Improvement of goiter volume reduction after 0.3 mg recombinant human thyrotropin-stimulated radioiodine therapy in patients with a very large goiter: a double-blinded, randomized trial

INTRODUCTION: The effect of (131)I therapy amplification by recombinant human (rh) TSH prestimulation in very large goiters has not been evaluated in a double-blinded, placebo-controlled study. METHODS: Twenty-nine patients (22 females; age range 37-87 yr) with a large multinodular goiter (median 160 ml, range 99-440 ml) were randomized to receive placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before (131)I administration. Goiter volume was monitored by magnetic resonance imaging. RESULTS: On average, the goiter volume was unchanged 1 wk after therapy in both groups, but the largest deviations from baseline were observed in the rhTSH group. After 12 months the median goiter volume was reduced from 170 to 121 ml in the placebo group and from 151 to 72 ml in the rhTSH group, respectively (within group: P = 0.001; between group: P = 0.019). This corresponds to reductions of 34.1 +/- 3.2 and 53.3 +/- 3.3%, respectively (between group: P < 0.001). In the placebo group, the goiter reduction correlated positively with the retained thyroid (131)I dose, whereas such a relationship was absent in the rhTSH group. Adverse effects, mainly related to thyroid pain and cervical compression, were more frequent in the rhTSH group. At 12 months, goiter-related complaints were significantly reduced in both groups without any between-group difference. One and three patients in the placebo and the rhTSH group, respectively, developed hypothyroidism. CONCLUSION: rhTSH-stimulated (131)I therapy improves the reduction of very large goiters by more than 50%, compared with (131)I therapy alone, but at the expense of more adverse effects after therapy. Our data suggest that rhTSH stimulation may work through mechanisms that go beyond the increase in thyroid (131)I uptake.     

Recombinant human thyrotropin markedly changes the 131I kinetics during 131I therapy of patients with nodular goiter: an evaluation by a randomized double-blinded trial

The present study compares, in a randomized double-blinded design, the expected and the actual absorbed thyroid radioactive dose in response to 0.3 mg recombinant human (rh)TSH (n = 35) or placebo (n = 28) given 24 h before (131)I therapy in patients with nodular goiter (median volume, 69 ml; range, 20-440 ml). The (131)I activity calculation was based on thyroid (131)I uptake (RAIU) at 24 and 96 h after a tracer dose of 0.5 MBq (131)I. After (131)I therapy, 24- and 96-h RAIU were repeated allowing a more exact assessment of the actual absorbed thyroid dose. The median (131)I activity was 617 and 632 MBq, respectively, in the rhTSH and the placebo group. At baseline, the 24- and 96-h RAIU and the expected thyroid dose were 32.8 +/- 9.1%, 32.1 +/- 8.2%, and 96.3 +/- 16.3 Gy, respectively, in the rhTSH group and 35.7 +/- 11.8%, 35.2 +/- 11.3%, and 94.1 +/- 18.5 Gy, respectively, in the placebo group (P value not significant between groups). After (131)I therapy, the 24- and 96-h RAIU and the actual absorbed thyroid dose were 46.9 +/- 11.7%, 45.0 +/- 12.1%, and 136.7 +/- 47.9 Gy, respectively, in the rhTSH group and 33.0 +/- 11.4%, 31.0 +/- 11.3%, and 76.9 +/- 27.5 Gy, respectively, in the placebo group (P < 0.001 between groups). Comparing the expected with the actual absorbed thyroid dose, this corresponds to a mean increase of 36.4% (95% confidence interval, 21.3-53.4) in the rhTSH group and a decrease of 21.5% (95% confidence interval, -33.9 to -6.6) in the placebo group (P < 0.001), equivalent to an increase of 73.8% in the absorbed thyroid dose in the rhTSH-treated group. We have thus for the first time shown that stimulation with rhTSH before (131)I therapy not only hinders the decrease in the thyroid RAIU observed with conventional (131)I therapy but in fact also significantly enhances the absorbed thyroid dose. Whether this also leads to a significant increase in goiter size reduction needs additional study.     

Radioiodine therapy for multinodular toxic goiter.

