Thyroid Pathophys Flashcards
ectopic thyroid tissue
- can be found anywhere along thyroglossal duct (thyroid tissue descends down this duct to its anatomical position during development)
- less functional than normal thyroid tissue
- a cause of congenital hypOthyroidism w/ elevated TSH (when most or all of the thyroid is ectopic)
- more prone to cysts, which can become infected or cancerous
T3 vs T4
T3
- more active
- shorter half life (1-2 days)
- synthesized from MIT + DIT (monoiodotyrosine + di-IT)
- – MIT = tyrosine with one iodine R group
- – DIT = tyrosine with two iodine R groups
- – note that this is a covalently linked iodine, not ionic iodide
- metabolically active without conversion
- directly binds thyroid hormone receptor, a TF
- present in small amounts (1/100th of amount of T4) in circulation
- is produced by thyroid, but most of the circulating levels come from conversion of T4 to T3
- weaker affinity for TBG transport protein, i.e. more exists as unbound (active) form in blood
T4
- aka thyroxine
- less active
- longer half life (6-8 days)
- synthesized from 2x DIT
- to function, T4 is converted to T3 by deiodinase
- T3 then binds thyroid hormone receptor
- difference in amount of T3 and T4 comes both from greater production of T4 by thyroid and longer t1/2 = more accumulation
both
- tyrosine-based
- iodine-containing
- essentially similar metabolic functions
- synthesized in thyroid follicles (by thyrocytes/follicular cells)
- stimulated by TSH
iodine uptake into thyroid follicle
basolateral (blood vessel side):
- sodium iodide symporter (NIS)
- 2 Na+ and 1 I-
apical (colloid side):
- pendrin
- 1 I- for 1 Cl- exchange
once in colloid (fluid at center part of follicle)
- thyroperoxidase oxides iodide (I-) to iodine (I)
- thyroperoxidase also covalently links iodine to tyrosine residues (iodination) on thyroglobulin
- thyroperoxidase then links ITs together to make T3/T4
- T3/T4 remains attached to thyroglobulin until cleavage, release, secretion
thyroid hormone synthesis
precursor: thyroglobulin
- massive dimeric protein with a ton of tyrosine residues that get iodinated then linked together to make T3/T4
- T3/T4 remain linked to thyroglobulin until TSH-induced cleavage, release, and secretion
enzyme: thyroperoxidase
- oxidizes iodide to iodine
- covalently links iodine to tyrosine residues on thyroglobulin
- links MIT (monoiodotyrosine) to DIT (di-IT) to make T3 or DIT to DIT to make T4
secretion:
- thyroglobulin is endocytosed into thyrocyte
- proteases in lysosome cleave T3/T4 from thyroglobulin
- T3/T4 transported into bloodstream by MCT transporter
regulation: TSH
- TSH activates every aspect of synthesis including iodine uptake, oxidation, iodination, T3/T4 synthesis, thyroglobulin endocytosis, and secretion via MCT
- binds TSH receptor on thyrocytes
- hypothalamic TRH (thyroid regulating hormone) activates TSH release from pituitary
- negative feedback: T3/T4 downregulates TSH, TSH downregulates TRH
location:
- thyroid follicles
- thyroglobulin is produced in thyrocytes (follicular cells), which line a central lumen containing colloid
- thyroglobulin is stored in colloid
- released back through thyrocyte and into bloodstream when TSH binds
thyroid hormone transport
bound to plasma proteins:
- thyroxine binding globulin (TBG)
- transthyretin
- albumin
bound form is INactive small fraction (<1%) is unbound, which is what is recognized by cells
thyroid histology
circular thyroid follicles comprise simple cuboidal epithelial thyrocytes (follicular cells) surrounding a central lumen filled with colloid, where T3/T4 synthesis occurs
- thyroglobulin produced in thyrocytes and transported to colloid
- iodine transported into colloid
- thyroperoxidase in colloid catalyzes reaction
NIS
- sodium iodide symporter
- responsible for I- transport into thyrocyte
- located in thyrocyte, mammary glands, placenta, small intestine among others
- upregulated by TSH
- inhibited by perchlorate and thiocyanate, which are found in some foods and in the environment
TPO
- thyroperoxidase
- enzyme responsible for catalyzing iodide oxidation, iodination of tyrosine residues on thyroglobulin, ether linkage of DIT/MIT to make T3/T4
- heme-containing
- H2O2 oxidant
- membrane-bound
- concentrated at apical surface of thyrocyte
D1, D2, and D3
D1 and D2 = type 1 and 2 deiodinases
