I. Thyroid Pathophysiology and Diagnostic Evaluation Flashcards
(182 cards)
1
Q
Phylogeny, Embryology, and Ontogeny important days and weeks to remember
A
Day 16 or 17 - Human thyroid anlage is first recognizable
Day 29 - Future follicular cells acquire the capacity form thyroglobulin
Day 50 - Primordium reaches its final position fusing with the ventral aspect of the 4th pharyngeal pouch
Second month - Thyroglossal duct undergoes dissolution and fragmentation
Week 10 - Thyroxine-binding globulin becomes detectable in the serum and increases in concentration progressively to term
Week 11 - Follicles acquire the capacity to concentrate iodide and synthesize thyroxine
Weeks 13-14 - Follicles begin to fill with colloid
Week 14 - Pituitary acquires capacity to synthesize and secrete TSH
Weeks 18-26 - Serum TSH increases and becomes higher than those in the mother
2
Q
TRUE or FALSE: Thyroid tissue is confined to, and is present in, all vertebrates.
A
TRUE
Although MIT and DIT are present in a variety of invertebrate species (most especially sea creatures), but no recognizable tissue is present
3
Q
Other glands in the body that are capable of concentrating iodide in their secretions
A
Salivary and gastric glands
Due to the phylogenetic association of the thyroid gland and the gastrointestinal tract
But the iodide transport in these sites is NOT responsive to stimulation by thyrotropin
Salivary gland contains enzymes that are capable of iodinating tyrosine in the presence of hydrogen peroxide, although it forms insignificant quantities of iodoproteins under normal circumstances
4
Q
Term used to refer to the thickening of the endodermal epithelium in the foregut, which will later on give rise to the anterior-most organ that buds from the gut tube
A
Thyroid anlage
5
Q
The primitive stalk connecting the primordium with the pharyngeal floor elongates into the ___.
A
Thyroglossal duct
When it persists:
Lingual thyroid tissue
Thyroglossal duct cysts
Ectopic thyroid tissue (may be present at any location in the mediastinum or, rarely, even in the heart)
6
Q
Normally the thyroglossal duct undergoes dissolution and fragmentation by about the second month after conception, leaving at its point of origin a small dimple at the junction of the middle and posterior thirds of the tongue, the ___.
A
Foramen caecum
7
Q
At this point in gestation, radioactive iodine inadvertently given to the mother would be accumulated by the fetal thyroid
A
11th week
(when follicular cells acquire capacities to concentrate iodide and synthesize thyroxine)
8
Q
Phylogeny, Embryology, and Ontogeny: When does the pituitary gland acquire the capacity to synthesize and secrete TSH?
A
Week 14
9
Q
Phylogeny, Embryology, and Ontogeny: When does Thyroxine-binding globulin become detectable in the serum?
A
Week 10
10
Q
Phylogeny, Embryology, and Ontogeny: When does the thyroglossal duct undergo dissolution and fragmentation
A
Second month of conception
11
Q
Phylogeny, Embryology, and Ontogeny: When does serum TSH increase?
A
Between 18 and 26 weeks of gestation
12
Q
Phylogeny, Embryology, and Ontogeny: When do follicles begin to fill with colloid?
A
13 to 14 weeks
13
Q
Phylogeny, Embryology, and Ontogeny: When does the Primordium reach its final position, fusing with the ventral aspect of the 4th pharyngeal pouch?
A
Day 50
14
Q
Phylogeny, Embryology, and Ontogeny: Thyroid anlage first becomes recognizable on
A
Day 16 or 17
15
Q
Phylogeny, Embryology, and Ontogeny: Future follicular cells acquire the capacity form thyroglobulin on
A
Day 29
16
Q
Phylogeny, Embryology, and Ontogeny: Follicles acquire the capacity to concentrate iodide and synthesize thyroxine on
A
Week 11
17
Q
Thyroid gland weighs approximately __ to __ g in North American adults.
A
15 to 20 g
18
Q
Approximate dimensions of the thyroid gland lobe and isthmus
A
Thyroid gland lobe: Approx 2 to 2.5 cm in thickness and width at its largest diameter and is approximately 4cm in length
Isthmus: Approximately 0.5 cm thick, 2 cm wide, and 1 to 2 cm high
19
Q
Usual location of the thyroid pyramidal lobe
A
Occasionally, especially when the remainder of the gland is enlarged, it is discernible as a finger-like projection directed upward from the isthmus, generally just lateral to the midline, usually on the left
20
Q
Which lobe of the thyroid gland is normally more vascular, often larger fo the two, and tends to enlarge more in disorders associated with a diffuse increase in gland size
A
Right lobe
21
Q
Blood supply of the thyroid gland and origin
A
2 pairs of vessels constitute the major arterial blood supply:
Superior thyroid artery, arising from the external carotid artery
Inferior thyroid artery, arising from the subclavian artery
22
Q
Estimates of thyroid blood flow
A
4-6 mL/minute/g
Well in excess of the blood flow to the kidney (3 mL/minute/g)
23
Q
In a diffuse toxic goiter due to Graves disease, blood flow may exceed ___.
A
1 L/minute
And be associated with an audible bruit or even a palpable thrill
24
Q
The gland is composed of closely packed spherical units termed ___.
A
Follicles
Average diameter 200 nm
Columnar when active and cuboidal when inactive
From 20 to 40 follicles are demarcated by connective tissue septa to form a lobule supplied by a single artery
The function of a given lobule may differ from that of its neighbors
25
Where does iodination, exocytosis, and colloid resorption (the initial phase of hormone secretion) occur?
At or near the surface of the apex of the follicular cell where numerous microvilli extend into the colloid
26
Stimulation by TSH leads to these changes in the thyroid follicles
Enlargement of the Golgi apparatus (where the carbohydrate component of the Tg is added to its precursor)
Formation of pseudopodia at the apical surface
Appearance in the apical portion of the cell of many droplets that contain colloid taken up from the follicular lumen
*ER, which is extensively present in the cytoplasm, contains the precursor of TG
27
Type of cells which produce calcitonin
Parafollicular cells, or C cells
Derived from the neural crest and also in the endoderm
Undergo hyperplasia early in the course of MEN2
28
How do the parafollicular cells (or C cells) differ from the cells of the follicular epithelium?
