Conventional medicine sees the goal of thyroid replacement therapy in bringing your lab test results into the normal reference range and after that the treatment is considered successful. However, many hypothyroidism and Hashimoto’s patients report having hypothyroid symptoms and not feeling well despite their TSH being normal and medication dose optimized.
There are many issues with relying on the TSH test alone in diagnosing and treating hypothyroidism and Hashimoto’s disease and you can read about them here. The truth is that often the problem why some patients continue to have persistent symptoms is an impaired T4 to T3 thyroid hormone conversion.
Thyroid hormone pathway is complex and is not limited only to relationships between TSH and thyroid hormones. It is also important to consider how effectively thyroid hormones reach our cells and perform their metabolic action.
In fact, after thyroid hormones are secreted by the thyroid gland or enter your body with thyroid medication there are many things that can go wrong and conventional medicine not only doesn’t have a solution but also doesn’t even test for it.
Your thyroid produces both T4 and T3 thyroid hormones in a certain proportion of 14:1 and the major part of metabolically inactive T4 has to be converted in your intestines, liver, muscles, kidneys, heart and brain into metabolically active T3 hormone.
This extrathyroidal pathway has been estimated to contribute to over 90% of T3 produced daily in healthy people when under normal circumstances 60% of T4 will convert to T3, 20% to reverse T3, leaving the remaining 20% to be activated in the small intestine.
Any problem in the thyroid hormone conversion can result in persistent hypothyroid symptoms that just don’t go away due to a lack of T3 hormones that your body desperately needs to function properly.
The most common symptoms associated with low T3 are:
- Fatigue
- Muscle pains and aches
- Hair loss
- Depression
- Weight gain
- Brain fog
There is a solid scientific evidence and studies in peer-reviewed medical journals that back up the fact that some people can have normal TSH and T4, however at the same time they have under-conversion of T4 into T3 thyroid hormone and experience hypothyroid symptoms listed above.
Table of Contents
5 Well-Known Major Causes Of T4 To T3 Underconversion
1. Th1 and Th2 types of inflammatory cytokines such as IL-6, TNF-alpha, IFN-gamma and IL-1 beta produced by our immune system are involved in the stress response and have been shown to down-regulate the HPA axis, lower TSH and decrease the conversion of T4 to T3.
2. Most T4 to T3 thyroid hormone conversions take place in your intestines but only in the presence of good bacteria. If the gut flora is disrupted and there is a shift in the good versus bad bacteria in your gastrointestinal tract, it may result in T4 to T3 underconversion. Primary causes of intestinal dysbiosis are use of antibiotics, antacid medications, reduced stomach acid and Standard American Diet (SAD).
3. Another source of thyroid peripheral underconversion is increased gastrointestinal lipopolysaccharides which are endotoxins produced from bacterial overgrowth and when a leaky gut is present. These harmful toxins interfere with the conversion from T4 to active T3 in the liver and may result in too much reverse T3. This is a very common situation in people with autoimmune Hashimoto’s disease because increased intestinal permeability is one of the causes of systemic and thyroid autoimmunity.
4. There is a 5′ deiodinase enzyme that is responsible for the T4 to T3 conversion and can activate or inactivate thyroid hormones. It comes in 3 forms: deiodinas type I (D1), type II (D2) and type III (D3) and they all have different mechanism of action.
In response to any kind of stress D1 becomes suppressed and down-regulated which results in a decreased T4 to T3 conversion and increased reverse T3 levels.
The D2 generates the active form of thyroid hormone T3 via deiodination of T4 in the cells. The D2 thyroid hormone conversion pathway is predominant source of the T3 in the brain, pituitary gland, brown adipose tissue, skeletal and heart muscles in humans.
Abnormal D2 activity happens in people who have critical illness, life-threatening trauma or major surgery sometimes referred to as the low T3 syndrome and those being treated with amiodarone which is an antiarrhythmic drug well known to alter thyroid function via both direct actions on the thyroid gland and by blocking T4 activation.
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5. Some medications can reduce T4 to T3 conversion and include: beta-blockers for high blood pressure, hormone replacement drugs prescribed to alleviate symptoms of menopause, oral contraceptives and corticosteroids.
A New T4 To T3 Conversion Blocker
New research studies show that there is a population with a defective DIO2 gene that blocks T4 to T3 conversion. Among other things this results in reduced T3 levels in the brain which can lead to mood disorders.
One large study used data from a Weston Area T4 T3 Study (WATTS) to analyze common variants in the 3 deiodinase genes and their connection to the well being. The results suggest that the DIO2 genes can explain why about 16% of patients on thyroid medication respond better to a combination therapy: the gene carriers have an impaired D2 function and have a lower circulating T3 toT4 ratio compared to healthy people due to impaired T4 to T3 conversion.
Researches concluded:
Our results require replication but suggest that commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on T4 and enhanced response to combination T4/T3 therapy, but did not affect serum thyroid hormone levels.
J Clin Endocrinol Metab 94: 1623–1629, 2009
What These Research Findings Mean For You?
1.It is possible to be functionally hypothyroid and experience symptoms even when your TSH and T4 are normal but your T3 is low.
2. Among other reasons there is a genetic variation in the DIO2 gene that can be responsible for a T4 to T3 underconversion.
3. According to estimates, between 16% and 20% of hypothyroid patients can be affected and may experience a symptoms relief and overall health improvements on a combination T4 and T3 thyroid therapy when their blood test results were initially “normal”.
4. The T3 thyroid test is seldom used and is NOT the part of a standard thyroid screening panel, so the T4 to T3 underconversion pattern is often missed or worse never discovered.
5. Learn about anti-thyroid side effects of antibiotics and make sure that when you are taking them there is no interference.
6. Consider taking a genetic test that could bring insight and more knowledge into your genetic background.
P.S.Get detailed DNA reports for insights into your health, traits and ancestry. Understand your genetics. Explore your DNA today at 23andMe.com.
References:
1.Common Variation in the DIO2 Gene Predicts Baseline Psychological Well-Being and Response to Combination Thyroxine Plus Triiodothyronine Therapy in Hypothyroid Patient. J Clin Endocrinol Metab 94: 1623–1629, 2009
2. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 2006 Oct 2; 116(10): 2571–2579.
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My name is Marina Gutner, PhD. I am a researcher, medical writer, Author of forthcoming series on thyroid, hypothyroidism and autoimmune disease. I was diagnosed with autoimmune Hashimoto’s disease and hypothyroidism in 2004 and soon got so sick that I was unable to function. It took me years of research to find how to recover from severe adrenal insufficiency, stop Hashimoto’s and reduce my high dose of thyroid medication. On my blog I show you exactly how I did it so you can learn how to get started. Read more in 
