Trait: Thyroid Function
Dr Haran Sivapalan
August 3, 2020
The thyroid gland is a key organ that regulates your body’s metabolism. Hormones produced by the thyroid gland influence how many calories you burn at rest (your basal metabolic rate), how you break down and store fat, and how you build and remodel bone tissue.
Your latest Thyroid Function trait analyses gene variants that are known to affect the production and conversion of the thyroid hormones T3 and T4. Changes in these processes can affect your risk of weight gain, fatigue and high blood cholesterol levels.
What is the thyroid gland?
The thyroid gland is a small organ in the neck (located just in front of the windpipe or ‘trachea’) that controls the body’s metabolism.
Metabolism refers to all the chemical reactions that keep us alive, and broadly involves those reactions that help us get energy from food and then use that energy for various cell processes.
- The thyroid is a gland in the neck that regulates your metabolism.
How does the thyroid control metabolism?
Your thyroid gland produces two main hormones (chemical messengers that are secreted into the bloodstream) that control metabolism and act on virtually every cell in the body.
These two hormones*, collectively called thyroid hormones, are:
- T3 (triiodothyronine)
- T4 (thyroxine)
Once secreted into the bloodstream, T3 and T4 enter cells in different types of tissue and bind to specialised thyroid hormone receptors. This then causes cells to switch different genes ‘on’ or ‘off’, leading to various metabolic changes in the body.
Some of the effects of thyroid hormones on metabolism include:
- Increased basal metabolic rate – resulting in you burning more calories at rest.
- Increased thermogenesis - meaning your body generates more heat energy.
- Increased breakdown of fat stores to release fatty acids
- Removal of ‘bad’ LDL cholesterol from the bloodstream – thyroid hormones enhance the clearance of LDL particles by the liver.
- Increased breakdown of glycogen stores to release glucose
- Increased production of glucose from the breakdown products of protein and fat – a process called gluconeogenesis.
- Increased heart rate and force of heart muscle contraction (contractility)
- Regulation of bone turnover – thyroid hormones influence the process of breaking down and building new bone tissue.
Of the two thyroid hormones, T3 has stronger effects in the body and is roughly 3-4 times more potent than T4 (thyroxine).
(* Note that your thyroid gland also produces another hormone, calcitonin, which helps to regulate levels of calcium and phosphate in the blood. Your Thyroid function trait will focus on the function of thyroid hormones (T3 and T4) only).
- Your thyroid gland produces two thyroid hormones: T3 and T4 (thyroxine)
- T3 and T4 increase your basal metabolic rate, speed up your heart rate, enhance the breakdown of fat, and other cause other metabolic changes in the body.
- T3 is much more potent than T4.
How are thyroid hormones produced?
Your thyroid gland makes thyroid hormones (T3 and T4) using two key molecules:
- Tyrosine – an amino acid produced by the body and also found in meat, dairy products, soybeans, and other protein-rich foods.
- Iodine – a mineral found in fish, seafood, seaweed, dairy products, iodized salt and cereals.
The production of thyroid hormones (and therefore the levels of thyroid hormones in the bloodstream) is tightly controlled by a system of organs and hormones called the hypothalamic-pituitary-thyroid axis.
Located in the base of your brain is small structure called the hypothalamus. This produces a hormone called thyrotropin-releasing hormone (TRH) that acts on one of our body’s major glands – the pituitary gland.
In response to TRH, the pituitary gland secretes another hormone called thyroid-stimulating hormone (TSH). TSH then travels in the bloodstream and acts on your thyroid gland to stimulate the production of the thyroid hormones, T3 and T4.
More specifically, TSH binds to specialized receptors in the thyroid gland called TSH receptors. When this occurs, the thyroid gland takes in more iodine, produces more T3 and T4, and releases them into the bloodstream.
How is thyroid hormone production regulated?
Our hypothalamic-pituitary-thyroid axis aims to maintain constant levels of T3 and T4 in the bloodstream. If levels of T3 and T4 in the blood become too high, the system reacts by reducing T3 and T4 production in the thyroid gland.
Conversely, if blood levels of T3 and T4 are too low, the system compensates by increasing thyroid hormone production.
This system is therefore a classic example of what is known in biology as a negative feedback loop.
