Low T3 within L-T4 therapy
The most surprising factor, rarely mentioned, is that Low-T3 hypothyroidism, induced by DIO3 epigenetic overexpression, can be maintained or deepened by L-T4 therapy.
As deiodinase researcher and endocrinologist Dr. Antonio Bianco explains, increased levels of the hormone T4 reduce D2 expression and enhance D3 expression.
An extreme illustration of L-T4 as trigger of DIO3 expression happens in extreme overdose. A 2018 case study featured a mentally ill, hospitalized patient who overdosed herself on 120 tablets of L-T4 equivalent to 6 mg (6000 mcg).  The huge among of L-T4 stimulated a strong response in Deiodinase Type 3 activity that her body was capable of handling over 302 nmol/L of total T4 (and >100 pmol/L of Free T4) without her Total T3 rising above reference at all on Day 1. Her TSH stayed normal until it was finally slightly depressed by day 3. Starting day 1, the doctors administered propranolol. They put her on hemodialysis, but it did not remove the excess T4 from her serum. Meanwhile, the patient had no metabolic signs of T3 overdose until day 6. On day 6, her Free T3 reached 16.14 pmol/L (more than twice the upper limit of the reference range 3.1-6.8), and she suffered an epileptic seizure. After that, she recovered and was normal by 4 weeks. The authors discussed similar cases reported in the past that illustrated the body’s response to levothyroxine excess through hormone inactivation. 
Three other physiological mechanisms also play a role in the body’s effort to protect from T4 and T3 overdose. First, the body increases thyroid binding globulin and other binding protein concentrations, which limits the portion of thyroid hormones that are free and able to be transported into cells. 
Second, it is hypothesized that an increased RT3/T3 ratio causes the inactive metabolite, RT3, to compete with the active metabolite T3 at thyroid hormone receptor sites, having an effect of competitively “blocking” Free T3 in serum from entering the receptor. [149, 112]
Thirdly, and most harmfully, the breakdown of T3 into T2 occurs simultaneously with the catabolism of T4 into RT3. These catabolic processes occur not only within serum, but within cells where blood tests cannot measure. 
When a symptomatic patient’s T3:T4 ratio is very low, even if both are still within reference range, Reverse T3 tests are a confirmation of excess hormone catabolism as the cause. Reverse conversion occurs continually at a normal rate in every healthy person, and thus there is a normal reference range for this metabolite. However, the most damaging result of this process is not the excess Reverse T3 hormone in circulation, but the net loss of the active hormone, T3.
Our understanding of DIO3’s effects helps us interpret blood tests. Wthe serum Free T3/Free T4 ratio is low, and Reverse T3 is high, it is likely that Free T3 in blood, although very low, is an overestimate of the amount of Free T3 that is able to enter receptors.
The upregulation of D3 also triggers the downregulation of D1 activity, which is the enzyme found in liver, thyroid, and kidneys that is responsible for the majority of T4-T3 conversion that occurs within the bloodstream. This is why the cardiovascular system, which depends on sensitive regulation of T3 serum levels, will be the first system affected by Low T3 hypothyroidism.
The D3-triggered downregulation of D1 also reduces the rate at which RT3 molecules are cleared from the bloodstream, since a secondary function of D1 is to catabolize RT3 into D2. This causes a rise in RT3 levels in serum.
If excess exogenous T4 is the main trigger of reverse conversion, rather than hypoxia or inflammatory cytokines, removal or reduction of the T4 stimulus can resolve the problem by resetting the deiodinase balance. To remove the T4 stimulus without causing hypothyroidism, one would need to increase T3 to the system while decreasing T4.
Excess hormone catabolism is known to occur even on desiccated thyroid extract therapy, which is one type of combination T4/T3 therapy. In the well established community of patients taking desiccated thyroid hormone, a course of T3-dominant therapy is recommended to “clear out” very high levels of reverse T3 for up to 12 weeks before the regular medication is reintroduced. 
These are the main reasons why treatment with thyroxine alone, L-T4, is usually incapable of resolving non-thyroidal illness and often makes no difference to the phases of illness and recovery. DIO3 not only responds very swiftly, but it also seems to be rather impervious to T4 in hormone treatment once it takes hold.
In contrast, treatment with short courses of L-T3 that are sufficient to overcome breakdown of T3 into T2 are effective in raising T3 from dangerously low levels. To the degree that this syndrome is initiated or maintained by L-T4, the correction of this syndrome can be difficult within L-T4 monotherapy.
In past research on critically ill patients, it was found that giving low-T3 patients combination L-T4-T3 therapy resulted in increasing their T3 levels in serum, liver, and skeletal muscle.  Recent clinical trials have shown that L-T3 aids in the recovery of heart failure patients, even if serum FT3 is maintained below normal range due to its continual reverse conversion into T2. [152, 153]
In contrast, other studies found that L-T4 monotherapy delayed the rise of T3 in serum by three days and made no difference to serum levels of T3 because the altered deiodinase activity converted the T4 into Reverse T3 (RT3); and to cause further harm, the treatment with T4 decreased TSH, the mechanism that would have aided recovery in a patient with a healthy thyroid gland. 
Therefore, a review of research in 2007 concluded that “T3 administration is preferred over T4 due to reduced 5’-deiodinase activity and hence decreased conversion of T4 to metabolically active T3 in the sick patient.”
Under the conditions of T4-monotherapy, the daily addition to the T4 supply artificially creates a slight peak in T4 levels shortly after ingestion, regardless of dose size.  Therefore, if the DIO3 becomes overexpressed by means of T4 stimulation, even in the absence of chronic or critical illness, DIO3 may remain chronically overstimulated by the daily pulses of T4.
Further, it may be unwise to vary T4 doses from one day to the next, especially if a patient is experiencing any of the additional health challenges, such as inflammation, that can stimulate DIO3 overexpression. Because DIO3’s main function is to be vigilant in monitoring T4 levels in order to carefully defend T3 levels in serum, a higher peak T4 every other day may stimulate the DIO3 gene on alternate days if the peak is higher than the patient’s T4 set point.
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