The thyroid gland - u-szeged.hu · Max: early morning Min: afternoon Cortisol High amount of Iodine Inhibitors of synthesis + + Permanent stress Fasting (AgRP) Warmth Dopamin, somatostatin

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• I. Anatomy

• II. Hormones

(synthesis, release, transport, metabolism)

• III. Regulation of hormone secretion

• IV. Action mechanism

• V. Effects

• VI. Hypothyreosis

• VII. Hyperthyreosis

The thyroid gland

Theodor Emil Kocher 1841-1917

1909 he was awarded the Nobel Prize

for his work on the thyroid gland.

His book Erkrankungen der

Schilddrüse (Diseases of the thyroid

gland ) discussed the etiology,

symptology and treatment of

goitres.

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I. AnatomyI. Anatomy

(15-25 g)

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Blood flow:

600 ml/100g/min

120 ml/min (2.5%)

StructureStructure

• Folliculus

– Thyroid cell (thyrocyte)

– Colloid

folliculus

Parafollicular (C) cells

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II. HormonesII. Hormones

Thyroxine (TThyroxine (T44) és triiodothyronine (T) és triiodothyronine (T33))

Iodine containing amino acid

derivatives

Lipophylic

3,5,3’ triiodothyronine

Thyroxine (3,5,3’,5’

tetraiodothyronine)

inactive reverse-3,3’,5’

triiodothyronine: rT3

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A/ SynthesisA/ Synthesis1. Iodide uptake into the thyreocyte

2. Iodide transport into the colloid

3. Iodide => iodine conversion (I- => I2)

4. Synthesis of thyroglobulin (glycoprotein) in the thyreocyte

5. Secretion of thyroglobulin into the colloid

6. Iodination of tyrosin side chains in thyroglobulin in the follicle (thyroid peroxidase in apical membrane)

7. Coupling of 3- monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT) → T3, T4 (coupling to protein)

Thyroglobulin (TG)

Tyrosine Tyrosine Tyrosine

I. I. I. I. I.

...

Iodine metabolism

Total body I: 8000-9000

µg

90% in the thyroid

gland (7500 µg)

Absorption: NIS

10%: GI glands

Kidney: filtration

(freely), passive

reabsorption

200-

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1. Iodide uptake into the thyreocyte (2Na+/1I-transporter). Inhibitors:

perchlorate (ClO4-), perchnetate (TcO4

-), sulfocyanate (SCN-) {cabbage}

2. Iodide transport into the colloid (I/Cl transporter = pendrin)

3. Iodide => iodine conversion (peroxidase); inhibitors: sulphur

containing organic compounds {propil-thiouracil,

mercaptoimidazole, sulfonilurea- and tiourea derivatives}

IODIDE TRANSPORT (20-40 times greater cc. IC)

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Thyroglobulin• 2 subunit (330-330 kDa)

• 10% carbohydrate

• 70-120 tyrosine resides (4-8 is incorporated into thyroid hormones)

• Iodinated thyrosin (10-20 %):

• Hormone storage (2-3 months)

Thyroglobulin (TG)

Tyrosine Tyrosine Tyrosine

I. I. I. I. I.

...

4. TG synthesis,

5. TG secretion

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6. Iodination of tyrosin side

chains (C3, C5) in

thyroglobulin in the follicle

(thyroid peroxidase in apical

membrane)

7. Coupling of 3,5-

diiodotyrosine (DIT) with

3,5-diiodotyrosine (DIT)

or 3- monoiodotyrosine (MIT)

(oxidative condenstation)→T3, T4 (coupling to protein)

23% MIT

33% DIT

35% T4

7% T3

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B/ ReleaseB/ Release• Endocytosis into the thyreocytes → Proteolysis of

TG, release of T3 and T4 → secreting T3 and

T4 into capillary blood

• Daily release:

– T4: 80 µg,

– T3: 4 µg,

– rT3: 2 µg

• In tissues:

