The brain maintains constant levels of T3 within its cells through the use of a high-affinity deiodinase known as type 2 deiodinase (D2). This enzyme is expressed in glial cells of the central nervous system (CNS). Even when circulating T4 levels are low, D2 ensures intracellular concentrations of T3 remain stable. D2 is also present in the thyrotropes of the pituitary gland, where it acts as a "thyroid axis sensor" by allowing circulating T4 to regulate the secretion of thyroid stimulating hormone (TSH). During hypothyroidism, the expression of D2 increases, aiding in the maintenance of constant T3 levels in the brain.

Another deiodinase, type 3 deiodinase (D3), functions as an "inactivating" enzyme. D3 is a high-affinity inner ring deiodinase that converts T4 into the inactive form rT3. During hyperthyroidism, D3 levels increase, helping to regulate the overproduction of T4. Eventually, all forms of iodothyronines are further deiodinated into noniodinated thyronine.

Iodide plays a vital role in thyroid physiology, and an understanding of iodide turnover is necessary to comprehend thyroid hormone synthesis. In the United States, an average of 400 µg of iodide per person is consumed daily. However, the minimum daily requirements differ, with adults needing 150 µg, children requiring 90 to 120 µg, and pregnant women needing 200 µg. In a steady state, the same amount of 400 µg is excreted in urine. Iodide is actively concentrated in various glands such as the thyroid gland, salivary glands, gastric glands, lacrimal glands, mammary glands, and choroid plexus. The thyroid gland uptakes around 70 to 80 µg of iodide daily from a circulating pool containing approximately 250 to 750 µg of iodide. The thyroid gland's total iodide content averages 7500 µg, mostly in the form of stored iodothyronine within colloid thyroglobulin. In a steady state, about 1% (70 to 80 µg) of iodide is released from the gland daily, with 75% being secreted as thyroid hormone and the remaining as free iodide. The substantial ratio of stored hormone to the daily turnover (100:1) safeguards against iodide deficiency for approximately 2 months. As serum concentration of iodide decreases, renal excretion of iodide reduces, thereby conserving iodide.

To understand the synthesis and secretion of thyroid hormone, it is important to grasp the directional movement within the polarized thyroid epithelial cell. The process requires two precursors: iodide and thyroglobulin. Iodide is transported across cells from the basal (vascular) side to the apical (follicular luminal) side of the thyroid epithelium. Thyroglobulin is synthesized and secreted across the apical membrane into the follicular lumen. Consequently, synthesis involves the movement of these precursors from the basal to apical direction into the follicular lumen. The actual synthesis of iodothyronines occurs enzymatically within the follicular lumen, near the apical membrane of the epithelial cells.
The brain maintains constant intracellular levels of T3 by a high-affinity deiodinase called type 2 deiodinase (D2) that is expressed in glial cells of the CNS. D2 has a Km of 1 nM and maintains intracellular concentrations of T3 even when circulating T4 falls to low levels. D2 is also present in pituitary thyrotropes. There, D2 acts as a “thyroid axis sensor” that mediates the ability of circulating T4 to feed back on secretion of thyroid stimulating hormone (TSH). Expression of D2 is increased during hypothyroidism, which helps maintain constant T3 levels in the brain.
There is also an “inactivating” deiodinase called type 3 deiodinase (D3). D3 is a high-affinity inner ring deiodinase that converts T4 to the inactive rT3. Type 3 deiodinase is increased during hyperthyroidism, which helps blunt overproduction of T4. All forms of iodothyronines are eventually further deiodinated to noniodinated thyronine.
Because iodide plays a unique role in thyroid physiology, a description of thyroid hormone synthesis requires some understanding of iodide turnover (
Fig. 42.4 ). An average of 400 µg of iodide per person is ingested daily in the United States, versus a minimum daily requirement of 150 µg for adults, 90 to 120 µg for children, and 200 µg for pregnant women. In the steady state, the same amount, 400 µg, is excreted in urine. Iodide is actively concentrated in the thyroid gland, salivary glands, gastric glands, lacrimal glands, mammary glands, and choroid plexus. About 70 to 80 µg of iodide is taken up daily by the thyroid gland from a circulating pool that contains approximately 250 to 750 µg of iodide. The total iodide content of the thyroid gland averages 7500 µg, virtually all of which is in the form of stored iodothyronine in colloid thyroglobulin. In the steady state, 70 to 80 µg of iodide, or about 1% of the total, is released from the gland daily. Of this amount, 75% is secreted as thyroid hormone and the remainder as free iodide. The large ratio (100:1) of iodide stored in the form of hormone to the amount turned over daily protects against iodide deficiency for about 2 months. Iodide is also conserved by a marked reduction in renal excretion of iodide as its concentration in serum falls.
•Fig. 42.2 Histologyofthethyroidglandatlow(upper panel) andhigh(lower panel) magnification.C,colloid;F,thyroidfollicles;S,connectivetissuesepta.(FromYoungBetal.Wheater’s Functional Histology. 5thed.Philadelphia:ChurchillLivingstone;2006.)
CHAPTER 42 The Thyroid Gland
Overview of Thyroid Hormone Synthesis
To understand thyroid hormone synthesis and secretion, one must appreciate the directionality of each process as it relates to the polarized thyroid epithelial cell (
Fig. 42.5 ). Synthesis of thyroid hormone requires two precursors: iodide and thyroglobulin. Iodide is transported across cells from the basal (vascular) side to the apical (follicular luminal) side of the thyroid epithelium. Thyroglobulin is synthesized and secreted across the apical membrane into the follicular lumen. Thus synthesis involves a basal-to-apical movement of these precursors into the follicular lumen (see
Fig. 42.5 ). Actual synthesis of iodothyronines occurs enzymatically within the follicular lumen close to the apical membrane of the epithelial cells (see