Thyroid Hormones: Biosynthesis and Metabolism

Biosynthesis and Metabolism of Thyroid Hormones

• The aim is focused on the biosynthesis of thyroid hormones and iodine metabolism; along with TSH, TRH.
• Focus also include, effects of thyroid hormones, basic clinical conditions and their laboratory diagnosis.

Thyroid Gland

• The thyroid gland is the largest endocrine organ
• It is involved in the production, storage, and thyroid hormone release.
• The thyroid Hormone function is influenced by several factors, including central axis (TRH), pituitary function (TSH), comorbid diseases (Cirrhosis, Graves, etc.), and environmental factors (iodine intake).

Thyroid Structure & Function

• Glandular tissue is composed of spherical follicles lined with cuboidal epithelial cells which are known as follicular epithelium.
• Lumen of each follicle is filled with a colloidal secretory material also known as colloid.
• Parafollicular cells (C cells) can be found on the outside of some follicles.
• Follicles constitute the main location where key thyroid elements like thyroglobulin (Tg), tyrosine, iodine, thyroxine (T4,) and triiodotyronine (T3) function.

Thyroid Hormones

• The main thyroid hormones include triiodothyronine (T3), thyroxine (T4, also known as tetraiodothyronine), and calcitonin.
• T3 and T4 contain iodine

Biosynthesis of T4 and T3

• The biosynthesis of T4 and T3 involves dietary iodine (I) ingestion.
• Active transport and uptake of iodide (I-) occurs by the thyroid gland.
• Oxidation of I- and iodination involves thyroglobulin (Tg) tyrosine residues.
• Coupling of iodotyrosine residues (MIT and DIT) forms T4 and T3.
• Proteolysis of Tg releases T4 and T3 into the circulation.

Iodine Sources

• Iodine is available through foods like seafood, bread, dairy products, and iodized salt or dietary supplements (trace mineral).
• The recommended minimum iodine intake is 150 µg/day.

Active Transport and Iodide Uptake by Thyroid

• Dietary iodine reaches the circulation as iodide anion (I-) at a concentration of 0.2-0.4 µg/dL.
• Active transport of iodide from the follicle cell is mediated by an iodide pump, where the concentration outside is 25 times lower than inside.
• Iodide accumulation is an active transport process stimulated by TSH.
• The thyroid gland transports I- to the sites of synthesis.

Sodium-Iodide Symporter (NIS)

• NIS mediates active iodide uptake, acting as a I- concentrating mechanism that enables it to enter the thyroid for hormone biosynthesis.
• Adequate dietary iodide accumulates in follicles through a specialized system that allows for T4 and T3 biosynthesis, due to basal cell membranes of thyroid follicular cells "iodide trapping".
• The Na+/I- symport protein controls serum I- uptake and is stimulated by TSH and inhibited by Perchlorate. Based on Na+/K+ antiport potential

Iodination and Oxidation

• Iodide must be oxidized to iodinate tyrosyl residues of Tg; reactions catalyzed by TPO.
• Iodination of tyrosyl residues forms monoiodotyrosine (MIT) and diiodotyrosine (DIT), then coupled to form T3 or T4.

MIT/DIT Information

• Thyroid Peroxidase (TPO) acts as an apical membrane protein which catalyses iodine organification to tyrosine residues of Thyroglobulin.
• TPO is antagonized by methimazole and PTU.
• Iodine then gets coupled to Thyroglobulin such as Monoiodotyrosine (Tg + one I-) & Diiodotyrosine (Tg + two I-).

Thyroperoxidase (TPO)

• TPO catalyzes oxidation steps in I- activation, iodination of Tg tyrosyl residues, and iodotyrosyl residue coupling.
• It also uses H2O2 to activate I- to hypoiodate (OI-), which acts as the iodinating species, and it has binding sites for I- and tyrosine.

Synthesis of T3 and T4

• Amine hormones synthesized from tyrosine: I + tyrosine produces monoiodotyrosine (MIT), MIT + I produces diiodotyrosine (DIT), DIT + DIT produces thyroxine (T4), and DIT + MIT produces triiodothyronine (T3).
• The hormones are still attached to thyroglobulin.

T4 from DIT

• During normal conditions, 70% of tyrosine residues of thyroglobulin include the form MIT and DIT.
• 30% include being thyroxine (T4), and a minor part of T3.

Proteolysis

• T4 and T3 are synthesized and stored within the Tg molecule.
• Tg, used to liberate T4 and T3, is resorbed into follicular cells as colloid droplets, fusing with lysosomes to form endolysosomes.
• Tg is hydrolyzed to T4 and T3, which are then secreted into circulation.

