This article is part of a special report on Thyroid Disorders. To see the other articles in this series, click here.
In the last article in this series we discussed some common myths and misconceptions about Low T3 Syndrome. In this article, we’re going to look at causes and mechanisms.
As I mentioned briefly before, researchers now believe that the fall in T3 seen in acute and chronic illness is most likely due to either impaired production of T3 in the thyroid (due to a change in the hypothalamic-pituitary-thyroid axis) or to a decrease in thyroid binding proteins. Both of these changes are caused by inflammation.
The thyroid set point
There’s been a lot of discussion recently in the blogosphere about the body fat set point, which is the complex neurobiological system that regulates weight. However, there is also a set point of the hypothalamic-pituitary-thyroid (HPT) axis that regulates the production of endocrine hormones, including TSH, T4 and T3.
It seems that the low TSH associated with illness, or the failure of TSH to rise in response to low T4 and T3, is caused by alterations in the set point of the HPT axis. There’s a set of neurons in the paraventricular nucleus (PVN) of the hypothalamus that is responsible for promoting TSH synthesis in the pituitary and regulating thyroid hormone synthesis.(1)
Post-mortem samples from patients who died after prolonged illness show a decrease of thyrotropin-releasing hormone (TRH) gene expression in the PVN.(2) Moreover, administering TRH and growth-hormone (GH) secretogogues to patients with prolonged illness at least partially restores TSH, T4 and T3 levels.(3) Both of these lines of evidence suggest that a change in the HPT axis is involved in the Low T3 Syndrome.
While there are multiple causes of such changes in the HPT axis, two of the more clinically relevant ones are inflammation and either a decline in serum leptin levels or leptin resistance.
Inflammatory cytokines released in the acute phase response (the inflammatory process) suppress the production of TRH in the PVN.(4) I’ll discuss the role of inflammation in more detail below.
Fasting or diminished calorie intake due to prolonged illness leads to decreased T3 levels, and this is thought to be mediated by a decrease in circulating leptin. Leptin prevents certain neurons (NPY/AgRP) from inhibiting TRH gene expression.(5)
Although I haven’t seen any studies on this specifically, it’s entirely conceivable that leptin resistance (which characterizes obesity) could have the same T3 decreasing effect. Most people are aware that poor thyroid function contributes to weight gain, but this mechanism suggests that it may also work in reverse: leptin resistance associated with overweight and obesity may contribute to poor thyroid function.
Thyroid binding proteins
When thyroid hormone is produced and released into the circulation by the thyroid gland, it’s bound (reversibly) to thyroxine-binding globulin (TBG), transthyretin and albumin. TBG is the major binding protein in humans, and under normal circumstances, less than 0.05% of thyroid hormone is unbound (“free”) in the blood.
It’s thought that only this tiny fraction of “free” thyroid hormone is able to enter the cell and perform the biological actions of thyroid hormone. This means that the concentration of total T4 and T3 (produced by the thyroid gland) is heavily dependent on the concentration of these binding proteins, while the free hormone concentrations are largely independent of them.
In Low T3 Syndrome, the concentration of thyroid binding proteins decreases as a consequence of the “acute phase response” (a.k.a. inflammation). For example, TBG levels decrease by as much as 60 percent in the 12 hours following bypass surgery.(6) In rodents, inflammation leads to a significant decrease in transthyretin, which is the major plasma thyroid hormone binding-protein in that species.(7) The fall in these binding proteins is probably what accounts for the decrease in total (protein-bound) T4 and T3 levels in acute and chronic illness.
Inflammation strikes again
Pro-inflammatory cytokines, which are chemical messengers involved in the inflammatory response, have been shown to contribute to Low T3 Syndrome in multiple ways.
Interleukin-6 (IL-6) is positively correlated with reverse T3 (an inactive form of T3) and negatively correlated with free T3.(8) In other words, the more IL-6 that is circulating in your blood, the less active thyroid hormone you’ll have available to your cells and tissues.
Administration of tumor necrosis factor alpha (TNF-alpha) to healthy individuals produces changes in thyroid hormones characteristic of Low T3 Syndrome.(9)
Administration of interferon alfa (IFN) to normal volunteers results in a decrease in T3 and TSH and a rise in reverse T3.(10)
Other studies have shown that lipopolysaccharide (LPS), a bacterial endotoxin, can downregulate TSH, T4 and T3 levels.(11) This explains the link between chronic bacterial infections and the Low T3 Syndrome, and it’s yet another connection between gut health and the thyroid (since many people with poor gut health have gut infections).
The takeaway of this article is that the primary mechanisms of Low T3 Syndrome are mediated by inflammation. That inflammation could be caused by an infection, autoimmune disease, obesity, diabetes or other chronic illness. Just about any disease you can think of is characterized by inflammation, so the list here is quite long.
In the next article I’ll discuss how – and if – Low T3 Syndrome should be treated.
Articles in this series: