Radioiodine 131 I Treatment for Large Nodular Goiter: Recombinant Human Thyrotropin Allows the Reduction of Radioiodine 131 I Activity to Be Administered in Patients with Low Uptake

Abstract

Background:

¹³¹I therapy is effective in reducing the volume of large nodular goiters (thyroid volume [TV]), mainly after stimulation with recombinant human thyrotropin (rhTSH). The amount of ¹³¹I to be administered inversely depends on thyroid radioactive iodine uptake (RAIU). In patients with low RAIU, we evaluated the efficacy of ¹³¹I treatment at lower doses with respect to those calculated on the basal RAIU, after rhTSH stimulation.

Methods:

Eighteen consecutive patients (17 women and 1 man, 49–83 years) with large nodular goiter were included in the study. At enrolment, 24th h RAIU, TSH, free thyroxine, free triiodothyronine, thyroglobulin antibodies, thyroid peroxidase antibodies, TSH receptors antibodies, urinary iodine, and TV were measured. RAIU was <40% in 11 patients (lower uptake group [LUG]) and >40% in 7 (higher uptake group [HUG]). RAIU difference in the two groups was significant (p < 0.0001). LUG patients were treated with rhTSH (0.03 mg i.m.) and RAIU was measured again after 24 hours. The administered amount of ¹³¹I was aimed to give the thyroid a dose of 100 Gy, by the formula: ¹³¹I activity = 370 MBq × TV (mL)/RAIU(%), taking into account RAIU value after rhTSH for LUG patients. Patients were re-evaluated 3 and 12 months after therapy.

Results:

At enrolment, LUG and HUG patients did not differ for TV, free thyroxine, free triiodothyronine, TSH, and urinary iodine. LUG patients were older than HUG patients (p = 0.027). In LUG, the uptake increased after rhTSH (42.8% [36%–47.5%] vs. 30% [23.4%–31.6%], p = 0.0044). The ¹³¹I activity was 1073 MBq (740–1103 MBq) in LUG and 851 MBq (677–918 MBq) in HUG (p = 0.22, NS), vs. 1300 MBq (1077–2150 MBq) in LUG, based on RAIU before rhTSH. At 3 and 12 months after radioiodine, TV was reduced to 74% [59%–84%] and 53% [42%–72%] in LUG and 75% [70%–77%] and 65% [54%–74%] in HUG, respectively. The reduction was significant with respect to the basal, both at 3 and 12 months, but not different between the two groups.

Conclusions:

One single dose of 0.03 mg of rhTSH increased the thyroid RAIU by 40% in patients with nodular goiter and low basal uptake. This allowed a mean reduction of 36% (26%–42%) in the administered ¹³¹I activity without loss of effectiveness. In patients with low RAIU, rhTSH pre-treatment may optimize ¹³¹I therapy.

Introduction

P atients with large nodular goiters who are treated with radioiodine instead of surgery have a greater reduction in goiter size when pre-treated with recombinant human thyrotropin (rhTSH) (1 –3). Thus, rhTSH has been proposed as an adjuvant in radioiodine therapy for large nodular goiters. rhTSH changes iodine kinetics, mainly by increasing 24 hours radioactive iodine uptake (RAIU) (4) and eliciting a more favorable redistribution of radioiodine in the goiter (5,6). Increased thyroid cell sensitization to ionizing radiation has also been advocated (3,7). Based on the amplification of ¹³¹I therapy effects, the use of rhTSH as an adjuvant can be discerned to obtain better results and to reduce the amount of administered activity, thus lowering the radiation burden to patients. From this point of view, the use of rhTSH is worthwhile in those patients with low RAIU as the amount of ¹³¹I administered needs to be relatively high to compensate for the low percentage of ¹³¹I retained in the thyroid. We studied the outcome of ¹³¹I therapy in patients with large nodular goiters and low RAIU (<40%) pre-treated with rhTSH. Their outcome was compared with a control group of goitrous patients with RAIU >40% who did not receive rhTSH.

