Toxic Nodular Goiter Clinical Presentation

Updated: Oct 14, 2016
  • Author: Philip R Orlander, MD, FACP; Chief Editor: George T Griffing, MD  more...
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Thyrotoxic symptoms - Most patients with toxic nodular goiter (TNG) present with symptoms typical of hyperthyroidism, including heat intolerance, palpitations, tremor, weight loss, hunger, and frequent bowel movements.

  • Elderly patients may have more atypical symptoms, including the following:

    • Weight loss is the most common complaint in elderly patients with hyperthyroidism.

    • Anorexia and constipation may occur, in contrast to frequent bowel movements often reported by younger patients.

    • Dyspnea or palpitations may be a common occurrence.

    • Tremor also occurs but can be confused with essential senile tremor.

    • Cardiovascular complications occur commonly in elderly patients, and a history of atrial fibrillation, congestive heart failure, or angina may be present.

  • F Lahey, MD, first described apathetic hyperthyroidism in 1931; this is characterized by blunted affect, lack of hyperkinetic motor activity, and slowed mentation in a patient who is thyrotoxic.

Obstructive symptoms - A significantly enlarged goiter can cause symptoms related to mechanical obstruction.

  • A large substernal goiter may cause dysphagia, dyspnea, or frank stridor. Rarely, this goiter results in a surgical emergency.

  • Involvement of the recurrent or superior laryngeal nerve may result in complaints of hoarseness or voice change.

Asymptomatic - Many patients are asymptomatic or have minimal symptoms and are incidentally found to have hyperthyroidism during routine screening. The most common laboratory finding is a suppressed TSH with normal free thyroxine (T4) levels.



Findings of hyperthyroidism may be more subtle than those of Graves disease. Features may include widened, palpebral fissures; tachycardia; hyperkinesis; moist, smooth skin; tremor; proximal muscle weakness; and brisk deep tendon reflexes.

The size of the thyroid gland is variable. Large substernal glands may not be appreciable upon physical examination.

A dominant nodule or multiple irregular, variably sized nodules are typically present. In a small gland, multinodularity may be apparent only on an ultrasonogram. Chronic Graves disease may present with some nodularity; therefore, establishing the diagnosis is sometimes difficult.

Hoarseness or tracheal deviation may be present upon examination.

Mechanical obstruction may result in superior vena cava syndrome, with engorgement of facial and neck veins (Pemberton sign). [4]

Stigmata of Graves disease (eg, orbitopathy, pretibial myxedema, acropachy) are not observed.



Functional autonomy of the thyroid gland appears to be related to iodine deficiency. Various mechanisms have been implicated, but the molecular pathogenesis is poorly understood.

The sequence of events leading to toxic multinodular goiter is as follows:

  • Iodine deficiency leads to low levels of T4; this induces thyroid cell hyperplasia to compensate for the low levels of T4.

  • Increased thyroid cell replication predisposes single cells to somatic mutations of the TSH receptor. Constitutive activation of the TSH receptor may generate autocrine factors that promote further growth, resulting in clonal proliferation. Cell clones then produce multiple nodules.

Somatic mutations of the TSH receptors and G α protein confer constitutive activation to the cyclic adenosine monophosphate (cAMP) cascade of the inositol phosphate pathways. These mutations may be responsible for functional autonomy of the thyroid in 20-80% of cases. [1]

  • These mutations are found in autonomously functioning thyroid nodules, solitary and within a multinodular gland. Nonfunctioning thyroid nodules within the same gland lack these mutations.

  • The reported frequency of these mutations varies widely, ranging from 10-80%. Higher incidence is reported in patients with iodine deficiency.

In addition to somatic mutations, polymorphisms of the TSH receptor have been studied in patients with toxic nodular goiter (TNG); notably, polymorphisms involving the carboxyl-terminal tail of the human TSH receptor have been found in nodular and genomic deoxyribonucleic acid (DNA).

  • Unlike the somatic mutations found in autonomously functioning nodules, these mutations have also been found in other cell lines, indicating a germline mutation. One of these, D727E, was present with greater frequency in patients with TNG than in healthy individuals; this suggests that this polymorphism may be associated with the disease. [5, 6]

  • The presence of the heterozygous state for the D727E variant of the human TSH receptor alone is not sufficient for the development of the TNG. Approximately 10% of healthy individuals have this polymorphism.

Possible mediators in growth include the following:

  • Endothelin-1 (ET-1) production is increased in rat thyroid glands that have undergone hyperplasia; this suggests that ET-1 production may be involved in thyroid gland growth and vascularity. In contrast to normal thyroid tissue and papillary thyroid cancer, thyroid tissue in patients with TNG shows markedly positive staining of the stroma but absent staining of the follicular cells. The significance of this finding is unclear, but ET-1 is, in addition to being a vasoconstrictor, a mitogen for vascular endothelium, smooth muscle cells, and thyroid follicular cells.

  • In vitro systems have shown stimulation of thyroid follicular cell proliferation with insulinlike growth factor-1, epidermal growth factor, and fibroblast growth factor. Reduced concentrations of transforming growth factor-β 1 or resistance to transforming growth factor-β have also been associated with follicular cell growth. The role of these multiple factors in the growth and secretory function of TNG needs further investigation.