a brief on thyroid gland covering following titles:
Introduction
Anatomy and physiology of thyroid gland
Synthesis of thyroid hormones
Regulation
Mechanism of action
Biological function
2. Overview
• Introduction
• Anatomy and physiology of thyroid gland
• Synthesis of thyroid hormones
• Regulation
• Mechanism of action
• Biological function
2
3. Introduction:
• Named after the thyroid cartilage
• Greek: Shield shaped
• One of the largest endocrine glands
• Produces Thyroid hormones and Calcitonin
• Plays role in metabolism, growth and calcium
homeostasis.
3
4. Anatomy:
• Brownish-red gland.
• Butterfly shape gland ( H or U shaped).
• Located anteriorly in the lower neck
• Extending from the level of the 5th cervical
vertebra down to the 1st thoracic vertebra.
• Two lobes attached to each other by
Isthmus.
• In some people a third “pyramidal lobe”
exists, ascending from the isthmus towards
hyoid bone
4
5. • Weighs between 15 and 20 g
• Right lobe somewhat larger than the left lobe
• Each lobe is 2–2.5 X 2-2.5 X 4 cm (thick, wide & high)
• Connected by isthmus 0.5 X 2 X 1-2 cm
• Parathyroid glands usually lie between posterior
border of thyroid gland and its sheath
• Usually 2 on each side of the thyroid.
5
6. Arterial Supply:
• Highly vascular
• Main supply from branches of carotid artery :
Superior thyroid arteries
Inferior thyroid arteries
Venous Drainage:
• Superior thyroid veins drain superior poles
• Middle thyroid veins drain lateral parts
• Inferior thyroid veins drain inferior poles
Lymphatic drainage:
Drain to:
• Prelaryngeal LN’s, Pretracheal and Paratracheal LN’s, Cervical LN’s
• Some drainage directly into brachio-cephalic LN’s
6
7. Histology
• Thyroid gland contains numbers of spherical structures i.e. Follicles.
• Follicles are the basic functional unit of this gland
• It consists of
1. Follicular cells
2. Parafollicular cells (C Cells)
3. Colloids
7
8. Follicular cells:
• Follicular cells are normally cuboidal in shape
• Contain many small apical vesicles
• It transports ions
• Synthesize thyroglobulin
Parafollicular cells or C cells:
• Secretes Calcitonin
• separated by connective tissue containing capillaries
Colloids:
• Viscous gel consisting mostly of iodinated thyroglobulin.
8
9. THYROID GLAND: STRUCTURAL AND FUNCTIONAL ONTOGENY
• Embryologically at day 24, the thyroid gland develops from an
anterior outpouching of the foregut.
• From this thyroid diverticulum, the thyroid gland descends, and the
process is usually complete at 7 weeks.
• The fetus is dependent on the transplacental passage of maternal
thyroid hormone for the first half of gestation.
• Maternal hypothyroidism in the first 20 weeks of gestation may
adversely impact fetal central nervous system (CNS) development,
leading to neuropsychologic impairment in infants and children.
• By 10 weeks, fetal thyroid follicles and thyroxine synthesis are
demonstrable.
9
10. • By the mid second trimester, maturation of the hypothalamic-
pituitary-thyroid axis occurs, so that by 20 weeks, the fetus is
becoming responsible for its own production of thyroid hormone.
• Thyroxine-binding globulin (TBG) and thyroxine are first detectable in
fetal serum at 8 to 10 weeks’ gestation and increase thereafter until
they plateau at 35 to 37 weeks.
• Thyroxine and TSH rise until birth and within hours of birth, TSH, T4 &
T3 rise rapidly which then concentration falls to normal by 2-3 days.
• The post-birth rise in T3 results from increased thyroid gland release
in response to the rising TSH concentration and increased conversion
of T4 to T3 due to maturation of the type 1 deiodinase enzyme (D1).
10
11. Thyroid Hormones
• 2 hormones:
1. Thyroxine (3,5,3’,5’-L-tetraiodothyronine) ;T4
2. Triiodothyronine (3,5,3’-L-triiodothyronine) ;T3
• Small amount of biologically inactive reverse T3
(rT3; 3,3’,5’-L-triiodothyronine)
• Minute quantities of monoiodotyrosine (MIT)and
diiodotyrosine (DIT); precursors of T3 and T4.
• Thyroid hormones have ubiquitous effects on
growth and development in the fetus, child, and
adolescent, and they regulate calorigenesis and
metabolic rate throughout life.
11
12. Synthesis, Storage and Release
1. Trapping of iodide
2. Oxidation of iodide to iodine by thyroid peroxidase
3. Incorporation of iodine into tyrosyl residue on thyroglobulin
4. Coupling of two iodotyrosyl residues in the thyroglobulin molecule
5. Internalization of Tg and release of T4 and T3
6. Delivery of T4 and T3 into the circulation
12
14. Biochemistry
• Thyroid hormone is derived from the amino acid tyrosine.
