11 Thyroid Pathophysiology and Diagnostic Evaluation Flashcards
When is the thyroid anlage is first recognizable
Embryonic day 16 or 17
When does the thyroid primordium come into fontact and fuse with the fourth pharyngeal pouch?
Embryonic day 50
Normally, the thyroglossal duct undergoes dissolution and fragmentation by about how many months after conception?
2nd month
The thyroid primordium comes into contact with which pharyngeal pouch?
4th pharyngeal pouch
In the thyroid, complex interconnecting cordlike arrangements of cells interspersed with vascular connective tissue replace the solid epithelial mass and become tubule/like structures at about what month of fetal life?
3rd month
At how many weeks of fetal life does colloid begin to fill thyroid follicles?
13-14 weeks
Future follicular cells acquire the capacity to form thyroglobulin as early as ____ day of gestation?
29th day
Follicular cells acquire the capacities to concentrate iodide and synthesize thyroxine at how many weeks’ gestation?
11th week
Capacity of pituitary to synthesize and secrete TSH is not apparent until the how many weeks of gestation?
14th week
As a consequence of hypothalamic maturation and increasing secretion of TRH, TSH concentration increases between ____ and ____ weeks of gestation.
Between 18 and 28 weeks
TBG is detectable in the fetal serum by ____ gestational week
10th gestational week
Normal thyroid gland weight
15-20 g
Normal isthmus dimensions (3)
0.5 cm thick
2 cm wide
1-2 cm high
Pyramidal lobe arises near the midline, usually on which side
Left
Thyroid lobe that is normally more vascular and is often larger
Right lobe
Normal blood flow range in the thyroid
4-6 mL/min/g
Superior thyroid artery arises from which artery
External carotid artery
Inferior thyroid artery arises from which artery
Subclavian artery
Average diameter of thyroid follicle
200 nm
Parafollicular or C cells are derived from: (2)
Neural crest
Endoderm
T4 is composed of how many percent iodine by weight?
65%
T4 and T3 are transported across the basolateral portion of the follicular cell through this channel
MCT8
Enzyme that deiodinates MIT and DIT
Iodine dehalogenase or DEHAL1
Quantity of daily iodine intake to allow thyroidal uptake
60-75 mcg
Usual fecal losses of iodine
10-20 mcg
Normal absorption of iodine in healthy adults
90%
Amount of iodine per day that is required to eliminate all signs of iodine deficiency
100 mcg
Iodine deficiency is common in these regions of the earth
Mountainous and formerly glaciated regions
Most prevalent preventable cause of mental impairment
Iodine deficiency
Most common thyroid-related human illnesses
Iodine deficiency disorders
How much of the filtered load of plasma iodide is reabsorbed?
60-70%
Where is iodide largely confined in the body?
Extracellular fluid
Normal concentration of iodide in ECF
10-15 mcg/L (~10^-7 mmol/L)
Content of peripheral pool of iodide (mcg)
250 mcg
Largest pool of body iodine
Thyroid
Normal pool of iodine in the thyroid
8 mg
Normal fractional turnover of iodine
1% per day
Recommended daily intake of iodine:
Adults
150 mcg
Recommended daily intake of iodine:
During pregnancy
220 mcg
Recommended daily intake of iodine:
Children
90-120 mcg
Gene that encodes sodium-iodide symporter NIS
SLC5A
Aside from iodine, NIS also transports these ions: (3)
Pertechnetate
Perchlorate
Thiocyanate
Highly hydrophobic membrane glycoprotein and multianion exchanger in the apical membrane of thyrocytes that facilitates transport of iodine into the follicular lumen
Pendrin
In addition to the thyroid, pendrin is also expressed in: (2)
Kidney
Inner ear
Gene that encodes pendrin
SLC26A4
Major phenotypic manifestation of Pendred syndrome
Deafness or hearing impairment
Calcium-activated anion channel involved in mediating apical efflux of iodine
Anoctamin 1
Oxidation of iodide into the incorporation of the resulting intermediate into the hormonally inactive iodotyrosines
Organification
Iodinations that lead to formation of iodotyrosines occur within this protein
Thyroglobulin
Enzymes (2) that generate H2O2 required during oxidation of thyroidal iodide
DUOX1 and DUOX2
The major thyroid microsomal antigen
TPO
Proposed evanescent products (3) of the peroxidation of iodide
Hypoiodite
Hypoiodous acid
Iodonium
Resident ER protein and maturation factor required for maturation, plasma membrane localization of DUOX2, and H2O2 generation
DUOXA2
TPO-catalyzed fusion of two DIT molecules
Coupling reaction
Catalyzes coupling reaction in the thyroid
TPO
Each molecule of human Tg normally contains how many T4 molecules?
