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Basic thyroid physiology

In order to understand Low T3 Syndrome, you’ll need a basic understanding of thyroid physiology. Regulation of thyroid metabolism can be broken down into the following five steps:

The hypothalamus (a pea-sized gland in the brain) monitors the levels of thyroid hormone in the body and produces thyrotropin releasing hormone (TRH).
TRH acts on the anterior pituitary (directly below the hypothalamus, but outside of the blood-brain barrier) to produce thyrotropin, a.k.a. thyroid stimulating hormone (TSH).
TSH acts on the thyroid gland, which produces thyroxine (T4) and triiodothyronine (T3), the primary circulating thyroid hormones. The thyroid produces T4 in significantly greater quantities (in a ratio of 17:1) than T3, which is approximately 5x more biologically active than T4.
T4 is converted into the more active T3 by the deiodinase system (D1, D2, D3) in multiple tissues and organs, but especially in the liver, gut, skeletal muscle, brain and the thyroid gland itself. D3 converts T3 into an inactive form of thyroid hormone in the liver.
Transport proteins produced by the liver – thyroid binding globulin (TBG), transthretin and albumin – carry T4 and T3 to the tissues, where they are cleaved from their protein-carriers to become free T4 and free T3 and bind to thyroid hormone receptors (THRs) and exert their metabolic effect.
Mechanisms of Low T3 Syndrome

As you can see, the production, distribution and activation of thyroid hormone is complex and involves several other organs and tissues other than the thyroid gland itself.

Hypothyroidism is a defect in step #3, because it typically involves a dysfunction of the thyroid gland itself – most often caused by autoimmune disease (Hashimoto’s, Ord’s, Graves’) and/or iodine deficiency.

However, in Low T3 Syndrome, the problem generally occurs in steps #1, #2, #4 and #5. None of those steps are directly related to the function of the thyroid gland itself.

More specifically, Low T3 Syndrome can include the following mechanisms:

Modifications to the hypothalamic-pituitary axis
Altered binding of thyroid hormone to carrier proteins
Modified entry of thyroid hormone into tissue
Changes in thyroid hormone metabolism due to modified expression of the deiodinases
Changes in thyroid hormone receptor (THR) expression or function