Radioiodine therapy in non-toxic multinodular goitre. The possibility of effect-amplification with recombinant human TSH (rhTSH)

Abstract

There is no consensus regarding the optimum treatment of benign non-toxic goitre. L-thyroxine suppressive therapy is widely used, but there is poor evidence of its efficacy, and it may have serious adverse effects on health. Surgery is first choice in large goitres or if malignancy is suspected. ¹³¹I therapy results in a one-year goitre reduction of around 40% in multinodular goitres, usually with a high degree of patient satisfaction and improvement of the inspiratory capacity. The effect is attenuated with increasing goitre size. The risk of hypothyroidism is 22–58% within 5–8 years. A sufficient thyroid ¹³¹I uptake is mandatory for ¹³¹I therapy to be feasible and pre-stimulation with recombinant human TSH (rhTSH) increases this considerably. This leads to an increased absorbed thyroid dose by approx.75%, mainly in those patients with the lowest thyroid ¹³¹I uptake, and a more homogeneous intrathyroidal isotope distribution. Pre-stimulation with even a small dose of rhTSH seems to allow a reduction of the ¹³¹I activity while still achieving a mean goitre reduction of approximately 40% within a year. A significantly lower extrathyroidal radiation is achieved by this approach. With an unchanged ¹³¹I activity, rhTSH pre-stimulation improves the goitre reduction by 30–50%. However, this is at the expense of a higher rate of hypothyroidism, cervical pain and transient thyrotoxicosis. Of particular concern is the observation made in healthy persons, that rhTSH results in a transient average thyroid volume increase of 35%. A similar goitre swelling may cause problems in susceptible patients during rhTSH-augmented ¹³¹I therapy. Thus, this concept still needs a closer evaluation before routine use.

Simple goitres are classified into diffuse, uninodular (solitary nodule or cyst), or multinodular goitre. In clinical practice most patients suffer from one of the two latter conditions. A comprehensive review of ‘the thyroid nodule’ has recently been published [1] and this condition will not be further discussed in this paper.

On the basis of genetic susceptibility [2], and in interaction with iodine deficiency – as the major environmental trigger – goitre prevalence increases with increasing age and decreasing iodine intake. With the application of ultrasound it is evident that most goitres have a nodular structure, particularly in the elderly [3]. There is no simple relationship between symptoms and goitre size [4], probably because the thyroid enlargement has evolved through several years. Thus, while a tiny thyroid nodule can be most annoying to some people, others with a monstrous goitre may deny any discomfort. A non-toxic nodular goitre may give rise to a variety of manifestations [5]. Typical local symptoms are dysphagia and dyspnea. Overt stridor often reflects severe compression or deviation of the trachea, while hoarseness due to vocal cord paralysis should raise suspicion of malignancy. The type and severity of symptoms greatly influence the choice of treatment, but the decision whether to treat a patient with goitre can be difficult. Presence of symptoms is a strong argument for offering treatment, but even with few or non-existing symptoms there are conditions (Table I) which should lead to a more active approach. If a patient with goitre is left untreated several risks exist. First, thyroid malignancy may be overlooked, although this can be minimized by fine needle biopsy of dominant or suspicious nodules [5]. Second, a significant upper airway obstruction may be undiagnosed since a patient with tracheal compression due to goitre may have very few or no symptoms [6]. Finally, without treatment goitre growth may continue, and approximately 10% of patients will develop hyperthyroidism within five years due to progressive autonomous function of the nodules [7–9].

Table I.  Factors suggesting the diagnosis of thyroid carcinoma in patients with nodular thyroid disease, according to degree of suspicion^a.

High suspicion

Family history of MTC or multiple endocrine neoplasia

Rapid tumor growth

Very firm nodule(s)

Fixation to adjacent structures

Vocal cord paralysis (laryngoscopy)

Regional lymphadenopathy

Distant metastasis (lungs or bones)

Moderate suspicion

Age <20 or >60 years

Male sex

Solitary nodule

History of head and neck irradiation

Firm texture, possible fixation

Nodule >4 cm in diameter and partially cystic

Compression symptoms: dysphagia, dysphonia, hoarseness, dyspnea, cough

^a Patients with a high suspicion of thyroid carcinoma are not offered ¹³¹I therapy, even if a fine-needle aspiration biopsy supports benign thyroid disease.