Secretion of Thyroid Hormones

• 70% of iodine bound by thyroglobulin is in the form MIT and DIT, after liberation from thyroglobulin, these compounds are deionidated by enzyme deionidase and tyrosine, then iodide is returned for further use.
• Secretion of Thyroid Hormone is stimulated by TSH; Coupling of MIT & DIT residues, then finally being released.
• TPO catalysis, MIT + DIT = T3, and DIT + DIT = T4
• Is then followed by endocytosis of colloid on the apical membrane, Hydrolysis of Thyroglobulin, then Release of T3 and T4 (which is now inhibited by Lithium)

Thyroid Hormones production

• The thyroid gland can produce approximately 70-90 µg of T4 per day.
• Two factors are required for homeostasis of all cells: cell differentiation & growth, and proper metabolism.
• It produces and secretes metabolic hormones (considered the major metabolic hormones), by targeting every tissue
• T3 is derived from 2 processes: the total daily production rate of T3 is about 15-30 µg, and about 80% stems from T4 deiodination in peripheral tissues, with 20% from direct thyroid secretion.

Thyroid Hormone Type

• Majority of circulating hormone is T4: 98.5% T4 and 1.5% T3.
• Total Hormone load is influenced by serum binding proteins such as: Thyroid Binding Globulin, Albumin, Transthyretin (TBP), and others.
• Regulation relies on the free component of the hormones.
• 4.5-11 µg/dL for T4.
• 60-180 ng/dL for T3.
• Circulating T4 and T3 are bound to plasma carrier proteins in high percentages: Thyroxine-binding globulin (TBG), binds about 75%, Transthyretin (TTR) binds about 10%-15%, Albumin binds about 7%, High-density lipoproteins (HDL), binds about 3%

Thyroid Hormone Functions

• Thyroid Hormones regulates the basal metabolic rate; Improves cardiac contractility; Increases the gain of catecholamines; Increases bowel motility; Increases speed of muscle contraction; Decreases cholesterol and Required for proper fetal neural growth

T4 as a prohormone

• Activation occurs with 5' deiodination of the outer ring of T4
• T4 Is is biologically inactive in target tissues until concerted to T3 (Which then become biologically active hormone responsible for the majority of thyroid hormone effects)
• Until T4 is deiodinated, it has no physiological effect because it does not enter the target nucleus at high enough concentrations to bind to the required thyroid receptors.

Deiodination

• Type I (D1), type II (D2), type III (D3) are identified as three 5'-deiodinase isoenzymes.
• Deiodinases modulate the thyroid status of the tissues depending on the iodine or thyroid hormone deficiency, or hormone excess.
• D1 and D2 activates T4 to T3 in target tissues.
• D3 and D1 inactivates T4 and T3 in the brain, skin, and placenta.
• Hormone inactivation occurs by removal of a single removed iodine (called 5 deiodination), and produces metabolically inactive reverse T3 (rT3).

T4 Conversion

• The major extrathyroidal T4 conversion site for production of T3 is The liver
• Some T4 to T3 conversion occurs in the kidneys and other tissues.
• Free hormone has a very tiny percentage of total hormone in plasma (about 0.03% T4; 0.3% T3).
• This is is is important that the total hormone concentration is Kept proportional to the carrier proteins & concentration
• Changes in TBG concentration will determine the influence T4 and T3 leve

TBG

• Increased TBG increases total serum T4 and T3 levels.
• This Increased TBG causes Free T4 (FT4), and free T3 (FT3) concentrations to remain unchanged
• Decreased TBG will cause Total serum T4 and T3 levels decrease & FT4 and FT3 levels to remains unchanged to some extent

Influence of Drugs with TBG

• Drugs that increase TBG include oral contraceptives or any other sources of estrogen; Some examples include: Methadone, Clofibrate, 5-Fluorouracil, Heroin & Tamoxifen
• Drug Use can cause conditions that increase TBG: Pregnancy, Infectious/chronic active hepatitis, HIV infection, Biliary cirrhosis, Acute intermittent porphyria & Genetic factors
• Drugs that decrease serum T4 and T3 will include: Glucocorticoids, Androgens, L-Asparaginase, Salicylates, Antiseizure medications for example: phenytoin, carbamazepine, and Furosemide
• If the drug use is chronic Conditions that decrease serum T4 and T3 include: Genetic factors,Acute and chronic illness

Metabolism

• It increases the gene expression of Na+/K+ ATPase in different tissues which leads to increased oxygen consumption, respiration rate, and body temperature.
• If Depending on the metabolic status, it can induce lipolysis or lipid synthesis.
• Thyroid hormones will stimulate the metabolism of carbohydrates and anabolism of proteins also.
• Higher doses of these hormones will increase thyroid hormone-mediated protein catabolism.

Metabolic Effects of T3

• Stimulates lipolysis and release of free fatty acids and glycerol
• Induces expression of lipogenic enzymes
• Effects cholesterol metabolism & Stimulates metabolism of cholesterol to bile acids
• Facilitates rapid removal of LDL from plasma
• Generally, stimulates all aspects of carbohydrate metabolism and the pathway for protein degradation

CH Metabolism

• Thyroid hormones do not change the blood glucose level; they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis and glucose oxidation.
• 41% can be converted to T3; 38% converts to reverse T3 (rT3)- which is metabolically inactive.