BACKGROUND: Radiolabeled iodine 131 therapy is used for treatment of multinodular toxic goiter, but long-term follow-up studies are lacking. METHODS: A prospective study of 130 consecutive patients (115 women) treated with 131I for multinodular toxic goiter and followed by evaluation of thyroid volume (determined using ultrasound) and thyroid function variables. RESULTS: The patients were observed for a median of 72 months (range, 12-180 months). Sixty-six patients received antithyroid drug pretreatment; 64 did not. Iodine 131 treatment (3.7 MBq/g thyroid tissue corrected to a 100% 24-hour 131I uptake) was given as a single dose in 81 patients, 2 doses in 38, and 3 to 5 doses in 11. One or 2 treatments cured 119 patients (92%), and 68 (52%) became euthyroid within 3 months after 131I treatment. The median 131I dose was 370 MBq (range, 93-1850 MBq). Forty-nine patients needing more than 131I dose had a reduction in median thyroid volume from 56 mL (range, 21-430 mL) to 44 mL (range, 15-108 mL), representing a 24% reduction related to the insufficient 131I dose. In all patients, the initial median thyroid volume of 44 mL (range, 16-430 mL) decreased to 25 mL (range, 8-120 mL) (P<.005), representing a median reduction of 43%, 24 months after the last 131I dose. Hypothyroidism evaluated using life-table analysis developed in 6% of patients who did not receive antithyroid pretreatment and 20% who did (P<.005) after a median of 42 months (range, 3-60 months), the total hypothyroidism frequency being 14% within 5 years of treatment. CONCLUSIONS: Ninety-two percent of patients with multinodular toxic goiter were cured with 1 or 2 treatments. The thyroid volume was reduced by 43%, with few side effects. Iodine 131 should be the choice of treatment in patients with multinodular toxic goiter.     

Randomized prospective study comparing a single radioiodine dose and a single laser therapy session in autonomously functioning thyroid nodules

OBJECTIVE: To compare the efficacy of interstitial laser photocoagulation (ILP) with radioiodine in hot thyroid nodules. DESIGN: Thirty consecutive outpatients with subclinical or mild hyperthyroidism and a scintigraphically solitary hot nodule with extraglandular suppression were randomized to either one ILP session or one radioiodine ((131)I) dose. METHODS: ILP was performed under continuous ultrasound-guidance and with an output power of 2.5-3.5 W. (131)I was given as a single dose based on thyroid volume and a 24-h thyroid (131)I uptake. Thyroid function and nodule volume were evaluated at inclusion and at 1, 3 and 6 months after treatment. RESULTS: Normalization of serum TSH was achieved in 7 out of 14 patients in the ILP group and in all 15 patients in the (131)I group (P=0.0025). In the ILP group, mean thyroid nodule volume reduction was 44+/-5% (s.e.m.; P<0.001), and in the (131)I group 47+/-8% (P<0.001), within 6 months, without between-group difference (P=0.73). The mean reduction of total thyroid volume was 7+/-5% in the ILP group (P=0.20) and 26+/-8% (P=0.006) in the (131)I group (P=0.06 between-group). Two patients in the (131)I group developed hypothyroidism but no major side effects were seen. CONCLUSIONS: This first randomized study, comparing ILP with standard therapy, demonstrates that ILP and (131)I therapy approximately halves thyroid nodule volume within 6 months; but in contrast to (131)I, extranodular thyroid volume is unaffected by ILP and no patient developed hypothyroidism. Using the present design, ILP seems inferior to (131)I therapy in normalization of serum TSH. The potential value of ILP as a non-surgical alternative to (131)I needs further investigation.     

Pretreatment with a single,low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter

In patients with nodular goiter, radioiodine ((131)I) therapy results in a mean reduction in thyroid volume (TV) of approximately 40% after 1 yr. We have demonstrated that pretreatment with a single, low dose of recombinant human TSH (rhTSH) doubles 24-h radioactive iodine uptake (RAIU) in these patients. We have now studied the safety and efficacy of therapy with a reduced dose of (131)I after pretreatment with rhTSH. Twenty-two patients with nodular goiter received (131)I therapy, 24 h after im administration of 0.01 (n = 12) or 0.03 (n = 10) mg rhTSH. In preceding diagnostic studies using tracer doses of (131)I, 24-h RAIU without and with rhTSH pretreatment (either 0.01 or 0.03 mg) were compared. Therapeutic doses of (131)I were adjusted to the rhTSH-induced increases in 24-h RAIU and were aimed at 100 micro Ci/g thyroid tissue retained at 24 h. Pretreatment with rhTSH allowed dose reduction of (131)I therapy by a factor of 1.9 +/- 0.5 in the 0.01-mg and by a factor of 2.4 +/- 0.4 in the 0.03-mg rhTSH group (P < 0.05, 0.01 vs. 0.03 mg rhTSH). Before and 1 yr after therapy, TV and the smallest cross-sectional area of the tracheal lumen were measured with magnetic resonance imaging. During the year of follow-up, serum TSH, free T(4) (FT(4)), T(3), and TSH receptor antibodies were measured at regular intervals. TV before therapy was 143 +/- 54 ml in the 0.01-mg group and 103 +/- 44 ml in the 0.03-mg rhTSH group. One year after treatment, TV reduction was 35 +/- 14% (0.01 mg rhTSH) and 41 +/- 12% (0.03 mg rhTSH). In both groups, smallest cross-sectional area of the tracheal lumen increased significantly. In the 0.01-mg rhTSH group, serum FT(4) rose, after (131)I treatment, from 15.8 +/- 2.8 to 23.2 +/- 4.4 pM. In the 0.03-mg rhTSH group, serum FT(4) rose from 15.5 +/- 2.5 to 23.5 +/- 5.1 pM. Individual peak FT(4) levels, reached between 1 and 28 d after (131)I treatment, were above the normal range in 12 patients. TSH receptor antibodies were negative in all patients before therapy and became positive in 4 patients. Hyperthyroidism developed in 3 of these 4 patients between 23 and 25 wk after therapy. In conclusion, in patients with nodular goiter pretreatment with a single, low dose of rhTSH allowed approximately 50-60% reduction of the therapeutic dose of radioiodine without compromising the efficacy of TV reduction.     

