Thyroid Metabolic Hormones

Front 1

How much does the thyroid weigh?

Back 1

15-20g in adults

Front 2

What does complete lack of thyroid secretion usually causes what to happen to the BMR? Extreme excess?

Back 2

Falls to 40-50% below normal

Increases 60-100% above normal

Front 3

How much of the thyroid hormones are T4? T?

Back 3

93% T4

7% T3: 4x as potent as thyroxine

Front 4

What type of epithelial cells secrete into the inner of the follicles?

Back 4

Cuboidal epithelial cells

Front 5

What is special about the thyroid gland's blood flow?

Back 5

It is 5x the weight of the gland each minute

Front 6

How much iodine is needed to form normal quantities of thyroid hormone?

Back 6

50 mg each year

1mg/week

Front 7

How much iodine is removed from the blood following absorption?

Back 7

About 1/5 the rest is excreted by the kidneys

Front 8

What transports iodine from blood into the cell?

Back 8

Sodium-iodide symporter (NIS)

Cotransports one iodide ion along with two sodium ions across the basolateral membrane into the cell

Encoded by the SLC5A5 gene

Front 9

Where does the energy for transporting iodide across a concentration gradient come from?

Back 9

Sodium-potassium ATPase pump

Front 10

What is iodide trapping?

Back 10

Process of concentrating iodide in the thyroid glandular cells

30x its concentration in the blood, sometimes rising as high as 250 times

TSH stimulates this process

Front 11

How is iodide tranported across the apical membrane into the colloid?

Back 11

By a chloride-iodide ion counter transporter called pendrin.

Coded by the SLC26A4 gene

Front 12

What is thyroglobulin?

Back 12

A large glycoprotein secreted into the follicles.

Has about 70 tyrosine amino acids that combine with iodine to form the thyroid hormones.

Front 13

What enzyme promotes the oxidation of iodide?

Back 13

Thyroid peroxidase with hydrogen peroxide

Located in the apical membrane of the cell or attached to it, oxidized iodine at the point in the cell where the TGB molecule comes from the golgi and through the cell membrane.

Front 14

What is an oxidized form of iodine?

Back 14

Nascent (I)

I(3)

Front 15

What occurs when the peroxidase system is blocked?

Back 15

The rate of formation of thyroid hormones falls to zero

Front 16

What is the binding of iodine with the thyroglobulin molecule called?

Back 16

Organification

Front 17

How much of the TGB is bound with iodine when it enters the colloid?

Back 17

1/6th of the tyrosine amino acids within the TGB molecule

Front 18

The coupling of what makes T4? T3?

Back 18

Coupling of two DITs = T4

Coupling of a MIT and DIT = T3 (1/15 of the final hormones)

Small amounts of RT3 are formed = coupling DIT with MIT but the active iodine is placed on the inner ring rather than the outer ring.

Front 19

How is the rate of iodide transport into the thyroid cell regulated?

Back 19

Internal autoregulatory mechanism decreases transport of iodide into the cell when the intracellular concentration exceeds a certain threshold and increases transport when the concentration falls lower than threshold.

Front 20

What is the sequence of organification of the TGB molecule?

Back 20

Two-electron oxidation step forming I+ (iodinium ion)

I+ reacts with tyrosine residue in the protein Tgb to form a tyrosine quinoid and a MIT residue.

Second iodide added to ring to from 3,5-diiodotyrosine residue.

Front 21

What happens if there is a mutation in pendrin?

Back 21

Leads to Pendred syndrome

Children have total loss of hearing, goiter, and metabolic defects in iodide organification.

Front 22

After synthesis of thyroid hormones each Tgb molecule contains?

Back 22

Up to 30 thyroxine molecules and a few T3 molecules.

Ratio of 13:1

Front 23

How long can the follicles provide thyroid hormone?

Back 23

2-3 months

Front 24

How are thyroxine and triiodothyronine cleaved from the Tgb molecule?

Back 24

Apical surface of thyroid cells send out pseudopod extensions that close around portions of the colloid => pinocytotic vesicles are fromed => vesicles enter the apex of the thyroid cell => Lysosomes fuse immediately with these vesicles => proteases digest the Tgb molecules and release the T4 and T3 in free from => diffuse through basolateral membrane of cell into capillaries

Front 25

Does all of the Tgb become hormones and diffuse into the blood?

