SUBJECT: PYSIOLOGY

TOPIC: THYROID GLAND AND PANCREAS

LECTURER: DR. GIGI FRANCISCO

DATE: JANUARY 2011

THYROID GLAND – secretion of this gland is dependent in a

micronutrient (iodine)

**Orientation of the cell- the site where the colloid is the

luminal site and the basal site is where the blood supply are
and lines the follicle.
**This orientation is important in the transport of material
which is unidirectional.
**The basal site which contains the blood supply is where the
iodine enter the follicle

**The figure above shows that in the diet 500 ug of iodide is

absorbed by the thyroid gland and 500 ug of iodide is also
excreted (480 ug in urine and 20 ug in stool). There is active
exchange of iodine between the thyroid and the ECF.

**The thyroid follicle is made up of secretory epithelial cell

and the colloid at the center (lumen). The colloid is where the
hormones are secreted and are stored
**Inactive - cells are flat and very distinct colloid material at
the center
** Active state (secretion or synthesis of hormone) – follicular
cells are columnar and the follicle is very little.

Thyroid hormone synthesis

**dietary iodine is in the form of I2 which is reduced in the
gut to I-. Iodine is absorbed, then passes through the
bloodstream and enter the follicular cells in the thyroid
 Thryoglobulin (TG)
o Synthesiszed by follicular cells (by the rER)
o Glycoproteins with 123 tyrosine units
 Only 4-8 are incorporated into
thyroid hormones
o Secreted into the colloid
**Tyrosine – backbone material in the synthesis of thyroid
hormone. The benzene ring is responsible for the activity of
the thyroid hormone.
**Thyroid Hormone behaves like a steroid hormones (which
has a series of benzene rings – cyclopentanopenantrene ring)

