- 3,5,3',5'-tetraiodothyronine (thyroxine, T4)
- 3,5,3'-triiodothyronine (T3)
- 3,3',5'-triiodothyronine (rT3, inactive, storage form, plenty)
Steady-state level of iodine in the body is _____. _______ proportion (~__%) is ____.
- A large
- in the thyroid
Most of the unincorporated iodine is in the form of _______.
Daily need is about __. Typical US diet contains ~____/day.
Normal thyroid uses ~____/day, most of which is used to _________.
Unused iodine and iodine released as a result of thyroid hormone degradation appears predominantly in the _____.
Iodine insufficiency can cause ______.
- iodide (I−), not iodine (I2)
- synthesize T3 and T4
Steps in the synthesis and release of thyroid hormones:
- 1. Active transport of iodine by thyroid follicular cell.
- 2. Synthesis and internal secretion of the tyrosine-containing precursor protein (thyroglobulin) into the colloid.
- 3. Iodination of thyroglobulin tyrosine residues within the colloid.
- 4. Coupling of two iodotyrosine residues of thyroglobulin.
- 5. Cellular uptake of iodinated thyroglobulin by reabsorption from the colloid.
- 6. Proteolytic release of iodinated thyronines in the lysozomes.
- 7. Release of T4 and T3 to the blood.
Iodine accumulation into thyroid _____ cells occurs through ______ via ______, which results in a 20-40 fold higher level of iodide in the cell compared to the serum concentration. Iodide then moves to the colloid by _____.
- secondary active transport
- I/Na symporter
- facilitated diffusion
Thyroglobulin synthesis and secretion
- ______ that contains ______ used to synthesize thyroid hormones (T3 and T4).
- large _____ (660 kDa) synthesized in the ER of the _____ cells.
- secreted into the ____ enclosed within the acinus created by these cells.
- contains 123 ______; not all are _____ to make the final T3 and T4.
- secreted with the enzyme that catalyzes ______, _______.
- protein precursor / the tyrosine residues
- glycoprotein / follicular
- tyrosine residues / iodinated
- iodination / thyroid peroxidase (TPO)
Iodination and coupling of thyroglobulin tyrosine residues
- 1. Thyroid peroxidase (TPO) catalyzes the oxidation of iodide (I−) to iodine, and its binding to tyrosine residues of thyroglobulin.
- 2. first iodination on the 3-position, yielding 3-monoiodotyrosine (MIT), then on the 5-position to yield 3,5-diiodotyrosine (DIT).
- 3. intra- or inter-molecular coupling, which may also be catalyzed by TPO. DIT+DIT gives T4. MIT+DIT gives T3 (or inactive reverse T3, rT3; minor). The products remain part of the thyroglobulin protein precursor.
Cellular reuptake of iodinated thyroglobulin and release of T3 and T4.
- active reuptake of iodinated thyroglobulin by endocytosis at the apical (colloid-facing) membrane of the follicular cells
- The colloid vacuoles fuse with lysozomes -> proteolytic degradation of the thyroglobulin -> release free T4 and T3.
- Residual iodinated tyrosines in the form of MIT and DIT are degraded by iodotyrosine deiodinase, and the iodine is recycled for new synthesis.
- Most of the thyroid hormone released is T4, but a significant proportion of this is converted to T3 and rT3 in other tissues of the body.
Deiodinase enzymes are found in the thyroid and ________ that process _____ or _____. Deiodinases are dependent on _____ for activity.
The _____ of deiodinase enzymes is an important control on thyroid hormone activity, and can differ between tissues and organs.
- in peripheral tissues
- T4 to T3
- degrade these thyroid hormones
- relative activity
A ______ converts T4 to T3, which is an _____ step because _______.
A ______ converts T4 to rT3, which is an _______ step because ______.
T3 is further inactivated by further deiodinated and can also conjugated to form sulfates and glucuronides in the liver.
- T3 is 4-fold more potent than T4
- rT3 has no activity
T3 and rT3 from T4 deiodination >> T3 and rT3 secreted from thyroid.
T3 is the predominant active form because:
- T3 is 4-fold more active than T4
- T3 is bound somewhat more weakly to plasma biding proteins than T4
vast majority of thyroid hormones are bound to plasma proteins; the free concentration is very much lower than the total and is the only biologically active form.
For __, ~0.02% is free
For __, ~0.2% is free
Thyroid hormones binding plasma proteins include
- Thyroxine Binding Globulin (TBG): most important; very high affinity for T4 (most) and a slightly lower affinity for T3.
