Thyroid Hormones: Biosynthesis and Metabolism

Biosynthesis and Metabolism of Thyroid Hormones

• Aims include the biosynthesis of thyroid hormones and iodine metabolism
• Regulation of thyroid hormone creation, TSH, receptor of TSH, TRH
• Understanding effects of thyroid hormones
• Basic clinical conditions of thyroid, and lab diagnosis

Thyroid Gland

• The largest endocrine organ in the body
• Production, storage, and release of thyroid hormone are key functions
• Influenced by central axis (TRH), pituitary function (TSH), comorbid diseases, and environmental factors (iodine intake)

Structure of the Thyroid

• Glandular tissue comprises spherical follicles lined with cuboidal epithelial cells
• The follicle lumen contains colloidal secretory material
• Parafollicular cells (C cells) exist on the surface of some follicles

Follicle Function

• Follicles are the sites where key thyroid elements function
• Functions of: Thyroglobulin (Tg), Tyrosine, Iodine, Thyroxine (T4), and Triiodothyronine (T3)

Thyroid Hormones

• Three main hormones produced are triiodothyronine (T3), thyroxine (T4, tetraiodothyronine), and calcitonin.
• T3 and T4 both contain iodine.

Biosynthesis of T4 and T3

• The process involves dietary iodine ingestion and active iodide uptake by the thyroid gland
• Oxidation of I- and iodination of thyroglobulin (Tg) tyrosine residues are required
• Coupling of iodotyrosine residues (MIT and DIT) occurs to form T4 and T3
• Proteolysis of Tg subsequently releases T4 and T3 into circulation

Iodine Sources

• Sources include seafood, bread, dairy, iodized salt and dietary supplements, as a trace mineral
• The recommended minimum intake is 150 µg/day

Active Transport and Uptake

• Dietary iodine reaches circulation as iodide anion (I-) at 0.2-0.4 µg/dL
• The thyroid gland transports I- to hormone synthesis sites
• I- accumulation is an active transport stimulated by TSH
• Active transport of iodide into the follicle cell is concentration gradient mediated-iodide pump

Sodium-Iodide Symporter (NIS)

• NIS is a membrane protein aiding active iodide uptake in the thyroid
• It operates as an I- concentrating mechanism for thyroid hormone biosynthesis
• NIS enables "iodide trapping" via active transport on thyroid follicular cell membranes
• The system ensures adequate iodide accumulation in follicles for T4 and T3 biosynthesis

Iodine Uptake Control

• Na+/I- symport protein regulates serum I- uptake
• Uptake relies on Na+/K+ antiport potential
• Process is TSH-stimulated, and perchlorate-inhibited

Oxidation and Iodination

• I- must be oxidized to iodinate tyrosyl residues of Tg
• Iodination of tyrosyl residues yields monoiodotyrosine (MIT) and diiodotyrosine (DIT), then either T3 or T4 forms
• Both reactions are catalyzed by TPO

MIT/DIT Formation

• Thyroid Peroxidase (TPO) is an apical membrane protein
• Catalyses iodine organification to tyrosine residues of Thyroglobulin
• Methimazole, PTU antagonize this process
• Iodine binds to thyroglobulin to form Monoiodotyrosine (Tg + one I-) and Diiodotyrosine (Tg + two I-)

Formation of T3 and T4

• Amine hormones are synthesized from the amino acid tyrosine
• I + tyrosine yields monoiodotyrosine (MIT)
• MIT + I yields diiodotyrosine (DIT)
• DIT + DIT yields thyroxine (T4)
• DIT + MIT yields triiodothyronine (T3)
• Hormones remain attached to thyroglobulin

T4 from DIT

• Under normal conditions, 70% of thyroglobulin tyrosine residues are in the form MIT and DIT
• 30% are in the form of thyroxine (T4)
• A minor part is T3

T4 and T3 Release

• T4 and T3 are synthesized and stored within the Tg molecule
• Proteolysis is essential for hormone release
• To liberate T4 and T3, Tg is resorbed into follicular cells as colloid droplets
• Colloid droplets fuse with lysosomes to form endolysosomes
• Tg hydrolyzes to T4 and T3, then secreted into the circulation

Secretion Regulation

• TSH stimulates secretion
• Coupling of MIT & DIT residues is catalyzed by TPO
• MIT + DIT = T3; DIT + DIT = T4
• Colloid endocytosis and thyroglobulin hydrolysis occur
• T3 and T4 are released; lithium inhibits release