Methods

Free triiodothyronine (FT3), free thyroxine (FT4), TSH, and anti-thyroid antibodies were determined using commercial kits. Serum FT4 and FT3 were determined by a chemiluminescent method (Vitros System; Ortho-Clinical Diagnostics, Johnson & Johnson, Amersham; normal ranges 7–17 and 2.7–5.7 pg/mL, respectively). Serum TSH was measured using an ultrasensitive commercial chemiluminescent method (Immulite 2000; Diagnostic Products Corporation; normal range 0.4–3.4 μU/mL). Thyroid peroxidase antibodies (TPO-Ab) and thyroglobulin antibodies (Tg-Ab) were measured using a two-step immunoenzymometric assay (TPO-Ab and AIA-Pack Tg-Ab; Tosoh) and expressed as U/mL. Normal values were <30 U/mL for Tg-Ab and <0 U/mL for TPO-Ab. Serum Tg was measured using an immunometric chemiluminescence assay (Immulite 2000; Diagnostic Products Corporation). TSH receptors antibodies (TRAb) were measured by Brahms TRAK human ria. Urinary iodine excretion was measured by a colorimetric assay using an autoanalyzer (Technicon) and results were expressed as micrograms of iodine per liter of urine. Thyroid volume (TV) was estimated by computed tomography (CT) scan summing the volume of the two lobes as estimated by the ellipsoid formula.

Patients

Eighteen consecutive patients with large nodular goiter who were euthyroid or with subclinical hyperthyroidism as defined by normal FT3 and FT4 and serum TSH values <0.4 U/l were scheduled for radioiodine therapy to reduce TV. Cancer was excluded by untrasound-guided fine-needle aspiration cytology of significant cold nodules and calcitonin determination. Before ¹³¹I therapy, we offered the patients the choice of undergoing rhTSH stimulus and obtained informed consent. rhTSH used as an adjuvant for ¹³¹I therapy in reducing goiter volume was approved by the local Ethics Committee.

At baseline, patients underwent thyroid function testing (FT3, FT4, and TSH), measurement of anti-thyroid antibodies (Tg-Ab, TPO-Ab, and TRAb), urinary iodine, and assessment of TV by CT scan. On day 1, patients received a tracer ¹³¹I activity of 1.85 MBq (50 μCi). On day 2, the RAIU was measured. Immediately after, patients with an RAIU of <40%, referred to as the lower uptake group (LUG), received rhTSH, 0.03 mg i.m. and then a second tracer of 3.7 MBq (100 μCi) ¹³¹I was administered. On day 3 the RAIU was measured again, after subtraction of the residual ¹³¹I activity in the thyroid corrected for decay. The therapeutic activity of ¹³¹I to be administered was calculated using the following formula, previously used also by other authors (1,8 –10).

¹³¹I activity = 370 MBq × TV (mL)/RAIU%.

The RAIU value after rhTSH administration was used for the calculation of the ¹³¹I dose in the LUG group. The protocol is depicted in Figure 1.

FIG. 1.

The study protocol.

Patients were evaluated 3 and 12 months after therapy with CT scan and determination of FT3, FT4, TSH, Tg-Ab, TPO-Ab, and TRAb.

Statistical analysis

Statistical analysis was carried out using Stat View 5.0.1 (SAS Institute, Inc.).

Descriptive data are reported as median (25–75 centiles). Significance of continuous variables between groups was tested by the Mann–Whitney test; Wilcoxon signed rank test was used for paired data. Correlations were evaluated by the Spearman rank correlation.

Results

Eleven patients had ¹³¹I uptake values <40% and were therefore assigned to the LUG. Seven patients had ¹³¹I uptake values of >40% and were therefore assigned to the higher uptake group (HUG). The characteristics of the patients are depicted in Table 1. Their mean age was 70.0 years (63.5–77.2 years) in the LUG and 58.0 years (54.8–68.0 years) in the HUG (p = 0.027). Their mean TV was 100 mL (77.3–123 mL) in the LUG and 100 mL (76–126 mL) in the HUG (p = 0.9, NS). Their mean serum TSH was 0.12 μU/mL (0.07–0.7 μU/mL) in the LUG and 0.21 μU/mL (0.05–0.44 μU/mL) in the HUG. The serum TSH concentrations were less than the lower limit of normal in 8 of the 11 patients in the LUG group and were undetectable in 5. Serum TSH concentrations were less than the lower limit of normal in five of seven patients in the HUG group and were undetectable in two. The mean serum FT3 concentration was 4.3 pg/mL (3.9–4.7 pg/mL) in the LUG and was 4.57 pg/mL (4.54–4.64 pg/mL) in the HUG group. The mean serum FT4 was 12.0 pg/mL (9.5–12.7 pg/mL) in the LUG and was 10.6 pg/mL (10.1–12.4 pg/mL) in the HUG group. The mean urinary iodine concentration was 56 μg/L (29–119 μg/L) in LUG group and 25 μg/L (25–62.3 μg/L) in the HUG. All the above parameters, except age, were not statistically different between the two groups. The mean basal RAIU value was 30% (23%–32%) in LUG group and 50% (45%–52%) in the HUG group (p = 0.0005). The ¹³¹I uptake and age were inversely related to each other (p = 0.018).

