THYROID GLAND

A detailed discussion regarding the thyroid gland and its associated diseases can be found in Chapter 114. The following discussion focuses on the endocrinology of the thyroid gland.

Physiology

Thyroid hormone affects the metabolic rate and plays a critical role in thermogenesis from increased energy release and higher oxygen consumption required by the stimulation of various processes. These processes include actions involved in fetal and neonatal growth, especially of the brain; glucose, amino acid, and electrolyte transport into the cell; oxidative phosphorylation; and protein, carbohydrate, and lipid metabolism. Thyroid hormone increases production of lipogenic enzymes and induces production and storage of fat in times of excess carbohydrate ingestion.

The thyroid gland converts iodine into thyroid hormone by organification. Oxidized iodine attaches to the 3 and 5 positions of tyrosine in the thyroglobulin molecules, which then couple by oxidation, forming tetraiodothyronine or T4 10 times more abundantly than T3. The hormone–thyroglobulin complex is stored as the colloid at the center of the cluster of thyroid follicle cells. To release thyroid hormone, thyroid follicular cells form pseudopodia, creating vesicles by endocytosis. These contain lysosomes that hydrolyze the thyroglobulin using hydrogen supplied by reduced glutathione, freeing thyroid hormone for release into the circulation by exocytosis. Organification is blocked by propylthiouracil and reducing substances used to treat hyperthyroidism. Release is inhibited by iodine, which affects production of glutathione reductase.

TSH from the pituitary stimulates the synthesis and release of thyroid hormone from the thyroid gland, which then exerts feedback inhibition directly on the pituitary thyrotropic cell by competing with thyrotropin-releasing hormone from the hypothalamus. After release into the circulation, thyroid hormone is bound to thyroid-binding proteins, mostly T4-binding globulin (70% to 80%), albumin, and transthyretin, to keep the hormone soluble in plasma and assist with distribution to the cells. A minute amount circulates freely in the plasma. It is this part that diffuses into the cell and is carried to the nucleus by binding proteins. Here it stimulates DNA transcription, resulting in the formation of messenger RNA and the production of various proteins. T4 binds with 10 times higher affinity to the thyroid-binding globulin, and T3 binds preferentially to intracellular sites. Therefore, most T4 is found in the circulation, and most T3 is found within the cells. The amount of free hormone can be affected by drugs that displace bound hormone (e.g., aspirin in high doses, phenytoin, carbamazepine) and severe nonthyroidal illness, which reduces the ability to bind thyroid hormone. Binding proteins are elevated by acute hepatitis, elevated estrogen (e.g., pregnancy, birth control pills, postmenopausal estrogen), or methadone and are reduced by anabolic steroids, nephrotic syndrome, or decreased production due to an inherited disorder.

Most T4 is secreted by the thyroid gland. It is functionally a prohormone but may have some metabolic activity itself. Conversion to T3, the more metabolically active form, occurs by monodeiodination in the liver, kidney, and possibly other organs, which accounts for 80% of the circulating T3. During stress or nonthyroid illness, T4 preferentially converts to inactive reverse T3 to conserve the body’s metabolism by removal of an iodide from the inner ring, instead of the outer ring as in T3. The deiodinase system is inhibited by fasting, systemic illness, kidney or liver disease, acute psychiatric illness, severe vomiting of pregnancy, and drugs (e.g., propylthiouracil, glucocorticoids, propranolol, iodine-containing agents), leading to the accumulation of reverse T3 and a fall in T3 levels. Large amounts of T4 are stored in the thyroid gland and bound in the circulation to thyroid-binding globulin, thereby prolonging the time for hormone deficiencies to manifest themselves clinically. Inflammation may cause injury to the gland with leakage of thyroglobulin, causing elevated levels of T4, T3, thyroglobulin, and other iodinated products in the serum.