Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

69.Clinical Manifestations and Treatment of Nontoxic Diffuse and Nodular Goiter

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).


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.

Laboratory Investigations

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).


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.







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.


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