Thyroid Hormone Production

• Two principal hormones produced are Thyroxine (T4) and triiodothyronine (T3)
• Essential for homeostasis and influence cell differentiation, growth, and metabolism
• Major metabolic hormones: target every tissue

Thyroid Hormone Characteristics

• T4 is the majority of circulating hormone
• 98.5% T4, while 1.5% is T3
• Total hormone load is influenced by serum binding proteins like Thyroid Binding Globulin, Albumin, and Transthyretin (TBP)
• Regulation relies on the free component of thyroid hormone

Thyroid Hormone Actions

• Regulates basal metabolic rate and improves cardiac contractility
• Increases gain of catecholamines and bowel motility
• Increases the speed of muscle contraction and decrease cholesterol (LDL)
• Required for proper fetal neural growth

TRH Function

• TRH, or Thyrotropin Releasing Hormone, is made by cell bodies in the periventricular nucleus (PVN) of the hypothalamus
• Release is pulsatile and circadian regulated
• T4 and T3 downregulate TRH
• This travels through portal venous system to adenohypophysis to stimulate TSH formation

TSH Function

• Stimulates the adenohypophysis thyrotrophs
• TRH upregulates TSH
• T4 and T3 downregulate TSH
• Moves via portal venous system to the cavernous sinus and body
• Stimulates Iodine uptake, organification, hormone synthesis and release, colloid endocytosis, and growth of thyroid gland

TSH as a Regulator

• A glycoprotein hormone (15% carbohydrate)
• It is the major external regulator of the thyroid gland
• Binds to TSH receptors on the basal surface of thyroid follicular cells
• It stimulates all phases of iodine metabolism
• Increases synthesis of fresh thyroid hormones to increase release within 1 hour

Hypothalamic-Pituitary-Thyroid Axis

• TRH, TSH, T3, and T4 form a negative feedback loop
• Small increases in T3 and T4 diminish the TSH response to TRH at the pituitary
• T3 and T4 inhibit mRNA for TRH synthesis at the hypothalamic level
• Only unbound fractions of hormone are metabolically active and have an inhibitory effect on the thyroid's secretory activity

TSH Subunits

• Alpha and beta generated in the thyrotrophs are regulated positively by TRH and negatively by T3
• CHO side chains on the TSH molecule determine its stability and biological activity

Low T3 or T4 Effects

• TSH subunit synthesis increases alongside thyrotroph hypertrophy
• It can cause tumor formation; cells desensitize to high T3 or T4
• Uncontrolled TSH release and thyroid enlargement and overactivity occut

High T3 or T4 Effects

• Decreased TSH subunit synthesis
• Inactive thyrotrophs may lose the capacity to respond to reduced T3 or T4 levels

Hypothalamopituitary Axis

• Dopamine physiologically inhibits TSH secretion
• Glucocorticoids dull the pituitary response to TRH
• Estrogens heighten thyrotroph's sensitivity to TRH

Additional Release

• Lowered temperature prompts the hypothalamus to increase TRH release at the hypothalamic thermoregulatory center
• Increases in temp have the reverse effect

Thyroid Hormone transport

• Carrier proteins are used to help transport hydrophobic hormones through the blood
• Thyroxine binding globulin (TBG) is the main transporter affinity is 10x higher for T4 than T3
• During this period, T4 is deionidated to T3 which is tentimes more metabolically active

Binding of Hormones

• Approximately 99.98% of T4 is bound to 3 serum proteins
• Only ~0.03% of the total T4 in blood is unbound, or free
• Only ~0.3% of total T3 in blood is free

Carriers for Transport

• More than 99% of circulating T4 and T3 is bound to plasma carrier proteins
• TBG binds about 75%
• Transthyretin (TTR), also called thyroxine-binding prealbumin (TBPA) amounts to 10-15%
• Albumin binds to about 7%
• HDL bind is about 3%
• Carrier proteins are also susceptible to physiologic changes, drugs, and disease

Hormone availability

• Only unbound (free) hormone has metabolic & physiologic effects
• Free hormone forms a tiny percentage of total hormone in plasma (About 0.0% T4; 0.3% T3)
• Total hormone concentration is generally proportionate to the concentration of carrier proteins
• Levels are kept appropriate to maintain a constant free hormone level

TBG influence.