Never bordering on the follicular lumen
Being rich in mitochondria
29
Formation of normal quantities of thyroid hormone requires the availability of adequate quantities of exogenous iodine to allow thyroidal uptake of approximately __ to __ μg daily.
60 to 75 μg daily, taking into account the fecal losses of about 10-20 μg iodine of iodothyronines as glucuronides and about 100-150 μg as urinary iodine in iodine-sufficient populations
30
Form of iodine in biologic solutions
Plasma iodide (I-)
Completely filterable with about 60-70% of the filtered load reabsorbed
31
At least __ μg of iodine per day is required to eliminate all signs of iodine deficiency.
100 μg
32
Recommended Daily Dietary Iodine Intake for:
Adults
During pregnancy
Children
Adults: 150 μg
During pregnancy: 220 μg
Children: 90-120 μg
33
Condition pertaining to TSH-induced compensatory enlargement of the thyroid in iodine-deficient areas
Endemic goiter
34
Term used to refer to the varying degrees of mental retardation caused by severe iodine deficiency during pregnancy which leads to low fetal thyroid hormone production and irreparable damage to the developing CNS
Endemic cretinism
35
Most common thyroid-related human illness
Iodine-deficiency disorders
36
Most common endocrine disorders worldwide
Iodine-deficiency disorders
37
Most prevalent preventable cause of mental impairment
Iodine deficiency
38
Most important source of plasma iodide
Diet
39
The thyroid contains the largest pool of body iodine, under normal circumstances approximately ___ μg, most of which is in the form of DIT and MIT.
8000 μg
Normally this pool of iodine turns over slowly (about 1% per day)
40
The functional unit of the thyroid
Spherical thyroid follicle, which is formed by a single layer epithelium of thyroid cells surrounding the lumen
41
Steps in thyroid hormone synthesis and release
SYNTHESIS:
1) Iodide trapping by NIS, from plasma through the basolateral membrane and into the cytosol
2) Iodide entry into follicular lumen at the apical membrane through PENDRIN
3) Oxidation of iodide (iodide combined with Tg) by TPO, which requires H2O2 generated by calcium-dependent DUOX1 and DUOX2 enzymes
4) Organification (incorporation of resulting intermediate into hormonally inactive iodotyrosines MIT and DIT)
5) Coupling of MITs and DITs to form T4 by TPO
RELEASE:
1) Endocytosis of colloid from the folicular lumen under TSH stimulation
2) Fusion of endocytotic vesicles with lysosomes and proteolysis by cathepsin D and D-like thiol proteases (iodotyrosines released from Tg are rapidly deiodinated by iodotyrosine deiodinase DEHAL1/IYD and the released iodine is recycled)
3) Exit of the thyroid hormone at the basolateral membrane through the thyroid hormone transported MCT8
42
Iodide trapping is accomplished by ___
Sodium-iodide symporter NIS
43
Downhill transport of __ Na+ ions results in the entry of __ iodide atom against an electrochemical gradient
2 Na+
1 I-
44
NIS has also been identified in other iodide-concentrating cells, including
Salivary and lactating mammary glands, choroid plexus, and gastric mucosa, and in the cytotrophoblast and syncytiotrophoblast
NIS is also expressed in the ovary and testis and in ovarian cancer and the majority of seminomas and embryonal testicular carcinomas
45
NIS also transports pertechnetate (TcO4-), perchlorate (ClO4-), and thiocyanate (SCN-). Relevance?
Radioactive pertechnate used in thyroid scanning
Potassium perchlorate used to block iodide uptake as a competitive inhibitor
46
Iodide uptake by NIS and the organification process are ___ (directly or inversely) regulated by high intracellular iodide concentrations.
Inversely
Iodide uptake by NIS and the organification process are inversely regulated by high intracellular iodide concentrations (Wolff-Chaikoff effect).
47
Organs affected and presentation of the Pendred syndrome
Mutation of the SLC26A4 gene
Pendrin is located in the:
Thyroid - entry of iodide into follicular lumen
Kidney - role in acid-base metabolism as chloride/bicarbonate exchanger
Inner ear - generation of endocochlear potential
Presentation:
Deafness or hearing impairment - major phenotypic manifestation / sensorineural deafness
Goiter
Partial defect in iodide organification
48
Major thyroid microsomal antigen
Thyroid peroxidase (TPO)
49
What catalyzes the fusion of 2 DIT molecules?
TPO
To yield a structure with 2 diiodinated rings linked by an ether bridge (the coupling reaction)
Efficient synthesis of T4 and T3 in the thyroid requires Tg
Because the coupling reaction is catalyzed by TPO, virtually all agents that inhibit organic binding (e.g., the thiourea drugs) also inhibit coupling.
50
Which is more abundant in each molecule of human Tg under normal conditions, T3 or T4?
T4
There are 3-4 T4 molecules in each molecular of human Tg under conditions of normal iodination, but only about 1 in 5 molecules of human Tg contains a T3 residue
Ratio of T4 to T4 in human Tg is 15:1
51
Which is more abundant in each molecule of human Tg in untreated Graves disease, T3 or T4?
T3
The content of T4 residues remains approximately the same, but the number of T3 residues doubles to an average of 0.4 per molecule.
52
Thyroid hormone turnover per day
1%
In normal humans, the administration of antithyroid agents for as long as 2 weeks has little effect on serum T4 concentrations.
53
The amount of T4 in the thyroid gland is sufficient to maintain a euthyroid state for at least __ days.
50 days
Approx 250 μg T4 per gram of wet weight in normal human thyroid, or 5000 μg of T4 in a 20-g gland
54
2 processes by which endocytosis of colloid from the follicular lumen occurs
Macropinocytosis by pseudopods formed at the apical membrane
Micropinocytosis by small coated vesicles that form at the apical surface - thought to predominate in humans
Both are simulated by TSH
55
Exit of thyroid hormone at the basolateral membrane involves this transporter
MCT8
56
How do the following agents inhibit T4 release from thyroid cells
- Iodide
- Lithium
Iodide - most important; inhibits the stimulation of thyroid adenylate cyclase by TSH and by the stimulatory immunoglobulins of Graves disease; increasing iodination of Tg also increases its resistance to hydrolysis by acid proteases in the lysosomes
Lithium - mechanism of action is poorly understood
57
Function of DEHAL1 (also called iodotyrosine deiodinase (IYD) enzyme)
Catalyzes NADPH-dependent deiodination of MIT and DIT, with greater activity against MIT
Iodide thereby released is immediately reconjugated to newly synthesized Tg
58
What class of drugs inhibit the reconjugation of released iodide into newly synthesized Tg?