As we’ll find out later, gene variants can affect this negative feedback loop, causing small changes in the production and blood levels of T3 and T4.
What happens when T3 and T4 levels are high?
The thyroid hormones T3 and T4 feedback on the hypothalamus to inhibit the production of TRH (thyrotropin-releasing hormone). As a result, the pituitary gland receives a weaker TRH signal and, in response, produces less TSH (thyroid-stimulating hormone). Furthermore, T3 and T4 also directly inhibit the pituitary gland, again reducing its production of TSH.
Therefore, due to this feedback mechanism, when blood levels of T3 and T4 are high, levels of TSH are typically low.
As a result of low TSH levels (under normal conditions), the thyroid gland is less stimulated and therefore produces less T3 and T4, thereby helping to normalise levels of T3 and T4 in the bloodstream.
What happens when T3 and T4 levels are low?
Low levels of T3 and T4 in the bloodstream lead to lesser inhibition of the hypothalamus and pituitary gland. Consequently, production of TRH (by the hypothalamus) and TSH (by the pituitary gland) increases.
Accordingly, when levels of T3 and T4 are low, levels of TSH are typically elevated.
Under normal conditions, higher levels of TSH (thyroid stimulating hormone) trigger the increased production of T3 and T4 by the thyroid gland, helping to restore levels of T3 and T4 in the bloodstream.
- Iodine from the diet is needed to make thyroid hormones (T3 and T4).
- Production of T3 and T4 by the thyroid gland is regulated by two other structures in the brain: the hypothalamus and pituitary gland.
- The thyroid produces T3 and T4 in response to TSH (Thyroid-stimulating hormone) secreted by the pituitary gland.
- Levels of T3 and T4 in the bloodstream are maintained within a narrow range through a process of negative feedback.
- When blood levels of T3 and T4 fall, TSH levels rise in an effort to increase thyroid hormone production.
- When blood levels of T3 and T4 are high, TSH levels fall in order to reduce thyroid hormone production.
How is T4 converted into T3?
Of the two thyroid hormones, the thyroid gland produces four times as much T4 compared to T3 (i.e. 80% of thyroid hormone production is T4, only 20% is T3).
Nevertheless, as mentioned earlier, T3 is more biologically active than T4. Therefore, in order to effect major metabolic changes in the body, T4 must first be converted into the more active T3.
This conversion process, called activation, is carried out by peripheral tissues, such as the liver, kidneys, brain, and skeletal muscle. These tissues produce a class of enzymes called deiodinases.
There are two main types of deiodinase enzyme that convert T4 into T3:
- D1 – Type I iodothyronine deiodinase
- D2 – Type II iodothyronine deiodinase
The activity of these enzymes can influence blood levels of both T3 and T4 and thereby impact upon your thyroid function.
- The thyroid gland produces more T4 than T3.
- T3 is much more active in the body compared to T4.
- Tissues in the body (e.g. liver, kidneys) convert T4 into the more active T3.
- Tissues produce deiodinase enzymes, including D1, which convert T4 into T3.
How do gene variants affect production of thyroid hormones?
One of the genes analysed in your Thyroid Function trait is the PDE8 gene. This gene encodes an enzyme, called phosphodiesterase 8 (PDE8), which is involved in the thyroid gland’s response to TSH.
Studies suggest that variants of your PDE8 gene can alter the production of T3 and T4 by your thyroid gland.
What does the PDE8 enzyme do?
As explained earlier, your pituitary gland releases a hormone called TSH (thyroid stimulating hormone) that, as its name suggests, stimulates your thyroid gland to produce the thyroid hormones T3 and T4.
TSH exerts its effects by binding to specialized TSH receptors in the thyroid gland. When TSH binds to the TSH receptor, it triggers a complex signalling cascade that results in the production of T3 and T4.
The PDE8 enzyme helps to terminate this signalling cascade, thereby halting the production of T3 and T4 in response to TSH.
How do changes in PDE8 activity affect thyroid function?
Changes in the activity of the PDE8 enzyme can slightly alter the response of the thyroid gland to TSH.