• Thyronine is produced by substitution of a second phenol moiety for
the phenolic hydrogen on tyrosine, producing a diphenyl ether having
two phenol rings attached to one another through an ether linkage
• There are four possible sites for iodine attachment to thyronine at the
meta positions on both phenyl rings, designated the 3, 5, 3′, and 5′
positions.
• The 3 and 5 positions are on the alpha (inner) ring, and the 3′ and 5′
positions are on the beta (outer) ring.
14
15. Production of Thyroglobulin:
• The follicle cells of the thyroid produce thyroglobulin
• Thyroglobulin is a very large glycoprotein released into colloid
• The 42-exon gene encoding Tg is located on chromosome 8q24 and
spans 250 kilobases
• Tg is a glycoprotein homodimer of 660 kDa.
• A total of 134 tyrosine residues are found in the homodimer, and 25 to 30 of
these residues are iodinated.
• TSH is the principal stimulator of Tg synthesis.
• Thyroid transcription factor 1 (TTF1) interacts with the Tg promoter to
stimulate Tg mRNA synthesis
15
16. • Once iodide is oxidized (“organified”) to an iodine radical by the
thyroperoxidase (TPO) enzyme, Hydrogen peroxide (H2O2) serves as
the terminal electron acceptor, forming H2O2−.
• Hydrogen peroxide is generated at the apical membrane by the action
of DUOX1 and DUOX2 (DUOX was previously known as THOX, or thyroid
oxidase).
• The follicular cell digests the intravesicular colloid containing Tg.
• primary lysosome digest vesical releasing T4, T3, MIT, DIT, and amino
acids.
• Only 0.03% of total T4 & 0.3% of total T3 is free (unbound and
bioactive).
16
17. • Within the cytoplasm of the follicular cell, the released MIT and DIT
are stripped of iodine by dehalogenase (Dhal) to produce free iodide
ions, which can be recycled immediately for the synthesis of new
thyroid hormone
• Two dehalogenase genes have been described: Dhal1 and Dhal1b
• mutations in the dehalogenase enzyme potentially lead to iodine loss
in the urine and increased concentrations of DIT and MIT in the
circulation
17
18. Wolff-Chaikoff Effect:
• It is an auto regulatory phenomenon that inhibits organification in the
thyroid gland.
• A large excess of iodide, when given acutely, results in acute inhibition
of thyroid hormone release.
• It also inhibits the adenylate cyclase response to TSH and iodination
of thyroglobulin;
• Lasts for 10 days, after which it is followed by an ‘escape phenomenon’
which is resumption of normal organification of iodine
• Escape phenomenon is believed to occur because of decreased inorganic
iodine concentration secondary to down-regulation of sodium-iodide
symporter.
18
19. Jod-Basedow Effect:
• Opposite of the Wolff-Chaikoff effect
• Excessive iodine loads induce hyperthyroidism
• Observed in hyperthyroid disease processes
– Graves’ disease
– Toxic multinodular goiter
– Toxic adenoma
• This effect may lead to symptomatic thyrotoxicosis in patients who receive
large iodine doses from
– Dietary changes
– Contrast administration
– Iodine containing medication ( Amiodarone )
19
22. • The liver is the major
extrathyroidal site for
production of T3.
• Some conversion also occurs in
the kidney.
• This conversion is possible in the
presence of iodothyronine
deiodinases (D1, D2 and D3).
• Approx 40% of T4 is deiodinated
to T3 by D1 or D2, and ≈45% is
deiodinated to rT3
• by D1 or D3. About 80% of
circulating T3 comes from 5′-
deiodination of T4;
• only ≈20% of T3 is released
directly fromthe thyroid gland
• By regulating the conversion of
T4 to T3, the body, in part,
regulates the metabolic rate
22
24. Thyrotopin Releasing Hormone:
• TRH; thyrotropin-releasing factor,
thyroliberin or protirelin
• Synthesized from a 29 kDa precursor
protein
• Produced by anterior Hypothalamus,
medial neurons of the paraventricular
nucleus (PVN).
• TRH is delivered to the anterior
pituitary gland via the
hypothalamic-pituitary portal
system.
• TRH increases with Thyroid deficiency
and vice versa
24
26. Influence of TRH on TSH Release:
• TRH is a hypothalamic releasing factor which travels through the pituitary
portal system to act on anterior pituitary thyrotroph cells.
• TRH acts through G protein-coupled receptors depolarizing thyrotrophs,
triggering calcium influx.
• This activates the IP3 cascade effecting TSH release, synthesis and
glycosylation of alpha and beta TSH subunit.
• Greater effect of glycosylation on TSH is necessary for normal TSH
bioactivity.