Thiourea drugs (since they inhibit TPO)
Causes intrathyroidal iodine deficiency
59
TSH receptor belongs to this receptor family
G protein-coupled receptor family
Mainly couples to Gs, but when activated by high concentrations of TSH (100x physiologic level), also couples to Gq/G11
Phospholipase C (PLC) and intracellular Ca2+ pathways: Regulates iodide eflux, H2O2 production, and Tg iodination
Protein kinase A (PKA) pathways: Stimulates growth and regulates iodine uptake and transcription of Tg, TPO, and the NIS mRNAs leading to thyroid hormone production
60
TRUE or FALSE: The wild-type TSHR displays constitutive activity.
TRUE
A phenomenon that is not shared by the closely related receptors for LH/CG/FSH.
61
Mechanism of physiologic hyperthyroidism of early pregnancy
The TSH receptor binds to chorionic gonadotropin when present at high levels
It also binds LH
62
Other tissues that express the TSHR
Osteoclasts, fibroblasts, and adipocytes, as well as retroorbital adipocytes and skin
63
Iodothyronine that is highest in concentration and the only one that arises solely from direct secretion by the thyroid gland
T4
64
Iodothyronine of which approximately 80% is derived from the periphera tissues by the enzymatic removal of a single 5' iodine atom (outer ring or 5' monodeiodination) from T4
T3
65
The major iodothyronines are poorly soluble in water and thus bind reversibly to plasma proteins which are ___
Thyroxine-binding globulin (principal; affinity for T3 is 20-fold less than that of T4)
Transthyretin
Albumin
*3-6% bound to lipoproteins
Protein binding facilitates the distribution of the hydrophobic thyroid hormones throughout the vascular system.
66
Number of iodothyronines that TBG and transthyretin can bind
TBG: 1 iodothyronine binding site per TBG molecule (hence the T4 or T3 binding capacity of TBG in normal human serum is equivalent to its concentration)
Transthyretin: Each mole of TTR binds to 1 mole of T4 with high affinity, and a second T4 molecule is bound with lower affinity at high concentrations of T4
67
Half-life of TBG and transthyretin
TBG: 5 days
Transthyretin: 2 days (decreases during illness)
68
TRUE or FALSE: Congenital deficiency of TBG is common.
TRUE
Associated with the complete absence of the protein in males
69
Drug/Agent that blocks the synthesis of TBG, hence patients receiving this agent have low T4 concentrations
L-asparaginase
70
These patients have increased prevalence of more acidic bands of TBG, hence higher total plasma T4 and T3 even though T4 and T3 production are little changed
Estrogen-treated patients
Women receiving OCPs
Pregnant patients
Acute hepatitis
71
Explanation why patients with acute illness have increased ratio of free to bound T4 even when TBG saturation studies or immunoassays indicate TBG concentration is normal
In septic patients or following cardiopulmonary bypass surgery, TBG is subjected to cleave by a serine protease released from PMN leukocytes, resulting in the release of a carboxy-terminal loop with a consequent decrease in affinity for T4.
72
The thyroid hormone-binding protein that is expressed in the choroid plexus and is the major thyroid hormone-binding protein in the CSF
Transthyretin
73
Drugs that can inhibit the binding of T4 and T3 by TBG
Phenytoin, salicylate, salsalate, furosemide, fenclofenac, mitotane
Complete with T4 and T3 binding and reduce total hormone levels, although free T4 remains normal
Euthyroid patients receiving these drugs may appear to have low total and free T4 or T3, whereas in vivo the free fraction is normal.
74
Changes in the level or the binding of which of the following binding proteins will lead to paralleled changes in total plasma T4 and T3?
a. TBG
b. TTR
c. Albumin
d. All of the above
A and B only
Changes in albumin concentration per se have little influence on total hormone levels, unless accompanied by alterations in TBG and TTR.
75
Conditions that can decrease the plasma concentration of all 3 major thyroid hormone-binding proteins
Hepatic failure
Nephrotic syndrome
Serum albumin concentration in patients with these illnesses may serve as a surrogate for estimating TBG concentrations.
76
Thyroid hormone profile of patients with familial dysalbuminemic hyperthyroxinemia (FDHT4) and hypertriiodothyroninemia
Dominantly inherited
High total T4 or T3
Normal FT3 and FT4
Euthyroid
At risk of erroneous treatment
77
*Table 11.4 Comparison of the Major Human Thyroid Hormone-Binding Proteins, pate 340*
*
78
Compare the 3 major thyroid hormone-binding proteins in terms of:
Plasma concentration
T4 binding capacity
Association constant of the major binding site for T4 and T3
Fraction of sites occupied by T4 in euthyroid plasma
Distribution volume
Turnover rate
Distribution of T4 and T3
Plasma concentration: TBG < TTR < Albumin
T4 binding capacity: TBG < TTR < Albumin (due to higher concentration)
Fraction of sites occupied by T4 in euthyroid plasma: TBG > TTR > Albumin
Distribution volume: Albumin > TBG > TTR
Turnover rate: Fastest Albumin > TTR > TBG
Distribution of T4 and T3: TBG>> TTR and Alb
79
Its concentration and degree of saturation are the major determinants of the free fraction of T4
TBG (because it binds most of the circulating T4 and T3)
~68% of total T4 is bound to TBG. Free T4 is approximately 0.02% of the total.
If a change in TBG occurs, the free T4 and T3 concentrations can be maintained at normal levels only if the bound hormone changes in the same direction.
80
TRUE or FALSE: The free fraction of T4 is inversely proportional to the concentration of unoccupied TBG binding sites.
TRUE - "Free thyroid hormone hypothesis"
81
TRUE or FALSE: It is the free hormone that is available to the tissues for cellular uptake and feedback regulation that induces its metabolic effects and that undergoes deiodination or degradation.
TRUE
The bound hormone acts merely as a reservoir.