Non-surgical approach to the benign nodular goiter: new opportunities by recombinant human TSH-stimulated 131I-therapy

The optimal treatment strategy in a goiter patient depends--among other factors--on goiter size, the degree of cosmetic or compressive symptoms, the age of the patient, the impact on the upper airways, the wish to maintain normal thyroid function, the ability of the thyroid gland to take up (131)I, and the possibility of thyroid malignancy. When treatment is warranted in a patient with benign goiter, the choice usually stands between surgery and (131)I-therapy. Focal destructive treatment, by ethanol sclerotherapy or interstitial laser photocoagulation, may be considered in patients with a solitary benign nodule. If thyroid hyperfunction due to nodular autonomy is the dominant problem, life-long anti-thyroid drug treatment may be relevant in elderly individuals. With the advent of recombinant human TSH (rhTSH) stimulation the goiter reduction following (131)I-therapy is significantly enhanced and this treatment is of particular benefit, as compared with conventional (131)I-therapy, in patients with a low baseline thyroid (131)I uptake and a large goiter. If the rhTSH dose does not exceed 0.1 mg the risk of temporary hyperthyroidism and acute thyroid swelling is low. Since patient satisfaction seemingly is not improved by the greater goiter reduction obtained by rhTSH-stimulated (131)I-therapy, and permanent hypothyroidism is more frequent, it may be more relevant to reduce the administered radioactivity equivalent to the rhTSH-induced increase in the thyroid (131)I uptake. Future large-scale well-controlled studies should explore this strategy, with focus on cost-benefit and quality of life. A major hindrance of widespread and routine use of rhTSH-stimulated (131)I-therapy is its present status as an off-label treatment.     

Transition of nodular toxic goiter to autoimmune hyperthyroidism triggered by 131I therapy.

The use of 131I treatment in nodular toxic goiter is widely accepted. In this article, we describe transition of nodular toxic goiter into an autoimmune toxic goiter with development of thyrotropin receptor antibodies (TRAb) as a side effect of 131I treatment. In this retrospective study, 149 patients with nodular toxic goiter (100 with multinodular goiter, 49 with a solitary autonomously functioning toxic nodule) were studied. Of these 149 patients 100 became permanently euthryoid after 1 dose of 131I, and due to persistent hyperthyroidism, 32 patients needed 2-5 doses to became euthyroid. After becoming euthyroid, none of these 132 patients had relapse of hyperthyroidism in the follow-up period. Based on evaluation of the thyroid hormone variables, 17 of 149 patients had a distinctly different pattern in the changes in thyroid hormones. They developed an increase in FT4I 3-6 months posttreatment after an initial fall in FT4I. Twelve of these 17 patients were treated with antithyroid drugs before the initial 131I dose. On samples of frozen sera (-20 degrees C) anti-thyroid peroxidase (TPO) and TRAb were followed for 6 months after 131I treatment in these 17 patients. A similar follow-up was done in 20 patients (10 with and 10 without antithyroid drug pretreatment), randomly selected from the patients who did not relapse. In the remaining 112 patients, anti-TPO and TRAb levels were measured only before the 131I treatment. Of the 17 patients with relapse, 6 developed TRAb concomitant with recurrence of hyperthyroidism (4% of the study group). In 5 of the 17 patients TRAb values remained absent throughout the follow-up period. The remaining 6 patients had elevated TRAb values before 131I treatment. Among the 132 patients who did not relapse, an additional 7 cases with presence of TRAb were found. A total of 9% of the study group was found to have TRAb before 131I pretreatment. Anti-TPO was found in 20 of 149 patients (13%) before 131I treatment. Complications, either hypothyroidism or TRAb-associated hyperthyroidism, were seen in 8 of 20 patients (40%) with anti-TPO before 131I treatment, compared to 9 of 129 (7%) without (p<0.005). In conclusion, TRAb and a Graves' like hyperthyroidism can be triggered by 131I treatment in patients with nodular toxic goiter. The presence of anti-TPO seem to be a marker of an increased risk of development of TRAb-associated hyperthyroidism as well as hypothyroidism, but both side effects can be seen despite the absence of anti-TPO autoantibodies.     

