Ad R. Hermus
Dyde A. Huysmans
Nontoxic diffuse and nodular goiters are common, even in areas in which iodine intake is sufficient. For example, in the 1950s in Framingham, Massachusetts, 1% of persons 30 to 59 years of age had a multinodular goiter (1). The prevalence of nontoxic goiter is higher in women than in men: in Whickham, in northeast England, palpable goiters were detected in 10% of adult women and in 2% of adult men (see Chapter 19) (2).
CLINICAL MANIFESTATIONS AND DIAGNOSTIC EVALUATION
The thyroid gland can easily grow outward because of its anterior location in the neck. In addition, it may grow downward through the thoracic inlet, perhaps facilitated by the negative intrathoracic pressure (3,4,5). Intrathoracic extension of a goiter is usually into the anterior mediastinum and less frequently into the posterior mediastinum. Isolated intrathoracic goiters (i.e., goiters arising from aberrant thyroid tissue in the thorax) are rare.
The diagnostic evaluation of a patient with a nontoxic goiter starts with the history and physical examination, with special attention to inspection of the neck and upper thorax and palpation of the thyroid gland to determine its size and nodularity. Many patients have had a goiter for many years; it was probably a diffuse goiter initially but gradually became nodular with time (see Chapter 68). The shape, degree of asymmetry, and consistency of nontoxic goiters vary greatly, and because of thyroid lobulation it may be difficult to distinguish between diffuse and true multinodular goiters. The goiters are rarely painful or tender, unless there has been recent bleeding into a nodule. Intrathoracic extension of a cervical goiter is suggested if the lower end of the thyroid gland cannot be palpated, even when the patient's head is hyperextended (see Chapter 18). Some goiters are palpable in the neck only when the patient swallows or coughs.
The most important symptoms and signs of nontoxic goiter are caused by compression of vital structures in the neck or upper thoracic cavity. In the absence of intrathoracic extension of the goiter, compression symptoms occur relatively late, characteristically developing insidiously in elderly patients with a long-standing goiter. However, when there is substantial growth of the goiter into the thorax, compression symptoms may occur at an earlier stage, and the thoracic inlet may become occluded, which is known as the “thyroid cork” phenomenon (6).
The symptoms of tracheal compression are dyspnea, stridor, cough, and a choking sensation. Patients with mild to moderate 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 primarily during maneuvers such as reaching that force the thyroid into the thoracic inlet. Hemorrhage into a nodule or a cyst within the goiter and upper respiratory infections may exacerbate upper airway obstruction, in exceptional cases necessitating emergency tracheal stenting or tracheostomy. Esophageal compression is less common than tracheal compression because of the posterior position of the esophagus.
Compression or thrombosis of the jugular or subclavian veins or the superior vena cava results in facial plethora and dilated neck and upper thoracic veins. Venous outflow obstruction can be revealed by Pemberton's maneuver, which involves elevating both arms until they touch the sides of the head for about 1 minute, thereby forcing the thyroid into the thoracic inlet. The test is considered positive if congestion or cyanosis and discomfort of the face and neck become apparent (7).
Vocal cord paralysis, which may be transient or permanent, can occur due to stretching or compression of one or both recurrent laryngeal nerves, resulting in hoarseness and dyspnea. Phrenic nerve paralysis and Horner's syndrome due to compression of the cervical sympathetic chain are rare complications of nontoxic goiter.
In any patient with a cervical goiter or a mediastinal mass that could be an intrathoracic goiter, serum thyrotropin (TSH) should be measured to detect clinically inapparent (subclinical) thyrotoxicosis or hypothyroidism. If the serum TSH concentration is low, measurement of serum free thyroxine (T4) is indicated to determine if the patient has subclinical or unsuspected overt thyrotoxicosis (see Chapter 13). In patients with low serum TSH and normal serum free T4 concentrations, serum free triiodothyronine (T3) may be measured to exclude T3 thyrotoxicosis. If the serum TSH concentration is high, chronic autoimmune thyroiditis or ingestion of an antithyroid compound such as lithium should be considered as a possible cause of thyroid enlargement. Routine measurement of serum thyroglobulin or calcitonin is not recommended (8). About 15% to 20% of patients with a multinodular goiter have high serum concentrations of antithyroid peroxidase antibody concentrations; if present, the patient is at risk for developing Graves'-like thyrotoxicosis or hypothyroidism after radioiodine therapy.
