Rethinking Hypothyroidism by Antonio C. Bianco MD

Author:Antonio C. Bianco, MD [Bianco,, MD, Antonio C.]
Language: eng
Format: epub
Tags: MED000000 MEDICAL / General, MED027000 MEDICAL / Endocrinology & Metabolism
Publisher: University of Chicago Press
Published: 2022-11-15T00:00:00+00:00

Chapter 10

TSH Isn’t a Magic Bullet

Measuring the circulating levels of TSH—the hormone that stimulates the thyroid gland to function—is a phenomenal tool to diagnose hypothyroidism. It became the gold standard adopted worldwide because of two facts: (1) Most of what the thyroid does is secrete T4; and (2) TSH secretion responds rapidly to minimal changes in T4 levels. Thus, monitoring TSH levels in the circulation to assess thyroid function makes sense.

The mechanisms explaining the exquisite TSH sensitivity of T4 were defined by Enrique Silva and Reed Larsen, both of whom I had the privilege of working with and learning from, for many years. In the early 1970s, they did not know each other, but they were both curious about observations they made independently, Silva in Santiago, Chile, and Larsen in Boston. They found that iodine deficiency produces a drastic drop in T4 (but not T3), and yet no signs (or symptoms) of hypothyroidism could be detected in rats (or humans) with this condition. They wondered how T4 could be so important for TSH regulation and yet, its drop in circulation did not cause signs or symptoms of hypothyroidism.1

Later, when working together at the Brigham and Women’s Hospital in Boston, they were inspired by Jack Oppenheimer’s recent discovery that organs respond to T3 but much less to T4. They predicted a mechanism inside the various organs (deiodination, which is the removal of an iodine atom from T4) that activates the actions of T4. In other words, they considered that even with low T4 levels, a deiodinase could amplify the effects of T4 (by converting it to T3).

But they were not sure how to proceed, how to test their idea. At that time, both Silva and Larsen were not known in the deiodinase field, and there was only one known deiodinase (D1), which they suspected was not involved.

Larsen went to Silva’s office to strategize. (His office was unusual, a wedge-shaped space behind an elevator shaft.) They discussed different possibilities and decided to do a test trial, first looking at the effects of T3 on TSH secretion. As planned, a few days later, Silva injected rats with radioactive T3 and saw a drop in circulating TSH at the same time that radioactive T3 was building up in the pituitary gland. This meant that T3 inhibits TSH through its actions in the pituitary gland. Part 1 of their plan was accomplished.

They continued with the strategy crafted in Silva’s office and moved to the second part of their plan: to test the hypothesis that the pituitary gland takes up T4 and converts it to T3, and that this could be the amplification mechanism they were looking for. But the technical details of the plan were still not clear.

Here is when fate took care of things by putting Silva and Larsen together. Their skills complemented each other’s. Silva has an analytical mind, capable of planning experiments and rapidly identifying and solving problems. Larsen has the ability to put things into perspective, always looking at the big picture when interpreting the results.

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