A randomized trial comparing levothyroxine with radioactive iodine in the treatment of sporadic nontoxic goiter

A randomized clinical trial was performed in consecutive patients with sporadic nontoxic nodular goiter to compare efficacy and side effects of iodine-131 ((131)I) therapy with suppressive levothyroxine (L-thyroxine) treatment. Sixty-four patients were randomized after stratification for sex and menopausal age to receive (131)I (4.44 MBq/g thyroid; group A) or suppressive L-thyroxine treatment aiming at TSH values between 0.01 and 0.1 mU/L (group B). The main outcome measurements after 2 yr were goiter size by ultrasound, serum thyroid function tests, markers of bone turnover, and bone mineral density (BMD). Fifty-seven patients completed the trial. Goiter size was reduced after 2 yr by 44% in group A and by 1% in group B (P< 0.001). Nonresponders (goiter reduction <13%) were 1 of 29 patients in group A and 16 of 28 patients in group B (P = 0.00001). In responders, goiter reduction in group A (46%) was greater than in group B (22%; P< 0.005). In group A, 45% of patients developed hypothyroidism. In group B, 10 patients experienced thyrotoxic symptoms, requiring discontinuation of treatment in 2 (in 1 because of atrial fibrillation). Markers of bone formation and bone resorption increased significantly in group B, related to a mean decrease of 3.6% of BMD at the lumbar spine after 2 yr (from 1.09 +/- 0.22 to 1.05 +/- 0.23 g/cm(2); P< 0.001), both in pre- and postmenopausal women. No changes in BMD were observed in group A. In conclusion, (131)I therapy is more effective and better tolerated than L-thyroxine treatment in patients with sporadic nontoxic goiter. Suppressive L-thyroxine treatment results in significant bone loss.     

The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function.

Some patients with very large goiters (>150 mL) are not candidates for surgery. We evaluated the feasibility of high dose 131I in such patients. Twenty-three patients (2 men and 21 women; median age, 67 yr; range, 42-86 yr) with very large goiter (8 toxic) were treated with calculated high dose 131I [median, 2281 megabecquerels (61.6 mCi); range, 988-4620 megabecquerels (26.7-124.9 mCi)]. During the 12-month observation period, goiter reduction and tracheal anatomy were monitored by magnetic resonance imaging, and the respiratory capacity was monitored by pulmonary function tests. Five patients (22%) developed hypothyroidism. Thyroid volumes were at baseline, after 1 week, and after 1 yr [mean +/- SEM, 311 +/- 28, 314 +/- 26 (P = NS), and 215 +/- 26 (P < 0.01) mL]. The relative changes 1 week after therapy ranged from -14.1% to 15.3%. After 1 yr the mean size was reduced by 33.9% (range, 13.5-61.4%). Only the initial goiter size showed a significant negative correlation to the percent reduction. The smallest cross-sectional area of the trachea decreased 9.2% within 1 week after treatment, but eventually emerged with a 17.9% larger area [mean +/- SEM, 84.3 +/- 4.8, 75.5 +/- 5.1 (P < 0.01), and 98.2 +/- 6.0 (P < 0.01) mm2]. The inspiratory parameter, FIF50%, improved after an initial insignificant decline [baseline therapy, after 1 week, after 3 months, and after 1 yr (mean +/- SEM), 2.37 +/- 0.24, 2.20 +/- 0.21 (P = NS), 2.51 +/- 0.23 (P = NS), and 2.76 +/- 0.25 (P = 0.01) L/s]. FIF50% correlated significantly with the smallest cross-sectional tracheal area (baseline, 1 week, and 1 yr: r = 0.74; P < 0.001, r = 0.63; P < 0.005, and r = 0.46; P < 0.05). Changes in tracheal anatomy did not correlate with changes in either lung dynamics or goiter size. In conclusion, very large goiters can be reduced by a third, on the average, with high dose 131I therapy without any initial clinically significant tracheal compression. Tracheal cross-sectional area as well as pulmonary inspiratory capacity improve. No serious adverse effects are seen.     

Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodide uptake in nontoxic nodular goiter