Thyroid Imaging and Pulmonary Function Tests
The possibility of tracheal compression and intrathoracic extension of the goiter should be considered in all patients with nontoxic goiters, particularly those with large multinodular goiters. Roentgenograms of the chest and trachea are simple, although not very sensitive, screening tests for tracheal compression. Functional evidence of tracheal compression can be obtained by pulmonary function tests, particularly flow-volume loop tracings (Fig. 69.1). These tracings may be abnormal even when the patient is asymptomatic (9). Computed tomography (CT) and magnetic resonance imaging (MRI) are more expensive but highly sensitive methods for detecting tracheal compression and intrathoracic extension of a goiter (Fig. 69.2). When CT is used, an iodinated radiographic contrast agent should not be given because of the risk for inducing thyrotoxicosis (see section Effect of Excess Iodide in Chapter 13). If administration of an iodinated contrast agent is required to identify vascular structures, pretreatment with an antithyroid drug is advised.
FIGURE 69.1. The results of flow-volume loop studies in a patient with upper airway obstruction caused by a multinodular goiter before (left) and after (right) subtotal thyroidectomy. (From Miller MR, Pincock AS, Oates GD, et al. Upper airway obstruction due to goitre: detection, prevalence and results of surgical management. QJM 1990;74:177, with permission.)
FIGURE 69.2. Coronal T1-weighted magnetic resonance image, showing a goiter with intrathoracic extension and bilateral tracheal compression (arrows). (From Huysmans DAKC, de Haas MM, van den Broek WJM, et al. Magnetic resonance imaging for volume estimation of large multinodular goitres: a comparison with scintigraphy. Br J Radiol 1994;67:519, with permission.)
Thyroid ultrasonography, although providing detailed information about the number and size of nodules within a goiter, is not indicated for routine clinical management. The technique is not satisfactory for evaluation of tracheal compression or for imaging of the posterior neck and intrathoracic regions. Esophageal x-rays with barium may be used to document esophageal compression from a goiter as the cause of dysphagia, but are seldom needed.
Thyroid scintigraphy is not routinely indicated, but is helpful when an anterior mediastinal mass is seen on x-ray or CT of the thorax. Radioiodine scintigraphy can prove that the mass consists of functional thyroid tissue. Thyroid imaging and measurements of thyroid radioiodine uptake are also of value when radioiodine therapy is being considered for thyroid volume reduction. Radioiodine therapy is less effective when radioiodine uptake is low or large parts of the thyroid are nonfunctioning on scintigraphy.
Fine-Needle Aspiration Biopsy
In selected groups of patients with multinodular goiter, such as those presenting to a thyroid clinic or those undergoing thyroid surgery, the incidence of thyroid carcinoma varies from 1% to 10% (10,11,12). However, some of these carcinomas are small, clinically unimportant papillary microcarcinomas. In unselected patients with nontoxic goiter, clinically important thyroid carcinomas must be rare, given the high prevalence of nontoxic goiter and the low incidence of clinically apparent thyroid carcinoma in the community.
In patients with classical nontoxic goiter (e.g., women with a history of long-standing, slowly growing goiter), fine-needle aspiration biopsy is not routinely indicated. It is indicated in patients with fast-growing or dominant nodules and nodules that have a firmer consistency from other nodules within the gland (13).
TREATMENT OF NONTOXIC DIFFUSE AND NODULAR GOITER
Nontoxic goiters usually grow slowly over decades, and many of them never cause any problems. Therefore, the presence of a diffuse or multinodular goiter is in itself not an indication for treatment. The main indications for treatment of patients with nontoxic goiter are compression of the trachea or esophagus and venous outflow obstruction. Therapy should also be considered when there is progressive growth of the entire goiter or of individual nodules, especially when there is substantial intrathoracic extension of the goiter. The intrathoracic parts of these goiters cannot be examined by palpation and fine-needle aspiration biopsy, and they may cause acute and life-threatening tracheal compression due to hemorrhage into a nodule or a cyst. Sometimes treatment is indicated because of neck discomfort or cosmetic concerns.