Back 25

No, about 3/4 of the iodinated tyrosine in the Tgb never becomes hormones but remains MIT and DIT

Front 26

What happens to the MIT and DIT that does not get released into the blood?

Back 26

These are released from the Tgb molecule as well during digestion and their iodine is cleaved from them by a deiodinase enzyme.

All iodine is made available again for recycling within the gland.

If this is absent people become iodine deficient.

Front 27

How much of thyroid hormone released into the blood is T4? T3?

Back 27

T4 = 93%

T3 = 7%
(after conversion of T4 => T3 35 micrograms of T3 is delivered to the tissues each day.)

This is a 10:1 ratio

Front 28

How much of thyroid hormone is bound to plasma proteins?

Back 28

Immediately entering the blood, 99% binds with proteins. T4 has a higher binding affinity than T3.

These are:
Mainly Thyroxine-binding globulin (70% of the hormones)

Also, thyroxine-binding prealbumin and albumin

Front 29

How much T4 and T3 is secreted each day?

Back 29

80-100 micrograms of T4 (half of this is released to the tissue cells about every 6 days)

5 micrograms of T3 (half is released about 1 day)

Additional 22-25 micrograms produced is from deiodination of the 5' carbon of T4 in peripheral tissues

Front 30

What are the plasma half lives of T4 and T3?

Back 30

T4 = 7 days
T3 = 1-1.5 days

Results from the binding to transport proteins.

Front 31

How much T3 and T4 are in the unbound state in blood?

Back 31

Approx .03 of total T4

Approx .3 of total T3

Front 32

When does exogenous thyroxine reach its maximum activity?

Back 32

After 10-12 dyas, has a long latent period.

Decreases after 15 days

Some of the activity can persist for 6weeks - 2months

Front 33

When does exogenous T3 reach its maximum activity?

Back 33

6-12 hours, clearance in 2-3 days.

It is 4 times as fast as T4

Front 34

How much T4 is deiodinated in tissue to make T3?

Back 34

35% at 5' position to make T3 (90% of thyroid hormone acting on receptors is T3)

43% at 5 position on inner ring to make inactive RT3

Front 35

What type of pattern is TSH secreted in?

Back 35

Circadian pattern: begins late in the afternoon and peaks before the onset of sleep.

Secreted in a pulsatile fashion with 2-6 hour intervals between peaks.

Front 36

What is the function of TSH?

Back 36

To stimulate:
Iodide trapping
Organification
Coupling reactions
Endocytosis
Proteolysis

Hypertrophy and hyperplasia of acinar cells =>Vascularity increase

Change from cuboidal to columnar cells and infolding of the thyroid epithelium into follicles

Most important early effect is to initiate proteolysis of Tgb => release of hormones into blood within 30 mins of TSH administration

Front 37

How does the TSH receptor work?

Back 37

TSH binds => Gprotein (stimulatory) => increase in cAMP (through GaS)

TSH binds => Gprotein =>activated PLC => increase in Ca (through GaQ) => MAP kinase pathway activation

Front 38

What happens if T3 levels become high?

Back 38

If T3 levels in the blood bathing the thyrotrops of the anterior pituitary gland rises => feedback loop closed => TSH secretion inhibited

T3 also inhibits TRH release

Front 39

What is the general effect of thyroid hormone?

Back 39

To activate nuclear transcription of large numbers of genes

Protein enzymes, structural proteins, transport proteins, and other substances are synthesized => increase in functional activity throughout the body

Front 40

How does thyroid hormone activate nuclear receptors?

Back 40

Forms a heterodimer with retinoid X receptor (RXR) at specific thyroid hormone response elements on the DNA => activates the receptors => initiate transcription

Front 41

What other cellular effects does thyroid hormone have?

Back 41

Nongenomic effects.

Some effects of these hormones happen within minutes.

Sites are: plasma membrane, cytoplasm, organelles like mitochondria.

Front 42

What are the nongenomic actions of the thyroid?

Back 42

Regulation of ion channels

Oxidative phosphorylation (cAMP or PKA/C)

Front 43

What effect does T4 have on mitochondria?

Back 43

The mitochondria increase in size, and number.

Membrane surface area also increases in proportion to the increased BMR.

This increases the rate of formation of ATP

Front 44

What is the most important enzyme that is affected by T4?

Back 44

Na-K-ATPase => increases the rate of transport

Increases the amount of heat produced in the body => increases BMR

Front 45

What does T4 do to the cell membranes of most cells?