Table 1.

Patients' Characteristics

Patient	Age (years)	TSH (μU/mL)	FT3 (pg/mL)	FT4 (pg/mL)	RAIU (%)	TV (mL)	UI (μg/L)
LUG
BE	65	0.9	4.13	9	35.7	100	25
BG	59	0.84	3.96	10.2	31.8	50	48
CN	83	0.17	3.59	9.2	31.1	237	56
CMR	68	0.08	4.7	14	30	128	41
DSA	80	0.33	3.94	12.8	29.8	97	25
DFE	62	0.12	4.79	10.8	30.8	108	25
GL	75	0.07	5.39	12	39	76	104
MG	78	0.12	4.57	12.5	21	104	187
RP	74	1.75	3.84	8.7	9.6	58.5	308
TL	70	0.02	4.28	14.6	23.8	176	124
TV	63	0.07	4.66	12.3	23.3	81	89
25th percentile	63.5	0.07	3.9	9.5	23.4	77	29
Median	70.0^a	0.12	4.3	12.0	30	100.0	56.0
75th percentile	77.3	0.7	4.7	12.7	31.6	123	119
HUG
CP	58	0.21	5.01	10.6	50	156	60
CM	65	0.26	4.53	13.2	50.4	92	100
PC	57	0.03	4.63	10	55	131	25
FMG	49	0.09	4.64	8.9	44.3	112	63
GG	70	0.03	4.57	12.8	47.8	100	25
GT	54	0.50	4.3	10.2	53	68	25
RMF	69	1.10	4.57	11.3	40	70	25
25th percentile	54.8	0.04	4.54	10.1	45.2	64.7	25.0
Median	58.0^a	0.20	4.57	10.6	50.0	100.0	25.0
75th percentile	68.0	0.44	4.64	12.4	52.4	93.5	62.3

BE, BG, CN, CMR, DSA, DFE, GL, MG, RP, TL, TV, CP, CM, PC, FMG, GG, GT, RMF: patients' names (initials).

p = 0.026.

FT4, free thyroxine; FT3, free triiodothyronine; LUG, lower uptake group; HUG, higher uptake group; RAIU, radioactive iodine basal uptake; TV, thyroid volume; UI, urinary iodine; TSH, thyrotropin.

After rhTSH administration, thyroid uptakes were increased to a mean of 43% (36%–47%). This was significantly higher than their basal value (p = 0.004), though not as high as the values of the HUG group (p = 0.026). After rhTSH administration there were significant increases in TSH and free thyroid hormones values compared to baseline (p < 0.004 for all). The mean serum TSH was 3.7 μU/mL (2.5–4.9), the FT3 was 6.7 pg/mL (4.9–7.6 pg/mL), and the FT4 was 16.2 pg/mL (12.9–18.9 pg/mL) after rhTSH (Fig. 2). Thyroid scans performed before and after rhTSH administration showed a striking increase of the thyroid/background activity ratio in all patients. Three of these scans are presented in Figure 3. None of the patients had overt hyperthyroidism after rhTSH administration. The administered ¹³¹I activities were similar in the LUG and HUG groups (p = 0.22). The median dose of ¹³¹I administered to the LUG was 1073 MBq (740–1103 MBq) (29 [20–29.8] mCi; range 444–1961 MBq, 12–53 mCi) and the median dose of ¹³¹I administered to the HUG was 851 MBq (677–918 MBq) (23.0 [18.3–24.8] mCi; range 481–1147 MBq, 13–31 mCi) (p = NS).