Mechanism of thyroid hormone action

• Receptors for thyroid hormones are nuclear and its affinity is ten times higher for T3 than T4
• The number of nuclear receptors is very low
• Four variants of nuclear receptor were observed and mitochondrial receptor for T3 was also described
• Free thyroid hormone receptor (TR) without bound hormone is bound to hormone response element of DNA (HRE) and corepressor (CoR)
• After binding T3 to receptor - CoR is liberated, and coactivators (CoA) is bound and the transcription to mRNA begins

Actions of thyroid hormones

• Hormone actions will will start through gene expression to produce: glycerol 3-phosphate dehydrogenase, component of glycerol 3-phosphate shuttle in mitochondria ; Cytochrome c oxidase, complex mitochondrial enzyme in the electron transport chain (from cytochrome c to oxygen) ; ATPases & Carbamyl phosphate synthase also occur depending on environmental factors.

Hyperthyrodism

• Increased synthesis of ATP, due to increases cytochrome c oxidase & oxidative phosphorylation with a higher increased consumption of oxygen.
• A higher ATP production will mean an increase of ATPAse & depletion of the store of ATP
• It also Increases oxygen consumption by most peripheral tissues and increase body heat production

Hypothalamic-Pituitary-Thyroid Axis

• A small increase in T3 and T4 produces a diminishing thyroid-stimulating hormone (TSH) response to TRH at the pituitary level.
• T3 and T4 act at the hypothalamic level by inhibiting messenger RNA (mRNA) for TRH synthesis.
• The hypothalamopituitary axis is regulated by neural influences which effect dopamine, that physiologically will inhibit TSH secretion while also effecting glucocorticoids that reduces pituitary response, and the sensitivity of throtrophs to TRH
• The hormone pathway works by T3 and T4 down regulating through portal venous system to cavernous sinus & body
• Downregulated also by somatostatin
• Positive feedback loop stimulates the pituitary gland & Thyroid Gland

Additional Hormone Release Release

• A decrease in temperature initiates hypothalamic thermoregulatory center to increase release of TRH while an increase will have the reverse effect

TSH

• Thyroid stimulating hormone (TSH acts as glycoprotein, & is produced by adenohypophysis thyrotrophs.
• Is the body's major regulator for the external thyroid and contains binding receptors where the follicular cell basal surface. Travels through portal venous system to cavernous sinus, body.
• It is important that TSH consists of an alpha and a beta subunit & CHO side chains as well as an adequate TRH with a normal T3 value for stability and biological activity

Thyroid Hormone and Influences in detail

• Initiates or sustains differentiation/growth & essential for childhood growth
• Patients that have hypothyroidism may experience: impairment of attention, slowed motor function & memory
• Stimulates respiratory pathway and leads to O2 stimulation: Increase heart stroke volume, beta sensitivity, cardiac output & blood rate
• Causes increased contraction on Fast twitch Fibers

Effects of Thyroid Hormone Deficiencies on Tissue and Systems

• Can cause neural development & decreased maturation, as well as CNS issues
• Decrease in thyroid hormone concentrations alter cognitive function and cause impaired memory/slow actions/poor cognitive skills, which is resolved by hormone replacement therapy.
• Deficient TH in female repdrouctive system: menstrual issues, higher risk of miscarriage and infertility
• Deficient TH in bone growth: skeletal maturation and issues in growth plate

Thyroid Hormones and the Central Nervous System (CNS)

• Thyroid hormones are needed for neural development & CNS function.
• Decreased thyroid hormone concentrations will alter cognitive function.
• A patient displaying hypothyroidism may develop memory impairment, slowed-down motor function, and suffer poor memory, making thyroid-replacement therapy vital for adequate cognitive function.

The different Hyper and Hypothyroidism.

• Hyperthyroidism symptoms include: palpitations, tremors, lids retraction, and heat intolerance. Diagnosis: Examine the serum levels: * TSH. * Free T4, also known as FTS4, * Free T3, also known as FTS3

• In Grave's disease you are most likely to also see exophthalmos and goiter) - In low TSH, normal/high FT4, anti-TSH antibodies can be observed

• When a patient display: palpatations, nervousness, and fatigue, - and no clinical findings are found it is vital that 1123(radioactive iodine) is used to detect abnormalities if not found

• Hypothyroidism diagnosis: fatigue, coldness & hair loss

• Signs can include: Face, hands, body dryness, slow function and reflexes

• In newborns one will observe issues in: Growth Stature & Defness

• High TSH & low T4 present : (Anti TPO) & (Anti TG) - most likely in Hashimoto's

• Can induce endemic goiter, subacute thyroiditis is present but in rare cases causes from Familial hormone synthesis and Genetic abnormalities*

Hashimotos

• Hashimotos occurs most likely in females 30-50 yrs.
• Displays an abnormal amount of antibiotics with: thyroid Ab.
• Most likely with be non-tender & asymptomatic, High TSH and low T4 value will be observed

Goiter

• There is an increased neck because of the amount if thyroid present, (Thyroid hyperprothy).
• Display hypo- and hyperthyroidism which results in cretinism.