PHYSIOLOGY:THYROID HORMONES Page 1

Steps in thyroid hormone synthesis
1. Synthesis of thyroglobulin (TG)
2. Iodide trapping
 Transport across basal (basolateral)
membraine of follicular cells
 Transport can be against concentration
gradient through NIS
 Na-Iodide symport (NIS) (transports
iodide along with Na inside)
o Secondary active transport with
Na-K ATPase (sodium is
transported outside to maintain
Na level inside low)
o Affected by TSH from pituitary
o Inhibited by PERCHLORATE,
PETECHNETATE, THIOCYANATE
and NITRATE.
3. Iodide oxidation at apical membrane (I -
→I2)
 Thyroid peroxidase (enzyme responsible
for the oxidation)
 Inhibited by:THIOURACIL and
SULFONAMIDES
 After oxidation, I2 or I0 is secreted into
the follicular lumen with the TG
4. Organification
 Iodination of tyrosine residues
(attachment of oxidized iodine to
tyrosine units of TG in the lumen)
o Monoiodotyrosine (MIT)
 Thyroid Peroxidase (the one responsible)
 Hormone precursor: MIT, DIT
**MIT – one iodine attached to benzen; DIT – 2 iodine.
5. Coupling reaction
 Conjugation of iodinated tyrosines (MIT,
monoiodotyrosine, and DIT,
diiodotyrosine)
o Trioiodothyronine, T3 (MIT + DIT
= T3)
o Thyroxine, T4 (DIT + DIT = T4)
PHYSIOLOGY:THYROID HORMONES
 Thyroid peroxidase (enzyme responsible)
 Storage in the colloid (yung nasa lumen)
6. Endocytosis of TG (by follicular cells)
 Iodinated TG is retrieved into the
follicular cell by endocytosis
7. Hydrolysis (proteolysis) and secretion of T4
and T3
 Fusion of TG vesicles with lysosomes
(they are called lysoendosomes)
 Lysosomal enzymes (lysosomal
peptidases specifically)
 Gives rise to TG+ T4 or T3 and TG + MIT
or DIT
 Release of T4 and T3 into the circulation
in the basilar site and is affected by TSH
**MIT and DIT are also released here
 Concentration of T4 is higher than T3
but T3 is biologically more favored.
8. Deiodination of residual MIT and DIT
 Recycling of I- and Tyrosine
REGULATION OF THYROID HORMONE SECRETION
 Thyrotropin Releasing Hormone (TRH) - hypothalamus
o Tripeptide
o Feedback control by levels of circulating T4
and T3
o Effect:
 Stimulates secretion of thyroid stimulating
hormone (TSH) from anterior pituitary.
 Thyroid stimulating Hormone
o Polypeptide, a and b chains
o Responds to level of circulating T4 and T3
o Effects:
 Stimulates iodide trapping
 Each step in T3/T4 synthesis catalyzed by
peroxidase
 Stimulates colloid endocytosis and TG
proteolysis
 Secretion of T3 and T4
 Enlargement of thyroid gland (hypertrophy)
**Hypothalamo-pituitary Thyroid axis – negative feedback
because of increased secretion of T3 and T4 from thyroid.
Causes inhibition on hypothalamus and anterior pituitary
gland from producing TRH and TSH respectively.
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 TRANSPORT OF THYROID HORMONE
Thyroxin binding proteins
o T4: Thyroxin binding Globulin, TBG (and TTR or
transthyretin – in CSF)
o T3: TBG and Albumin
EFFECT OF IODIDE ON THYROID HORMONE SYNTHESIS  Provides storage for the hormone in the circulation
 Biphasic Effect of iodide (in addition to colloid in the gland)
1. Wolff-Chaikoff Effect  Prolongs half-life of T4 and T3
 Inhibition of thyroid hormone synthesis by iodide  Prevents renal loss
 Dose: 2mg/day (normal iodine intake: 250  Protection from hepatic metabolism
ug/day) **protein bound THYROID HORMONE are inactive
o Decreased organification, then **the free or unbound thyroid hormone is biologically active
o Decreased iodide trapping
o Reduces cAMP response to TSH FREE FORM VS PROTEIN-BOUND
o Inhibits thyroglobulin proteolysis  Equilibrium
 Clinical application: Thyrotoxicosis o FREE T4 (0.02%)/BOUND T4 (99.98%)
o FREET3 (0.05%)/BOUND T3 (99.5%)
2. Jodd-Basedow Effect
 Decreased iodide trapping (eventual effect) TRANSPORT OF THYROID HORMONE
 Release from inhibitory effect of iodine  Flunctuation in thyroid binding proteins, (TBPr)
o Increased TBG
 Applies to THYROTOXICOSIS
 Decreases free T4 and T3
**Other factors that affect thyroid gland activity:
 Stimulate Pituitary TSH
i. Increase level of TG – inhibits binding of TSH to its
o Decreased TBG
receptor on the follicular cell in thyroid
 Increase free T4 and T3
ii. Epinephrine / VIP – stimulates release of T4 through
 Suppress pituitary TSH
cAMP
iii. Acetylcholine – inhibits T4 release through cGMP
iv. Excess carbohydrate – increase of T3 Condition Normal Estrogens Cortisol
v. Cold – increased production of T3 and increase TSH Androgens
responsiveness to TRH Concentration Normal High Low
of Binding
THYROID HORMONES Proteins
1. Triiodothyronine, T3 Total Plasma Normal High Low
 Biological activity (responsobe for the effects of T4, T3, RT3
hormone) Free Plasma Normal Normal Normal
T4, T3, RT3
 10% of hormone secretion
Plasma TSH Normal Normal Normal
 RT3: has no biological activity and is less than
1% Clinical State Euthyroid Euthyroid Euthyroid
2. Thyroxine, T4 (tetraiodothyronine)
Transport of Thyroid Hormone
 90% of hormones secreted (higher concentration
than T3)  Flunctuation in TBPr
o Increase in TBPr
 No biological activity
 Eg, Pregnancy
 Can be conver to T3 or RT3
 Decrease in free T4 and T3
 Prohormone
 TSH stimulation of synthesis
 Increased estrogen and hCG
 Low iodine
 Plasma T4 and T3, normal (euthyroid)
 Goiter in pregnancy

PHYSIOLOGY:THYROID HORMONES Page 3

Condition Normal Hyperthyroid Hypothyroid
Concentration Normal Normal Normal
of Binding
Proteins
Total Plasma Normal High Low
T4, T3, RT3
Free Plasma Normal High Low
T4, T3, RT3
Plasma TSH Normal Low High
Clinical State Euthyroid Hyperthyroid Hypothyroid