Radioiodine (131I) is increasingly used as treatment for volume reduction of nontoxic, nodular goiter. A high dose of 131I is often needed because of low thyroid radioiodide uptake (RAIU). We investigated whether pretreatment with a single, low dose of recombinant human TSH (rhTSH; Thyrogen, Genzyme Transgenics Corp.) enhances RAIU in 15 patients with nontoxic, nodular goiter (14 women and 1 man; aged 61+/-11 yr). Four patients were studied twice, and 1 patient was studied 3 times. RAIU was measured both under basal conditions and after pretreatment (im) with rhTSH, given either 2 h (0.01 mg; n = 7) or 24 h [0.01 mg (n = 7) or 0.03 mg (n = 7)] before 131I administration (20-40 microCi). Serum levels of TSH, free T4 (FT4), and total T3 were measured at 2, 5, 8, 24, 48, 72, 96, and 192 h after rhTSH administration. After administration of 0.01 mg rhTSH, serum TSH rose from 0.7+/-0.5 to a peaklevel of 4.4+/-1.1 mU/L (P < 0.0001), FT4 rose from 16.0+/-2.6 to 18.5+/-3.7 pmol/L (P < 0.0001), and T3 rose from 2.10+/-0.41 to 2.63 - 0.66 nmol/L (P < 0.0001). After administration of 0.03 mg rhTSH, TSH rose from 0.6+/-0.4 to 15.8+/-2.3 mU/L (P < 0.0001), FT4 rose from 15.2+/-1.5 to 21.7+/-2.9 pmol/L (P < 0.0001), and T3 rose from 1.90+/-0.43 to 3.19+/-0.61 nmol/L (P < 0.0001). Peak TSH levels were reached at 5-8 h and peak FT4 and T3 levels at 8-96 h after rhTSH administration. Administration of 0.01 mg rhTSH 2 h before 131I increased 24-h RAIU from 30+/-11% to 42+/-10% (P < 0.02), 0.01 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 29+/-10% to 51+/-10% (P < 0.0001), and 0.03 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 33+/-11% to 63+/-9% (P < 0.0001). After administration of 0.01 mg rhTSH 2 h before 131I, 24-h RAIU did not increase in 1 patient, whereas the increase in 24-h RAIU was less than 10% in 2 other patients. In contrast, administration of rhTSH 24 h before 131I increased 24-h RAIU by more than 10% in all 14 patients (by >20% in 10 and by >30% in 6). In conclusion, pretreatment with a single, low dose of rhTSH in patients with nontoxic, nodular goiter increased RAIU considerably. Our observations hold promise that administration of rhTSH before 131I therapy for nontoxic, nodular goiter will allow treatment with lower doses of 131I in these patients.     

An outline concerning the potential use of recombinant human thyrotropin for improving radioiodine therapy of multinodular goiter

Radioiodine ((131)I) treatment for nontoxic and toxic multinodular goiter (MNG) is an alternative therapeutic procedure used especially for patients with contraindication for surgery. Several studies have been conducted in recent years assessing the use of recombinant human TSH (rhTSH) in increasing (131)I uptake in MNGs. This procedure also decreases the activity level of the administered (131)I, changes the distribution of (131)I in the thyroid, lowers the absorption dose, and dramatically reduces the volume of the goiter (50-75% of the baseline volume). A major disadvantage, however, is the induction of hypothyroidism in a relatively large number of patients. A transient increase in thyroid volume and tenderness was noted in the first week of treatment. Also a short period (2-4 weeks) of hyperthyroidism was observed in most patients with potential consequences particularly for the elderly. Still, there has been no evidence to date that the adverse effects outweigh the positive results of using rhTSH. The use of rhTSH in benign goiter disease has not yet been approved worldwide, but its positive activity in MNG is remarkable and promising.     

Continuous methimazole therapy and its effect on the cure rate of hyperthyroidism using radioactive iodine: an evaluation by a randomized trial

BACKGROUND: A randomized clinical trial was performed to clarify whether continuous use of methimazole (MTZ) during radioiodine ((131)I) therapy influences the final outcome of this therapy. DESIGN: Consecutive patients with Graves' disease (n = 30) or a toxic nodular goiter (n = 45) were rendered euthyroid by MTZ and randomized to stop MTZ 8 d before (131)I (-MTZ; n = 36) or to continue MTZ until 4 wk after (131)I (+MTZ; n = 39). Calculation of the (131)I activity included an assessment of the (131)I half-life and the thyroid volume. RESULTS: The 24-h thyroid (131)I uptake was lower in the +MTZ group than in the -MTZ group (44.8 +/- 15.6% vs. 62.1 +/- 9.9%, respectively; P < 0.001). At 3 wk after therapy, no significant change in serum free T(4) index was observed in the +MTZ group (109 +/- 106 vs. 83 +/- 28 nmol/liter at baseline; P = 0.26), contrasting an increase in the -MTZ group (180 +/- 110 vs. 82 +/- 26 nmol/liter; P < 0.001). The number of cured patients was 17 (44%) and 22 (61%) in the +MTZ and -MTZ groups, respectively (P = 0.17). Cured patients tended to have a lower 24-h thyroid (131)I uptake (50.1 +/- 13.8% vs. 56.4 +/- 17.1%; P = 0.09). By adjusting for a possible interfactorial relationship through a regression analysis (variables: randomization, 24- and 96-h thyroid (131)I uptake, type and duration of disease, age, gender, presence of antithyroid peroxidase antibodies, thyroid volume, dose of MTZ), only the continuous use of MTZ correlated with treatment failure (P = 0.006), whereas a low 24-h thyroid (131)I uptake predicted a better outcome (P = 0.006). CONCLUSION: Continuous use of MTZ hinders an excessive increase of the thyroid hormones during (131)I therapy of hyperthyroid diseases. However, such a strategy seems to reduce the final cure rate, although this adverse effect paradoxically is attenuated by the concomitant reduction of the thyroid (131)I uptake.     