82
TRUE or FALSE: In the steady state, the rate of T3 and T4 metabolism, not the dissociation rate from plasma proteins, is rate limiting in the exit of hormones from the plasma.
TRUE
83
What is the mutation in Allan-Herndon-Dudley syndrome
- X-linked condition
- Mutation in monocarboxylate transporter 8 (MCT8) which facilitates entry of thyroid hormone across the plasma membrane
- Elevated serum T3 leading to severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia
- Coexistence of thyroid hormone excess and deprivation in different tissues is a distinct characteristic of this syndrome
- Treatment: PTU combined with levothyroxine T4 (L-T4) and a thyromimetic compound, diiodothyropropionic acid (DITPA)
*MCT 8 mutations are also associated with ADHS
84
In most cells, about 90% of the intracellular T3 is located in the cytosol. The known exception is in the ___, where approximately 50% of the intracellular T3 is present in the nucleus.
Pituitary
85
Thyroid hormones transporter through the blood-brain and blood-CSF barriers
Blood-brain barrier: organic anion transporting polypeptide (OATP)
* OATP1C1 - transporter specific for T4
Blood-CSF barrier: OATP and MCT8
86
Differentiate the human iodothyronine selenodeiodinases in terms of:
- Physiologic role
- Subcellular location
- Susceptibility to PTU
- Response to increased T4
- Half-life
Type I (Outer and Inner Ring)
- Physiologic role: rT3 and T3S degradation; the source of plasma T3 in thyrotoxic patients
- Subcellular location: Plasma membrane
- Susceptibility to PTU: High
- Response to increased T4: Increased
- Half life: >12 hours
Type 2 (Outer Ring)
- Physiologic role: Provide intracellular T3 in specific tissues, a source of plasma T3
- Subcellular location: Endoplasmic reticulum
- Susceptibility to PTU: Absent
- Response to increased T4: Decreased
- Half life: 20-30 minutes (rapid ubiquitination)
Type 3 (Inner Ring)
- Physiologic role: Inactivate T3 and T4
- Subcellular location: Plasma membrane
- Susceptibility to PTU: Absent
- Response to increased T4: Increased
- Half life: >12 hours
87
Which of the deiodinases is NOT present in the CNS?
Type I
88
*Table 11.2 Human Iodothyronine Selenodeiodinases, page 338*
*
89
Most important pathway for T4 metabolism
Outer ring (5') monodeiodination to the active thyroid hormone, T3
- catalyzed by D1 and D2
90
Action of D3
Inner ring deiodination, which inactivates T3 and prevents activation of T4 by converting it to rT3
91
Common properties of deiodinases
- Similar structure, all homodimers and integral membrane proteins
- All require thiol cofactor for successful catalysis
- All contain the rare amino acid selenocysteine in the active catalytic center (hence selenium deficiency will inhibit synthesis of deiodinases)
92
Predicted topologies (cellular location) of the 3 deiodinases and implications
D1 - plasma membrane; active center is in the cytosol; T3 produced preferentially enters the plasma pool
D2 - endoplasmic reticulum; active center is in the cytosol; intracellular location close to the nucleus makes the T3 it produces especially effective in entering the nucleus
D3 - plasma membrane; active center is extracellular
93
While D2 has principally been thought of as an enzyme that provides intracellular T3, which deiodinase is the major extrathyroidal source of T3?
D1
Explains why D1-inhibitor PTU causes a much more rapid fall in circulating T3 than does methimazole in patients with Graves disease
Of the T3 generated via T4 5' deiodination in euthyroid hormones, only about 70% is inhibited by PTU, consistent with a significant contribution of D2-dependent T3 production.
94
The most important thyroid hormone-inactivating enzyme catalyzing deiodination of the inner ring of both T3 and T4
D3
While expression is higher in fetal tissues, D3 expression may be reinduced under conditions in which cellular proliferation is required (malignancies and tumors). Highest D3 activity reported in any human tissue to date has been in infantile hemangiomas, wherein D3 may overwhelm the secretory capacity of the infant's thyroid, causing hypothyroidism - "consumptive hypothyroidism"
95
What is consumptive hypothyroidism?
Condition wherein high levels of D3 may overwhelm the secretory capacity of the infant's thyroid, causing hypothyroidism. Usually occurs in infants with extensive hepatic hemangiomas
96
Compare T3 and T4 in terms of:
Production rate
Fraction produced from thyroid
Relative metabolic potency
Serum concentration, total and free
Fraction of total hormone in free form
Distribution volume
Fraction intracellular
Half-life (days)
Production rate: T4>T3
Fraction produced from thyroid: T4>T3
Serum concentration, total and free: T4>T3
Relative metabolic potency: T3>T4
Fraction of total hormone in free form: T3>T4
Distribution volume: T3>T4
Fraction intracellular: T3>T4
Half-life (days):
- T4 6.7 days
- T3 0.75 day
Daily production of T3 is ~46% that of T4.
About 80% of T3 and all of rT3 production in humans can be accounted for by peripheral deiodination of T4, findings consonant with the high ratio of T4 to T3 (15:1) and rT3 (100:1) in human Tg.
97
Agents that enhance glucuronide conjugation of thyroid hormones through induction of uridine diphosphate glucuronyl transferases (UDPGTs), leading to biliary excretion of T4-glucuronide (T4-G) into the intestines
Phenobarbital, phenytoin, rifampin, and possibly sertraline
Therapy which such agents will generally increase Lt4 requirements. In patients with an intact thyroid, this will not be apparent. In patients with hypothyroidism, an increase in LT4 dosage will often be required.
98
Production of this deiodinase increases rapidly in brown adipose tissue under stimulation by the sympathetic nervous system
D2
This response is critical to adaptive thermogenesis during cold exposure in the human neonate and lifelong in the rodent.
99
Effects of amiodarone (has structural similarity with T4) on deiodination
Inhibits deiodination of T4 and rT3 by D1 and possibly by D2 --> Increased plasma T4 to maintain serum T3 in normal range
TSH increases within the first weeks of therapy but gradually returns to normal as the thyroid axis reequilibrates
T4 and rT3 metabolic clearance rats are reduced by 20-25%, with a reduction in the fractional T4 to T3 conversion rate of about 50%
Inhibits the active transport of T4 and T3 into hepatocytes
May interfere with T3 binding to TRs
100
TRUE or FALSE: Iopanoic and iopodipic acid inhibit all the deiodinases by competing with the iodothyronine substrates.
