Dr M: Thyroid Gland and Thyroid Hormones

what are the names of the 3 hormones released from the thyroid

T3: triiodothyronine

T4: thyroxine

calcitonin

what are T3 and T4 important gfor?

growth and development, regulate energy metabolism, maintain body temperature

calcitonin function

important in regulating calcium metabolism

structure of the thyroid gland

consists of follicles (vesicles) made up of thyroid follicular cells and filled with thyrocolloid fluid

how are T3 and T4 stored

they're stored as amino acid residues in the thyroglobulin

what is thyroglobulin

a protein exclusively made by the thyroid gland that stores T3 and T4

constitutes the majority of thyroid follicular colloid content

iodothyronines, what are they?

iodinated tyrosine residues

where is thyroglobulin synthesized?

in the colloidal material fo cuboidal cells

thyroid hormone structure

made of a thyroglobulin with tyrosine residues attached

is T3 or T4 more potent

T3

binding areas of T3 and T4

both bind to specific cell surface receptors on sensitive target tissues which leads to increased uptake of glucose and amino acids

T3 also binds to cytoplasmic binding protein and nuclear receptor, leads to increased or decreased protein thesis

what does starvation do regarding thyroid hormones?

it decreases T3 and T4 receptors

iodide content and release in the thyroid

we have lots of iodide i the thyroid but only a small amount is released daily (to avoid Iodine deficiency)

what are the 6 steps to thyroid hormone synthesis

1. uptake of iodide (iodide trapping)

2. iodide organification (oxidation and iodination)

3. coupling of MIT and DIT

4. secretion of thyroid hormones

5. conversion of T4 to T3 (peripheral)

sodium iodide symptorter (NIS)

transports I with energy from Na/K ATPase

1 molecule of I brought in for every 2 molecules of Na brought in

how does iodide trapping work (uptake of iodide)

- blood iodide levels are usually very low

-the thyroid gland actively concentrates and stores iodide

-uptake occurs from the blood into the thyroid follicular cell

auto-regulatory control of iodide uptake

-low iodide storage increases iodide uptake

-uptake is stimulated by TSH (AP)

-monovalent anions (perchlorate, thiocyanate, pertechnetate) inhibit uptake

what enzyme is responsible for iodide organification

thyroid peroxidase (TPO)

thyroid peroxidase (TPO) function

-oxidizes iodide into iodine (blocked by thionamides)

-iodinates tyrosine residues in thyroglobulin to form MIT (mono-iodotyrosine) and DIT (di-iodotyrosine)

-coupling of MIT and DIT

what is the most sensitive step/ most blocked by drugs in thyroid hormone synthesis

coupling of MIT and DIT

what are the 2 parts that make triiodothyronine (T3)

MIT + DIT

what are the 2 parts that make thyroxine (T4)

DIT + DIT

where are T3 and T4 stored

in thyroglobulin in colloid matrix

ratio of T4:T3 synthesis

synthesis is 5 T4: 1 T3

mostly T4 is released

secretion of T4 and T3 in thyroid hormone synthesis

-endocytosis of TG (thyroglobulin) /colloid from follicular lumen

-fusion with lysosomal granules containing proteolytic enzymes

-breakdown of TG and release of T4 and T3

-MIT and DIT deiodinated; iodine re-utilized

-T4 and T3 reversibly bind to specific serum proteins thyroxine binding globulin (TGBG) and transthyretin; protect against metabolism and elimination

conversion of T4 to T3

-occurs peripherally

-de-iodination to active T3 and to reverse/inactive T4

thyroxine binding globuliin affinities

T4> T3

transthyretin

T4 and T3 binding protein but lower affinity than thyroxine binding globulin

autoregulation of the thyroid

increased iodine: decreased iodine uptake, conversion to iodine (oxidation) and organification

Graves Disease thyroid regulation

production of thryoid stimulating immunoglobulin (antibodies) by lymphocytes; mimics action of TSH; longer duration of action; autoimmune ddisease

tumors in thryoid regulation

thyrotoxicosis- excessive hormone production

what are 4 effects of thyroid hormones

-growth and development

-calorigenic effects

-CV effects

-metabolic effects

what are the 4 types of target tissues of thyroid homrone

-heart

-liver

-bone

-CNS

what is the "Wolff-Chaikoff Effect"

high levels of Iodine inhibit thyroid peroxidase and shut down glan uptake, synthesis, and release

can undergo escape and become hyperactive

whta happens when T3 binds to the nuclear thyroid receptor

creates a heterodimer with RXR

effects transcription of proteins

deiodinase (D2 ad D3)

removes iodine from iodothyronines (converts T4--> T3-->T2)

thyroid hormone functions in growth and development

o Promotes optimal growth and development in all body tissues

o Stimulates protein synthesis, likely by enhancing DNA transcription

o Critical for the health of the nervous system, skeletal system, and reproductive organs

what are the 2 causes of cretinism

-Iodine deficiency

-Improper development (or failure to develop) of the thyroid glad

what are 2 characteristics of cretinism

-Dwarfism

-Mental impairment

calorigenic effects of thyroid hormoen

Thyroid hormones increase resting or basal metabolic rate of whole organism

increase body temperature

what happens to thyroid hormone if you're cold

increased production of T3 and T4

what 4 tissues are most sensitive to the calorigenic effects of thyroid hormone

heart, skeletal muscle, liver, and kidneys

3 CV effects of thyroid hormone

· Increase HR

· Increase force of contraction

· Increased cardiac output

mechanism of the direct effect of thyroid hormone on CV

binding to thyroid hormone receptors in the heart; not just response to increased basal metabolism

mechanism of the indirect effect of thyroid hormone on CV

increased number of B-adrenergic receptors in the heart

what are 4 metabolic effects of thyroid hormone

· Stimulates metabolism of cholesterol to bile acids

· Increase binding of LDL by liver

· Increase carbohydrate metabolism

· Increase glucose uptake

What is Grave's disease?

