12 - Thyroid Gland Physiology Flashcards
The thyroid gland produces the prohormone __________ and the active hormone __________.
Tetraiodothyronine (T4 or Thyroxine)
Triiodothyronine (T3)
The thyroid ________ is the functional unit of the gland. It is surrounded by a single-layer of epithelial cells.
Follicle
The thyroid follicular lumen itself is filled with ________.
Colloid
T/F. The size of the epithelial cells and amount of colloid in the thyroid follicle stays the same.
False. The size of the epithelial cells and the amount of colloid changes with activity.
The thyroid gland also contains _________ cells, which secrete ________.
Parafollicular (C cells)
Calcitonin
T/F. The thyroid gland receives a rich blood supply.
True
The thyroid hormones are synthesized by what?
Follicular epithelial cells
Colloid is composed of newly synthesized thyroid hormones attached to _________.
Thyroglobulin
The thyroid follicle epithelium sits on a…
Basal lamina (outermost part of the follicle)
The thyroid follicle cell secretes 60 ug of new hormone/day. Enough hormone is stored as ________ ________ in the follicular colloid to last the body 2-3 months.
Iodinated Thyroglobulin
***Iodine is stored iodinated as tyrosine of thyroglobulin
When iodinated TG is stored in the follicular colloid, 8,000 ug total is stored and of this 600 ug is _____ and _____.
T4
T3
From the ECF, 120 ug of _________ is trapped in the thyroid gland.
Iodide
From the thyroid gland, 60 ug of ________ is leaked into the ECF.
Iodide
Iodine and Tyrosine react together to form what?
MIT (Monoiodotyrosine) or DIT (Diiodotyrosine)
DIT + DIT forms…
T4 (Thyroxine)
***This is a fast reaction! 10x more T4 is produced than T3!
DIT + MIT forms…
T3 (Triiodothyronine)
Thyroid hormones contain large amounts of iodine, and the major secretory product is _______.
T4
Where does synthesis of the hormones occur?
Part intracellularly and part extracellularly
______ percent of T3 production is produced by peripheral conversion from T4. ______ percent of circulating T3 comes from direct secretion from the thyroid gland. Provides circulating T3 for uptake by other tissues in which T3 supply is too low.
80-90
10-20
T4 is converted to T3 via _________.
Deiodinase
What types of deiodinase create active T3?
Type 1 and 2
***Outer ring deiodination
What types of deiodinase create inactive T3 (reverse T3)?
Type 3
***Inner ring deiodination
There are some clinical states associated with a reduction in the conversion of T4 into T3, which are…
Fasting
Medical and surgical stress
Catabolic diseases
Step 1 of thyroid hormone production – Multiple tyrosines create _________, which exits the follicular epithelial cell into the follicular lumen via the rough ER and golgi.
Thyroglobulin
Step 2 of thyroid hormone production – ATP produced from the Na/K pump allows for the secondary active transport of Iodide as a symporter with 2 Na+. This is called the…
Na+ Iodide Symporter
***This occurs at basolateral membrane
Step 3 of thyroid hormone production – Iodide that was trapped from the symporter is then transferred from the follicular epithelial cell to the follicular lumen. This transport is done by a ________ pump, and _________ converted the Iodide to I2.
Pendrin
Peroxidase
Step 4 of thyroid hormone production – In the follicular lumen, the Thyroglobulin and I2 with peroxidase creates what?
MIT and DIT attached to Thyroglobulin
Step 5 of thyroid hormone production – In the follicular lumen, the MIT/DIT and Thyroglobulin complex along with peroxidase creates what?
T4, T3, MIT, and DIT all attached to Thyroglobulin — This is stored as Colloid
Step 6 of thyroid hormone production – ______ stimulation causes the pinocytosis of Colloid into endosomes within the follicular epithelial cell.
TSH
Step 7 of thyroid hormone production – Proteases lyse the Colloid within the endosomes, which allows the release of ______ and ______ into circulation.