Regulation of Thyroid Secretion

TARGET EFFECT MECHANISM

TISSUE
LEPTIN HEART CHRONOTROPIC 1. Increased B-adrenergic
INOTROPIC receptors
2. Enhanced lipolysis
ADIPOSE CATABOLIC Stimulate lipolysis
TISSUE
MUSCLE CATABOLIC Increased protein breakdown
BONE DEVELOP- Promote normal growth and
MENTAL skeletal development
NERVOUS DEVELOP- Promote normal brain
SYSTEM MENTAL development
GUT METABOLIC Increased rate of
carbohydrate absorption
LIPO- METABOLIC Stimulate formation of LDL
PROTEIN receptors
OTHERS CALORIGENIC 1. Stimulate O2 consumption
by metabolically active
tissues (except: testes,
uterus, lymph nodes, spleen,
anterior pituitary)
2. Increase metabolic rate

ACTIONS OF THYROID HORMONE

A. Regulates BMR (basal metabolic rate)
a. Stimulates catabolic and anabolic pathways
like Carbohydrates, proteins and lipid
metabolism
b. Stimulates activity of Na-K pump for
increase in synthesis of transporter protein
B. Thermogenesis
a. Increased sensitivity to adrenergic stimulus
b. Increased synthesis of B-adrenergic
receptors
C. Normal maturation of nervous system in fetus and
infants
a. If Thyroid hormone is deficient it can cause
mental retardation and also cretinism
D. Normal growth and development
a. Facilitate the secretion and response to
growth hormone

PHYSIOLOGY:THYROID HORMONES Page 4

 b. Stimulate linear growth of bones,
endochondral ossification, and maturation of
epiphysis
E. Role on effect of other hormones
a. Reproductive function
b. Glucocorticoids
F. Stimulates degradative processes in skin and hair
G. Inhibits synthesis of Mucopolysaccharides in
intercellular ground substance

EFFECT OF COLD
 Thermogenesis
o Uncoupling protein
 Dissociates oxidative phosphorylation from
ATP generation

METABOLISM OF THYROID HORMONE

 T4
o Prohormone
 Sequential Deiodination (conversion of T4 to T3 or RT3)
o Peripheral deiodinases
 Deiodotyrosines
**the activity of peripheral deiodinases is influenced by other
physiologic factors like caloric restriction or stress
HYPERTHYROIDISM
**decrease in conversion of T4 to T3 is often enhanced with
conversion to RT3  Elevated T4 or T3; low TSH
o First Step  Causes
 T3, Biological activity o Thyroid overactivity, Primary
 RT3, inactive  Grave’s Disease
 Hepatic Conjugation  Autoimmune stimulation by antibodies to
o Biliary secretion as sulfates and glucoronides TSH
 Thyroid stimulating immunoglobulin, TSI
(stimulates TSH receptor which forms
excess T3 and T4)
 Mimics action of TSH, w/o negative-
feedback inhibition
 Thyroid Adenoma
 Exophthalmos

PHYSIOLOGY:THYROID HORMONES Page 5

  Symptoms
o Excitability
o Heat intolerance
o Increased sweating
o Weight loss
o Diarrhea
o Muscle weakness
o Nervousnee or other psychic disorders
o Extreme fatigue/insomia
o Fine hand tremor
 Diagnosis
o Increased thyroxine
o Decreased TSH
 Treatment
o Propylthiouracil, PTU
 Inhibits peroxidase
o Iodide: WOLFF-CHAIKOFF effect
o Surgery
o Radioactive Iodine

HYPOTHYROIDISM
 Low serum T4/T3; elevated TSH
 Causes
o Dietary iodine deficiency
o Iatrogenic
 Surgical removal
 Irradiation
o Sequelae of Hashimoto’s Thyroidits
 Autoimmune thyroditis
 Goiter
 Symptoms
o Fatigue
o Somnolence
o Sluggishness
o Slowed Heart Rate
o Decreased cardiac output
o Failure of Trophic functions (hair, skin)
o Myxedema
 Diagnosis
o Decreased thyroxine
o Increased TSH
 Treatment
o Thyroxine oral supplementation
o Iodine in the diet

CREATINISM (hypothyroidism in infants)

 Causes
o Maternal Iodine Deficiency
o Fetal thyroid dysgenesis
o Inborn error of thyroid hormone synthesis
o Maternal antithyroid antibodies
o Fetal hypopituitary hypothyroidism

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STEPS IN SYNTHESIS OF THYROID

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