TRUE
For acute treatment of severe hyperthyroidism
101
TRUE or FALSE: High dosages of glucocorticoids (10 times replacement) chronically reduces the ratio of T3 to T4 in plasma.
FALSE
High dosages of glucocorticoids (10 times replacement) will acutely reduce the ratio of T3 to T4 in plasma, suggesting that conversion of T4 to T3 is blocked. The ratio of rT3 to T4 increases, raising the possibility that D3 action is also increased. These effects resolve during the long-term therapy such that thyroid function is little affected and thyroid hormone requirements are not increased by chronic glucocorticoid therapy.
102
Which among the following increases the circulating T3:T4 ratio:
a. Growth hormone deficiency
b. Recombinant growth hormone
B
Recombinant growth hormone increases the circulating T3:T4 ratio. Growth hormone deficiency is associated with a decrease in the ratio of T3 to T4 in serum, possibly associated with a decrease in outer ring deiodination.
*Growth hormone decreases D3 activity
103
The protein structure of TRs includes 3 major functional domains:
1 binding DNA
1 binding ligand
1 major transcriptional activation domain
104
Which has a 15-fold higher binding affinity for TRs than the other, T3 or T4?
T3, explaining its function as the active thyroid hormone
105
There are tissue-specific preferences in expression of the various TRs, suggesting that they subserve different functions in different tissues. In general, ___, is thought to be important in the hypothalamus and pituitary, in which regulation of thyroid function occurs.
TRβ2
106
What is the relationship between the iodine level in the thyroid and the fractional rate of hormone formation? (direct or reverse)
There is an INVERSE relationship between the iodine level in the thyroid and the fractional rate of hormone formation.
107
What is the source of the TRH that regulates TSH secretion?
The parvocellular region of the paraventricular nuclei (PVN) of the hypothalamus is the source of the TRH that regulates TSH secretion.
(Aside from the hypothalamus, TRH is also expressed in the brain, C cells of the thyroid gland, beta cells of the pancreas, myocardium, reproductive organs (including prostate and testis) and the spinal cord.)
108
3 ways by which TRH secretion is regulated
1) T3 suppresses the levels of prepro-TRH mRNA in the hypothalamus, but normal feedback regulation of prepro-TRH mRNA synthesis by thyroid hormone requires a combination of T3 and T4 in the circulation, the latter giving rise to T3 via T4 5' deiodination in the CNS in astrocytes and tanycytes.
2) Thyroid hormone-mediated induction of the TRH-inactivating pyroglutamyl peptidase II (PPII) in the hypothalamic tanycytes
(No other octopeptidase known capable of degrading TRH, and TRH is the only known subtrate of this unique enzyme)
3) Thyroid hormone also blocks the capacity of TRH to stimulate TSH release from the thyrotroph.
109
What is the major regulator of the morphologic and functional states of the thyroid?
TSH
110
Where is TSH secreted?
It is a glycoprotein secreted by the thyrotrophs in the anteromedial portion of the adenohypophysis.
111
Which of the TSH subunits is similar to other hormones and which is specific?
TSH is composed of an α-subunit that is common to LH, FSH, HCG, and a specific β-subunit synthesized only in the thyrotrophs.
Quantity of β-subunit is rare limiting for TSH secretion
112
2 most important influences on TSH synthesis
TRH increases and thyroid hormone suppresses the transcription of both subunits of TSH
Glycosylation is required for full biologic activity, and TRH is required for this process
Both T4 and T4 mediate the feedback regulation of TSH secretion, and TRH determines its set-point.
Gene-targeting studies show that TRH secretion is likely to be the dominant factor mediating the thyroid hormone feedback regulation of TSH secretion.
113
Normal concentration and half-life of TSH
In normal serum, TSH is present at concenrations between 0.4 to 4.2 mU/L.
Half-life: 30 minutes
114
Describe the secretion pattern of TSH and the factors that can affect this
Circulating TSH displays both pulsatile and circadian variation
Pulsatile:
- Fluctuations at intervals of 1 to 2 hours
- Magnitude of TSH pulsations is decreased during fasting (along with a fall in leptin levels), during illness, or after surgery
Circadian variation:
- Nocturnal surge that precedes the onset of sleep and appears to be independent of the cortisol rhythm and fluctuations in the serum and T4 and T3 concentrations
- Peak values in the late evening and a nadir in the afternoon
- Shows parallelism with changes in T3 levels
- When the onset of sleep is delayed, the nocturnal TSH surge is enhanced and prolonged, and the early onset of sleep results in a surge of lesser magnitude and shorter duration
TSH levels also show seasonal changes in humans with a decrease during the summer and increase during winter, changes that correlate with daily temperatures.
115
TRUE or FALSE: The degree of thyroid hypofunction after destruction of the hypothalamus is less severe than that which follows hypophysectomy.
TRUE
116
What is the relationship between serum free T4 concentration and the log of the TSH, direct or inverse?
There is a linear inverse relationship between the serum free T4 concentration and the log of the TSH, making the serum TSH concentration an exquisitely sensitive indicator of the thyroid state of patients with an intact hypothalamic-pituitary axis.
117
Drugs or hormones that can suppress TSH secretion
Transient:
- Somatostatin (somatotropin release-inhibiting hormone [SRIH]), through inhibitory G protein (Gi), but prolonged treatment with somatostatin analogue does not cause hypothyroidism
- Dopamine infusion, through adenylate cyclase
- Bromocriptine, a dopamine agonist, through adenylate cyclase
- Glucocorticoids in high doses (presumably by reducing TRH release, and may also increase D3 activity; will decrease serum T3 concentration)
Chronic?:
- Cushing disease, but with minimal effects on T4 production
- Bexarotene, a RXR agonist used for treatment of T-cell lymphoma, suppresses TSH sufficiently to cause central hypothyroidism
- Neurotransmitters
118
Drugs or hormones that can stimulate TSH secretion
TRH
Prostaglandins
α-Adrenergic agonist
Opioids
Arginine vasopressin
GLP1
Galanin
Leptin
Glucocorticoids (in vitro but not in vivo)
119
*Table 11.6 Endogenous and Exogenous Agents That May Stimulate or Inhibit Thyrotropin Secretion, page 349*
*
120
Drug that can suppress TSH sufficiently to cause central hypothyroidism
Bexarotene
A retinoid X-receptor (RXR) agonist used for treatment of T-cell lymphoma
121
Effects of iodine deficiency on thyroid function
Removal of iodine from the diet causes a rapid decrease in T4 concentrations and a simultaneous increase in serum TSH. Interestingly, no detectable decrease in T3 occurs.
