of group A but persisted in 2 of 3 patients of group B. The remaining complaints after 2 yr of treatment were significantly less frequent in group A than in group B (3 of 32 vs. 16 of 32, respectively; P < 0.05).
Side effects
Clinical and biochemical data. One week after
131I treatment, four patients noted anterior neck
tenderness and slight symptoms of thyrotoxicosis lasting 1–3 weeks,
compatible with mild radiation thyroiditis. No obstructive symptoms
were noted. No patient developed Graves’-like hyperthyroidism. Of the
eight patients who developed TSH values below 0.4 mU/L 6 weeks to 9
months after 131I treatment, de novo
serum TSH-binding inhibiting immunoglobulins appeared in one without
symptoms (TRAK before treatment, <5 U/L; after 9 months, 29 U/L; after
12 months, 20 U/L). After 2 yr, 16 patients were euthyroid (55%), 10
patients had developed hypothyroidism (35%), and 3 patients developed
subclinical hypothyroidism (10%) in the first year after
131I treatment. Patients with a normal
pretreatment TSH had a significantly higher risk of developing
hypothyroidism after 131I treatment than patients
with a suppressed baseline TSH (2,
P < 0.005). The presence of TPO antibodies at baseline
also carried a higher risk of developing hypothyroidism after
131I (2,
P < 0.05).
In group B, 10 patients experienced symptoms of mild thyrotoxicosis, disappearing after dose adjustment in all but 1 patient. A small but significant increase in pulse rate of 9% was observed during treatment, without changes in body weight. Serum SHBG and IGF-I concentrations did not indicate tissue thyrotoxicosis in either group because no significant changes were found during follow-up [group A, SHBG as mean (SD): at baseline, 58 (24) nmol/L; at 2 yr, 67 (29) nmol/L; group A, IGF-I: at baseline, 28 (12) nmol/L; at 2 yr, 27 (11) nmol/L; group B, SHBG: at baseline, 64 (45); at 2 yr, 78 (69) nmol/L; group B, IGF-I: at baseline, 22 (8) nmol/L; at 2 yr, 23 (9) nmol/L]. Serum lipids (total cholesterol, low-density lipoprotein cholesterol, and triglycerides) did not change either in both treatment groups.
Markers of bone turnover
Markers of bone formation and resorption are listed in Table 3. Males (n = 2) and perimenopausal
women (n = 4) were excluded from evaluation as well as two other
patients, one because of hypoparathyroidism due to previous
thyroidectomy and one because of the appearance of bone metastases of
breast cancer. Baseline values in group A (n = 24; 13 pre- and 11
postmenopausal women) and group B (n = 25; 15 pre- and 10
postmenopausal women) did not differ. Daily calcium intake (group A,
1110 mg; range, 418–2440 vs. group B, 886 mg; range,
480–1905) and serum 25-hydroxyvitamin D concentrations [group A,
55 (22) nmol/L, mean (SD), vs. group
B, 53 (30) nmol/L] were similar in both groups. Markers of bone
turnover did not change in group A, except an increase in total and
BAP, although less marked than in group B (P <
0.0005). Serum osteocalcin, total and BAP, and urinary hydroxyproline
increased in group B. After 2 yr of treatment with
L-thyroxine, TSH values were inversely correlated
with alkaline phosphatase (r = -0.70, P <
0.001), BAP (r = -0.72, P < 0.001), osteocalcin
(r = -0.36, P = 0.08), and the hydroxyproline to
creatinine (Hp/Cr) ratio (r = -0.62, P <
0.001). At 2 yr, a positive correlation was noted between osteocalcin
and the Hp/Cr ratio (r = 0.70, P < 0.001) in
group B, but not in group A.
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Measurements of BMD are given in Table 3
. No differences between
groups A and B were noted in smoking history, alcohol and coffee
intake, physical activity, body weight, menarche, time and duration of
menopause, and use of oral contraceptives. Pretreatment values of
patients of groups A and B were not different. Z-scores in groups A and
B were not different either: lumbar spine as mean (SD),
0.22 (1.02) vs. 0.19 (1.18); femoral neck, 0.34 (1.10)
vs. 0.32 (0.94); and trochanter, 0.23 (0.90) vs.
