Thyroid Flashcards
retinoid X receptor
thyroid hormone receptor
Activation of the THR (receptor)’s activity requires:
1) dimerization with the retinoid X receptor (RXR).
2) They bind to the Thyroid response element (TRE)
3) Stimulation or inhibition of a whole variety of genes
lab findings in grave’s disease
low serum TSH
high T4
use radioactive iodine to determine etiology (diffusely increseed in graves)
graves disease
obviously hyperfunctioning gland, hyperplasia, and hypertrophy of follicular cells.ar cells
follicular carcinoma
2nd ost common form of thyroid ca
slowly enlarging painless nodule
more common in areas w iodine deficiency
range from encapsulated to widely invasive tumors with necrosis and hemorrhgage
lower survival (age, size, invasion, metastasis)
prevalence of hypothyroid
10% gen population
hashimoto’s thyroiditis pathogensesis
CD8+ cytotoxic t cell mediated cell death
ck mediated cell death (Th1)
binding of anti-thyroid abs
MIT
in colloid, when 1 iodine bound to a tyrosine ring
MIT + DIT = T3
if not made into TH, recycle iodine and tyrosine
follicular carcinoma
genetic mutations in papillary carcinoma
activation of MAP kinase pway - RET and BRAF
NOT seen in follicular adenoma/carcinoma - diagonsis!
RET/PTC rearrangements and BRAF point mutations are more or less specific for papillary carcinoma. Usually they’re not seen in follicular adenoma or carcinoma.
This is important because we use diagnostically and it is something I expect you to know.
subacute thyrodiitis
painful thyroiditis
due to release of pre-formed thyroid hormone (low radioactive iodine uptake)
may be associated with infections
parafollicular cells
C cells
1)deal with calcitonin hormone (calcium metabolism)
regulation of synthesis and secretion of TH
- availability of iodide
- stimulation by TSH
What is the most common subtype of graves disease?
thyroid stimulating immunoglobulin (TSI)
binds to the TSH receptor and mimics its actions stimulating the gland to release thyroid hormone
genetic mutations in graves
CTLA4
PTPN22
HLA-DR3
biochemical makeup of reverse T3
Reverse T3: inactive b/c you remove one inner iodine
Type I Deiodinase
5’ and 5
generate T3, Inactive T4 and T3
- Type 1 (mixed activator or inactivator) can take off 5 (inner ring) or 5’ (outer ring): present in liver, kidney, thyroid, and brain
- If 5’ à generates T3 active hormone
- If 5 (inner) à generates rT3 (inactive)
basic structure of thyroglobulin
lots of tyrosine!
Mild hyperthryodiism
still dangerous
risk of a fib, tachycardia, APBs, reduced bone density
esp in elderly
Standard treatment for hypothyroidism
L Thyroxine (narrow TI, diff bioavailabilities)
May need to add Liothyronine (T3) - if deoidinase enzyme type 1 deficiency (rare)
Armour thyroid (natural products from animal thyroid - diff doses
iodine deficiency
endemic goiter with hypothyroidism
most common in areas away from sea water
available through certain foods, with supplments
hashimoto
diffusely enlarged gland: pale, nodular, rubbery
you would see diffusely enlarged thyroid gland which is pale and nodular because of the inflammation, fibrosis, and lymphocyte accumulation.
undifferentiated carcioma
Undifferentiated carcinoma is a very aggressive tumor that presents as a rapidly enlarging mass. It is seen in older patients. Mean survival is 6 months.
It just is a very ugly tumor and a very aggressive disease.
Which papillary carcinoma mutation is associated with papillary carcinoma most?
RET/PTC rearrangement
goiter - variably sized follicles some distended with colloid
Histologically you see variably sizes of thyroid follicles. Some of them are very big, some of them are ruptured, the colloid is in the stroma. Small ones. Then you see fibrosis.
what is the most common thyroid carcinoma?
papillary (>85%)
thyroid surgery complications
blood loss
anesthesia rsik
transient hyperthyroid/thyroid storm (from TH release)
hypoparathyroidism - transient or permanent
recurrent laryngeal nerve damage (hoarseness)
hypothyroid
inorganic stable iodine (SSKI)
for hyperthyroid
10 drops daily for up to 10 days before surgery
decrease vascularity of the thyroid gland and surgical blood loss
must treat with goitrogen first - iodine MAY exacerbate hyperthyroid
serum binding proteins
binding of a hormone to a serum protein renders it inactive
only free hormone is able to enter cells
increasing binding proteins increases total hormone concentration but NOT of the active portion
papillary carcinoma
classic intranuclear pseudoinclusions
. There are intra-nuclear inclusions which are cytoplasmic extensions into the nucleus. It is sort of an optical illusion that looks like a hole when cytoplasm goes in even though there are no holes.
