Thyroid Physiology: T3 & T4

How T3 receptor affinity and transport protein affinity compare to that of T4 and why does this make sense when considering the role of T4 as a reservior?

T3's receptor affinity is much higher than that of T4, but its transport protein affinity is much lower than T4. T4's higher affinity for transport protein makes it harder to degrade while in circulation which complements its role as a reservoir for conversion to T3.

Why are T3 and T4 so important to CNS development?

T3/T4 play a critical role in the growth and myelination of neurons. Lack of these hormones will permenantly retard the development of the nervous system.

What would the results of a hormone panel look like for a patient with primary hyperthyroidism and how can you explain this finding?

T3/T4 will be high which will provide strong negative feed back to the pars distalis and hypothalamus resulting in low TSH and TRH levels.

If the body primarily uses T3, then why is 75% of secreted thyroid hormone T4?

T4 has a much longer half life and is more readily bound by transport proteins which makes it ideal to serve as a readly reservoir for conversion to T3 when needed.

If only 20% of circulating T3 hormone is directly released from the thyroid gland, where does the remaining 80% come from?

T4 serves as the reservoir for T3 hormone. The majority of T3 hormone used by the body is the result of deiodization of T4 into T3.

What are the formal names of T3 and T4 hormones?

T4: Thyroxine. T3: Triiodothyronine

How will a patient with primary hyperthyroidism respond to a TRH challenge and why?

TRH response will be negative or blunted due to the increased negative feedback from high plasma T3/T4 levels.

How long will it take a patient to present with symptoms if their thyroid suddenly stops releasing T3/T4?

The body has about a 2 week supply of thyroid hormone in circulation. Symptoms will present around this timeframe.

In primary hypo or hyperthyroidism the root of the pathology is with what anatomical structure?

Thyroid Gland.

What hormone controls the release of Thyroid Stimulating Hormone, what type of signaling cascade does it activate, and what type of cells does it target?

Thyroid Releasing Hormone from the hypothalamus ligates with Gq coupled receptors on Thyrotropes of the anterior pituitary to release TSH

What enzyme is responsible for the conversion of T4 into T4?

Deiodinase enzyme converts T4 into T3 and comes in three different isoforms. Type 1: Low affinity for T4. Type 2: High affinity for T4. Type 3: Deactivates both T3 and T4.

True or False. The thyroid horone feed back system is unique in that the hypothalamus and pars distalis are sensitive to both free and protein bound thyroid hormones.

False. Hypothalamus and pars distalis only respond to free thyroid hormone levels in the blood. Protein bound thyroid hormones are effectively masked and do not provide any feed back stimulus.

What transport proteins are employed by the follicular cell to move iodide from the blood and into the colloid follicle where it can combine with thyroglobulin?

Follicular cells use Na/I symporters on their basolateral membrane to move iodide into the cell via secondary active transport. Pendrin channels allow the pasage of iodide ions into the colloid follicle where they are quickley converted into iodine by Thyroid Peroxidase.

What type of transport process is utlized by follicular cells to absorb iodide and what transport proteins are involved?

Follicular cells use secondary active transport to absorb iodide. Sodium/Iodide symporter uses the chemical potential generated by basolateral Na/K ATPase to drive iodide against its concentration gradient.

A patient with defects in the NaI symporter or Pendrin channels is likely to have what type of presentation?

Goiter. Goiters form when iodine is deficient or is unable to be utilized to make thyroid hormones. Low levels of T3 and T4 stimulate TSH release which upregulates follicular cell activity resulting in an increase in size of the colloid follicle leading to the formation of a Goiter.

What are the two outcomes of auto antibodies that react to the thyroid gland?

Hyperthyroidism will result if the antibodies are directed against the TSH receptor. Hypothyroidism will result if the antibodies are directed against the follicular cells or stroma of the thyroid gland itself.

In teritary hypo or hyperthyroidism the root of the pathology is with what anatomical structure?

Hypothalamus

A TRH challenge in determining the type of hyperthyroidism that a patient has is testing what part of the HPA?

Hypothalamus.

What happens to thyroid hormone binding protein levels in plasma during pregnancy and why is this important?

In pregnancy, binding protien levels increase which results in a corresponding decrease in free thyroid hormone levels. A patient that is dependent on exogenous thyroid hormone must be monitored since they are unable to compensate on their own.

Why would hyperthyroidism increase respiratory rate and tidal volume?

Increased metabolic activity means the cells are producing more CO2. Central chemoreceptors will respond by increasing the respiratory drive.

How does low T3/T4 levels in the blood effect dopamine and prolactin levels and what impact does this have on the menstrual cycle of women?

Low T3 and T4 levels will result in low dopamine levels. Since dopamine inhibits prolactin, low levels ot T3 and T4 will cause high levels of prolactin. High prolactin levels will inhibit ovulation, although menstration will still occur.

Justify why low levels of T3/T4 will decrease protein synthesis and proteolysis.

Low T3/T4 will lead to a lower metabolic rate. A lower metabolic rate means that enzymes and receptors are not used as much and therefore last longer which means that their rate of catabolism and synthesis is decreased. Amino acids used as a fuel source for TCA cylce is also decreased due to lower metabolic demand and decreased gluconeogenesis.

Why would a patient with Phenylketouria be at risk of hypothyroidism?

PKU results from the body's inability to metabolize phenylalanine from which tyrosine is synthesized. Tyrosine is the starting material for several neurotransmitters and hormones.

