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Physio Exam 3 - Endocrine > 21 | Thyroid > Flashcards

21 | Thyroid Flashcards

1
Q

major secretory product + forms

A

fully iodinated thyronine, [T4 - thyroxine]
(derived from AA tyrosine)
-most physiologically active T3 (one less iodine on outer ring)
-reverseT3 physiologically inactive (one less iodine on outer ring)

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2
Q

iodide v. iodine

A

I- (iodide, anion)

I (iodine, neutral)

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3
Q

TH biosynthesis location

A

only in thyroid gland

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4
Q

thyroid hormonogenesis

A

iodination and coupling of tyrosine rings to make thyronine
-can produce T3 and rT3 from T4 in peripheral tissues with deiodinase enzymes
(most T3 from T4 extrathyroidal deiodinase, liver rather than in the gland)
-thyrotropes synthesize and store TSH in secretory granules

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5
Q

role of hypothalamus

A

synthesize and secrete thyrotropin-releasing hormone (TRH)

  • neurogenic input, pulsatile secretion of TRH
  • principal regulator of thyroid function at this level
  • carried in hypophyseal portal system to anterior pituitary
  • TRH rapidly degraded in circulation
  • TRH inh by high GC levels, and TRH can be used to stim GH sec
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6
Q

role of anterior pituitary

A

TRH arrives, stimulates secretion of TSH in thyrotropes (peptide hormone)

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7
Q

catecholamines + TRH

A
  • alpha-adrenergic catecholamines and ADH stim TRH sec

- alpha-adrenergic blockers are inhibitory

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8
Q

negative feedback loop of TRH

A
  • long loop negative feedback: plasma levels of T3 + T4

- TRH inactive rapidly through TRH-degrading ectoenzyme, also under hormonal regulation

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9
Q

TSH structure

A

glycoprotein, two dissimilar subunits - alpha + beta

  • alpha subunit common to TSH, LH, GSH, hCG
  • beta subunit dif in each hormone
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10
Q

physiologic role of TSH

A

stimulate thyroid follicular cells

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11
Q

negative feedback loop of TSH

A

controlled by levels of free (unbound) thyroid hormones

  • T3 produces negative feedback
  • binding of intrapituitary converted T3 to nuclear receptors suppresses expression of both a+b subunits, inhibiting TSH production. travels to nucleus to dec trascription/translation of proteins that will inh receptors
  • TRH antagonizes neg control, promotes expression of a+b, stim TSH synth + sec
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12
Q

TSH secretion pattern

A
  • pulsatile
  • circadian rhythm consistent with changes in TRH responsiveness (sensitivity)
  • TSH levels higher at night than daytime
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13
Q

TSH + TRH reg from exogenous substances

A
  • DA, SS inhibit TSH sec
  • glucocorticoids inhibit hypothalamic expression + synthesis of TRH
  • GCs dec responsiveness of thyrotropes in pituitary to TRH
  • GCs dec plasma T3 levels by inh deiodinase activity in pituitary and periphery
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14
Q

thyroid storm

A

life-threatening crisis, extremely high plasma levels of free T3 and T4

  • GCs dec plasma T3 levels by inh deiodinase activity in pituitary and periphery
  • potassium iodine, triggers wolff-chaikoff
  • give potassiumiodide after PTU (biosynthesis inh)
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15
Q

thyroid gland structure

A

-gland contains many follicles
-each follicle has a central glycoprotein core (colloid) surrounded by cuboidal epithelium of follicular cells
-follicular cells are functionally polar, basolateral and apical membranes
-capillaries permeate the thyroid gland and perfuse follicles at basolateral surface
-following biosynthesis, TH can be sec into the blood stream
thyroid follicular cells make THs and thyroglobulin (large glycoprotein), role in biosynthesis and storage of TH

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16
Q
  1. iodide pump

[TH biosynthesis]

A
  • iodide (I-) uptake across basolateral PM into follicular cell
  • Na/I symporter (against I- gradient), secondary active
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17
Q
  1. thyroglobulin synthesis + secretion