3-4
Each molecule of human Tg normally contains how many T3 molecules in normal individuals
0.2 (only 1 in 5 Tg molecule contains a T3 molecule)
Each molecule of human Tg normally contains how many T3 molecules in those with Graves disease
0.4
Amount of T4 in per g of wet weight of normal human thyroid
250 mcg
Amount of T4 in normal human thyroid
5000 mcg
Normal Tg concentration
50 ng/mL
First step in thyroid hormone release
Endocytosis of colloid
Predominant process in the endocytosis of colloid in humans
Micropinocytosis
Most important inhibitor of T4 release
Iodide
Induction of signal by the TSHR via these pathways (2) regulates iodide efflux, H2O2 production, and Tg iodination
Phospholipase C pathway
Intracellular Ca2+ pathway
Induction of signal by the TSHR via this pathway stimulates growth and regulates iodine uptake and transcription of Tg, TPO, and NIS
Protein kinase A pathway
Type of human iodothyroinine selenodeiodinase that has high susceptibility to PTU
Type 1
Type of human iodothyroinine selenodeiodinase decreases in response to increased T4
D2
Type of human iodothyroinine selenodeiodinase that is not found on the CNS
Type 1
Subcellular location of type 1 deiodinase
Plasma membrane
Subcellular location of type 2 deiodinase
Endoplasmic reticulum
Subcellular location of type 3 deiodinase
Plasma membrane
Deiodinase type that is found in the heart
Type 2
Deiodinase type that is found in brown adipose tissue
Type 2
Gene that encodes TBG
SERPINA7 gene
Gene that encodes TBG is found in this chromosome
X chromosome
Normal human serum concentration of TBG
270 nmol/L (21 mcg/dal)
Prevalence of congenital deficiency of TBG
1 in 5000 newborns
Population groups with increased fractions of acidic TBG (3)
Pregnant patients
OCP use
Acute hepatitis
Cleaved TBG that has lower affinity to T4 is found in: (2)
Septic patients
Following cardiopulmonary bypass surgery
Protein with the highest T4 binding capacity
Albumin (50,000 mcg T4/dL)
Thyroid hormone-binding protein with the highest T4 turnover rate
Transthyretin
Major thyroid hormone-binding protein in the CSF
Transthyretin
Drugs that inhibit binding of T4 and T3 to TBG (6)
Phenytoin
Salicylate
Salsalate
Furosemide
Fenclofenac
Mitotane
Albumin binds how many percent of the plasma thyroid hormones?
10%
How much of plasma T4 and T3 are bound to lipoproteins?
3-6%
Percent of T3 derived from peripheral tissues
80%
Percent of total T4 normally bound to TBG
68%
Free T4 is approximately __% of the total
0.02%
X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia, spastic paraplegia, and elevated serum T3
Allan-Herndon-Dudley syndrome
Transfer of T4 into the choroid plexus or into the tanycytes is mediated by this protein
OATP1C1
MCT8 mutation is associated with this psychiatric disorder
ADHD
Enzyme that primarily catalyzes inner ring deiodination of T4
D3
Most important pathway for T4 metabolism
Outer ring 5’ monodeiodination
Iodine acceptor during deiodination reactions
Selenium
TFTs in biallelic mutation of SECIS-binding protein 2
⬆️ TSH, T4, fT4, rT3
⬇️ T3, fT3
General mechanism of TSH stimulation:
⬆️ iodide in follicular lumen
PLC
General mechanism of TSH stimulation:
Delayed ⬆️ in NIS expression
cAMP
General mechanism of TSH stimulation:
⬆️ thyroid blood flow
⬆️ nitric oxide synthesis
General mechanism of TSH stimulation:
Hydrogen peroxide stimulation
PLC
General mechanism of TSH stimulation:
Thyroglobulin and TPO synthesis
cAMP
General mechanism of TSH stimulation:
Pinocytosis of thyroglobulin
cAMP
General mechanism of TSH stimulation:
Release of Tg into plasma
cAMP
Subcellular location of 90% of intracellular T3
Cytosol
90% of intracellular T3 is located in the cytosol, except in this organ
Piuitary
(50% are in the nucleus)
Preferred substrates of D1 (2)
rT3
T3SO4
Deiodinase that has access to extracellular thiols
D3
Most important thyroid hormone deactivating enzyme
D3
Thyroid receptor expressed in hypothalamus, pituitary, cochlea, and retine
TR beta 2
Increased / decreased / unchanged:
Effect of recombinant growth hormone on T3:T4 ratio
Increased
Half-life of T4
6.7 days
Volume of distribution of T4
10 L
Volume of distribution of T3
40 L
T3 or T4?
Higher production rate (nmol/L)
T4
T3 or T4?
Higher metabolic potency
T3
T3 or T4?
Higher fraction of total hormone in free form
T3
T3 or T4?
Higher volume of distribution
T3
Half-life of T3
0.75 days
Half-life of D2
20-30 mins
Half-life of D1 and D3
> 12 hours
Half-life of TBG
5 days
Fraction of T3 bound by TBG
75-80%
Escape from Wolff-Chaikoff effect does not occur in:
Third trimester fetus
Normal TSH concentration
0.4-4.2 mU/L
Plasma TSH half life
30 mins
TSH pulsatility is characterized by fluctuations at intervals of:
1-2 hours
Magnitude of TSH pulsations is decreased by (3)
Fasting
Stress
Surgery
Circadian variation of TSH is characterized by
Nocturnal surge that precedes the onset of sleep
Pharmacologic agent used in the treatment of T-cell lymphoma that suppresses TSH sufficiently to cause central hypothyroidism
Bexarotene
Increased / decreased / unchanged:
T3 levels during iodine deficiency
Unchanged
Compensatory alterations in thyroid function come into operation when total iodine intake falls below:
75 mcg/day
Organic iodine content of one 200-mg tab of amiodarone
75 mg
Iodine content of povidone-iodine
10 mg/mL
Quantity of iodine required to suppress radioactive iodine uptake to <2%
> 30 mg/day
Drug that blocks synthesis of TBG
L-asparaginase
