The thyroid is particularly susceptible to changes in physiology. There are numerous things that can alter its normal function. Hashimoto’s Autoimmune Thyroiditis is the most common autoimmune disorder in the USA, with an estimated 6-8% of the population affected. The vast majority are female. Some authorities believe that the incidence of functional hypothyroidism (where the thyroid is not functioning normally) is as high as 40% of the population. (Read: “Overcoming Thyroid Disorders,” by Dr. David Brownstein and “ Hypothyroidism Type 2” by Dr. Mark Starr).
Thyroid hormones have many functions. Every cell in the body has thyroid receptors. Thyroid hormone is critical for proper development and differentiation of every cell. Thyroid hormones increase basal metabolic rate and body temperature. They stimulate protein synthesis and increase sensitivity to catecholamines. Proper development of the brain requires thyroid. Most mental retardation in the world (called cretinism) is due to thyroid deficiency.
Thyroid function is negatively affected by many factors, including: imbalances in other hormones (Cortisol, estrogen, progesterone, pregnenolone, testosterone, insulin and growth hormone); immune over activity (autoimmunity), chronic inflammation (which produces chemicals that affect the hypothalamic-pituitary- thyroid axis); iodine, iron or selenium deficiency; neurotransmitter deficiency, (serotonin and dopamine), failure to convert T4 into T3, excess reverse T3 (rT3), receptor site resistance, decreased receptor site expression, xenotoxins (mercury, lead, fluoride, bromide, xenoestrogens, and thiocyanates); and many different drugs.
You are beyond frustrated. You have many hypothyroid symptoms, have been to your doctor and have been told that there is nothing wrong with your thyroid. You have done enough research to believe otherwise. Today’s standard of care is to simply measure TSH. If it is abnormal, synthetic T4 is prescribed to bring the range into normal. Remaining symptoms are ascribed to other causes, and medications given for each symptom. It is critical to understand thyroid physiology. Once you learn how complex and intricate the thyroid gland is, you will also realize that you were probably right all along- there is something wrong and your doctor doesn’t appreciate the steps needed to properly assess and treat your condition. So, without having to read an entire endocrinology textbook, let’s learn thyroid basics!
Dr. Datis Kharrazian has outlined 10 steps that are required for normal thyroid synthesis, release, deiodinization, receptor binding and activity. In addition to these steps, there are additional nutritional and hormonal requirements for normal function. Various toxins can impair normal function. The 10 steps are:
- Correct release of neurotransmitters in the hypothalamus to release TRH
- Proper response of the pituitary to release TSH
- Normal Thyroid Peroxidase (TPO) activity to create T4 and T3
- Correct Sodium/Iodine Symporter (NIS) function to concentrate iodide
- Adequate levels of the amino acid tyrosine
- Proper levels of thyroid binding globulin
- Normal function of 5’-deiodinase conversion of T4 to T3
- Normal function of intestine acetylase and sulfatase enzymes
- Correct receptor response to stimulus
- Proper thyroid proteomic response
To that list I would also add an 11th step: optimal response of the mitochondria to thyroid hormones.
Let’s go through each of these steps to better understand thyroid physiology and to see where things can go wrong. Your thyroid gland (thyroid for short) is one of the body’s largest endocrine glands. It is found in all vertebrates and is probably the first hormone to have evolved. It is the only hormone that has receptors on every cell of the body. It is located in your neck just below your Adam’s apple.
It produces two primary thyroid hormones: thyroxine (T4) and triiodothironine (T3). About 93% of the hormone produced is T4. The majority of T3 is made from T4 in the peripheral tissues, including kidney, liver and spleen. This is absolutely critical to understand, as T4 is not the major active thyroid hormone. It is actually a prohormone. It is converted into T3 by a selenium-dependent enzyme, 5’- deiodinase. T3 may be 4-10 times more active than T4.
Thyroid hormone is made from the amino acid tyrosine, and iodide (the ionized form of iodine).
Optimal levels of iodine are critical for the formation of thyroid hormone. You will learn that iodine deficiency is common, and is a major reason for functional hypothyroidism. The thyroid is made of follicles that actively absorb iodide via a sodium/iodide symporter (NIS) system. The follicles act as a reservoir for iodide, which is stored in a protein called thyroglobulin, (Not to be confused with thyroid binding globulin), which also contains tyrosine. Obviously an iodide deficiency can reduce the amount of hormone made. Normally iodide is concentrated up to 50 times higher inside the follicles than in plasma (one good reason that measuring plasma concentrations of iodine is not an accurate assessment of whole body stores).
