Nontoxic, nodular goiter may be defined as a structurally and functionally heterogeneous thyroid enlargement in an euthyroid patient, which is not caused by an autoimmune, inflammatory or neoplastic process. Worldwide, the most frequent cause of goiter is iodine deficiency. In nonendemic areas the etiology of goiter is multifactorial with a hereditary predisposition and a female preponderance. The initially diffuse goiters tend to grow gradually and to become more nodular. This can lead to compression of the trachea and esophagus and obstruction of venous outflow. With time, thyroid function often becomes more autonomous , and euthyroidism may gradually change into subclinical and eventually into overt hyperthyroidism.
A nontoxic goiter is often discovered incidentally in an asymptomatic patient. The clinical manifestations of nontoxic, nodular goiter are caused by compression of vital structures in the neck or upper thoracic cavity (trachea, esophagus, and neck veins). Patients with mild tracheal compression are usually asymptomatic. When tracheal narrowing becomes more severe, dyspnea and stridor develop, initially only on exertion, but later also at rest. In patients with intrathoracic extension of a goiter, dyspnea and stridor may be nocturnal or positional, occurring especially during maneuvers that force the thyroid into the thoracic inlet, like reaching. Esophageal compression is less common than tracheal compression because the esophagus is positioned more posteriorly in the neck. Obstruction of the jugular or subclavian veins or the superior vena cava results in facial plethora and dilated neck and upper thoracic veins. Vocal cord paralysis, either transient or permanent, can occur because of stretching or compression of a recurrent laryngeal nerve and results in hoarseness and dyspnea.
The diagnostic evaluation of a patient with a nontoxic, nodular goiter starts with a careful history and physical examination. Serum thyrotropin (TSH) and free thyroxine levels should be measured to identify (subclinical) hyperthyroidism. Thyroid scintigraphy and ultrasonography are not routinely indicated. Patients who have symptoms and signs of tracheal compression (inspiratory stridor and dyspnea) should have radiographs taken of the trachea or CT or MR imaging of the neck and upper thorax. Iodinated contrast agents should be avoided because of the risk for inducing hyperthyroidism. Pulmonary function tests, especially flow-volume loops, are useful to evaluate airway obstruction. Fine-needle aspiration biopsy may be helpful when thyroid cancer is suspected. Cytology should be obtained from dominant nodules and those with a firmer consistency within the thyroid gland .
The main indications for treatment of patients with nontoxic, nodular goiter are compression of the trachea or esophagus and venous outflow obstruction. Other indications are goiter growth, neck discomfort, and cosmetic concerns. There are three treatment options: thyroidectomy, suppression therapy with L-thyroxine, and administration of radioactive iodine. These will be discussed here.
Surgery is standard therapy for patients with nontoxic, nodular goiter. Surgical treatment, usually consisting of bilateral subtotal thyroidectomy, leads to fast decompression of vital structures. A second advantage of surgical treatment is the possibility of histopathological examination of the removed tissue.
Resection of goiters, even of substernal ones, can usually be accomplished through a transcervical approach, either by digital mobilization or by using a spoon technique . Therefore, thoracotomy is rarely needed. However, surgical treatment is not without risk. Surgical morbidity (vocal cord paralysis, hypoparathyroidism, tracheal obstruction caused by tracheomalacia, and hemorrhage) is higher in patients with large goiters and in case of subsequent operations. The rate of postoperative hypothyroidism depends on the extent of surgery. The mortality for bilateral thyroid operations in nontoxic, nodular goiter is less than 1%.
The rate of goiter recurrence increases with the duration of follow-up after surgery. With adequate surgery, the recurrence rate should not be higher than approximately 10% after 10 years. Postoperatively, L-thyroxine is frequently prescribed to decrease the chance of goiter recurrence. However, several studies have yielded no convincing evidence that this treatment is effective [4,5].
Thyroid hormone therapy is the second treatment option for patients with nontoxic, nodular goiter. The hypothesis underlying L-thyroxine treatment is that growth of a nontoxic, nodular goiter, like that of normal thyroid tissue, is dependent on TSH secretion and therefore, that suppression of TSH secretion will cause shrinkage of the goiter.
Only two randomized trials on the effect of Lthyroxine therapy in patients with nontoxic goiter using objective thyroid volume measurements have been reported. In a study by Berghout et al.  thyroid volume -decreased significantly after 9 months of L-thyroxine treatment in TSH-suppressive doses in approximately half of the patients (mean decrease 25% in the responders). Goiter size returned to baseline after discontinuation of therapy. In a recent study by Wesche et al.  a significant decrease in goiter size was observed in 43% of patients after 2 years of L-thyroxine therapy (mean decrease 22% in the responders). In the nonresponders a mean increase in thyroid volume of 16% was found.
