the thyroid gland huiping wang ( 王会平 ), phd department of physiology rm c516, block c,...

The Thyroid Gland

Huiping Wang ( 王会平 ), PhD

Department of Physiology

Rm C516, Block C, Research Building, School of Medicine

Tel: 88208252

Email: wanghuiping@zju.edu.cn

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

• Maintains thyroid/plasma ratio of 30:1

• Oxidation of iodide

– Peroxidase: 2I- + H2O2 I2

• Iodination of tyrosine

– Peroxidase

– MIT and DIT

• Formation of T3 , T4 by coupling

– Peroxidase

– MIT + DITT3

– DIT + DITT4

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 developmentshort, 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 onCardiovascular 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 withHyperthyroidism

Nervousness

Heat intolerance

Palpitation(heart rate, >100 per minute)

Muscle weakness

Diarrhea

Increased BMR

Increased appetite

Weight loss(protein)

Common Symptoms Associated withHyperthyroidism

Goiter (enlarged thyroid )

Tremor

Fatigue

Moist skin(metabolism)

Exophthalmos(eye signs; extra-thyroidal)

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, lidretraction and stare

Is not reduced bypropranolol 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 withHypothyroidism

Decreased BMR

Mental slowness

Cold intolerance(metabolism)

Dry cold skin( protein)

Weight gain ( metabolism)

Acroparesthesia (numbness/tingling of hands)

Common Symptoms Associated withHypothyroidism

Thick tongueMyxedema(due to glycosaminoglycan

accumulation in the interstitial space)GoiterSlow speechAmenorrheaConstipation( GI motility)Low sex driveArteriosclerosisprolongation 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

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.

QUIZ

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