TSH increases NIS, Tg, and TPO synthesis and iodine organification and Tg turnover.
TSH also stimulates cell division, leading to goiter.
In the rat model, the fall in plasma T4 increases D2 from 5-fold to 20-fold in the CNS, hypothalamus, and pituitary, increasing the efficiency of T4 conversion to T3. With moderately severe iodine deficiency, D3 in the CNS is also reduced, prolonging the mean resident time of T3 in that organ. This permits T3 to remain normal and the CNS T3 to be only moderately reduced despite up to a 10-fold decrease in circulating T3.
122
The compensatory alterations in thyroid function come into operation when total iodine intake falls below ___.
75 μg/day
123
Why is T3 increased as opposed to T4 in the compensatory response to iodine deficiency?
T3 has approximately 10 times the potency of the prohormone T4 and contains only 3 iodine atoms, which means a more efficient use of the iodine atom.
The physiologic response to iodine deficiency is similar to that which occurs during development of primary hypothyroidism, in Hashimoto disease, or in Graves disease receiving thiourea drugs.
124
Most common sources of excess iodine
Pharmaceutic, with radiographic dyes, amiodarone, and povidone-iodine
125
How much iodine is in a 200-mg tablet of amiodarone?
75 mg organic iodine, 8-17% released as iodide
126
Quantity of iodine required to suppress radioactive iodine uptake to <2%
>30 mg/day
127
Effect of iodine excess on thyroid function
The quantity of iodine organified in Tg, which includes T4 and T3, displays a biphasic response to increasing doses of iodide, at first increasing and then decreasing as a result of a relative blockade of organic binding. This decreasing yield of organic iodine from increasing doses of iodide, the Wolff-Chaikoff effect, results from a high concentration of inorganic iodide within the thyroid cell. High iodide concentrations have inhibitor effects on TPO and DUOX2.
This is reversible over time. This escape or adaptation phenomenon occurs because iodide transport activity decreases probably through a decrease in NIS expression.
128
What is the Wolf-Chaikoff effect?
The decreasing yield of organic iodine from increasing doses of iodide, which results from a high concentration of inorganic iodide within the thyroid cell
129
The Wolf-Chaikoff effect is usually followed by the escape or adaptation phenomenon EXCEPT in
Third-trimester fetus
Chronic high iodine intake during pregnancy must be avoided because it will cause fetal hypothyroidism and compensatory potentially obstructive goiter in the newborn.
130
Practical effects of pharmacologic doses of iodide
Prompt inhibition of thyroid hormone release (occurs to some extent normally but is especially apparent in patients with Graves disease or toxic nodules)
Decrease in hypervascularity and hyperplasia that characterize the diffuse toxic goiter of Graves disease
131
Thyroid function changes during pregnancy
TBG increases in first trimester --> Total T4 and T3 concentrations rise to levels about 1.5-fold
High hCG cross-reacts with TSHR --> Small and transient increase in free T4 levels near the end of the first trimester, resulting in partial TSH suppression
132
Effects of hCG on thyroid function during pregnancy
Small and transient increase in free T4 levels near the end of the first trimester, resulting in partial TSH suppression
Can induce transient gestational thyrotoxicosis
Trophoblast tumors (hydatidiform moles, choriocarcinomas) can rarely lead to severe hyperthyroidism
133
There is increased accelerated inactivation of T3 and T4 during pregnancy because of
D3 expression in the fetal-placental-uterine unit
The estimated increase in T4 production required during this period is 20-40%
134
Why are there increased iodine requirements during pregnancy?
Due to increased requirement for T4 secretion (due to increased inactivation)
High GFR during gestation also enhances renal iodide clearance
High requirement of fetal thyroid during the second and third requirements
*If these increased requirements for iodide are not met, serum T4 falls and TSH rises --> in one study, women had 20% or greater increase in thyroid volume during pregnancy
*Basal metabolic rate also increases during 2nd trimester, and symptoms may suggest thyrotoxicosis but are actually physiologic.
135
After delivery, the changes in thyroid function gradually return to normal, and serum TBG values reach normal levels __ to __ weeks postpartum.
6 to 8 weeks
136
What happens to Graves disease and Hashimoto disease during pregnancy?
In general TSHR antibody-mediated thyroid stimulation in the Graves disease patient is exacerbated during the first trimester and is attenuated during the second and third trimesters only to exacerbate in the first several months postpartum.
Thyroid autoantibody titers fall during gestation in patients with Hashimoto disease only to rise sharply postpartum in association with a phase of acute T-cell-mediated thyroid cell destruction - postpartum thyroid disease (PPTD) - which occurs in about 30% of patients with Hashimoto disease and significant residual thyroid tissue.
137
Fetal thyroid function (and levels of T3, rT3, and fT4)
Fetal thyroid function begins at about the end of the first trimester.
Overall, rates of production and degradation of T4 in terms of units per body mass exceed those in the adult by 10-fold
D1 catalysis is reduced and D3 is enhanced (D3 is highly expressed in fetal tissues). This change permits the highly regulatable conversion of T4 to T3 by D2 to be the major pathway for generating tissue T3.
Permanently low T3, elevated serum rT3
Despite this, the fetal free T4 concentrations approximate those in the maternal circulation from the gestational age of 28 weeks and onward.
138
TRUE or FALSE: The fetal pituitary-thyroid axis functions as a unit that is essentially independent from the mother.
TRUE
139
Which of the following can pass through the placenta:
a. TSH
b. T4
c. Both
d. Neither
Transplacental passage of TSH from mother to fetus is negligible, but the same is not true of maternal T4.
This transfer may be significant, given the capacity of the fetal brain to increase the efficiency of T4-to-T3 conversion.
The major factor limiting T4 and T3 transfer from mother to fetus is the D3 expressed in the uterus, placenta, and fetal epithelium.