There is no ideal treatment for goitre and no consensus exists [5], [10–12]. This is reflected by the fact that a third of clinicians would refrain from treatment facing a patient with moderate discomfort due to a multinodular non-toxic goitre of 50–80 g where malignancy has been ruled out [10], [11]. In the present review the advantages and disadvantages of each treatment option will be discussed, with emphasis on rhTSH-augmented ¹³¹I therapy – a novel and exciting perspective. The non-toxic and the toxic multinodular goitre should be regarded as the same disease but at different evolutionary stages. Here we will focus on the former.

Iodine supplementation

Iodine supplementation is used by some clinicians, particularly in Germany [10]. At first glance, this approach seems rational, since goitre development is strongly associated with even mild iodine deficiency [3]. In a placebo-controlled trial [13] the median volume of diffuse goitres was reduced from 29 to 18 ml but thyroid dysfunction and antibodies appeared in 10% of the patients. The efficacy of iodine supplementation, once a nodular goitre has developed, has only very scarcely been evaluated. It seems that iodine is no better than L-thyroxine (L-T4) for goitre reduction in comparative trials [14]. A major hindrance in the use of iodine supplementation, however, is the fact that a sudden increase of the iodine intake may induce thyrotoxicosis in predisposed individuals [15].

L-thyroxine suppressive therapy

A beneficial effect of thyroid hormones in diffuse non-toxic goitres has been demonstrated in several controlled trials [14], [16–18]. In general, a goitre reduction of 15–40% can be expected within three months, but the gland returns to the pretreatment size just as soon after withdrawal of treatment [18], [19]. The effect of triiodothyronine alone or in combination with L-T4 does not differ from that of L-T4 alone [17], [18], but the goitre reduction may be more sustained after cessation of triiodothyronine therapy [18]. The efficacy of thyroid hormones depends on the degree of TSH suppression [17], [18], although results have been conflicting [20]. In some of the studies, in which L-T4 was compared [14], [20] or combined [14] with iodine supplementation, no substantial differences were found between the regimens, but L-T4 resulted in a more pronounced depression of serum TSH than did iodine. Comparing nodular and diffuse goitres, the effect of L-T4 is clearly more convincing in diffuse glands.

There are very few controlled studies in non-toxic multinodular goitre [16], [21], in which a precise goitre size estimation has been applied. In the study of Berghout et al. [16], 58% of patients had a significant (> 13%) decrease in thyroid volume. In these responders the mean decrease was 25% after nine months of TSH suppression and was followed by regrowth after discontinuation of therapy. In a randomized trial comparing L-T4 and ¹³¹I therapy [21], the median reduction of goitre volume in the ¹³¹I treated group was 38% and 44% after one and two years, respectively, while there was no significant reduction in the L-T4 treated group.

L-T4 dose is often targeted towards a partly suppressed serum TSH level [10], [11]. The consequence is subclinical hyperthyroidism affecting adversely the skeleton [22] and the cardiovascular system [23], at least in the elderly. Additionally, life-long therapy is probably needed to avoid goitre recurrence [5], [16], and the natural history of the disease is progression towards hyperthyroidism due to autonomous function of the thyroid nodules [7–9]. For these reasons, and considering the low efficacy, L-T4 treatment is not feasible in many patients and cannot be recommended.