FIG. 2.

Free triiodothyronine (FT3), free thyroxine (FT4), TSH, and 24-hour radioactive iodine uptake (RAIU) changes in patients with uptake <40% before (b) and after (p) recombinant human thyrotropin (rhTSH), 0.03 mg, administration.

FIG. 3.

Thyroid scan and RAIU (%) before (left panels) and after rhTSH (right panels) in three patients with ¹³¹I uptake <40%.

In the LUG, the ¹³¹I dose calculated on the pre-rhTSH RAIU was 1300 MBq (1077–2150 MBq) (35.1 [29.1–58.1] mCi) (p < 0.005). For each patient, comparison between the doses calculated on the post- and pre-rhTSH RAIU is presented in Figure 4. In the 10 out of 11 patients where the administered ¹³¹I dose was lower than the calculated dose, a dose reduction ranging from 17% to 56% was achieved (median 36% [26%–42%]). In the remaining patient RAIU did not change after rhTSH administration.

FIG. 4.

¹³¹I activity to be administered based on pre- (darker columns) and post-rhTSH (lighter columns) RAIU. After rhTSH, in 10/11 patients the dose was consistently lower.

Three and 12 months after therapy, the mean TV was reduced by 26% (41%–16%) and 48.5% (65%–35%), respectively, in the LUG group. After the same time periods it was reduced by 25% (30%–22.5%) and 35.5% (46%–26%), respectively, in the HUG group (Fig. 5). The differences in TV before and after ¹³¹I were significant at both 3 and 12 months (Fig. 5), but the degree of volume reduction after ¹³¹I was similar in the LUG and HUG (p = 0.89 at 3 months and 0.35 at 12 months).

FIG. 5.

Thyroid volume before and 3 and 12 months after ¹³¹I treatment in patients with low RAIU pre-treated with rhTSH (LUG) and in controls (HUG). Vertical bars represent the interquartile range (IQR).

In both groups, no relationship was found between the goiter reduction and the basal parameters of age, TV, uptake, urinary iodine, and TSH level.

The tests for TPO-Ab were positive in one patient in the LUG and in two patients in the HUG at the start of the study. After ¹³¹I therapy, the titer of TPO-Ab increased in one patient from the LUG and one patient from the HUG. In LUG, Tg-Ab were positive in 3/11 at baseline; after therapy five more patients became positive, but their Tg-Ab titer was reduced or reverted to basal after 1 year. In HUG there were two Tg-Ab-positive patients before therapy; all increased their antibody titer at 3 months, and all, but one reverted to pre-therapy values at 1 year.

At the start of the study, test results for TRAb were negative in all patients. One patient in each group became hyperthyroid, the LUG patient at 6th month, and the HUG patient at the 2nd month after ¹³¹I therapy. Hypothyroidism was more frequent in LUG than in HUG patients (5/11 vs. 2/7), but the difference was not significant.

Discussion

The effectiveness of rhTSH in increasing RAIU for ¹³¹I treatment of large nodular goiter has been reported many times (1,4,6,11 –14). In the present work we studied the benefit of the rhTSH pretreatment in patients with low RAIU. In these patients the rhTSH pretreatment increased the uptake, allowing a 30% reduction of the ¹³¹I administered activity. In the literature, rhTSH doses for goiter reduction tested until now range from 0.01 to 0.45 mg (1 –3,6,12 –16) and uptake is related to rhTSH dose. However, higher rhTSH doses have been shown to significantly increase circulating thyroid hormone, possibly causing side effects related mostly to the cardiovascular system. Recently, Braverman et al. demonstrated that rhTSH doses higher than 0.03 mg did not significantly increase RAIU more than the 0.03 mg dose, but did cause more adverse effects apparently due to greater effects on serum thyroid hormone concentrations (17). In the present study we choose the dose of 0.03 mg. This was associated with a mean increase in the RAIU of 40% but no signs of overt hyperthyroidism.