– 30% of T4 is converted to T3, 45% to RT3

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T3

31 µg T4

80 µg

RT3

38 µg

4

80

2

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Thyroid

27 36

T4 T3 RT3

Plasma concentration

Total (µg/dl) 8 0,12 0,04

Free (ng/dl) 2 0,28 0,20

Half-life time (day) 7 1 0,80

Turnover per day (%) 10 75 90

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C/ Transport in the bloodC/ Transport in the blood• Hydrophobic => bind to plasma proteins => inhibit the excretion by urine, buffer

(stabilization of the free hormone level), solubility

• 0.02-0.03 % of the total T4 and 0.2-0.3 % of the total T3 is free.

• Transport proteins:

– Thyroxine Binding Globulin (TBG) low capacity, high affinity (alpha-globulin)

• 67% T4, 46% T3

– Thyroxine Binding Prealbumin (TBPA), transthyretin: low affinity, high capacity

• 20% T4, 1% T3:

– Albumin: high capacity, low affinity

• 5- 13% T4, 53% T3

– Estrogen (pregnancy) increases the synthesis of TBG

– Androgens, cortisol decrease the synthesis of TBG

D/ MetabolismD/ Metabolism

• Deiodination: deiodinases (D1, D2, D3)

selenocysteine containing enzimes

• D1: RT3 => 3.3’T2; T4=> T3; MIT/DIT breakdown

– Adenohypophysis, thyroid gland, liver, kidney

• D2: T4=>T3

– Adenohypophysis, skeletal muscle, brain (astroglia),

brown fat tissue

• D3: T4=> RT3

– Brain, skin, reproductive tissues, placenta

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• Roles:

– Conversion T4 to T3 or RT3 (intracellularly)

– Production of deiodotyrosine

– Iodine release from MIT and DIT

Deficiency causes Iodine deficiency. Thiourea inhibits

D1

Decreased deiodination: selenium deficiency, burns,

trauma, cancer, renal failure, myocardial infaction,

febrile states

• Fasting: decreased T3, increased RT3 conversion

• Desamination (-NH2): iodoacetic acid

• Liver: conjugation to form sulfates and

glucuronides => bile => intestine =>

enterohepatic circulation

These hormone can be absorbed in the

intestine!!!

Direct passage of T4, T3 into the

intestine

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III. Regulation of hormone secretionIII. Regulation of hormone secretion

Hypothalamus

Adenohypohysis

TRH (tripeptide)

Portal circulation

TSH

T3 és T4

Permanent cold

Birth

Excess calory intake

Leptin, MSH

Low circadian

Rhythm

Max: early morning

Min: afternoon

Cortisol

High amount of Iodine

Inhibitors of synthesis

+

+

Permanent stressFasting (AgRP)

Warmth

Dopamin, somatostatin

Growth

factors

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TSH (glycoprotein, 211 AA)

TSH LH FSH

Pulsatile secretion

Action mechanism: metabotropic receptor Gs=> cAMP↑; PLC

T1/2: 60 min; metabolism: liver, kidney

TSH EffectsTSH Effects

TSH + TSH-receptor complex ⇒ cAMP level ↑

A/ acute/fast effects:- Activity of iodide pump ↑=> Iodide uptake ↑

- Synthesis of thyroglobulin ↑

- Iodination of thyroglobulin (peroxidase) ↑

- Formation of thyronin ↑

- Colloid endocytosis (Megalin) ↑

- Secretory activity of thyroid cells ↑

- T4 => T3 ↑ (5’-deiodinase)

– Result: levels of T3 and T4 ↑↑

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B/ Chronic effects:

• Trophic effects

– Increased cell volume (hypertrophia)

– Increased cell number (hyperplasia)

– Increased vascularisation, blood flow

– Proliferation of connective tissue

– Hyperfunction: goiter

• Lack of TSH: thyroid hypofunction

• Overproduction: thyroid hyperfunction

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Effects of iodide uptake

• Low or normal iodide uptake (400-500 µg)

