Thyroid Hormone (Week 5--Brent)

Question 1

Normal levels of thyroid hormones

Answer 1

TSH: 2-11 ulU/ml

T4: 5-12 ug/dl

T3: 80-180 ng/dl

Question 2

What would cause swelling above the thyroid?

Answer 2

Since the thyroid develops from base of the tongue (foramen cecum), can get thyroid tissue above where it is supposed to be

Thyroglossal duct (down the midline) can contain thyroid cancer/ectopic thyroid tissue

Thyroid gland doesn’t function as well if it’s not in the right place

Question 3

Thyroid follicle

Answer 3

Large, spherical, filled with colloid and other components needed for thyroid hormone synthesis

Reservoir for iodine which is bound by protein called thyroglobulin

This is where thyroid hormone is actually synthesized

Question 4

Sodium/Iodide Symporter (NIS)

Answer 4

Brings 2 Na+ and 1 iodide into follicular cell from bloodstream

Uses Na+ gradient within cell created by Na/K ATPase, so is “passive transport” of iodide

13 transmembrane domains

Perchlorate blocks NIS

Question 5

Follicular cell

Answer 5

Basolateral membrane (between blood and cell) has TSH receptor, NIS, Na/K ATPase, T4/T3 transporter to get them into blood

Apical membrane (between cell and follicle) has THOX2 (thyroid oxidase 2) and TPO (thyroid peroxidase), pendrin

Question 6

How is dietary iodide taken up and concentrated?

Answer 6

I is absorbed in digestive tract and gets into bloodstream –> NIS brings in I (with 2 Na+) to follicular cell –> I is taken out of follicular cell and into thyroid follicle by pendrin

Question 7

How much is the thyroid gland able to concentrate iodide?

Answer 7

Concentrates iodide 30-35 fold!

This is important because can keep making thyroid hormone even when iodine supply is low

Question 8

What happens if you don’t have enough nutritional iodide?

Answer 8

Since you don’t have enough I, there is not enough T3/T4 so not any feedback on TSH, so TSH increases and causes thyroid to expand to try to be able to concentrate more iodide

Upregulation of D2 so get more T3 compared to T4

Specifically in iodine deficiency get preferential release of T3

Question 9

How exactly does TSH stimulate more T3/T4 to be made?

Answer 9

TSH directly signals for more NIS to be made and for NIS to be moved to the membrane –> more I in the follicular cell –> I gets into follicle via pembrin, and more T3/T4 synthesized

TSH also stimulates TPO gene expression

Question 10

TPO (thyroid peroxidase)

Answer 10

Catalyzes reaction between H2O2 and I- to make MIT and DIT (THOX2 helps with this step as well?)

Also couples MIT and DIT to make T3 and T4

TPO sits on apical membrane of follicular cell, and reactions occur in follicle

Question 11

Which coupling reactions create T3 vs. T4

Answer 11

MIT + DIT = T3

DIT + DIT = T4

Note that both of these coupling reactions are done by TPO!

Question 12

How much of what actually comes out of the thyroid is T3 vs. T4?

Answer 12

Mostly T4, only 20% is T3

Question 13

What kind of hormone is thyroid hormone?

Answer 13

Not peptide and not steroid

Circulates bound to serum proteins

Binds nuclear receptor

Question 14

T4, T3, reverse T3

Answer 14

T4 is pro-drug

T3 is active drug

Reverse T3 is inactive

Question 15

How do you get T3?

Answer 15

T4 is acted on by D1 or D2 to remove an outer ring iodine

This reaction occurs in brain, brown fat, and can rapidly turn on thyroid hormone activation

Question 16

How do you get reverse T3?

Answer 16

T4 is acted on by **D3 ** which removes an inner ring iodine

(inner ring inactivates!)

Question 17

When is D1 vs. D2 used?

Answer 17

D1 used to provide circulating T3 (liver, kidney, thyroid)

D2 used to provide T3 to tissues rapidly (brain, pituitary, heart, BAT, skeletal muscle, thyroid)

Question 18

When you have hyperthyroidism, which enzyme (D1, D2, D3) is cranked up?

Answer 18

D2

(5’-deiodinase 2)

Question 19

What causes a decrease in T4 to T3 conversion and when would you want to do this?

Answer 19

Want to decrease T4 to T3 when you’re sick to slow metabolism and conserve energy

Causes: caloric restriction, major systemic illness, severe hepatic disease, fetal life, drugs (GCs), selenium deficiency

Question 20

Some children have hepatic hemangioma (liver tumor) secreting what that caused hypothyroidism?

Answer 20

Tumor was secreting D3, which caused T4 to reverse T3 conversion so had very low T4 and T3 but high reverse T3

Question 21

Where does most of our circulating T3 come from?

Answer 21

Most T3 is made locally in tissues by D2

Question 22

What are the serum proteins that T3 and T4 bind to?

Answer 22

Most is bound to thyroid binding globulin (TBG), but also transthyretin and albumin

All 3 of these serum proteins are made by the liver

Note: only 0.04% T4 and 0.4% T3 is free hormone

Question 23

What is responsible for feedback of T3 and T4 onto the hypothalamus and pituitary?