A second thing that can go wrong is that the NIS may not be functioning correctly. Certain chemicals including perchlorate, pertechnetate , and thiocyanate can inhibit the NIS. In environmental illnesses (Lyme Disease, mold and chemical sensitivity) there is a protein called Transforming Growth Factor- beta (TGF-B) that can become highly elevated. TGF-B inhibits the NIS. Certain foods, in excess and when uncooked, may inhibit NIS in individuals who are already hypothyroid. Cruciferous vegetables (including broccoli, cabbage, kale, and cauliflower) should be cooked. Soy contains isoflavones that may inhibit NIS and the enzyme thyroid peroxidase (TPO).
There is a single layer of thyroid epithelial cells surrounding the follicle that produce and release T4 and T3. TPO attaches iodide to tyrosine to create T4 and T3. In the process, hydrogen peroxide is created. This is a highly reactive molecule called a free radical. It has the capability of oxidizing other molecules, thereby causing tissue damage, inflammation and death. This is a two-edged sword; hydrogen peroxide is critical for the formation of thyroid hormone, but left unchecked it can cause cell damage and death. There is another enzyme called glutathione peroxidase that normally converts hydrogen peroxide to water, thereby eliminating this damaging free radical. . This enzyme requires the micronutrient selenium, to do its job. Like iodine, selenium is frequently deficient.
Thyroid hormones are stored in the follicles until they are needed. There is a mechanism called a negative feedback loop that normally maintains thyroid hormones within a physiological range (called homeostasis). This is often where things go awry. Theoretically, Thyroid Stimulating Hormone (TSH) is supposed to regulate the production and release of thyroid hormone. TSH is not a thyroid hormone, rather it is one produced by the anterior pituitary gland in the brain. TSH stimulates the NIS to take up iodide, and TPO to make thyroid hormones. It gets more complicated, because the hypothalamus (which lies above the pituitary in the brain) produces two additional hormones that control production of TSH.
Thyroid Releasing Hormone (TRH) stimulates the release of TSH while Somatostatin (also called Growth Hormone Inhibiting Hormone) inhibits TSH release. So it is actually the brain that controls thyroid function. Correct modulation of TRH release is under the control of a group of cells called the paraventricular nucleus. Dopamine and serotonin are the neurotransmitters involved with control of TRH release, so anything that affects their levels, such as depression, can affect TRH release. Iron is necessary for production of serotonin and dopamine so an iron deficiency at the cellular level can cause a neurotransmitter deficiency.
When the system is operating normally, TSH stimulates the production and release of mainly, T4. Elevated levels of thyroid hormone are supposed to then reduce the production of TSH. There are many reasons why TSH and T4 levels are not in harmony. This will be discussed in detail subsequently. Utilizing TSH only to evaluate the entire system misses many possible problems with thyroid function. Some of the things that abnormally reduce TSH levels include: elevated Somatostatin, glucocorticoids, estrogen, testosterone, and excessively high levels of iodine, neuroinflammation, Dopamine, L-dopa, and lithium therapy, to name a few. Therefore it is critical to fully assess the thyroid.
If your doctor doesn’t perform a complete lab assessment, he/she will miss most of the reasons that your thyroid isn’t functioning properly. A “normal” TSH may not be normal at all. For example, a low-normal TSH together with a low-normal T4 may signal a hypothalamic-pituitary dysfunction and a TRH to TSH problem. Elevated reverse T3 (rT3) together with low or low-normal TSH and low or low-normal T3, T4 values is now actually called euthyroid sick syndrome.
After T4 (and a little T3) is produced and released from the thyroid, it enters the circulatory system. Here is another step where something can go wrong! The vast majority of thyroid hormones are attached or bound to carrier proteins. The major one is thyroid-binding globulin, which binds about 70% of circulating thyroid hormone. Two other proteins, prealbumin and transthyretin bind all but a small fraction. Only about 0.03% of T4 and 0.3% of T3 are unbound or free. Only free hormones are active- bound hormones are essentially in jail.
Anything that increases the level of thyroid binding reduces the free thyroid levels. Elevated testosterone and estrogen increase thyroid-binding globulin and reduce free hormone levels. Normal levels of total T3 and T4 coupled with lower levels of free T3 and T4 indicate a potential problem with excess binding. The T3 Uptake (T3U) test is useful for determining binding protein levels. A low T3U means elevated binding proteins.
For the prohormone T4 to become metabolically active, it must be converted into T3 by a process called deiodination. There is a family of three enzymes, called deiodinases that converts T4 into T3. Two of these enzymes require the micro mineral selenium to function. Outright selenium deficiency is rare, but sub-optimal levels are common, so a normal T4 with reduced T3 should signal a problem with conversion.
