Download Thyroid gland

The Thyroid Gland
Huiping Wang (王会平), PhD
Department of Physiology
Rm C516, Block C, Research Building, School of
Medicine
Tel: 88208252
Email: [email protected]
Outline
• Thyroid Hormones
– Types
– Biosynthesis
– Storage and Release
– Transport
– Physiological Functions
• Mechanisms of TH action
• Regulation of thyroid hormone secretion
• Thyroid disorders
The Thyroid Gland
• Located at anterior part of neck on either side of trachea
– The thyroid gland straddles the esophagus, just below the larynx,
in the neck.
• One of the largest endocrine glands
• Comprised of 2 lobes; 20 g wt
• Rich in blood supply
The Thyroid Gland
• Thyroid follicular cell
– T4 and T3 increase metabolic rate
• Parafollicular cell (C cell)
– Calcitonin regulates calcium metabolism
Thyroid Gland Follicle
• The thyroid gland is composed of many follicles
• Each follicle contains colloid (thyroglobulin +hormones)
• Colloid is absorbed back into the follicle epithelial cells upon
stimulation
• Follicular cells take part in almost all stages of TH synthesis and
secretion
Types of Thyroid Hormones
•
•
•
90% of metabolically active hormones secreted by thyroid is thyroxine
(T4), 10% is triiodothyronine (T3), and less than 1% is rT3
Iodide is required (1mg/week) for thyroid hormone synthesis
Thyroid Hormones
• Thyroxine (T4)
– Major hormone released from thyroid follicles
– Contains 4 iodine atoms
– More abundant than T3
– Synthesis occurs in follicular cell colloid via the
combination of DIT + DIT
Thyroid Hormones
• Triiodothyronine (T3)
– Generally formed from T4 by cleaving an iodine
molecule (deiodinase in target cells)
– 4 times more potent than T4
– Contains 3 iodine atoms
– Synthesis occurs in the follicular cell colloid via the
combination of DIT + MIT
Biosynthesis of Thyroid Hormones
• Materials
– Iodine (in the form of iodide—I-)
• 50mg/year
• Iodized table salt (1 sodium iodide/100,000 NaCl)
– Tyrosine
• Thyroglobulin (TG)
>70 tyrosines
Biosynthesis of Thyroid Hormones
•
Iodine/iodide trapping
–
Iodide pump
•
•
Oxidation of iodide
–
•
•
Maintains thyroid/plasma ratio of 30:1
Peroxidase: 2I- + H2O2 I2
Iodination of tyrosine
–
Peroxidase
–
MIT and DIT
Formation of T3 , T4 by coupling
–
Peroxidase
–
MIT + DITT3
–
DIT + DITT4
Storage and Release of Thyroid
Hormones
• Storage
– In the follicles
– In the form of TG (30 T4)
– For 2 ~3 months
• Release
– Stimulated by TSH
Concentration in plasma
T3: 1.2 ~3.4 nmol/L
T4: 85 ~142 nmol/L
Transport of T4 and T3 to the Tissues
• Binding form:99%
– Most T4 and T3 bound to plasma proteins synthesized by liver:
• Thyroxine-binding globulin (TBG): mainly
• Thyroxine-binding prealbulmin (TBPA)
• albulmin
– Slowly released to the tissue cells, slower for T4 due to its higher
affinity
– Slow onset and long duration of action
• Free form:1% ( T3)
Physiological Functions of TH
• Effect on
– Growth
– Metabolism
– Nervous System
– Cardiovascular System
– GI
– Muscles, sexual function
Effects of TH on Growth
• Is essential for growth in children
– Promote bone formation and maturation
– Promote growth and development of brain
(fetus and baby)
• Have synergistic effect with GH, IGF-1,
insulin and other growth factors
Tadpole  frog
Effects of TH on Growth
Cretinism:
deficiency of thyroid hormone during the period of fetal and early neonatal development
short, stocky stature & mental retardation
Metabolic Effects of TH
• Increase cellular metabolic activity
– Calorigenic action
• ↑ number & activity of mitochondria →
ATP ↑
• ↑ Na+, K+ -ATPase and active transport of
ions (Na, K) → heat production ↑
• ↑ O2 consumption & BMR
Metabolic Effects of TH
• Carbohydrate metabolism
– glucose oxidation
– gluconeogenesis and glycogenolysis
Too much blood glucose (Diabetes)
• Fat metabolism
–  lipolysis （Triglyceride  FFA + glycerol）
– Oxidation of free fatty acid
–  serum cholesterol（excretion into GI）
• Protein metabolism
–  Protein synthesis (normal)
–  Protein catabolism (hyperthyroidism)
hyperthyroidism
Effects of TH on Nervous System
• Important for maturation of CNS in perinatal period
• Enhance wakefulness, alertness, responsiveness to various stimuli,
auditory sense, awareness of hunger, memory and learning capacity
• Normal emotional tone also depend on proper thyroid hormone
• Increase the speed and amplitude of peripheral nerve reflexes
• Hyperthyroidism: hyperexcitability, insomnia, loss of concentration
• Hypothyroidism: mental retardation, sleepiness
Effects of Thyroid Hormones on
Cardiovascular System
•
Increase blood flow and cardiac output
– ↑ metabolism → ↑ utilization of O2 & ↑ metabolic end products from tissue →
vasodilatation
– ↑ cardiac output ensures sufficient O2 delivery to the tissues
•
Increase heart rate (easy to detect!)
