Goiter is defined as enlargement of the thyroid gland. It generally results from focal follicular cell hyperplasia at one or multiple sites within the thyroid gland, and it usually develops over years. Endemic goiter refers to enlargement of the thyroid gland secondary to iodine deficiency affecting more than 10% of the population in a defined geographic area. Sporadic goiter develops in subjects living in iodine-sufficient areas. Goiter encompasses a spectrum of entities, including diffuse, uninodular, or multinodular enlargement of the thyroid gland. The overall hormonal status of the thyroid nodules within the goiter determines the function of the gland and the definition. When enlargement of the thyroid gland is present without clinical or laboratory evidence of thyroid dysfunction, it is euthyroid multinodular goiter (MNG); when accompanied by hyperthyroidism, it is toxic nodular goiter (TNG). Less frequently, thyroid enlargement is caused by two other disorders such as fibrous chronic Hashimoto’s thyroiditis, Graves’ disease, or neoplasia. Retrosternal or substernal goiter refers to goiter that is associated with extension into the mediastinum.

This chapter discusses the pathogenesis, clinical manifestations, and management of nontoxic goiter.

Goiter prevalence in the general population is estimated to be 15.8%, varying between 4.7% in the Americas to 28.3% in Africa. When comparing current total goiter prevalence (TGP) estimates with the data from 1993, TGP has increased by 31.7% worldwide, but when analysis is restricted to surveys carried out in the past 5 years, TGP shows a decrease of 28.9% compared with 1993.1 Sporadic goiter is the most common form of goiter in the United States, affecting 5% of the population. Goiter is 2- to 10-fold more prevalent in women than in men.2 The association between age and goiter prevalence is dependent on iodine status: in areas of severe iodine deficiency, the prevalence of goiter is maximal in the teenage years,3 but the peak appears around middle age or later in mildly iodine deficient areas.2 African-American ethnicity has been shown to be an independent risk factor for the development of large nodular goiter.4

Iodine deficiency is the most important risk factor for goiter worldwide. The mechanism by which the thyroid gland adapts to an insufficient iodine supply is to increase the trapping of iodide, as well as the subsequent steps of the intrathyroidal metabolism of iodine. This process is triggered and maintained by increased secretion of thyroid-stimulating hormone (TSH), which is ultimately responsible for the development of goiter. The acceleration of the main steps of iodine kinetics and the degree of hyperstimulation by TSH are greater in the pediatric age groups than in adults, and the development of goiter appears as an unfavorable side effect in the process of adaptation to iodine deficiency during growth.3

In patients with sporadic goiter, the cause is usually unknown and involves a combination of environmental and genetic factors. TSH is considered to be the main growth factor in goiter development, but goiter is frequently seen in patients with normal or low TSH levels. It has been suggested that an imbalance in the interactions between the various growth factor axes that favors cell replication exists in patients with MNG.5

The role of naturally occurring goitrogens has been documented in the case of certain foods (e.g., milk, cassava, millet, nuts), smoking, and bacterial and chemical water pollutants. The goitergenic effects of tobacco smoke on the thyroid could be explained by the generation of thiocyanate, which competitively inhibits iodine uptake and organification, thereby mimicking a lower iodine intake.2 Lithium has also been associated with the development of goiter.

A genetic predisposition for goiter development is evident from family and twin paired studies. The genes coding for proteins involved in thyroid hormone synthesis, such as thyroglobulin (Tg), thyroid peroxidase, sodium iodide symporter, pendrin, and the TSH receptor, are thought to be involved in the molecular etiology of familial euthyroid goiter. Familial euthyroid goiter has been linked to a multinodular nontoxic goiter locus (MNG-1) on chromosome 14q6 and to defects in Xp22 with an X-linked autosomal pattern.7 Recently, genetic factors on chromosomes 2q, 3p, 7q, and 8p have been suggested to confer susceptibility for euthyroid goiter in some families.8 These data suggest genetic heterogeneity in euthyroid familial goiter.