Back 45

Causes them to become leaky to sodium ions, which activates the Na/K pump further and increases heat production more.

Front 46

The oxidation of fuels converts approx what percentage of potential energy in the foods ingested to ATP?

Back 46

25%

Inefficiency of the human engine leads to production of heat, but allows homeothermic animals to maintain a constant body temperature.

Front 47

How does thyroid hormone effect growth?

Back 47

Mainly manifests in children who are growing. Without thyroid growth is retarded, and with too much the child shoots up in height but the plates close early resulting in a short stature.

Promote growth and development of brain during fetal life and first few years of postnatal life. Without it the brain will be small, and the child will be mentally deficient.

Front 48

What is the effect of thyroid on carb metabolism?

Back 48

Stimulates all aspects.

Rapid uptake of glucose
Increased glycolysis (liver)
Enhanced gluconeogenesis
Increased rate of absorption from GI tract
Increased insulin secretion

Front 49

What is the effect of thyroid hormone on fat metabolism?

Back 49

All aspects enhanced.

Lipids mobilized from fat tissue
Fat stores are decreased
Increases free fatty acid in plasma
Stimulates oxidation of FFAs by cells
Increased cholesterol synthesis (liver)

Front 50

What effect does thyroid hormone have on fats in blood and liver?

Back 50

Decreases concentrations of cholesterol, phospholipids, TGs
Increases FFA's
Increases the rate of cholesterol secretion in the bile => loss in feces

Increases numbers of LDL receptors on liver cells => rapid removal of LDL from plasma by liver

Increased secretion of cholesterol in lipoproteins by liver cells

Front 51

What other effects does thyroid have on the liver?

Back 51

Increases the sensitivity of the hepatocyte to the gluconeogenic and glycogenolytic actions of epinephrine.

T3 indirectly increases hepatic glucose production

T3 increases the flow of fatty acids to liver => increases liver TG synthesis

Increased amount of glycerol to liver (from increased lipolysis) enhances gluconeogenesis

Front 52

What are the effects of thyroid on adipose cells?

Back 52

T3 amplifies lypolytic action of epinephrine on fat cells.

Also increases the availability of glucose to fat cells => FA and glycerol-3-phosphate synthesis

BIPOLAR effect!

Front 53

What is the effect of thyroid hormone on muscle?

Back 53

T3 increases glucose uptake by muscle cells.

Stimulates protein synthesis => growth of muscle

Sensitizes muscle to glycogenolytic actions of epinephrine => increased glycolysis

Muscles react with vigor.

Hyper = muscle become weak from catabolsim
Hypo = muscles become sluggish because they cannot relax after contraction (lack of ATP)

Front 54

What are the effects of thyroid hormone on the pancreas?

Back 54

Increases the sensitivity of the B-cells to stimuli that normally promote insulin release

It is required for optimal insulin secretion.

Front 55

What effect does T3 have on vitamins?

Back 55

Increased enzymes means increased vitamins for essential parts of the enzyme or for coenzymes.

So need for vitamins is increased. And deficiency can occur when there is excess thyroid.

Front 56

What effect does T3 have on the BMR?

Back 56

Increased metabolism in cells = increase in BMR

Front 57

What effect does thyroid have on body weight?

Back 57

Increased hormone = decreased body weight
Decreased hormone = increased body weight

Thyroid hormone does increase appetite so this may balance the change in BMR

Front 58

What effects does thyroid have on the cardiovascular system?

Back 58

Increased metabolism of cells => increased release of metabolic end products => release of vasodilators => increasing blood flow => increase in cardiac output (60% or more why hyper/ 50% of normal with hypo)

Increased excitability of heart => increased heart rate

Increased enzyme activity => increased heart strength (same as with a fever/exercise)

Mean arterial pressure remains the same.
Increased pulse pressure (systolic elevated, and diastolic depressed)

Front 59

What is the effect of excess thyroid hormone on the heart?

Back 59

Hear muscle strength becomes depressed because of long-term excessive protein catabolism.

Most thyrotoxic patients die fo cardiac decompensation secondary to myocardial failure and increased cardiac load.

Systolic pressure can rise 10-15mmHg and diastolic can also fall this much. (increased pulse pressure)

Front 60

What is the effect of thyroid on GI?

Back 60

Increases the rate of secretion of digestive juices.

Increases the motility of the GI tract.