Abnormal H2O2 supply in the thyroid of a patient with goiter and iodine organification defect

A 71-yr-old man, clinically euthyroid, with a 570-g goiter causing severe mechanical neck compression underwent thyroidectomy. His total serum T4 level was 1.8 micrograms/dL, T3 was 200 ng/dL, and TSH was 35 microU/mL, and a perchlorate test was markedly abnormal. The excised thyroid tissue had normal peroxidase activity in the tyrosine iodinase and guaiacol assays. [131I]Iodide, given 24 h before surgery, was distributed in thyroglobulin isolated in vitro as follows: monoiodotyrosine, 71.6%; diiodotyrosine, 26.7%; T3, 1.05%; and T4, 0.65%. The [131I]iodide content of the whole thyroid homogenate was 59%. The goiter content of thyroglobulin was 94.7 mg/g tissue. The thyroglobulin reacted normally with antihuman thyroglobulin antiserum. Fresh goiter slices and slices from five normal human thyroid specimens were incubated with 10(-6) M KI and [131I]iodide (tracer) containing medium alone (basal), medium plus 1 mg/mL glucose oxidase (GO), and medium plus 10(-4) M NADPH and 10(-5) M vitamin K3 (NA-K3). The percentages of organic iodine in the slices, measured as protein-bound 131I, were: basal: goiter, 0.8%; normal, 6.9 +/- 1.8% (+/- SE); GO: goiter, 15.1%; normal, 17.4 +/- 3.1%; and NA-K3: goiter, 16.7%; normal, 4.6 +/- 1.14%. We conclude that an abnormal H2O2 supply may be the cause of the iodine organification defect in this goiter.     

Influence of compensated radioiodine therapy on thyroid volume and incidence of hypothyroidism in Graves' disease

Abstract. Objectives . To investigate the long-term effect of radioactive iodine (¹³¹I) on thyroid function and size in patients with Graves' disease. Setting . Out-patient clinic in Herlev Hospital. Subjects . One hundred and seventeen consecutive patients (104 women) with Graves' disease selected for ¹³¹I treatment and followed for a minimum of 12 months (range 1–10 years, median 5 years). Interventions . ¹³¹I dose was calculated based on thyroid volume and 24-h ¹³¹I uptake. Main outcome measures . Standard thyroid function variables and ultrasonically determined thyroid volume before treatment as well as 0.75, 1.5, 3, 6 and 12 months after treatment, and then once a year were investigated. Results . Seventy-eight patients were cured by one ¹³¹I dose and 30 by two doses, while the remaining nine patients received additional doses (range one to five doses, median one dose). Within one year, 25% developed hypothyroidism, and hereafter, hypothyroidism developed at a constant rate of 3% per year independent of antithyroid pretreatment. The cumulative 10-year risk of hypothyroidism was 60%. Initial median thyroid volume was 33 mL (range 9–106 mL). At 12 months after the last ¹³¹I dose, median thyroid volume was reduced to 14 mL (range 6–36 mL) (P < 0.00001). The median reduction being 58% (range 0–80%,), hereafter no further reduction occurred. A significant reduction in thyroid volume was also noted in patients needing subsequent ¹³¹I doses and in those developing hypothyroidism within the first year. Conclusions . ¹³¹I normalizes thyroid volume in patients with Graves' disease. Hypothyroidism seems an inevitable end result of this treatment. The present study suggests that it will be impossible to modify ¹³¹I therapy in a way to achieve both early control of hyperthyroidism and a low incidence of hypothyroidism.     

Does radioiodine therapy have an equal effect on substernal and cervical goiter volumes? Evaluation by magnetic resonance imaging.

Most often thyroidectomy is recommended in patients with large goiters. However, high-dose (131)I therapy may be used in case of contraindications to surgery. Large goiters are often partially located in the mediastinum. The aim of this study was to evaluate the impact of (131)I therapy on the cervical and the substernal goiter volume, separately. Fourteen patients (median age, 69 years; range, 52-86 years) with a large multinodular goiter (three hyperthyroid) and with a substernal extension greater than 15 mL were included. T1-weighted magnetic resonance (MR) estimates of the thyroid volume in the cervical and substernal compartments were obtained before and 1 year after high-dose (131)I therapy. The total goiter volumes ranged from 182 to 685 mL. The median substernal volume was 66 mL (fraction of total volume, 17.6%; range, 8.0%-78.9%). One year after treatment, the median substernal goiter volume was reduced by 29.2% (range, -6.1%-59.4%, mean: 26.1% +/- 6.0%), and the cervical goiter volume by 30.3% (range, 6.0%-75.4%, mean, 35.6 +/- 5.6%) compared to baseline values; p = 0.25 for difference in a regional effect. The volume reduction was unrelated to initial substernal goiter size. Likewise, deterioration of the inspiratory capacity did not correlate with the magnitude of the substernal goiter extension. In conclusion, high-dose (131)I therapy seems as effective in reducing the substernal as the cervical goiter volume. However, because the overall effect is modest, this therapy should primarily be considered for the patient with a high surgical risk.     

