Thyroid Disorders

Question 1

Name 3 thyroid hormones

what are they important for?

Answer 1

▪ Thyroxine (T4)
▪ Tri-iodothyronine (T3)
▪ Calcitonin

T4 & T3 are important for normal growth/development and the control of energy metabolism

Question 2

what are the main steps of synthesis of thyroid hormone?

Answer 2

– Uptake of plasma iodide by follicle cells
– Iodination of thyroglobulin
– Secretion of thyroid hormone

• Thyrotropin (TSH) regulates uptake of iodine into follicular cells
• Viscous liquid surround follicular lumen called colloid
• Thyrotropin stimulates NIS (sodium iodine symporter) causing it to be taken up
• PDS is iodide chloride transporter, thyroperoxidase and H2O2
• Iodine gets oxidized and incorported into tyrosine residues of thyroglobulin

Thyroperoxidase + H2O2 oxidizes iodine and incorporates iodine radicals into tyrosine residues of thyroglobulin incorporates iodine radicals into tyrosine residues of thyroglobulin

Question 3

how is MIT or DIT formed?

Answer 3

tyrosine to tyrosine radical by Thyroperoxidase + H2O2 and ionizes iodide to make monoiodotyrosine (MIT) or diiodotyrosine (DIT) depending on 1 or 2 iodides

Question 4

describe the pathway to regulate thyroid function

Answer 4

• cold, trauma, stress signal to hypothalamus to release TRH or somatostatin (neg effects)
  – Thyrotrophin-releasing hormone (TRH) and protirelin
  (synthetic tripeptide) causes the anterior pituitary to release thyroid-stimulating hormone (TSH)
  TSH acts on GPCRs in thyroid follicle cells
  linked to increases in cAMP and activation of
  PI3K

Question 5

what trophic actions does TSH have on thyroid cells? (6)

what transports iodine?

Answer 5

– Increases NIS expression (NIS transportes iodine into follicular cell)
– Synthesis/secretion of thyroglobulin (TG) (increase TG secretion into foll lumen)

Thyroglobulin is the other major component needed for synthesis of thyroxine and triiodothyronine.

– Generation of H2O2 & iodination of tyrosine
– Endocytosis/proteolysis of TG
– Secretion of T3 & T4
– Increased blood flow through the gland

Question 6

what is protirelin used for?

Answer 6

Protirelin used diagnostically to see if there are problems with its function
- analouge of TRH

• Hyperthyroid - neg feedback, protirelin will not stimulate as much of T3, T4
• Hypothyroid - can’t make thyroid hormones - no response in protirelin

Question 7

what causes hypothyroidism?

Answer 7

Hashimoto’s disease (autoimmune disorder)
- Auto antibodies produced against thyrotropin receptor on follicular cells, inhibit fxn of receptor and release of thyroid hormone

Leads to enlargement of the thyroid gland (goitre)
- overstim of thyroid with hormones (TSH)

Question 8

symptoms of hypothyroidism? (5)

Answer 8

– Low metabolic rate, lethargy
– Slow speech
– Bradycardia
– Sensitivity to cold
– Myxedema (severe cases), swelling of skin with waxy composition - use IV T3 in severe cases

Question 9

what are 2 hormone replacements?

which is faster acting?

Answer 9

T3 rapid acting
T4 slower - pro hormone for T3
- De-iodinated to T3
- T3 activates thyroid hormone receptors to regulate gene transcription

– Levothyroxine (T4) (most common)
– Liothyronine (T3) (more active)

Question 10

T4 and T3 MOA?

Answer 10

– Exogenously administered T4 is deiodinated to T3
– Bind to intracellular nuclear thyroid hormone receptors (10x more affinity for T3 than T4)

• Thyroid hormone receptor is ALWAYS bound to DNA and on its own it represses transcription
• when T3 is absent, the receptor is associated with hDAC and causes deacetylation = repression
• when T3 is present, the hDAC dissociates and HATs associate with dNA to acetylate it = transcription

Question 11

Effects of T3 in our numerous bodily systems? (5)

Answer 11

▪ Metabolism: Increased body temperature & reduced weight - T3 leads to greater basal metabolic rate initially vs T4
- Metabolism - not due to expression of more metabolic enzymes but interaction of other hormonal systems, increasing other receptors for hormones

▪ Cardiovascular: Increased heart rate & blood pressure
▪ GI: Increased motility
▪ Musculoskeletal: Required for skeletal development and peak bone mass
▪ Reproductive: Enhance ovulation & spermatogenesis