• TSH may lack potency due to insufficient glycosylation when TRH is deficient
causing retention of its immunoreactivity.
• Therefore, TSH assay may not reflect the activity of hormone when injury or
disease results in a TRH deficiency.
26
27. Hormonal Transport:
• More than 99% of circulating T4 and T3 is bound to plasma carrier proteins
• Thyroxine-binding globulin (TBG), binds about 75%
• Transthyretin (TTR), also called thyroxine-binding prealbumin (TBPA),
binds about 10%-15%
• Albumin binds about 7%
• High-density lipoproteins (HDL), binds about 3%
• Carrier proteins can be affected by physiologic changes, drugs, and disease
27
29. Mechanism of Action
• T3 enters plasma membrane then to nucleus
• Specific transporters facilitate the entry into cell.
• The organic anion transporting polypeptides (OATPs) and human
monocarboxylate transporter 8 (MCT8) are active transporters
• OATPs are specific for T4 and rT3 whereas MCT8 for T3
• In nucleus it interacts with thyroid hormone receptor (THR)
• Several alpha and beta isoforms of THR are produced.
• THR usually dimerize with the retinoid X receptors(RXRs)
• The formation of the T3-THR/DNA (thyroid hormone receptor element)
complex with recruitment of transcriptional coactivators leads to activation
of target genes
• Giving rise to mRNA and protein production.
29
31. • 4 functional intranuclear T3 receptors: α1, α2, β1 and β2;
• TRα is abundant in brain, kidney, gonads, muscle and heart
• TRβ expression is relatively high in pituitary and liver
• The different forms of thyroid receptors have patterns of expression that vary
by tissue and by developmental stage.
• The TR β2 isoform, which has a unique amino terminus, is selectively
expressed in the hypothalamus and pituitary, where it plays a role in feedback
control of the thyroid axis.
• The TR α2 isoform contains a unique carboxy terminus that prevents thyroid
hormone binding
• The presence of multiple forms of the thyroid hormone receptor, with tissue
and stage-dependent differences in their expression, suggests an
extraordinary level of complexity in the physiologic effects of thyroid
hormone.
31
35. Thyroid Stimulating Hormone:
• TSH is a 30kDa heterodimeric glycoprotein that shares a subunit with LH, FSH,
and hCG.
• All four hormones contain a 14.7 kDa alpha subunit (gene location:
chromosome 6q21.1-q23) with unique beta subunit
• The 15.6 kDa TSH beta chain is encoded by a three-exon gene located on
chromosome 1p. The alpha chain contains two oligosaccharides,
• and the TSH beta subunit contains one oligosaccharide modification.
• It is a glycoprotein hormone synthesized and secreted by thyrotrope cells in the
anterior pituitary gland.
• Its secretion follows circardian rhythm, highest between midnight and 4 AM
and lowest at midday
35
36. • The α (alpha) subunit is nearly identical to that of human chorionic
gonadotropin (hCG), luteinizing hormone (LH), and follicle-stimulating
hormone(FSH).
• The α subunit is thought to be the effector region responsible for stimulation
of adenylate cyclase (involved the generation of cAMP)
• The β subunit is unique to TSH, and therefore determines its receptor
specificity
• The α chain has a 92-amino acid sequence.
• The β chain has a 118-amino acid sequence.
36
37. Mechanism of Action of TSH:
• TSH binds to a plasma membrane-bound, G protein—adenyl cyclase-coupled
receptor on thyroid follicle cells.
• TSH stimulation increases the size and number of thyroid follicular cells.
• Likewise, follicular cellular hyperplasia is seen in Graves’ disease, when
an agonistic autoantibody stimulates the TSH receptor
TSH phospholipase C
G protein-coupled
receptor
IP3 calcium
H2O2 generation & iodide efflux
Na-Iodine symporter and synthesis of thyroglobulin and TPO
37
38. Action of TSH on the Thyroid:
• TSH acts on follicular cells of the thyroid.
- increases iodide transport into follicular cells
- increases production and iodination of thyroglobulin
- increases endocytosis of colloid from lumen into follicular cells
I-
thyroglobulin
T3 T4
Na+
I-
thyroglobulinfollicle
cell
gene
endocytosis
colloid droplet
I-I+
iodination
thyroglobulin
Na+ K+
ATP
38
39. Regulation of Thyroid Hormone Levels:
• Thyroid hormone synthesis and secretion is regulated by two main
mechanisms:
1. an “autoregulation” mechanism, which reflects the available levels of
iodine
2. regulation by the hypothalamus and anterior pituitary
1. Autoregulation:
• The rate of iodine uptake and incorporation into thyroglobulin is influenced
by the amount of iodide available:
• low iodide levels increase iodine transport into follicular cells
• high iodide levels decrease iodine transport into follicular cells
• Thus, there is negative feedback regulation of iodide transport by iodide.
