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SFM5 > Thyroid Pathophys > Flashcards

Thyroid Pathophys Flashcards

1
Q

ectopic thyroid tissue

A
  • 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
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2
Q

T3 vs T4

A

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
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3
Q

iodine uptake into thyroid follicle

A

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
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4
Q

thyroid hormone synthesis

A

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
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5
Q

thyroid hormone transport

A

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
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6
Q

thyroid histology

A

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
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7
Q

NIS

A
  • 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
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8
Q

TPO

A
  • 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
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9
Q

D1, D2, and D3

A

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
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10
Q

TBG

A
  • 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
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11
Q

thyroid hormone regulation

A

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

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12
Q

factors that increase T3/T4 release

A

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
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13
Q

factors that decrease T3/T4 release

A

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
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14
Q

thyroid labs

A
  • 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
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15
Q

congenital hypothyroidism

A

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
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16
Q

physiological thyroid changes in pregnancy

A
  • 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
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17
Q

iodine deficiency in pregnancy

A

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
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18
Q

gestational hypothyroidism

A
  • 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

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19
Q

iodine deficiency

A

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
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20
Q

Wolff-Chaikoff effect

A
  • 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
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21
Q

Jod-Basedow effect

A
  • 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
22
Q

effects of excess iodide

A

¯_(ツ)_/¯

  • 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
23
Q

thyroid nodule

A
  • 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
24
Q

multinodal goiter

A
  • 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)
25
Q

“hot” thyroid nodule

A
  • 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)
26
Q

myxedema

A

severe hypo-t
may cause coma
rare b/c physicians have high index of suspicion for thyroid problems

27
Q

Hashimoto’s thyroiditis

A
  • 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
28
Q

secondary hypothyroidism

A

pituitary failure

29
Q

tertiary hypothyroidism

A

hypothalamic failure

30
Q

hypothyroidism

A

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
31
Q

primary hyperthyroidism

A

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’)
32
Q

24-hour RAIU test

A
  • 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
33
Q

low-RAIU thyrotoxicosis

A
  • 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
34
Q

Graves’ disease

A

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
35
Q

exophthalmos

A
  • 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
36
Q

silent subacute thyroiditis

A
  • 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
37
Q

painful subacute thyroiditis

A
  • 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
38
Q

types of thyroid cancer and their prognosis

A

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
39
Q

best to worst px thyroid cancer

A

papillary > follicular ~ early medullary > metastatic medullary&raquo_space; anaplastic

40
Q

tx thyroid cancer

A

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

41
Q

thyroid cancer dx and monitoring

A
  • 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
42
Q

types/features of thyroid eye disease (TED)

A

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
43
Q

comprehensive optic neuropathy

A
  • 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
44
Q

aggravating fx TED

A
  • cigarette smoking
  • radioactive iodine tx
  • anti-IGF-1 Abs (pathophysiologic or exogenous)
  • anti-TSH-1 Abs
45
Q

tx TED

A

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
46
Q

thyroid follicles are filled w/ …, lined by

A

colloid, follicular cells

47
Q

parafollicular cells

A

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)

48
Q

parathyroid gland gross histology

A

look similar to an islet, surrounded by thyroid follicles

entire gland is surrounded by a capsule

49
Q

principal cells (PTH gland)

A

aka chief cells
more numerous
lightly staining cytoplasm
make PTH (raise blood calcium)

50
Q

oxyphil cells

A

eosinophilic
larger than principal cells
fx not known, increase w/ age

51
Q

multinodular goiter histology

A

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

52
Q

papillary thyroid carcinoma histology

A

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

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