Thyroid Physiology Flashcards
Thyroid gland location
Follicular vs parafollicular cell secretions
Other things that make up thyroid gland (LAF)
Follicular cells make thyroid hormone; Parafollicular cells make calcitonin
Others: fibroblasts, lymphocytes, adipocytes
Thyroid gland structure
What’s colloid?
Thyroid follicle is basically the functional unit of the thyroid;
it’s a closed sac filled w/ colloid, which is pre-made/inactive thyroid hormone that’s stored there
Thyroid hormone is one of 3 essential hormones for life; what are the other 2? (hint: CIT)
Effects of thyroid hormone on the following:
Bone
Cardiovascular system
Liver
Fat
Brain
Gut
(T4 is clasty. She also likes a lot of blood and not so much resistance. She likes to stay lean, she’s super brilliant and she has regular bowel movements?)
Bone: + osteoclasts
Cardiovascular: decreased systemic vascular resistance, so we can have increased blood volume and cardiac output
Liver: regulates LDL receptors (lipid metabolism)
Fat: lipid storage, lipolysis, adipocyte proliferation
Brain: stimulates axonal growth and development (important for baby in utero; lack of thyroid hormone = congenital hypothyroidism = cognitive delay)
Gut = bowel regularity
Hypothyroidism definition
Causes
Symptoms by system
Hypothyroidism: too little T3 and T4;
caused mostly by autoimmunity (antibody against TPO) or thryodectomy
“everything’s slow and cold”
Constitutional: fatigue and lethargy
Vision: blurry
Head and Neck (H&N): throat fullness; hoarseness
Pulmonary
Cardiovascular (C/V): slow heart rate
Gastrointestinal: constipation, decreased appetite (+ weight gain)
Genito-Urinary : Greater intervals between menstrual periods
Hematology/Oncology
Ob/Gyn/Breast: impaired fertility
Neurological: forgetfulness and can’t concentrate
Endocrine: cold intolerance
Musculoskeletal: muscle and joint pain; weakness in extremities, difficulty ambulating
Mental Health: depression
Skin and Hair: dry skin + hair loss
Hyperthyroidism definition, symptoms, causes
Hyperthyroidism: too much T4/T3; caused also mostly by autoimmunity (Grave’s disease; antibody against TSH receptor)
Other causes: toxic nodule; medication induced
Symptoms
Head/Neurological- poor concentration
Cardiovascular - Palpitations
GI - diarrhea (otherwise increased bowel movements); increased appetite, weight loss
Endo – heat intolerance
Musculoskeletal – fatigue/weakness, tremor
Ob/Gyn: decreased menstrual flow (oligomenorrhea)
Others: hyperactivity/nervousness + anxiety; increased perspiration
Psych: insomnia
Hypothyroidism physical signs
Hyperthyroidism physical signs
Hypothyroidism:
Non pitting edema
Bradycardia
Goiter
Hypothermia
Weight gain
Dry skin and coarse hair
Hyperthyroidism:
Hypertension
Tachycardia
Lid lag
Tremor
Where’s the TSH receptor on the follicular cell?
Functions of follicular cells
On BLM of follicular cell
- Collect and transport iodine
- Synthesize thyroglobulin and secrete it into colloid
- Remove thyroid hormones from iodinated thyroglobulin and secrete thyroid hormones into circulation
Steps in thyroid hormone synthesis
(just list them)
Iodine trapping and absorption into colloid
Oxidation and organification of iodine
***synthesis of TG and transport into colloid
Iodination of thyroglobulin
Endocytosis of TG into follicular cell
Diffusion of T3/T4 into bloodstream
Binding of T3/T4 to plasma proteins
Thyroid hormone synthesis step 1 and 2 details
Step1: iodine trapping from diet and absorbed thru BLM
Taken up into the cell via Na/I symporter (uses Na+ gradient)
To move iodine across the cell and into the colloid, the cell uses Pendrin, a transport protein that fuses w/ exocytotic vesicles at the apical membrane
Step2: Organification done by thyroid peroxidase (TPO); **is the source of autoimmune hypothyroidism
***
This is actually step 1 because thyroglobulin is being made in the ER at the same time that iodine is being transported and turned into tyrosyl residues
When thyroglobulin is made, its packaged into and released in a vesicle and when the vesicle fuses w/ the apical membrane and TG will get exocytosed
Step 3 details in TH synthesis
Basically adding a bunch of iodine to tyrosine
Tyrosine + I= Mono-iodotyrosine (t1)
Tyrosine + I + I= Di-iodotyrosine (t2)
t1+t2: T3
t2+t2: T4
Mature hormone sits in the colloid until needed; bound to TG
Step 4 TH synthesis
The TG that you put into the colloid just sits there real quick
The iodine you put into the colloid gets tacked on to Tyrosine
Then the 2 things (T3/T4 + TG) couple up and get endocytosed via the apical membrane into follicular cells
Endocytic vesicles fuse w/ lysosomes, and then the TG will get hydrolyzed to T4 and T3 + a bunch of AA’s
Step 5 TH synthesis details
T4/T3 diffuse across the BLM via the MCT8 transporter to the bloodstream
Step 6 TH synthesis details
Binding of T3/T4 to plasma proteins
Mostly bound to Thyroxine binding globulin (TBG)
5-10% carried by Transthyretin (TTR)
The rest by albumin and lipoproteins
Sources of thyroid hormone
(where is T4 mainly made? If T3 isn’t made in huge amounts in the thyroid, where does it come from? What’s rT3)
Between T4 and T3, who’s the most biologically active?
