Did you know that T4 to T3 conversion happens inside the body? Let’s say you are fatigued and running low on thyroid hormone, your brain through your pituitary gland sends out a message to your thyroid gland to produce thyroid hormones. The thyroid gland begins to produce a lot of inactive thyroxine (T4) then sends it out to the liver where the deiodinase converts it to active triiodothyronine (T3). Now let us delve into why these deiodinase enzymes are essential to control points of cellular thyroid activity.
T4 to T3 Conversion | Deiodinases Essential Functions
1. Deiodinase Type I (D1)
D1 converts inactive T4 to active T3 throughout the body, but D1 is not a significant determinant of pituitary T4 to T3 conversion, which is controlled by Deiodinase type II (D2). D1 but not D2 is suppressed and down-regulated (decreasing T4 to T3 conversion) in response to physiologic and emotional stress like depression, weight gain and leptin resistance, insulin resistance, obesity, and diabetes.
2. Deiodinase Type II (D2)
Thyroid stimulating hormone (TSH) is produced by the pituitary and is regulated by intra-pituitary T3 levels, which often does not correlate or provide an accurate indicator of T3 levels in the rest of the body. Using the TSH as an indicator for the body’s overall thyroid status is not supposed to be the case since the pituitary is different than every other tissue in the body.
3. Deiodinase Type III (D3)
— Johannes W. Dietrich (@drjwdietrich) June 18, 2016
The pituitary is the only tissue that does not contain Deiodinase type III (D3), which converts T4 to reverse T3 and competes with D1 that converts T4 to T3. Reverse T3 is a competitive inhibitor of T3; blocking T3 from binding to its receptor and blocking T3 effect, reduces metabolism, suppresses T4 to T3 conversion, all reducing intracellular T3 levels and thyroid activity.
The reduced immunity from chronic stress has been thought to be due to excess cortisol production, but the associated reduction in tissue thyroid levels are shown to play a larger role in the decreased immunity seen with stress, and thyroid supplementation is shown to reverse the stress-induced reduction in immunity.
Many depressed and bipolar patients have undiagnosed thyroid dysfunction as the underlying cause or major contributor to their depression that is not detected by standard thyroid tests. The dysfunction present with these conditions includes downregulation of D1 (reduced T4 to T3 conversion) and reduced uptake of T4 into the cell. Studies show that depressed patients have reduced T4 transport across the blood brain barrier due to a defective transport protein, transthyretin, resulting in significantly reduced thyroid levels in the brains of depressed patients.
Chronic pain will significantly suppress D1 and increase D2, resulting in a reduction in tissue T3 without a change in TSH. Thus, the significant cellular hypothyroidism is not detected by serum TSH and T4 testing. This cellular hypothyroidism, which again is undiagnosed by standard blood tests, increases the risk of the associated fatigue and depression seen with chronic pain.
Acute or chronic dieting can result in a significant decrease in intracellular and circulating T3 levels by up to 50%, which significantly reduces the basal metabolic rate (number of calories burned per day) by 15-40%. With chronic dieting, the thyroid levels and metabolism often do not return to normal levels; the body stays in starvation mode for years with significantly reduced metabolism despite the resumption of normal food intake, making it very difficult to lose or maintain lost weight.
8. Insulin Resistance/Diabetes/Metabolic Syndrome/Obesity
As with leptin resistance, it has been shown in numerous studies that insulin resistance, diabetes, or metabolic syndrome have associated significant reduction in T4 to T3 conversion. Additionally, the elevated insulin will increase D2 activity and suppress TSH levels, further decreasing thyroid levels and making it inappropriate to use the TSH as a reliable marker for tissue thyroid levels.
The hormone leptin has been found to be a major regulator of body weight and metabolism. The body secretes leptin as weight is gained to signal the brain (specifically the hypothalamus) that there are adequate energy (fat) stores.
The hypothalamus should then stimulate metabolic processes that result:
- In weight loss
- Including a reduction in hunger
- Increased satiety with eating
- An increase in resting metabolism
- An increase in lipolysis (fat breakdown)
New research has found that this leptin signaling is dysfunctional in the majority of people who have difficulty losing weight or are unable to lose weight.
It has been shown that women or men who perform more than moderate exercise, especially when associated with dieting, have reduced T4 to T3 conversion and increase reverse T3, counteracting many of the positive effects of exercise in women including weight loss. Consequently, T3 and reverse T3 levels should be evaluated in individuals who exercise and/or diet to better determine cellular thyroid levels, as TSH and T4 would not necessarily reflect tissue levels in such patients.
11. Iron Deficiency
Iron deficiency is shown to significantly reduce T4 to T3 conversion, increase reverse T3 levels, and block the thermogenic (metabolism boosting) properties of thyroid hormone. Thus, iron deficiency, as indicated by an iron saturation below 25 or a ferritin below 70, will result in diminished intracellular T3 levels. Additionally, T4 should not be considered adequate thyroid replacement if iron deficiency is present.
12. Inflammation Associated with Common Conditions
Any person with an inflammatory condition — including:
- Physical or emotional stress
- Menopause (surgical or natural)
- Heart disease
- Autoimmune disease (lupus, Hashimoto’s, multiple sclerosis, arthritis, etc)
- Chronic infection
— will have a decreased T4 to T3 conversion in the body and a relative tissue hypothyroidism.
13. Environmental Toxins
Numerous toxins, including plastics such as bisphenol-A, pesticides, mercury, and flame retardants such as PBDE, are shown to block tissue thyroid receptors and reduce T4 to T3 conversion with resultant low tissue levels of the thyroid not detected by standard blood tests.
In addition to being 1000 times more efficient at converting T4 to T3, D2 is 100 to 1000-fold less sensitive to suppression by toxins or by mineral or hormonal.
14. Growth Hormone
Growth hormone deficiency reduces T4 to T3 conversion and increases reverse T3 while supplementation with growth hormone improves T4 to T3 conversion and reduces reverse T3. The age-associated decline in growth hormone certainly contributes to the reduced T3 levels with age not detected by TSH and T4 testing.
15. Individual Variations in Deiodinase
The relative amounts of D1, D2, and D3 vary in different tissues among different individuals and under varying conditions, resulting in hundreds of possible symptoms with hypothyroidism; some people have one symptom, some have a few, and some people have many, depending on the relative level of T3 in each tissue.
Learn more about T4 to T3 conversion with this video from Dr. Don Davis:
With an improved understanding of thyroid physiology including the local control of intracellular activation and deactivation of thyroid hormones by deiodinases, it becomes clear that standard thyroid tests often do not reflect the thyroid status in the tissues of the body, other than the pituitary. This is especially true with:
- Physiologic and emotional stress
- Leptin insulin resistance
- Chronic fatigue syndrome
- Autoimmune disease
- Systemic illness
In order to be appropriately and thoroughly evaluated for thyroid dysfunction and obtain optimal treatment, it is important that patients find a thyroid oligist who understands the limitations of standard thyroid testing.
Do you think you are correctly diagnosed by your physician with your thyroid dysfunction? Please let us know your thoughts by leaving us your comments below.
Share on Pinterest!