The main therapeutic options are thyroidectomy, administration of radioiodine, or administration of T4. In patients with a small, diffuse, nontoxic goiter due to iodine deficiency, an additional option is low-dose iodine treatment (14). However, when the goiter is multinodular, iodine supplementation is not advisable because it is rarely effective and it may induce thyrotoxicosis.
Surgical treatment leads to rapid decompression of vital structures and provides tissue for pathologic examination (15,16). Usually bilateral subtotal thyroidectomy is performed, with removal of all grossly abnormal tissue. Some surgeons advise more extensive resection (near-total or even total thyroidectomy) in order to minimize the risk for recurrent goiter (17,18,19). Nearly all nontoxic goiters can be removed through a collar incision, even those with substantial intrathoracic extension. However, thoracotomy must be performed in the rare patients who have goiters that arise from aberrant thyroid tissue within the thorax or who have recurrent intrathoracic goiter after earlier thyroidectomy (3,4,15,20).
The mortality rate after thyroid surgery in patients with nontoxic goiter is low (< 1) (15,16). The most important complications of thyroid surgery for nontoxic goiter are tracheal obstruction due to hemorrhage, tracheomalacia, recurrent laryngeal nerve injury, hypoparathyroidism, and hypothyroidism (15,16). Permanent lesions of the recurrent laryngeal nerve and the parathyroid glands occur in less than 1% of patients treated in specialized units (21). Persistent voice changes (dysphonia, hoarseness, fatigue, or reduction of voice range) are not uncommon. The rate of postoperative hypothyroidism is determined mainly by the extent of surgery. Surgical morbidity is highest in patients with large goiters and in those who undergo reoperation (21,22,23,24).
The rate of goiter recurrence depends on the duration of follow-up after surgery. With adequate surgery, the recurrence rate should not be higher than approximately 10% after 10 years (25). Postoperatively, T4 is often prescribed to prevent goiter recurrence, but at best it seems only modestly effective for this purpose (26,27). Therefore, there is no indication for routine T4 therapy after surgery for nontoxic goiter (27,28). An exception should be made for patients who had previous head and neck radiation for benign conditions; in one large, randomized study of these patients, T4 therapy prevented goiter recurrence after subtotal thyroidectomy for benign nodular disease (29).
During the 1990s, measurements of thyroid volume (see Chapter 16) convincingly demonstrated that radioiodine treatment is effective in reducing thyroid volume in over 90% of patients with nontoxic goiter (30,31,32,33,34,35,36,37,38,39). Usually single doses of approximately 100 to 120 mCi (3.7–4.4 MBq) of radioiodine (131I) per gram of thyroid tissue (corrected for the percentage uptake of radioiodine in the thyroid at 24 hours) are given, but multiple fractionated doses also may be effective (40).
In patients with nontoxic diffuse goiters treated in this way, thyroid volume decreases on average by 50% to 60% in 12 to 18 months (35,36). In patients with nontoxic multinodular goiters, radioiodine treatment results in a reduction in goiter volume of approximately 40% after 1 year (30,31,32,33,34,37,38) and 50% to 60% after 3 to 5 years (31,41) (Fig. 69.3). Half of the effect appears within the first 3 months (31). The decrease in goiter size is positively correlated with the dose of radioiodine per gram of thyroid tissue (34,39) and negatively correlated with pretreatment goiter volume (37,38,39).
FIGURE 69.3. Median thyroid volume before and after radioiodine treatment in 39 patients with nontoxic multinodular goiter who remained euthyroid after a single dose. Bars are quartiles. (From Nygaard B, Hegedüs L, Gervil M, et al. Radioiodine treatment of multinodular non-toxic goitre. BMJ 1993;307:828, with permission.)
In the majority of patients, radioiodine treatment decreases not only thyroid volume, but also compressive symptoms (32,39). The decreases in compressive symptoms are accompanied by substantial tracheal widening, as measured by MRI (32) and improvement in respiratory function (32,42).