- convert T4 to T3
D1
- liver, kidney, thyroid
- upregulated in hypERthyroid
- downregulated in hypOthyroid
- in plasma membrane
- T3 it produces equilibrates rapidly with plasma levels
D2
- CNS, brown fat, thyroid, skeletal muscle
- in ER
- facilitates T3 –> nucleus i.e. functional intracellular accumulation
- downregulated in hypERthyroid
- upregulated in hypOthyroid
- i.e. autoregulates to maintain mostly consistent concentration of intracellular/nuclear T3
D3
- type 3 deiodinase aka 5’-deiodinase
- inactivates T4 (–> dT3)
- CNS, placenta, skin, uterus
TBG
- thyroxine binding globulin
- transports most of the T4 in the blood
- also transports T3 but binds less avidly, i.e. a greater proportion of T3 exists unbound
- TBG deficient/defective patients are normally fine d/t presence of alternate binding proteins and same total T3/T4 levels
thyroid hormone regulation
hypothalamus: TRH
- thyrotropin-releasing hormone
- positively regulated by circadian cycle (highest at night)
- negatively regulated by TSH
pituitary: TSH
- thyroid stimulating hormone
- dimeric glycoprotein
- positively regulated by TRH: stimulates release and synthesis of both subunits
- negatively regulated by:
- - *free T3/T4 (therefore total hormone labs can be misleading, free hormone more useful)
- - somatostatin
- - dopamine
- - pharmacological doses of glucocorticoids
thyroid: T3/T4
- positively regulated by TSH
- TSH binds TSH-R
- TSH-R cascade activates all aspects of T3/T4 production, starting with upregulation of NIS
- negatively regulated by iodi(d/n)e levels
factors that increase T3/T4 release
physiological:
TRH
- circadian (night)
TSH
- low T3/T4
pathological:
- tumors (TRH, TSH, T3/T4)
- autoantibodies (Graves’)
- defects in cellular sensitivity e.g. thyroid hormone receptor
factors that decrease T3/T4 release
physiological:
TRH: - circadian (daytime) TSH: - somatostatin - dopamine - high T3/T4
pathological:
- iodi(d/n)e deficiency
- glucocorticoid therapy
- destructive autoantibodies
- non-secretory tumors
- genetic defects: TPO, NIS, pendrin, MCT, thyroglobulin, TSH-R, TRH-R
thyroid labs
- TSH great first-line, cheap
- T3/T4 more expensive and imperfect but useful when:
- – TSH is abnormal
- – pituitary, hypothalamus, or thyroid pathology is known or strongly suspected
- – TSH does not match clinical picture
- iodine useful when deficiencies or toxicities suspected
- autoantibodies when autoimmune pathologies suspected
congenital hypothyroidism
defects in:
- thyroid formation and migration, including ectopic thyroid tissue
- synthesis
- action
- iodine uptake
- most common preventable cause of cognitive defect worldwide
- newborn screening is standard in US and developed world
- fetal development is fine if mother is euthyroid since a sufficient placental concentration gradient exists for maternal-fetal T4 transfer (normally T4 transfer does not occur)
- prenatal deficits occur if mother is also hypothyroid or iodine deficient and are irreversible
sx, first few weeks of life:
- feeding problems
- failure to thrive
- sleepiness
- constipation
sx, ongoing:
- cognitive deficits irreversible if not identified w/in 2 weeks of life, hence screening
tx:
- hormone replacement w/ close f/u for
- bone development
- physical growth
- motor dev
- dev milestones
physiological thyroid changes in pregnancy
- increase in total T3 and T4 d/t:
- increased serum t1/2 of TBG d/t
- increased glycosylation of TBG d/t estrogen
- free T3 and T4 remain constant or possibly elevated d/t
- hCG directly stimulates T3/T4 production (hCG and TSH have similar structure, so hCG is a weak TSH-R agonist)
- -> transient TSH suppression d/t increased T3/T4 is seen in 10-15% of women in 1st trimester
- baby relies on mom’s T3/T4 during 1st tri
- starts producing own @ ~12 wk
- at same time D3 (inactivates T4) is UPregulated in placenta/uterus to increase free iodine available for baby to make T3/T4
- this generally does not impact mother’s thyroxine levels b/c of increase in maternal production, BUT can exacerbate preexisting hypothyroidism
- iodine intake req’ increase in pregnancy d/t
- increased maternal and fetal T3/T4 synthesis
- increased GFR/renal excretion
iodine deficiency in pregnancy
results in gestational hypothyroidism
iodine intake req’ increase in pregnancy d/t
- increased maternal and fetal T3/T4 synthesis