Question 12

half life of T3 vs T4? (approx)

when is it active

Answer 12

T4 half life 7 days in a person w/ normal health
3-4 days for hyperthyroidism
9-10 days for hypothyroidism

T3 a few hours
T4 is preferred, circulating

Thyroid hormone is strongly bound to thyroxine-binding
globulin (unbound hormone is active)

Question 13

T3, T4 AE? (2)

Answer 13

– *Tachycardia (contraindicated)
– *Atrial Fibrillation

elevate heart rate

Question 14

causes of Hyperthyroidism (Thyrotoxicosis)

Answer 14

– Diffuse toxic goitre (Graves’ Disease)
– Toxic nodular goitre

Auto antibodies against thyrotropin receptor - stimulates increase in T3 or T4 secretion

Graves’ disease is an autoimmune disorder in which antibodies produced by your immune system stimulate your thyroid to produce too much T4.

If you have Graves’ disease, your thyroid-stimulating hormone (TSH) level will probably be very low because the pituitary gland will try to compensate for the excess T3 and T4 hormones in the blood. It’ll stop producing TSH in an attempt to stop production of the thyroid hormones.

Question 15

Hyperthyroidism (Thyrotoxicosis) symtpoms

Answer 15

– High basal metabolism (increased appetite associated with body weight loss)
– Increased skin temperature
– Heat intolerance
– Sweating
– Nervousness & tremor
– Tachycardia

Question 16

Hyperthyroidism

Surgery

Answer 16

– Only really used now if mechanical problems (thyroid

compressing the trachea), obstructed breathing, pressing on trachea

Question 17

Hyperthyroidism

Radioiodine (131I)

when to avoid use? what happens after?

Answer 17

– 1st line treatment for hyperthyroidism
– Dose generally 5 – 15 mCi

– Avoid in children and in pregnant mothers
– Following use and destruction of the gland, individuals will become hypothyroid and require administration of levothyroxine (T4)

Question 18

Hyperthyroidism

Radioiodine (131I)

MOA?

Answer 18

– Taken up and processed the same way
as normal iodine by the thyroid
• Isotope emits beta-particles that have a short range and cytotoxic actions within thyroid follicle cells
– Half-life of 8 days
– Given as a single dose that takes at least 1 month to start mediating its actions

• beta radiation is cytotoxic but acts within gland only
• gamma is very low but spreads out

Question 19

Hyperthyroidism

Antithyroids (Thioamides)

name 1 and 2 prodrugs

Answer 19

– Propylthiouracil

– Methimazole, Carbimazole (prodrug converted to methimazole)

Question 20

Hyperthyroidism

Antithyroids (Thioamides)

MOA?

Answer 20

– Contain a thiocarbamide (S-C-N) group required for antithyroid activity
– Prevent synthesis of thyroid hormone
• Inhibit thyroperoxidase
• Block iodine oxidation
• Block coupling of iodinated tyrosines
• Inhibit peripheral deiodination of T4 to
T3 (propylthiouracil - active form)

Question 21

Hyperthyroidism

Antithyroids (Thioamides)

how long does it take to work?

Answer 21

3-4 weeks

Preventing synthesis
The pool is still secreting and circulating T4 so it takes some time to work
Propylthiouracil is slightly faster as it inhibits deionization T4 to T3

Question 22

Hyperthyroidism

Antithyroids (Thioamides)

AE? (3 main)

Answer 22

– *Skin rash: 25% common
– Fever
– Arthralgia
– *Neutropenia: low neutrophils, WBCs
– *Agranulocytosis: low granulocytes
– Hepatotoxicity
– Vasculitis

Question 23

Hyperthyroidism

Antithyroids (Lugol Iodine)
describe use

Answer 23

– Solution of potassium iodide with iodine in water
– Symptoms of thyrotoxicosis subside within 1-2 days
– Used for either severe thyrotoxicosis or preparation for surgery

Question 24

Hyperthyroidism

Antithyroids (Lugol Iodine)

MOA?

Answer 24

– Iodide in excess amounts inhibits thyroid hormone secretion
– Reduces vascularity of the thyroid gland
– May also inhibit iodination of thyroglobulin by reducing generation of H2O2

If exposed to radioactive iodine, this is used to outcompete them and not get incorporated

Question 25

Name 4 treatments for hyperthyroidism

Answer 25

surgery
radioiodine
Antithyroids (Thioamides)
Antithyroids (Lugol Iodine)