Multinodular goiter (MNG) and diffuse goiter are defined as the enlargement of the thyroid gland, in the absence of autoimmune thyroid disease, malignancy, or inflammation. MNG is associated with more than one nodule identified clinically or surgically. In contrast, a “diffuse” goiter is said to occur when the thyroid gland is enlarged, but there are either no or only scattered subcentimeter nodules within the gland, typically detected only by ultrasound (US). This discussion will focus primarily on MNG. Thyroid function is normal in MNG, but subclinical or overt hyperthyroidism can evolve due to autonomously hyperfunctioning nodules – a clinical entity that is termed “toxic” MNG. Both genetic and environmental factors are involved in the goitrogenic process, but iodine deficiency is the most important risk factor.

The clinical presentation of a patient with MNG can vary from a completely asymptomatic goiter to a life-threatening disease due to upper airway compression. The diagnostic evaluation is based on thyroid function tests, US and cross-sectional imaging, pulmonary function tests, and cytologic analysis. The management of a patient with MNG is guided by the clinical presentation, findings of the diagnostic work-up, the patient’s preferences, and accessibility to therapy.

By definition, nodular goiter occurs endemically when the goiter prevalence in children from 6 to 12 years old is more than 5%, or sporadically, when this number is less than 5%. It is more prevalent among older individuals and women, especially those living in iodine-deficient areas. Epidemiologic studies of MNG are hampered by limitations such as the method employed for the determination of thyroid volume (palpation, ultrasound, scintigraphy), selection criteria, environmental factors, and thyroid function (1). US is a very accurate method, and studies employing this method have shown that the frequency of thyroid nodular disease (with or without increased thyroid volume) can be as high as 30% to 40% in women and 20% to 30% in adult men living in iodine-deficient areas, with approximately half of that prevalence in younger individuals living in areas with milder iodine deficiency (2). It is estimated that the prevalence of thyroid nodular disease (with increased thyroid volume) is approximately 4% in iodine-sufficient countries (3); this prevalence can be four- to fivefold higher in iodine-deficient areas. In a study evaluating 419 children and 992 adults from an iodine-deficient village of southern Italy, nodular goiter was found in 0.5% of children and 17.0% of adults, by US (4).

In the Wickham study, a population survey of 2,749 persons living in an iodine-sufficient area in Northern England, the prevalence of small goiters (palpable but not visible) was 8.6%, whereas palpable and/or visible goiters were identified in 6.9%. Goiters were four times more common in females (5).

US screening of 635 adults (medium age 56.7 years) without previous history of thyroid disease in Germany (considered as a country with iodine-insufficiency) showed a prevalence of 17% for goiter and of 68% for thyroid nodules, with 25% of women and 40% of men presenting nodular goiter (6). Screening of 101 middle-aged healthy Finnish women identified 3 cases of toxic MNG (7).

In the Framingham Study, conducted in an iodine-sufficient area (Massachusetts in the United States), the prevalence of MNG was 1% by palpation. By US, 3% of men older than 60 years and 36% of women aged 49 to 58 years had thyroid nodules (8). In a prospective study involving 1,544 patients in a general practice in Connecticut, the prevalence of MNG was 0.84% (1.6% in females and 0.1% in males) (9). In a recent review on the prevalence and incidence of endocrine disorders in the United States, no recent data could be found on the prevalence of benign nodular goiter (10).

The pathogenesis of nontoxic diffuse and nodular goiter is determined by exogenous and endogenous factors. Worldwide, iodine deficiency is the most important factor that increases the
risk for the development of endemic and sporadic goiter, and their prevalence are inversely proportional to the iodine intake (14). According to the World Health Organization, in 2007, nearly 2 billion individuals had insufficient iodine intake (15). In adults, the recommended intake of iodine ranges between 150 and 200 μg/day, with lower values for younger children and higher values for pregnant and lactating women (16).

There is a direct correlation between the degree of iodine deficiency and the prevalence and size of the goiter, which is a physiologic adaptation to the lack of iodine. A decrease in blood iodine levels leads to a decrease in thyroxine levels (T4), which in turn stimulates the secretion of TSH, in an effort to enhance iodine uptake and restore T4 blood levels. In turn, TSH also stimulates thyroid follicular cell hyperplasia and hypertrophy. In the initial stages, the thyroid parenchyma is diffusely and homogeneously enlarged, but over time nodules often develop. Subsequently, thyroid nodules may become autonomous and secrete thyroid hormones independently of TSH due to activating mutations of the thyrotropin receptor. On the other hand, iodine excess, observed in many countries such as Brazil, Chile, Algeria, Ivory Coast, Zimbabwe, and Uganda, also has a goitrogenic effect due to its action in decreasing the synthesis and secretion of thyroid hormones (17) (see Chapters 11D and 11E).