Surgery

A large goitre causes most clinicians to recommend surgery, and certainly if thyroid malignancy is suspected [10], [11]. Besides leading to rapid cervical decompression thyroid surgery allows confirmation of the benign nature of the gland. Usually, a unilateral hemithyroidectomy and subtotal resection of the contralateral lobe is performed. A bilateral subtotal resection cannot be recommended [24]. Only extremely rarely is a thoracic approach necessary. A thyroidectomy carries the general risks and side effects of a surgical procedure. Specific risks, at most centres with vast experience, include transient or permanent vocal cord paralysis, hypoparathyroidism, and postoperative bleeding [25], [26]. Complications are positively related to the goitre size and extent of the resection [25], [26]. Some degree of postoperative respiratory distress has been reported in up to 30% of the patients in some series, and postoperative tracheomalacia, necessitating intubation, may occur in up to 5% of patients operated for a large goitre [27], [28]. The apparently high prevalence (7–17%) of thyroid carcinomas in substernal goitres [29], [30] is probably due to selection bias, and the natural history and clinical relevance of these carcinomas is unclarified.

Recurrence of multinodular goitre is seen in 15–40% of patients with long-term follow-up and positively correlated with the volume of the postoperative thyroid remnant [31]. Postoperative use of L-T4 in euthyroid patients cannot generally be recommended based on results from randomized trials [31]. The effect of iodine prophylaxis tested in iodine deficient areas does not differ from that of L-T4 [32]. Reoperation for the recurrent goitre results in a 3–10 fold increase in risk of permanent vocal cord paralysis or hypoparathyroidism [25], [26]. For such patients, ¹³¹I therapy seems to be a favourable alternative. Goitre recurrence can be completely avoided if a total thyroidectomy is carried out initially, apparently with the same low rate of complications as with subtotal thyroidectomy, at least in some centres [33]. The long term risk of hypothyroidism after subtotal resection of multinodular goitres is insufficiently described, but is approximately 10–20%, as reported for toxic multinodular goitres [5]. The risk is positively related to the extent of the resection.

Percutaneous interventional therapy

Percutaneous ethanol injection therapy (PEIT) has been used for more than a decade in solitary hot, toxic and even cold thyroid nodules [1], [5]. The most convincing effect is seen in solitary thyroid cysts [1], [34]. Theoretically, PEIT could be used in multinodular goitre. Drawbacks are related to pain, risk of recurrent laryngeal nerve damage, and the possibility of extrathyroidal fibrosis complicating subsequent surgery. Interstitial laser photocoagulation was introduced recently and seems to have the same effect as PEIT and possibly fewer side-effects [1], [34]. There have been no controlled studies in multinodular goitre with either technique.

Radioiodine therapy

Besides being able to cure the hyperthyroidism, it has long been recognized that ¹³¹I results also in shrinkage of the thyroid gland. Some studies of ¹³¹I therapy in non-toxic goitre are listed in Table II. Following ¹³¹I therapy the size reduction of the non-toxic multinodular goitre is approximately 40% after one year [21], [35–39] and 50–60% after two years, without further reduction [38], [39]. Sixty percent of this decrease is seen within three months [38], [39]. In the diffuse non-toxic goitre the volume reduction continues for at least three years and reaches approximately 70%, in most cases leading to a normalization of the thyroid volume [4]. Relief of compressive symptoms, a decrease in upper airway obstruction – as estimated by pulmonary function testing and flow-volume loops – and an increase in cross-sectional area of the tracheal lumen can be expected in most patients suffering from a compressive goitre treated with ¹³¹I [35], [36]. Also, patients with very large and/or substernal goitres have been treated with beneficial results [35], [36], [40]. Although normalization of the thyroid volume is only rarely achieved by ¹³¹I therapy of multinodular goitre, symptoms are in most cases improved considerably and patient satisfaction is high [4], [36], [37]. If a secondary increase in thyroid volume is seen, this should raise suspicion of malignancy. Generally, ¹³¹I doses of 3.7 MBq per gram of thyroid tissue corrected for 100% 24-hour ¹³¹I uptake, have been given [21], [35–39]. However, whether such dose adjustment is worth while has been questioned [41], and fixed doses are given in a number of centres. The treatment can be repeated if further goitre reduction in a euthyroid patient is required [38].