– increase adrenergic activity（  response to adrenaline/noradrenaline）
– increase enzymatic activity
•
Affect heart strength
– slightly increase of thyroid hormone increases heart strength
– marked increase of thyroid hormone decreases heart strength
•
↑stroke volume + ↓peripheral resistance → pulse pressure ↑
Effects of Thyroid Hormones on GI
• Increase appetite and food intake
• Increase secretion of digestive juices
• Increase mobility of GI
– Diarrhea often results from hyperthyroidism
Effects of Thyroid Hormones
• On muscles
– hyperthyroidism → muscle weakening (catabolic effect)
– fine muscle tremor is a characteristic sign for hyperthyroidism
– hypothyroidism → muscles sluggish
•
On other endocrine glands
– ↑ secretion of insulin and cortisol
•
On sexual function
– loss of libido
– impotency
– abnormal menstruation
Mechanisms of TH action
– T3 and T4 act by binding to nuclear receptors which are
expressed in most tissues
– T3 has 10 times the affinity for thyroid receptor as T4
– Transcription of large numbers of genes
– Synthesis of great numbers of proteins
Regulation of thyroid hormone secretion
• Hypothalmico-pituitary-thyroid axis
– TRH  TSH  T3/T4
– Negative feed-back of T3/T4
• Environmental factors
– cold, stress
• Wolff-Chaikoff Effect
– autoregulation by I
Hypothalmico-pituitary-thyroid axis
• Hypothalamus
– TRH
• Tripeptide
• TSH secretion
– Cold:  TRH release
Hypothalmico-pituitary-thyroid axis
• Pituitary
– TSH
• Glycoprotein
•  T3, T4 synthesis and release
•  Size of the thyroid cells
• cAMP mediated mechanism
– Hyperthyroidism
• thyroid stimulating immunoglobulin (TSI)
Hypothalmico-pituitary-thyroid axis
• Thyroid
– Feedback effect of thyroid
hormone
T4 is converted into T3 in
pituitary and T3 acts as the
final effector to turn off TSH
Iodine-Deficient Goiter
TSH is a trophic hormone, it stimulates not only T3/T4 secretion but also protein
synthesis in follicular cells. Therefore,  exposure in thyroid  size
Wolff-Charkoff effect
• autoregulation by I
– low I intake stimulates
synthesis of iodide trap
– high I intake (>2 mg/day)
inhibits trap function and
synthesis
Thyroid disorders
Hyperthyroidism
Hypothyroidism
Hyperthyroidism
• The most common cause
– B lymphocytes synthesize immune globulins
(Ab called thyroid stimulating
immunoglobulin, TSI) that bind to and active
the TSH receptor, producing all the actions of
TSH on thyroid (Graves’ disease).
Common Symptoms Associated with
Hyperthyroidism
Nervousness
Heat intolerance
Palpitation(heart rate, >100 per minute)
Muscle weakness
Diarrhea
Increased BMR
Increased appetite
Weight loss(protein)
Common Symptoms Associated with
Hyperthyroidism
Goiter (enlarged thyroid )
Tremor
Fatigue
Moist skin(metabolism)
Exophthalmos(eye signs; extrathyroidal)
Graves’ Eye Disease
An abnormal protrusion of the
eyeball in the orbit when
observed from the side.