[TH biosynthesis]

A
  • thyroglobulin (TG) synthesize and glycosylated in follicular cells, packaged in secretory vesicles
  • exocytosed into colloid at apical PM
  • contains many tyrosine residues in AA seq, many eventually iodinated to form THs
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18
Q

thyroid peroxidase enzyme (TPO)

A

-multifunctional, catalyzes processes of oxidation, iodination and coupling in TH synthesis, all in lumen
-heme containing
-enzyme reactions catalyzed by TPO on outer apical membrane surface, mediated by H2O2 generated by NADPH oxidase
(compartmentalization of H2O2, any in follicular cell is reduced by cytosolic glutathione peroxidase. prevents inappropriate organification, iodine into protein) from occurring in follicular cells)

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19
Q
  1. iodide oxidation

[TH biosynthesis]

A
  • iodine efflux across apical membrane into colloid via Cl/I transport protein, pendrin
  • iodine first oxidized to iodine by TPO and H202
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20
Q
  1. tyrosine iodination (organification)

[TH biosynthesis]

A

-second TPO catalyzed reaction adds iodine into aromatic tyrosine rings in thyroglobulin w/ covalent attachment
-max 1 or 2 iodine atoms into each ring
-yields MIT (monoiodotyrosine) or DIT (diiodotyrosine)
(inefficient, 20% of TGs are iodinated)

21
Q
  1. coupling + storage

[TH biosynthesis]

A

-coupling reaction, 3rd catalyzed by TPO combines two iodinated tyrosine rings while still attached to TG, gives precursor/storage forms of TH
-2DIT will give T4
-DIT+MIT gives T3, less frequent
(coupling also inefficient, 20%, each TG produces only 0.5 T4)
-colloid can store 2-3 mo supply or organified TG. storage for TH and iodine

22
Q
  1. colloid reabsorption + lysosomal proteolysis

[TH biosynthesis]

A
  • when THs needed for sec into blood stream, endocytotic vesicle taken back into follicular cell
  • fuse with intracellular lysosomes, TG undergoes proteolysis
  • releases T3, T4, TG, MIT, DIT into follicular cell cytosol
23
Q
  1. secretion + recycyling

[TH biosynthesis]

A
  • mature T4 and T3 enter blood stream w/ specific transporters at basolateral mem
  • DIT + MIT stay in follicular cell, deiodinated enzymatically by cytosolic thyroid deiodinase (can also rT3 -> T3)
  • iodide atoms reused for TH biosynthesis
24
Q

metabolic disease from defects in TH biosynthesis

A
  • mutations of TPO, TG, NIS, NADPH oxidase, pendrin
  • significant thyroid dysfunction
  • specific steps
  • may be targeted pharmacologically to treat
25
Q

regulation of iodide uptake by thyroid gland

A
  • iodine is impt regulator of TH production
  • rate limiting step in synthesis is iodide transport from bloodstream into follicular cell
  • competitive inhibitors of NIS (perchlorate, can cause hypothyroidism if at toxic levels, also can be given clinically for hyperthyroidism) can sig. affect thyroid gland function
26
Q

Wolff-Chaikoff effect + thyroid escape

A
  • protection against sudden excess in I- intake, which would cause excess TH output
  • involves inhibition of iodination
  • physiological inhibition of hormonogenesis by WC effect w/ normal function is only 26-50 hrs
  • after, thyroid escapes from inh by adapting to higher I- levels, and resumes almost normal synthesis
  • may be due to down-regulation of NIS prod. would dec I- transported into follicle regardless of high serum I- levels, return biosynthesis to normal and release inh
27
Q

secretion and transport of THs

A
  • T3 + T4 secretion at 80-100 and 5 microgm/day
  • majority is bound to circulating plasma proteins (thyroxine binding globulin TBG, albumin + transthyretin, prod by liver)
  • tiny unbound amount determines metabolic rate of many tissues
  • all T4 in bloodstream from gland sec vs only 20% of T3. rest of T3 from intracellular deiodinase activity in periphery
  • T3 is physiologically relevant TH at tissue level, 90% of occupancy of nuclear thyroid hormone rec bound by T3
28
Q