T4
T3
Step 8 of thyroid hormone production – Proteases lyse the Colloid within the endosomes, which allows the release of ______ and ______ within the follicular epithelial cell. These are then reacted with intrathyroidal deiodinase and converted back to Tyrosine and Iodide to start the process over again.
MIT
DIT
When there is a deficiency of deiodinase, what does it mimic clinically?
Dietary Iodide deficiency
When the availability of Iodide is restricted, the formation of (T3/T4) is favored.
T3
This is a chloride/iodide pump that is located in the apical membrane of thyroid follicular cells.
Pendrin
Mutation in the Pendrin gene (SLC26A4, also called PDS) causes defects in the transport across the ________ _______.
Apical membrane
Mutation in the Pendrin gene also affects the ________, where it results in a sensorineural hearing loss.
Cochlea
Patients with this syndrome usually have hypothyroidism with goiter.
Pendred Syndrome
This occurs due to high levels of Iodide inhibiting organification and synthesis of thyroid hormones.
Wolff-Chaikoff Effect
This inhibits Iodide and Peroxidase from their normal interactions from Thyroglobulin to prevent formation of T3 and T4. It is an effective treatment for hyperthyroidism.
PTU (Propylthiouracil)
***Good for Graves’ Disease
These can inhibit the Na+ Iodide Transporter and prevent the trapping of Iodide into follicular epithelial cells.
Perchlorate, Thiocynate
Review the slide on thyroid gland activity by radioactive iodine uptake (Slide 14).
Review 5 minutes
Thyroid hormones circulate in the bloodstream either bound to ______ ______ (99 percent) or free (1 percent). There is an equilibrium between bound and free circulating T3 and T4 in the bloodstream.
Plasma proteins
What are the main binding proteins for thyroid hormones?
Thyroxine-binding globulin (TBG) – 70 percent
Transthyretin (TTR) – 10-15 percent
Albumin – 15-20 percent
This thyroid hormone binding protein is synthesized in the liver and has a higher affinity for T4 than T3.
Thyroxine-binding globulin (TBG)
Most circulating thyroid hormone is ______.
T4
What is the 1/2 life for T4?
6 days
What is the 1/2 life for T3?
1 day
What happens to free T4 in the circulation?
It relocates to the tissues where it is converted to active T3 and inactive T3 (reverse T3).
This hormone in the hypothalamus stimulates the release of TSH from the pituitary, which then stimulates the thyroid gland to produce thyroid hormones.
TRH (Thyrotropin-Releasing Hormone)
In hepatic failure, there are decreased levels of ______ in the blood which causes a transient increase in the levels of free T3 and T4. The increased levels of these creates a negative feedback loop which inhibits the synthesis of T3 and T4.
TBG
Pregnancy causes increased levels of _______ in the blood, which results in increased bound T3 and T4 and decreased free T3 and T4.
TBG
During pregnancy, the transient decrease in free T3 and T4 causes an increase in synthesis and secretion of T3 and T4. There is an increase in the total levels of T3 and T4, but the levels of free physiologically active thyroid hormones are normal. This person is said to be clinically…
Euthyroid
The hypothalamus, specifically the _________ nucleus, produces TRH when then stimulates the ________ pituitary to secrete TSH. TSH then stimulates the thyroid gland to produce and release T3 and T4. These hormones will then create a negative feedback loop that will stop the hypothalamus and pituitary from being further stimulated.
Paraventricular
Anterior
The role of TSH is to regulate, functioning specifically in…
The growth of the thyroid gland (trophic effect)
The secretion of thyroid hormones
What is TSH regulated by?
TRH
Free T3
T/F. TSH secretion, in contrast to the secretion of GH, occurs at a very rapid rate.
False. TSH secretion, in contrast to the secretion of GH, occurs at a steady rate.
