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BMS 460 > Thyroid Hormones and Thyroid Disorders > Flashcards

Thyroid Hormones and Thyroid Disorders Flashcards

1
Q

describe the inside of the thyroid gland

A
  • follicles: contain colloid, which is a protein-rich fluid. TH is made in the follicles
  • between the follicles: medulla, which has parafollicular C cells that release calcitonin
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2
Q

how are parafollicular C cells derived?

A
  • these are in the medulla of the thyroid, which is the space in between the follicles
  • these specific cells are derived from the neural crest
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3
Q

reverse T3….

A

has no biological activity

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4
Q

go over the charts on slide 41

A

IMPORTANT!!

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5
Q

what causes C cells to release calcitonin?

A

increased serum calcium

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6
Q

what is the main function of calcitonin?

A
  • antagonize the effects of PTH
  • it decreases bone resorption and increases renal calcium excretion
  • overall goal: decrease serum calcium (whereas PTH wants to increase it)
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7
Q

how can hypercalcitoninemia be caused by nutrition?

A
  • high-calcium diet will cause lots of calcitonin release
  • causes mineral imbalance
  • leads to osteopetrosis of vertebrae and tibia
  • this is “stone-like” bone, which occurs because calcitonin decreases bone resorption in order to decrease serum calcium levels
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8
Q

thyroid neoplasia and calcitonin

A
  • humans: calcitonin-secreting medullary thyroid carcinoma leads to hypercalcitoninemia
  • caused by ultimobranchial tumors in bulls (ultimobranchial bodies fuse with the thyroid glands and we think they develop into parafollicular cells (secrete calcitonin)
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9
Q

describe the calcitonin gene

A
  • calcitonin is 32 amino acids
  • encoded by a gene on chromosome 11p
  • the calcitonin gene is also expressed in other tissues (other than thyroid) as calcitonin gene-related peptide (CGRP, 37 amino acids)
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10
Q

properties of CGRP

A
  • firstly, this is calcitonin gene-related peptide
  • this is how calcitonin is expressed in tissues other than thyroid (which has actual calcitonin gene)
  • has neurotransmitter and vasodilator properties
  • involved in completion of the process of testicular descent
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11
Q

describe the process of TH production and secretion

A
  • iodide is cotransported into thyroid follicular cells with sodium
  • ions diffuse into lumen of follicle
  • iodide gets oxidized and attached to rings of tyrosines on thyroglobulin (TG)
  • the iodinated ring of one MIT or DIT is added to a DIT (so there are two rings per thyroid hormone, either both have two iodines or one has two and the other has one - T3 or T4)
  • TG containing T3 and T4 molecules gets endocytosed back into the follicle cell
  • lysosomal enzymes release T3 and T4 from TG
  • T3 and T4 get secreted into the bloodstream
  • free amino acids are re-used for TG synthesis (TG is synthesized in the follicle cell and then secreted to colloid in the lumen))
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12
Q

what is TPO and what does it do?

A
  • thyroid peroxidase
  • located at the apical plasma membrane of follicle cells (facing the colloid)
  • it reduces hydrogen peroxide, which elevates the oxidation state of iodide to an iodinating species
  • then, it attaches the iodine to tyrosyls in TG (part of TG active site) in a nonspecific manner
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13
Q

how do iodide and sodium get into the follicle cell from the bloodstream?

A
  • ATP-drive sodium-iodide symporter
  • creates “iodide trap”
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14
Q

what are the three thyroid-binding proteins in the blood?

A
  • first of all, TH is lipid-soluble, so is not soluble in the blood, which is why it needs to be bound to something in order to circulate
  • thyroxin-binding globulin
  • trans-thyretin
  • albumin
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15
Q

ratio of T4 to T3 released into the blood?

A

20:1 (much more T4!!)

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16
Q

why is more T4 released than T3?

A

T4 is much less potent, but has a longer plasma half life (5-7 days for T4 and only 18 hours for T3)

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17
Q

effects of TH?

