Confirming the Diagnosis of Hyperthyroidism: Thyrotropin-Releasing Hormone (TRH) Stimulation Test

In my last blog post, I discussed use of dynamic test, the T3 suppression test. Suppression testing can be helpful in confirming the diagnosis when we suspect that a cat has mild hyperthyroidism but serum concentrations of total and free T4 are either normal or borderline.

An alternative dynamic test that can be used to help diagnose cats with mild or occult hyperthyroidism is the thyrotropin-releasing hormone (TRH) stimulation test (1-3). Compared with the T3 suppression test, this test takes the opposite approach — now we are stimulating, rather than suppressing, the secretion of TSH from the pituitary, which in turn, would lead to increased T4 secretion.

Thyrotropin-Releasing Hormone (TSH) Stimulation Test

TRH is the hormone released by the hypothalamus that subsequently stimulates the release of thyrotropin (TSH) from the pituitary gland (4). When administered intravenously to normal cats, TRH causes an prompt increase in TSH secretion and serum T4 concentrations (see Figure 1, left panel).

Figure 1: TRH tests in normal cats (left) & cats with hyperthyroidism (right)

In contrast to the situation in normal cats, administration of large doses of TRH to hyperthyroid cats has little or no effect on TSH or T4 secretion. The reason for this that pituitary TSH secretion has already been completely and chronically suppressed by the higher-than-normal thyroid hormone secretion characteristic of hyperthyroidism (see Figure 1 above, right panel).

Administration of only a single dose of TRH is not enough to stimulate chronically suppressed TSH-secreting cells.

Testing Protocol for the TRH Stimulation Test

To perform the TRH stimulation test in cats, the following protocol is recommended:

1. The veterinarian draws a blood sample for determination of baseline serum concentrations of total T4 (and T3).
2. TRH (Protirelin) is administered to the cat at the dosage of 100 μg/kg, IV.
3. Four hours later, the veterinarian again draws a blood sample for serum T4 (and T3) determinations.

One may ask: but what about measuring TSH? Indeed, that would be a more direct measure and would shorten the testing time from 4 hours to less than an hour (4). However, because use of TSH measurements in cats with thyroid disease have only recently been advocated, studies looking the serum TSH response to TRH have yet to be published in cats.

Interpretation of Results of TRH Stimulation Testing

When the TRH stimulation test is performed in normal cats and sick cats without hyperthyroidism (1), there is a consistent rise in serum T4 concentrations (approximately 2-fold rise). In contrast, when the test is performed in cats with hyperthyroidism, even in cats with only slightly high or high-normal resting serum T4 concentrations, there is little, if any, rise in serum T4 values after the administration of TRH (see Figure 2, below).

Figure 2 — Box plots of the serum T4 concentrations before (A) and after (B) TRH stimulation in 31 clinically normal cats, 35 cats with hyperthyroidism, and 15 cats with nonthyroidal disease. The "box" represents the interquartile range from the 25th to 75th percentile (represents the middle one-half of the data). The horizontal bar through the box is the median. The "whiskers" represent the main body of data, which in most cases is equal to the range. Outlying data points are represented by open circles. To convert serum T4 concentrations from nmol/L to µg/dl, divide the given values by 12.87.

Regarding interpretation of the TRH stimulation test results, we found that the relative rise (per cent increase) in serum T4 concentration after administration of TRH was the best (most sensitive) criteria for predicting whether or not cats are hyperthyroid (1). A percent rise in serum T4 of less than 50 per cent is consistent with mild hyperthyroidism, whereas a value of greater than 60 per cent is seen in normal cats; values between 50 and 60 per cent are equivocal or borderline responses.

The serum T3 response to TRH is less helpful in separating normal from hyperthyroid cats, because many normal cats have only a small and inconsistent rise in serum T3 concentrations after TRH administration. Therefore, I do not recommend determining the serum T3 response as part of the TRH stimulation test.

In another study of 36 cats with severe critical illness (5), half of the severely sick cats showed an inadequate T4 response to TRH stimulation test (i.e., a percent rise in serum T4 of less than 50 per cent). Unfortunately, this could create a situation where mild hyperthyroidism is falsely diagnosed in a cat with critical illness.  Although the reason for this is unclear, critical nonthyroidal illness may render pituitary TSH secretion unresponsive to the stimulatory effects of TRH administration.

