Thyroid physiology

This PPT gives the students the basic physiology of the Thyroid gland. It is the only Endocrine gland that can be palpable with your hands. Very useful to M.B.B.S; B.D.S as well as PG students.

2. Objectives
Formation of Thyroid hormones
Peripheral Conversion
Hormonal transport
Actions of Thyroid hormones
Regulation of Thyroid hormones

3. Thyroid
Essential for:
Development & Regulation
of Metabolism
Constant supply is essential
for
Normal growth
Brain development
Maintenance of
metabolism
Functional activity of
many organs

4. Follicles: the Functional Units of the
Thyroid Gland
Follicles Are the Sites
Where Key Thyroid
Elements Function:
• Thyroglobulin (Tg)
• Tyrosine
• Iodine
• Thyroxine (T
4
)
• Triiodotyrosine (T
3
)

5. Iodine
Necessary – synthesis – thyroid
hormones.
Iodine → iodide & absorbed
SI – stomach & jejunum
90-95% - absorbed iodide taken up by
thyroid

6. Iodine Sources
Available through certain foods (eg,
seafood, bread, dairy products, eggs),
iodized salt, or dietary supplements,
drinking water as a trace mineral
The recommended minimum intake is
0.1mg/day

8. Biosynthesis of T
4
and T
3
1. Iodide Trapping

Dietary iodine (I) ingestion
Active transport and uptake of iodide
(I
-
) by thyroid gland – First step
Dehalogenase enzyme
Thiocyanates + Perchlorates ≠ block

9. Biosynthesis of T
4
and T
3
2. Oxidation
Iodide → Inorganic iodine
Thyroperoxidase (TPO) enzyme
Thioamides ≠ block
Sulphonamides / PAS / Carbimazole / PT

10. Biosynthesis of T
4
and T
3
3. Binding - Iodination
Binding with tyrosine
Formation of iodotyrosines
Thyroperoxidase (TPO) enzyme
Iodine + tyrosine ═ MIT & DIT
Thiourea groups ≠ block
Carbimazole

11. Biosynthesis of T
4
and T
3
4. Coupling
2 molecule – DIT ═ T4
1 molecule ═ T3
Dehalogenase enzyme
Thiourea groups ≠ block
Carbimazole

12. Biosynthesis of T
4
and T
3
5. Proteolysis / Hydrolysis
Hormones + globulin ═ colloid ( Tg )
Stored in thyroid gland
Proteolysis of Tg with release of T
4
and
T
3
into the circulation - required

13. Plasma iodide enters
through the sodium iodide
symporter (NIS).
•Thyroglobulin (Tg), a
large glycoprotein, is
synthesized within the
thyroid cell.
•Thyroid peroxidase (TPO)
sits on the lumenal
membrane. It iodinates
specific tyrosines in Tg,
creating mono-and di-
iodotyrosines.
•The iodotyrosines
combine to form T3 and
T4 within the Tg protein

15. TSH
TSH receptor
Iodination of
Tyr residues of Tg
COLLOID
TPO
THYROGLOBULIN SYNTHESIS IN THE
THYROID FOLLICULAR CELL

16. In response to TSH,
pseudopodia form and
endocytose colloid.
•In the cell, colloid
droplets fuse with
lysosomes and thyroid
hormone is cleaved
enzymatically from Tg.
•T4 and T3 are released
into the circulation.
•TSH stimulates
iodide trapping, as
well as thyroid
hormone synthesis
and secretion

18. Active Transport and I
-
Uptake by the
Thyroid
Dietary iodine reaches the
circulation as iodide anion (I
-
)
The thyroid gland transports I
-
to the
sites of hormone synthesis
I
-
accumulation in the thyroid is an
active transport process that is
stimulated by TSH
NIS is a membrane protein that
mediates active iodide uptake by the
thyroid

19. ION TRANSPORT BY THE
THYROID FOLLICULAR CELL
I
-
I
-
organification
Propylthiouracil (PTU)
blocks iodination of
thyroglobulin
COLLOID
BLOOD
NaI symporter (NIS)
Thyroid peroxidase (TPO)
ClO
4
-
, SCN
-