TSH binds to a GPCR, which then activates ________ as its second messenger. This induces the Na+ Iodide Transporter.
cAMP
What are the actions that TSH has on the thyroid gland?
Increases the synthesis and secretion of thyroid hormones
Trophic effect on thyroid gland
What are the stimulatory factors affecting thyroid hormone secretion?
TSH
Thyroid-stimulating Immunoglobulins
Increased TBG levels (i.e., pregnancy)
What are the inhibitory factors affecting thyroid hormone secretion?
Iodide deficiency
Deiodinase deficiency
Excessive Iodide intake (Wolff-Chaikoff effect)
Perchlorate, thiocyanate (inhibits Na+ Iodide cotransport)
Propylthiouracil (PTU, inhibits peroxidase enzyme)
Decreased TBG levels (i.e., liver disease)
What new proteins are synthesized under the direction of thyroid hormones?
Na+/K+ ATPase Transport proteins B1-Adrenergic receptors Lysosomal enzymes Proteolytic proteins Structural proteins
In most tissues, synthesis of _______ ATPase is stimulated by thyroid hormones.
Na+/K+ ATPase
What new proteins are synthesized under the direction of thyroid hormones in cardiac muscle cells?
Myosin
B1-Adrenergic receptors
Ca+ ATPase
In the _______ and _______ tissue, thyroid hormones induce the synthesis of key metabolic enzymes.
Liver
Adipose
What are the actions of thyroid hormones for growth?
Growth formation
Bone maturation
What are the actions of thyroid hormones for the CNS?
Maturation of CNS
What are the actions of thyroid hormones for BMR?
Increase Na+/K+ ATPase
Increase oxygen consumption
Increase heat production
Increase BMR
What are the actions of thyroid hormones for metabolism?
Increase glucose absorption Increase glycogenolysis Increase gluconeogenesis Increase lipolysis Increase protein synthesis and degradation (net catabolic)
What are the actions of thyroid hormones for cardiovascular?
Increase cardiac output
Upregulation of B1-Adrenergic receptors
The increased activity of Na+/K+ ATPase accounts for most of the increase in metabolic rate. It leads to increased ________ consumption and _______ production.
Oxygen
Heat
The increase in BMR by a single dose of _________ occurs after several hours but it is long-lasting (greater than 6 hours).
Thyroxine (T4)
Hyperthyroidism leads to a (LOW/HIGH) BMR, while hypothyroidism causes a (LOW/HIGH) BMR.
High
Low
For lipid metabolism, thyroid hormones stimulate fat mobilization which results in…
Increased concentration of FAs in plasma
Increased concentrations of FAs in the plasma causes an enhanced oxidation of FAs. Plasma concentration of cholesterol and triglycerides are (DIRECTLY/INVERSELY) correlated with thyroid hormones.
Inversely
***The more thyroid hormones, the more FAs are being broken down. Less hormones, more FAs are still floating around.
In hypothyroidism, would there be an increased or decreased level of blood cholesterol?
Increased
***Remember, thyroid hormones are inversely proportional to cholesterol and triglycerides!
Thyroid hormones are important for the conversion of carotene to _________. This is why hypothyroid patients can suffer from blindness and yellowing of the skin.
Vitamin A
Thyroid hormones are important for carbohydrate metabolism because they increase gluconeogenesis and glycogenolysis to generate free ________. This causes and enhancement of ________-dependent entry of glucose into cells.
Glucose
Insulin
For cardiovascular effects of thyroid hormones, what are the indirect steps leading to increased blood volume?
Increased heat production and CO2 in tissues — Decreased peripheral vascular resistance —
Decreased diastolic blood pressure —
Reflex increased adrenergic stimulation —
Increased cardiac rate and output —
Increased blood volume
For cardiovascular effects of thyroid hormones, what are the direct steps leading to increased blood volume?
