Aetiology
A toxic multinodular goitre (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.[10] In addition, activating mutations of the TSH receptor have been found in non-adenomatous hyperfunctioning nodules in patients with toxic or autonomous MNGs.[11] Non-functioning nodules in the same goitre lack these mutations.
Patients with toxic multinodular goitre usually have a history of long-standing goitre, and worldwide, iodine deficiency is the most common cause of nodular goiter.[8] 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 (3% to 15% of cases of thyrotoxicosis) in areas with sufficient iodine supply.[2][10][12] Observational evidence indicates that correction of iodine deficiency has correlated with declines in prevalence of toxic multinodular goitre.[12][13]
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).[14]
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 sub-unit of stimulating G protein.[15] G proteins are a family of molecular switches that mediate actions of many different cell surface receptors.[16] Signals from these receptors are sensed by G proteins and transduced to an effector, which, in thyroid cells, is cAMP.[15][16] In toxic adenomas, activating germline mutations lead to increased cAMP levels, which in turn causes growth and excess function of thyrocytes.[17][18][19] Other mechanisms, including alterations of G protein signalling as well as genetic and environmental influences (e.g., iodine deficiency) and thyrocyte heterogeneity, may be involved in the development of hyperfunctioning thyroid nodules.[15][20]
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