- increased GFR/renal excretion
maternal sx:
- goiter
- increased TSH
- increased serum thyroglobulin
fetal or neonatal sx:
- profound neurological deficits, irreversible if not corrected early
- goiter
tx:
- iodine supplementation
- hormone replacement if needed
gestational hypothyroidism
- maternal and fetal demand for T3/T4 increases in pregnancy
- esp in 1st trimester when baby relies solely on maternal T3/T4
- fetus relies on maternal TSH through 5 mo
- in 2nd and 3rd trimester, baby increases break-down of maternal T3/T4 (via D3) to get iodine
- healthy thyroid/pituitary increase production to keep up with demand, but exacerbates pre-existing hypo-t
maternal sx:
- fatigue
- weight gain
- can be difficult to identify that these are d/t hypo-t and not normal pregnancy
fetal sx:
- neurological deficits, irreversible if not corrected early
tx:
- hormone replacement
iodine deficiency
mild:
- goiter
- elevated TSH
- normal T3/T4
moderate:
- possible hypothyroidism
severe:
- hypothyroidism w/ cognitive sx
in children:
- potentially irreversible cognitive deficits, if not treated early
epidemiology:
- Central and South America
- Europe
- Africa
- China
- Southeast Asia
foods high in iodine:
- dairy
- fish
- iodized salt (required by law in some countries; optional in US)
- vegetables can be an okay source in areas with iodine-rich soil, especially when a lot of veg are consumed, but in general they are not considered a high-iodine food
foods lacking sufficient iodine:
- meat
- poultry
- vegetables, in general
Wolff-Chaikoff effect
- acute inhibition of IT synthesis d/t excess intracellular (vs extracellular) iodiDe accumulation
- generally transient, 2 day d/t adaptive NIS downregulation
- in Hashimoto’s or other thyroid impairment, NIS downregulation may not occur and long-term hypo-t develops
Jod-Basedow effect
- hypER-t d/t excess iodiDe
- commonly seen in elderly a few hours after iodine load
- also in pts w/ multinodal goiter, Graves’, rarely normal thyroid
effects of excess iodide
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- Wolff-Chaikoff effect: acute hypo-t, may become chronic in individuals w/ preexisting thyroid impairment
- Jod-Basedow effect: hypER-t in elderly pts, goiter, Graves’, occasionally normal thyroid
- more often minimal effect, just excreted
thyroid nodule
- common, mostly benign
- usually asymptomatic
- possible neck discomfort, dysphagia, choking sensation
- normally euthyroid
eval:
- US
- fine-needle aspiration biopsy
- check TSH
epidemiology:
- ~50% of people have them by age 60
- ~10% of those rise to level of clinical attention (~5% of people; rest of stat comes from autopsy and incidental US findings)
- ~5% of clinically apparent nodules (0.5% of all nodules) are malignant
multinodal goiter
- enlarged, multiple nodule
- usually function normally, benign
possible:
- tracheal displacement and narrowing
- hyper-t
- hypo-t
- malignancy
- impaired venous drainage from head (Pembert’s sign)
“hot” thyroid nodule
- excess T3/T4 production
- lights up on radioiodine scan
- i.e. increased iodine uptake relative to surrounding tissue
- surrounding tissue is abnormally dim b/c TSH is low from all the extra T3/T4 production (but the hot nodule is not driven by TSH so it has increased uptake anyways)
- mostly d/t acquired activating mutation of TSH-R
- mostly clonal (come from same cell)
myxedema
severe hypo-t
may cause coma
rare b/c physicians have high index of suspicion for thyroid problems
Hashimoto’s thyroiditis
- aka chronic autoimmune thyroiditis
- most common cause of hypo-t in areas with sufficient iodine intake
- autoimmune destruction
- anti-TPO* or thyroglobulin
- primary hypo-t i.e. failure of thyroid, not pituitary
secondary hypothyroidism
pituitary failure
tertiary hypothyroidism
hypothalamic failure
hypothyroidism
sx:
- fatigue, lethargy
- brain fog
- depression
- cool, dry skin
- cold intolerance
- constipation
- weight gain
- fluid retention
- muscle aches, stiffness
- irregular menses
- infertility
- goiter (primary)
- bradycardia
- delayed relaxation of deep tendon reflexes
- htn
- non pitting edema
- facial puffiness
in children:
- delayed linear growth
- delayed bone maturation
dx primary:
- elevated TSH + concordant clinical picture
- may f/u w/ free T3/T4, US, anti-TPO, anti-thyroglobulin, etc.
