An understanding of Low T3 syndrome, and the gene that is responsible for it, DIO3, is essential to understanding effective monitoring and treatment for hypothyroidism.
We all have the DIO3 gene. It normally functions quite well.
However, the DIO3 gene can be overexpressed by illness and by excess thyroid hormones.
Therefore, it is possible, and more common than believed, for patients on thyroid hormone therapy to suffer symptoms from chronically low T3, especially within L-T4 monotherapy.
In healthy hormone metabolism, the DIO3 gene and its product, Deiodinase Type 3 (D3), play a crucial role in maintaining thyroid homeostasis by moderating fluctuations in T4 blood levels in order to maintain serum T3 within a narrow healthy range.
In particular, the function of DIO3 expression is “critical to protect many tissues and cell types from excessive thyroid hormone action.” [102 (p4)]
When the organism senses T4 or T3 levels above its set point (which could be anywhere within or beyond the “normal” laboratory reference range that represents 95% of the population), D3 is upregulated in order to protect the organism from thyrotoxicosis, which would occur if the excess T4 were converted to excess T3 hormone.
In good health, the three deiodinases, D1, D2 and D3, work together in active, healthy balance, adjusting to each other as the body requires more or less hormone within blood and/or bodily tissues and cells.
Unlike the DIO2 and DIO2 variants that handicap the D1 and D2 enzymes and can hinder hormone conversion, DIO3 polymorphisms do not have any known functional effects. That means we haven’t found any genetic variants that cause D3 dysfunction.
However, DIO3 is extremely sensitive to epigenetic influence. It is oversensitive to its environment, vigilant, ready to become more active. As researchers explained in 2013:
“a puzzling observation about the D3 gene (Dio3) is that it is subject to genomic imprinting, an epigenetic phenomenon affecting a small number of genes […]. This characteristic sets the D3 apart from other determinants of thyroid hormone action, and raises the possibility that the epigenetic mechanisms governing the allelic expression of Dio3 are an important determinant of thyroid hormone levels in tissues, and are critical to ensure normal development and physiology.” [102 (p2)]
Because DIO3 is part of a healthy regulation of thyroid hormones, many doctors are given the impression that it is benign as long as a patient is not critically ill. Indeed, for decades, researchers of non-thyroidal illness also thought it was benign.
However, as of 2014, leading researchers in the field have started to change their mind about Low T3 syndrome to consider both its process and consequences “pathological,” especially in its harm to the heart [142, 82]
Research has conclusively proven that Low T3 is dangerous—any level below the normal reference range is associated with high risk. As we mention in other sections, the normal T3 range is quite narrow in the upper middle portion of the statistical range. In any human being, the lower the T3 falls, the higher the rate of mortality is, and morbidity rises as well. The studies of Low T3 syndrome / non-thyroidal illness show such a strong association that it often shows a predictive effect independent of all other risk factors the researchers consider for cardiac and kidney diseases. [143, 142]
If low T3 below the reference range is dangerous and deadly for these patients, it is more dangerous to some thyroid patients on therapy. Thyroid patients are more likely to have a very low T3 even before becoming critically ill, undetectable under a normal TSH (see our discussion of the Free T3 test and the T3:T4 ratio).
Because a functional thyroid gland plays a key role in normal patients’ recovery from this syndrome, a hypothyroid patient whose gland has been destroyed by autoimmunity or removed by thyroidectomy, will be more vulnerable to Low T3. A healthy thyroid gland’s direct secretion of T3 into the bloodstream, in response to a recovered TSH, is an essential early phase of recovery from “low T3 syndrome” in critical illness. The addition of endogenous T3 begins to correct the T3 deficiency before recovery from reverse thyroid metabolism begins.  Therefore, the best experts in this field doubt that athyreotic patients can recover as easily from low T3.
Some doctors seem to have picked up the strange theory that “non-thyroidal illness,” (low T3 syndrome), does not occur in patients with primary thyroid dysfunction, because of the term, “nonthyroidal illness.” Research on this condition has usually excluded anyone diagnosed with a diagnosis of hypothyroidism. It is also called “euthyroid sick syndrome,” but researchers exclude “euthyroid” thyroid patients.
A related misconception is that thyroid patients cannot experience hormone depletion because they always have an incoming supply through their medication. But even with continually maintained doses of L-T4, thyroid patients can experience hormone depletion as well. In one rare study, researchers examined this syndrome in a few hypothyroid men on L-T4 therapy. Within 3 days, this syndrome depleted both T4 and T3, much as it does in normal people.  But apparently these patients had sufficient residual thyroid tissue, since their TSH increased by day 7, and without any change in their dose, the TSH alone stimulated secretion of sufficient T3 for recovery. 
There is also a mistaken belief that this this syndrome is always an acute condition seen in intensive care units, and that it is always temporary (that is, if patients don’t die from the low T3).
However, chronic low T3 and high Reverse T3 has been reported in long-term conditions such as chronic fatigue syndrome, exposure to toxic environments, and sleep apnea. [145, 146, 147]
Next page: Rationale: Deiodinase Type 3, part 2
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