In our study the LUG and the HUG were similar with respect to basal TV, urinary iodine excretion, and serum TSH concentrations. Patients in the LUG were older than those in the HUG, an outcome not related to selection criteria. It is widely recognized that a predilection to large nodular goiters occurs in the elderly (18); perhaps, this process and changes in RAIU are related, but studies regarding this are required. Data on the influence of age on the response to ¹³¹I therapy are scarce and conflicting. In a article on the effects of rhTSH (0.3 mg) administered before ¹³¹I therapy, age was inversely related to the subsequent reduction in TV (2). More recently, however, the same authors did confirm this finding (3).

Mean goiter size was reduced by 48.5% in the LUG group and 35.5% in the HUG group 12 months after ¹³¹I therapy. Thus, the reduction in goiter size was satisfactory in the LUG who required similar ¹³¹I doses as the HUG, in all probability because they received rhTSH pre-treatment for their ¹³¹I therapy.

Tg-Ab and TPO-Ab increased after ¹³¹I therapy in some patients, with no difference between the two groups. TRAb became positive in one of two patients who developed hyperthyroidism after therapy. ¹³¹I treatment itself may induce the surge of autoantibodies against thyroid antigens (19 –21), independently of rhTSH treatment (22). In agreement with other authors (2,3), we found a higher percentage of hypothyroid patients in the group pre-treated with rhTSH, but the difference was not significant in our study.

In conclusion, in patients with large nodular goiters and low uptake, we observed a satisfactory reduction of TV after ¹³¹I treatment with rhTSH as an adjuvant. rhTSH administration before ¹³¹I is estimated to permit a saving of 36% of the ¹³¹I that needs to be administered. This reduces costs, radiation exposure to the patient, and a better quality of life surrounding the treatment period because of the reduction in isolation time.

Footnotes

Acknowledgments

This work was supported by the following grants: Ministero dell'Università e della Ricerca Scientifica (MURST), Programma di ricerca: Protein, Metabolomic, Fingerprints, and Gene Expression Profile of Thyroid Nodules with Follicular Proliferation Cytology: Identification of New Markers to Distinguish Benign and Malignant Thyroid Nodules. The authors wish to thank Prof. Marco Ferdeghini for his useful suggestions.

Disclosure Statement

The authors declare that no competing financial interests exist.

References

Silva

, Rubio

, Romão

, Gebrin

, Buchpiguel

, Tomimori

, Camargo

, Cardia

, Medeiros-Neto

. 2004. Administration of a single dose of recombinant human thyrotropin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. Clin Endocrinol (Oxf), 60:300–308.

Nielsen

, Bonnema

, Boel-Jorgensen

, Grupe

, Hegedus

. 2006. Stimulation with 0.3-mg recombinant human thyrotropin prior to iodine ¹³¹ therapy to improve the size reduction of benign nontoxic nodular goiter: a prospective randomized double-blind trial. Arch Intern Med, 166:1476–1482.

Bonnema

, Nielsen

, Boel-Jorgensen

, Grupe

, Andersen

, Bastholt

, Hegedus

. 2007. 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. J Clin Endocrinol Metab, 92:3424–3428.

Nielsen

, Bonnema

, Boel-Jorgensen

, Veje

, Hegedus

. 2005. Recombinant human thyrotropin markedly changes the ¹³¹I kinetics during ¹³¹I therapy of patients with nodular goiter: an evaluation by a randomized double-blinded trial. J Clin Endocrinol Metab, 90:79–83.

Nieuwlaat

, Hermus

, Sivro-Prndelj

, Corstens

, Huysmans

. 2001. Pretreatment with recombinant human TSH changes the regional distribution of radioiodine on thyroid scintigrams of nodular goiters. J Clin Endocrinol Metab, 86:5330–5336.

Albino

, Mesa

Jr. , Olandoski

, Ueda

, Woellner

, Goedert

, Sousa

, Graf

. 2005. Recombinant human thyrotropin as adjuvant in the treatment of multinodular goiters with radioiodine. J Clin Endocrinol Metab, 90:2775–2780.

Fast

, Nielsen

, Grupe

, Bonnema

, Hegedüs

. 2009. Optimizing 131I uptake after rhTSH stimulation in patients with nontoxic multinodular goiter: evidence from a prospective, randomized, double-blind study. J Nucl Med, 50:732–737.