140
Thyroid function in the newborn
After delivery, the serum TSH level in the neonate increases rapidly to a peak at about 2 to 4 hours after birth, returning to its initial value within 48 hours (probably in response to the rapid reduction in environmental temperature after delivery).
In response, the serum T4, T3, and Tg concentrations increase rapidly during the first few hours after delivery and are in the hyperthyroid range by 24 hours of life.
141
Thyroid function in the premature infant
Serum T4, TBG, and free T4 all tend to correlate with gestational age.
Premature infants have an immature hypothalamic-pituitary-thyroid axis with low T4, T3, and TSH.
Will also have an attenuated TSH surge after delivery.
*Changes are in many respects similar to those in adults with severe illness
142
Daily levothyroxine requirement in newborns and in adults.
Thyroid hormone production rates are higher per unit of body weight in neonatal infants and children than in adults.
Newborn: 10 μg/kg
Adult: 1.6 μg/kg
143
Thyroid function in the elderly
There is a reduction in the weight of the gland, in the size of the follicles, and in the content of colloid, and there is increased fibrosis, often with marked lymphocytic infiltration. However, these changes do not correlate with thyroid function.
In the healthy elderly patient, there is a normal level of free T4, but serum T3 levels appear to be lower. TSH may increase or decrease with age in relation to the iodine intake.
Some other studies have suggested that both subclinical hypothyroidism and subclinical hyperthyroidism might be associated with increased mortality in the elderly.
144
*Table 11.9 Changes in Thyroid Hormone Levels During Illness, page 353*
8
145
Constellation of findings in low T3 syndrome / euthyroid sick syndrome / nonthyroidal illness
Central reduction in TSH secretion
Decrease in plasma T3 levels
Decrease in T4 and T3 binding in serum
146
Thyroid function during fasting / illness
Reduction of 50% or more in serum T3 and an increase in serum rT3 without initial changes in serum total or free T4
May be due to decreases in peripheral T4-to-T3 conversion by both D1 and D2 and a reduced clearance of rT3 by D1
Decrease in T3 can be viewed as a beneficial energy-sparing and nitrogen-sparing adaptation
TSH concentrations remain in reference range, although inappropriate low in the context of the reductions in circulating T3
Severe decreases in serum T4 are associated with a high probability of death.
*Changes can be prevented by NAC infusion?
Further exaggerated by agents such as dopamine or glucocorticoids
147
Thyroid function during overfeeding, particularly with carbohydrates
Increased T3 production rates and serum T3 concentration
Reduced serum rT3
Increased basal thermogenesis
148
Changes in deiodinases during fasting/illness
Postmortem studies show that hepatic D1 activity is reduced by about 50%, skeletal muscle D2 is absent, and D3 is present in liver and skeletal muscle.
149
Changes in Thyroid Hormone Levels During Illness
Mild: High rT3, Low fT3, N fT4, N TSH
Moderate: High rT3, Low fT3, N/Low/High fT4, N/Low TSH
Severe: High rT3, Very Low fT3, Low fT4, Low TSH
Recovery: High rT3, Low fT3, Low fT4, High TSH
*Cautious use of thyroid hormonal therapy in patients with low T3 syndrome or a stunned myocardium has been proposed (due to benefit in patients after CABG in one study).
150
Which of the following increases above normal range during recovery from illness?
a. T3
b. T4
c. TSH
An increase in TSH above the normal range may appear during recovery, with the elevation in TSH concentration persisting until circulating free T4 and T3 levels return to normal.
May be confusing since all laboratory criteria for primary hypothyroidism are met, with the exception of the clinical context.
Follow-up generally reveals a normalization of TSH and T4 within 1 to 2 months.
151
TRUE or FALSE: Patients with neuropsychiatric disease can present with any of a number of abnormalities in thyroid function.
Bipolar disorder: Slight elevations in serum TSH and reductions in free T4
Severe depression: Slight elevation in serum in serum T4 and reduced serum TSH
152
How does primary adrenal insufficiency affect thyroid function?
Primary adrenal insufficiency may be associated with reduced serum T4 and elevated serum TSH concentrations. Treatment of AI can lead to complete resolution of these abnormalities (so not necessarily coexist with primary hypothyroidism but may happen, and vice versa).
153
Effect administration of androgens to women's levothyroxine requirement
Administration of androgens to women decrease TBG and decreases T4 turnover and levothyroxine requirements in patients with primary hypothyroidism. (in contrast to estrogen)
154
PE: Neck position when inspecting the neck during swallowing
Slightly extended
155
PE: Inspection finding if with a thyroglossal duct remnant or cyst
Midline mass high in the neck, which rises further when the patient extends the tongue
156
Movement on swallowing is a characteristic of the thyroid gland because it is ensheathed in the ___.
Pretracheal fascia
157
The pyramidal lobe is usually palpable in patients with
Generalized thyroid disease, such as Hashimoto or Graves disease
158
PE: How can we distinguish thyroid bruit from a venous hum?
Venous hum can be obliterated by gentle compression of the external jugular vein or by turning the head
A venous hum is generally found in younger patients with high cardiac output, such as occurs in Graves disease or with severe anemia.
159
Pemberton sign (arm-raising test) is positive in
Retrosternal goiter
The basis for this maneuver is that if the size of the thoracic inlet is already reduced by such a goiter, raising both arms until they touch the sides of the head further narrows the thoracic inlet and causes congestion and venous engorgement of the face and sometimes respiratory distress or even (rarely) syncope.
160
TRUE or FALSE: The rate of TSH secretion is exquisitely sensitive to the plasma concentrations of free thyroid hormones, thus providing a precise and specific indicator of the thyroid status of the patient.
TRUE
161
High levels of serum biotin can both result in very low ___ levels and artifactually raise free ___ measured in robotic assays based on biotin/streptavidin chemistry.
High levels of serum biotin can both result in very low TSH levels and artifactually raise free T4 measured in robotic assays based on biotin/streptavidin chemistry.
162
TRUE or FALSE: A borderline abnormal TSH value should always be repeated within a week or so to be certain that it is representative.
TRUE
163
Which of the TSH subunits are detectable in serum and can be used to differentiate between neoplastic and nonneoplastic causes of TSH excess.