Answer 23

It is T4 that gets into the hypothalamus and pituitary (so we say it is T4 that regulates TRH and TSH) but once T4 gets there, D2 converts it to T3 and T3 is what actually binds to nuclear receptor and regulates gene expression of TRH and TSH

Question 24

Does the body regulate free or bound hormone?

Answer 24

Free!

Even when changes in serum proteins that bind thyroid hormone (due to liver disease, kidney diease, born with defective TBG), have same AMOUNT of free hormone because that’s what the body regulates

Question 25

What tests do we do for thyroid function?

Answer 25

TSH, free thyroxine (FT4) and free triiodothyronine (FT3) **TSH** is the best measure of thyroid function, partially because is has a close (log) relationship with T4

Question 26

What is the relationship between T4 and TSH?

Answer 26

Log relationship Small change in T4 creates HUGE change in TSH This relationship is why you can test TSH to tell you how much T4 you have

Question 27

Definition of hypo and hyperthyroidism

Answer 27

**Hyper**: TSH \<0.5 mU/L **Hypo**: TSH \>5.0 mU/L Note: can only use TSH if your pituitary is normal, obviously

Question 28

Thyroid hormone receptors

Answer 28

**Nuclear receptors** with DNA binding domain and ligand binding domain **Alpha** type (cardiac effects) and **beta** type (metabolism effects) are different

Question 29

What exactly do T3 and T4 do?

Answer 29

Lots of things (all tissues have thyroid receptor) Cardiovascular: **CO, HR, contractility, SVR** (T3 increases synthesis of beta1 receptors) Liver: **cholesterol** metabolism All organ systems: thermogenesis (**heat** **production**) and **O2 consumption** (tissues make Na/K ATPase bc of T3!) Bone: **bone growth** (synergism with GH) Pituitary gland: TSH suppression (just feedback...)

Question 30

How does thyroid hormone interact with adrenergic system in hypo and hyper?

Answer 30

**Hyper**: weight loss because of **increased lipolysis**, weight loss because of brown adipose tissue increased **fatty acid oxidation**, tachycardia bc of **cardiac stim**, bone loss/osteoporosis because of **increased bone turnover** **Hypo**: weight gain because of **decreased lipolysis**, weight gain because of brown adipose tissue **decreased fatty acid oxidation**, bradycardia bc of **decreased cardiac stim**, unknown bone effects

Question 31

How does T3 regulate metabolism?

Answer 31

Promotes **cholesterol** **synthesis**, efflux Promotes **lipolysis** and **beta-oxidation** Increases **fatty acid oxidation** Stimulates **heat production** (BAT, skeletal muscle)

Question 32

How might we use thyroid hormone receptor beta in the future as a drug?

Answer 32

**TR-beta analog lowers cholesterol!** Might be used in addition to statins in the future

Question 33

Congenital hypothyroidism

Answer 33

No thyroid gland function (**defect in thyroid hormone synthesis** or **no thyroid** at all) Clinical manifestations: cleft palate, spiky hair, renal anomaly, neonatal respiratory distress/chorea/ataxia Causes: defect in any **step in pathway**, **iodine deficiency**, or rarely because **antibody that blocks TSH receptor**, or because mother and fetus are hypothyroid Must give **T4 treatment promptly** to ensure normal brain development

Question 34

Goiter

Answer 34

Just means **big** thyroid gland Can be caused by **hypo** **or hyperthyroidism** (Graves' disease), **simple nodular goiter** (thyroid working fine?)

Question 35

What can iodine deficiency cause?

Answer 35

Goiter Cretinism (due to maternal and fetal I deficiency)

Question 36

How is iodine related to intelligence?

Answer 36

Need iodine for intelligence! Low iodine areas have mental impairment

Question 37

Where is there a lot vs. a little iodine naturally?

Answer 37

Lots of iodine by the ocean Not enough iodine in the mountains

Question 38

What happens if your thyroid gland isn't working (because of I deficiency vs. throid antibodies against TPO)

Answer 38

With **both** I deficiency and thyroid autoantibodies against TPO: **increased TSH**, increased **T4 to T3 conversion** (**upregulation of D2**), **goiter** because TSH promotes thyroid follicular cell growth/proliferation In **iodine deficiency** only: get perferential release of **T3**

Question 39

Progression of mild thyroid failure

Answer 39

First, **T4** starts to drop so **TSH** goes way up (remember log relationship) Body compensates by **making more T3** (**upregulation of D2**) Very end stage, **T3 goes down too** (rare to see this these days)

Question 40

Imaging of the thyroid gland

Answer 40

**Ultrasound**: commonly used **Iodine scan**: ingest radioactive iodine and gets concentrated in thyroid gland; functional and structural image; not used unless specifically indicated

Question 41

Danger of goiter

Answer 41

Can compress trachea If compressing trachea, etc can use **Pemberton's sign** of flushed face when preson makes "touchdown" sign with arms up

