Physiology, Thyroid Function

T3 is responsible for affecting many organs and tissues throughout the body, which can, in summary, is the effect of increasing metabolic rate and protein synthesis. Parafollicular cells, or C cells, are responsible for the production and secretion of calcitonin. Calcitonin opposes parathyroid hormone to decrease blood calcium levels and maintain calcium homeostasis.[4][5]

The thyroid gland is responsible for the production of iodothyronines, of which there are three. The primary secretory product is inactive thyroxine, or T4, which is a prohormone of triiodothyronine, or T3. T4 is converted to T3 peripherally by type 1 deiodinase in tissues with high blood flow, such as the liver and kidneys. In the brain, T4 is converted to active T3 by type 2 deiodinase produced by glial cells. The third iodothyronine is called reverse T3, or rT3. rT3 is inactive and forms by type 3 deiodinase activity on T4.

These iodothyronines are composed of thyroglobulin and iodine. Thyroglobulin is formed from amino acids in a basal to apical fashion within the thyroid cells themselves. Thyroglobulin is then secreted into the follicular lumen, where it is enzymatically combined with iodine to form iodinated thyroglobulin. Endosomes containing this iodinated thyroglobulin then fuse with lysosomes, which enzymatically release the thyroglobulin from the resultant thyroid hormone. The thyroid hormones are next released from the cell while the remaining thyroglobulin is deiodinated and recycled for further use.[6][7][8]

When testing for thyroid function, most clinicians rely on serum thyroid-stimulating hormone (TSH) and serum free T4. Thyroid-stimulating hormone is responsible for the stimulation of the thyroid to produce more iodothyronines. Therefore, levels inversely correlate with active thyroid hormone concentrations; as T3 increases, TSH decreases, and vice versa. Free levels of thyroxine are measured in the serum rather than total T4 levels, which would include protein-bound T4, which is not available to enter tissues. Free T4, on the other hand, can be a proxy for serum T3 levels. Most often, thyroxine levels are the last to become abnormal in thyroid disorders as the upstream products, TSH and T4, maintain available T3 at their own expense.[9]

Hypothyroidism is an endocrine disorder with resultant under-production of thyroid hormone. Common symptoms of hypothyroidism include cold intolerance and weight gain due to decreased basal metabolic rate and thermogenesis, depression, fatigue, decreased peripheral reflexes, and constipation, due to decreased stimulation of the central and peripheral nervous system. Many other consequences of hypothyroidism can manifest secondary to the lack of activated thyroid hormone on various tissues and organs of the body.[10]

Hyperthyroidism is an endocrine disorder with excess thyroid hormone production. In contrast to hypothyroidism, hyperthyroidism often causes heat intolerance, weight gain, anxiety, hyperreflexia, and diarrhea, as well as palpitations. Increased stimulation of basal metabolic rate, thermogenesis, resting heart rate, and cardiac output, and central and peripheral nervous systems result in the most common symptoms. However, a multitude of symptoms can present, including brittle hair, dry skin, and pretibial myxedema.[11] In Graves disease, an autoimmune condition where the TSH-receptor becomes activated by an auto-antibody, additional pathophysiology of orbitopathy can be present. The TSH-receptor antibody also activates T cells and causes fibroblast proliferation and accumulation of glycosaminoglycans in the extraocular muscles and retroocular connective tissue leading to proptosis. Hashimoto thyroiditis is a primary cause of hypothyroidism, which is associated with HLA-DR5. The presence of anti-thyroglobulin and thyroid peroxidase antibodies suggest Hashimoto thyroiditis.[12]

Proper thyroid function is necessary for the proper development of the growing brain throughout embryologic development. Both iodine deficiency and congenital hypothyroidism, due to absence, malpositioning, underdevelopment, or failure to make thyroid hormones, can cause fetal hypothyroidism. Hypothyroidism during embryologic development may result in intellectual disability, dwarfism, deafness, and muscle hypertonia.

If a portion of the thyroglossal duct fails to obliterate during the fifth week of development, an enclosed thyroglossal cyst or a thyroglossal sinus, which opens to the skin, may form. Alternatively, a portion of the developing thyroid gland may detach at any point along its descent, forming hormone-producing ectopic thyroid tissue. Most commonly, this occurs at the superior pole of the thyroid gland, forming the pyramidal lobe, which may be considered a normal anatomic variant and is present in up to half of adults.[13][14][15]