pool of T3 vs. T4 in circulation

A
  • T4 has a larger, more tightly bound extracellular pool with slower (t1/2=7days) turnover rate (T3 t1/2=1day)
  • metabolic rate is much faster for T3 than T4 (22 vs 1 L/day)
29
Q

thyroid hormone action

A
  • THs into cells via PM carrier, cellular uptake plays role in regulating TH bioactivity
  • THs bind to non-histone protein nuclear receptors in conjuction w/ thyroid hormone response elements (TRE)
  • binding activity affects types and rates of translation of various RNAs in cells for enz and other cellular products
  • TH + its receptor interact with genes uniquely responsive to TH
  • response of tissue varies and is proportional to amount of nuclear TH rec in specific tissue
    ex: liver + myocardial tissue have large amount, and respond with large changes in protein synth and enzyme patterns. spleen + testis have small amounts, not very influenced by TH
30
Q

TH + physiological function

A
  • TH stimulates anabolic and catabolic pathways of metabolism, supports balance
  • in adults, regulates body weight, basal metabolism, oxygen req
  • physiological effects from
    1. TH action on protein expression an activity
    2. metabolic increase due to increase body temp
    3. enhanced sensitivity to catecholamines
  • inc metabolic activity inc body’s need for O2, met by various inc.
  • stimulation of metabolic pathways by TH is accompanied by inc need for energy
31
Q

TH actions to inc fuel

A

increases

  • glycogenolysis
  • gluconeogenesis
  • glucose oxidation
  • lypolysis
  • protein synthesis + degredation (net tends to be catabolic)
32
Q

TH + beta-adrenergic activity

hyper vs. hypo

A

hyper: tachycardia, hand tremors
hypo: bradycardia, slow physical response

33
Q

TH + GI

hyper vs. hypo

A
  • TH maintains normal gut motility and intestinal transit time
  • hyper: diarrhea
  • hypo: constipation
34
Q

TH + CVS

A

TH acts on multiple different effects to produce desired physiological response

  • TH stimulates CVS activity by increasing HR, stroke vol, CO, pulse pressue
  • concerted response by influencing electrical activity, cardiac contractility, NT activity, O2 use, alteration of cardiac tissue and proteins in myocytes
35
Q

TH + growth

A
  • normal whole body growth can’t happen without enough TH even with normal GH levels
  • without TH, normal differentiation is impaired, decreased height + physical maturation. bone age of hypothyroidic children is lower.
36
Q

TH + brain development

A
  • begins prenatal , completed 2-3 yo
  • untreated hypothyroidism leads to sever and irreversible mental retardation
  • iodide deficiency is major preventable cause in the world
  • may impair function in adults
  • treat with oral T4 or iodine
37
Q

fetal thyroid developemnt

A
  • axis dev independently from moths
  • thyroid gland early in first trimester
  • fetal TSH in pituitary and iodine conc in thyroid at end of first trimester
  • axis actively functioning by mid-gestation
  • as its developing, during first half, TH is fetal plasma derived from months
38
Q

pregnancy + TH

A
  • during pregnancy, mother’s thyroid gland inc production of TH
  • might lead to hyperthyroidism if not for parallel inc in thyroxine binding globulin (TBG)
  • compensatory mechanism that allows total TH pool to inc without raising free TH levels
39
Q

fetal exposure to excess iodine

A
  • immature fetal thyroid lacks auto-reg mechanisms
  • can’t regulate large exogenous loads of iodine
  • down regulation of NIS as an escape mechanism from Wolff-Chaikoff inhibition isn’t fully dev in fetus
  • chronic fetal exposure to excess iodine can lead to prolonged inhibition, causing hypothyroidism in utero
40
Q

