the thyroid gland - phys.szote.u-szeged.hu · max: early morning min: afternoon cortisol high...
TRANSCRIPT
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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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5
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)