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82. Thyroid hormones: biosynthesis, regulation, effects

Ferenc Domoki February 19, 2019

Learning objectives

� Functional morphology

� Hormone biosynthesis and metabolism

� Regulation of thyroid function

� Effects of thyroid hormones

� Medical Physiology aspects (1 in 3 people has thyroid dysfunction)

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<25 g weight, 2 lobes + isthmus4 supplying artery, highly vascularized!, large blood flow:5-7 ml/min/g blood flow (brain: 0.5 ml/min/g!)large metabolic activityclosely associated parathyroid glands

Follicle: lined with single layer of epithelium, height depends on activity (cubic shape on average)Apical membrane microvilli – large surface area – site of synthesisLumen: filled with „colloid”, contains thyreoglobulin (TG)Parafollicular connective tissue: dense capillary network, C cells (clear cells), calcitonin

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The products of the follicles: T4

and T3 : special amino acids

Overview of hormone synthesis: T4/T3 are synthesized in the TG EXTRAcellularly, in the colloid!!!

1. Iodide trapping (uptake)

2. Thyreoglobulin (TG) synthesis and secretion

3. Organification of iodine and coupling

4. Storage

5. Endocytosis and proteolysis of TG, release of free T4/T3

6. Deiodination of T4 to T3 or rT3 (in the thyroid and target cells).

A TSH-R activity stimulates all steps save the storage!

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Iodine metabolism

� ~ 0.5 mg consumed (RDA!!!), 0.4 mg absorbed

� ~20%t taken up by thyroid (NIS), most built into T4/T3

� Inorganic I is excreted through the urine, small amounts of organified I through GIS

~9 mg!

Iodide trapping: secondary active transport by NIS

� Basolateral membrane: Na+-I- symporter (NIS), Na+-K+ pump

� Apical membrane: pendrine: I--Cl-? antiporter (facilitated diffusion)

� NIS inhibitors: Li+, perchlorate (ClO4

-), thiocyanate (SCN-), nitrate (NO3

-); pertechnate (99mTcO4

-)

Na+

Na+

K+I-

I- K+K+

I-

I-

cAMP↑

colloid

X-

X-

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Synthesis and iodination of thyreoglobulin (TG)

� 660 KD (!!) Tyr rich (~ 100 aa) glycoprotein consisting two equal-sized subunits

� Secreted by exocytosis into the colloid

� Iodination of TG takes place extracellularly at the luminal membrane of follicular cells in the colloid.

� 4 components: 1. TG, 2. Iodide, 3. Thyreoperoxidase (TPO) a membrane bound enzyme (complex) and 4. dual-oxidase 2 (DUOX).

Steps:

� 1. Iodide peroxidation (electron transport) produces reactive I• radicals (needs H2O2 produced by DUOX)

� 2. Iodination: production of MIT and DIT from tyrosine residues of the TG

The coupling reaction: iodothyronine formation

� Transfer of iodophenol moiety from one iodotyrosine to the phenolic OH group of a second iodotyrosineresidue

� This step is also catalysed by the TPO

� Production of TG bound T4, T3 and rT3

� TG contains app. 100 Tyr; 20% is iodinated and only 4-8 participate in the iodo-thyronine synthesis

� TPO has pharmacological inhibitors: thionamides

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Release of T4/T3 � TG uptake through pinocytosis (“colloid

droplets”)

� Enzymatic proteolysis in phagolysosomes – liberation of T4 /T3,

MIT, and DIT into the cytoplasm

� T4 will be in part converted to T3 by deiodinase (5’ deiodinase, typ. I.) enzyme (TSH sensitive)

� Both T4 and T3 pass the basolaterall membrane with facilitated diffusion (MCT8)

� Recycling of iodine: MIT/DIT deiodination by the iodotyrosine-dehalogenase

� Iodide and tyrosine will be available for de novo TG synthesis (MIT, DIT can not be used)

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TSH effects:

1. All aspects of T4/T3

synthesis and release are

stimulated.

2. Trophic and cell

proliferation effect

3. Vascularization via VEGF

release

4. high TSH results in:

GOITER (hypertrophy and

hyperplasia

Regulation of the thyroid gland

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Details..

TRH is a tripeptide, the TRH receptor is a metabotropic receptor coupled to IP3/Ca2+ signalling.

The TRH and TSH gene is repressed by T3 LOCALLY produced from T4 by Type II 5’ deiodinase

TSH belongs to the glycoprotein hormons, its receptor is a metabotropic receptor coupled to cAMP

Other hypothalamic hormons like dopamine and somatostatin can affect TSH

Transport in blood� T4 >>T3 10 :1 ratio in blood

� 99.98% of circulating T4 and 99.5% T3 are protein-bound, 0.02 and 0.5% FREE in plasma

� LIVER is responsible for the production of thyroid binding globulin (TBG), transthyretin (TTS) and albumin

� Changes in TBG affect blood total hormone levels, but not free hormone levels

� Large protein-bound fraction ensures even delivery

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Metabolism of T4: peripheral production of T3: the last step of synthesis inside the target cells INTRACRINE effect

� Type 1: kidney, liver, skeletal muscle, thyroid

� Type 2: brain, pituitary

Active!

