Thyroid Hormone 2013

7/28/2019 Thyroid Hormone 2013

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There are two biologically active thyroidhormones:- tetraiodothyronine (T4; usually calledthyroxine)- triiodothyronine (T3)

Derived from modification of tyrosine.


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The thyroid secretes about 80 microg of T4, butonly 5 microg of T3 per day.

However, T3 has a much greater biologicalactivity (about 10 X) than T4.

An additional 25 microg/day of T3 is producedby peripheral monodeiodination of T4

T4

thyroid

I-T3


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Thyroid hormones are unique biological moleculesin that they incorporate iodine in their structure.

Thus, adequate iodine intake (diet, water) isrequired for normal thyroid hormone production.

Major sources of iodine:- iodized salt

- iodated bread- dairy products

- shellfish Minimum requirement: 75 micrograms/day US intake: 200 - 500 micrograms/day


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Dietary iodine is absorbed in the GI tract, thentaken up by the thyroid gland (or removedfrom the body by the kidneys).

The transport of iodide into follicular cells isdependent upon a Na+/I- cotransport system.

Iodide taken up by the thyroid gland isoxidized by peroxide in the lumen of thefollicle:

peroxidaseI- I+

Oxidized iodine can then be used inproduction of thyroid hormones.


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Pituitary produces TSH, which binds tofollicle cell receptors.

The follicle cells of the thyroid produce

thyroglobulin. Thyroglobulin is a very large glycoprotein.

Thyroglobulin is released into the colloidspace, where its tyrosine residues are

iodinated by I+. This results in tyrosine residues which have

one or two iodines attached(monoiodotyrosine or diiodotyrosine).


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Squamous epithelial cells, cuboidal cells (follicle cells)

Follicle cells produce thyroglobulin ---- TH

I

Colloid fills the follicle cavities


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Thyroid hormones are not very soluble in water(but are lipid-soluble).

Thus, they are found in the circulation associatedwith binding proteins:- Thyroid Hormone-Binding Globulin (~70% of

hormone)- Pre-albumin (transthyretin), (~15%)- Albumin (~15%)

Less than 1% of thyroid hormone is found free inthe circulation.

Only free and albumin-bound thyroid hormone isbiologically available to tissues.


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T3 has much greater biological activity than T4.

A large amount of T4 (25%) is converted to T3in peripheral tissues.

This conversion takes place mainly in the liverand kidneys. The T3 formed is then released tothe blood stream.

In addition to T3, an equal amount of reverse

T3 may also be formed. This has no biologicalactivity.


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The thyroid gland is capable of storingmany weeks worth of thyroid hormone

(coupled to thyroglobulin).

If no iodine is available for this period,thyroid hormone secretion will bemaintained.


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Thyroid hormone synthesis and secretionis regulated by two main mechanisms:

- an autoregulation mechanism, whichreflects the available levels of iodine

- regulation by the hypothalamus andanterior pituitary


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The rate of iodine uptake and incorporationinto thyroglobulin is influenced by the

amount of iodide available:- low iodide levels increase iodine transportinto follicular cells

- high iodide levels decrease iodine

transport into follicular cellsThus, there is negative feedback regulation of

iodide transport by iodide.


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Thyroid-stimulating hormone (TSH) is produced bythyrotroph cells of the anterior pituitary.

TSH is a glycoprotein hormone composed of twosubunits:

- alpha subunit (common to LH, FSH, TSH)- TSH beta subunit, which gives specificity ofreceptor binding and biological activitya

LHb

FSHbTSHb

LH FSH TSH


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TSH binds to a plasma membrane-bound, Gprotein-coupled receptor on thyroid folliclecells.

Specifically, it activates a Gs-coupled receptor,

resulting in increased cAMP production andPKA activation.

TSH

Gsa

AdenylylCyclase

ATP cyclic AMP

Protein kinaseA

Follicle cell


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TSH release is influenced by hypothalamicTRH, and by thyroid hormones themselves.

Thyroid hormones exert negative feedback onTSH release at the level of the anterior pituitary.

- inhibition of TSH synthesis

- decrease in pituitary receptors for TRH

hypothalamus

TRH

TRH receptor

TSH synthesispituitary T3/T4

+

-

-


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Thyrotropin-releasing hormone (TRH) is a

hypothalamic releasing factor which travelsthrough the pituitary portal system to act onanterior pituitary thyrotroph cells.

TRH acts through G protein-coupled receptors,activating the IP3 (Ca2+) and DAG (PKC) pathways

to cause increased production and release of TSH.

TRH phospholipase C

G protein-coupled

receptor

IP3 calcium

DAG PKC

calmodulin

Thyroid hormones also inhibit TRH synthesis.


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hypothalamus

TRH

TRH receptor

TSH synthesispituitary

T3/T4

+

-

-

-

TRH synthesis

Thyroid glandfollicle cell receptors

TSH binds


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PITUITARY-THYROTROPE CELL

HM Goodman, BASIC MEDICAL ENDOCRINOLOGY 3rd


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Diet: a high carbohydrate diet increases T3levels, resulting in increased metabolic rate(diet-induced thermogenesis).

Low carbohydrate diets decrease T3 levels,resulting in decreased metabolic rate.

Cold Stress: increases T3 levels in otheranimals, but not in humans.

Other stresses: increased or decreased?

Any condition that increases body energyrequirements (e.g., pregnancy, prolongedcold) stimulates hypothalamus TRHTSH (Pit)


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Thyroid hormones are essential for normalgrowth of tissues, including the nervoussystem.

Lack of thyroid hormone duringdevelopment results in short stature andmental deficits (cretinism).