– The rate of hormone synthesis is directly

related ot iodide availability

• High iodide uptake (above 2 mg)

– It inhibits the hormone synthesis (Wolff

Chaikoff effect)

• Inhibition of NADPH oxidase,

• Inhibition of NIS and peroxidase genes

IV. Action mechanismIV. Action mechanismIntake: passive + transporter

Receptors:

TRα1 (heart, skeletal)

TRα2 (inhibits the others)

TRβ1 (brain, liver, kidney)

TRβ2: hypothalamus,

hypophysis)

Hormone-sensitive

Nuclear transcription

Factor

T3: more potent

acts more rapidly

TRE: thyroid hormone

response/regulatory element

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V. EffectsV. Effects

a) Regulation of gene transcriptions

b) Na-K pump activity ↑

c) Number of mitochondria ↑

d) UCP proteins ↑ → decoupling of

oxidative and phosphorilating processes

e) Sensitivity and number of β1-receptors ↑

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V/1. Calorigenic actionsV/1. Calorigenic actions• Increased rate of basal metabolism (except: adult

brain, testis, uterus, lymph nodes, spleen, anterior

pituitary)

– Increased heat production => body temperature ↑=>

vasodilation, sweating

– Increased O2 consumption

– Increased CO2 production

– (cold adaptation)

V/2. Intermediary metabolismV/2. Intermediary metabolism

Fat:

– Lipolízis in adipose tissue (β3-rec.): ↑ (decreased fat storage)

– Endothelial lipoprotein lipase ↑

– Se triglyceride ↓ (increased synthesis in the liver)

– FFA synthesis ↑=> Se FFA level ↑

– Oxidation of FFA ↑ => ketogenesis ↑

– Chylomicron clearance ↑

– Se Cholesterol ↓• liver LDL-rec. ↑=> increased LDL intake

• Cholesterol oxydation ↑

• Cholesterol synthesis ↑

• Biliary secretion of cholesterol ↑

– Potentiation of the effects of adr., noradr, glucagon,

cortisol, GH.

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Carbohydrate =diabetogenic

– glycogenolysis ↑– gluconeogenesis ↑– Glucose oxydation ↑– Insulin sensitivity ↓– Potentiation of the effects of adr., noradr, glucagon, cortisol,

GH.

Protein:

– Each process ↑ (synthesis and proteolysis) ⇒ Increased protein turnover;

– (negative N-balance in hyperfunction)

– Increased uric acide in urine (in hyperfunction)

– Potentiation of the effects of adr., noradr, glucagon, cortisol, GH.

• Vitamins: increased need

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V/3. Cardiovascular effectsV/3. Cardiovascular effects

• Heart contractility ↑ => Stroke volume↑– β1-receptor ↑

– α MHC ↑ (increased ATP-ase activity)

– β MHC ↓

– SR Ca2+-ATP-ase ↑

– Na+-K+-ATP-ase ↑

– K+-channels ↑

– Na+-Ca2+-exchanger ↓

• Heart rate ↑

• Cardiac output ↑

• Release of vasodilator factors in tissues and effect of

heat ⇒ vasodilation (mainly in the skin vessels)

=> Peripheral resistance ↓ increased water and

Na+ reabsorption) => blood volume ↑

• Pulse pressure ↑

• Mean arterial blood pressure: No change

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V/4. Respiratory effects

• Resting respiratory rate ↑

• Minute ventilation ↑

• Ventilatory responses to hypoxia and

hypercapnia ↑

V/5. GI effectsV/5. GI effects

• Intestinal motility ↑

• Glucose absorption ↑

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V/6. Effects on nervous systemV/6. Effects on nervous system

• Postnatal development (normal neural, mental

development!!)