Early side effects (radiation thyroiditis and esophagitis) are usually mild and transient (32,41,43). Exacerbation of compressive symptoms after radioiodine administration is rare; therefore, glucocorticoids should not be given routinely. The development of autoimmune (Graves') hyperthyroidism, with thyrotoxicosis presumably triggered by radiation-induced release of thyroid antigens, is the most important late complication, occurring several or more months after radioiodine therapy in approximately 5% of patients (44,45). The thyrotoxicosis may be severe. Therefore, informing patients to be alert to symptoms and signs of thyrotoxicosis is important to recognize this complication promptly. Patients with high serum antithyroid peroxidase antibody concentrations before treatment are at greater risk for this complication (44). The incidence of posttreatment hypothyroidism is 20% to 50% at 5 years (31,39); it is more common in patients with small goiters and those with high pretreatment serum antithyroid peroxidase antibody concentrations (39,44). In approximately 10% of patients the nodular goiters enlarge again after 3 to 5 years (39), and in them a second dose of radioiodine may be effective (33).
There are no follow-up data on the risk of thyroid or other cancers after radioiodine treatment of patients with nontoxic goiter. The lifetime risk for radiation-induced cancer depends not only on the administered dose of radioiodine but also on the age of the patient. It has been estimated that the lifetime risk for radiation-induced cancer in extrathyroidal tissues in people 65 years of age or older who are treated with high doses of radioiodine is similar to the surgical mortality of subtotal thyroidectomy (46).
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 this mode of therapy. 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., in patients with small goiters and sufficient radioiodine uptake). In this respect, the observations that pretreatment with a single, low dose (0.01 or 0.03 mg) of recombinant human TSH doubles thyroid radioiodide uptake (47) and results in a more homogeneous uptake of radioiodide (48) in nontoxic goiter is of interest. Indeed, pretreatment with these doses 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 goiters (49). Such a strategy decreases the radiation dose to extrathyroidal organs (50). Alternatively, one may hypothesize that the efficacy of thyroid volume reduction can be increased when pretreatment with recombinant human TSH is given without reducing the therapeutic dose of radioiodine (50,51).
Thyrotropin is the main stimulator of growth of normal thyroid tissue. The hypothesis underlying T4 treatment in patients with nontoxic goiter is that growth of goitrous tissue is also dependent on TSH and therefore that suppression of TSH secretion will result in a decrease in goiter size or at least prevent further enlargement of the goiter.
Thyroxine therapy may be effective in reducing the thyroid volume in patients with diffuse nontoxic goiters, as measured by ultrasonography (52,53). Nonrandomized studies suggest that it is also effective in some patients with multinodular goiters (26). However, most of the studies did not exclude patients with iodine deficiency or subclinical hypothyroidism (i.e., those with TSH-dependent thyroid enlargement), and none had adequate control groups or objective measurements of thyroid volume. Only two randomized trials on the effect of T4 therapy in patients with nontoxic goiter using objective thyroid volume measurements have been reported. In a placebo-controlled double-blind randomized trial in patients with relatively small nontoxic multinodular goiters, thyroid volume, as measured by ultrasonography, decreased substantially in 58% of the T4-treated patients, as compared with 5% of those given placebo (54); the mean decrease in thyroid volume in the patients who responded was 25% after 9 months of T4 treatment. Goiter size returned to baseline within 9 months after discontinuation of therapy, demonstrating that maintenance of volume reduction requires long-term T4 treatment. In a more recent study (37), a significant decrease in goiter size was observed in 43% of patients after 2 years of T4 therapy (mean decrease 22% in the responders). In the nonresponders, a mean increase in thyroid volume of 16% was found.
Long-term T4 therapy in doses sufficient to reduce serum TSH concentrations to below normal may have adverse skeletal and cardiac effects. It may decrease bone mineral density, particularly in postmenopausal women (55). Furthermore, it increases left ventricular mass, causes cardiac dysfunction or arrhythmias, especially atrial fibrillation (56,57,58) (see Chapter 79).
