Thyroid gland
• Glandula thyroidea (15 - 20 g, frontal side of
trachea under thyroid cartilage
• Two lobes connected by thyroidal isthmus,
lobus pyramidalis
• Strong vascularization
• Round follicles (acini) with one layer of
follicular cells (T3/T4)
• Cavity filled with colloid
• Capillaries with fenestrations
• Parafollicular (C-) cells (calcitonin)
• From day 29 of gravidity (Tg), T4 – 11th week
Follicles are the basic functional units of thyroid gland
Iodine and hormone secretion – general view
• NIS (Na+/I- symporter)
• PDS (pendrin)
• TPO (thyroidal peroxidase)
• TG homodimers and their iodation –
MIT and DIT
• DUOX1 and 2 – together with TPO
oxidation of iodide and
transportation to TG structure
• TPO - connection DIT+DIT (T4) or
DIT+MIT (T3)
• Pinocytosis and phagolysosomes
• Deiodation of MIT and DIT – DEHAL1
(iodotyrosine dehalogenase)
• Other proteins (TSHR)
• Transcriptional factors (TTF-1, TTF-2,
PAX8, HNF-3)
Dietary iodine
- Bioavailability of organic and inorganic I
- ECF + Ery, saliva, gastric juice
- breast milk
- I- filtered with passive reabsorption 60 – 70 %
- loss through stool (10 – 20 mg/day)
- Highest daily intake in Japan (several mg)
- In many countries on decrease – eating habits
Clinical relevance
- Endemic goiter
- Endemic cretinism
Iodine fate in follicular cells
NIS
- Concentration of I in follicular cells
- Transport of other ions (TcO4
-, ClO4
-, SCN-) – clinical significance
- Salivary glands, mammary gland, choroid plexus, gastric
mucosa, cytotrophoblast, syncytiotrophoblast
- Loss of ability to concentrate I in thyroid gland tumors
- TSH
- (+) transcription
- (+) prolonged stay in PM
Pendrin
- also kidneys (Cl-/HCO3
- exchanger) and inner ear
Chloride channel 5 (ClCn5)
- ?
DEHAL1
-MIT and DIT, iodine recyclation
IYD
-iodotyrosine deiodinase
-MIT (+++), DIT (+)
Clinical relevance
-Mutation
-Thiourea derivatives – methimazole,
carbimazole, propylthiouracil (TPO)
Oxidation, organification of iodine and MIT/DIT
synthesis
- Organification = incorporation I in MIT and DIT
- TPO in cooperation with DUOX1 and DUOX2 – peroxide
generation
- DUOX1/2 – NADPH, Ca2+-dependent oxidases
- generation of I2 and I+
- DUOXA2 – maturation and DUOX2 incorporation
-TSH stimulation
- T3 and T4 –TPO catalysis
- Tg – tyreoglobulin, 660 kDA homodimer
- Tg – 134 tyrosines / 25 – 30 iodinated / only 3, resp. 4,
participate in T4 and T3
- 3 – 4 molecules of T4 in Tg (physiological conditions)
- Only 1 T3 in Tg
T3 and T4 secretion
- High supply vs low daily turnover (about 1 %)
- Supply ca 5000 mg T4 – euthyroid state for ca 50 days
- Macropinocytosis and micropinocytosis (apical membrane)
- Endocytosis
- Lysosomes fusion
- Selective proteolysis (cathepsin D and D-like thiol proteases,
active at low pH)
- Release of hormones from Tg in lysosomes
- Potential cytosolic transporter? (MCT8)
- T4 available to deiodases D1 and D2 – modulation of systemic
conversion?
- Inhibition of T4 secretion by iodide
TSH and T3, T4 secretion
- TSHR
- TSH binding
- TRAb (TSHR-stimulating antibody )
- TBAb (thyroid-blocking antibodies )
-LH (+)
-hCG (+)
- G prot. – 11 subtypes of a subunit
- Gs
- Gq/11
- PLC + Ca2+
- iodide efflux, peroxide generation,
iodation of Tg
- PKA
- iodide uptake
- Tg transcription
- transcription and generation of TPO
and NIS
T3 and T4 transport
TBG
- Glycoprotein
- One binding site for iodothyronine
- Half-life ca 5 days
- Clinical significance – sepsis, cardiopulmonary
surgery – cleavage by polymorphonuclear
proteases – part of defensive reaction?
Transthyretin
- Binds one T4 molecule, low affinity
- Half-life ca 2 days
- CSF – relevance ?
- Clinical significance – amyloid polyneuropathy
Albumin
- Low affinity
- Little relevance for T3/T4 transport (max. 10 %)
Low solubility of iodothyronines determines their reversible binding and transport by plasmatic proteins.