20. Proteolysis of Tg With Release of
T
4
and T
3
T
4 and T
3 are synthesized and stored within the Tg
molecule
Proteolysis is an essential step for releasing the
hormones
To liberate T
4
and T
3
, Tg is resorbed into the follicular
cells in the form of colloid droplets, which fuse with
lysosomes to form phagolysosomes
Tg is then hydrolyzed to T
4 and T
3, which are then
secreted into the circulation

21. THYROID HORMONE SECRETION BY THE
THYROID FOLLICULAR CELL
COLLOID
TSH
TSH receptor
DIT
MIT
I
-
T
4
T
3

23. Production of T
4
and T
3
T
4
is the primary secretory product of the
thyroid gland, which is the only source of T
4

The thyroid secretes approximately 70-90 mg of
T
4
per day
T
3
is derived from 2 processes
The total daily production rate of T
3
is about 15-30 mg
About 80% of circulating T
3
comes

from deiodination
of T
4
in peripheral tissues
About 20% comes from direct thyroid secretion

24. Sites of T
4
Conversion
The liver is the major extrathyroidal T
4

conversion site for production of T
3
Some T
4
to T
3
conversion also occurs in the
kidneys / heart / muscle and other tissues

25. Peripheral Conversion - process
Although T4 is the principal hormone from
Thyroid, T3 is the main hormone for regulation of
metabolism
T3 is produced by de-iodination of T4, by the
enzymes T4 -5’De-iodinase Type I & Type II
Type I T4 -5’De-iodinase is found in the Liver &
Kidneys. It is responsible for the production of
⅔
of the total T3 in the body
Type II T4 -5’De-iodinase is responsible for most
of the T3 found in the Pituitary, Brain & Brown
Fat
T3 either enters the cell or locally produced,
which is transported into the nucleus
Type III – which converts T4 → rt3 which is
biologically inactive

26. THYROID HORMONE
DEIODINASES
Three deiodinases (D1, D2 & D3) catalyze
the generation and/disposal of bioactive
thyroid hormone.
D1 & D2 “bioactivate” thyroid hormone by
removing a single “outer-ring” iodine atom.
D3 “inactivates” thyroid hormone by
removing a single “inner-ring”iodine atom.
All family members contain the novel
amino acid selenocysteine (SeC) in their
catalytic center.

27. O
O
H
N
H
2
I
I
I
I
O
H
O
T
4
I
I
O
H
O
R
3,3’-T
2
I
I
I
O
H
O
R
T
3
“Step up”
I
I
I
O
H
O
R
rT
3
“Step down”
THYROID HORMONE METABOLISM
O
O
H
N
H
2
R =

28. Thyroxine (T
4
)
3,5,3’,5’ tetraiodo-L-thyronine
THYROID HORMONES
•Derived entirely
from the thyroid
gland
•Is a pro-hormone

29. THYROID HORMONES
*Is the biologically
active thyroid
hormone
*•20% of plasma T3
comes from
thyroidal secretion
•80% comes from
T4 5’-deiodination in
peripheral organs

30. T3 & T4
Iodinated aminoacids
With in thyroid, integral part of TG, in which they are
synthesized & stored
In plasma, circulate as free amino acids in equilibrium
with THBP
Free forms:
Penetrate cells-induce & stimulate Oxygen
consumption,
Body heat,
Metabolism of CHO/Fat/Protein
Stimulates feedback mechanisms with Pituitary

32. T
4
Disposition
Normal disposition of T
4
About 41% is converted to T
3

38% is converted to reverse T
3
(rT
3
), which is
metabolically inactive
21% is metabolized via other pathways, such as
conjugation in the liver and excretion in the bile
Normal circulating concentrations
T
4
4.5-11 mg/dL
T
3
60-180 ng/dL (~100-fold less than T
4
)

33. Carriers for Circulating Thyroid
Hormones
More than 99% of circulating T
4
and T
3
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

34. Free Hormone Concept
Only unbound (free) hormone has metabolic
activity and physiologic effects
Free hormone is a tiny percentage of total hormone in
plasma (about 0.03% T
4
; 0.3% T
3
)
Total hormone concentration
Normally is kept proportional to the concentration of
carrier proteins
Is kept appropriate to maintain a constant free
hormone level

35. Thyro-Globulin
It is a dimeric Glyco-Protein
M.wt: 660000
Contains about 120 Tyrosyl units
30% of Tyrosyl will undergo iodination
After the synthesis of the Hormones and its
intracellular transport, exophytic residues
discharge their contents in the Folliclle
TG accumulates in the lumen
Colloid, which fills the Follicular lumen is
almost exclusively composed of Iodinated TG