The bottom line: This test is not meant to differentiate normal and hyperthyroid cats from cats with severe critical illness. I do not recommend doing this test in severely ill cats, inasmuch as the test results may be invalid.

Which is Better: TRH Stimulation Test vs. the T3 Suppression Test?

Advantages of the TRH stimulation test over the T3 suppression test include the shorter time needed to perform the test (4 hours vs. 3 days), and the fact that the TRH stimulation test is not dependent upon the owner's ability to administer oral medication.

The major disadvantage of the TRH stimulation test in cats is that side effects almost invariably occur immediately after administration of the TRH (1, 6-8). These adverse effect include the following:

• Excessive salivation (see Figure 3)
• Vomiting
• Induced defecation
• Rapid breathing (tachypnea); open mouth breathing

Fortunately, all of the adverse side effects are transient and completely resolve by the end of the 4-hour test period. Because of these adverse effects, however, I generally do a T3 suppression test over the TRH stimulation test for dynamic testing of the pituitary-thyroid axis.

Figure 3: Cat showing increased salivation after TRH administration

Our studies show a close relationship between the presence (or absence) of suppressed serum T4 concentrations in response to T3 suppression and stimulated T4 values in response to TRH stimulation. Therefore, although the two tests evaluate the pituitary-thyroid axis in different ways, our findings indicate that the two screening tests provide similar information and can probably be used interchangeably for diagnosing mild hyperthyroidism in cats.

Future Investigations: Serum TSH Response to TRH Stimulation in Cats

In human beings, the TRH stimulation test is generally done by directly evaluating the change in serum TSH concentrations, not indirectly by measuring serum T4  values.  When this is done, the TRH stimulation test is one of the most sensitive tests in detecting early or mild hyperthyroidism in human patients. Again, because TSH production is completely suppressed in hyperthyroid patients, they will not show a rise in serum TSH when TRH is administered, whereas normal individuals will respond with a brisk rise in circulating TSH within 30 minutes of TRH injection. The new, ultra-sensitive human TSH assays have largely eliminated the need for TRH stimulation testing, but it still remains a useful and time-proven test.

Similar serum TSH responses to TRH have been reported in normal dogs — baseline serum TSH concentrations increase 2- to 3-fold when measured 30 minutes after administration of TRH at doses ranging from 1-10 μg/kg. There are two major advantages of evaluating the TSH response rather than the T4 response to TRH:

1. The test period is shorten from 4 hours to only 15-30 minutes.
2. A much lower dose of TRH is needed, greatly reducing or eliminating the adverse signs commonly seen with the higher doses needed to elicit a serum T4 response.

Measuring the serum TSH response to TRH has not been reported in cats with hyperthyroidism. Obviously, this is an area that needs to be investigated, now that we know that the canine TSH assay can be used to measure circulating TSH in cats.

Because the canine TSH assay is not designed to measure low values, basal TSH measurements are not very useful as a diagnostic test in feline hyperthyroidism (see my previous blog on TSH in cats). However, measuring the response to TRH may turn out to be a extremely useful and sensitive test for this disease.

References:

1. Peterson ME, Broussard JD, Gamble DA: Use of the thyrotropin releasing hormone stimulation test to diagnose mild hyperthyroidism in cats. Journal of Veterinary Internal Medicine 1994;8:279-286.
2. Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:2-9.
3. 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.
4. Utiger RD: Tests of thyroregulatory mechanisms. In Ingbar SH and Braverman LE (eds): The Thyroid: A Fundamental and Clinical Text, pp 511-523. Philadelphia, JB Lippincott, 1986.
5. Tomsa K, Glaus TM, Kacl GM, et al. Thyrotropin-releasing hormone stimulation test to assess thyroid function in severely sick cats. Journal of Veterinary Internal Medicine 2001;15:89-93.
6. Holtman JR, Buller AL, Hamosh P, et al: Central respiratory stimulation produced by thyrotropin-releasing hormone in the cat. Peptides 1986;7:207-212.
7. Beleslin DB, Jovanovic-Micic D, Tomic-Beleslin N: Nature of salivation produced by thyrotropin-releasing hormone (TRH). Brain Research Bulletin 1987;18:463-465.
8. Beleslin DB, Jovanovic-Micic D, Samardzic R, et al: Studies of thyrotropin-releasing hormone (TRH)-induced defecation in cats. Pharmacology Biochemistry & Behavior 1987;26:639-641.
9. Yagi K, Ohashi E, Tanabe S, Uzuka Y, Sarashina T. Serum thyrotropin response to TRH administration in six healthy beagle dogs. Veterinary Record 2000;146:706-707.

