Confirming the Diagnosis of Hyperthyroidism in Cats: Serum Free T3 Concentrations

As I discussed in my recent posts on diagnostic testing for hyperthyroidism, the feline thyroid gland makes two active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). T4 makes up 90% of the circulating thyroid hormones, while T3 makes up less than 10%. In cats, all circulating T4 originates from thyroid secretion but almost all T3 in the cat is produced extrathyroidally from T4 deiodination (1).

Although only 10% of the circulating thyroid hormone is T3, this thyroid hormone is 3-10 times more active than T4; T4 can be considered a prohormone whose main function is only to be converted into active T3. In order for the body’s cells and tissues to use more of this active form of thyroid hormone, T4 (which contains 4 iodine molecules) is converted to T3 (which contains 3 iodine molecules) by losing an iodine molecule. This function is performed in peripheral tissues (such as the liver and kidney) by deiodinases (enzymes that act to remove an iodine group from the thyroid hormone molecule). See my previous blog post on total T3 for more information.

Despite the fact that T3 is more potent than T4, use of total T3 concentrations are not a good diagnostic test for hyperthyroidism in cats. Over 30% of hyperthyroid cats have a normal serum T3 concentration even when they have clearly high total and free T4 values (2-4).

But what about free T3 concentrations? Would measuring free T3 be a better indicator of what's happening at this tissue level?

Physiology of T3, Total T3, and Free T3 in the Body

What's the difference between total and free T3? It's the same situation as with total T4 and free T4, which I discussed in a recent post.

When we measure a serum T3 level, we are checking the total amount of T3 hormone circulating in the blood—both the bound and unbound T3 molecules (5). More than 99% of T3 hormone in the circulation is “bound,” meaning that it is attached to thyroid-binding proteins in the bloodstream. When bound, this T3-thyroid binding protein complex is too large to enter the body's tissues (see Figure).

For circulating T3 to do its functions and regulate metabolism, the hormone must first break loose from its binding proteins (i.e., become “free” T3) in order to leave the bloodstream and enter the body’s tissues and cells. Only then can intracellular free T3 have its effect on the body’s metabolism (see Figure).

Total T3 circulates mostly bound to thyroid binding protein, with a small proportion  being unbound or "free." It is only the free T3 that can pass into the tissues and cells to complete its functions to regulate metabolism.

Serum free T3 represents the tiny fraction (less than 1%) of T3 hormone that is unbound and therefore is biologically active. It is important to realize that a dynamic equilibrium exists between free and protein-bound T3 that depends on the amount of thyroid-binding proteins in the blood stream, as well as the affinity of the thyroid binding proteins for T3. In other words, a T3 molecule circulating in the bloodstream may be free (unbound) one minute, protein-bound the next, and free again shortly thereafter.

Again, it is only the free T3 portion of the total T3 measured in the blood that can pass into the cells and act on the body’s tissues to influence metabolism (see Figure).

Serum Free T3 Concentration as a Diagnostic Test in Hyperthyroidism

The use of total T3, as noted above, is not a very useful diagnostic test for hyperthyroidism in cats (2-4). Similarly, total T3 are rarely useful in the routine diagnosis of human patients with hyperthyroidism either (6-8). Rarely, an occasional human patient with hyperthyroidism will develop a syndrome called "T3 toxicosis" in which circulating total and free T4 concentrations remain normal but serum concentrations of total and free T3 are very high (6-8). Such a syndrome of T3 hyperthyroidism has never been reported and does not appear to develop in cats (2-4).

In hyperthyroidism, the increases in free T4 and free T3 concentrations are usually more marked than the increases in total hormone concentrations. In human patients, progressive increases in serum total T4 can eventually exceed the limited binding capacity of thyroid binding globulin, the major serum binding protein for T4 and T3 in people (5), This leads to disproportionate increases in the free serum concentrations of T4 (9) and T3 (10). Although similar studies have not been reported in cats, similar findings could be expected.

The questions remains — would determination of free T3 be of any added benefit over the use of T4 and free T4 concentrations for diagnosis of hyperthyroidism in cats? No one knows the answer for sure, primarily due to the fact that most diagnostic laboratories do not offer free T4 measurements. However, one large diagnostic laboratory, the Michigan State University's Diagnostic Center for Population and Animal Health (DCPAH) does offer complete feline thyroid profiles that include T4, T3, free T4, and free T3). Click this link to see their lab submission form.

Recently, I called Dr, Kent Refsal, an endocrinologist who has worked at the DCPAH for many years and a leading expert in this field of diagnostic endocrinology. I asked Dr. Refsal if he had any evidence that adding free T3 test as part of the "Feline Thyroid Profile" increased the diagnostic accuracy of their thyroid panel for cats with hyperthyroidism. The short answer is no — adding free T3 might help in other situations, such as monitoring thyroid hormone replacement, but it does NOT appear to add any diagnostic advantage of the use of total and free T4 concentrations in cats.

Bottom Line: Free T3 determinations, at least by themselves, do not appear to be a useful test for hyperthyroidism in cats.

References: 

1. Foster DJ, Thoday KL, Beckett GJ. Thyroid hormone deiodination in the domestic cat. Journal of Molecular Endocrinology 2000;24:119-126.
2. Peterson ME, Melian C, Nichols R. Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease. Journal of the American Veterinary Medical Association 2001;218:529-536.
3. Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:2-9.
4. Peterson ME: Diagnostic testing for feline hyper- and hypothyroidism. Proceedings of the 2011 American College of Veterinary Internal Medicine (ACVIM) Forum. pp. 95-97, 2011
5. Stockigt JR. Free thyroid hormone measurement. A critical appraisal. Endocrinology and metabolism clinics of North America 2001;30:265-289.
6. Dunlap DB. Thyroid Function Tests. In: Walker HK, Hall WD, Hurst JW (eds). Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, 1990.
7. Klee GG. Clinical usage recommendations and analytic performance goals for total and free triiodothyronine measurements. Clinical Chemistry 1996;42:155-159.
8. Sapin R, Schlienger JL. Thyroxine (T4) and tri-iodothyronine (T3) determinations: techniques and value in the assessment of thyroid function. Annales de Biologie Clinique 2003;61:411-420.
9. Inada M, Sterling K. Thyroxine transport in thyrotoxicosis and hypothyroidism. The Journal of Clinical Investigation 1967;46:1442-1450.
10. Nauman JA, Nauman A, Werner SC. Total and free triiodothyronine in human serum. The Journal of Clinical Investigation 1967;46:1346-1355.