Thyroid Hormone (Week 5--Brent) Flashcards
Normal levels of thyroid hormones
TSH: 2-11 ulU/ml
T4: 5-12 ug/dl
T3: 80-180 ng/dl
What would cause swelling above the thyroid?
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
Thyroid follicle
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
Sodium/Iodide Symporter (NIS)
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
Follicular cell
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
How is dietary iodide taken up and concentrated?
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
How much is the thyroid gland able to concentrate iodide?
Concentrates iodide 30-35 fold!
This is important because can keep making thyroid hormone even when iodine supply is low
What happens if you don’t have enough nutritional iodide?
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
How exactly does TSH stimulate more T3/T4 to be made?
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
TPO (thyroid peroxidase)
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
Which coupling reactions create T3 vs. T4
MIT + DIT = T3
DIT + DIT = T4
Note that both of these coupling reactions are done by TPO!
How much of what actually comes out of the thyroid is T3 vs. T4?
Mostly T4, only 20% is T3
What kind of hormone is thyroid hormone?
Not peptide and not steroid
Circulates bound to serum proteins
Binds nuclear receptor
T4, T3, reverse T3
T4 is pro-drug
T3 is active drug
Reverse T3 is inactive
How do you get T3?
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
How do you get reverse T3?
T4 is acted on by **D3 ** which removes an inner ring iodine
(inner ring inactivates!)
When is D1 vs. D2 used?
D1 used to provide circulating T3 (liver, kidney, thyroid)
D2 used to provide T3 to tissues rapidly (brain, pituitary, heart, BAT, skeletal muscle, thyroid)
When you have hyperthyroidism, which enzyme (D1, D2, D3) is cranked up?
D2
(5’-deiodinase 2)
What causes a decrease in T4 to T3 conversion and when would you want to do this?
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
Some children have hepatic hemangioma (liver tumor) secreting what that caused hypothyroidism?
Tumor was secreting D3, which caused T4 to reverse T3 conversion so had very low T4 and T3 but high reverse T3
Where does most of our circulating T3 come from?
Most T3 is made locally in tissues by D2
What are the serum proteins that T3 and T4 bind to?
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
What is responsible for feedback of T3 and T4 onto the hypothalamus and pituitary?
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
Does the body regulate free or bound hormone?
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
What tests do we do for thyroid function?
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
What is the relationship between T4 and TSH?
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
Definition of hypo and hyperthyroidism
Hyper: TSH <0.5 mU/L
Hypo: TSH >5.0 mU/L
Note: can only use TSH if your pituitary is normal, obviously
Thyroid hormone receptors
Nuclear receptors with DNA binding domain and ligand binding domain
Alpha type (cardiac effects) and beta type (metabolism effects) are different
What exactly do T3 and T4 do?
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…)
How does thyroid hormone interact with adrenergic system in hypo and hyper?
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
How does T3 regulate metabolism?
Promotes cholesterol synthesis, efflux
Promotes lipolysis and beta-oxidation
Increases fatty acid oxidation
Stimulates heat production (BAT, skeletal muscle)
How might we use thyroid hormone receptor beta in the future as a drug?
TR-beta analog lowers cholesterol! Might be used in addition to statins in the future
Congenital hypothyroidism
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
Goiter
Just means big thyroid gland
Can be caused by hypo or hyperthyroidism (Graves’ disease), simple nodular goiter (thyroid working fine?)
What can iodine deficiency cause?
Goiter
Cretinism (due to maternal and fetal I deficiency)
How is iodine related to intelligence?
Need iodine for intelligence!
Low iodine areas have mental impairment
Where is there a lot vs. a little iodine naturally?
Lots of iodine by the ocean
Not enough iodine in the mountains
What happens if your thyroid gland isn’t working (because of I deficiency vs. throid antibodies against TPO)
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
Progression of mild thyroid failure
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)
Imaging of the thyroid gland
Ultrasound: commonly used
Iodine scan: ingest radioactive iodine and gets concentrated in thyroid gland; functional and structural image; not used unless specifically indicated
Danger of goiter
Can compress trachea
If compressing trachea, etc can use Pemberton’s sign of flushed face when preson makes “touchdown” sign with arms up
TSH receptor
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
Graves’ disease
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
Toxic nodule
Mutation of TSH receptor gene (intracellular mutation) that makes it constitutively active
Resistance to thyroid hormone
“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)
Prevalence of thyroid diseases
Hypothyroidism: 2%
Mild hypothyroidism: 5-17%
Hyperthyroidism: 0.2%
Mild hyperthyroidism: 1-6%
Hypothyroidism
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
Treatment of hypothyroidism
Levothyroxine (T4)
Cytomel (L-T3)
Thyrolar (synthetic T4 and T3; not used anymore)
Armour: dessicated animal thyroid
Why might someone not feel right on T4 as therapy for hypothyroidism?
If their D2 is defective, they’ll need to be give T3 directly because they can’t make it from T4
Hyperthyroidism
Too much T3 and T4
Causes: most commonly Graves’ disease, could be toxic nodule
Clinical manifestations: hot easily, palpitations, tremor, weight loss, tachycardia, goiter
Subacute Thyroiditis
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
How do you distinguish between Graves’ disease and Subacute Thyroiditis?
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
Hamburger thyrotoxicosis
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.
Hashimoto’s thyroiditis
Autoimmune disease that causes destruction of thyroid gland
Antibody against thyroid peroxidase (TPO)
Causes hypothyroidism with bouts of hyperthyroidism
Hot vs. cold nodule on radionucleotide scan (using iodide)
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!
Thyroid antibodies to look for
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??)