Before T4 therapy is begun in patients with nontoxic goiter, serum TSH should be measured. Many patients with multinodular goiters have autonomous thyroid hormone production and subclinical thyrotoxicosis. In them, T4 therapy is inadvisable because it is likely to cause overt thyrotoxicosis, and no shrinkage of the goiter can be expected when TSH secretion is already suppressed (59). For patients who have normal serum TSH concentrations, the optimal level of TSH suppression has not been defined. Suppression of serum TSH concentrations to less than 0.1 mU/L is probably unnecessary; lowering the concentrations to between 0.1 and 0.5 mU/L may be adequate and is safer (28).
Choice of Treatment
The advantages and disadvantages of the three treatments—thyroidectomy, radioiodine, and T4—should be carefully weighed when advising an individual patient with a nontoxic goiter (60) (Table 69.1). Thyroidectomy is standard therapy for young and otherwise healthy patients, especially when prompt decompression of vital structures is required. Radioiodine therapy is an attractive alternative to surgery in older patients, in those with cardiopulmonary disease, and in those with recurrent goiter. The indication for T4 therapy in patients with nontoxic goiter is limited. It may be tried in young patients with small, diffuse goiters who have normal serum TSH concentrations. In patients with nodular goiters, it is less effective and associated with significantly more adverse effects than radioiodine treatment (37). Therefore, T4 therapy should no longer be recommended for patients with nodular goiters.
TABLE 69.1. TREATMENT OPTIONS FOR PATIENTS WITH NONTOXIC GOITER
Rapid decompression of vital structures; allows pathologic examination
Surgical mortality (< 1); postoperative tracheal obstruction; recurrent laryngeal nerve injury (1%–2%); hypoparathyroidism (0.5%–5%); hypothyroidisma; goiter recurrencea
Standard therapy, especially when rapid decompression of vital structures is required
Substantial decrease in thyroid volume and improvement of compressive symptoms in most patients
Only gradual decrease in thyroid volume; radiation thyroiditis (usually mild); radiation-induced thyroid dysfunction (thyrotoxicosis in 5%, hypothyroidism in 20%–50%); theoretic risk for radiation-induced cancer (< 1% in elderly people)
Alternative to surgery in older patients and those with cardiac or pulmonary disease
Easiest treatment option
Only small decrease in thyroid volume; probably only effective if goiter is small; long-term efficacy unknown; decrease in bone mineral density in postmenopausal women; possible cardiac side effects
Alternative to surgery in young patients with a small, diffuse goiter
aThe percentage of patients affected depends on the extent of surgery.
Modified from Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med 1998;338:1438, with permission.
1. Vander JB, Gaston EA, Dawber TR. Significance of solitary nontoxic thyroid nodules: preliminary report. N Engl J Med 1954;251:970.
2. Vanderpump MPJ, Tunbridge WMG, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995; 43:55.
3. Katlic MR, Wang C, Grillo HC. Substernal goiter. Ann Thorac Surg 1985;39:391.
4. Katlic MR, Grillo HC, Wang C. Substernal goiter: analysis of 80 patients from Massachusetts General Hospital. Am J Surg 1985; 149:283.
5. Humphrey ML, Burman KD. Retrosternal and intrathoracic goiter. Endocrinologist 1992;2:195.
6. Blum M, Biller BJ, Bergman DA. The thyroid cork: obstruction of the thoracic inlet due to retroclavicular goiter. JAMA 1974; 227:189.
7. Pemberton HS. Sign of submerged goitre. Lancet 1946;251:509.
8. Hegedüs L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: current status and future perspectives. Endocr Rev 2003;24:102.
9. Miller MR, Pincock AC, Oates GD, et al. Upper airway obstruction due to goitre: detection, prevalence and results of surgical management. Q J Med 1990;74:177
10. Rojeski MT, Gharib H. Nodular thyroid disease: evaluation and management. N Engl J Med 1985;313:428.
11. Belfiore A, La Rosa GL, La Porta GA, et al. Cancer risk in patients with cold thyroid nodules: relevance of iodine intake, sex, age, and multinodularity. Am J Med 1992;93:363.
12. Franklyn JA, Daykin J, Young J, et al. Fine needle aspiration cytology in diffuse or multinodular goitre compared with solitary thyroid nodules. BMJ 1993;307:240.
13. Singer PA, Cooper DS, Daniels GH, et al. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med 1996;156:2165.
14. Kahaly G, Dienes HP, Beyer J, et al. Randomized, double blind, placebo-controlled trial of low dose iodide in endemic goiter. J Clin Endocrinol Metab 1997;82:4049.