The efficacy of L-thyroxine treatment in patients with large, nodular goiters is probably even less than found in the above mentioned randomized studies in which most patients had relatively small goiters. Many patients with large nodular goiters have a serum TSH level below the normal range, and no shrinkage of the goiter can be expected when TSH secretion is already suppressed . Furthermore, L-thyroxine therapy is inadvisable in patients with a suppressed serum TSH level, because it may cause overt thyrotoxicosis.
There is no evidence that L-thyroxine therapy alters the natural history of nodular goiter. Therefore, lifelong treatment is probably necessary. Long-term treatment with L-thyroxine in doses sufficient to suppress serum TSH may have adverse effects on bone mineral density and on the heart. A meta-analysis, comprising all controlled cross-sectional studies on the effects of L-thyroxine therapy on bone mineral density published between 1982 and 1994, demonstrated significant decreases in bone mineral density at the lumbar spine, the proximal femur, and the radius in postmenopausal women receiving long-term thyroid hormone suppression therapy . No negative effect of therapy on bone mineral density was found in premenopausal women and in men. In contrast, a recent longitudinal study showed also in premenopausal women a decrease in bone mineral density after only 2 years of suppression therapy with L-thyroxine .
A low serum TSH concentration in persons 60 years of age or older is associated with a threefold increased risk for developing atrial fibrillation in the subsequent decade . Therefore, it is not unreasonable to assume that thyroid hormone suppression therapy might have cardiac adverse effects. This therapy does indeed increase left ventricular mass. Whether it also causes cardiac dysfunction is not clear. Studies on this subject have yielded discordant results [11–13].
In the first studies on radioiodine therapy for nontoxic goiter, which appeared in the German literature, satisfactory clinical results with response rates ranging from 65% to 99% were reported in large numbers of patients [14–16]. Several years later, two retrospective studies were published in the Anglo-Saxon literature, comprising 14 and 15 patients, respectively [17,18]. Response rates in these studies were fairly high (79% and 100%, respectively). In these early studies the effects of radioiodine therapy were evaluated by measurements of neck circumference and by thyroid volume measurements using palpation and planar scintigraphy, methods that are known to be inaccurate.
In later studies, comprising a total of 252 patients, accurate measurements of thyroid volume were performed by ultrasonography, CT, and MRI (Table 1). Ultrasound was used in the studies on relatively small nodular goiters (mean thyroid volumes varying from 56 to 88 mL), whereas MRI and CT were used in the studies on large nodular goiters (mean thyroid volumes varying from 194 to 311 mL).
Radioiodine treatment resulted in a mean reduction in thyroid volume of approximately 40% after 1 year [7,19–24]. A positive correlation between the reduction in goiter volume and the dose of radioiodine per gram of thyroid tissue was found [23,25], and a negative correlation between the decrease in goiter volume and pretreatment goiter volume [7,25]. Furthermore, the degree of nodularity of the goiter appeared to influence the result of radioiodine therapy. In a study by Hegedüs et al.  on nontoxic, diffuse goiters thyroid volume reduction was 60% on average at 1 year after radioiodine therapy, which is considerably larger than the above mentioned 40% found in studies on nontoxic, nodular goiters.
In most studies, iodine-131 doses were aimed at an absorbed dose of 3.7 to 4.4 MBq (100 to 120 μCi) iodine-131 per gram of thyroid tissue, corrected for the percentage uptake of radioiodine in the thyroid at 24 hours. Standard, fractionated doses may also be effective . However, studies on this issue with accurate measurements of thyroid volume are lacking.
In most patients, not only thyroid volume but also compressive symptoms decreased. In one study, there was a significant tracheal widening as measured by MRI  (Fig. 1), and improvement in respiratory function was found in two studies [21,28].
Long-term results of radioiodine treatment for nontoxic, nodular goiter are also satisfying. Decreases in thyroid volume of 50% to 60% after 3 to 5 years have been reported [20,25,29]. In the study by Nygaard et al.  it was observed that thyroid volume decreased during the first 2 years after radioiodine treatment (Fig. 2). Thereafter no significant further changes were observed.
Early side effects (pain in the thyroid region, radiation thyroiditis, increase in compression symptoms, esophagitis) were usually mild and transient [21,29,30]. In studies on the effects of radioiodine therapy on thyroid volume and thyroid hormone levels in the first weeks after therapy, only small increases in thyroid volume and serum thyroid hormone levels were found [24,30]. The development of autoimmune (Graves) hyperthyroidism is the most important late complication, occurring several months after therapy. It is probably triggered by radiation-induced release of thyroid antigens, and elevated serum levels of TSH receptor antibodies have been found at the time of thyrotoxicosis [31,32]. The incidence of this complication is approximately 5%. The hyperthyroidism may be quite severe. Therefore, informing patients to be alert on symptoms and signs of hyperthyroidism is important to promptly recognize this complication.
