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Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy of Large Nodular Goiters Facilitates Tracheal Decompression and Improves Inspiration

Departments of Endocrinology and Metabolism (S.J.B., V.E.N., L.H.), Radiology (P.B.A.), Oncology (L.B.), and Nuclear Medicine (H.B-J., P.G.), Odense University Hospital, DK-5000 Odense C, Denmark

Address all correspondence and requests for reprints to: Steen J. Bonnema, M.D., Ph.D., Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: steen.bonnema{at}dadlnet.dk.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Introduction: The impact on tracheal anatomy and respiratory function of recombinant human (rh)TSH-stimulated ¹³¹I therapy in patients with goiter is not clarified.

Methods: In a double-blinded design, patients (age 37–87 yr) with a large multinodular goiter (range, 99–440 ml) were randomized to placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before ¹³¹I therapy. The smallest cross-sectional area of the trachea (SCAT; assessed by magnetic resonance imaging) and the pulmonary function were determined before, 1 wk, and 12 months after therapy.

Results: Data on goiter reduction have been reported previously. In the placebo group, no significant changes in the lung function or SCAT were found throughout the study. In the rhTSH group, a slight decrease was observed in the forced vital capacity 1 wk after therapy, whereas the mean individual change in SCAT was significantly increased by 10.5% (95% confidence interval = 0.9–20.0%). A further increase in SCAT to 117 ± 36 mm² (P = 0.005 compared with 92 ± 38 mm² at baseline) was seen at 12 months, corresponding to a mean of 31.4% (95% confidence interval = 16.0–46.8%). The expiratory parameters did not change significantly, whereas forced inspiratory flow at 50% of the vital capacity (FIF50%) increased from initially 3.34 ± 1.33 liters/sec to ultimately 4.23 ± 1.88 liters/sec (P = 0.015) in the rhTSH group, corresponding to a median increase of 24.6%. By 12 months, the relative improvements in FIF50% and in SCAT were inversely correlated to the respective baseline values (FIF50%: r = –0.47, P = 0.012; SCAT: r = –0.57, P = 0.001).

Conclusion: On average, neither compression of the trachea nor deterioration of the pulmonary function was observed in the acute phase after rhTSH-augmented ¹³¹I therapy. In the long term, tracheal compression is diminished, and the inspiratory capacity improved, compared with ¹³¹I therapy alone.

	Introduction

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Several studies have demonstrated that prestimulation with recombinant human TSH (rhTSH) can augment the reduction of a benign nodular goiter after ¹³¹I therapy (1, 2, 3, 4, 5, 6). Thus, we recently showed in two separate double-blind placebo-controlled trials (5, 6) that rhTSH-stimulated ¹³¹I therapy improves the goiter reduction by 34% (goiters <100 ml) and 56% (goiters above 100 ml), respectively, compared with conventional ¹³¹I therapy. However, an unrestricted use of rhTSH-stimulated ¹³¹I therapy should raise concern. rhTSH (7, 8) as well as ¹³¹I therapy (9, 10) per se may induce an acute swelling of the thyroid tissue. Indeed, patients receiving rhTSH-stimulated ¹³¹I more often report thyroid growth or even cervical pain in the early phase after therapy (4, 5). The potential risk and severity of an acute tracheal compression due to thyroid swelling has not been investigated in any trial. By further analyses of data from our trial (6), we here report for the first time the acute and late impact on tracheal anatomy and respiratory function of this treatment modality.

	Patients and Methods

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Study design

The study was performed in a randomized, placebo-controlled, double-blinded set-up. Twenty-nine patients (22 women and seven men; median age 60 yr; range 37–87 yr.) with a large multinodular goiter (median 160 ml; range 99–440 ml) were randomized to receive an im injection with either isotonic saline (n = 15) or 0.3 mg rhTSH (n = 14; Thyrogen; Genzyme Transgenics Corp., Cambridge, MA) 24 h before ¹³¹I therapy. The study population and the effects on the goiter volume and patient satisfaction have previously been described in detail (6). In short, the goiter volume was on average unchanged in both groups 1 wk after ¹³¹I therapy. After 1 yr, the relative reduction was 34.1% in the placebo group and 53.3% in the rhTSH group (P < 0.001).

In addition, the smallest cross-sectional area of the trachea (SCAT) and pulmonary function were measured before, 1 wk, and 12 months after treatment.

SCAT

Magnetic resonance T1-weighted images [1.5 Tesla; TR (repetition time) = 680 msec; TE (echo time) = 12 msec; Gyroscan Intera; Philips, Eindhoven, The Netherlands] were obtained of the neck and the proximal part of the thorax in the axial and coronal planes. The slice thickness was 8 mm, with an interslice gap of 0.8 mm. The SCAT was measured manually by drawing a line along the contours of the tracheal lumen. Images and data were generated by a single operator blinded toward the randomization. By this method, the coefficient of variation of the SCAT is 10.3% (11).