• With Increased TBG, total serum T4 and T3 levels increase
• Free T4 (FT4), and free T3 (FT3) concentrations remain unchanged
• With Decreased TBG, Total serum T4 and T3 levels decrease
• However, FT4 and FT3 levels remain unchanged

Increased TBG

• Drugs like oral contraceptives and methadone can increase TBG
• Conditions include pregnancy, Biliary cirrhosis and Infectious/chronic active hepatitis can

Decreased TBG

• Drugs like glucocorticoids, Androgens and Salicylates can Decrease TBG
• Conditions that decrease Genetic factors and Acute and chronic illness can

Production Factors

• T4 is the primary secretion, and the thyroid is the only source
• 70–90 µg of T4 are secreted per day
• T3 comes from 2 processes: -15-30 µg in daily production.
  • About 80% comes from the deiodination of T4in peripheral tissues -About 20% from direct thyroid secretion

T4 as a Prohormone

• T4 is biologically inactive until converted to T3
• Activation occurs with 5' deiodination of the outer ring of T4
• T3 becomes biologically active, causing most thyroid hormone effects

Deiodination

• T4 must be deiodinated in order to have any effect
• There are three 5' deiodinase isoenzymes which have been identified: type I (D1), type II (D2), type III (D3).
• They regulate the thyroid status in reaction to iodine.

Deiodination

• D1 and D2 are responsible for the greater portion of the activation of T4 to T3 in target tissues
• D3 and D1 inactivate T4 and T3 in the brain, skin, and placenta.
• Hormone deactivation occurs by iodine removal of the inner tyrosyl ring
• The results produces metabolically inactive reverse T3(rT3).

T4 Conversion

• The Liver is a major site for conversion for the production of T3.
• It also occurs in the Kidney or other tissues at a smaller rate.

T4 Disposition

• About 41% is converted to T3
• 38% is converted to metabolically inactive reverse T3
• 21% is metabolized into other pathways

Other facts

• • T₄ = 4.5-11 µg/dL, and T₃ = 60-180 ng/dL
• FT4 = 0.8-2.8 ng/dL and FT3 = 260-480 pg/dL

Hormone Degradation

• T4 converts to T3 which is active through 5' deiodinase
• T4 converts T3 to rT3 which is inactive by 5 deiodinase
• 3 is converted to rT2 by 5 deiodinase
• rT3 is inactive, but is detectable by serum tests.

Mechanism Actions

• Receptors are nuclear and its are affinity is ten times higher for T3
• The number of nuclear receptors is very low.
• Mitochondrial Receptor for 3 was also described.
• Free Thyroid hormones are bound to hormone response Element with in the CORE
• TR is also known as a CORE repressor.

Gene Protein Expression:

• Glycerol 3-phosphate dehydrogenase: Main component of Gly shuttle from Mitochondria -Cytochrome C Oxidase complex -Mitochondrial Enzyme -ATPases -Ca+ ATpase: Ca+ pumps! -Carbamoyl phosphate synthetase

Mechanisms increasing the body during hyperthyroidism

• Reducing efficiency of ATP synthesis which leads to elevated levels levels of glycerol 3-phosphate dehydrogenase is increased NADH transport by this shuttle Malate is increased with transport shuttle. ATP is synthesized at higher rate.
• ATP are consumed at high rate.
• Phosphorylation and oxidation are uncoupled in the mitochondria.

Growth

• Thyroid hormone starts/ maintains Growth/ differentation.
• Stimulates production of trophic effects on tissues
• Is essential to brain differentation.
• Is required for childhood growth and bone density

Effects

• Thyroid hormones are key for natural development, in-addition Maturation function in the CNS,. Leads of patient Impairment, poor memory function, slow functions.

Heart Effects

• Thyroid Hormones- permissive effects on Beta receptor of heart volume/ stroke volume, cardiac output + contractility.
  • Lungs-Respiratory centers Increased rate of oxygen.
  • Hemodynamic Influences

Hemodynamic Influences

T3 increases vasodilation which decreases vascular resistance to ensure blood flow to body parts

• Thyroidhormones cause increased development of type II Fast twitch muscle

• The muscles are more powerful and can resist fast twitch contractions. Thyroid affects reproductive system to cause complications such as miscarriage,

Bone Growth

• T3 is a key growth maturation regulator.
• Can lead to Thyroid hormone expression factor and linear growth for development cells. • Increase bone ossidication, differentiation and puberty development.

Thyroid Hormone Regulates and Controls

A major regulator a potent transcription factor Stimulates - Oxygen/ Mitochondria which aids DNA functions

• Can lead to a potent stimulant