Table II.  Studies of ¹³¹I therapy (without rhTSH stimulation) in non-toxic and/or very large multinodular goitre employing an imaging method for monitoring. The last four studies predominantly include very large goitres.

Author	n	Age (years)	Goitre size (ml)	131I dose (pr. g thyroid)	Follow up (years)	Evaluation	Goitre reduction ^a
Hegedüs et al. 1988 [63]	25	56 (41–79)	73±6 SEM	3.7 MBq	1	sonography	41% ^b
Nygaard et al. 1993 [38]	69	57 (30–81)	74 (21–296)	3.7 MBq	2	sonography	55% ^b
Wesche et al. 1995 [64]	10	48 (40–74)	88±15 SEM	4.4 MBq	1	sonography	48%
Le Moli et al. 1998 [37]	50	53 (30–82)	82 (17–325)	4.4 MBq	2	sonography	49%
Wesche et al. 2001 ^c [21]	29	50±13 SD	56 (17–198)	4.4 MBq	2	sonography	44%
Verelst et al. 1990 [65]	15	67 (62–86)	175±13 SEM	2.8–3.7 MBq	2.5	scintigraphy	39%
Huysmans et al. 1994 [36]	19	66±14 SD	269±153 SD	3.7 MBq	1	MRI	40%
de Klerk et al. 1997 [66]	27	60 (36–81)	194±138 SD	1.1–4.8 MBq	1	CT	34%
Bonnema et al. 1999 [35]	23	67 (42–86)	311±133 SD	3.7–5.5 MBq	1	MRI	34%

Values are given as mean±SD/SEM or median (range).

^a Mean or median values.

^b Some patients were treated with more than a single ¹³¹I dose.

^c Randomized study including a control group treated with L-T4.

Radiation thyroiditis is seen in 3% within the first months of ¹³¹I therapy [42], and is easily treated with salicylates or corticosteroids. Another complication is a Graves’-like autoimmune hyperthyroidism, which is seen in 5% [42], [43]. Rare cases of ¹³¹I-induced Graves’ ophthalmopathy have also been reported [44]. Pre-treatment presence of anti-TPO antibodies confers a significantly increased risk for this complication [42], [43], which is most likely triggered by ¹³¹I-related release of thyroid antigens and is associated with the appearance of TSH receptor antibodies, typically three to six months after ¹³¹I therapy.

There has been concern of an early goitre enlargement caused by the radiation therapy, but on average ¹³¹I therapy is not followed by any significant acute thyroid enlargement [35], [45]. The risk of permanent hypothyroidism after ¹³¹I therapy in multinodular goitres ranges from 14% to 58% within 5–8 years [5], [37–39], occurring more commonly in those patients with an initially smaller goitre size and with presence of anti-TPO antibodies [42], [43]. ¹³¹I therapy, given for Graves’ disease for decades, is not followed by any clinically significant increased risk of cancer deaths [46], [47]. Data on the multinodular goitre are sparse and in the case of non-toxic goitre, nonexistent. In the study by Ron et al. [47], 1 089 patients were treated for a toxic nodular goitre, and these individuals had a 31% increase in overall cancer mortality, nearly exclusively attributable to thyroid malignancy. However, a similar pattern was seen in patients with the same disease but not treated with ¹³¹I. Hence, the disclosure of a thyroid cancer in a nodular goitre after ¹³¹I therapy raises the question, whether malignancy in a nodule was overlooked at the time of therapy.