Swelling within the orbital
cavities and enlargement of
the perorbital muscles behind
the eyes
Note the proptosis, lid
retraction and stare
Is not reduced by
propranolol treatment
Diagnose of Hyperthyroidism
• Diagnoses
– Assessment of thyroid function
•  serum T4 and T3
•  serum TSH
Treatment of Hyperthyroidism
• Drugs
– Treatment of symptoms
• β-blocker (propranolol)
– Inhibition of thyroid hormone synthesis by inhibiting thyroid
peroxidase
• Propylthiouracil (PTU)
• Methimazole
• Radioactive iodine
– to radiate the gland with high energy gamma rays, 3 months
max. effect
• Surgery
– partial thyroidectomy
Hypothyroidism
• Causes
– Primary (thyroid; autoimmune disease,
partial thyroidectomy)
– Secondary (pituitary gland) or tertiary
(hypothalamus)
– Common cause
• an autoimmune disorder called Hashimoto’s
thyroiditis. Antibodies against the thyroid are not
stimulatory, but are part of an immune process that
blocks and destroys thyroid function
Common Symptoms Associated with
Hypothyroidism
Decreased BMR
Mental slowness
Cold intolerance(metabolism)
Dry cold skin( protein)
Weight gain (  metabolism)
Acroparesthesia (numbness/tingling of
hands)
Common Symptoms Associated with
Hypothyroidism
Thick tongue
Myxedema(due to glycosaminoglycan
accumulation in the interstitial space)
Goiter
Slow speech
Amenorrhea
Constipation( GI motility)
Low sex drive
Arteriosclerosis
prolongation of tendon reflex
 cardiac output (remember permissive
effect of TH to
epinephrine/norepinephrine).
Hypothyroidism
• Assessment of thyroid function
– low serum free T4
– greatly elevated serum TSH
• Treatment
– thyroxine (T4) replacement
QUIZ
An absence of thyroid hormones during fetal
development leads to
a. acromegaly.
b. Cushing's Syndrome.
c. cretinism.
d. Grave's disease.
e. Addison's disease.
QUIZ
An absence of thyroid hormones during fetal
development leads to
a. acromegaly.
b. Cushing's Syndrome.
c. cretinism.
d. Grave's disease.
e. Addison's disease.
QUIZ
A subject consuming a diet deficient in iodine is likely to have
a.
a low plasma concentration of thyroxine due to reduced secretion of TSH by the
pituitary gland.
b.
a low plasma concentration of thyroxine and an enlarged thyroid gland.
c.
a high plasma concentration of TSH.
d.
a low plasma concentration of thyroxine due to reduced secretion of TSH by the
pituitary gland and a low plasma concentration of thyroxine and an enlarged thyroid
gland.
e.
a low plasma concentration of thyroxine and an enlarged thyroid gland and a high
plasma concentration of TSH.
QUIZ
A subject consuming a diet deficient in iodine is likely to have
a.
a low plasma concentration of thyroxine due to reduced secretion of TSH by the
pituitary gland.
b.
a low plasma concentration of thyroxine and an enlarged thyroid gland.
c.
a high plasma concentration of TSH.
d.
a low plasma concentration of thyroxine due to reduced secretion of TSH by the
pituitary gland and a low plasma concentration of thyroxine and an enlarged thyroid
gland.
e.
a low plasma concentration of thyroxine and an enlarged thyroid gland and a high
plasma concentration of TSH.
Summary
• Types of Thyroid Hormones
– thyroxine (T4)
– triiodothyronine (T3)
• Biosynthesis of Thyroid Hormones
–
–
–
–
Iodine/iodide trapping
Oxidation of iodide
Iodination of tyrosine
Formation of T3 , T4 by coupling
• Storage and Release of Thyroid Hormones
• Transport of T4 and T3
Summary
• Physiological Functions of TH
– Effect on Growth, Metabolism, Nervous System, Cardiovascular
System, GI
• Mechanisms of TH action
• Regulation of thyroid hormone secretion
– Hypothalmico-pituitary-thyroid axis
– Wolff-Chaikoff Effect
• Thyroid disorders
– Hyperthyroidism
– Hypothyroidism