Reported incidences of posttreatment hypothyroidism after radioiodine therapy for nontoxic, nodular goiter in literature vary from 8% to 100% [7,18–20,22–25]. Nygaard et al. , using the life table method, calculated a cumulative risk for hypothyroidism of 22% at 5 years after radioiodine treatment for small nontoxic goiters. However, in more recent studies higher incidences were found, e.g., 22% after 1 year  and 45% after 2 years . Posttreatment hypothyroidism appears to be more common in patients with small goiters and in those with high pretreatment serum antithyroid peroxidase antibody concentrations .
An important issue is the risk for induction of cancer by radioiodine therapy for volume reduction of nontoxic, nodular goiters, because large doses of radioiodine are used, especially for large goiters with low radioiodine uptake. There are no follow-up data on cancer incidence in patients with nontoxic, nodular goiter treated with radioiodine. The risk for induction of thyroid cancer is not higher than that after radioiodine therapy of patients with small, toxic nodular goiters, because the absorbed doses in the thyroid are similar. The lifetime risk for radiationinduced cancer in extrathyroidal tissues and organs strongly depends on the administered dose of radioiodine and on the age of the patients. It has been estimated that the lifetime risk for radiation-induced cancer in extrathyroidal tissues in people of 65 years and older, treated with high doses of radioiodine, is similar to the surgical mortality of subtotal thyroidectomy .
Until now, most clinicians have restricted radioiodine therapy for nontoxic goiter to elderly patients, especially those who have a high operative risk or refuse surgery. In these patients, the benefit of noninvasive radioiodine treatment outweighs the lifetime risk for radiation-induced cancer. However, radioiodine may prove to be an attractive alternative to surgery in younger patients, provided that the dose of radioiodine administered is relatively low (e.g., patients with small goiters and sufficient radioiodine uptake).
In this respect, it is of interest to explore strategies to enhance radioiodine uptake in patients with nontoxic, nodular goiter. One of the causes of a low uptake in patients with nontoxic, nodular goiter is the fact that the serum TSH level is in the low-normal range or even below normal in most of these patients. Therefore, the administration of recombinant human TSH (rhTSH; Thyrogen, Genzyme, Cambridge, MA) before radioiodine therapy for nontoxic goiter can be expected to increase the uptake of radioiodine in the thyroid.
The Use of Recombinant Human Thyrotropin (rhTSH) as an Adjunct to Radioiodine Therapy in Nontoxic, Nodular Goiter
In a recent study, , it was investigated whether the administration of a single, low dose of rhTSH enhanced radioiodine uptake in patients with nontoxic, nodular goiter. Twenty-four-hour thyroid radioiodine uptake was measured both under baseline conditions and after pretreatment (im) with rhTSH, given either 2 hours (0.01 mg; n = 7) or 24 hours (0.01 mg, n = 7 or 0.03 mg, n = 7) before administration of a diagnostic dose of iodine-131.
After administration of 0.01 mg rhTSH, the serum TSH level increased from 0.7 ± 0.5 mU/L to a peak level of 4.4 ± 1.1 mU/L, and the serum free T4 level rose from 16.0 ± 2.6 pmol/L to 18.5 ± 3.7 pmol/L. After administration of 0.03 mg rhTSH, the serum TSH level increased from 0.6 ± 0.4 mU/L to 15.8 ± 2.3 mU/L, and the serum free T4 level rose from 15.2 ± 1.5 pmol/L to 21.7 ± 2.9 pmol/L. Peak serum TSH levels were reached at 5 to 8 hours and peak free T4 levels at 8 to 96 hours after rhTSH administration.
Administration of 0.01 mg rhTSH 2 hours before radioiodine increased the 24-h radioiodine uptake from 30% ± 11% to 42% ± 10%. However, radioiodine uptake did not increase in one patient, whereas the increase in radioiodine uptake was less than 10% in two other patients. In contrast, administration of rhTSH 24 hours before radioiodine increased 24-h radioiodine uptake by more than 10% in all 14 patients (by more than 20% in 10 and by more than 30% in 6). After 0.01 mg rhTSH the 24-h radioiodine uptake increased from 29% ± 10% to 51% ± 10%, and after 0.03 mg rhTSH the 24-h radioiodine uptake increased from 33% ± 11% to 63% ± 9% (Fig. 3). Thus, pretreatment with a single, low dose of rhTSH given 24 hours before radioiodine administration doubled 24-h thyroid radioiodine uptake in patients with nontoxic, nodular goiter.
