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6 Factors Which Can Affect The Conversion of T4 to T3

For those people who have normal T4 levels, but low or depressed T3 levels, a thyroid hormone conversion problem needs to be suspected.  The thyroid gland mostly produces thyroxine, which is also known as T4.  The thyroid gland also produces a small amount of triiodothyronine, which is T3.  Most of the T3 is produced by the conversion of T4 to T3.  But there are numerous factors which can affect the conversion of T4 to T3, which I’ll be discussing in this post.

Before I discuss some of the factors which can affect the conversion of T4 to T3, I’d like to briefly talk about this process.  The enzyme 5′ -deiodinase is responsible for this conversion process.  There are three forms of this enzyme, which include deodinase type I, deodinase type II, and deodinase type III.  The type 1 and type II deiodinases are primarily responsible for the conversion of T4 to T3, whereas the type III deiodinase is mainly involved in the inactivation of T4 and T3 (1) [1] (2) [2].  Most of this conversion takes place in the liver, although some of the conversion also takes place in the gastrointestinal tract.  As a result, if someone has liver problems and/or gut dysbiosis then this can potentially affect the conversion of T4 to T3.  A certain percentage of T4 is also converted into reverse T3, which I have spoken about in a different post entitled “Reverse T3: What You Need To Know About It [3]“.

So why is it a concern if someone has problems converting T4 into T3?  Well, T3 is the active form of thyroid hormone.  Unfortunately not all endocrinologists test for T3, but when they do they will either test for total T3, where most of T3 is bound to a protein, or free T3, which isn’t bound to a protein.  Free T3 is what actually binds to the thyroid receptor.  If someone has normal T4 levels but low T3 levels then this is considered to be a hypothyroid condition.  Many medical doctors will only test the TSH and T4 levels, and the reason for this is because if the T3 is low then the TSH will typically be elevated, although this isn’t always the case.  I always recommend testing both the free T3 and free T4, along with the TSH.  If doing an initial thyroid panel it’s also a good idea to test the reverse T3, along with the thyroid antibodies.

Why Do Most Medical Doctors Give Synthetic T4?

When someone presents with hypothyroidism, most medical doctors will recommend a form of levothyroxine, which is synthetic T4.  A common brand is Synthroid, although there are other forms as well.  But if T3 is what actually binds to the receptor, wouldn’t it make sense to give the person T3 instead?  Well, some medical doctors will recommend synthetic T3 in the form of Cytomel.  However, many doctors are understandably cautious about doing this, as too high of a dosage can put the person into a hyperthyroid state.  Synthetic T4 will convert into T3, but of course if someone has a conversion problem then this won’t be the case.  Plus, even if someone doesn’t have a conversion problem they might do better taking a natural form of thyroid hormone such as Armour or Nature-Throid, which consists of both T4 and T3, along with T1, T2, and calcitonin.

Now that you have a better understanding of the importance of T3, I’d like to discuss the five factors which can have a negative effect on the conversion of T4 to T3.

Factor #1: Problems with the liver.  Since most of the conversion of T4 to T3 takes place in the liver, it would make sense that some health conditions affecting the liver can decrease the conversion of T4 to T3.  However, this isn’t always the case, as one study which investigated the relationships between thyroid function in obese adolescents with non-alcoholic fatty liver showed that they had a  higher conversion of T4 to T3 due to increased deiodinase activity as a compensatory mechanism for fat accumulation (3) [4].  With that being said, if someone has problems converting T4 to T3 it usually is a good idea to give some liver support, such as milk thistle and N-acetylcysteine.

Factor # 2: Gut dysbiosis. As I mentioned earlier, the good bacteria in the gut helps to convert T4 into T3 through the help of an enzyme called intestinal sulfatase.  There isn’t much evidence in the literature showing that gut dysbiosis negatively affects the conversion of T4 to T3, but obviously if someone has dysbiosis then this should be addressed even if they aren’t having a conversion issue.  I did come across one study which showed that Crohn’s disease can affect the conversion of T4 to T3 (4) [5].

Factor # 3: Selenium deficiency.  The iodothyronine deiodinases all contain selenium in the form of selenocysteine, and they play crucial roles in determining the circulating and intracellular levels of T3 (5) [6].  Numerous studies show that a selenium deficiency can affect the conversion of T4 to T3 (6) [7] (7) [8] (8) [9].  However, this might only be the case with a severe selenium deficiency, as one study showed that only when selenium levels were decreased by more than 80% was deiodinase activity markedly decreased (5) [6].

Factor # 4: Stress.  Elevated cortisol levels can affect the conversion of T4 to T3.  Studies show that stress can inhibit both type I iodothyronine 5′-deiodinase activity (9) [10], as well as type II 5′-deiodinase activity (10) [11] (11) [12].  This is yet another reason why it’s important to improve your stress handling skills.

Factor # 5: Certain medications.  Amiodarone is an anti-arrhythmic compound, and due to the structural similarity between this and thyroid hormone it apparently inhibits the activity of 5′-deiodinase (12) [13].  Beta blockers are commonly taken in hyperthyroid conditions, and certain ones such as propranolol, alprenolol, atenolol, and metroprolol can affect the conversion of T4 to T3 (13) [14].

Factor # 6: Pro-inflammatory cytokines.  There is also evidence that certain pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) can inhibit type 2 5′-deiodinase (5’D-I) enzyme activity (14) [15] (15) [16] (16) [17].  These cytokines are commonly present in autoimmune conditions, including Hashimoto’s Thyroiditis and Graves’ Disease.

In summary, normal T4 levels along with low T3 levels frequently indicate a conversion problem.  This involves the enzyme 5′-deiodinase, and is one reason why when obtaining a thyroid panel you want to not only look at the TSH and free T4 levels, but also the free T3.  And it usually is a good idea to look at the reverse T3 as well.  Six common factors which affect the conversion of T4 to T3 include problems with the liver, gut dysbiosis, a selenium deficiency, high cortisol levels, certain medications, and pro-inflammatory cytokines.