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Episode 19: Thyroid physiology and Deiodinase enzymes
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Endocrine Review Course Learning Objectives:
- Discuss thyroid hormone axis
- Discuss how thyroid hormone is produced
- Discuss the differences between T4 and T3
- Discuss the types of diodinase enzyme
- Discuss how thyroid hormone enters the cell
- List actions of thyroid hormone (on a molecular level)
TRANSCRIPT
Hello, my name is Kristen Lee and I am an Endocrinology fellow at Northwestern University in Chicago, Illinois. I am joining the Endocrine Review team and hope to help my colleagues pass the endocrine boards!
Todays question is: which of the diodinase enzymes is most active in illness?
Diodinase 1, 2 , 3 or 4.
And the Answer is Diodinase THREE
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The learning objectives today:
In order to better understand and interpret thyroid laboratory findings we first need to take a step back and discuss the thyroid hormone regulatory pathway.
In particular the thyroid hormone axis
Starting at the hypothalamus, thyrotropin-releasing hormone (TRH) induces the pituitary to secrete thyroid stimulating hormone (TSH). TRH interacts with the thyrotrophic cell receptor to influence TSH glycoclysation which informs TSH bioactivity.
TSH production is made in a pulsatile circadian fashion with its peak between 2am-4am (referred to as the nocturnal TSH surge) and its trough between 4p and 8p. In a euthyroid human, TSH is produced at between 50-200 milliunits/day and can increase to up to > 4000 mU/day in primary hypothyroidism. The half-life of TSH is betwee n 50 and 80 minutes. TSH bioactivity changes based on TSH glycosylation variability; due to different glycosylation nocturnal TSH is less bioactive which is why TSH does not lead to increased thyroid hormone production at night.
After TSH production, T SH binds to thyroid releasing hormone receptors on the thyroid follicular cells activating the thyroid synthesis cascade.
The Thyroid Synthesis Cascade
There are five steps in the thyroid synthesis process. First the precursor protein thyroglobulin (TG) is made from thyrocytes in the thyroid follicular cells; this precursor protein does not yet contain iodine. Step #2 iodide is brought from the circulation to the thyrocytes and into the follicular cells. Step 3: the enzyme thyroid peroxidase (TPO) is activated and exacts three roles: oxidation, organification, and coupling reaction to ultimately form the four-iodine atom containing Thyroxine (T4). T4 is the major thyroid hormone product of the thyroid synthesis circulating in the bloodstream. T4 the inactive form of thyroid hormone is converted to the active form of thyroid hormone triiodothyronine (T3), comprised of 3 iodine atoms.
The thyroid produces 90% inactive T4 thyroid hormone and 10% active thyroid hormone T3. Thyroid hormone is stored bound to thyroglobulin in the follicular stores. Upon TSH stimulation proteolytic enzymes cleave thyroglobulin and T4 and T3 are released into the bloodstream. Thyroid hormones are lipophilic and are transported in the blood via transport proteins. Both circulating thyroid hormones (T4 and T3) exert direct negative feedback on TRH synthesis in the hypothalamus. Peripheral deiodination of T4 to T3 in the liver and kidney accounts for approximately the other 80-90% of circulating T3.
There are three types of deiodinase enzymes, type I (DIO1), II (DIO2), and III(DIO3).
DIO1 primarily functions in the liver, kidney, and thyroid. DIO2 predominates in the brown adipose tissue, skeletal muscle, heart, and CNS. DIO3 is primarily located in the CNS, skin, and placenta. The majority of T4 to T3 conversion is through catalyzation by deiodinase ty
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