It was also investigated whether rhTSH pretreatment induced changes in the regional distribution of radioiodine as visualized on thyroid scintigrams in patients with nontoxic, nodular goiter . Anterior planar thyroid scintigrams were obtained 24 hours after administration of a diagnostic dose of iodine-123. All patients were studied twice: first, without rhTSH pretreatment, and second, after an im injection of 0.01 mg (n = 10) or 0.03 mg (n = 16) rhTSH given 24 hours before radioiodine administration. Quantification of regional radioiodine uptake by a region of interest method showed that pretreatment with rhTSH caused a larger increase in radioiodine uptake in relatively “cold” areas and a smaller increase in radioiodine uptake in relatively “hot” areas, compared with the increase in radioiodine uptake in the entire thyroid (Fig. 4). So, rhTSH caused a more homogeneous distribution of radioiodine within the thyroid gland in patients with a nodular goiter by stimulating radioiodine uptake in relatively “cold” areas more than in relatively “hot” areas. This was most marked in patients with a low baseline serum TSH level. These data suggest that pretreatment with rhTSH may improve the efficacy of radioiodine treatment for volume reduction of nodular goiters, especially in patients with a low baseline serum TSH level.
The first results of treatment of patients with nontoxic, nodular goiter with a reduced dose of radioiodine after pretreatment with rhTSH are promising [36,37]. Twenty-two patients were treated with radioiodine 24 hours after im administration of 0.01 (n = 12) or 0.03 (n = 10) mg rhTSH. Therapeutic doses of radioiodine, aimed at 100 μCi per gram of thyroid tissue retained at 24 hours, were adjusted to the rhTSH-induced increase in 24-h radioiodine uptake, as determined in a diagnostic study using a tracer dose of iodine-131. In the diagnostic study 24-h radioiodine uptake increased from 27% ± 8% to 50% ± 11% in the 0.01 mg and from 22% ± 4% to 54% ± 9% in the 0.03 mg rhTSH group. The therapeutic doses of radioiodine were reduced accordingly with factors of 1.9 ± 0.5 and 2.4 ± 0.4, respectively, to 39.4 ± 16.8 mCi (0.01 mg rhTSH group) and 22.8 ± 5.7 mCi (0.03 mg rhTSH group).
In the first weeks after radioiodine therapy only mild increases in serum thyroid hormone levels were observed in most patients. There was a small increase in thyroid volume (measured by MRI) 1 week after therapy, but this was not accompanied by narrowing of the tracheal lumen . One year after radioiodine therapy thyroid volumes had decreased with 35% ± 14% in the 0.01 mg rhTSH group (from 143 ± 54 mL to 91 ± 41 mL) and with 41% ± 12% in the 0.03 mg rhTSH group (from 103 ± 44 mL to 62 ± 35 mL). In both groups significant tracheal widening was observed. TSH-receptor binding antibodies were negative in all patients before therapy and became positive in four patients. Hyperthyroidism developed in three of these four patients between 23 and 25 weeks after therapy .
These preliminary results show that pretreatment with a single, low dose of rhTSH allowed a 50% to 60% reduction of the therapeutic dose of radioiodine without compromising the efficacy of thyroid volume reduction in patients with nontoxic, nodular goiter. Further studies are needed whether treatment with larger doses of rhTSH, radioiodine, or both results in larger thyroid volume reductions in these patients.
Surgery is standard therapy for patients with nontoxic, nodular goiter, especially when rapid decompression of vital structures is required. L-thyroxine is frequently used , especially in young patients with a small goiter (not larger than 50 ml), who have a normal serum TSH level. However, it should be kept in mind that the efficacy of L-thyroxine treatment is at best modest and that lifelong L-thyroxine treatment may cause bone loss and cardiac adverse effects.
Radioiodine therapy is an attractive alternative to surgery. For each individual patient the estimated risks of both surgery and radioiodine therapy should be weighed carefully. In younger patients surgery is still to be preferred, especially when the amount of radioiodine to be administered as calculated from a radioiodine tracer study is high. However, for elderly patients, especially those with cardiopulmonary disease, the profits of radioiodine treatment will outweigh the lifetime risk for this mode of therapy.
Preliminary data show that the administration of a single, low dose of recombinant human TSH may be a useful adjunct to radioiodine therapy in patients with nontoxic, nodular goiter, allowing an approximately 50% reduction of radioiodine doses needed to reduce thyroid volume. This may extend the indication for radioiodine therapy for nontoxic goiter to the younger age groups.
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