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Thyroid hormone receptor regulates gene expression

T3 >>T4 10 :1 ratio at receptor binding!

T3/T4 effects: overview

� Pleiotropic: effect in virtually all organs

� Promotes metabolism to provide energy for growth, development, renewal (turnover), heat production

� Normal levels required for the normal function of many other endocrine systems and the CNS as well

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T3/T4 effects: thyroid regulation

� T3 inhibits TRH production in the hypothalamus

� inhibits TSH production in the pituitary

� induces a TRH degrading enzyme in the pituitary

T3/T4 effects: calorigenic effect

� Increased thermogenesis, core temperature, basal metabolic rate, oxygen consumption

� Plays a role in climatic cold adaptation.

� Mechanism: Increased ATPase activity (Na-K ATPase, other ATPases), increased thermogenin (UCP) expression (brown adipose tissue, skeletal muscle mitochondria), increased futile metabolic circuits (eg glycogenesis-glycogenolysis) temperature per se.

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T3/T4 effects: carbohydrate metabolism

� Increased intestinal glucose absorption (postprandial hyperglycemia)

� increased hepatic glygogenesis, gluconeogenesis, hepatic and muscular glycogenolysis

� increased glucose oxydation

� Increased metabolism of glucoseaminoglycans (GAG)-s (myxedema)

T3/T4 effects: protein metabolism

� Increased protein turnover

� increased amino acid oxydation

� may result in negative protein balance

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T3/T4 effects: lipid metabolism

� Increased lipolysis: brown and white adipose

tissue (β3-rec.)

� increased free fatty acid oxydation (skeletal musle, liver) – increased lipogenesis too

� increased cholesterol biosynthesis (HMG-CoA reductase) and elimination (LDL receptors). Net effect: decreased serum cholesterol.

� Increased bilirubin and beta-carotin metabolism.

T3/T4 effects: on cardiovascular system direct and indirect effects

� Increase the number and affinity of β-adrenergic receptors, and Gs proteins in the heart HR, Contractility ↑

� increased α-myosin heavy chain(MHC) and sarcoplasmic Ca-ATPase (SERCA) expression.Contractility ↑

� increased metabolism and heat production of

the body: TPR ↓

� Cardiac output ↑ =Stroke volume↑*Heart rate ↑

� SABP ↑, DABP↓, MABP~, PP↑ ↑

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T3/T4 effects: other endocrine systems

� Increased bone maturation, advanced bone-age. Indirectly act on growth through permissive effects on IGF-1 and maintaining GH secretion

� RBC production (erythropoetin)

� sexual hormones (gonadotropin) secretion, fertility

� physiological ADH response

T3/T4 effects: CNS

� Fetus+ early childhood : Terminal differentiation of brain (synaptogenesis, myelination). Cretinism!

� In adult life: maintenance of normal cognitive and affective functions, normal sensitivity of respiratory centers, normal proprioceptive reflexes...

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Hypothyreosis-Hyperthyreosis� Cold intolerance

� weight gain

� bradycardia

� cool, dry, yellowish skin, balding

� obstipation

� mental slowness

� myxedema (husky voice)

� high cholesterol

� Heat intolerance

� weight loss

� tachycardia

� warm, wet velvety skin,

� diarrhoea

� nervousness, fatigue

� decreased glucose tolerance

Thyroid diseases I: What can possibly go wrong?

� Reduced thyroid hormone synthesis: genetic factors, iodine deficiency, toxins inhibiting NIS or TPO, autoimmune disease reducing hormone production, reduced TRH or TSH

� Except last case, as free T4/T3 reduces TSH will elevate and goiter/struma will develop

� Cretinism - myxedema

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Thyroid diseases II: What can possibly go wrong?

� Increased thyroid hormone synthesis: autoimmune stimulation of TSH receptors (TSI), or pathologically high TRH and/or TSH

� goiter/struma will develop

Change in BMR during hypo- and hyperthyreosis : used to be diagnostic

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Cretinism: congenital hypothyreosisdysproportional dwarfism, mental retardationsubstitution therapy can prevent it, every newborn is screened for TSH!

Too late substitution!

Immune thyreoditises:

Most common type:

Graves-Basedow disease:

autoimmunity against

TSH receptors

1. Goiter/Struma

2. Exopthalmus (orbital

TSH receptors)

3. pretibial myxedema

4. Tachycardia

5. Etc…

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Before thyroid surgery: Plummer-therapy!

� High daily intake of Iodine (2-6 mg/day) can transiently suppress thyroid function. 1. TSH sensitivity decreases2. Decreased organification (Wolff-Chaikoff effect)3. decreased VEGF, and vascularization4. NIS down-regulation→escape, after few weeks