Other – lipoproteins (3 – 6 %)
Free T3/T4
TBG concentration and saturation is the main free-T4 determinant.
Importance of glomerular filtration
Glucuronidation of T4 = elimination of T4G
through bile
T4/T3 transport across PM and their cell fate
Transport systems:
- MCT8 (monocarboxylate transporter 8)
- MCT10 (monocarboxylate transporter 10)
- OATP1C1 (organic anion transporting polypeptide 1C1)
(HEB)
Expression in various tissues T3, T4, rT3
CNS (astrocytes) T4
Two-way transport of T3
Role of deiodinase type II
Extrahypophyseal tissues
- 90 % T3 in cytosol
- 10 % T3 in nucleus
Hypophysis
- 50 % T3 in cytosol
- 50 % T3 in nucleus
Deiodination and (seleno-)deiodinases
- all deiodinases require thiol presence as cofactor
(glutathione (GSH), thioredoxin (TRX), glutaredoxin (GRX))
- D1 - main source of plasmatic T3
- D3 - most important „deactivating“ enzyme over-expressed
in tumor tissue
Sources of intracellular T3 and T4
D2 as a source of supplementary
nucleic T3
T3 supply critical for tissues:
- cortex
- BAT
- PIT
Physiological relevance:
- Normal development
- Thyroid gland function regulation
- Cold
Preferential plasmatic T3 utilization
Clinical relevance
- Amiodarone (D1/D2 (-))
- Propylthiouracil (D1 (-))
- Glucocorticoids (D3 (+))
T3/T4 – mechanism of action
-TR
-TRa1
-TRb1
-TRb2
-TRb3
-Heterodimer with RXR
-TRs binding
- T3 with 15-fold affinity compared to T4
CNS, BAT, skeletal muscle, GIT,
lungs, heart
All tissues, mainly kidneys, liver
Hypothalamus and hypophysis
Very low expression, mainly liver,
kidneys, lungs
FeedbackregulationofT3/T4bradycardia,hypothermia
Physiological effects of thyroid hormones
- Non-nuclear receptors
- Interactions with adaptor proteins
- Regulation of transcriptional activity
- cAMP
- MAPK
- Ca2+-ATPase (+)
- Na+/H+ antiporter (+)
Cell response
- Normal growth and development
- Regulation of metabolism
Organ-specific effects of thyroid hormones
Bones
- Bone growth and development
- regulation of activity of osteoblasts/clasts, chondrocytes
- hyperthyroidism – risk of osteoporosis
Cardiovascular system
- Inotropic and chronotropic effect
- (+) cardiac output and IVF
- (-) vascular resistance
- changes in transcriptional activity:
-Ca2+-ATPase
-Phospholamban
-Myosin
−b-AR
-AC
-Na+/Ca2+ exchanger
-Na+/K+-ATPase
-Voltage-gated ion channels
Adipose tissue
- (+) differentiation of adipose tissue, adipocytes proliferation
- (+) lipogenic enzymes
- (+) cell accumulation of lipids
- (+) uncoupling proteins, uncoupling of oxidative phosphorylation
- Hyperthyroidism (+) lipolysis
- (+) b-AR
- (-) phosphodiesterase activity
- (+) cAMP
- Hypothyroidism (-) lipolysis
(+) activity HSL
Liver
- regulation of triglyceride, lipoprotein and cholesterol
metabolism
- (+) fatty acids metabolism
- (+) gluconeogenesis
- (+) mitochondrial respiration
CNS
- expression of genes related myelination, cell differentiation,
migration and signaling
- Axonal growth and further development
GIT
- (+) monosaccharides resorption
- (+) motility
TG regulation – hypothalamo-hypophyseal axis
Synthesis and secretion of thyroid hormones is regulated by feedback mechanism.