A patient with hyperthyroidism and low levels of TSH shows no response to a TRH challange. Which type of hypothyroidism do they have what structure is dysfunctional and how do you know?

Patient has secondary hypothyroidism. TRH challenge is designed to provide TRH to the pars distalis and increase their low TSH levels. If no response is observed after TRH administration, then the issue is with the anterior pituitary.

From what amino acids does the body synthesize tyrosine?

Phenylalanine and Tryptophan

A patient with low levels of T3/T4 and high levels of TSH has what type of hypothyroidism?

Primary. Low T3/T4 but high TSH indicates that the thyroid gland is unable to respond appropriately.

Given that Thyroid Hormone Receptors and Retinoid X Receptors are bound to the same Thyroid Response Element, what cofactor would you expect to be required by Thyroid hormones to initiate a genomic response from a cell?

RXR's are sensitive to Vitamin A, so therefore, it would not be surprising to find that

What would the results of a hormone panel look like for a patient with secondary hyperthyroidism and how can you explain this finding?

Secondary hyperthyroidism results from an over production of TSH from pars distalis which causes elevated T3/T4 in the blood. TRH levels will be low due to negative feedback regulation.

How would a patient with secondary hyperthyroidism respond to a TRH challenge and why?

Secondary hyperthyroidism results from an over production of TSH from pars distalis which indicates an issue with negative feedback control. TRH challange will illicit a proportional increase in TSH levels. In a normally functioning anterior pituitary, negative feedback from T3/T4 would inhibit or blunt TRH challenge response.

What are the two isoforms of T3 and which one is physiologically active and which one is used to measure T4 to T3 conversion rates?

T3 and Reverse T3 are the two isoforms. T3 is physiologically active, but is tough to measure given that it is consumed by tissues. RT3 is not physiologically active as so can be used as a marker to measure T4 to T3 conversion rate.

How do T3 and T4 effect the number of mitchondria in a cell and why does this make sense physiologically?

T3 and T4 increase the number of mitochondria. Thyroid hormones increase the activity of their target tissues which will in turn require more ATP as energy.

How will low levels of T3/T4 effect gluconeogenesis and glycogenolysis and why does this make sense physiologically?

Both gluconeogenesis and glycogenolysis will decrease because low T3/T4 will lower the basal metabolic rate leading to a decreased demand for glucose. Lower glucose needs means the processes to produce glucose in the fasting state will be decreased.

How will low levels of T3/T4 impact lipogenesis and lipolysis and why does this make physiological sense?

Both lipogenesis and lipolysis rates will decrease. T3/T4 regulates nearly all cells to include adipocytes. Lower adipocyte activity will lead to lower rates of lipolysis and lipogenesis.

If low T3/T4 decreases the rates of lipogenesis and lipolysis, then why does serum cholesterol levels increase?

Cholesterol is absorbed by hepatocytes and coverted into bile acids. Low T3/T4 levels will suppress hepatocyte activity leading to less cholesterol being eliminated from plasma, thus leading to higher observed serum cholestrol levels.

Where are thyroid hormone receptors located within the cell?

Thyroid hormone receptors are located within the nucleus?

How would you expect Thyroid Hormones to influence the activity of Na/K ATPase and why?

Thyroid hormones increases Na/K ATPase activity due to the increased activity of the cell. This makes sense because many cellular processes are dependent on the electrogenic activity of Na/K ATPase.

Are thyroid receptors Type 1 or Type 2 steroid receptors and what is the difference between the two in terms of location?

Thyroid receptors are type 2 receptors and are found inside the nucleus bound to DNA, specifically the Thyroid Response Element. Type 1 steroid receptors are found in the cytoplasm and move to the nucleus after ligation.

What hormone stimulates the release of thyroid hormone, what type of signaling cascade does it initiate, and what type of cell does it target?

Thyroid stimulating hormone, from the anterior pituitary, targets follicular cells of the thyroid gland where it initiates a Gs signaling pathway which results in T3 and T4 release.

In descending order, list the thyroid hormone binding proteins according to their affinity.

Thyroxine Binding Globulin. Albumin. Transthyretin.

What type of deiodinase enzyme is responsible for deactivation of T3 and T4 hormones?

Type 3 Deiodinase.

T3 and T4 are hormones derrived from what amino acid residue?

Tyrosine

Why would a person with hyperthyroidism be at risk for vitamin deficiency?

Vitamins serve as cofactors or coenzymes for many metabolic processes. Hyperthyroidism increases metabolic activity and therefore increases the demand for vitamins which can be consumed in the process.

Will patients with primary hypothyroidism respond to a TRH challange, why or why not?

Yes, patients with primary hypothyroidism will respond to TRH challange as the problem is not in the hypothalamus, but in the thyroid gland itself.

Relative to normal, what TRH and TSH levels would you expect to see in a blood panel? Justify your answer interms of feedback mechanisms.

Both TRH and TSH will be higher than normal. Low T3/T4 levels means that there is less feedback inhibition to the hypothalamus and pars distalis which causes increased secretion of TRH and TSH.

How can you distinguish between secondary and tertiary hypothyroidism using a TRH challange?

Administration of TRH to a patient with secondary hypothyroidism will have no effect on TSH levels because the thyrotropes are incapable of producing TSH or responding to TRH. In tertiary hypothyroidism, the hypothalamus is not producing TRH and so the administration of exogenous TRH will see TSH levels increase to normal or above normal levels.

In secondary hypo or hyperthyroidism the root of the pathology is with what anatomical structure?

Anterior Pituitary, also called the adenohypophisis or pars distalis.