α-subunit
The free α-subunit common to TSH, FSH, LH, and hCG is generally detectable in serum, but the TSH β-subunit is not. The α-subunit level may also be increased in patients with glycoprotein-producing tumors of the anterior pituitary. Its measurement may be useful in the rare patient with hyperthyroidism and a normal or elevated TSH to differentiate between neoplastic and nonneoplastic causes of TSH excess.
164
TSH values fall into 2 general categories:
1) those between lower limit of normal and 0.1 mU/L
- may be asymptomatic = subclinical hyperthyroidism
2) those less than 0.1 mU/L
- usually have symptomatic thyrotoxicosis and a significant elevation in free T4
*If 5-15 mU/L
- have few if any symptoms, and the serum free T4 and T3 are typically low-normal = subclinical hypothyroidism if T4 is in normal range; may indicate early thyroidal failure with a compensatory increase in TSH secretion
165
Interpretation if both serum TSH and free T4 are elevated
Either 1) autonomous TSH production (due to a TSH-secreting pituitary tumor, resistance to thyroid hormone) or 2) hyperthyroidism with an artifactual elevation in TSH
Differentiating between these diagnoses may require MRI of the hypothalamic-pituitary region, markers of thyroid hormone action (e.g., ferritin or sex hormone-binding globulin), or consultation with the clinical chemistry laboratory to rule out an assay artifact.
166
TRUE or FALSE: Patients with hypothalamic or pituitary hypothyroidism often have normal or possibly even slightly elevated serum TSH
TRUE
Explanation for the paradox:
The circulating TSH generally has reduced biologic activity due to abnormal glycosylation, reflecting the impaired access of TRH to the thyrotroph.
167
Which of the following more closely correlates with the severity of the hormone excess or deficiency:
a. Free T4
b. Free T3
c. TSH
The degree of abnormality int he free T4 generally correlates with the severity of the hormone excess or deficiency, whereas the serum TSH concentration is an indicator of the impact of this abnormality in that specific patient.
The TSH assay is an indirect reflection of thyroid hormone supply and does not, by itself, permit a conclusive diagnosis of a specific disorder of thyroid hormone production.
168
The most accurate and direct measurements of the concentrations of free T4 and free T3 in serum are performed by assay of these hormones in a ___
dialysate or ultrafiltrate of serum.
Alternative assays are subject to artifacts from endogenous antibodies to T4, abnormal binding proteins, or severe illness.
169
For pregnant or severe ill patients, the automated methods typically give falsely low results. A reasonable alternative for pregnancy is to use the normal range for the serum total T4 concentration multiplied by ___ in lieu of an automated free T4 assay.
1.5
170
How to compute for the free T4 or T3 index (FT4I or FT3I)
Quantitate the proportion of labeled T4 or T3 bound by solid phase in unknown sera and in control sera
Divide the result for the unknown sample by that obtained for control sera in the same assay. This quotient is the thyroid hormone-binding ratio (THBR) which typically has a normal range of 0.85 to 1.10.
Because the THBR is proportional to the free fraction of the endogenous thyroid hormones in the serum, it can be multiplied by the total T4 or T3 concentration to estimate the free thyroid hormone concentration.
The FT4I and FT3I have a normal range in units that are identical to that of the total T4 or T3.
171
Changes in free thyroid hormone fraction and THBR when TBG-binding capacity is increased and when it is decreased
During pregnancy, the TBG-binding capacity, the serum T4, and the number of unoccupied TBG-binding sites approximately double --> ~50% reduction of free T4 fraction. If the reduced THBR is multiplied by an increased total T4, the FT4I estimate is normal, an accurate reflection of the free T4 concentration.
In patients in whom the serum T4 concentration is reduced owing to a low TBG, the concentration of unoccupied binding sites is reduced to an even greater extent --> Increase in free T4 and T3 fractions and THBR, and both the free T4 and FT4I remain in the normal range.
172
When concentrations of TBG are altered, the deviation of the total T4 measurements from normal is in the ___ direction to that of the THBR. (same or opposite)
Opposite
173
When the T4 level is elevated due to increased T4 secretion or overreplacement, the concentration of unoccupied TBG binding sites is reduced, and both the free fraction and the total T4 are altered in the ___ direction. (same or opposite)
Same
174
*Table 11.1 Circumstances Associated with Altered Binding of Thyroxine by TBG, page 358*
*
175
3 situations that would render interpretation of results of labeled T3 assays difficult
1) In cases of familial dysalbuminemic hyperthyroxinemia
- Abnormal albumin binds T4, but NOT T3, with increased avidity --> Elevated total T4, reduced free fraction of T4 (when measured by FT4I) but not T3
2) In the presence of endogenous antibodies against T3
3) In sick patients
*Normal concentrations of TBG are only slightly higher in women than in men
176
Most common cause of a reduction in serum TSH
Excess supply of thyroid hormone
177
The hypothalamic-pituitary axis may remain suppressed for several months after complete resolution of the thyrotoxic state. The best test for assessing the physiologic state in such patients is the ___.
Free T4 (or FT4I)
178
In pregnancy, when does TSH return to normal?
TSH returns to normal in the second and third trimesters in the euthyroid patient. A persistently suppressed TSH (<0.1 mU/L) in the pregnant patient after the first trimester suggests that the hyperthyroidism is due to autonomous thyroid function.
179
If the serum TSH is suppressed and the serum free T4 is low, one should be suspicious of this before assuming pituitary of hypothalamic dysfunction.
Ingestion of liothyronine (triiodothyronine)
Desiccated thyroid also has a high T3:T4 ratio and if given in excess may cause a similar abnormality.
180
Most common cause of an elevation in TSH worldwide (but not in North America)
Iodine deficiency
181
Resistance to Thyroid Hormone (RTH) due to mutation in THRβ gene (RTHβ)
Signs of hypothyroidism in some tissues and hyperthyroidism in others
Most common laboratory pattern: Normal TSH, or mild elevated in absolute terms but inappropriately high for the elevated free T4
Must be differentiated from the patient with a thyrotroph tumor in whom the persistent secretion of TSH causes hyperthyroidism
182
Resistance to Thyroid Hormone (RTH) due to mutation in THRα gene (RTHα)
Normal TSH, free T3, but a low free and total T4