Nuclear clearing plus nuclear groups plus inclusions are pathomnemonic of papillary carcinoma.
These things that are typical tend to pop up on exams.
Cretinism
if mom is euthyroid - good prognosis if Rx at birth, develop normally until birth, rarely found on fetal u/s
if mom is hypothyroid - usually iodine deficiency, more severe mental retardation, poorer prognosis (less respinsive to Rx), deaf mutism and rigidiy
hypothyroidism and goiter
impaired cognitive function
retarded mental and physical development
impaired growth (short stature)
increased infant mortality
low birth weight, spontaneous abortion, decreased mortality
congenital abnormalities
deaf-mutism
hyperthyroidism symptoms
lymphocytic painless thyroiditis
“silent thyroiditis”
due to release of pre-formed thyroid hormone (low reactive iodine uptake, self limited - subsides in a few weeks!)
goiterous thyroid enlargement and mild hyperthyroidism
less common
post partum and middle aged
variant of hashimotos (1/3 evolve into hypothyroid, majoriyt have circulating anti thyroid abs)
PTU vs methimazole
more side effects with PTU - use methimazole EXCEPT use PTU in pregnancy
both can harm fetus
graves disease
diffusely and symmetrically enlarged gland with beefy red parenchyma
How much iodine needed er day?
150 mcg (200 if pregnant)
genetic mutation in medullary carcinoma
RET mutations - lead to activation of the reeceptor
hashimoto’s thyroiditis
chrominc autoimmune thyroiditis
chronic inflammatory autoimmune disease characterized by destruction of the thyroid gland with acquired defect in thyroid immune synthesis
medullary carcinoma
neuroendocrine tumor derivd from C (parafollicular) cells
secrete calcitionin
can be sporadic or associated with MEN (familial)
Amour thyroid
natural from animals
diff amts of everything in diff batches
endocrinologists don’t like it!!
Which iodinations are required for T3 and T4 activity?
-3’ and 5’ ionidation of inner ring (2 purple circles on the inner ring) are both required for activity, but only one outer iodine is need for activity, so both T3 and T4 are active
Graves disease
most common ause of endogenous hyperthyroidism
F> M
ab binds to TSH receptor in the thyroid and stimulates the thyroid gland to produce too much thyroid hormone
lab tests in hashimoto’s
high TSH
low T4
[anti-thyroglobulin, anti-thyroid peroxidase]
beta blockers
for hyperthyroid
usefull in all etiologies of hyper, start ASAP even before determinimg cause
decrase symptoms caused by icreased beta-adrenergic tone
decrease vasculariyt of thyroid
circulation of TH
water insoluble
long half life (T4-8d, T3-1d)
circulates bound to proteins!!
TBG (thyroid binding protein)
Tyroid binding prealbumin
albumin
DIT
in colloid, when 2 iodines bound to a tyrosine ring
DIT + MIT = T3
DIT + DIT = T4
if not made into TH, recycle iodine and tyrosine
multinodular goiter
repeated episodes of hyperplasia and involutionlead to long standing
preceded by diffuse goiter
endemic or sporadic forms
older individuals as late complication of simple goiter
may be really big! compress esophagus
evaluation of thyroid nodules
- u/s and fna
- fna sample submitted for molecular testing
- cold nodules by radionucleotide scan
- suspected tumors need surgical resection - entire capsule should be evalulated histologically for capsular and vascular invasion
exogenous hyperthyroid
taking too much thyroid hormone - T4, T3, both
riedel’s thyroiditis
rare fibrosing process
Riedel’s thyroiditis is a very rare disease where the thyroid gland becomes fibrotic and stuck to other neck organs. It can be confused with an anaplastic carcinoma. It is associated with another strange disease, idiopathic fibrosis in the retroperitoneal area.
psammoma body - papillary carcinoma
calcified structures (tumor cell necrosis)
Psammoma calcifications in papillary carcinomas. These tumors grow so slowly that as they grow they start dying and outgrow their blood supply. They form lamellar calcifications, or psammoma bodies.
papillary carcinoma
papillary architecture and overlapping oval nuclei with clearing are seen
Nuclear clearing plus nuclear groups plus inclusions are pathomnemonic of papillary carcinoma.