36. Thyroid Physiology
Hormone Binding proteins are the principal
factors influenzing total hormone
concentration, which is normally maintained
at a level appropriate for the concentration of
carrier proteins, to maintain a constant free
hormone level
Various factors may cause changes in the
concentrations of TBG & changes in TBG level
may alter the total hormone concentration,
irrespective of the metabolic status or free
hormone level
TBG estimation is a more accurate indicator
of the Thyroid Hormone dependant
metabolic state

37. Changes in TBG Concentration Determine Binding
and Influence T
4
and T
3
Levels
Increased TBG
Total serum T
4
and T
3
levels increase
 Free T
4
(FT
4
), and free T
3
(FT
3
) concentrations remain
unchanged
Decreased TBG
Total serum T
4
and T
3
levels decrease
 FT
4
and FT
3
levels remain unchanged

38. Drugs and Conditions that Increase Serum T
4
and
T
3
Levels by Increasing TBG
Drugs that increase TBG
Oral contraceptives and
other sources of estrogen
Methadone
Clofibrate
5-Fluorouracil
Heroin
Tamoxifen
Conditions that increase
TBG
Pregnancy
Infectious/chronic active
hepatitis
HIV infection
Biliary cirrhosis
Acute intermittent porphyria
Genetic factors

39. Drugs and Conditions that Decrease Serum T
4
and T
3
by
Decreasing TBG Levels or Binding of Hormone to TBG
Drugs that decrease serum
T
4
and T
3

Glucocorticoids
Androgens
L-Asparaginase
Salicylates
Mefenamic acid
Antiseizure medications, eg,
phenytoin, carbama-zepine
Furosemide
Conditions that decrease
serum T
4
and T
3

Genetic factors
Acute and chronic illness

41. ACTIONS
 BMR due to O2, Heat, Temp & Heat
intolerance. Optimum level is necessary for
balanced growth & maturation
Stimulates Lipogenesis & Lipolysis,
Lowers serum Cholesterol by enhancing
Excretion thro’ Faeces
Conversion to Bile Acids
 Catecholamine effect
Brain / retina / lungs / spleen & testes are
unaffected by thyroid hormones

42. ACTIONS
Site Actions Outcomings
Brain Effects on activity &
mood
Hyperactivity & Mood
changes
Pituitary ↓TSH release ↓TSH level
Heart Rate; changes in
proteins
Tachycardia,
Arrhythmia, Failure
Liver LDL Receptors,
Cholesterol
synthesis,
Cholesterol excretion
& conversion to Bile
acids
↓Cholesterol
Muscle Changes in Protein Myopathy
Bone Osteoblastic & 2º
Osteoclastic activity
Osteoporosis

43. ACTION OF THYROID HORMONES
Parameter/ organ system
Action
Developmental Essential for normal neural and skeletal development
Calorigenesis Oxygen consumption
Basal Metabolic Rate
Intermediary Metabolism Protein Synthesis
Synthesis/ Degradation of cholesterol
Lipolysis
Glycogenolysis
Cardiovascular Heart rate and myocardial contractility
Sympathetic Nervous System Sensitivity to catecholamines
Catecholamine receptors in cardiac muscle
Amplification of catecholamine effects at postreceptor site
Endocrine Steroid hormone release
Hematopoietic Erythropoiesis
2,3 DPG production
Maintain hypoxic and hypercapnic drives
Musculo skeletal Bone turnover
Urinary hydroxy proline excretion
Increased rate of muscle relaxation

45. REGULATION OF THYROID HORMONE
SECRETION
Classic feed back loop that involves pituitary and
hypothalamus
Intrinsic thyroid autoregulatory process

46. FEEDBACK REGULATION
THE HYPOTHALAMIC-PITUITARY-THYROID AXIS
Hormones derived from the pituitary that regulate the
synthesis and/or secretion of other hormones are known as
trophic hormones.
Key players for the thyroid include:
TRH - Thyrophin Releasing Hormone
TSH - Thyroid Stimulating Hormone
T
4
/T
3
- Thyroid hormones