Thyroid hormone stimulates basal metabolicrate.


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Mechanisms of Hormone Actions

1. Nuclear (regulate gene transcription)

2. Ribosomal (regulate gene translation)

3. Regulate enzymatic activity4. Alter membrane characteristics

protein synthesis

membrane receptors

Thyroid hormones appear to act directly via T3 receptors, but

also indirectly by altering expression of genes for neurotrophinsor their receptors.


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Required for GH and prolactin productionand secretion

Required for GH action

Increases intestinal glucose reabsorption(glucose transporter)

Increases mitochondrial oxidativephosphorylation (ATP production)

Increases activity of adrenal medulla(sympathetic; glucose production)

Induces enzyme synthesis Result: stimulation of growth of tissues

and increased metabolic rate. Increasedheat production (calorigenic effect)


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Effects on protein synthesis anddegradation:-increased protein synthesis at low thyroidhormone levels (low metabolic rate; growth)-increased protein degradation at highthyroid hormone levels (high metabolic rate;energy)

Effects on carbohydrates:-low doses of thyroid hormone increase glycogen

synthesis (low metabolic rate; storage of energy)- high doses increase glycogen breakdown(high metabolic rate; glucose production)


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Thyroid hormone receptors are found inmany tissues of the body, but not in adult

brain, spleen, testes, uterus, and thyroidgland itself.

Thyroid hormone inhibits thyroidhormone receptor expression (TRE on

THR genes).


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Pumps sodium and potassium across cellmembranes to maintain resting membranepotential

Activity of the Na+/K+ pump uses up energy, in

the form of ATP About 1/3rd of all ATP in the body is used by

the Na+/K+ ATPase T3 increases the synthesis of Na+/K+ pumps,

markedly increasing ATP consumption. T3 also acts on mitochondria to increase ATP

synthesis The resulting increased metabolic rate increases

thermogenesis (heat production).


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Increase mitochondrial size, number and keyenzymes

Increase plasma membrane Na-K ATPase

activity Increase futile thermogenic energy cycles

Decrease superoxide dismutase activity


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Increase heart rate

Increase force of cardiac contractions

Increase stroke volume

Increase Cardiac output

Up-regulate catecholamine receptors


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Increase resting respiratory rate

Increase minute ventilation

Increase ventilatory response to hypercapnia

and hypoxia


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Increase blood flow

Increase glomerular filtration rate


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Increase RBC mass

Increase oxygen dissociation fromhemoglobin


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Increase glucose absorption from the GI

tract Increase carbohydrate, lipid and protein

turnover

Down-regulate insulin receptors

Increase substrate availability


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Increase growth and maturation of bone

Increase tooth development and eruption Increase growth and maturation of

epidermis,hair follicles and nails

Increase rate and force of skeletal muscle

contraction Inhibits synthesis and increases degradation

of mucopolysaccharides in subcutaneoustissue


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Critical for normal CNS neuronaldevelopment

Enhances wakefulness and alertness

Enhances memory and learning capacity

Required for normal emotional tone

Increase speed and amplitude of peripheralnerve reflexes


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Required for normal follicular development

and ovulation in the female Required for the normal maintenance of

pregnancy

Required for normal spermatogenesis in the

male


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Specimen collection : Specimens are routinely collected in a clot tube, although

anticoagulants can be used . Specimens free of lipemia or hemolysis are preferred .

The tests used to investigate thyroid function can begrouped into: Tests that establish whether there is thyroid dysfunction (

TSH,T4 and T3 measurements)

Tests to know the cause of thyroid dysfunction(thyroid auto-antibody and serum thyroglobulin

measurements, thyroid enzyme activities, biopsy of thethyroid, ultrasound and isotopic thyroid scanning )

TSH :


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TSH :- The single most sensitive, specific and reliable test of thyroid

status .

- In primary hypothyroidism, [TSH] is increased.- In primary hyperthyroidism, [TSH] is decrease orundetectable

Total T4 and Total T3 :- More than 99% of T4 and T3 circulate in plasma bound to

protein

- Both [total T4] and [total T3] change if [TBG] alters, e.g. inpregnancy

Free T4 and Free T3Free thyroid hormone concentrations are independent of

changes in the concentration of thyroid-hormone bindingproteins more reliable for diagnosis of

thyroid dysfunction


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Primary hyperthyroidism- Plasma [TSH] : due to feedback inhibition on the

pituitary

- Plasma free and total T4 and T3 concentrations :

In a very small percentage of hyperthyroid patients,plasma [total T4] and [freeT4] are both normal,

whereas both plasma [total T3] and [freeT3] areincreased ; this condition is known as

T3 hyperthyroidism or T3 thyrotoxicosis .

Primary hypothyroidism :


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Primary hypothyroidism :

Plasma [TSH] :

Plasma [free T4] and [total T4] :

Plasma free T3 and total T3 measurements are of no

value here, since normal concentrations are oftenobserved .

Sub clinical primary thyroid disease


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Sub clinical primary thyroid disease

Plasma [TSH] : abnormalThyroid hormone levels : normal

[TSH] : low sub clinical hyperthyroidism

[TSH] : elevated sub clinical hypothyroidism

Before the diagnosis of sub clinical thyroid disease can

be made, causes of an abnormal plasma [TSH] otherthan thyroid disease must be excluded

eg : - pregnancy

- drug treatment


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Central (pituitary) hypothyroidism :

[TSH] & thyroid hormone levels low

Hyperthyroidism due to a TSH-secreting tumor

very rarely

Thyroid Hormone 2013

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