Two of the enzymes (deiodinase Type 1 & 3) can convert T4 into reverse T3, which binds to thyroid receptors but does not activate the receptor. It blocks the metabolically active T3 from doing so, thereby having exactly the opposite effect. Instead of acting like a metabolic throttle, it is a metabolic brake. Severe or prolonged stress, inflammation, surgery, and elevated cortisol all stimulate production of rT3. It really doesn’t matter if your free T3 levels are within the normal limits if there is excess rT3 blocking the receptor. Unless an rT3 test is performed you can miss a cause of functional hypothyroidism.
In addition to T4 being converted into T3 and rT3, a significant portion is also converted in the liver to T3 sulfate (T3S) and triiodothyroacetic acid (T3AC). These are inactive forms of thyroid. They may act as a reservoir for thyroid hormone. They may be activated by normal gut flora to FT3. Dysbiosis, Leaky Gut Syndrome or GI inflammation may affect this conversion.
FT3 is considered to be the major bioactive thyroid hormone, whereas T4 is mainly a prohormone that becomes activated upon its conversion to T3. Most thyroid hormone actions are initiated by binding of T3 to its nuclear receptors in target cells. Therefore, the biological activity of thyroid hormone is determined largely by the intracellular FT3 concentration, which depends on: 1) circulating concentrations of T3 and T4; 2) the activities of deiodinase enzymes that catalyze the production or degradation of T3; and c) the activities of transporters, which control the cellular uptake of T3.
Proper binding of FT3 to the cell receptor, and transport into the cell is required for the next step in the process of proper thyroid function. As mentioned above, elevated rT3 is one of the things that prevent this from occurring properly. In addition, other substances can inhibit FT3 transport into the cell, including Amiodarone (the drug used commonly for atrial fibrillation), aromatic amino acids, benzodiazepine (Valium and similar drugs), iodine-containing X-ray contrast agents, certain fatty acids, indoxyl sulfate and bilirubin.
Reduced sensitivity to thyroid hormone means reduced effectiveness at the cellular level. It is critical to understand that the central control mechanism discussed above, involving the hypothalamus, pituitary and thyroid glands, and the hormones TRH, TSH and T4; do not respond to intracellular requirements for thyroid hormone. In other words: the lab tests that we have available do not measure the level of, or the effect of thyroid hormone inside the cell!
None of the lab tests performed have the ability to actually determine how well your thyroid hormones are working at the cellular level. In other words lab test numbers do not directly correspond to function. The step from binding of the hormone to the receptor, thereby activating the receptor is not one that there is a lab test for. There are two functional tests for this, the Basal Metabolic Temperature test (BMT) and the Resting Metabolic Rate (RMR) test.
Since thyroid controls your metabolism and the level of your metabolism determines your body temperature, the BMT test is an indirect measure of overall metabolism. For every degree your temperature is below normal, your metabolism slows down 10-15%.
The RMR test is a direct measure of how many calories you are burning per day at rest. It is a simple, safe, non-invasive test that takes only 10 minutes. You simply relax and breathe into a tube. The RMR test machine measures how much carbon dioxide you exhale, which is a direct measure of how many calories you are burning.
Example: You take your basal temperature for 5 days per instructions. Your average temperature is 96.3 degrees Fahrenheit. The normal is 97.8-98.2. You are at least 1.5 degrees below normal. This translates to a metabolic rate that is 15-22.5% below normal. You do an RMR test that shows your daily caloric expenditure to be 1500 Kcal. The average for your age, height, weight and sex is 1750, so you are 250Kcal/day below average or 86% of average. If you consume the same calories per day as a person with an average metabolism, you will gain 25 pounds per year!
In the final stage, thyroid hormone receptors (THR) are normally bound to DNA in the nucleus of the cell the absence of thyroid hormone. The binding of the receptor to DNA is dependent upon the essential trace element, zinc. When there is no hormone present, the receptor blocks the DNA from activity (inhibits DNA transcription). When a molecule of T3 attaches to the receptor, it is activated, leading to DNA being transcribed into RNA. RNA is then translated into protein. Thyroid stimulates the production of many different proteins that act to increase metabolic rate, increase fat and carbohydrate metabolism, increase oxidative metabolism of fats, increase insulin-dependent entry of glucose into cells, are necessary for normal growth and development, increases heart rate and contraction, causes vasodilation, affects mental state and fertility.
Now you certainly know more than your doctor about thyroid physiology! The next thing you need to know, so you can be better prepared to do battle with him/her is to learn why relying on the TSH test alone to completely assess thyroid function is a very bad idea! Our blog “The Trouble With TSH” explains this.