15. Studley J, Lynn J. Surgical anatomy of the thyroid gland and the technique of thyroidectomy. In: Lynn J, Bloom SR, eds. Surgical endocrinology. Oxford, UK: Butterworth-Heinemann, 1993:231.
16. Kaplan EL, Shukla M, Hara H, et al. Surgery of the thyroid. In: DeGroot LJ, ed. Endocrinology, 3rd ed. Vol. 1. Philadelphia: WB Saunders, 1995:900.
17. Delbridge L, Guinea AI, Reeve TS. Total thyroidectomy for bilateral benign multinodular goiter: effect of changing practice. Arch Surg 1999;134:1389.
18. Mishra A, Agarwal A, Agarwal G, et al. Total thyroidectomy for benign thyroid disorders in an endemic region. World J Surg 2001;25:307.
19. Hisham AN, Azlina AF, Aina EN, et al. Total thyroidectomy: the procedure of choice for multinodular goitre. Eur J Surg 2001; 167:403.
20. Mack E. Management of patients with substernal goiters. Surg Clin North Am 1995;75:377.
21. Al Suliman NN, Ryttov NF, Qvist N, et al. Experience in a specialist thyroid surgery unit: a demographic study, surgical complications, and outcome. Eur J Surg 1997;163:13.
22. Thomusch O, Machens A, Sekulla C, et al. Multivariate analysis of risk factors for postoperative complications in benign goiter surgery: prospective multicenter study in Germany. World J Surg 2000;24:1335.
23. Beahrs OH, Vandertoll DJ. Complications of secondary thyroidectomy. Surg Gynecol Obstet 1963;117:535.
24. Wilson DB, Staren ED, Prinz RA. Thyroid reoperations: indications and risks. Am Surgeon 1998;64:674.
25. Röjdmark J, Järhult J. High long term recurrence rate after subtotal thyroidectomy for nodular goitre. Eur J Surg 1995;161: 725.
26. Ross DS. Thyroid hormone suppressive therapy of sporadic nontoxic goiter. Thyroid 1992;2:263.
27. Hegedüs L, Nygaard B, Hansen JM. Is routine thyroxine treatment to hinder postoperative recurrence of nontoxic goiter justified? J Clin Endocrinol Metab 1999;84:756.
28. Gharib H, Mazzaferri EL. Thyroxine suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998;128: 386.
29. Fogelfeld L, Wiviott MB, Shore-Freedman E, et al. Recurrence of thyroid nodules after surgical removal in patients irradiated in childhood for benign conditions. N Engl J Med 1989;320:835.
30. Hegedüs L, Hansen BM, Knudsen N, et al. Reduction of size of thyroid with radioactive iodine in multinodular non-toxic goitre. BMJ 1988;297:661.
31. Nygaard B, Hegedüs L, Gervil M, et al. Radioiodine treatment of multinodular non-toxic goitre. BMJ 1993;307:828.
32. Huysmans DAKC, Hermus ARMM, Corstens FHM, et al. Large, compressive goiters treated with radioiodine. Ann Intern Med 1994;121:757.
33. Wesche MF, Tiel-van Buul MM, Smits NJ, et al. Reduction in goiter size by 131I therapy in patients with non-toxic multinodular goiter. Eur J Endocrinol 1995;132:86.
34. de Klerk JMH, van Isselt JW, van Dijk A, et al. Iodine-131 therapy in sporadic nontoxic goiter. J Nucl Med 1997;38:372.
35. Nygaard B, Faber J, Veje A, et al. Thyroid volume and function after 131I treatment of diffuse non-toxic goitre. Clin Endocrinol (Oxf) 1997;46:493.
36. Hegedüs L, Bennedbaek FN. Radioiodine for non-toxic diffuse goitre. Lancet 1997;350:409.
37. Wesche MFT, Tiel-van Buul MMC, Lips P, et al. A randomized trial comparing levothyroxine with radioactive iodine in the treatment of sporadic nontoxic goiter. J Clin Endocrinol Metab 2001;86:998.