A
  • the effects are chronic!
  • biological effect of T3 is more rapid and requires 3 days for peak effect
  • T4 requires 11 days for peak effect
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18
Q

how is T4 converted to T3?

A
  • T4 gets converted to T3 at target tissue
  • enzyme that does this is 5’-monodeiodinase
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19
Q

how does T3 exert its function?

A
  • binds to nuclear receptors and initiates transcription of many proteins and enzymes
  • overall effects are increase in metabolic rate and oxygen consumption
  • wide variety of general effects of TH in different target organs
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20
Q

selenium and TH production

A
  • selenium-containing deiodinases are involved in T4 metabolism
  • this means that dietary selenium is needed for T3 production
  • i think a selenium deficiency would result in lack of conversion of T4 to T3
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21
Q

how do steroid hormones, prostaglandins, vitamin D, retinoic acid, and TH work?

A
  • all of these bind to intracellular receptors (aka nuclear receptors that are transcription factors)
  • produce mRNA, which can be used to make other proteins and hormones that are needed for normal growth and development
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22
Q

what are some of the functions of T3?

A
  • increase: mitochondria, respiratory enzymes, Na/K ATPase, other enzymes
  • these will all increase oxygen consumption and metabolic rate
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23
Q

what does T3 do to the lungs?

A

increases CO2 (because increasing metabolic rate, and CO2 is a byproduct) and ventilation (to remove CO2)

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24
Q

what does T3 do to the heart?

A

increase cardiac output

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25
Q

what does T3 do to the kidneys?

A

increases urea (in urine) and renal function in general

26
Q

hyperthyroidism symptoms

A
  • nervousness
  • weight loss
  • diarrhea
  • tachycardia
  • insomnia
  • increased appetite
  • heat intolerance
  • oligomenorrhea (sparse or infrequent menstrual cycles)
  • muscle wasting
  • goiter
  • exophthalmos (eyes bulge)
27
Q

hypothyroidism symptoms

A
  • lethargy, slow cerebration
  • weight gain
  • constipation
  • bradycardia
  • sleepiness
  • anorexia
  • cold intolerance
  • menorrhagia (heavy menstrual cycles)
  • weakness
  • dry, course skin
  • goiter
  • facial edema
28
Q

most common cause of hypothyroidism

A
  • hashimoto’s (autoimmune)
  • aka autoimmune lymphoytic thyroiditis
29
Q

other causes of hypothyroidism

A
  • iatrogenic: surgery or radioactive iodine treatment, or drugs like lithium
  • dietary: deficiency of iodine or goitrogen (anti-thyroid) vegetables
30
Q

overall sequelae of hypothyroidism

A
  • generally slows metabolism
  • actual clinical presentations depend on how severe the deficiency is and how long it lasts
31
Q

cretinism

A
  • TH deficiency during fetal development
  • usually caused by maternal hypothyroidism before fetal thyroid is developed
  • fetal self-sufficiency of thyroid hormones protects fetus against abnormalities that can be caused by maternal hypothyroidism
  • however, preterm births due to maternal hypothyroidism can cause neurodevelopmental disorders because the thyroid was not sufficiently developed to meet postnatal needs
  • hypothyroidism during fetal development and childhood leads to stunted growth and mental retardation
  • if diagnosed early and treated with TH, physical and intellectual development can be normal
32
Q

thyroid during fetal life

A
  • thyroid is active during this time
  • uses iodide from maternal circulation
  • fetal T4 production reaches a clinically significant level at 18-20 weeks
33
Q

myxedema

A
  • TH deficiency in adulthood
  • this manifests as corse skin and puffy appearance of the face due to fluid retention in the dermis of the skin
34
Q