Majority of T4 is made by the Thyroid; only minority of T3 is made by thyroid; T3 is mostly made by deiodination of T4 in other tissues
rT3 is inactivated T4 that has no biological function and so it gets excreted
T3
Enzyme that converts t4 to t3
group that’s required as a cofactor on this enzyme
types of this enzyme. who are the main players?
what’s the big deal about type 3 enzyme (2 functions w/ converting t4/t3); its role in the placenta
when is type 3 upregulated? what does that result in?
5’ deiodinase converts T4 to T3; deiodinase enzymes have sulfhydryl group as cofactor
Type 1 and Type 2 deiodinases are the main players
Type 3 acts to protect baby from having hyperthyroidism (stops too much T3 from mom from getting to the baby); converts T4 to rt3, or T3 to T2
Upregulated in tumors; results in consumptive hypothyroidism
Pathway of T4 metabolism
T4 will be deiodinated to T3, which will then be deiodinated to T2, which is not biologically active and will be excreted
Alt pathway: T4 can be inactivated to T2
Activation = removal of iodine from outer ring. Inactivation happens by removal of iodine from inner ring
Reversible changes that occur when TH levels are altered in critically ill patients = ?
When else would you induce the state above?
Which version of TH would exist when pt is critically ill? how are the TSH levels? why are they at this level?
Role of steroids in this pathway
Non thyroidal illness
If you’re on beta blockers or glucocorticoids; if you have the following: uremia, starvation
rT3 dominates; T3/T4 low; TSH levels low generally; When critically ill, rT3 is made, which can feedback to the pituitary and prevent thyroid hormone synthesis by lowering TSH
Steroids are a big influence on shunting this pathway away from making active T3 and towards rT3 instead
Events that incite non-thyroidal illness
(hint for the 1st four: if u get shot, you got trauma and you’ll need surgery. if things go sideways, you could get an infection that causes sepsis)
Trauma
Sepsis
Infection
Surgery
Chronic disease
Degenerative conditions
Metabolic disorders – DM, malnutrition, fasting
TH mechanism of action (which receptor type does it work thru?)
Who initiates this action, T4 or T3?
Which kinds of receptors are they? what’s the subunits?
where are the most/least receptors expressed?
Nuclear receptor binding
T3
T3 receptor expressed as dimer of alpha and beta subunits (can be a/b homodimers, or ab heterodimer)
More receptors on tissue that require a lot of thyroid hormone (pituitary, kidneys, heart and skeletal muscle, lungs, gut)
Fewer receptors on unresponsive tissues (places where it’s not really needed), e.g. spleen and testes
Ultimate effect of T3 binding to its receptor
what are the downstream proteins made after TH hormone binding?
Binds to DNA response elements to control RNA synthesis
NA-K ATPase
Cardiac and smooth muscle contractile proteins
Enzymes for lipid metabolism
Gluconeogenic enzymes
β adrenergic receptors
Types of regulation of TH (explain each)
(peripheral is pretty variable; the axis is central)
Central regulation = HPT axis
Peripheral regulation = body’s conversion of T4 to T3 ; basically controlled by whatever the situation is (nutrition status, meds, if you’re sick, hormones etc)
TSH; T4/T3 levels in the following (and why)
Primary hypothyroidism
Primary hyperthyroidism
TSH = high; t4/t3 = low; TSH high b/c negative feedback is lost
TSH = low; t4/t3 = high; TSH is low b/c negative feedback is in overdrive
3 things inhibit TSH (TSH sits on dope sugar)
2 functions of TSH (one explains why pts get goiter)
time when TSH peaks vs low
Inhibited by somatostatin, dopamine, glucocorticoids
Growth of thyroid cells and thyroid hormone synthesis
***If TSH stimulates growth of thyroid, then high TSH can result in a goiter. Or a TSH mimicker can also result in a goiter.
TSH (like cortisol) peaks at night/early AM, lower during the day
In low T3/T4 state, what happens to the following:
IGF1 and IGF 1 BP
FSH/LH/sex steroids
ACTH/Cortisol
Decreased IGF1 and IGF1BP,
Decreased FSH/LH and sex hormones,
Increased cortisol and ACTH
Whole effects of Thyroid hormone
(think of: growth, the brain, the heart and blood pressure, body weight (fat vs ms), 3 big components of your diet aside from greens)
Linear growth/maturation proteins (e.g. growth hormone)
Proteins involved in growth and maturation of CNS
Beta adrenergic receptors; cardiac ms proteins (myosin, actin, Ca2+ stimulated ATPase, myosine stimulated ATPase)
Body heat regulation
Regulation of carbs, fats, proteins***
(when you have too much TH, you’re regulating too much that’s why you lose weight, muscle and fat tissue; the opposite is true)
NIS mutation effects
Goiter also or naw? How?
Defect in iodine transport or trapping bc of mutation in Na/I symporter gene. Results in congenital hypothyroidism and goiter (still have TSH)
Grave’s disease
TSH levels? Goiter or naw?
The TRAb mimics TSH and turns the thyroid permanently on.
Negative feedback inhibition results in a low to undetectable TSH.
**One of the main causes of hyperthyroidism. + goiter
(Even if its not TSh bound to the receptor, the downstream effects of TSH – receptor binding are going to be the same)
Hashimotos disease
TSH levels? Goiter or naw?
Antibody directed against TPO resulting in diminished thyroid hormone production and primary hypothyroidism. (a high TSH with a low t4); Goiter = plus/minus
Pendred Syndrome
Why would you be deaf in this disorder?
Mutation in the Pendrin (protein that allows us to get iodine into the colloid)
Hypothyroidism, goiter and sensorineural deafness
Pendren also found inner ear (in the ear it is important for normal endolymph composition and maintenance of the endocochlear potential)