These things that are typical tend to pop up on exams.
Type II Deiodinase
5’
generate T3
- Type 2 (activator): in pituitary
- only 5’ à generates active T3
hypothalamic pititary thyroid axis
Again, T3 and T4 feedback to the thyroid to inhibit TSH secretion
T4 works b/c de-iodinase in pituitary converting T4à T3
hypothyroid
follicular adenoma
benign
solitary, discrete, well demarcated nodule cmpressing the surrounding tissue
derived from follicular epithelium
presents as a painless mass
adenoma vs carcinoma: vascular and capsular invasion!! cells inside look the same, call it a “follicular neoplasm” then remove t in surgery and look at it again and if invaded capsule it is a carcinoma, if didn’t it is an adenoma
TH and BMR
increase Na/K ATPase
increase O2 consumption
increase heat production
increase BMR
1)in the case of BMR, too much thyroid hormone leads to increased heat production (these people will feel hot) vs. less production (pts will feel cold). One way to do this is by increasing the number of Na/K ATPases on the plasma membrane
graves disease - FNA
sheets of benign follicular cells - hyperfuncitoning
You would see benign follicular cells in sheets called fire flares. These cytoplasmic extensions pink in color tells you that the cells are actively secreting thyroid hormones. It’s a sign of hyperfunctioning state.
You can see them here as well (Pink blob on right) This is colloid.
medullary carcinoma
polygonal/spindle cells arranged in nests, follicles
amyloid common - results from altered calcitonin proteins
will stain positive for calcitonin
Hashimoto - atrophic, small gland
In later stages, the gland shrinks due to fibrosis and scarring. This is the hypothyroid stage of the disease.
TSH
from pituitary
binds to TSH receptor on the thyroid follicular epithelium which causes acivation of G proteins and cAMP mediated synthesis and release of T3 and T4
At Every level of TH synthesis/secretion, TSH stimulates via GPCR mechanism
-It also increases DNA, RNA, protein, and phospholipid secretion à increased cell size, cell number, and number of follicles
At normal levels of TSH, this is not relevant. However, with excessive TSH -à develop goiter, because all of the trophic hormones can stimulate the gland to hypertrophy
Most follicular carcinomas look like this. They look like adenoma with a capsule, but there’s a little bit of capsular invasion. This is normal thyroid (right), this is your nodule (left), this is your capsule (magenta curve down the middle). Inside of it looks like an adenoma but it is pushing through (up towards right upper corner).
This is capsular invasion so by definition this is follicular carcinoma.
TH Receptor
Activation of the THR (receptor)’s activity requires:
1) dimerization with the retinoid X receptor (RXR).
2) They bind to the Thyroid response element (TRE)
3) Stimulation or inhibition of a whole variety of genes
deiodinases
activate and/or degrade
Deiodination is a pathway of degradation, but also this pathway of degradation leads to activation in the case of TH à diodinases can determine whether the hormone is inactive or active
Here, T4 can be converted to T3, but it can also be converted to rT3 (inactive). Eventually free thyronine can be generated
Another pathway of inactivation: in liver and kidney, T3 and T4 can undergo glucuronidation to solubilize them for excretion through the urine
Steps of TH formation
- Synthesis of TG, extrusion into follicular lumen
- Na/I cotransport
- Oxidation of I- to I2
- Organification of I2 into MIT and DIT
- Coupling reaction of MIT and DIT to T3 and T4
- Endocytosis of TG back into follicular cell
- Hydrolysis of T4 and T3; Enter circulation
- Deiodination of residual MIT and DIT - recycling of I- and tyrosine
OR
1) Iodine uptake
2) Thyroglobulin secretion into lumen (look at right side of diagram)
3) Peroxidase enzymes here shown
4) When gland stimulated by TSH à
1) new thyroid hormone made
2) and existing thyroid hormone present in thyroidglobulin is endocytosed back into the cell (as thyroidglobulin) where it merges with the a lysosome that hydrolyzes the proteinà T3 + T4 released
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5)There are also some mono- and diiodotyrosines whose iodines are recycled for future use (deiodination)
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hashimotos
exuberant lymphoplasmacytic infiltrate . Lymphocytes form follicles. You would see a lymph node with germinal centers
These are follicular cells, but in contrast to normal follicular cells, they get these pink eosinophilic granular cytoplasm due to accumulations of cytoplasmic mitochondria.