Goiters vary greatly in their size, growth rate, and symptomatology. Most patients with MNG are asymptomatic. Clinical manifestations of nontoxic goiter are usually attributed to thyroid enlargement. Patients may present with a neck lump or disfigurement of the neck (Figure 2-1) or with pressure symptoms, including dysphagia and breathing difficulties because of local esophageal or tracheal compression, respectively. The compression symptoms are most often seen when an intrathoracic extension of the goiter, termed a substernal or retrosternal goiter, is present. This is more common in elderly individuals with long-standing goiters. Dyspnea and stridor initially develop on exertion and later may also occur at rest. Vocal cord paralysis is rare in patients with benign goiter but may be caused by stretching or compression of the recurrent laryngeal nerves (RLNs). More rarely, compression of the phrenic nerve or the cervical sympathetic chain resulting in Horner’s syndrome has been described. Bleeding within the goiter is associated with acute painful swelling in the neck and may cause dyspnea. Rapidly enlarging goiter that appears within weeks to months must increase the suspicion of anaplastic or lymphomatous malignancy. Patients with nontoxic nodular goiter may become hyperthyroid or, less commonly, hypothyroid. However, thyroid dysfunction usually develops only after the nontoxic goiter has existed for many years.9 Hyperthyroidism often develops insidiously with a prolonged period of subclinical hyperthyroidism.

The differential diagnosis of a patient with nontoxic nodular goiter includes diffuse goiter, benign nodular goiter, Hashimoto’s thyroiditis, follicular adenoma, and carcinoma. The history should include any symptoms of thyroid dysfunction, including hypo- or hyperthyroidism; family history of thyroid disease; multiple endocrine neoplasia (MEN) syndrome; thyroid cancer; and history of radiation exposure to the head or neck.

Thyroid enlargement is often best observed when the patient swallows. With practice, the thyroid gland can be palpated in normal size, but for most clinicians, the thyroid gland does not become palpable until the volume has doubled. Examination of the goiter should focus on symmetry, solitary nodule versus MNG, fixation of the goiter, presence of tracheal deviation, consistency of the nodules, and associated lymphadenopathy. The presence of a retrosternal extension is suggested by an inability to palpate the lower thyroid border. Venous outflow obstruction may be evident by Pemberton’s sign. The Pemberton maneuver is a physical examination method that elicits manifestations of latent increased pressure in the thoracic inlet by altering the patient’s arm position to further narrow the aperture. The maneuver involves extending both arms over the head, and a positive sign occurs when the patient experiences marked facial congestion, cyanosis, and venous engorgement. Physical examination should include findings compatible with Graves’ disease that may coexist and may require a different therapeutic approach. The patient should also be examined for the presence of wheezing or stridor.

The diagnosis of thyroid carcinoma should be strongly considered when there is a family history of medullary thyroid cancer (MTC) or MEN, rapid tumor growth, a firm nodule within the goiter, vocal cord paralysis, or the presence of regional lymphadenopathy.

Laboratory evaluation should include TSH measurement to determine whether the patient is euthyroid, hypothyroid, or hyperthyroid. Patients with endemic goiter are usually euthyroid; however, mildly elevated TSH, low thyroxine (T4), and normal or moderately elevated triiodothyronine (T3) serum levels are common. With sporadic goiter, many patients who are clinically euthyroid have biochemical evidence of hypo- or hyperthyroidism. The degree of thyroid dysfunction is often mild or subclinical and evidenced only by an isolated TSH abnormality. If the TSH level is found to be outside the normal range, assays for T3 and T4 are also justified. With a moderately enlarged and firm gland, one should consider Hashimoto’s thyroiditis. Increased levels of antithyroid peroxidase antibodies or Tg antibodies help confirm the diagnosis.

The routine use of calcitonin measurement in patients with nodular goiter is controversial but should be considered in any patient with a family history of thyroid cancer. Hahm et al.10 performed routine measurement of serum calcitonin in 1448 patients with nodular thyroid diseases, with fine-needle aspiration (FNA) done in all patients with palpable or ultrasound-visible nodules. Ten cases of histologically confirmed MTC were detected by routine measurement of serum calcitonin; FNA suggested MTC in only two patients. The authors concluded that routine measurement of serum calcitonin is useful in the early detection of MTC among patients with nodular thyroid disease.

Ultrasonography has become a first-line method in thyroid imaging. Ultrasound examination is used to measure the size of the gland, establish the presence and size of thyroid nodules, and provide a baseline for follow-up. Many patients who present with a solitary palpable nodule are found to have multiple nodules on ultrasonography. A diffuse goiter appears with normal echogenicity, but degenerative alterations usually lead to a more heterogeneous appearance to the gland. Thyroid nodules may appear hypoechoic, isoechoic, or hyperechoic. Features seen on ultrasonography that are suspicious for thyroid cancer include microcalcifications, local invasion, lymph node metastases, a nodule with anteroposterior dimension greater than its transverse dimension, markedly reduced echogenicity, absence of a halo, ill-defined or irregular margins, solid composition, and central vascular flow.11