Question 42

TSH receptor

Answer 42

In the **thyroid gland** of course Has extracellular and intracellular domains **Extracellular** mutations **inactivate** receptor = **hypothyroidism** = usually acquired, somatic mutation **Intracellular** mutations **activate** receptor = **hyperthyroidism** (thinks TSH is there always) = usually genetic, germline mutation

Question 43

Graves' disease

Answer 43

**Immunoglobulin** **stimulates TSH constitutively** (fairly common) More females than males Most common cause of **hyperthyroidism** Goiter is usually **symmetric** (batman sign!) To test for Graves, look for **TSI** (thyroid stimulating immunoglobulin) and **TBII** (TSH binding inhibitory immunoglobulin) antibodies Treatment: antithyroid drugs (lower T3, T4, TSI), radioiodine, surgery

Question 44

Toxic nodule

Answer 44

**Mutation of TSH receptor gene** (intracellular mutation) that makes it constitutively active

Question 45

Resistance to thyroid hormone

Answer 45

**"Dominant negative" mutation** of thyroid hormone receptor beta gene (**TR-beta**) so T3 and T4 can't bind their receptors in target tissue and on anterior pituitary? **Elevated T3, T4** Normal TSH **Feedback impaired** so don't get decrease in TSH that you should Since heart uses TR-alpha, you get cardiac symptoms (**tachycardia**) Get goiter Clinical manifestations: ADHD, growth and skeletal defects Note: this mutation is on the TISSUES!! (not TSH on thyroid cells like the other diseases)

Question 46

Prevalence of thyroid diseases

Answer 46

Hypothyroidism: 2% **Mild hypothyroidism: 5-17%** Hyperthyroidism: 0.2% Mild hyperthyroidism: 1-6%

Question 47

Hypothyroidism

Answer 47

Too little T3 and T4 Causes: **autoimmune thyroiditis**, **radioactive treatment** (of Graves' or goiter or cancer), lithium carbonate therapy, **iodide** or iodide-containing medications Clinical manifestations: cold easily (cool, dry pale skin), dry skin, fatigue, constipation, facial puffiness, weight gain, bradycardia, coarse hair, delayed relaxation of deep tendon reflexes, goiter

Question 48

Treatment of hypothyroidism

Answer 48

Levothyroxine (T4) Cytomel (L-T3) Thyrolar (synthetic T4 and T3; not used anymore) Armour: dessicated animal thyroid

Question 49

Why might someone not feel right on T4 as therapy for hypothyroidism?

Answer 49

If their **D2 is defective**, they'll need to be give T3 directly because they can't make it from T4

Question 50

Hyperthyroidism

Answer 50

Too much T3 and T4 Causes: most commonly **Graves' disease**, could be **toxic nodule** Clinical manifestations: hot easily, palpitations, tremor, weight loss, tachycardia, goiter

Question 51

Subacute Thyroiditis

Answer 51

First you get **hyperthyroid** then **hypothyroid** **T4 release** increases because of **inflammation** of thyroid gland --\> TSH suppressed and also iodine uptake is low (not MAKING more T4 just RELEASING more T4) Then, **thyroid is shut down** and T4 goes down while TSH goes up (and iodine goes up too--but why?) Occurs most commonly **post partum** (immune suppression then after delivery, activation can cause autoimmune) **Only treat this if hypothyroid is bad** enough, otherwise will go away on its own within a few months

Question 52

How do you distinguish between Graves' disease and Subacute Thyroiditis?

Answer 52

Do iodine scan **Graves**: **high I** because TSH receptor antibody lead to NIS activity and I getting concentrated **Subacute thyroiditis**: just release of T4 that is already there, **no increase in I** concentration

Question 53

Hamburger thyrotoxicosis

Answer 53

Weird outbreak of thyrotoxicosis (increased thyroid hormones) without evidence for Graves' Happened in Minnesota, South Dakota, Iowa Was because there was cow thyroid in the hamburgers they were eating. Yuck.

Question 54

Hashimoto's thyroiditis

Answer 54

**Autoimmune** disease that causes **destruction** of thyroid gland Antibody against thyroid peroxidase (**TPO**) Causes **hypothyroidism** with bouts of **hyperthyroidism**

Question 55

Hot vs. cold nodule on radionucleotide scan (using iodide)

Answer 55

**Cold**: hypofunctioning; **need** to be **aspirated**; 90% of nodules are cold **Hot**: hyperfunctioning (making excess thyroid hormone); **don't** need to be aspirated; note that the rest of the thyroid tissue will NOT be making lots of thyroid hormone because negative feedback of very little TSH works there!

Question 56

Thyroid antibodies to look for

Answer 56

Anti thyroid peroxidase antibody (TPO): replaces anti-microsomal antibody (AMA) Anti-thyroglobulin antibodies: measure these along with thyroglobulin to look for thyroid cancer Thyroid stimulating immunoglobulin (**TSI**): bioassay for Gaves' disease due to **TSH receptor stimulation by TSI** TSH binding inhibitory immunoglobulin (**TBII**): measured to diagnose Graves' also; Graves' immunoglobulin **inhibition** **of TSH binding** (but TSI binding instead??)