- inconcordant clinical picture need T4 to confirm this vs secondary hyper-t
dx secondary:
- low TSH
- need decreased T4 to confirm this vs primary hyper-t
tx:
- levothyroxine
- dosing based on lean body mass, highly variable, f/u serum testing after 6 weeks of each dose adjustment to ensure correction
primary hyperthyroidism
aka thyrotoxicosis (when severe)
causes
- Graves’ disease (60-90% of all primary hyperthyroidism): anti-TSH stimulating Abs
- somatic activating TSH receptor mutations
- common thread is increased TSH-R stimulation
special tests
- RAIU: 24 hour radioactive iodine uptake test; increase in percent uptake of 123-I or 131-I
- anti-TSH-R titers (for Graves’)
24-hour RAIU test
- 24-hour radioactive iodine uptake test
- measures uptake of radioactive 123-I or 131-I over 24-hour period
- thyroid fx
- true primary hyperthyroidism: increase
- low-RAIU thyrotoxicosis due to inflammation or destruction of thyroid –> “leak” of thyroid hormones
- low RAIU also seen in subacute thyroiditis
low-RAIU thyrotoxicosis
- actually due to damage or inflammation of thyroid
- results in leak of thyroid hormones
- generally will cause hypothyroidism in short course
- decreased uptake on RAIU
Graves’ disease
primary hypERthyroidism d/t anti-TSH stimulating antibodies
sx
- diffuse goiter
- exophthalmos - autoimmune inflammation of periorbital connective tissue and extraocular muscles
- – clinically noticeable in ~50%, seen on imaging in ~100%
- – eye prominence, swelling
- – double and blurry vision
- – d/t TSH-R in retro-orbital tissues
epidemiology
- 6:1 F>M
- 20-50 y/o
- 0.02-0.4% incidence in US (relatively common)
- most common cause of primary hypERthyroidism
- decreased incidence in areas of iodine deficiency
special tests
- RAIU: 24 hour radioactive iodine uptake test; increase in percent uptake of 123-I or 131-I
- anti-TSH-R titers (for Graves’)
tx
thioureylenes: antithyroid drug
- TPO inhibitors (inhibit iodination and IT coupling)
- methimazole = preferred
- propylthiouracil = thyroid storm, 1st tri pregnancy (methimazole is embryotoxic); not preferred d/t risk of hepatic failure
- continue until remission, usually 6-12 mo
- sfx/aes: leukopenia/agranulocytosis, usually early in therapy
other tx
- radioactive iodine: 131-I - thyroid ablation
- – 123-I is used only for imaging b/c of shorter half life
- surgery: definitive
exophthalmos
- Graves’ eye disease
- autoimmune inflammation of periorbital connective tissue and extraocular muscles
- d/t TSH-R in retroorbital tissues
sx:
- blurry vision
- double vision
- clinically apparent eye prominence and swelling in ~50% of Graves’ pts
- inflammation of retroorbital tissues observed in almost all Graves’ pts
silent subacute thyroiditis
- elevated –> low –> normal T3/T4/TSH within a matter of weeks to months
- low RAIU
- self-limited, no treatment needed
- asymptomatic, no thyroid tenderness
- usually d/t anti-TPO or other anti-thyroid Abs
- generally postpartum
- 5-10% incidence in postpartum period
painful subacute thyroiditis
- elevated –> low –> normal T3/T4/TSH within a matter of weeks to months
- low RAIU
- self-limited, no treatment needed
- tender/painful thyroid
- post-viral
types of thyroid cancer and their prognosis
papillary (70%)
- not aggressive
- 10 year survival >80%
follicular (20%)
- more aggressive
- potentially metastatic
- fair prognosis
- long-term survival common
- 131-I therapy very effective even in metastatic disease
anapestic (5%)
- highly malignant
- <1 year survival
medullary (5%)
- no I- accumulation (affects calcitonin-producing cells)
- can’t be treated w/ 131-I
- prognosis dependent on stage (moreso than for the others)
- surgery curative if caught early, poor prognosis if metastatic
best to worst px thyroid cancer
papillary > follicular ~ early medullary > metastatic medullary»_space; anaplastic
tx thyroid cancer