(hyper = diarrhea. Hypo = constipation)

Front 61

What is the effect of thyroid on the CNS?

Back 61

Increases the rapidity of cerebration, but also often dissociates it.

Hyper = extreme nervousness and psychoneurotic tendencies (anxiety, worry, paranoia)

Hypo = decreases

Front 62

What is the most characteristic sign of hyperthyroidism?

Back 62

A fine muscle tremor.

Rapid frequency = 10-15 times per second.

Caused by increased reactivity of the neuronal synapses in the areas of the spinal cord that control muscle tone.

Front 63

How does thyroid hormone effect sleep?

Back 63

Hyperthyroid = constantly tired because the muscles/CNS are exhausted and the person has difficulty sleeping

Hypothyroid = extreme somnolence (drowsyness), sleep lasting 12-14 hours per day

Front 64

What effect does thyroid hormone have on other tissues?

Back 64

Increases bone formation = increases need for PTH

Increases inactivation of adrenal glucocorticoids = leads to increase in ACTH production => increased rate of glucocorticoid secretion by adrenal glands

Front 65

What effect does thyroid have on sexual functoin?

Back 65

Hyper = impotence in men, oligomenorrhea in women (sometimes amenorrhea)

Hypo = loss of libido in men and women, menorrhagia/polymenorrhea in women (some may have amenorrhea)

Front 66

What effect does thyroid hormone have on the sympathetic nervous system?

Back 66

Sensitizes the NS to the stimulatory effects of cold exposure.

Increases the release of norepinephrine => stimulates uncoupling protein thermogenin in brown adipose tissue => increased heat production from the uncoupling of oxidative phosphorylation

Front 67

What does norepinephrine do when sensitized by thyroid hormone?

Back 67

Increases permeability of brown adipose and skeletal muscle to sodium => stimulates Na,K-ATPase => increased hydrolysis of ATP stimulates oxidation of fuels => more ATP regenerated and heat from oxidative phosphorylation => large increase in BMR and heat production

Front 68

How else can thyroid hormone produce heat?

Back 68

By stimulating ATP use in futile cycles

Reversible ATP-consuming conversions of substrate to product and back to substrate uses up fuel and produces heat

Front 69

What is Refetoff disorder?

Back 69

Mutation in the portion of the gene that encodes ligand-binding domain of the B-subunit of the thyroid hormone-receptor protein

This causes a relative resistance to the suppressive action of T3 on TSH and therefore the gland releases more TSH than normal.

Elevated TSH causes goiter and increased T4/T3 secretion.

Hypothyroid symptoms exist because of the relative resistance of peripheral tissues to the hormone, and the body attempts to correct this by increasing the amount of hormone.

Front 70

Why do hyperthyroid individuals develop glucose intolerance?

Back 70

Degradation and clearance of insulin are increased, so demand for insulin is increased, so glucose intolerance occurs.

This is called metathyroid DM

Front 71

Where is TRH secreted from?

Back 71

Nerve endings in the median eminence and transported by way of hte hypothalamic-hypophysial portal blood

Front 72

What is TRH?

Back 72

Tripeptide amide

Pyroglutamyl-histidyl-proline-amide

Front 73

What is the mechanism of the TRH receptor in the anterior pituitary?

Back 73

Activates the phospholipase second messenger system => cells produce Phospholipase C => IP3 and DAG => calcium ions => TSH release

Front 74

What can effect the output of TRH?

Back 74

Exposure to cold
Emotional reactions:
excitement/anxiety = stimulation of sympathetics = acute decrease of TSH = increase metabolic rate/body heat = inverse effect on heat control center

If hypophysial stalk is cut, these are not functional

Front 75

How high does T3 have to get to shut off TSH?

Back 75

About 1.75 times normal.

Depressant effect happens even when anterior pituitary is separated from hypothalamus (independent).

Front 76

How does thiocyanate work?

Back 76

Thiocyanate, perchlorate, nitrate ions compete for the iodide transporter in the basolateral membrane of the cell.

Inhibits the iodide-trapping mechanism

Causes goiter from high TSH

Front 77

How does proylthiouracil work?

Back 77

Methimazole and carbimazole also do the same.

Prevents formation of thyroid hormone from iodides and tyrosine by blocking the peroxidase enzyme.

Can lead to goiter from Tgb stimulating TSH release

Front 78

High amounts of iodides do what to the thyroid's function?

Back 78

100x the normal level decreases thyroid activity.

