Department of Endocrinology and Metabolism Odense University Hospital DK-5000 Odense C, Denmark
Address correspondence to: Steen Bonnema, M.D., Odense University Hospital, Department of Endocrinology and Metabolism, Odense C, DK-5000, Denmark. E-mail: steen. bonnema{at}dadlnet.dk.
To the editor:
We have with great interest read the paper by Nieuwlaat et al. (1). Their study and the recent one by Duick and Baskin (2), are the first demonstrating that recombinant human TSH (rhTSH) may be highly useful in relation to 131I therapy for benign goiter. Nieuwlaat et al. (1) show that prestimulation with a very small amount of rhTSH (0.01 or 0.03 mg) in patients with a nontoxic nodular goiter allowed the 131I activity to be halved, while still attaining a goiter reduction of approximately 40%. Such an effect of the 131I therapy was to be expected, because the same group previously reported that an increased radioiodine uptake by the goiter can be obtained after rhTSH stimulation (3). However, before rhTSH stimulation is routinely used by clinicians to optimize the 131I therapy in benign thyroid disorders, we wish to emphasize that several aspects with this combination have not yet been sufficiently enlightened. Furthermore, both studies (1, 2) have serious shortcomings.
Although the use of rhTSH has been extensively evaluated in the monitoring and therapy of differentiated thyroid cancer, complications may arise when patients with an intact thyroid function and/or goiter are stimulated with this agent. Although 131I therapy is used routinely in some countries (e.g. Denmark and The Netherlands) for treatment of nontoxic goiter, this is clearly not the case in many parts of the world, as documented by recent questionnaire surveys (4). Additionally, the evidence for this strategy almost exclusively relies on uncontrolled studies (4). Therefore, before introducing a novel principle in this setting, indisputable evidence based on well-designed controlled trials should be provided. Unfortunately, no control group was included in the study by Nieuwlaat et al. (1) which predisposes to overlook confounding factors. For example, the goiter-reducing effect obtained by the 131I therapy may have been blurred by a possible dependency on the pretreatment goiter volume, as described in other studies (4).
An issue largely overlooked is the fact that upper airway obstruction is present in a large fraction of patients with goiter, despite absence of symptoms (4). Some reports have suggested that stimulation with rhTSH causes significant swelling of tumor tissue in patients with papillary thyroid carcinoma (5, 6). It is plausible, but not proved, that a similar situation can occur in patients with a benign goiter. Considering that 131I therapy in some cases causes a transient goiter growth (without prior rhTSH stimulation) of 1525% within the first week (4), the combination with rhTSH may lead to severe tracheal compression resulting in acute respiratory distress in susceptible individuals. In the study by Nieuwlaat et al. (1), the goiter enlargement as well as the smallest tracheal cross-sectional area was estimated by magnetic resonance 1 wk after the 131I therapy. On average, both structures were insignificantly altered, although a goiter growth up to 17% and a tracheal area reduction by 13% were observed (1). These figures are very similar to previous findings by us (7). However, it is our experience that the thyroid gland in some individuals may respond profoundly to rhTSH stimulation per se by an acute enlargement of more than 100% (8). This appears within 48 h and is fortunately followed by a rapid reversion to normal size. Thus, it is possible that a transient but significant goiter increase in fact did occur immediately before or during the 131I therapy in the study by Nieuwlaat et al. (1) but was overlooked because patients were scanned at the earliest 1 wk after therapy. It is reassuring that rhTSH stimulation in the low doses that were used in that study seemingly was well tolerated, but the number of patients was small (n = 22) and only few suffered from a goiter larger than 150 ml (1). Should it be confirmed that rhTSH stimulation may give rise to a significant acute thyroid enlargement, it must be investigated in detail whether this can be prevented successfully by e.g. corticosteroids or nonsteroid antiinflammatory drugs, as suggested by two recent reports (2, 8).
Besides this potential problem of goiter swelling and tracheal compression due to rhTSH stimulation, particularly in combination with 131I therapy, other issues also need to be clarified. The aim in the study by Nieuwlaat et al. (1) was to reduce the 131I activity through a higher rhTSH-induced radioiodine thyroid uptake. The average goiter reduction obtainable by 131I therapy is 3550% (4), which still may leave some patients with compressive symptoms, particularly those with large goiters. Although some studies have indicated a dose-relationship between 131I and goiter reduction (4), this remains to be proven in a prospective controlled set-up. Because some areas in a goiter simply may not be susceptible to 131I therapy due to inactive and degenerated nodular tissue, it may well be that the thyroid irradiation usually employed (approximately 100 Gy) is sufficient to obtain the maximum goiter reduction. Thus, it is presently an open question whether the goiter reduction can be amplified by the use of rhTSH prestimulation. A previous study by Nieuwlaat et al. (9) demonstrating a more homogenous distribution of 131I in the nodular goiter after rhTSH stimulation holds promise in this setting. To estimate the impact of rhTSH stimulation on the thyroid irradiation, it would have been highly interesting if Nieuwlaat et al. (1) had measured the 131I kinetics during the 131I therapy of the patients with nontoxic multinodular goiter and compared data with a control group not receiving rhTSH prestimulation. Finally, the optimal dose of rhTSH remains to be determined. By using small amounts of rhTSH, thyrotoxicosis can be avoided in most individuals with an intact thyroid gland (1), but this must of course be balanced against the overall purpose of a sufficient increase of thyroid 131I uptake.
Thus, evidence of a beneficial effect of rhTSH prestimulation awaits properly conducted randomized trials before routine use can be recommended. In addition, cost-benefit, optimum rhTSH dose, and most important, safety issues need to be clarified.
Received August 4, 2003.
References
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