Nontoxic goiter, also known as simple goiter, refers to diffuse or nodular enlargement of the thyroid gland caused by non-inflammatory and non-tumorous factors, with normal thyroid function. This condition includes diffuse nontoxic goiter and nontoxic multinodular goiter (MNG). The prevalence in women is 3 to 5 times higher than in men. Based on its occurrence, simple goiter is classified into endemic goiter and sporadic goiter. Endemic goiter is diagnosed when the prevalence of simple goiter in children and adolescents within a region exceeds 5%, or when the total prevalence among the general population exceeds 10%.
Etiology and Pathogenesis
Iodine Deficiency
Iodine deficiency disorder (IDD) is the primary factor contributing to endemic goiter. Insufficient iodine results in inadequate thyroid hormone synthesis, which leads to increased TSH secretion from the pituitary as a feedback mechanism, stimulating thyroid hypertrophy and hyperplasia.
Iodine nutritional status can be assessed through urinary iodine concentration. The median urinary iodine (MUI) can be used to evaluate iodine levels within a population. MUI levels between 100–199 μg/L indicate an adequate iodine supply, MUI below 100 μg/L signifies iodine deficiency, MUI between 200–299 μg/L suggests iodine excess, and MUI of 300 μg/L or higher indicates severe iodine overload.
Genetic and Environmental Factors
Sporadic goiter has a complex etiology. Genetic defects or mutations can impair thyroid hormone synthesis, leading to the development of goiter. Common mutations associated with goiter involve genes such as the sodium-iodide symporter (NIS), thyroglobulin (Tg), thyroid peroxidase (TPO), dual oxidase 2 (DUOX2), TSH receptor (TSHR), and pendrin. Elevated levels of cytokines like insulin-like growth factor-1 (IGF-1) can also contribute to goiter formation. Environmental factors, including dietary and waterborne iodine, goitrogenic foods (e.g., cabbage, bok choy, cauliflower, kale), and certain medications (e.g., thiocyanates, perchlorates, lithium salts), can inhibit thyroid hormone synthesis or cause direct thyroid enlargement. Smoking may also be associated with goiter development.
Pathology
The thyroid gland exhibits diffuse or nodular enlargement. The pathological mechanism involves TSH and other thyroid growth-promoting factors inducing the proliferation of thyroid follicular epithelial cells. In the early stages, the gland shows diffuse follicular hyperplasia with vascular congestion in the stroma. As the condition progresses, some follicles enlarge and become colloid-rich, while others undergo degeneration. In advanced cases, some areas of the gland may develop hemorrhage, necrosis, cystic degeneration, fibrosis, or calcification, resulting in nodular formation.
Clinical Presentation
Most patients are asymptomatic. However, in cases of severe enlargement, the thyroid gland may compress the trachea or esophagus, causing difficulty in breathing or swallowing. The thyroid gland may appear diffusely or nodularly enlarged, and its consistency ranges from soft to moderately firm. A retrosternal goiter may compress the thoracic inlet, obstructing venous return from the head and upper limbs. This can result in facial congestion and jugular venous distension when patients raise their arms above their heads, a phenomenon known as Pemberton's sign.
Diagnosis and Differential Diagnosis
Serum T4, T3, and TSH levels are generally normal. In iodine-deficient patients, TT4 levels may show a slight decrease, while the T3/T4 ratio increases. Serum thyroglobulin (Tg) levels are normal or elevated. TPOAb and TgAb measurements assist in determining the presence of Hashimoto's thyroiditis. Assessments of serum iodine and urinary iodine levels provide information about iodine nutritional status.
Thyroid ultrasound is the preferred method to evaluate the characteristics and extent of goiter, determine whether it compresses other neck structures, and assess for cervical lymphadenopathy. The risk of malignancy in nodules within nontoxic multinodular goiter is similar to that of solitary nodules. Fine-needle aspiration (FNA) under ultrasound guidance is considered when necessary. Radionuclide scans (99mTcO4-, 123I, or 131I) help assess thyroid functional status and underlying causes; 123I or 131I scans can also confirm whether a mediastinal mass originates from thyroid tissue. CT or MRI is primarily used to outline the relationship between the thyroid and adjacent structures. Barium swallow X-ray helps assess esophageal compression. Flow-volume loop pulmonary function tests can determine tracheal compression, with symptoms typically occurring when tracheal luminal narrowing exceeds 70%.
Prevention and Treatment
Most cases of goiter do not require treatment. For individuals with iodine deficiency, iodine nutritional status requires correction. Iodized salt is recognized globally as an effective measure for preventing iodine deficiency disorders.
In pregnant and lactating women, increased urinary iodine excretion and higher fetal thyroid iodine requirements may lead to relative maternal thyroid hormone insufficiency. Increased iodine intake is therefore necessary for these groups. The WHO recommends a daily iodine intake of 250 μg for pregnant and lactating women.
In cases where goiter causes compressive symptoms, retrosternal goiter, or cosmetic concerns, surgery is the first-line treatment. For patients who cannot tolerate surgery, radioactive iodine therapy is an alternative, with thyroid volume typically reducing by approximately 50% within 1–2 years. Complications such as radioactive thyroid swelling and aggravated local compression are rare. The use of supraphysiologic doses of thyroid hormone for TSH suppression therapy is not recommended, as it is only effective in some patients, and symptoms tend to recur after withdrawal. Excessive thyroid hormone use also increases the risk of arrhythmias and bone mass loss.