If the activity of the PDE8 enzyme is higher, it terminates the TSH receptor signalling cascade more quickly. As a result, the thyroid gland may become less responsive to TSH and it becomes harder to stimulate the production of T3 and T4. Consequently, levels of T3 and T4 in the bloodstream may fall. Furthermore, through a process of negative feedback, your pituitary gland may compensate for lower T3 and T4 levels by increasing its production of TSH.
Conversely, if the activity of your PDE8 enzyme is lower, it becomes harder to terminate the TSH response and switch off the thyroid gland’s production of T3 and T4. Consequently, your T3 and T4 levels may be slightly higher. Furthermore, due to the negative feedback mechanism, your pituitary gland may respond by reducing its production of TSH.
How do PDE8 gene variants affect thyroid hormone production?
Variants of your PDE8 gene can alter the activity of the PDE8 enzyme, and thereby affect the production of T3 and T4 by the thyroid gland.
In this respect, a SNP (Single Nucleotide Polymorphism) of the PDE8 gene (designated rs4704397) creates two different gene variants or ‘alleles’: the ‘G’ allele and the ‘A’ allele.
Studies show that the ‘A’ allele is associated with increased activity of the PDE8 enzyme, which makes the thyroid gland less responsive to TSH.
People who inherit two copies of the ‘A’ allele (i.e. the AA genotype) are shown to have lower levels of T3, due to reduced thyroid hormone production, and higher levels of TSH, as the pituitary gland compensates.
Other SNPs of the PDE gene can also affect the production of thyroid hormones.
Depending on which PDE8 gene variants you have, your Thyroid Function trait will classify your production of thyroid hormones as:
- Mildly increased
- Mildly decreased
- Variants of your PDE8 gene affect the production of thyroid hormones.
- The PDE8 gene encodes an enzyme that helps terminate the production of T3 and T4 in response to TSH.
- PDE variants alter the activity of this enzyme, which can enhance or blunt the production of T3 and T4 in response to TSH.
- Depending on which PDE8 gene variants you inherit, you may have mildly increased, average, or mildly decreased thyroid hormone production.
How do gene variants affect conversion of thyroid hormones?
Your peripheral tissues (e.g. liver, kidney, skeletal muscle) produce enzymes that convert T4 into the more active T3. One of these enzymes is D1 (Type I iodothyronine deiodinase), which is coded for by your DIO1 gene.
Studies suggest that variants of your DIO1 gene can alter the activity of the D1 enzyme and thereby affect the rate at which your peripheral tissues convert T4 into T3.
How do changes in DI activity affect thyroid hormone levels?
If the activity of the D1 enzyme is higher, you will more readily convert T4 into T3. As a result of this, the ratio of T3 to T4 in your bloodstream will be higher.
As T3 is much more biologically active than T4, a higher T3:T4 ratio is associated with more pronounced metabolic effects of thyroid hormones.
How do DIO1 gene variants affect thyroid hormone levels?
Variants of the DIO1 gene have been shown to change the activity of the D1 enzyme and thereby alter levels of T3 and T4.
In this respect, a Single Nucleotide Polymorphism (SNP) of the DIO1 gene (designated rs2235544) creates two gene variants or “alleles”: the ‘C’ allele and the ‘A’ allele.
The ‘C’ allele is associated with relatively higher D1 enzyme activity, and therefore increased conversion of T4 into T3. Studies suggest that inheriting two copies of the ‘C’ allele (i.e. CC genotype) results in a relatively higher T3:T4 ratio.
Depending on which DIO1 gene variants you inherit, your Thyroid Function trait will classify your conversion of thyroid hormones as:
- Your DIO1 gene encodes the D1 enzyme that converts T4 into T3.
- Variants of the DIO1 gene are associated with greater conversion of T4 into T3.
- As T3 is more active, increased conversion of T4 into T3 is linked to more pronounced effects of thyroid hormones in the body.
Your Thyroid Function trait
Your Thyroid function trait looks at both the production of T3 and T4 by the thyroid gland as well as the conversion of T4 into T3 by peripheral tissues.
Given that thyroid hormones have a variety of effects on your metabolism, your gene variants and overall Thyroid Function trait result will influence multiple aspects of your metabolism, including your risk of weight gain, energy levels, and blood cholesterol levels.
To view your trait results, please login to Truefeed.