Physiology, Thyroid Function

Development

The thyroid diverticulum first forms at the end of the fourth week of development as a solid, proliferating mass of endoderm at the foramen cecum on what will become the tongue. This mass of endoderm migrates down through the developing neck via the thyroglossal duct toward its eventual home, just inferior to the cricoid cartilage. In normal development, the thyroglossal duct deteriorates by the end of the fifth week. The only remaining aspect of the thyroid’s embryonal development will be the foramen cecum at the base of the developed tongue. The isolated thyroid gland develops two distinct lobes connected by an isthmus of tissue by this time and continues to descend and reaches its final destination by the end of the seventh week of development. Cells from the ultimobranchial bodies invade the developing thyroid and form the parafollicular cells, or C cells, which will produce calcitonin. The connective tissue of the thyroid gland forms from invading neural crest cells.[1]

Organ Systems Involved

Thyroid hormone induces effects on practically all nucleated cells in the human body, generally increasing their function and metabolism.

• Cardiac output, stroke volume, and resting heart rate increase through positive chronotropic and inotropic effects. Active thyroid hormone increases myocardial intracellular calcium to increase contraction force and speed. Concomitantly, vasculature in the skin, muscle, and heart dilate, resulting in decreased peripheral vascular resistance while blood volume increases through activation of the renin-angiotensin-aldosterone system.
• Basal metabolic rate (BMR), heat production, and oxygen consumption elevate through thyroid hormone activation of mitochondrial uncoupling proteins. Glucose and fatty acid uptake and oxidation also increase, which results in increased thermogenesis and necessitates increased heat dissipation. Heat intolerance in hyperthyroidism is attributable to this increase in thermogenesis. Compensation for increased thermogenesis is also mediated by thyroid hormone through increases in blood flow, sweating, and ventilation.
• Resting respiratory rate and minute ventilation undergo stimulation by active thyroid hormone, triiodothyronine (T3), to normalize arterial oxygen concentration in compensation for increased rates of oxidation. T3 also promotes oxygen delivery to the tissues by stimulating erythropoietin and hemoglobin production and promoting folate and cobalamin absorption through the gastrointestinal tract.
• T3 is responsible for the development of fetal growth centers and linear bone growth, endochondral ossification, and epiphyseal bone center maturation following birth. Additionally, T3 simulates adult bone remodeling and degradation of mucopolysaccharides and fibronectin in extracellular connective tissue.
• T3 stimulates the nervous system, resulting in increased wakefulness, alertness, and responsiveness to external stimuli. Thyroid hormone also stimulates the peripheral nervous system, resulting in increased peripheral reflexes and gastrointestinal tone, and motility.
• Thyroid hormone also plays a role in reproductive health and other endocrine organ function. It allows for the regulation of normal reproductive function in both men and women by regulating both the ovulatory cycle and spermatogenesis. Thyroid hormone also regulates pituitary function; growth hormone production and release are stimulated by thyroid hormone while inhibiting prolactin production and release. Additionally, renal clearance of many substances, including some medications, can be increased due to activated thyroid hormone stimulation of renal blood flow and glomerular filtration rate.[2][3]

Function

T3 is responsible for affecting many organs and tissues throughout the body, which can, in summary, be 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]

Mechanism

The thyroid gland is responsible for the production of iodothyronines, of which there are three. The primary secretory product is inactive thyroxine, or T4, 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. 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]

Related Testing

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]

Pathophysiology

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 loss, anxiety, hyperreflexia, and diarrhea, as well as palpitations. Increased stimulation of basal metabolic rate, thermogenesis, resting heart rate, 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]

Clinical Significance

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]