A high thyroid hormone level in the blood does not tell the whole story. Severity is not only the hormone level. Think of the thyroid as a factory that runs on iodine and is switched on by TSH. Normally feedback tells the factory to slow down when enough hormone is in the blood. When that feedback is lost, the factory overproduces. The sections below trace the ways that it happens, one at a time.
What makes severity?
Four things set severity: the iodine supply reaching the gland, the gland’s production capacity, the TRAb level, and the sensitivity of peripheral tissues. Production capacity grows with gland size.
How do tissues adapt?
The tissues change their handling of hormone when it is in excess. In hyperthyroidism DIO2, which converts T4 to T3 inside cells, falls. In hyperthyroidism DIO3, which inactivates thyroid hormone, rises.
The cell activates less hormone and breaks it down faster. A high circulating level produces a smaller cellular effect than it otherwise would.
Why does iodine matter?
Iodine supply is a determinant of severity. In one setting iodine supply is the cause of hyperthyroidism.
How does a goiter form when iodine is low?
Where dietary iodine is insufficient, the gland enlarges to compensate. TSH drives the proliferation of thyroid tissue. The result is a simple goiter.
How does the goiter become nodular?
Over time part of the thyroid tissue becomes nodular: this is multinodular goiter (MNG).
What changes inside a nodule?
Some nodules carry an activating mutation in the TSH receptor itself. Other nodules carry an activating mutation in Gsα.
Either way, the mutant nodules take up iodine and produce hormone without waiting for TSH. They are autonomous. Autonomous tissue ignores the usual feedback.
When does the gland turn toxic?
When enough autonomous tissue accumulates, the gland turns toxic. Toxic multinodular goiter is the second most common cause of hyperthyroidism, after Graves disease.
What happens when iodine suddenly rises?
A sudden increase in iodine supply lets autonomous tissue overproduce hormone. This iodine-induced hyperthyroidism is the Jod-Basedow phenomenon.
Where does extra iodine come from?
Several sources can supply it:
- Drugs. Amiodarone supplies 30-100 times the normal daily physiological need for iodine.
- Iodine-containing contrast agents.
- Iodine-rich foods such as sushi and algae.
- Disinfectants.
What are the two routes to hormone without feedback?
Autonomous nodules are one route to a gland making hormone without feedback. The autoimmune route is the other route, and the most common one. In it, antibodies stimulate the TSH receptor. How are those antibodies made, and how do they act on the receptor?