39
40. Feedback mechanism:
• Increase and decrease in the thyroid hormone level can itself maintain its
level.
• When there is increase in Thyroid hormone level in blood it inactivates TRH
and TSH synthesis
• As a result there will be decrease production of thyroid hormones
• And vice-versa.
• Thyroid hormones exert negative feedback on TSH release at the level of the
anterior pituitary.
40
41. Drugs:
Mechanism Example of Drugs
Decrease in TSH secretion Dopamine, glucocorticoids, cytokines
Decrease in thyroid hormone secretion Lithium, amiodarone, iodine
Increase in thyroid hormone secretion Lithium, iodine
Displacement of thyroid hormone from
plasma proteins
Furosemide, salicylates, NSAIDS
Increase hepatic metabolism Phenytoin, rifampicin, barbiturates
Impaired T4 and T3 conversion Beta antagonist, radiocontrast die
Impaired absorption of thyroxine Calcium, sucralfate, soya protein
Modified thyroid hormone action amiodarone
41
42. Other factors:
• Thyroid hormone metabolism is markedly affected by fasting and illness.
• There is release of dopamine, cortisol, somatostatin along with cytokines
which suppress TSH.
• Decrease production of T3, changes in function of T3 receptors leads to
low T3.
• Catecholamines and leptin stimulate TRH production hence regulate TSH
42
43. BIOLOGICAL FUNCTION (at molecular level)
1. increase oxygen consumption within tissues via increased
membrane transport
2. enhance mitochondrial metabolism
3. increase sensitivity to catecholamines with increased heart rate and
myocardial contractility
4. stimulate protein synthesis and carbohydrate metabolism
5. increase synthesis and degradation of cholesterol and triglycerides
6. increase vitamin requirements
7. regulate calcium and phosphorous metabolism.
43
44. Thyroid hormone actions:
1. Growth and development:
• Stimulates formation of proteins,
which exert trophic effects on
tissues
• Increase growth and maturation of
bone
• Increase tooth development and
eruption
• Increase growth and maturation of
epidermis, hair follicles and nails
2. Nervous System:
• Critical for normal CNS neuronal
development
• Enhances wakefulness and
alertness
• Enhances memory and learning
capacity
• Required for normal emotional
tone
• Increase speed and amplitude of
peripheral nerve reflexes
44
46. 5. Renal System:
• Increase blood flow
• Increase glomerular filtration
rate
6. Reproductive System:
• Required for normal follicular
development and ovulation in
the female
• Required for the normal
maintenance of pregnancy
• Required for normal
spermatogenesis in the male
Thyroid hormone actions:
46
47. 7. Calorigenic effects:
• T3 increases oxygen
consumption by most
peripheral tissues
• Increases body heat production
8. Metabolic effect:
• Stimulates lipolysis and release
of free fatty acids and glycerol
• May leads to fall in plasma
cholesterol
• Increase glucose absorption.
• Increase gluconeogenesis and
glycogenolysis.
• Increase insulin breakdown.
Thyroid hormone actions:
47
48. 9. Basal metabolic rate:
• T3 increases basal metabolic rate
• Activity of the Na+/K+ pump uses up energy, in the form of
ATP
• About 1/3rd of all ATP in the body is used by the Na+/K+
ATPase
• T3 increases the synthesis of Na+/K+ pumps, markedly
increasing ATP consumption.
48
49. Reference:
• Burtis CA, Ashwood ER, Burns DE. Tietz Textbook of Clinial Chemistry and
Molecular Diagnostics. 4th & 5th ed. United Stated of America: Elsevier; 2012.
• Harrison's Principles of Internal Medicine, 16th Edition
• William J. Marshall, Clinical Biochemistry: Metabolic and Clinical Aspects. 3rd
Ed. Churchill Livingstone: Elsevier ; 2014.
• Internet sources
49
Small amount Tg in follicular cells and increased dietary iodine exposure associated with development of Hashimoto thyroiditis.
Hypothyroidism due to DUOX mutations has been reported.
Large excess of iodide given acutely inhibits the adenylate cyclase response to TSH.
Not seen in normal individual
TSH (tropin hormone) helps in synthesis of thyroid hormones. Synthesis of TSH is itself controlled by other hormone
Thyrotropin Releasing Hormone (TRH) is responsible for production of TSH.
T4 is more tightly bound to thanT3
OATP1C1 brain and BBB
MCT in kidney
Transport of thyroid hormone into neurons is especially critical for normal CNS development and function
Replication of thyroid follicular cells is stimulated by cAMP, phospholipase C, insulin-like growth factor-I (IGF-I), and a fibroblastic growth factor (FGF)-mediated kinase.
1 cycling of sodium/potassium ATPase with increased synthesis and consumption of adenosine triphosphate),
2 stimulation of mitochondrial respiration and oxidative phosphorylation