Prevalence of thyroid dysfunction in elderly subjects from the general population in an iodine deficiency area.

The prevalence of thyroid disorders was investigated in 466 (403 female, 63 male) subjects over the age of 60 years (79.2 +/- 7.5 years; mean +/- SD) from the general population in an area of iodine deficiency. In addition to thyroid hormone assays, thyroid antibodies and urinary iodine excretion were determined. In cases with thyroid dysfunction, ultrasound investigations were performed. Twenty-two of the 466 subjects (4.7%) showed hyper- or hypothyroidism; 7 subjects were hyperthyroid (1.5%), 5 had primary hypothyroidism (1.1%), and 10 showed "subclinical" hypothyroidism (2.2%). The latter constellation is defined as an elevation of thyrotropin (TSH) with normal values for thyroxine and triiodothyronine. Most subjects with hyperthyroidism had a goiter by palpation (6/7); thyroid volume by ultrasound (median) was 26.2 mL with an inhomogeneous echo pattern in 6 of the 7 subjects. In 4 cases, a rise in urinary iodine excretion was documented; none had TSH-receptor antibodies. Most subjects with overt or subclinical hypothyroidism had a homogeneous or low-echogenic pattern by ultrasound; thyroid volume (median) was 12.9 mL and 12.7 mL, respectively. By palpation, 8 of the 15 subjects had no goiter. In general, these persons had no rise in urinary iodine excretion (11/13), but most showed an elevation of antibodies against the microsomal antigen and/or thyroglobulin (11/15).(ABSTRACT TRUNCATED AT 250 WORDS)     

Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goitre

OBJECTIVE: Radioiodine treatment is effective in reducing the size of sporadic nontoxic goitre, albeit at the expense of a high incidence of postradiation hypothyroidism. The decrease in goitre size, however, is not observed in all subjects, and little is known about recurrent goitre growth after 131I therapy. The aim of the present study was to evaluate which factors determine the longterm outcome of 131I treatment in patients with sporadic nontoxic nodular goitre, in terms of changes in both thyroid size and thyroid function. STUDY DESIGN: Retrospective follow-up study. PATIENTS: Fifty patients with sporadic nontoxic nodular goitre were evaluated who had been treated in our institution with 131I (mean dose 4.4 MBq/g thyroid) in the period 1988-95. Nine patients received a second dose of 131I and one a third. Median follow-up time was 41 months (range 24-115). MEASUREMENTS: Thyroid function was assesed by TSH and FT4 index, and thyroid volume by ultrasound in 46 patients, by scintiscan using the Himanka formula in three and by CT-scan in one. The response to treatment was defined as a decrease in thyroid volume of greater than 13% (i.e. the mean + 2SD of the coefficient of variation of volume measurements), and recurrent goitre as an increase in thyroid volume greater than 13% after an initial response. RESULTS: Goitre size decreased from a median value of 82 ml (range 17-325) to 37 ml (range 6-204) two years after 131I treatment, a median reduction of 49%. The decrease in goitre size was directly related to the dose of 131I (r = 0.50, P = 0.0003) and indirectly to baseline goitre size (r = - 0.35, P = 0.006). Seven patients (14%) were nonresponders, and four (8%) experienced recurrent goitre growth after 3-5 years. These 11 patients (22%) when compared to the remaining 39 responders (78%) had larger goitres with more often a dominant nodule, and had received a lower 131I dose. The efficacy of a second dose of 131I (median reduction in goitre size 37%) was comparable to the first dose. Hypothyroidism occurred in 24 patients (48%), mostly in the first two years after treatment; 11 had overt and 13 subclinical hypothyroidism. Kaplan Meier statistics indicated a probability of 58% for developing hypothyroidism after 8 years. Hypothyroid patients had a smaller initial goitre size and a higher prevalence of TPO antibodies and a family history of thyroid disease than the patients who remained euthyroid; the 131I dose did not differ between the two groups. CONCLUSIONS: The size of sporadic nontoxic goitres is reduced on average by 50% after a single dose of 4.77 MBq 131I/g thyroid. Independent determinants of the relative decrease in thyroid volume are administered 131I dose and initial goitre size. Nonresponders (14%) and those with late recurrence of goitre growth (8%) have larger goitres and more often dominant nodules than responders. Determinants of postradioiodine hypothyroidism (cumulative risk 58% after 8 years) are the presence of TPO antibodies, a family history of thyroid disease and a relatively small goitre.The implications of these findings are that the efficacy of a given 131I dose can be enhanced when administered at an earlier stage when the goitre is still smaller, albeit at the expense of an increased risk for developing hypothyroidism.     