Confirming the Diagnosis of Hyperthyroidism: The T3 Suppression Test

Yawning Cat at
the Hypurrcat Spa

In most cats with hyperthyroidism, the diagnosis is easily confirmed by measuring a single serum T4 concentration. Measuring serum free T4, T3, and TSH adds more diagnostic information that can be used to help confirm the diagnosis in cats with borderline hyperthyroidism.

Occasionally, cats suspected of having hyperthyroidism can be difficult to diagnose, even when repeated serum thyroid tests are run. Many of these cats have early or mild hyperthyroidism and show only mild clinical signs, whereas others appear to have more severe clinical features of hyperthyroidism but also have another obvious (or not so obvious) concurrent disease.  The finding of concomitant disease (kidney, liver, or gastrointestinal disease) is relatively common in hyperthyroid cats, which is not surprising given the fact that many of these cats are middle-aged to older.

In the majority of these hyperthyroid cats in which a normal total T4 concentration is found, simply repeating the total T4 analysis with simultaneous measurement of free T4, as well as ruling out any concurrent disease, will easily confirm the diagnosis. Further diagnostic tests for hyperthyroidism are rarely required. However, if we still still suspect that a cat has mild hyperthyroid but serum concentrations of total and free T4 are either normal or equivocal, dynamic testing can be used to help make the diagnosis.

Dynamic Testing for Diagnosis of Hyperthyroidism

Two dynamic tests can be used in cats with mild or "occult" hyperthyroidism — both of these tests  act on the hypothalamic-pituitary-thyroid axis (see Figure 1) to either suppress or stimulate pituitary TSH and thyroid hormone secretion.

• Triiodothyronine (T3) suppression test
• Thyrotropin-releasing hormone (TRH) stimulation test

Figure 1: Hypothalamic-Pituitary-Thyroid axis
Normally, TRH stimulates the secretion of TSH from the pituitary, which in turn, stimulates the thyroid to secrete T4 and T3. Both circulating T4 and T3 "feed-back" to the hypothalamus and pituitary to shut off the secretion of TRH and TSH respectively.

Triiodothyronine (T3) Suppression Test

The T3 suppression test operates on the principle that administration of relatively high doses of exogenous T3 will suppress (lower) the secretion of pituitary TSH in normal cats. Such inhibition of pituitary TSH secretion by high circulating concentrations of thyroid hormone is a characteristic feature of normal hypothalamic-pituitary-thyroid regulation (see Figure 1).  The fall in circulating TSH levels results in lowered T4 secretion from the normal feline thyroid gland (see Figure 2, below, left panel).

Because resting serum TSH concentrations are already very low in normal cats (see my previous post on serum TSH measurements in cats), it would not be possible to use TSH measurement as an endpoint for interpretation of this test.

Figure 2: T3 suppression tests in normal cats (left) & cats with hyperthyroidism (right)

In contrast to the situation in normal cats, when thyroid function is autonomous — as it is in hyperthyroid cats, administration of large doses of exogenous T3 has little or no effect on T4 secretion. The reason for this that pituitary TSH secretion has already been completely suppressed by the higher-than-normal thyroid hormone secretion characteristic of hyperthyroidism (see Figure 2 above, right panel).

Testing Protocol for the T3 Suppression Test

To perform the T3 suppression test in cats, the following protocol is recommended:

• One day 1, the veterinarian draws a blood sample is drawn for determination of baseline serum concentrations of total T4 and T3. This serum sample is not yet submitted to the laboratory but kept refrigerated (or frozen) until day 4.
• Owners are instructed to give 7 doses of a T3 pill (liothyronine sodium; Cytomel) to their cat, beginning on the following morning.
• On day 2 and 3, the owners administer the liothyronine at a dosage of 25 µg every 8 hours for 2 days (6 doses). 
• On the morning of day 4, a seventh 25-µg dose of liothyronine is given and the cat returned to the veterinary clinic within 2 to 4 hours.
• The veterinarian again draws a blood sample for serum T4 and T3 determinations. 
• Both the basal (day 1) and post-liothyronine (day 4) serum samples are submitted to the laboratory together to eliminate the effect of between assay variation in hormone concentrations.