Radioiodine therapy with recombinant human TSH pre-stimulation

The efficacy of ¹³¹I therapy on the multinodular goitre is hampered by the irregular ¹³¹I uptake in the gland, and the relative goitre reduction is inversely correlated with the initial goitre size [35]. The number of suppressed nodules and the extent of degenerated tissue probably set an upper limit for the obtainable reduction with this treatment. A high dietary iodine intake also makes ¹³¹I therapy less feasible. However, the recent advent of recombinant human TSH (rhTSH) which has the potential of increasing the 24-hour ¹³¹I uptake by more than four-fold [48] opens new avenues. The effect is inversely correlated to the initial thyroid ¹³¹I uptake RAIU, meaning that patients with the lowest ¹³¹I uptake benefit most from rhTSH stimulation [48–50]. In combination with ¹³¹I-therapy we have shown, in a randomized double-blinded trial [49], that 0.3 mg rhTSH injected 24 hours before the therapy increased the retained thyroid dose by 75% compared with placebo (Figure 1), without affecting the ¹³¹I half-life [49]. Pretreatment with rhTSH causes a more homogeneous distribution of ¹³¹I within the nodular gland by stimulating the ¹³¹I uptake relatively more in cold areas than in hot areas [51].

Figure 1.  Difference in expected thyroid dose (Gy) and actual absorbed thyroid dose (Gy) during ¹³¹I therapy of multinodular non-toxic goitre after prestimulation with 0.3 mg rhTSH or placebo. From Nielsen et al. [49]. With permission from The Endocrine Society.

Recent studies have investigated whether rhTSH stimulation influences the effect of ¹³¹I therapy in patients with benign nodular goitre [48], [52], [53]. Only one of these was randomized [53]. Some conclusions, as described in a recent review [54], can be drawn from these studies. Pre-treatment with small amounts of rhTSH allows a reduction of the ¹³¹I activity while still achieving a mean goitre reduction of approximately 40% within the first 12 months. In addition, the extrathyroidal radiation is diminished when using rhTSH prestimulation, especially in the stomach and the urinary bladder [55]. Such an approach may render ¹³¹I therapy more attractive for younger patients. Using a conventional dose of ¹³¹I, the goitre size reduction seems to be amplified from approximately 40% to 60% within a year, if rhTSH pre-stimulation is applied. This may lead to more satisfactory results of ¹³¹I therapy in patients with very large goitres, in whom thyroidectomy otherwise would be the treatment of choice [10], [11]. Even patients with a very low baseline thyroid ¹³¹I uptake can be treated successfully [48]. We demonstrated very recently [56], in a randomized double-blinded trial, that 0.3 mg rhTSH before ¹³¹I-therapy improves the goitre reduction by 33%. Our data indicate that this effect of rhTSH prestimulation is mediated through factors beyond the increase in the thyroid iodine uptake [56] – an observation also found by others [57].

Adverse effects of recombinant human TSH

Generally, rhTSH is well tolerated in patients with differentiated thyroid cancer treated with repeated doses of 0.9 mg rhTSH. In addition, no adverse effects have been reported when testing similar or lower doses of rhTSH in subjects with an intact benign thyroid gland [50], [58]. There have been recent reports, however, of more serious reactions such as tumour swelling and pain from metastases, resulting from injections of rhTSH in patients with differentiated thyroid cancer [59], [60]. Recently, in a blinded randomized study, we investigated the acute effects of 0.9 mg rhTSH on thyroid size and function in nine healthy subjects [61], illustrated in Figure 2. Injection of rhTSH resulted in a significant increase in ultrasonically determined mean thyroid size by 35% at 48 hours. On Day 4, thyroid size had reverted to baseline values. One individual developed a very profound and tender thyroid enlargement from 22 ml to 90 ml which was sore and tender on palpation [61]. The most likely explanation of this short-lived acute effect of rhTSH is an exaggerated vascular response, possibly leading to an interstitial fluid accumulation. The transient goitre enlargement of 5% in patients with nodular goitre one week after ¹³¹I therapy, reported in the study of Nieuwlaat et al. [52], may have been even more pronounced had the measurements been performed within the first days after therapy. In fact, we have just confirmed this adverse effect, using but 0.3 mg rhTSH, in patients with non-toxic multinodular goitre and employing a similar design [62]. Future studies need to clarify this issue in order to rule out the possibility of serious adverse respiratory problems due to goitre swelling.

Figure 2.  Changes in thyroid volume in healthy subjects after administration of 0.9 mg rhTSH (dashed lines) and isotonic saline (solid lines). From Nielsen et al. [61]. With permission from The Endocrine Society.