TSH in hypothyroidism

A
  • it is increased because TH levels are low so it is trying to get the thyroid to secrete TH
  • increased TSH causes goiter: enlargement of the thyroid gland
35
Q

labs for primary hypothyroidism

A
  • first of all, primary indicates there is an issue with the thyroid itself!
  • decreased T4
  • increased TSH
36
Q

iodine deficiency in the US

A
  • very rare because of the widespread use of iodized sea salt
  • in this salt, one in every 10,000 molecules of NaCl is replaced with NaI
37
Q

go over manifestations on slide 46

A

YES

38
Q

goiter in hypothyroidism

A
  • lack of negative feedback on anterior pituitary causes excessive TSH, which causes enlargement of the thyroid
  • note: this can also happen in hyperthyroidism (thyrotoxicosis (TH excess), regardless of the cause)
39
Q

how does hypothyroidism in hashimoto’s usually develop

A
  • usually develops gradually
  • in some cases, it can be preceded by transient (temporary) thyrotoxicosis (too much TH)
  • thryotoxicosis can be caused by disruption of thyroid follicles, which leads to release of thyroid hormones
  • during this phase, free T4 and T3 are elevated, TSH is diminished, and radioactive iodine uptake is decreased
  • hashitoxicosis: brief period of hyperthyroidism that occurs in the early states of hypothyroidism!
40
Q

histology of hashimoto’s thyroiditis

A
  • infiltrate of lymphocytes throughout thyroid gland
  • destroys thyroid follicles (by compressing them)
41
Q

what is the overall cause of hashimoto’s thyroiditis?

A
  • sensitization of autoreactive CD4+ T cells to thyroid antigens (specifically thyroid peroxidase and thyroglobulin)
  • though this sensitization is necessary, it happens too much in this case. i think that there is an issue with the suppressors of sensitization, so it is overactive
42
Q

what are the three mechanisms of thyroid cell death caused by sensitization of T cells to thyroid antigens?

A
  1. T-cell mediated cytotoxicity: the T-helper cells activate CD8+ T cells, which express FasL, which binds Fas on thyroid cells, killing them
  2. thyrocyte injury: the T-helper cells secrete antibodies to activate macrophages, which injure thyrocytes
  3. antibody-dependent cell-mediated cytotoxicity: the T-helper cells activate plasma cells, which secrete anti-thyroid antibodies. when NK cells see these antibodies on thyroid cells, they kill these cells
43
Q

causes of hyperthyroidism

A
  • most cases are caused by Graves’ disease, which is an autoimmune disease where there are autoantibodies against TSH receptors
  • there could also be a nodular goiter or hyper-functioning adenoma in the thyroid or pituitary gland that causes hyperthyroidism
44
Q

sequelae of hyperthyroidism

A
  • increased metabolic rate and acceleration of lots of different physiologic functions
  • exopthalmos: eye bulging, proptosis
  • tachycardia: increase heart rate
  • goiter: enlarged thyroid gland
45
Q

labs for hyperthyroidism

A
  • decreased TSH
  • increased T3 and T4
  • increased antibodies to thyroid
46
Q

go over hyperthyroidism manifestations on slide 49!!

A

PLZ

47
Q

pathogenesis of graves’ disease

A
  1. autoantibodies (thyroid-stimulating immunoglobulins or TSI’s) are made by plasma cells from sensitized T cells. these antibodies are against TSH receptors at the basal surface of thyroid follicular cells. the antibodies bind TSH receptors and mimic effect of TSH, stimulating cAMP production
    - this causes thyroid follicular cells to become columnar and secrete lots of TH into the blood (unregulated)
    - also have goiter, exophthalmos, tachycardia, warm skin, fine finger tremors
  2. inflammatory cells in stroma of thyroid gland make cytokines that cause thyroid cells to make more cytokines, which increases the autoimmune process
48
Q

what are the cytokines made by inflammatory cells in the stroma of the thyroid gland?

