Thyroid Hormone Overview and Structure

Thyroid Hormone Overview

• Thyroid hormone includes T3, T4, and rT3.
• T4 is secreted in larger quantities than T3.
• 1% of secreted thyroid hormone is rT3, which is inactive.
• T3 is more potent than T4.
• T4 is converted to T3 by a deiodinase enzyme.
• T3 binds to T3 receptors in cell nuclei.
• Calcitonin is secreted by parafollicular cells.

Thyroid Gland Structure

• C cells (parafollicular cells) secrete calcitonin.
• Thyroid epithelial cells (thyrocytes) are organized into follicles.
• Colloid is a glycoprotein.
• The thyroid secretes T3 and T4 and calcitonin.
• Thyroid follicles contain colloid.
• Follicular cells secrete thyroid hormone.
• A capsule of connective tissue surrounds the thyroid follicles.
• Capillaries are present in the connective tissue.

Thyroid Hormone Biosynthesis

• Thyroglobulin (TG) is synthesized in thyroid epithelial cells and secreted into the follicle lumen.
• Iodide (I−) is taken up from blood via a sodium-iodide symporter (iodine trap).
• Synthesis of thyroid hormones involves iodination and coupling of tyrosine residues on thyroglobulin by thyroid peroxidase.
• Thyroid epithelial cells ingest colloid, fuse with lysosomes which contain digestive enzymes, and thyroid hormones diffuse into the blood by carrier proteins like TBG (major).
• Transthyretin (minor, deliveries to the CNS); and albumin (minor)

Iodine Distribution and Turnover

• 400 µg of iodide is ingested and excreted daily.
• Daily minimum requirement: 150 µg for adults, 90-120 µg for children, and 200 µg for pregnant women.
• About 70-80 µg of iodide is taken up daily by the thyroid gland.
• The thyroid gland stores about 7500 µg of iodide in iodothyronines.
• 70–80 µg is released daily. (1% of total)

Thyroid Hormone Action (Mechanism)

• TR functions as a heterodimer with the Retinoic Acid X receptor (RXR).
• TR-RXR binds to thyroid response element (TRE) on the target gene.
• In the absence of TH, TR−RXR represses gene transcription through the recruitment of a corepressor complex.
• When TH is present, the corepressor complex is released and coactivator complexes increase histone acetylation to promote transcription.

Physiological Effects of Thyroid Hormones

• Effects on cellular differentiation and development, especially in the nervous system.
• Effects on metabolic pathways and use of carbohydrates, lipids, and proteins.
• Accelerated metabolism by increasing carbohydrate, fat, and protein turnover to provide adequate cellular energy.
• Increased oxygen consumption and generation of heat.
• Regulates basal metabolic rate and body temperature.
• Promotes growth and maturation of the central nervous system (especially essential during gestation).
• Stimulates the autonomic nervous system and catecholamine action, increasing β-adrenergic receptor numbers and cAMP production in the heart and increasing the response to catecholamine.
• Affects cardiovascular and respiratory effect by altering the expression of ryanodine channels in the sarcoplasmic reticulum to enhance Ca2+ release. Also enhances sensitivity of adrenoceptors (especially B1 receptors)

Regulation of Thyroid Hormone Secretion

• TRH (thyrotropic releasing hormone) from the hypothalamus stimulates the anterior pituitary.
• TSH (thyroid stimulating hormone) from the anterior pituitary stimulates the thyroid.
• Peripheral tissues use/metabolize T4 and T3.
• Low BMR, cold, trauma, and stress trigger TRH release, which stimulates the release of TSH and subsequently, T3/T4.
• Glucocorticoids and estrogens affect the thyroid hormone levels by regulating TRH and TSH receptors.
• Iodide uptake, peroxidase, thyroglobulin synthesis are temporarily inhibited when the serum iodine uptake is high (Wolff-Chaikoff effect).

Thyroid Disorders and Treatment

• Hyperthyroidism (overactive thyroid): Autoimmune disease (Graves Disease), benign tumor, excessive TSH production.
• Hypothyroidism (underactive thyroid): Inflammatory/Autoimmune disease (Hashimoto disease), hypothalamic/pituitary dysfunction, dietary iodine deficiency.
• Treatment of Hyperthyroidism:
  • Surgery (partial or complete removal of gland).
  • Medications: Thioureylene compounds, iodine-containing preparations, and beta-adrenergic antagonists (propranolol).
• Treatment of Hypothyroidism: L-thyroxine (T4), L-triiodothyronine (T3), or L-iothyronine, used as "replacement therapy."

MCT8 Mutations

• Males with one copy of the MCT8 gene and a deleterious mutation can have Allan-Herndon-Dudley syndrome.
• Affected males experience neurological abnormalities, failure to deliver TH to foetal brain areas, and global developmental delay.
• Affected females with one mutated copy of the gene have only mild thyroid phenotype and no neurological effect with a 50% chance of passing the mutation onto a child.