TRH
- hypothalamus, CNS, C cells of TG, b cells of
pancreas, myocardium, reproductive organs
(prostate, testes), spinal cord
- Necessity of T3 and T4, relevance of D2
- TRH-DE (TRH-degrading ectoenzyme)
TSH
- Half-life ca 30 min
- Pulsatile secretion, connected to circadian rhythms
- Magnitude changes – starvation, disease, surgery
- Leptin, ADH, GLP-1, glucocorticoids, a-adrenergic
agonists, prostaglandins, TRH (+)
- T3/T4, gastrin, opioids, glucocorticoids (high doses),
serotonin, CCK, IL-1b a 6, TNF-a, somatostatin (-)
Iodide deficit and excess
Deficit
- Rapid T4 decrease, TSH increase
- No change in T3
- Increased synthesis of NIS, TPO, Tg, organification of iodide
and Tg turnover
- Increase D2 in CNS, hypothalamus and hypophysis
- Stimulation of follicular cells (TSH)
- Long-term deficit – decreased D3
- Decrease supplementation under 75 µg/day (China, India,
Indonesia, Africa)
- hypothyroidismus
Excess
- At first increase, then decrease of iodide organification
(Wolff–Chaikoff effect)
- Long-term high iodide supplementation = hypothyroidism
and goitre
- decreased NIS generation
- Immediate inhibition of thyroid hormones secretion
Functions of thyroid gland in fetus and newborn
Thyroid gland and development stages
Fetal thyroid gland - qualitative and quantitative differences
- 10-fold higher T4 production
- D1 (-), D3 (+; liver, skin, tracheobronchial system, urothelial system, GIT epithelium) – T3(-), rT3 (+)
- D2 – generation of T3 in tissues
- Start at the beginning of the 3rd trimester
- TSH during whole development higher than in mother
- Almost no interaction with mother (exception placental transport of T4), high expression of D3 in uterus
and placenta
Thyroid gland in newborns - qualitative and quantitative differences
- Increased TBG level
- Lower T4 levels compared to mother
- Low T3 level in serum, increased levels of rT3 and T3SO4
- Rapid increase TSH 2 – 4 hours after birth, decrease in 48 hours
- Rapid increase T4, T3, Tg – 24 hours (+D1 a D2, adrenergic stimulation of D2 in BAT)
Thyroid gland and aging
- Normal T4 level, decreased T3 level
- TSH according to iodide supplementation
- Benefit of decreased thyroid hormones - longevity
Thyroid gland functions during disease and starvation
Starvation
- Decreased plasmatic T3, increased rT3,
T4 no change
- Upregulation of D3
- Decreased oxygen consumption
- Slower heart rate
- More positive nitrogen balance
= mechanisms to save energy and proteins
- Chronic malnutrition – decreased
plasmatic T3
Disease
- Changes in T4 to T3 D2) conversion – TSH binding
- IL-6
- Increased intra-/extracellular ROS = changes in deiodinase activity – decreased T4 to T3 conversion
BUT! no change in D3
- potential therapy – infusion of TSH + GHRP2
- Bipolar disorder – (+) TSH, (-) T4
- Severe depression – (-) TSH, (+) T4
Hormones and
thyroid gland
Glucocorticoids
- Decreased pulsatile secretion of TSH and TRH
secretion
- Increased activity (expression) of D3
Sex steroids
- Estrogens
- increased TBG
- TSH (+ 15 – 20 %)
- Androgen
- decreased TBG
GH
- (+) T3, (-) T4
- Deiodinase
Hypothyroidism
Disruptions of HYP-ADH-TG axis including
mutations
Goitrogens and treatment
Primary versus secondary
- Cold sensitivity
- Dry cold skin
- Slower movements
- Slow quiet speech
- Bradycardia
- Water retention
- Psychomotoric retardation (children)
- Myxedema (accumulation of protein
complexes, polysaccharides, hyaluronic
acid and chondroitin sulfuric acid in
skin)
- Hypothyroidism since birth = cretinism
Hyperthyroidism
Graves disease, diffusion toxic goiter,
toxic nodular goiter, inappropriate
pharmacotherapy, excessive iodide intake,
thyroiditidis, follicular carcinoma, tumors
producing TSH
- increased BMR
- Changes in catecholamines reactivity
- Exophthalmos - infiltration of lymphocytes
and periocular fibroblasts into extraocular
muscles and tissue
- unrest
- Tachycardia
- Hyperventilation
Hypo- versus hyperthyroidismus
Parameter Hypothyroidism Hyperthyroidism
BMR (-) (+)
Carbohydrate metabolism Gluconeogenesis (-)
Glycogenolysis (-)
Glycemia (N)
Gluconeogenesis (+)
Glycogenolysis (+)
Glycemia (N)
Protein metabolism Proteosynthesis (-)
Proteolysis (-)
Proteosynthesis (+)
Proteolysis (+)
Muscle mass (-)
Lipid metabolism Lipogenesis (-)
Lipolysis (-)
Serum cholesterol (+)
Lipogenesis (+)
Lipolysis (+)
Serum cholesterol (-)
Thermogenesis (-) (+)
Autonomic nervous system Plasmatic catecholamines (N) Increased reactivity – b-AR (+)
Plasmatic catecholamines (-)
Examination of hypothalamus –
adenohypophysis – thyroid gland axis
TSH – immumometric methods
Overall T3 and T4 – immunochemical methods (immunoassays)
Free T3 and T4
rT3
Antibody levels - (anti-Tg, anti-TPO, TSIs – thyroid-stimulating
immunoglobulins
Thyroid nodules – ultrasound, biopsy, scan – I-123, Tc-99