A
  • IL-1
  • TNF-alpha
  • interferon-Y
49
Q

anti-thyroid drugs in hyperthyroidism

A
  • decrease cytokine production (this is an immunosuppressive effect)
  • in some patients, this can lead to remission
50
Q

go over the chart on the right side of slide 50

A

PLZ it’s a lot

51
Q

describe the process of graves’ opthalmopathy? (slide 51)

A
  • PULL UP CHART ON SLIDE 51 WHILE GOING THROUGH THIS
  • inflammation of extraocular muscles
  • increase in orbital adipose tissue and CT
  • circulating anti TSH receptor antibodies bind to TSH receptors on fibroblasts in retrobulbar tissue
  • cytokines from T-cells in the inflammatory infiltrate stimulate adipogenesis from the preadipocyte fibroblasts (basically differentiation of fibroblasts into adipocytes)
  • fibroblasts also produce proteoglycans and collagen fibers, causing retrobulbar edema and fibrosis of the extraocular muscles, leading to bulging eyes
52
Q

what is the most common and important manifestation of graves’ disease outside of the thyroid?

A

orbitopathy!

53
Q

describe the process of tachycardia in hyperthyroidism (slide 52)

A
  • T3 enters nucleus of a cardiocyte
  • it binds nuclear receptors, then binds thyroid hormone response element in its target gene
  • stimulates phospholamban phosphorylation, which is a protein needed for release and uptake of calcium into sarcoplasmic reticulum
  • this increases systolic contraction and diastolic relaxation
54
Q

increased diastolic function in patients with hyperthyroidism?

A
  • related to phospholamban
  • ultimately goes back to TH-mediated changes in cardiac muscle contractility
55
Q

what does TH regulate in cardiomyocytes other than phospholamban?

A

expression of genes for beta-adrenergic receptors, calcium ATPase, etc.

56
Q

what is the thyroid storm?

A
  • lots of TH in short period of time
  • complication of hyperthyroidism/thyrotoxicosis
  • can be precipitated by infection of physical manipulation of thyroid gland
  • leads to fever, confusion, agitation, irregular pulse, heart failure
57
Q

how to prevent thyroid storm?

A
  • suppress thyroid function with anti-thyroid drugs (thionamides)
  • beta blocker: inhibits beta-adrenoreceptors, which get upregulated by elevated TH
  • PTU: inhibits iodination and conjugation steps of TH production, so stop making TH
  • sodium iodide: acutely blocks release of already synthesized TH. also temporarily blocks TH synthesis by preventing iodine organification
58
Q

note on catecholamines, calcium, and the heart muscle (fine print on slide 52)

A
  • catecholamines induce calcium uptake in sarcoplasmic reticulum
  • this increases myocardial relaxation (called lusitropy)
  • do not confuse this with increase uptake of calcium by the cytosol of cardiomyocytes. this increases contractility, increasing lusitropy, and decreases myocardial relaxation
    (this is related to beta blockers!!)
59
Q

fine-needle aspiration

A
  • minimally invasive
  • can provide clinically useful risk stratification by telling us whether thyroid nodule is benign or malignant
60
Q

hormonal evaluation tells us…

A
  1. primary condition: thyroid issue, look at TH levels
  2. secondary condition: anterior pituitary issue, look at TSH
  3. tertiary condition: hypothalamus issue (can’t measure levels of TRH because it gets secreted straight into portal circulation, does not enter peripheral circulation)
61
Q

what does radioactive iodine uptake measure

A
  • thyroid function
  • hyperactive: increased uptake
  • hypoactive: decreased uptake
62
Q

what do the different doses of radioactive iodine detect

A
  • low dose: hot/functioning nodule is benign, while a cold/nonfunctional nodule is likely malignant
  • if it is hyperthyroidism, low dose tells us if it is because of thyroiditis (minimal uptake) or graves’ (increased uptake)
  • high dose to treat hyperthyroidism: this can kill the thyroid, but synthetics can maintain TH and other risks are minimal

BMS 460 (34 decks)

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