Several other substances have been known to have goitrogenic effects, such as (i) thiocyanate from cigarettes, (ii) perchlorate from fertilizers, solid propellants for rockets and missiles, fireworks, road flares, matches, and airbag inflation systems, (iii) disulphides from coal processes, (iv) flavonoids from soy, (v) glucosinolates from cruciferous vegetables such as cabbage, kale, cauliflower, broccoli, turnips, and rapeseed, (vi) cyanogenic glucosides from cassava, lima beans, linseed, sorghum, and sweet potato, and (vii) drugs such as lithium and aminoglutethimide (18). Some other environmental pollutants, such as nitrates, are also involved in goitrogenesis (19) (see Chapter 57). The effects of those substances are attributed to their effects on inhibiting iodine uptake and thyroperoxidase activity, on displacing T4 from the serum thyroid-binding protein transthyretin, and on reducing T4 half-life. Those changes lead to a state of hypothyroidism and to an increase in TSH, which stimulates thyroid growth. Moreover, deficiency of selenium, iron, and vitamin A may also predispose to the development of goiter, by (i) increasing peroxides that damage the thyroid gland and impairing deiodinase activity (selenium deficiency), (ii) reducing thyroperoxidase activity (iron deficiency), and (iii) decreasing vitamin A-mediated suppression of the pituitary TSHβ gene (15). The pathogenesis of MNG has also been associated with alterations in the expression of proteins involved in thyrocyte proliferation and in the regulation of TSH receptor, such as Fas and DREAM (downstream regulatory element antagonist modulator), respectively (20,21).

The 2- to 10-fold higher prevalence of goiter in women leads to the assumption that female sex hormones have a direct effect on the pathogenesis of goiter (22). Estrogens stimulate normal and thyroid cancer cell growth (23). However, more recent studies have shown that estrogens can have opposite effects on thyroid cancer cell growth, depending on the balance between ERα and ERβ (24). Moreover, in premenopausal women, estrogen therapy for 1 year did not affect thyroid volume (25), and the use of oral contraceptives seemed to be associated with a decreased risk of goiter (22). The effects of estrogens on the pathogenesis of goiter seem to be determined by several complex pathways, depending on whether endogenous or exogenous estrogens are involved.

TSH is the most important growth factor involved in the pathogenesis of nodular goiter. However, most patients with goiter have normal levels of TSH, and TSH suppression by the administration of levothyroxine may not stop thyroid growth. Therefore, other growth factors are also implicated in the disease. Insulin-like growth factor-1 (IGF-1) levels are positively correlated with thyroid volume in both genders, and with the presence of nodules in men (26,27) (see Chapters 11D and E). Increased levels of IGF-1, as seen in acromegalic patients (28) and in transgenic mice overexpressing IGF-1/IGF-1 receptor (29), are also associated with increased thyroid volume. Not only IGF-1 but also epidermal growth factor (EGF) and fibroblast growth factor (FGF) stimulate proliferation of thyroid follicular cells in vitro and in vivo (30), and the expression of several growth factors is increased in thyroid hyperplasia and nodular goiters (31).

Other growth factors, such as transforming growth factor (TGF), impair thyroid growth by inhibiting thyroid cell growth, increasing apoptosis and blocking TSH-stimulated cAMP accumulation (32). Patients with nodular goiter may have decreased production of TGF, but may be resistant to it, explaining the potential role of TGF in the pathogenesis of goiter (33).

Genetic factors also play a significant role in the pathogenesis of nodular goiter (34) as shown by a study that evaluated twins, and demonstrated that genetic factors accounted for 71% (61% to 78%) of the individual differences in thyroid volume (35). The occurrence of familial cases of nodular goiter, at early ages in many cases, strengthens the hypothesis that genetic factors are involved in the pathogenesis of goiter (36).