Pulmonary function

Flow volume loops were recorded instantaneously by a precision pneumotachograph (Jaeger MasterScreen PFT/Body; VIASYS Healthcare GmbH, Hoechberg, Germany). On each occasion, the patient performed at least three respiratory maneuvers consisting of a forced maximal expiration followed by a forced maximal inspiration. The procedure was standardized to ensure optimal respiratory movements, i.e. the upper extremities of the patient were fixed at a horizontal level, and it was ensured that no flexion of the head took place during respiration. The maximal values of each of the following parameters were extracted from the best performed curves: vital capacity (VC), forced VC (FVC), forced expiratory volume in 1 sec (FEV1sec), forced expiratory flow at 50% of the VC (FEF50%), forced inspiratory volume in 1 sec (FIV1sec), forced inspiratory flow at 50% of the VC (FIF50%).

Statistical analysis

The SPSS version 10 statistical software program was used. Nonparametric (Wilcoxon’s and Mann-Whitney U tests) or parametric (one-way ANOVA) statistical tests, depending on the normality of the data, were used to detect within-group and between-group differences. A stepwise linear regression analysis was employed for testing interfactorial correlations. The level of statistical significance was chosen as a P value < 0.05.

	Results

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Effect on SCAT (Table 1 and Fig. 1)

At baseline, median SCAT was 110 ± 52 mm² in the placebo group and 92 ± 38 mm² in the rhTSH group (P = 0.31). One week after therapy, no significant difference was observed either within or between groups (Table 1). The individual changes of the SCAT were, however, significantly increased by a mean of 10.5% [95% confidence interval (CI) = 0.9–20.0%] in the rhTSH group. Thus, SCAT increased at this time point in nine of the 14 patients in the rhTSH group compared with eight of the 15 patients in the placebo group (Fig. 1). Noteworthy, one patient in the placebo group with a very large goiter of 440 ml experienced a decrease in SCAT by 61% (Fig. 1), from 216 to 85 mm², but had no respiratory discomfort from this. At 12 months, SCAT remained unchanged in the placebo group. In the rhTSH group mean SCAT had further increased to 117 ± 36 mm² (P = 0.005 compared with baseline), corresponding to a mean increase of 31.4% (95% C = 16.0–46.8%). The between-group difference did not reach statistical significance (P = 0.09) due to the wide individual variation. Before therapy and throughout the study, SCAT showed no correlation with the goiter volume. However, by 12 months, the relative increase in SCAT was inversely correlated to the baseline SCAT (r = –0.57; P = 0.001).

View larger version (14K): [in this window] [in a new window]   FIG. 1. The individual deviation from baseline of the SCAT 1 wk after 131I therapy, stratified according to the randomization. Each bar represents a patient. P = 0.14 between groups.

Effect on pulmonary function (Table 1)

At baseline, there was no significant between-group difference in any of the recorded parameters (Table 1). During the study period, neither the inspiratory nor the expiratory function changed significantly in the placebo group. In the rhTSH group, a slight decrease was seen in FVC 1 wk after therapy (3.70 ± 1.05 vs. 3.87 ± 1.07 liters at baseline, P = 0.002). At 12 months, no change in the expiratory parameters was found, whereas FIF50% had increased significantly from initially 3.34 ± 1.33 to 4.23 ± 1.88 liters/sec (P = 0.015). The individual median increase in FIF50% was 24.6% (range, –22.7–86.2%) in the rhTSH group and 8.7% (range, –24.4–179.8%) in the placebo group. The between-group difference was statistically insignificant (P = 0.52) due to the wide individual variation of the pulmonary parameters after therapy. At baseline, FIF50% showed an inverse correlation with the goiter volume (P = 0.038; r = –0.40). Similarly, a highly significant positive correlation existed between SCAT and FIF50% (P < 0.001; r = 0.65). Such a correlation persisted throughout the study although with slightly lower strength (at 1 wk, P = 0.014, r = 0.46; at 12 months, P = 0.037, r = 0.40). A multiple regression analysis revealed that FIF50% was determined mainly by age and gender, whereas SCAT as an independent determinant no longer existed (data not shown). By 12 months, the relative increase in FIF50% was inversely correlated to the baseline FIF50% (r = –0.47; P = 0.012).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In patients with goiter, an unrestricted air flow may be jeopardized due to deformation of the trachea. Although the anatomical relationship between the thyroid gland and the trachea is of great clinical importance, studies on this issue are sparse. In a previous study (12), one third of consecutive patients with goiter had upper airway obstruction detected by lung function tests. Surprisingly, these patients did not have more respiratory complaints than did patients with a normal lung function (12). Thus, many individuals with a compressive goiter do not have respiratory symptoms. Nevertheless, both thyroidectomy (13, 14, 15, 16) and ¹³¹I therapy (9, 17, 18) may relieve the upper airway obstruction caused by the goiter. We previously described (9) the acute and late impact of high-dose ¹³¹I therapy (but without rhTSH stimulation) on SCAT and flow volume loops in patients with goiters even larger than in the present study. In that study, SCAT was diminished by 9% 1 wk after ¹³¹I therapy due to goiter enlargement in a subgroup of patients. In parallel, the inspiratory capacity showed a slight deterioration. One year after the therapy, both SCAT and the inspiratory parameters were significantly improved (9). We demonstrated more recently (7, 8) that rhTSH stimulation, in doses of 0.3–0.9 mg, results in a 25–35% thyroid swelling within 48 h, with a subsequent decline to the baseline volume at d 4. Therefore, the combination of rhTSH and ¹³¹I therapy may cause a critical thyroid swelling resulting in tracheal compression and respiratory deterioration.