- Albumin: much lower affinity but much greater amounts; least for T4, most for T3
- Transthyretin: thyroxine-binding prealbumin, TBPA; least for T3
Regulation of homeostasis of thyroid hormone:
- Thyrotropin-Releasing Hormone (TRH) [hypothalamus] -> receptor on thyrotroph cells of the anterior pituitary -> synthesis and secretion of Thyroid-Stimulating Hormone (TSH) -> thyroid gland synthesis & secretion of T3 & T4
- Free T3 & T4 inhibit the release of TRH and TSH
What is the widely used test of thyroid function?
- measurement of TSH level
- due to the close relationship between T3 & T4 levels and TSH
- Free T3 & T4 too little
Regulation of thyroid activity:
TSH, temperature, iodide
TSH affects the thyroid by increasing:
- Release of preformed T3 & T4.
- Rate of iodide uptake.
- Rate of tyrosine iodination and coupling.
- Endocytosis of colloid.
- Thyroglobulin proteolysis.
- Follicular cell height.
Temperature affects thyroid hormone secretion. Decreased temperature acts via the _____ to _______, which ________.
- hypothalamic thermoregulator center
- stimulate TRH release
- elevates TSH, and hence T3 & T4
Thyroid function is regulated by iodide. Iodine deficiency can limit thyroid hormone synthesis.
The physiological effects of T3 and T4 are _______, except that ______ (higher affinity for target cell receptors) and acts more rapidly (________)
- essentially the same
- T3 is more potent
- less binding to plasma proteins
Thyroid hormones act by binding to intracellular receptors, with the principal target being _______. Thus, most effects of thyroid hormones are mediated by ______.
There are also believed to be _____ receptors that mediate _________.
- activation of gene transcription at the DNA level
- increases in the synthesis of specific proteins (eg. enzymes involved in carbohydrate metabolism)
- direct actions of thyroid hormones on mitochondrial oxidative capacity
Thyroid hormones are essential for growth and development in childhood. Some examples are:
- • Enhance bone growth and epiphyseal closure.
- • Stimulate Growth Hormone secretion & potentiate its tissue effects.
- • Necessary for brain development, especially cerebral cortex.
- • Required for proper formation of cochlea.
The primary effects in adults are _____, including:
- metabolic, catabolic
- • Elevate Basal Metabolic Rate (BMR).
- • Increase heat production -> temperature
- • Activate mitochondrial metabolism.
- • Enhance absorption of carbohydrates from intestine.
- • Increase breakdown of carbohydrates and lipids.
- • Enhance sensitivity to catecholamines via increasing number and affinity of β-adrenergic receptors and Enhance responses to circulating catecholamines.
- Calorigenic: Stimulate oxygen consumption by metabolically active tissues (exceptions: testes, uterus, lymph nodes, spleen,anterior pituitary). Increase metabolic rate.
Hypothyroidism during pre- and postnatal development of children can have ______, known as ________, characterized by ________ and other physical abnormalities.
- severe physical and mental effects
- mental retardation, dwarfism, deaf-mutism
Causes of cretinism include:
- maternal iodine deficiency
- fetal congenital abnormalities of the thyroid or pituitary/hypothalamus
- maternal antithyroid antibodies that cross the placenta and damage the fetal thyroid gland
When the thyroid deficiency is fetal in origin, _________ can compensate prior to birth, and subsequent treatment can allow _______.
- maternal T3 and T4
- normal postnatal development
diagnosed by (differentiate)
- low metabolic rate, poor cold tolerance, drying and yellowing of the skin, thinning hair and sometimes mental symptoms.
- direct disease of the thyroid gland, or be secondary to failure at the level of the hypothalamus or pituitary.
- Hypothalamic or pituitary hypothyroidism can be identified by a normal response of T3 and T4 to injected TSH.
In cases of iodine deficiency, there can be ___________, which can be also seen in _____, because low thyroid output leads to _______, which _______. This is known as _________.
- enlargement of the thyroid
- elevated TSH
- stimulates hypertrophy of the thyroid gland
- iodine deficiency goiter
Most common form
Another cause of hyperthyroidism
- increased BMR, increased food intake, weight loss,heat-intolerance, sweating, nervousness.
- Grave's Disease, caused by autoimmune antibodies that stimulate the TSH receptor. Stimulated thyroid leads to goiter in these patients. Also, protrusion of eyeballs due to TSH receptors in cells of the orbits that elicit inflammation and edema.
- TSH-secreting pituitary tumor
Since a large proportion of ingested iodine is normally sequestered in the thyroid gland, radioactive iodine can be used to _______.
monitor thyroid function
High levels of radioactive iodine are used to ______.
destroy the thyroid in cases of thyroid cancer and Grave's disease
Use of radioactive iodine w/ low iodine diet
hyperthyroidism vs hypothyroidism
- In hyperthyroidism, plasma radioactivity falls rapidly and then rises again as a result of release of labeled T4 and T3 from the thyroid.
- In hypothyroidism, the uptake of radioactive iodine from blood is low, and most ends up being excreted in urine.