47. TSH
TSH (Thyroid Stimulating Hormone or Thyrotrophin)
Normal Level = 0.5 to 4.5 μUnits/ML
Normal daily production & degradation is 40 to 150 μUnits
Circardian rhythm-raise 2 hours after sleep, peak from 2 to 4
AM
Initial effect of TSH is in Iodide transport
Glycoprotein
Like LH / FSH / HCG, TSH also has α & β subunits
α subunits of all the said hormones are identical
β subunits of each are responsible for biological &
immunological specificities
TSH is required for normal production & secretion of T3 & T4
Mostly influezed by tonic stimulation by TRH and feedback
inhibition by T3 & T4
T3 regulates the transcription of the GENES for both the
subunits of TSH

48. Effects of TSH
 Iodine binding to TG
 coupling of MIT & DIT
Activation of Exocytosis
 Transfer of proteins into the follicles
 Secretion of T3 & T4
Major factor in the growth of thyroid
Iodine & Drugs blocking the binding of Iodine to TG cause
↓
TSH & diffuse enlargement of Thyroid
When TSH is low or absent (Hypophysectomy, inactive TSH) the
Thyroid gland in size
↓
Prolonged TSH administration will the ↑ weight of the Thyroid
Gland
Chronic TSH leads to: proliferation of capillaries & fibroblasts
rather than Follicles

49. TSH binds to specific cell surface receptors that
stimulate adenylate cyclase to produce cAMP.
TSH increases metabolic activity that is required to
synthesize Thyroglobulin (Tg) and generate peroxide.
TSH stimulates both I
-
uptake and iodination of
tyrosine resides on Tg.
TSH REGULATION OF
THYROID FUNCTION

50. TRH
Tripeptide- (pyroglutamyl-histidyl-proline amide)
First Hypothalamic hormone isolated
Produced at Supra-Optic & Para-Ventricular Nuclei
Passes thro’ their axons to median eminence and
stored
Reach the Pituitary via hypophyseal portal vessels &
binds to receptor sites
Increases the synthesis & secretion of TSH
Increases the synthesis & secretion of Prolactin
Tonic stimulation of TSH producing cells

51. Auto-Regulation
In Humans, the Wolff-Chaikoff’s block(acute
block of Iodide binding) is induced by
elevated plasma iodide level to ≥ 25 μGm%
Aftert the critical level of iodide, there is a
progressive inhibition of iodide binding to
tyrosyl residues in TG
Iodide adminisration leads to:
↓Iodine containing compounds from thyroid
↓ serum T3 & T4
↓in Hypervascularity Seen in
↓in Hyperplasia Hyperthyroidism
May induce Hyperthyroidism
May cause Nodularity in Goitres

52. WOLFF CHAIKOFF’S EFFECT
TSH independent manner by availability &
glandular content of iodide
Iodide depletion enhances iodide transport &
stimulate hormone synthesis
In the presence of excess iodide, iodide causes
suppression of both transport & hormone
synthesis

53. Hypothalamic-Pituitary-Thyroid Axis
Negative Feedback Mechanism

55. CALCITONIN
Secreted By: Parafollicular cells of Thyroid
gland
Regulation: Negative feedback mechanism
High calcium levels in blood stimulated
secretion & vice versa
Action: Decrease blood level of ionic Ca2+ &
PO4 by inhibiting bone reabsorption by
osteoclasts and uptake of Ca & PO4 in bone
matrix.

56. ANTI THYROID COMPOUNDS
PROCESS
AFFECTED
EXAMPLES OF INHIBITORS
Active Transport of IodideComplex anions: Perchlorate, fluoborate, pertechnetate,
thiocyanate
Iodination of thyroglobulinThionamides: Propylthiouracil, methimazole, carbimazole.
Thiocyanate, Aniline derivatives, Sulphonamides, Iodide.
Coupling reaction Thionamides, Sulphonamides,
Hormone release Lithium salts, Iodide
Iodotyrosine deiodinationNitrotyrosines
Peripheral iodothyronine
deiodination
Oral cholecystographic agents
Thiouracil derivatives, Amiodarone
Hormone excretion/
inactivation
Inducers of Hepatic drug metabolizing enzymes:
Phenobarbital, rifampin, carbamazepine, phenytoin
Hormone Action Thyroxine analogs, Amiodarone, Phenytoin,
Binding in gut: Cholestyramine.