Thyroid Biochemistry

Question 1

What is the only structural difference between T3 and T4?

Answer 1

T4 has an extra 5’ iodide group attached

- this gets cleaved by 5-deionase enzymes into T3 which actually does cellular actions

Question 2

Thyroglobulin

Answer 2

Precursor glycoprotein to T3/T4

Produced in follicular cells and secreted into follicular lumen to induce its job (really to just get tyrosine molecules boudn to it)

Question 3

Iodination and coupling

Answer 3

Occurs in follicle lumens with thyroglobulin (Tgb)

Requires iodide anions in the follicle lumen also

• iodide gets in via sodium-iodide symporters or pendrin transporters
• iodide also needs to be organified by thyroid peroxidase enzymes (ionizes iodide molecules and binds it to tyrosyl residues on Tgb to form MIT or DIT molecules)

MIT/DIT = tyrosine molecules with either one or two iodine molecules bound to it

• MIT + DIT = T3
• DIT + DIT = T4

Question 4

What happens once TSH reaches Thyroid gland?

Answer 4

Tgb from colloid lumen in thyroid is pinocytosis into the thyroid follicular cells

Tgb fuses with lysosomes and Tgb undergoes proteolysis to release T4/T3 bound to it in order for it to become free

Question 5

What is iodine salvage?

Answer 5

Iodotyrosine deiodinase enzymes break down excess T4/T3 into DIT and MIT and then eventually into iodine and tyrosine molecules to be used in building up of new thyroid hormone as needed and for protein synthesis else where int he body (tyrosine only)

Question 6

What are cathepsins?

Answer 6

Small proteolysis molecules that target cysteine/serine and aspartic acid AAs (Cys/Ser/Asp respectively)

Action decreases with age*

These molecules also “crosstalk” or compensate for deficiencies

These are found in endoscopes/lysosomes and sometimes extracellular
- if extracellular = usually cancer, osteoporosis or lysosomal storage disorders

Question 7

Where is iodine absorbed

Answer 7

By intestinal enterocytes

Requires 150 micrograms per day

Question 8

How does Thyroid hormone actually induce DNA transcription?

Answer 8

1) thyroid hormones (both forms but T3 is better at doing this) bind to nuclear retinoid thyroid receptors

2) heterodimers of T3/T4:THR’s bid to o thyroid response elements (TREs) in target cell DNA
- this upregulates DNA polymerase to start worker more

3) TH-TR heterodiumers can also activate non genomic signaling pathways
- such as cGMP and PI3K increase levels

dysregulation of Thyroid hormone receptors leads to multiple types of cancers

Question 9

What is the most commonly intracellular pathway activated with T3/T4 binding to THR’s?

Answer 9

1) T3 especially gets into the cell and binds to TR(beta) receptors which are bound to PI3K
2) PI3K gets stimulates and both activates AKT proteins and also upregulates Na/K+ ATPase channels

3) AKT induces mTOR which helps transcribe the following:
- HIF-1a/GLUT1/PFKP/MCT4 proteins

Question 10

Thyroid hormone and cancer inhibition

Answer 10

TH signaling suppresses apoptosis in cancer cells
- this is done via upregulation MAPK/ERK1/2 (anti-apoptosis genes)

Use of tetracyclines or resveratrol (both are THR antagonists) inhibit THR signaling which limits cell/tumor growth
- this allows for PI3K-AKT to activate (pro-apoptosis genes) and suppresses MAPK/ERK1/2

Question 11

Transthyretin

Answer 11

A carrier molecule found in blood stream for two secreted T4s

Has tight binding and many contact points which allows it to be a very effective carrier of T4

T4 is the primary form int he body and is converted to T3 by deiodinases in effector cells

Question 12

Deiodinases

Answer 12

Three types (D1-3)

D1:

• found in liver/kidney/thyroid
• converts T4 into T3 and rT3
• heavily affected by inhibtors
• in hypothyroidism = decreased levels
• in hyperthyroidism = increased levels

D2:

• found in brain/pituitary/skeletal muscle and heart muscles
• converts T4 into T3 and rT3 into T2
• not heavily affected by inhibitors
• in hypothyroidism = increases levels
• in hyperthyroidism = decreases levels

D3:

• found in brain/placenta/fetal tissues
• converts T4 into rT3 and T3 into T2
• not really effected by inhibtors that well
• in hypothyroidism = decreased levels
• in hyperthyroidism = increased levels