However this only lasts for a few weeks.

Reduce rate of iodide trapping, normal endocytosis is paralyzed by high iodide concentrations.

Thyroid gland size decreased, and so is blood supply.

Administered 2-3 weeks before surgical removal to decrease the amount of tissue that needs to be removed, and decrease bleeding.

Front 79

In hyperthyroidsim how much do the glands increase secretion?

Back 79

5-15 times normal

Front 80

How long to TSI antibodies bind the receptors for?

Back 80

12 hours

TSH only stimulates for a little over an hour.

Front 81

What is an interesting effect of adenoma?

Back 81

Continued secretion of thyroid hormone inhibits the secretory function of the rest of the gland because it is inhibited by the suppression of TSH

Front 82

Symptoms of hyperthyroidism?

Back 82

1) excitable state
2) intolerance to heat
3) increased sweating
4) mild/extreme weight loss
5) diarrhea
6) muscle weakness
7) nervousness/psychic disorders
8) extreme fatigue coupled with insomia
9) fine tremor of the hands
10) exopthalmos

Front 83

How does exopthalmos occur?

Back 83

1/3 of hyperthyroid patients develop

Protrusion can become so severe it stretches the optic nerve and damages vision. Eyelids not closing also ulcerates eyes.

Edematous swelling of retro-orbital tissues and degenerative changes in the extraocular muscles. IgG reacts with eye muscles.

Front 84

How can you test for hyperthyroidism?

Back 84

1) Free T4 or T3
2) BMR increase
3) TSH concentration by radioimmunoassay.
4) TSI by radioimmunoassay

Front 85

Treatment course for hyperthyroidism?

Back 85

1)Propylthiouracil for several weeks until BMR is low.
2)Administration of iodides for 1-2 weeks to shrink gland.
3)Surgery to remove.

OR

Administration of 80-90% of radioactive iodine. Will be absorbed within one day (5 millicuries is given to patient).

Front 86

Where is iodine insufficient?

Back 86

Swiss alps
Andes
Great lakes region of US

People can get endemic goiters (increase of 10-20x normal size)

Front 87

What is the characteristic of an idiopathic nontoxic colloid goiter?

Back 87

Nodular growth in areas where there is no inflammation of the thyroid gland.

Inflammation = no T4/T3 = increased TSH

Front 88

What are the abnormalities that can lead to a colloid goiter?

Back 88

1) Deficient iodide-trapping mechanism
2) Deficient peroxidase
3) Deficient coupling of tyrosines
4) Deficiency of deiodinase (2/3 of iodine needed is recycled)

Foods:
Contain goitrogenic substances that have a propylthiouracil-type of antithryroid activity (turnips and cabbages)

Front 89

Why does a myxedema appearance develop with hypothyroid?

Back 89

Increased quantities of hyaluronic acid and chondroitin sulfate bound with protein form excess tissue gel in the interstitial spaces, and this causes total quantity of interstitial fluid to increase.

The gelled fluid is immobile and leads to nonpitting edema

Front 90

What does increased quantity of blood cholesterol in myxedema lead to?

Back 90

Artherosclerosis
Peripheral vascular disease
Deafness
Coronary artery disease

Front 91

What special test can be done to determine hypothyroidism is coming from the gland?

Back 91

Dose of TRH administered that will increase TSH by the pituitary.

Rules out depressed response of the pituitary to TRH.

Front 92

How do you treat hypothyroidism?

Back 92

Daily oral ingestion of a tablet of thyroxine.

Front 93

What is cretinism?

Back 93

Extreme hypothyroidism during fetal life, infancy, or childhood.

Failure of body growth, mental retardation.

From lack of thyroid gland or failure of the gland to produce thyroid hormone (congenital), or lack of iodine (endemic)

Front 94

When does cretinism manifest?

Back 94

A few weeks after birth because the neonate loses mom's thyroid hormone influence.

Movements become sluggish and growth starts to slow down.

Treatment with thyroxine will completely resolve this.

Front 95

Why does lack of thyroid hormone cause mental retardation?

Back 95

Retardation of the growth, branching and myelination of the neuronal cells of the CNS.

Front 96

What other symptoms does a cretin child have?

Back 96

Inhibited skeletal growth and normal soft tissue growth.

Soft tissues enlarge excessively causing obese, stocky, short appearance with large tongue that can obstruct swallowing and breathing.

Causes guttural breathing that can choke the child.