In a nodular thyroid, individual nodules can begin to make hormone without waiting for TSH. Toxic multinodular goiter (MNG) is the state in which autonomous nodules within the gland produce thyroid hormone on their own. Its pathogenesis is very similar to that of non-toxic MNG, and, like non-toxic MNG, it is made out of multiclonal nodules. What drives the autonomous cells is a set of activating mutations in the TSH receptor (TSH-R), mostly in the transmembrane region through which the receptor couples to its G protein; the receptor signals continuously, as if TSH were always bound, so the cells produce hormone independently of TSH.
The result is the picture of hyperthyroidism: a decreased level of TSH, an increase in thyroid hormones (T3 and also T4, which is more prominent for T3), and the classic complaints of hyperthyroidism — weight loss, tremor, tachycardia, atrial fibrillation and nervousness. Toxic MNG is mostly seen in elderly patients.
Hyperfunctioning solitary nodules
A solitary, autonomous functioning nodule in the thyroid gland is a toxic adenoma. Its pathogenesis is the same kind of activating mutation in the TSH-R, which leaves the receptor’s intracellular pathways active without TSH. Most of the mutations found in toxic adenoma are in the transmembrane domains of the TSH-R, and in a minority of cases the mutation lies instead in the Gs protein the receptor couples to. Thyrotoxicosis, the state of thyroid hormone excess, from a toxic adenoma is usually rare and becomes likely only once the single nodule is larger than 3 cm. In a toxic adenoma the TSH level is mostly slightly subnormal.
Whether a nodule makes hormone is only one of the two questions about it; the other is whether it is malignant.