in most cases:
- surgery curative: total or near total lobectomy
- may f/u w/ 131-I tx w/ stimulation of TSH-R to increase uptake
advanced:
- often not responsive to 131-I d/t poor fx/poor I- concentration
- TYRK, VEGF(-R) inhibitors ~30% success
long-term maintenance:
- levothyroxine: TSH suppression, hormone replacement for thyroidectomy
thyroid cancer dx and monitoring
- clinically apparent or incidental nodule finding on imaging usually first sign
in hypothyroid pts:
- total-body 131-I scanning
- serum thyroglobulin
- these can identify metastatic disease or residual thyroid bed tissue
- serum calcitonin for medullary
in non-hypothyroid:
- thyrotropin alfa (recombinant TSH) to test ability of normal or malignant tissue to take up radioactive iodine and secrete thyroglobulin
- this allows for same testing as above to be done without having to stop levothyroxine and b//c clinically hypothyroid
long-term f/u:
- elevated thyroglobulin usually first sign of recurrence
- regular total-body 131-I scans are also done
- serum calcitonin for medullary
types/features of thyroid eye disease (TED)
all or some of the following may be present
severe, sight-threatening
- corneal ulceration secondary to exposure
- comprehensive optic neuropathy
can be severe, sight-threatening
- exophthalmos/proptosis
- conjunctival infection
- chemosis/conjunctival edema
- periorbital swelling
- upper eyelid retraction
- eyelid lag
- double vision
active/inflammatory phase - 1-2 years
static phase
- proptosis
- eyelid retraction
- eyelid lag
- double vision
comprehensive optic neuropathy
- decrease in optic nerve fx d/t
- swelling of extraocular muscle in orbital apex and
- compromised blood flow to nerve and retina
- can result in permanent vision loss
clinical
- RAPD: relative afferent pupillary defect
- not seen in bilateral, symmetric compressive optic neuropathy
- decreased eye movements
aggravating fx TED
- cigarette smoking
- radioactive iodine tx
- anti-IGF-1 Abs (pathophysiologic or exogenous)
- anti-TSH-1 Abs
tx TED
meds
- T3/T4 control: thiourelenes or levo as appropriate
- inflammatory control: corticosteroids, possible radiotherapy
- lubricating eyedrops
- teprotumumab: pro-IGF-1R
surgery
- decompressive orbital surgery
- strabismus/muscle correction
- eyelid surgery to correct position and corneal protection
- delay surgery to static phase, unless vision threatened by compressive optic neuropathy or exposure - don’t want to make the inflammation worse unless immediate sight threat
thyroid follicles are filled w/ …, lined by
colloid, follicular cells
parafollicular cells
aka C cells
arise from neural crest
literally “next to follicle” (in clumps in stroma, but does not comprise entire stroma)
make calcitonin (lowers blood calcium)
parathyroid gland gross histology
look similar to an islet, surrounded by thyroid follicles
entire gland is surrounded by a capsule
principal cells (PTH gland)
aka chief cells
more numerous
lightly staining cytoplasm
make PTH (raise blood calcium)
oxyphil cells
eosinophilic
larger than principal cells
fx not known, increase w/ age
multinodular goiter histology
varying follicle sizes, distended by colloid
fibrous scarring
flattened/inactive or hypertrophied follicular cells
can be quite large - concern for tracheal compression
may arise from simple goiter
concern for malignant conversion
generally mild hypER to euthyroid
sometimes hypO
tx: generally thyroidectomy
papillary thyroid carcinoma histology
normal follicular architecture completely disrupted in favor of papillary (finger-like) glands
grooved nuclei
psudonuclear inclusions
*psammoma bodies (calcium deposits, with concentric lamellar rings)
most common thyroid carcinoma
often multifocal
rarely metastatic
generally caught early
solitary “cold” nodule - do not take up radio-labeled iodine
tx: generally thyroidectomy