Question 13

How are bile salts affected by hyper/hypothyroidism

Answer 13

In euthyroid= normalized balanced levels of both chenodeoxycholic acid and deocycholic acid

Hyperthyroidism = chenodeoxycholic acid dominated

Hypothyroidism = deoxycholic acid dominated

Question 14

Most common cause of hyperthyroidism

Answer 14

Graves’ disease

Extreme severity = causes thyroid storm effects

Question 15

Other casues of hyperthyroidism

Answer 15

Injuries to thyroid

Heredity

Infectious disease

Dames to pituitary gland

Menopause/pregnancy

Chronic inflammation of thyroid gland

Question 16

Most common cause of hypothyroidism

Answer 16

Hashimoto thyroiditis

• chronic lymphocytic thyroiditis
• is environmental and genetic based

Is believed to be caused by environmental triggers which cause APCs to bring thyroid antigens to lymph nodes and react with autoreactive CD4 Tcell to produce anti thyroid B-cells
- induce CD4 cells which in turn induce a CD8 cytotoxic damage to thyroid cells overtime

Question 17

Why does hypothyroidism sometimes present with goiter?

Answer 17

Excessive TSH stimulation from the anterior pituitary causes thyroid hyperplasia (but not increased output)

Question 18

Aging and thyroid gland

Answer 18

Gland naturally shrinks and shifts lower in the neck

T4 production falls 50% with old age however T3 levels remain normal

BMR and THR levels also decrease with age

Thyroid disorders become more common with age as well

Question 19

How to measure thyroid hormones?

Answer 19

Radioimmunoassay via IRMA standard curve is used usually

• introduce radioactive T4 to patient isolated T4 from blood samples
• antibodies against T4 are then added and radioactive T4 levels that are bound to antibodies is measured (remeber that radioactive T4 will compete with patient no radioactive T4 for the antibody

More radioactive T4 bound or measured = low natural T4 levels in the patient

Less radioactive T4 bound rio measured = high natural T4 levels in patient

Question 20

TH sensitivity syndromes

Answer 20

1) natural resistance to TH
- autosomal dominant
- effects TR-B genes the most
- shows elevated levels of T4/T4 and rT3 in blood with normal or slightly elevated TSH
- is eumetabolic though

2) TH cell transporter defect
- X-linked recessive
- effects the MCT8 (monocarboxylate transporter 8) gene which is used to transport T3 into neurons of brain
- shows elevated T3, but lowered T4 and rT3 levels
- TSH is normal or slightly elevated
- manifests as severe psychomotor impairment

3) TH metabolism defects
- autosomal recessive
- affects the SBP2 (selenocysteine insertion sequence protein) gene which helps synthesis Selenoproteins
- shows elevated T4 and rT3 levels, but lowered T3 levels
- TSH is normal or slightly elevated
- puberty delayed infertility

Question 21

Transthyretin amyloidosis

Answer 21

Transthyretin (TTR) proteins become unstable and subunits break apart into clumped pieces and deposit into tissues

Symptoms vary broadly depending on which organ the amyloidosis is deposited into
- can hit the following: heart/liver/kidney/GI tract/Soft tissues/Nerves

Question 22

Refetoff disorder

Answer 22

A disruption of the thyroid hormone axis caused by a generalized but incomplete resistance of cells to thyroid hormone that shows all the following elevated:

• free T3/T4
• total T3/T4
• serum TSH

Is caused by a mutation in the portion of the gene encoding ligand-binding domain of the beta-subunit of the thyroid hormone receptor proteins
- it makes it so that thyroid hormone cant bind as well to the THR as well as limits the suppressive action that thyroid hormone on the secretion of TSH by thyrotroph syndrome in the anterior pituitary.

TSH increase causes goiter and increases T3/T4 levels (just the body cant uptake T3/T4 well)

Patient has mild hypothyroidism symptoms with a diffuse palpable goiter.

Question 23

Thyroid disorders and glucose intolerance

Answer 23

Hypothyroid: suboptimal insulin release although glucose intolerance is usually not clinically significant

Hyperthyroid: increased clearance and degradation of insulin
- causes “metathyroid diabetes mellitus” which is sort of like “pseudodiabetes” that shows some symptoms of it but not significantly