This is a typical look. They are called Hurthle cells or oxyphilic cells.
The combination of this lymphoplasmacytic inflammation with this Hurthle cell change is indicative of Hashimoto Thyroiditis. Confirm it with serum antithyroid antibodies.
biochemical makeup of T3
T3: one outer iodine; active
follicles
1) Follicles: consist of epithelial cells (green cells) making thyroid hormones (T3, T4).
2) Follicles surround a lumen where thyroid hormones are stored being readily accessible in case you need it
papillary carcioma
lymphoma
rapidly enlargining mass
appears as fleshy and tan
subacute thyroiditis
also subacute and dequervain
granulomatous
related to viral or post viral inflammation
self limited
**sudden painful thyroid enlargement, hyperthyroidism returm to normal thyroid function
Pendrine
After Iodine pumped into the cell, Iodine then comes to the apical side where Pendrine shuttles iodine into the lumen where its converted to iodide
lymphoma
diffuse large cell lymphoma
often arises in background of lymphocytic or hashimoto thyroiditis
Here’s an example of diffuse large cell lymphoma.
It is important to recognize this because treatment is obviously different from other cancers of the thyroid gland.
Effect of more BP?
Increased binding protein (BP)à fall in free T3à causes increased pituitary secretion of TSHà normalizes free-T3 levels
Which is why lower BP levels do not affect the level of effective T3 hormone
thyroglobulin
Another level of regulation: Thyroid hormone in pre-pro state is thyroglobulin (pro state would be T4, inactive/low activity)
This (bottom right molecule) is how T4 would be stored in the colloid (lumen of the follicle)à as a part of a larger molecule called thyroglobulin
NIS
Na/I Symport
plasma membrane protein on the basolateral membrane of follicular cells which catalyzes the accumulation of iodine into thyroid cells against a chemical and electrical gradient (concentrate I 20-40x)
TSH upregulates NIS gene expression stimulating iodine uptake
*first step in thyroid hormone formation
requires E (Na/K ATPase
biochemical makeup of T4
T4: two outer iodine ; active
TH and proteins
3) Protein synthesis (normally levels à stimulates protein synthesis):
1) High levelsà stimulates protein catabolism
histo in goiter FNA
In goiter we see a lot of colloid, histiocytes, lymphocytes, and sheets of benign follicular cells
- abundant colloid
- macrophages (inflam)
- sheets of benign follicular cells
Type III deoidinase
5
inactivate T3 and T4
–Type 3 (inactivator): in brain, placenta, skin)
Only 5 à only generates
thyroid peroxidase
Thyroid peroxidase is located on the surface of this membrane (pointing to “Exocytosis”/red arrow pointing to the left)
It’s the same enzyme that:
1) oxidizes the iodide and causes organification (iodine being added to carbon compounds)
2) Causes conjugation or condensation of two of these
1) Iodide (pointing at I- directly left of yellow square/pendrin in the mid-left area of the diagram) is oxidized to form iodine.
2) It’s placed onto tyrosines, which are then condensed or conjugated
thyroid hormone on growth
growth formation, bone maturation
permissive for action of GH
TH and metabolism
increase glucose absorption, glycogenolysis, gluconeogenesis, lipolysis, protein synthesis
1) Glucose (TH considered a diabetogenic hormone by antagonizing insulin effects)
1) increases glucose absorption from the gut, so will need to monitor glucose serum levels
2) increases glycogenolysisà increases glucose levels
3) Also increases gluconeogenesisàincreased glucose levels
pretibial myxedema
assocoated with graves’ disease