0.26 (0.94). Postmenopausal women had significantly lower BMD values
than premenopausal women. In group A, BMD did not change during
treatment. In group B, BMD at the lumbar spine was reduced by 3.6%
after 2 yr (P < 0.001; Fig. 4); the decrease was similar in pre- and
postmenopausal women [from 1.19 (0.19) to 1.16 (0.19)
g/cm2 (P = 0.002; mean decrease,
2.6%) and from 0.93 (0.17) to 0.89 (0.18) g/cm2
(P = 0.003; mean decrease, 5.0%), respectively]. BMD
of femoral neck and trochanter also decreased in group B, although not
significantly (Fig. 4). Patients in group B with a baseline TSH below
0.4 mU/L had a lower baseline BMD at the lumbar spine
(P < 0.05) and a larger decrease in BMD at the lumbar
spine after 2 yr of treatment [from 0.94 (0.19) to 0.88 (0.21)
g/cm2, P = 0.002] than patients
with a normal baseline TSH value [from 1.15 (0.21) to 1.12 (0.20)
g/cm2, P = 0.001; mean change,
-7.2% vs. -2.2%, P < 0.05]. An inverse
relationship was found between the changes in BMD at the lumbar spine
and the changes in BAP (r = -0.42, P < 0.05) or
the Hp/Cr ratio (r = -0.48, P < 0.05) in group
B, but not in group A.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The present study demonstrates that radioiodine treatment is far more effective in reducing the size of SNGs than suppressive doses of L-thyroxine: in the 131I-treated patients, there were 97% responders with a decrease in goiter size of 46% compared with 43% responders in the L-thyroxine-treated patients in whom goiter size decreased by 22%. The observed effect size of both treatment modalities is in good agreement with earlier studies: a reduction in goiter size of 40–60% has been reported in 80–100% of the patients treated with 131I in open studies (19, 20, 21, 22, 23) and of 25% in 59% of the patients treated with L-thyroxine in a placebo-controlled trial (12).
Chances for goiter reduction on T4 treatment were less if pretreatment TSH was already suppressed. Moreover, patients with a suppressed baseline TSH value had a larger decrease in BMD at the lumbar spine after 2 yr of treatment, and one patient of 55 yr developed atrial fibrillation after 15 months of L-thyroxine treatment. Our observations extend on an earlier finding that among people 60 yr of age and older, a serum TSH of less than 0.1 mU/L is associated with a 3-fold higher risk for developing atrial fibrillation in the next decade (13). We conclude that T4 treatment is apparently contraindicated if TSH is below 0.1 mU/L, irrespective of age.
The administered dose of 131I is obviously a determinant of goiter reduction by radioiodine treatment (23). This could not be evaluated in the present study because all patients received the same dose of 4.44 MBq/g thyroid. We calculated the 131I dose on goiter size measured by ultrasonography. Scintigraphic measurement of the size of nodular goiters may differ considerably from ultrasonographic measurements (25, 26, 27). The precise method of assessing nodular goiter size should, thus, be taken into account when comparing literature data on the outcome of 131I therapy. In our series, the outcome of radioiodine treatment was inversely related to goiter size: the larger the goiter, the smaller the relative decrease in size. To enhance the efficacy of 131I therapy and to limit the theoretical risk of cancer induction through the radiation burden of large doses of 131I, one could argue to administer radioiodine at an earlier stage when the goiter is still smaller, allowing a lower 131I dose. The gain, however, must be weighted against an increased risk on postradioiodine hypothyroidism, because patients with smaller goiters are less likely to have suppressed TSH values, which in the present study protected against the development of hypothyroidism.
Side effects
The price to be paid for the good efficacy of 131I therapy is the rather high incidence of hypothyroidism. Our figure of 45% is relatively high compared with some, but not all, previous studies (17, 19, 20, 23); the differences may be explained by the fact that in our study 131I-treated patients were given L-thyroxine as soon as TSH rose above 4.0 mU/L, aiming at TSH levels in the normal range to prevent regrowth of the goiter. Knowing that hypothyroidism may be transient after 131I treatment for hyperthyroidism (28), we, thus, could have overestimated the percentage of patients with permanent hypothyroidism in our study. Determinants of postradioiodine hypothyroidism in our series were baseline TSH and the presence of TPO antibodies, as reported before (29). Other side effects of 131I therapy were transient in nature and limited in number.