Increased cardiac muscle, Myosin heavy chain alpha/beta ratio, Na+/K+ ATPase, Sarcoplasma Ca-ATPase, B-Adrenergic signaling, G-protein stimulatory/inhibitory ratio ——
Increased ventricular contractility and function —-
Decreased peripheral vascular resistance —-
Increased cardiac rate and output —-
Increased blood volume
When thyroid hormone levels are high, the myocardium has an increased number of ______ receptors and is more sensitive to stimulation by sympathetic nervous system.
B1-Adrenergic
***Remember, these receptors bind NE while M2 receptors bind ACh (parasympathetic).
Thyroid hormones act synergistically with growth hormone and _________ to promote bone formation.
Somatomedins
Thyroid hormones are important for CNS maturation. Deficiency of thyroid hormones during the perinatal period leads to abnormal development of ________ and decreased ________ branching and myelination.
Synapses
Dendritic
Neural changes induced by thyroid hormone deficiency during the perinatal period are irreversible and lead to ________ unless replacement therapy is started soon after birth.
Cretinism
For metabolism, what happens when there is an excess of thyroid hormones?
Heat intolerance
Weight loss
Increased BMR
For metabolism, what happens when there is a deficiency of thyroid hormones?
Cold intolerance
Weight gain
Decreased BMR
For bones, what happens when there is an excess of thyroid hormones?
Osteoporosis
For bones, what happens when there is a deficiency of thyroid hormones?
Stunted growth
For the CNS, what happens when there is an excess of thyroid hormones?
Agitation
Anxiety
Difficulty concentrating
Hyperreflexia
For the CNS, what happens when there is a deficiency of thyroid hormones?
Cretinism (congenital)
In adults – Listlessness, slowed movement, somnolence, impaired memory, and decreased mental capacity
For skin, what happens when there is an excess of thyroid hormones?
Sweating
For skin, what happens when there is a deficiency of thyroid hormones?
Dry skin
Myxedema
For the cardiovascular system, what happens when there is an excess of thyroid hormones?
Tachycardia
Atrial fibrillation
Palpitations
High-output heart failure
For the cardiovascular system, what happens when there is a deficiency of thyroid hormones?
Bradycardia
Decreased contractility
Decreased cardiac output
Heart failure
For the intestines, what happens when there is an excess of thyroid hormones?
Diarrhea
For the intestines, what happens when there is a deficiency of thyroid hormones?
Constipation
Hyperthyroidism (thyrotoxicosis) occurs due to thyroid hormone overproduction. Primary hyperthyroidism is known as ________ ________ and is the most common cause. Secondary hyperthyroidism is often due to the TSH-secreting _________.
Graves’ disease
Pituitary
In hyperthyroidism, TSH levels are (INCREASED/DECREASED) due to negative feedback of T3 on the anterior lobe of the pituitary gland (primary). However, if the defect is in the anterior pituitary then TSH levels are (INCREASED/DECREASED) (secondary).
Decreased
Increased
The major clinical signs of this disease are exophthalmos (abnormal protrusion of the eyeball) and periorbital edema (due to recognition by the anti-TSH receptor antibodies of a similar epitope within the orbital cells).
Graves’ disease
How is Graves’ disease diagnosed?
Elevated serum free and total T4 or T3 levels
Clinical signs of goiter and ophthalmopathy
The presence of circulating _______ helps distinguish Graves’ disease from adenoma or pituitary thyrotrophs.
TSI (Thyroid-Stimulating Immunoglobulins)
What are the primary causes of hypothyroidism?
Gland destruction
Inhibition of thyroid hormone synthesis and release
Transient
Agenesis
This is the most common cause of hypothyroidism in iodine-sufficient areas of the world.
Hashimoto’s thyroiditis
What are other causes of hypothyroidism that are less common?
Hypothalamic disease
Pituitary disease (i.e., Sheehan’s syndrome)
Resistance to thyroid hormones
How is hypothyroidism treated?