– Development of synapses

– Differentiation

– Myelinisation

• Development of the ear

• Reflex response

• Muscle tone

• Cognitive function: memory, learning

• Increased response to catecholamines

• Increased activation of reticular activating system

• Growth/ maturation– Ossification

– Linear growth of bones

– Tooth development

– Increases GH secretion and effect

– It is necessary for normal maturation of edidermis, hair follicles, nails

• Synthesis of mucopolysaccharides (hyaluronic acid, chondroitin sulfuric acid) in the subcutaneous tissue ↓

• Degradation of mucopolysaccharides in subcutaneous tissue ↑

• Normal body weight

V/7. EtcV/7. Etc

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• Erythropoietin secretion ↑ => red blood cell ↑ => O2

carrying capacity ↑• Necessary for hepatic conversion of carotine to

vitamin A

• Necessary for milk secretion

• Essential for normal menstrual cycle and fertility

• Skeletal muscle: increased protein metabolism, influence of MHC genes.

• Normal kidney function

• It enhances the metabolism of insulin, ACTH, PTH in the liver

V/7. EtcV/7. Etc

VI. HypothyreosisVI. Hypothyreosis

Causes: thyroid, pituitary, hypothalamic

iodide deficiency, autoimmune disease

A/ Hypothyroid in utero/newborn:

• Cretin/cretinism – dwarf with

abnormal stature and neural functions

(including cognition: mentally

retarded)– Decreased secretion of GH

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Characteristics• Decreased myelinisation and synapsis formation

– Mental retardation

– Increased reflex latency

– Dull expression of face

• Marked delay in development of the bones– Short stature, malformed legs

– Flat broad nose, hypoplastic mandible

• Deafness

• Muscle weakness– Sluggish movement,

– Decreased muscle tone, (stiffness)

– Prominent abdomen

• Obesity

• Cold intolerance

• Dry scaly skin

• Delayed puberty

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B/ In adult

Causes:

Hypothalamus

Hypophysis

Radiation

Surgical removal

Iodine deficiency

Autoimmune disease

Signs• Decreased basal metabolism (40%), O2-consumption =>

weight gain

• Decreased thermogenesis => cold intolerance

• Heart: HR ↓, contractility ↓ => CO↓

• Hypovolemia/ anemia

• Neuronal disfunctions

– Abnormal mental functions

– Bad memory

– Depression

– Fatigue

– Sleepiness

– Sluggishness

– Hyporeflexia

• Muscle weakness=> extreme muscular sluggishness

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• Constipation

• Elevated Se cholesterol level=> atherosclerosis

• Hair is coarse and sparce

• Skin is dry and yellowish

(carotenemia)

• Voice is husky and slow

• Myxedema: nonpitting type of edema

– Joint stiffness

– Enlarges tongue

– Neural pression

• Decreased sexual functions,

menstrual disfunction

VII. HyperthyreosisVII. HyperthyreosisCauses: thyroid, pituitary, hypothalamic

autoimmune: Graves’ disease (thyroid

stimulating immunoglobulin)

tumor

Signs:

Increased basal metabolic rate => O2

consumption and CO2 production ↑=>

weight loss, hyperphagia

Increased heat production => vasodilation,

sweating, heat intolerance, warm, red, soft

skine

Increased heart rate, Peripheral resistance ↓

Increased pulse pressure; Normal blood

presure

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Normal level of cathecholamines

Hyperreflexia, fine tremor of the outstretched fingers

High state of excitability, restlessness, nervousness, psychic disorders

Decreased concentration capacity; attention deficit

Hyperactivity disorder

Insomnia

Muscle weakness (Myopathia thyreotoxic)

Fatigue

Diarrhea

Karl Adolph von Basedow

(German) 1799-1854

Robert James Graves

(Irish) 1796-1853

Autoimmune disease (antibody against TSH) Exophtalmos:

activation of TSH receptors on preadipocytes (fibroblasts) => cytokine release => inflammation, edema

Basedow-Graves’-disease

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GOITER:

Increased volume of thyroid gland (TSH)

– Graves’ disease: hyperfunction,

– Iodide deficiency goiter: hypofunction

– Goitrogens: All of the substances which inhibit the

iodide uptake (thiocyanate: competition for pump) or

the peroxidase enzyme (propylthiouracil)