Among the patients of group B receiving T4, 10 developed thyrotoxic symptoms, necessitating premature discontinuation of T4 in 2 (in 1 because of atrial fibrillation). The administration of TSH-suppressive doses of T4 did not change serum concentrations of SHBG, lipids, and IGF-I. These markers for the effect of thyroid hormones on peripheral tissues, thus, did not indicate tissue thyrotoxicosis in the liver. Our findings are in disagreement with two previous cross-sectional studies reporting lower total and (low-density lipoprotein) cholesterol values in spontaneous subclinical hyperthyroidism (30) and in L-thyroxine-treated patients with suppressed TSH compared with controls (31). A longer exposure time in these studies than the 2 yr in the present study might explain the discrepancy.
In bones, however, the consequences of induced subclinical hyperthyroidism maintained for 2 yr were striking. Stratification for sex and menopausal age at randomization allowed us to compare BMD and bone turnover in two homogeneous groups composed of pre- and postmenopausal women, who had received radioiodine or T4 treatment. BMD and markers of bone turnover did not change in the 131I-treated group, except for an increase of total and BAP, which remains unexplained. In the T4-treated group, the increase of BAP was larger than after 131I (P < 0.005) and was accompanied by an increase in serum osteocalcin and urinary hydroxyproline, indicating a rise of both bone formation and bone resorption, which were related to the fall of TSH. The inverse relationship between serum TSH and bone turnover has been noted before (32). The increased bone turnover was associated with a decrease of BMD at the lumbar spine, which was present both in pre- and postmenopausal women (2.6% and 5.0%, respectively); a decrease of BMD at the femoral neck and trochanter was also observed but failed to reach significance, probably due to a small sample size. Two meta-analyses of published studies (all cross-sectional) on suppressive thyroid hormone therapy showed significant bone loss in postmenopausal, but not in premenopausal, women (14, 15). The authors recommended a large, double-blind, placebo-controlled trial (in patients with benign nodules, receiving suppressive T4 treatment for at least 2 yr), to get definitive answers. Our trial seems to meet this ideal study design to a large extent and demonstrates that prolonged subclinical hyperthyroidism has an adverse effect on bone mass not only in post- but also in premenopausal women. Two other recent prospective, although nonrandomized, trials are in agreement with our findings. A longitudinal study in premenopausal women indicated spinal bone loss of 0.2 ± 1.2% per year in controls, significantly less than 2.6 ± 1.9% in patients on suppressive T4 therapy after (sub)total thyroidectomy for goiter or cancer (33). Another study in nontoxic goiter patients on suppressive therapy with T4 also suggests reduction of BMD relative to age-matched controls, in both pre- and postmenopausal women (34). One may question the appropriateness of the radioiodine-treated patients as a control group in our study. One could argue that the preserved BMD in the radioiodine group is explained by correction of slight thyroid hormone excess (35) and that the observed bone loss in the T4-treated patients is due to natural history. However, a decrease in BMD at the lumbar spine of 2.6% in premenopausal women treated with L-thyroxine is far more than expected by aging with 2 yr, and the absence of any change in BMD in our radioiodine-treated patients was found irrespective of baseline TSH levels, both in pre- and postmenopausal women.
Treatment perspectives
The side effects of suppressive T4 therapy are not negligible, because suppressed TSH levels (defined as <0.1 mU/L) increase the risk for atrial fibrillation and the observed bone loss constitutes a risk factor for fractures. Because reduction of goiter size during T4 treatment is lost on discontinuation of the drug (12), continuous treatment is necessary; long-term exposure to suppressed TSH values raises concern as to the safety of this treatment modality for nontoxic goiter. Taken together with the modest efficacy of T4, we do not recommend it any longer for the treatment of nontoxic nodular goiter, also because an attractive nonsurgical alternative is available: radioactive iodine. 131I therapy is simple, devoid of major side effects, and effective. Although hypothyroidism develops in approximately half of the patients, it is easily treated with T4, not requiring TSH-suppressive doses. The efficacy of 131I can be enhanced by treatment at an earlier stage when the goiter is still smaller; this will also add to the long-term safety of radioactive iodine, by allowing the application of a lower dose of 131I.
Received April 17, 2000.
Revised August 15, 2000.
Revised October 16, 2000.
Accepted October 30, 2000.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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