Despite several studies on rhTSH-stimulated ¹³¹I therapy (1, 2, 3, 4, 5, 6) in patients with a benign nodular goiter, the present double-blind placebo-controlled trial is the first to investigate this pertinent issue in more detail. One week after ¹³¹I therapy, there was no major changes in the respiratory function or in the tracheal dimension in either the placebo group or the rhTSH group. In the latter group, only five of 14 patients showed a reduction of SCAT at this time. We cannot exclude the possibility that our results may have been different if we had done the assessments earlier than 1 wk after the ¹³¹I therapy. Although our results are reassuring, an occasional critical tracheal compression cannot be ruled out. Thus, the most pronounced reduction of SCAT in the rhTSH group, by 19% compared with baseline, was observed in a patient who developed a severe thyroiditis, as previously reported (6). In cases with a large goiter and/or a very small SCAT, prophylactic use of glucocorticoids should be considered to lower the risk of thyroid swelling. However, the response to rhTSH may be unpredictable, as reported in our previous trial in which a young healthy subject developed a severe thyroid swelling from 21 to 90 ml after injection of 0.9 mg rhTSH (7). It is important to emphasize that the dose of rhTSH in this context probably will be well below 0.9 mg, resulting in fewer adverse events (2, 19, 20).

Whereas the acute impact of rhTSH-stimulated ¹³¹I therapy may raise concern, our trial on the other hand clearly demonstrates that the superior long-term effect (compared with conventional ¹³¹I therapy) is not restricted to the effect on goiter reduction. Thus, the improved goiter reduction 12 months after the rhTSH-stimulated ¹³¹I therapy was associated with a beneficial effect on the tracheal deformation as well as on the inspiratory capacity, in contrast to insignificant changes in the placebo group. The absence of a statistically detectable between-group difference is most likely due to the wide individual dispersion of the data.

In conclusion, we demonstrate for the first time that rhTSH-stimulated ¹³¹I therapy of large goiters significantly facilitates tracheal decompression and improves inspiration. In this trial, we did not find that rhTSH prestimulation in general, opposed to plain ¹³¹I therapy, increases the risk of an acute deterioration of the upper airways. Taken together and awaiting further studies, we still recommend that rhTSH-stimulated ¹³¹I therapy is used with caution in patients with a large compressive goiter.

	Footnotes

 
This study was supported economically by research grants from The Agnes and Knut Mørk Foundation, Hans Skouby’s and Wife Emma Skouby’s Foundation, Dagmar Marshall’s Foundation, King Christian the X’s Foundation, Oda Pedersens Research Foundation, Frode V. Nyegaard and Wife’s Foundation, The Research Foundation of the County of Funen, The Institute of Clinical Research–University of Southern Denmark, The National Thyroid League, The Novo Nordisk Foundation, and The A. P. Møller Relief Foundation.

Disclosure Statement: S.J.B., V.E.N., H.B-J., P.G., P.B.A., and L.B. have nothing to declare. L.H. has received consultancy fees from Genzyme Corp., Cambridge, MA.

First Published Online July 29, 2008

Abbreviations: CI, Confidence interval; FIF50%, forced inspiratory flow at 50% of the vital capacity; FVC, forced vital capacity; rhTSH, recombinant human TSH; SCAT, smallest cross-sectional area of the trachea; VC, vital capacity.

Received March 3, 2008.

Accepted July 17, 2008.

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