Replacement doses of T4
Metabolism of T4 decreases and the plasma half-life increases with age, so (HIGHER/LOWER) doses are required for younger patients.
Higher
In women beyond menopause, overprescribing T4 can contribute to the development of ________.
Osteoporosis
In this disease, thyroid hormone synthesis is impaired by thyroglobulin or TPO antibodies, which leads to decreased T3, T4 secretion. TSH levels are high and this has a trophic effect (Goiter).
Hashimoto’s Thyroiditis
What are causes of congenital hypothyroidism?
- Iodide deficiency
- Maternal intake of anti-thyroid medication
- Impaired development of thyroid gland
- Inherent deficits in the synthesis of thyroid hormones
What are symptoms of congenital hypothyroidism?
- Feeding problems
- Respiratory difficulty
- Protruding tongue
- Curse facial features
- Growth retardation
- Mental retardation
- Jaundice
- Dry skin
- Hypotonia
Untreated postnatal hypothyroidism results in…
Cretinism
Hypothyroidism due to iodine deficiency leads to transient decrease in synthesis of thyroid hormones. _____ levels are elevated and a _______ presents.
TSH
Goiter
In hypothyroidism due to iodine deficiency, if the gland maintains normal blood levels of thyroid hormones then the patient is ________ and asymptomatic. If the gland cannot maintain normal blood levels of thyroid hormones then the patients exhibit hypothyroid.
Euthyroid
This is a postpartum hypopituitarism due to necrosis of the pituitary gland. Most patients present with agalactorrhea (low milk supply) or difficulties in lactation. Amenorrhea is also commonly presented. Some patients present with hypothyroidism and other endocrine dysfunctions.
Sheehan syndrome
What are the main instances that goiter will present?
Hyperthyroidism (Graves’ disease, TSH-producing tumor)
Primary Hypothyroidism
Explain how the T3 resin uptake test works.
TBG is taken from serum (could be free or bound), then unbound and labeled T3 is added. T3 will bind to available TBG. An Anti-T3 Ab is added that adsorbs the rest of the T3 that didn’t bind to TBG. The adsorbed T3 on the Ab is precipitated and the TBG bound with T3 (and some T4) is removed.
Why is there increased T3 resin uptake for hyperthyroidism?
Because there is a lot of T4, and this T4 binds to the TBG taking all the available binding sites. This leaves a lot of the free T3 available to bind to the Anti-T3 Ab.
***Basically, too much hormone and not enough TBG
Why is there decreased T3 resin uptake for hypothyroidism?
Because there is less T4, meaning there is a lot more available TBG for the labeled T3 to bind to. More T3 is bound to TBG, so less will bind to the Anti-T3 Ab.
Explain how hepatic failure alters the fraction of free thyroid hormones.
Hepatic failure causes decreased blood levels of TBG. This allows a transient increase in the level of free T3 and T4. Because there is an increase in these hormones, then negative feedback will inhibit the production of them.
If there is high TBG, what will the T3 resin uptake look like?
High TBG means there is increased T4, which results in a decreased T3 resin uptake (because there is a lot of available TBG for the T3 to bind).
If there is low TBG, what will the T3 resin uptake look like?
Low TBG means there is decreased T4, which results in increased T3 resin uptake (because there is less TBG available for the T3 to bind).
Explain how pregnancy alters the fraction of free thyroid hormones.
Pregnancy causes increased TBG levels, which results in increased bound T3/T4 and less free T3/T4. The transient decrease in free T3/T4 will cause an increase in the synthesis and secretion of T3/T4. This causes an increase in the TOTAL levels of T3/T4, but levels of free hormones are normal so person is said to be clinically euthyroid.
Why does pregnancy cause decreased T3 resin uptake?
Pregnancy causes increased TBG levels, which means there is a lot of available sites for the T3 to bind. This results in less T3 binding to the Anti-T3 Ab, making a low T3 resin uptake.