Interpretation of Results of T3 Suppression Testing

When the T3 suppression test is performed in normal cats and sick cats without hyperthyroidism, there is a marked fall in serum T4 concentrations after exogenous T3 administration (Figures 2 and 3). In contrast, when the test is performed in cats with hyperthyroidism, even in cats with only slightly high or high-normal resting serum T4 concentrations, minimal, if any, suppression of serum T4 concentrations is seen.

Figure 3: Box plots of the serum T4 concentrations before (A) and after (B) administration of liothyronine to 44 normal cats, 77 cats with hyperthyroidism, and 22 cats with nonthyroidal disease (from data in Reference no. 4). Data is plotted as box plots, in which the "box" represents the interquartile range from the 25th to 75th percentile (represents the middle one-half of the data). The horizontal bar through the box is the median. The "whiskers" represent the main body of data, which in most cases is equal to the range. Outlying data points are represented by open circles. To convert serum T4 concentrations from nmol/L to µg/dl, divide the given values by 12.87.

Regarding interpretation of T3 suppression test results, we find that the absolute serum T4 concentration after liothyronine administration is the best means of distinguishing hyperthyroid cats from normal cats or cats with nonthyroidal disease. Cats with hyperthyroidism have post-liothyronine serum T4 values greater than 20 nmol/L (greater than 1.5 μg/dl), whereas normal cats and cats with nonthyroidal disease have T4 values less than 20 nmol/L (Figure 3B). There may be a great deal of overlap of the per cent decrease in serum T4 concentrations after liothyronine administration between the three groups of cats, but suppression of 50 per cent or more only occurs in cats without hyperthyroidism.

Serum T3 concentrations, as part of the T3 suppression test, are not useful in the diagnosis of hyperthyroidism per se. However, these basal and post-liothyronine serum T3 determinations can be used to monitor owner compliance with giving the drug. If inadequate T4 suppression is found, but serum T3 values do not increase after treatment with liothyronine, problems with owner compliance should be suspected and the test result considered questionable.

Disadvantages of the T3 Suppression Test

Overall, the T3 suppression test is very useful for diagnosis of mild hyperthyroidism in cats, but the test does come with disadvantages:

1. T3 suppression testing is a relatively long test (3 days)
2. Owners are required to give multiple doses of liothyronine
3. Cats must swallow the tablets if the test is going to be meaningful. 

If the liothyronine is not administered properly or the cat does not swallow the liothyronine tablet, circulating T3 concentrations will not rise to decrease pituitary TSH secretion, and the serum T4 value will not be suppressed, even if the pituitary-thyroid axis is normal. Failure of a cat to ingest the liothyronine could result in a false-positive diagnosis of hyperthyroidism in a normal cat or cat with nonthyroidal disease.

References:

1. Graves TK, Peterson ME: Occult hyperthyroidism in cats. In Kirk RW and Bonagura JD (eds): Current Veterinary Therapy XI, pp 334-337. Philadelphia, WB Saunders Co, 1992.
2. Peterson ME, Melián C, Nichols CE: Measurement of serum concentrations of total and free T4 in hyperthyroid cats and cats with nonthyroidal disease. Journal of Veterinary Internal Medicine 1998;12:211.
3. Utiger RD: Tests of thyroregulatory mechanisms. In Ingbar SH and Braverman LE (eds): The Thyroid: A Fundamental and Clinical Text, pp 511-523. Philadelphia, JB Lippincott, 1986.
4. Peterson ME, Graves TK, Gamble DA: Triiodothyronine (T3) suppression test. An aid in the diagnosis of mild hyperthyroidism in cats. Journal of Veterinary Internal Medicine 1990;4:233-238.
5. Refsal KR, Nachreiner RF, Stein BE, et al: Use of the triiodothyronine suppression test for diagnosis of hyperthyroidism in ill cats that have serum concentration of iodothyronines within normal range. J Am Vet Med Assoc 1991;199:1594-1601.
6. Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:2-9.
7. 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
8. Peterson ME: Hyperthyroidism in cats, In: Rand, J (ed), Clinical Endocrinology of Companion Animals. New York, Wiley-Blackwell, in press.

