T3 and T4 are thyroid hormones. In the bloodstream, most of it is reversibly bound to thyroid-binding globulin or TBG. Only free TH is physiologically active. An increase in TBG may result in an increase in total T4 and T3 without an increase in hormone activity in the body. Increased TBG levels may be due to hypothyroidism, liver disease, estrogens, and pregnancy. Decreased TBG levels may be due to hyperthyroidism, testosterone, renal disease, liver disease, severe systemic illness, Cushing syndrome, medications, and malnutrition.
Synthesis of TH: Most dietary iodine is reduced to iodide before absorption throughout the gut, principally in the small intestine. The normal thyroid can maintain a concentration of free iodide 20 to 50 times higher than that of plasma. The thyroid actively concentrates the iodide across the basolateral plasma membrane of thyrocytes by the sodium/iodide symporter or NIS, which uses Na±dependent active transport. NIS expression is increased in Grave’s disease and hyperactive nodules and decreased in adenomas and carcinomas. Intracellular iodide is then transported into the lumen of thyroid follicles by pendrin and anoctamin, a calcium-activated Cl- channel.
The thyrocyte endoplasmic reticulum synthesizes two key proteins, topoisomerase or TPO or microsomal antigen, and thyroglobulin or Tg. Tg is a 660kDa glycoprotein secreted into the lumen of follicles, whose tyrosyl residues serve as substrates for iodination and hormone formation. TPO oxidizes iodide in the presence of H2O2 and attaches the iodide to tyrosyls in Tg. It is present at the apical plasma membrane. TPO enzyme activity is dependent on the association with a heme, ferriprotoporphyrin IX. Initial iodination of Tg produces MIT and DIT. Further iodination couples two residues of DIT to produce T4. When thyroid hormone is needed, Tg is internalized at the apical pole of thyrocytes, conveyed to endosomes and lysosomes, and digested by proteases, particularly the endopeptidases like cathepsins and exopeptidases. After Tg digestion, T4 and T3 are released into the circulation. Iodine is recycled within the thyroid gland.
In the presence of excessive iodine, thyroid hormone synthesis is impaired. This is called the Wolff-Chaikoff effect. It has been postulated that iodination of lipids, due to excess iodine, impairs H2O2 production and therefore decreases further Tg iodination. On the other hand, excess iodine can cause hyperthyroidism, especially in endemic goitre patients treated with iodine. This phenomenon is called Jod-Basedow phenomenon.
Regulation: The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH. TRH, secreted from the hypothalamus, acts upon the pituitary gland, binding to G protein-coupled TRH receptors on the thyrotrope, resulting in an increase in intracellular cAMP and subsequent thyrotropin (TSH) release. TSH binds to a G protein-coupled TSH receptor on the thyroid follicular cell, stimulating the production and release of TH (thyroid hormone). T4, a prohormone, is the primary secretory product of the thyroid gland. TSH is the stimulator that affects virtually every stage of thyroid hormone synthesis and release. TSH stimulates the expression of NIS, TPO, Tg, and the generation of H2O2 and increases the formation of T3 relative to T4. TSH promotes the growth of the thyroid gland. The effects of TSH on secretion appear to be mediated through the cAMP cascade while the effects on synthesis are mediated by the Gq/phospholipase C cascade. TSH secretion, and its sensitivity to TRH stimulation, is affected by renal failure, starvation, sleep deprivation, depression, and hormones, including cortisol, growth hormone, and sex steroids.
T4 is converted to metabolically active T3 by the enzyme deiodinase. Three types of deiodinases are present - D1, D2, and D3. D1 and D2 convert T4 to its bioactive form, T3, and degrade metabolically inactive rT3 (reverse T3). D3 degrades T4 to rT3 and T3 to T2. Local conversion of T4 to T3 by deiodinase 2 or D2 provides negative feedback at the level of both thyrotrophs in the pituitary and tanycytes in the hypothalamus. This results in a reduction in TRH and TSH secretion in response to adequate tissue levels of TH. Deiodinase requires selenium for catalytic activity.
Thyrotoxic patients have normal plasma norepinephrine (NE) levels, while hypothyroid patients have elevated plasma NE levels, perhaps to compensate for reduced adrenergic sensitivity. Follicular cells of the thyroid gland are also innervated by sympathetic fibers containing NE, which can influence the mitotic response to TSH stimulation. Catecholamines increase T4 to T3 conversion, by stimulating activity of a specific deubiquitinase that acts on the D2 protein, upregulates D2 activity, and increases T3 levels in the nucleus. Humans who are anorexic or undergo severe caloric restriction exhibit reductions in TH levels, which likely functions to protect energy stores.
Thyroid hormone effects on metabolism: TH action is exerted primarily via the nuclear thyroid receptor or TR. The structure of TR includes a zinc finger motif DNA binding domain and a COOH-terminal domain that mediates ligand interactions as well as the binding of coactivators and corepressors. TR forms a heterodimer complex with retinoid X receptor or RXR, which binds to a thyroid response element (TRE), stimulating or inhibiting gene transcription. The intracellular action of TH is regulated by the amount of local T3 available for receptor binding.
Nongenomic mechanisms have been identified through which TH regulates growth, development, and metabolism via phosphorylation and activation of kinase pathways and neural proteins by interacting with integrins and mTOR, p70, etc. TR is present in distinct isoforms in tissues. TRβ is the predominant TR isoform expressed in the liver and cardiac ventricles. TRα1 is preferentially expressed in brain and white adipose tissue and the atria, while BAT contains both TR α and β. TR β2 is predominantly expressed in the brain and pituitary.
TH regulates cholesterol and carbohydrate metabolism through direct actions on gene expression and cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH stimulates transcription of the LDL-R gene resulting in increased uptake of cholesterol and enhanced cholesterol synthesis. TH also induces SREBP-2 gene expression that, in turn, modulates LDL-R expression.
TH opposes the action of insulin and stimulates hepatic gluconeogenesis and glycogenolysis. It up-regulates the expression of genes such as GLUT -4 and phosphoglycerate kinase, which are involved in glucose transport and glycolysis, respectively. TH stimulates BMR by increasing ATP production for metabolic processes and generating and maintaining ion gradients. The two ion gradients that TH stimulates, either directly or indirectly, are the Na+/K+ gradient across the cell membrane and the Ca2+ gradient between the cytoplasm and sarcoplasmic reticulum. TH increases the amount and activity of ryanodine receptors in the heart and skeletal muscle.
Nonalcoholic fatty liver disease (NAFLD) is related to insulin resistance and is seen in both clinical and subclinical hypothyroidism and shows a direct correlation with the TSH level. Impaired TH signalling is seen in NAFLD.