38. Bonnema SJ, Bertelsen H, Mortensen J, et al. The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function. J Clin Endocrinol Metab 1999;84:3636.
39. Le Moli R, Wesche MF, Tiel-van Buul MM, et al. Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goitre. Clin Endocrinol (Oxf) 1999;50:783.
40. Howarth DM, Epstein MT, Thomas PA, et al. Outpatient management of patients with large multinodular goitres treated with fractionated radioiodine. Eur J Nucl Med 1997;24:1465.
41. Huysmans D, Hermus A, Edelbroek M, et al. Radioiodine for nontoxic multinodular goiter. Thyroid 1997;7:235.
42. Nygaard B, Søes-Petersen U, Høilund-Carlsen PF, et al. Improvement of upper airway obstruction after 131I-treatment of multinodular nontoxic goiter evaluated by flow volume loop curves. J Endocrinol Invest 1996;19:71.
43. Nygaard B, Faber J, Hegedüs L. Acute changes in thyroid volume and function following 131I therapy of multinodular goitre. Clin Endocrinol (Oxf) 1994;41:715.
44. Nygaard B, Knudsen JH, Hegedüs L, et al. Thyrotropin receptor antibodies and Graves' disease, a side-effect of 131I treatment in patients with nontoxic goiter. J Clin Endocrinol Metab 1997;82: 2926.
45. Huysmans DAKC, Hermus ARMM, Edelbroek MAL, et al. Autoimmune hyperthyroidism occurring late after radioiodine treatment for volume reduction of large multinodular goiters. Thyroid 1997;7:535.
46. Huysmans DAKC, Buijs WCAM, van de Ven MTJ, et al. Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters. J Nucl Med 1996;37:2072.
47. Huysmans DA, Nieuwlaat W-A, Erdtsieck RJ, et al. Administration of a single low dose of recombinant human thyrotropin significantly enhances thyroid radioiodide uptake in nontoxic nodular goiter. J Clin Endocrinol Metab 2000;85:3592.
48. Nieuwlaat W-A, Hermus AR, Sivro-Prndelj F, et al. Pretreatment with recombinant human thyrotropin changes the regional distribution of radioiodine on thyroid scintigrams of nodular goiters. J Clin Endocrinol Metab 2001; 86:5330.
49. Nieuwlaat W-A, Huysmans DA, van den Bosch HC, et al. 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 2003;88:3121.
50. Huysmans DA, Nieuwlaat WA, Hermus AR. Towards larger volume reduction of nodular goitres by radioiodine therapy; a role for pretreatment with recombinant human thyrotropin? Clin Endocrinol (Oxf) 2004;60:297.
51. Silva MNC, Rubió IGS, RomMāo R, et al. Administration of a single dose of recombinant human thyrotropin enhances the efficacy of the radioiodine treatment of large compressive multinodular goitres. Clin Endocrinol (Oxf) 2004;60:300.
52. Hansen JM, Kampmann J, Madsen SN, et al. L-thyroxine treatment of diffuse non-toxic goitre evaluated by ultrasonic determination of thyroid volume. Clin Endocrinol (Oxf) 1979; 10:1.
53. Perrild H, Hansen JM, Hegedüs L, et al. Triiodothyronine and thyroxine treatment of diffuse non-toxic goitre evaluated by ultrasonic scanning. Acta Endocrinol (Copenh) 1982;100:382.
54. Berghout A, Wiersinga WM, Drexhage HA, et al. Comparison of placebo with L-thyroxine alone or with carbimazole for treatment of sporadic non-toxic goitre. Lancet 1990;336:193.
55. Uzzan B, Campos J, Cucherat M, et al. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 1996;81:4278.
56. Biondi B, Fazio S, Carella C, et al. Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993;77:334.
57. Ching GW, Franklyn JA, Stallard TJ, et al. Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis. Heart 1996;75:363.
58. Shapiro LE, Sievert R, Ong L, et al. Minimal cardiac effects in asymptomatic athyreotic patients chronically treated with thyrotropin-suppressive doses of L-thyroxine. J Clin Endocrinol Metab 1997;82:2592.
59. Toft AD. Thyroxine therapy. N Engl J Med 1994;331:174.
60. Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med 1998;338:1438.