A high frequency of hypothyroidism, around 65%, was seen in the studies in which rhTSH was used to increase the thyroid irradiation [48], [53], [56]. However, since L-T4 replacement therapy is usually uncomplicated without adverse effects this should not withhold clinicians from using rhTSH-augmented ¹³¹I therapy. Other adverse effects, like cervical pain or sense of compression, are more commonly encountered than with conventional ¹³¹I therapy [53], [56]. Presumably this is due either to higher thyroid ¹³¹I retention, a local thyroid reaction to rhTSH, or a combination of these factors acting in a synergistic fashion. A rise in serum T4 within the first week after ¹³¹I therapy is also seen with rhTSH-augmented ¹³¹I therapy [48], [53], [57], but using a rhTSH dose of 0.03 mg or below seems to annul this risk [52], [57].

Concluding remarks

Treatment of non-toxic goitre is controversial. Since comparative studies are very sparse the choice must at present be based on individual factors and guided by the prevailing traditions at the individual institution. The advantages and disadvantages of surgery, L-T4 suppressive therapy and ¹³¹I therapy are listed in Table III. During the last 20 years, ¹³¹I therapy for symptomatic benign multinodular non-toxic goitre has replaced surgery as the treatment of choice in many patients in a number of mainly European centres [5]. The goitre reduction following ¹³¹I therapy seems to be markedly improved by rhTSH pre-stimulation. Although this approach is promising, rhTSH-augmented ¹³¹I therapy still needs a closer evaluation before it can be implemented as a routine. Some potential problems with this concept are tracheal compression due to a transient goitre enlargement, transient thyrotoxicosis, and a higher incidence of permanent hypothyroidism. Other issues related to rhTSH-augmented ¹³¹I therapy, such as the optimal rhTSH dose and the most favourable time interval between the rhTSH injection and ¹³¹I, need to be clarified.

Table III.  Treatment options for patients with non-toxic multinodular goitre.

Treatment	Advantages	Disadvantages	Comments
Surgery	Significant goitre reduction	Not all patients eligible	Standard therapy for large goitres or when rapid decompression is required
	Rapid decompression of vital structures	Postoperative haemorrhage (1%)	Total thyroidectomy should be considered to avoid goitre recurrence
	Allows pathologic examination	Recurrent laryngeal nerve injury (1%–2%)
		Hypoparathyroidism (0.5%–5%)
		Hypothyroidism* and goitre recurrence*
		Postoperative tracheomalacia (rare)
		Risk is slightly increased in case of a large goitre, intrathoracic extension, or reoperation
L-T4	Outpatient	Low efficacy	Its role on the wane due to adverse effects and lack of efficacy
	Low cost	Mainly impact on the perinodular volume
	May prevent new nodule formation	Treatment should be life-long and aimed at TSH suppression, which induces side effects caused by subclinical hyperthyroidism and inadvertent effects on bone and the heart
Radioiodine ^a	40% reduction of thyroid volume within 1 year	Gradual reduction of the goitre	Has replaced surgery as the standard therapy in some European countries. Should be contemplated instead of reoperation and in those not fit for surgery, also in case of a very large goitre (high-dose radioiodine)
	Improves inspiratory capacity in the long term	Decreasing effect with increasing size
	Most often outpatient basis	Small risk of acute goitre enlargement
	Can be repeated successfully	Risk of thyroiditis: 3%
	Few subjective side effects	Risk of transition into Graves’ disease: 5%
		One year risk of hypothyroidism: 15–20%
		Small risk of radiation-induced ophthalmopathy
		Treatment needs to be repeated in some
		Risk of radiation-induced malignancy unsettled

*The percentage of patients affected depends on the extent of surgery. TSH, thyroid-stimulating hormone. ^a Relates only to non-rhTSH stimulated therapy.

The authors acknowledge the financial support of the Novo Nordisk Foundation, the Agnes and Knut Mørks Foundation, and the A.P. Møller Relief Foundation.