Hegedus

, Hansen

, Knudsen

, Hansen

. 1988. Reduction of size of thyroid with radioactive iodine in multinodular non-toxic goitre. Br Med J, 297:661–662.

Nygaard

, Hegedus

, Gervill

, Hjalgrim

, Soe-Jensen

, Hansen

. 1993. Radioiodine treatment of multinodular non-toxic goitre. Br Med J, 307:828–832.

10.

Huysmans

, Hermus

, Corstens

, Kloppenborg

. 1993. Long-term results of two schedules of radioiodine treatment for toxic multinodular goitre. Eur J Nucl Med, 20:1056–1062.

11.

Huysmans

, Nieuwlaat

, Erdtsieck

, Schellekens

, Bus

, Bravenboer

, Hermus

. 2000. Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodide uptake in nontoxic nodular goiter. J Clin Endocrinol Metab, 85:3592–3596.

12.

Nieuwlaat

, Huysmans

, van den Bosch

, Sweep

, Ross

, Corstens

, Hermus

. 2003. Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter. J Clin Endocrinol Metab, 88:3121–3129.

13.

Cohen

, Ilany

, Hoffman

, Olchovsky

, Dabhi

, Karasik

, Goshen

, Rotemberg

, Zwas

. 2006. Low-dose recombinant human thyrotropin-aided radioiodine treatment of large, multinodular goiters in elderly patients. Eur J Endocrinol, 154:243–252.

14.

Paz-Filho

, Mesa-Junior

, Olandoski

, Woellner

, Goedert

, Boguszewski

, Carvalho

, Graf

. 2007. Effect of 30 mCi radioiodine on multinodular goiter previously treated with recombinant human thyroid-stimulating hormone. Brazil J Med Biol Res, 40:1661–1670.

15.

Duick

, Baskin

. 2003. Utility of recombinant human thyrotropin for augmentation of radioiodine uptake and treatment of nontoxic and toxic multinodular goiters. Endocr Pract, 9:204–209.

16.

Giusti

, Cappi

, Santaniello

, Ceresola

, Augeri

, Lagasio

, Minuto

. 2006. Safety and efficacy of administering 0.2 mg of recombinant human TSH for two consecutive days as an adjuvant to therapy with low radioiodine doses in elderly out-patients with large nontoxic multinodular goitre. Miner Endocrinol, 31:191–209.

17.

Braverman

, Kloos

, Law

Jr. , Kipnes

, Dionne

, Magner

. 2008. Evaluation of various doses of recombinant human thyrotropin in patients with multinodular goiters. Endocr Pract, 14:832–839.

18.

Fenzi

, Ceccarelli

, Macchia

, Monzani

, Bartalena

, Giani

, Ceccarelli

, Lippi

, Baschieri

, Pinchera

. 1985. Reciprocal changes of serum thyroglobulin and TSH in residents of a moderate endemic goitre area. Clin Endocrinol, 23:115–122.

19.

Huysmans

, Hermus

, Edelbroek

, Tjabbes

, Oostdijk , Ross

, Corstens

, Kloppenborg

. 1997. Autoimmune hyperthyroidism occurring late after radioiodine treatment for volume reduction of large multinodular goitres. Thyroid, 7:535–539.

20.

Nygaard

, Knudsen

, Hegedus

, Scient

, Hansen

. 1997. Thyrotropin receptor antibodies and Graves' disease, a side-effect of ¹³¹I treatment in patients with nontoxic goiter. J Clin Endocrinol Metab, 82:2926–2930.

21.

Chiovato

, Fiore

, Vitti

, Rocchi

, Rago

, Dokic

, Latrofa

, Mammoli

, Lippi

, Ceccarelli

, Pinchera

. 1998. Outcome of thyroid function in Graves' patients treated with radioiodine: role of thyroid stimulating and thyrotropin-blocking antibodies and of radioiodine-induced thyroid damage. J Clin Endocrinol Metab, 83:40–46.

22.

Rubio

, Perone

, Silva

, Knobel

, Medeiros-Neto

. 2005. Human recombinant TSH preceding a therapeutic dose of radioiodine for multinodular goiters has no significant effect in the surge of TSH-receptor and TPO antibodies. Thyroid, 15:134–139.