Because of their important role in thyroid physiology and hormone synthesis, genes involved in various aspects of thyroid physiology such as TG (thyroglobulin), TPO (thyroperoxidase), SCL5A5 (solute carrier family 5, member 5), SLC26A4 (solute carrier family 26, member 4), dual oxidase 2 (DUOX2), and TSH receptor (TSHR) (36) are major candidate genes for familial euthyroid goiters. However, in familial goiter, most cases have an autosomal-dominant pattern of inheritance. Besides the aforementioned genes, other candidate loci as determinants of nodular goiter are the multinodular goiter 1 (MNG1) locus on chromosome 14, and loci on chromosomes Xp22 (MNG2), 2q, 3p, 3q, 7q, and 8p (31,37,38,39). In genome-wide association studies, four genetic loci were associated with thyroid volume: Two independent loci located upstream of and within capping protein, beta (CAPZB), one within fibroblast growth factor 7 (FGF7), and one on chromosome 16q23 (39,40). Figure 48.1 illustrates the natural history of MNG, and Table 48.1 summarizes examples of situations predisposing to goitrogenesis.

The clinical manifestations observed in patients with MNG are heterogeneous. Patients with relatively small goiters and with normal thyroid function are usually asymptomatic. On the other hand, patients with large goiters may develop compressive symptoms, such as dyspnea, dysphagia, neck pain or pressure, and hoarseness. Clinical manifestations are influenced not only by the size of the goiter but also by its substernal extension,
since compression of the trachea, esophagus, and great vessels is more likely to occur in the confined space of the thoracic inlet.

There is not a definitive consensus regarding the classification of goiters that extend into and beyond the retrosternal, substernal, intrathoracic, or mediastinal regions (41,42). The most widely used definition of substernal goiter is the one wherein >50% of the total bulk of the thyroid gland extends into the mediastinum. Others consider a substernal goiter as one that descends below the plane of the thoracic inlet. Due to this lack of consensus, the prevalence of intrathoracic goiters, with substernal or mediastinal extension, ranges between 2.6% and 30.4% (43). Goiters that have intrathoracic extension usually lead to the development of earlier and more severe symptoms. Most frequently, the intrathoracic extension occurs into the anterior mediastinum, but about 10% of substernal goiters can be located in the posterior mediastinum (44).

Thyrotoxicosis (i.e., “a clinical state that results from inappropriately high thyroid hormone action in tissues generally due to inappropriately high tissue thyroid hormone levels”) may develop (45), particularly in older patients, and can present from asymptomatic subclinical hyperthyroidism to overt hyperthyroidism. Pain or tenderness are rare manifestations, and occur in the presence of recent intrathyroidal bleeding.

The close relationship of the thyroid gland with adjacent structures is the key factor that determines the most significant clinical manifestations. The symptoms of tracheal compression are dyspnea, wheezing, stridor, cough, and a choking or pressure sensation. These symptoms vary in intensity and may be triggered by exercise or be present even at rest, depending on the gland volume and degree of tracheal compression. A maximal tracheal diameter of <8–10 mm can cause exertional dyspnea, and when the diameter is <5 mm, dyspnea at rest and stridor occur (46).

Goiters with intrathoracic extension may have their symptoms exacerbated during the night when the patient is supine or
lies on one side or the other, or by certain positions that increase tracheal compression. Similarly, acute airway compression may occur (47) particularly if there is a sudden increase in thyroid volume due to thyroid hemorrhage (48) or upper respiratory tract infections contributing to a decrease in tracheal lumen. Compression of the esophagus from retrotracheal growth of a goiter may cause dysphagia. However, this manifestation is less common than the respiratory complications due to the posterior localization of the esophagus. Odynophagia is not a manifestation of thyroidal compression, and is more likely related to inflammatory processes within the pharynx or the esophagus, or acute/subacute thyroiditis.

The close relationship of the thyroid gland with the recurrent laryngeal nerves may lead to unilateral or bilateral vocal cord paralysis, which can be transient or permanent. The clinical presentation of recurrent laryngeal nerve compression is dyspnea and hoarseness (49). Similarly, compression of the cervical sympathetic chain may cause paralysis of the phrenic nerve (which can be asymptomatic or present with dyspnea) (50) or Horner’s syndrome (ptosis, miosis, and decreased sweating of the face on the same side) (51). Paralysis of the phrenic nerve and Horner’s syndrome are rare manifestations of goiter and few reports can be found in the literature (52). Thrombosis of the jugular vein and superior vena cava syndrome have also been described (53).