diffuse toxic goiter caused by autoimmune antibodies (thyroid stimulating immunoglobulins) overstimulating the thyroid gland

Has prominent in-folding of the hyperplastic epithelium

key symptoms of Grave's disease

weight loss, rapid HR, nervousness/irritability, and protruding eyes (exophthalmos), goiter

TSI (thyroid stimulating immunoglobulins MOA in Grave's disease

they mimic TSH stimulation but are constant instead of pulsatile

what is Plummer's disease

a toxic nodular goiter caused by one or more hot/overactive nodules in the thyroid gland which produce excessive thyroid hormones

nodule is an adenoma (benign)

key symptoms of Plummer's disease/toxic nodular goiter

weight loss, rapid HR, heat intolerance, tremors, often without exophthalmos (unlike in Graves)

whta is the difference in symptoms between Grave's and Plummer's disease

Grave's presents with exophthalmos (bulging eyes) while Plummer's doesn't

what are the 3 MOA's of treating hyperthyroidism

·      Agents that interfere with production of T3 and T4

·      Agents that modify tissue responses to T3 and T4

Destructionof thyroid gland

what is a thyroid storm (thyrotoxic crisis)

life-threatening form of thyrotoxicosis

what is needed to treat a thyroid storm

immediate treatment with propaolol

goitrogens

· agents that decrease production of thyroid hormones

o Produce enlargement of the glands in patients with normal thyroid function

what are the 4 thionamides/thioureas

o Methimazole (10x more potent)

o Propylthiouracil (PTU)

o Carbimazole (UK)

o Ethylenethiourea or ETU & 3-aminotriazole

MOA of thionamides

accumulate in the thyroid and inhibit synthesis of T3 and T4 (inhibit thyroid peroxidase)

block Iodine organification and coupling of MIT and DIT

also decreases TSI tier

what effect do thionamides have in people with normal thyroids

·      Inhibition of T4 and T3 synthesis- low levels of circulating hormones- increase in TSH release in normal people- sustained glandular stimulation- glandular enlargement (“non-productive”)

thyroid peroxidase inhibition

· Inhibits this enzyme (especially affects coupling)

· Doesn't affect the intake of iodine or already formed hormones

· Not immediate due to 1% release/day

monovalent anion inhibitor MOA

resemble iodide; competitive inhibitors inhibit transport of iodide into thyroid. can be overcome by increased Iodide

diagnostic use

what are the 4 anion inhibitors

§  Perchlorate (ClO4-)

§  Pertechnetate(TcO4-)

§  Thiocynanate (SCN-)

§  Cesium

Iodide MOA in hyperthyroidism treatment

·      Inhibit iodide uptake, organification of iodide, and release of thyroid hormones into the bloodstream

·      Decreased size and vascularity of hyperplastic gland

o   Preoperative preparation of thyrotoxic patients

·      Should not be used alone (thioamides)

how does reactive iodide get into the thyroid

is has sleective uptake into the thyroid and gets concentrated there because it's indistinguishable from normal iodide

MOA of reactive iodide (I-131)

emits beta radiation which destroys the thyroid gland

what is the 1 disadvantage of reactive iodide

can cause delayed hypothyroidism

adrenoreceptor blocking agents in hyperthyroidism

· Many symptoms of thyrotoxicosis mimic sympathetic stimulation

· Need to use agents that rapidly delete catecholamines or B-blockers

· Block physiological effects of sympathetic nervous system stimulation

propanolol and guanethidine

what can happen to the thyroid in nuclear disasters

· Radioactive iodine can get into the gland and cause glandular destruction

KI (potassium iodide) MOA

salt of stable, non-radioactive, iodine that blocks radioactive iodine from being absorbed by the thyroid gland, thus protecting this gland from radiation injury

o Shuts down gland so radioactive can't be absorbed

what is myxedema

a severe/advanced form of hypothyroidism

key symptoms of myxedema and Hashimoto's

weight gain, cold intolerance, lethargy/fatigue, slowed HR, dry skin

Hashimoto's also can have a goiter

what is Hashimoto's thyroiditis/ chronic lymphocytic thyroiditis

an autoimmune disorder in which the body's immune system attacks the thyroid gland

what is the most common cause of hypothyroidism in the US?

hashimoto's

what is endemic goiter

hypothyroidism due to deficiency in iodide intake

less common in developed countries

diagnosis of hypothyroidism

decreased T4 production; presence of anti-thyroid antibody (autoimmune)

treatment of choice for hypothyroidism

levothyroxine (T4)