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.

Confirming the Diagnosis of Hyperthyroidism in Cats: Serum T3 Concentrations

As I discussed in my last post, the feline thyroid gland makes two active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). T4 makes up nearly 90% of the circulating thyroid hormones, while T3 makes up less than 10%.

Although only 10% of the hormone produced in the thyroid gland is T3, this thyroid hormone is three to ten times more active than T4. In order for the body’s cells and tissues to use more of this active form of thyroid hormone, T4 (which contains four iodine molecules) is converted to T3 or (which contains three iodine molecules) by losing an iodine molecule. In cats, this function is performed in the liver and kidney by deiodinase enzymes that act to remove an iodine group from the thyroid hormone molecule (1).

The deiodination of T4 to T3, reverse T3, and other iodothyronines is an integral component of thyroid hormone metabolism. This deiodination, depending on whether it occurs at the outer or inner rings of the T4 molecule, serves to either activate or inactivate this hormone (see Figure above). Again, T3 is the most active thyroid hormone, whereas reverse T3 (rT3) is considered to be metabolically inactive.

There are 3 different thyroid deiodioinase enzymes:

• Iodothyronine deiodinase type I (IDI) is commonly found in the liver and kidney. It is also present in the thyroid of many species including dogs and humans, but IDI is not present in the feline thyroid gland (1).
• The type II enzyme (IDII) in skeletal muscle and thyroid gland (but again, cats do not appear to have IDII in their thyroid gland).
• Type III (IDIII) is found in the fetal tissue and brain matter.

IDII can only deiodinate the outer ring of T4 or rT3. IDIII can only deiodinate the inner ring of T4 or T3. IDI can deiodinate both the outer and inner rings.

But the real question is this: If T3 is three to ten times more active than T4, shouldn’t we be measuring serum T3 to better diagnose hyperthyroidism in cats?

Measuring the Serum Triiodothyronine (T3) Concentration

Although T3 is the important thyroid hormone for regulation of a cat's metabolic state, this hormone reflects tissue thyroid activity. Unfortunately, measuring the serum levels of T3 are a poor reflection of what is happening in the tissues.

Compared to the serum T4,  measuring the serum T3 concentration is much less useful as a diagnostic test for hyperthyroidism (2-7). Over 30% of hyperthyroid cats have normal circulating T3 concentrations (See Figure, below).

Box plots of total T3 concentrations in 172 clinically normal cats, 917 cats with hyperthyroidism, and 221 cats with nonthyroidal disease. The T-bars represent the main body of data. The box represents the interquartile range (25th percentile to 75th percentile range or the middle half of the data). The horizontal bar in the box is the median. Outlying data points are represented by open circles. The shaded area indicates the reference interval (normal range). From reference 3.

None of the cats with high serum T3 values have normal serum T4 concentrations, so measuring T3 test does not provide any additional information not gained from measuring T4 alone.

Bottom line: Measuring total T3 alone is not recommended for investigation of hyperthyroidism in cats.

The reason for this is unknown, but based on studies of normal cats (1), it is likely that most of the circulating T3 in these hyperthyroid cats comes from conversion from T4 in peripheral tissues, and is not secreted directly by the thyroid tumor.  That could explain why measurement of T4 is a better diagnostic test for hyperthyroidism than is T3.

In my next posts, we will discuss the use of free T4, then look at the use of serum TSH measurements. I’d end this section on diagnostic testing with a post on the value of thyroid scintigraphy (thyroid nuclear imaging or scanning) in the diagnosis of hyperthyroidism.

References:

1. Foster DJ, Thoday KL, Beckett GJ. Thyroid hormone deiodination in the domestic cat. Journal of Molecular Endocrinology 2000;24:119-126.
2. Baral R, Peterson ME: Thyroid Diseases, In: Little, S. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders, in press.
3. Graves TK, Peterson ME. Diagnostic tests for feline hyperthyroidism. The Veterinary Clinics of North America: Small Animal Practice 1994;24:567-576.
4. 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.
5. Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:2-9.
6. 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
7. Peterson ME: Hyperthyroidism in cats, In: Rand, J (ed), Clinical Endocrinology of Companion Animals. New York, Wiley-Blackwell, in press.