Use of adjunctive potassium iodide after radioactive iodine (131I) treatment of Graves' hyperthyroidism

One hundred and nineteen patients with Graves' hyperthyroidism who were treated with 131I alone or 131I followed by potassium iodide (131I + KI) were studied retrospectively. Patients in both groups who required only a single dose of 131I for successful treatment of hyperthyroidism had similar age, gland size, 24-h radioactive iodine uptake, pretreatment serum T4 concentrations, and radioactive iodine treatment dose. Seven weeks after 131I, mean serum T4 concentrations were 12.3 +/- 6.1 micrograms/dl (mean +/- SD) in patients who received 131I alone and 8.0 +/- 3.9 micrograms/dl in patients who received 131I + KI (p less than 0.001). Sixty percent of the patients who received 131I + KI and remained euthyroid 1 yr after 131I treatment developed documented transient hypothyroidism while receiving KI (serum T4, 1.4 +/- 0.9 micrograms/dl). Patients with transient hypothyroidism receiving KI had larger estimated thyroid gland weights when hypothyroid than patients whose hypothyroidism was permanent (32 +/- 6 vs. 16 +/- 11 g; P less than 0.001). The overall incidence of hypothyroidism 1 yr after treatment with 131I was 58% in each of the two groups. Sixteen percent of each group were not successfully treated by a single dose of 131I and required further therapy. Adjunctive KI effectively treated thyrotoxicosis more rapidly than 131I alone without adversely affecting outcome at 1 yr; however, patients taking KI more often develop transient hypothyroidism.     

The effect of methimazole on cure rates after radioiodine treatment for Graves' hyperthyroidism: a randomized clinical trial.

Forty-two newly diagnosed patients with Graves' hyperthyroidism were randomly assigned to receive 131I therapy after pretreatment with methimazole (21) or beta-blocker alone (21) and prospectively evaluated, to determine possible effects of methimazole on 131I treatment outcome. After randomization, 8 patients were excluded from the study (5 from pretreatment group and 3 from nonpretreatment group). Radioactive iodine (baseline dose 15 mCi, adjusted for goiter size and/or 131I uptake) was administered after pretreatment with methimazole (30 mg initial dose for at least 2 months and stopped 6 days before treatment) and beta-blocker or pretreatment with beta-blocker alone (atenolol 50-100 mg/d). All but one patient in each group became hypothyroid. A similar length of time was required by both groups to achieve hypothyroidism (112 days, [95% confidence interval [CI] = 28 to 196 days) in the pretreated group and 106 days, [95% CI = 45 to 167 days] in nonpretreated patients). Free thyroxine (T4) normalized 44 +/- 39 days after therapy in the nonpretreated group and 35 +/- 30 days in the pretreated group (p = 0.57) and decreased to subnormal levels 80 +/- 70 days in nonpretreated and 65 +/- 32 days in pretreated patients (p = 0.46). We conclude that pretreating patients with methimazole before radioactive iodine therapy does not interfere with the final outcome. Similar cure rates and time required to achieve hypothyroidism after radioiodine were observed when patients were pretreated with methimazole compared to nonpretreated patients.     

Transient goiter enlargement after administration of 0.3 mg of recombinant human thyrotropin in patients with benign nontoxic nodular goiter: a randomized, double-blind, crossover trial

BACKGROUND: Recombinant human (rh) TSH, in doses from 0.01 to 0.9 mg, has been used to augment the effect of radioiodine ((131)I) therapy in patients with a benign nontoxic nodular goiter. Transient thyroid enlargement and thyrotoxicosis may be seen following (131)I therapy. AIM: The aim of the study was to investigate whether rhTSH per se causes goiter enlargement, until now an issue evaluated only in healthy nongoitrous subjects. METHODS: In random order, 10 patients with nontoxic nodular goiter [mean 39.8 +/- 20.5 (sd) ml] received either 0.3 mg rhTSH or isotonic saline in a double-blinded crossover design. Thyroid volume (by ultrasound) and function were closely monitored during the following 28 d. RESULTS: Saline injection did not affect thyroid function or size. After rhTSH, median serum TSH increased from baseline 0.97 mU/liter (range 0.39-1.56) to 37.0 mU/liter (range 18.5-55.0) at 24 h (P < 0.01), with a subsequent decline to subnormal levels at d 7. Mean free T(4) and free T(3) increased significantly from baseline to a maximum at 48 h. Twenty-four hours after rhTSH, the mean goiter volume was significantly increased by 9.8 +/- 2.3% (sem) (P = 0.01) and after 48 h by 24.0 +/- 5.1% (P = 0.002). The goiter enlargement had reverted at d 7. Nine patients had symptoms of hyperthyroidism and/or cervical compression after rhTSH, as opposed to one during placebo treatment (P < 0.02). CONCLUSIONS: A transient average goiter enlargement of up to 24% is seen after 0.3 mg rhTSH. This may lead to a significant cervical compression when used for augmentation of (131)I therapy in patients with goiter. The use of lower doses of rhTSH needs to be explored.