Thyroid Hormone (T3 AND T4) Mechanism of Action & Metabolism
Upon entering the bloodstream, >99% of the T4 and T3 are bound (Figure 3) to Serum proteins (primarily Thyroid Binding Globulin) as follows:
- Thyroid Binding Globulin (TBG)-75%
- Thyroid Binding Pre-Albumin(TBPA)-15%
The Bound hormone is Inactive (Biologically NOT active)
Only 0.04% of T4 and 0.4% of T3 is FREE (Unbound, biologically active) and is available for the body to use (Figure 1).
More than 80% of the Serum FT3 comes through conversion of T4 to T3 in the Liver and Kidney. There are several factors that regulate the conversion of T4 to T3 as listed in Table 1 below.
T3 binds to receptors located in the nucleus of every cell in the body producing a hormone-receptor complex. This complex binds to the DNA to change (modulate) the expression of specific genes, either by stimulating or inhibiting them. These genes produce proteins that bring about the various effects of T3.
It is very important to note that ONLY the Free T3 binds to the receptors in the Nucleus of EVERY cell of the body.
Most of the T3 in the peripheral tissues (Cells) is obtained by peripheral conversion of T4 to T3 by the enzyme 5’ Deiodinase. (Figure 1)
This complex Deiodinase enzyme system is critical in controlling the Tissue (Cellular) levels of T3.
There are 3 types of Deiodinases (D1, D2 & D3).
D1 and D2 increase Thyroid activity at the Cellular level by converting T4 to T3.
D3 decreases Thyroid activity at the Cellular level by converting T4 to rT3 (Figure 2).
D1 activity is lower in Females, making them more prone to Tissue.
Hypothyroidism. This explains the increased percentage (Incidence) of Depression, Fatigue,
Fibromyalgia, Chronic fatigue syndrome and Obesity despite having normal TSH levels.
A good understanding of the Deiodinase system helps understand the critical importance of Tissue (cellular) levels of T3, explaining why patients experience symptoms of Hypothyroidism (Low Thyroid) despite normal Serum/Blood levels of TSH, T4 and T3.
T4 and T3 are metabolized mainly by Peripheral DE iodination (80%), Glucoronidation (20%) and sulfation (20%) in the Liver and Kidney.
About Sixty (60) percent of the T4 is converted to T3 in the Liver by D1. Twenty (20) percent of the T4 is converted to rT3 (Reverse T3) which is an Inactive form & is excreted from the body.
Twenty (20) percent is converted to T3S and T3AC (Inactive forms) by the Liver and Kidney. T3S and T3AC are converted into T3 by the Bacteria in the Gut (Gastrointestinal Tract).
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