hyperthyroidism

A
  • increased basal metabolic rate
  • increased appetite to maintain weight, weight loss, hyperdefecation, nervousness, tremors, tachycardia, larger pulse pressure, increased SV + CO, lower systemic vascular resistance, dec circ times, thin + smooth skin, inc heat production + intolerance
  • older patients may have “non-classical” symptoms: atrial fibrillation, weight loss, and muscle weakness as only manifestations
  • acute emergency: thyroid storm (grave’s test for Ab to distinguish)
41
Q

hypothyroidism

A
  • slowing of metabolic rate with cold intolerance, lethargy, fatigue, dementia, thick + dry skin, constipation, bradycardia
  • slower metabolic rate may inc cholesterol levels and slower metabolism of drugs and toxins
  • thin hair, puffy face, mental changes, mood disturbance
  • LDL is markedly decreased, reduced clearance of cholesterol, inc risk of atherosclerosis
  • acute emergency: myxedema coma
42
Q

Grave’s disease

A
  • most common cause of hyperthyroidism
  • cause by autoantibodies against TSH receptor
  • Abs bind to rec and activate it, mimicking action of TSH
  • goiter caused by over-stim of thyroid
  • patients show signs and symptoms of hyperthyroidism and exophthalmos - deposition and accumulation of mucopolysaccharides behind eyes, causing to protrude out
  • if untreated can lead to systolic hypertension, cardiac arrhythmias, remodeling of heart muscle and congestive heart failure. also at risk of osteoporosis, both osteoclastic and osteoblastic activity inc - net effect is catabolic.
43
Q

Hashimoto’s disease

A
  • most common cause of hypothyroidism
  • characterized by non-stimulating autoantibodies against thyroid gland proteins (anti TPO, peroxidase, TSH-rec, NIS) that eventually destroy the gland
  • goiter due to inflammation and lymphocytic infiltration of the gland due to immune attack in early stage
  • later, the destroyed gland atrophies
44
Q

autoimmune thyroidities

A
  • inflammation of thyroid gland
  • i.e. silent and post-partum thyroiditis
  • may show over months hyperthyroidism followed by hypothyroidism then return to euthyroidism
  • hyperthyroidism not caused by excess hormone biosynth b/c inflammation reduces ability to synth new TH
  • rather, autoimmune attack on gland leads to “leaking” of pre-synthesized hormone stored in gland
  • initially leads to hyperthyroidism, lasts 2-3 mo
  • as stored supply is depleted and while biosynth is low, hypothyroid state produced
  • as inflammation goes away, gland resumes normal fucntion and euthyroid state reach
  • often self-resolves, can treat with beta-blockers to reduce symptoms
45
Q

post-partum thyroiditis (PPT)

A
  • occurs in susceptible women in first year after childbirth, 9%
  • since symptoms mimic others (i.e. depression), many cases may be unnoticed
  • during pregnancy, immune suppression dev in mother to tolerate fetus, but after birth rebounds and in predisposed women can lead to autoantibody prod and thyroid inflammation
  • after a year treated as chronic hypothyroidism
46
Q

thyroid + sex hormones

A
  • in thyroid dysfunctional states, can affect reproductive function
  • most females with thyroid disease present during reproductive years, can appear as altered menstrual cycle
  • primary hypothyroidism, feedback from low free T3 can stim hypothalamic overproduction of TRH, leading to overprod of prolactin
  • can lead to galactorrhea and inh GnRH sec, causing amenorrhea (loss of period)
  • hyperthyroidism can cause altered sex hormone levels that can interfere with normal gonadotropin secretion + reproductive function
  • either extreme can cause impotence and/or infertility
47
Q

hyperthyroidism treatment

A
  • aim to decrease overproduction of THs w/ drugs that inh TH synthesis and/or drugs that inhibit peripheral effect of TH
  • surgery or radioactive iodine therapy to desotroy tissue can dec excessive TH production
  • create stable hypothyroid state than can be treated
48
Q

hypothyroidism treatment

A
  • hormone replacement therapy with exogenous oral T4

- has longer half life

Physio Exam 3 - Endocrine (8 decks)

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