Etiology
A toxic multinodular goiter (MNG) contains multiple autonomously functioning nodules, resulting in hyperthyroidism. Hyperfunctioning nodules in MNGs develop in a similar way to single toxic nodules. Most hyperfunctioning nodules have thyroid cell germline mutations that affect the thyroid-stimulating hormone (TSH) receptor.[9] In addition, activating mutations of the TSH receptor have been found in nonadenomatous hyperfunctioning nodules in patients with toxic or autonomous MNGs.[10] Nonfunctioning nodules in the same goiter lack these mutations.
Patients with toxic multinodular goiter usually have a history of longstanding goiter, and worldwide, iodine deficiency is the most common cause of nodular goiter.[7] Iodine Global Network: Global scorecard of iodine nutrition in 2021 in the general population based on school-age children (SAC) Opens in new window Thyroid autonomy is uncommon (about 3% to 15% of cases of thyrotoxicosis) in areas with sufficient iodine supply.[2][9][11] Observational evidence indicates that correction of iodine deficiency has correlated with declines in prevalence of toxic multinodular goiter.[11][12]
In individuals with autonomous nodules, an iodine load (from iodinated radiographic contrast, amiodarone, or a change in diet) may cause iodine-induced hyperthyroidism (the Jod-Basedow phenomenon).[13]
Pathophysiology
Thyroid cell growth and function are mainly stimulated by thyroid-stimulating hormone (TSH) via the TSH receptor.[3] TSH receptor activity is mediated through the alpha subunit of stimulating G protein.[14] G proteins are a family of molecular switches that mediate actions of many different cell surface receptors.[15] Signals from these receptors are sensed by G proteins and transduced to an effector, which, in thyroid cells, is cAMP.[14][15] In toxic adenomas, activating germline mutations lead to increased cAMP levels, which in turn causes growth and excess function of thyrocytes.[16][17][18] Other mechanisms, including alterations of G protein signaling as well as genetic and environmental influences (e.g., iodine deficiency) and thyrocyte heterogeneity, may be involved in the development of hyperfunctioning thyroid nodules.[14][19]
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