Confirming the Diagnosis of Hyperthyroidism: The T3 Suppression Test

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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 TSH Concentrations

Measuring TSH in Human Patients with Thyroid Disease

In human patients, measurement of circulating thyroid stimulating hormone (TSH; also called thyrotropin) is commonly used as a front-line test of thyroid function. This hormone is secreted by the pituitary gland and, as its name suggests, acts to stimulate the thyroid gland to secrete T4 and T3.

The pituitary gland constantly monitors the circulating levels of T4 and T3, and if it senses the slightest increase in serum thyroid hormone concentrations, it stops producing TSH. In contrast, if the pituitary senses even a slight decrease in circulating T4 and T4 concentrations, it increases the secretion of TSH in an attempt to increase thyroid hormone levels back to normal.

Consequently, the finding of a low to undetectable blood TSH value in a human patient is diagnostic for hyperthyroidism, whereas a high serum TSH concentration is diagnostic for hypothyroidism. When testing human patients, the finding of a normal TSH result excludes both hypo- or hyperthyroidism.

TSH Concentrations as a Diagnostic Test for Cats

A species-specific feline TSH assay has not yet been developed for use in cats, and human TSH assays cannot be used to measure feline TSH. However, assays for measuring canine TSH (cTSH) are widely available, and studies have investigated the use of cTSH measurements as a diagnostic test for cats with suspected thyroid dysfunction — both hyperthyroidism or hypothyroidism (1-3).

However, there are many problems with the use of the cTSH assay, both in dogs as well as in cats.

First Problem: The first issue or problem with the use of the canine TSH assay is that this test, although first developed in 1997 (now 14 years ago), is still a considered "first generation" assay. Overall, this assay is not considered very reliable for the following reasons:

• It has a diagnostic test sensitivity of only 60-75% in canine hypothyroidism, a very common endocrine problem in dog (4-6). Because 25% to 40% of dogs with confirmed hypothyroidism do not have the high serum TSH concentrations (> 0.6 ng/ml) that we expect to find with thyroid failure, it's possible that some isoforms of the TSH hormone are not being detected with this assay.
• In addition to this high incidence of false-negative results, cTSH levels appear to be falsely-high in 10% to 20% of dogs with normal thyroid function (4). Some of these dogs have other nonthyroidal illnesses; however, falsely high serum cTSH values have even been reported in clinically normal dogs that had completely normal total and free T4 concentrations.
• The high prevalence of false-negative and false-positive test results make this assay unreliable to use as a sole diagnostic test for dogs with suspected hypothyroidism.

Second Problem: It is important to remember that the current canine TSH assays only detects approximately 35% of the circulating feline TSH. In other words, the current cTSH assay does not completely cross-react with feline TSH; therefore, the assay is not measuring the total amount of TSH present in the cat's serum.

This poor cross-reactivity of feline TSH in the canine assay explains why the upper limit of the reference range for TSH is so much lower in cats (0.15-0.3 ng/ml) than it is in dogs (0.5-0.6 ng/ml). Again, the cTSH assay is only measuring about a third of the feline TSH present in the circulation.

Third Problem: A major problem with the canine TSH assay, being a first generation assay, is that its detection limit (assay sensitivity) is not very good.  In fact, it's really poor! Therefore, this assay does not perform well when we are trying to measure very low concentrations of TSH.

In cats this issue is again made even worse by the fact that only 35% of the cat's TSH will be detected by the cTSH assay. As a consequence of this poor cross-reactivity, the assay sensitivity, which is already considered poor at 0.03 ng/ml in the dog, equates to only 0.10 ng/ml of TSH in the cat (7).  With such a "high" detection limit, we cannot reliably distinguish a normal TSH concentration from a low or undetectable value in cats with this cTSH assay. In other words, this assay just cannot accurately measure low enough to distinguish between normal and low feline TSH concentrations.

All human TSH assays currently used are second or even third generation assays. Like the cTSH assays, the first generation human TSH assays were also unable to distinguish low-normal from low TSH concentrations. The major advantages of the second to third generation TSH assays is their 10- to 100-fold improvement in assay sensitivity (8); this much lower detection limit greatly improves their ability to accurately distinguish between normal and even partially suppressed TSH results.

Hopefully, we will also be moving on to a second generation of TSH assays for dogs (and cats), which should improve the sensitivity (detection limit) of the assay. This will also help make this a better test for hyperthyroidism, as well as hypothyroidism in cats.

Using TSH Concentrations as a Diagnostic Test for Hyperthyroidism in Cats

Of course, the poor detection limit of the current cTSH assay represents a major issue in cats with hyperthyroidism, where low suppressed values are expected. In one of the best studies of cTSH concentrations in cats (2), all of the hyperthyroid cats tested had cTSH concentrations at or below the limit of detection of the assay (0.03 ng/ml).  However, of the 40 cats without hyperthyroidism tested in that same study, 5 cats also had undetectable levels of TSH, indistinguishable from the values in the hyperthyroid cats (see Figure below).

TSH values in normal cats, hyperthyroid cats, and cats with chronic kidney disease. Notice that  all hyperthyroid cats have very low TSH concentrations. However, there is much overlap between the TSH values in the hyperthyroid cats and the values in the cats without hyperthyroidism. Modified from data in reference 2.

Obviously, a better TSH assay for feline hyperthyroidism is needed— specifically, a feline-specific TSH assay that has adequate sensitivity to reliably distinguish a normal value from a low one. However until better TSH assays for cats are available, caution is advised in over interpreting values in cats since can be so difficult to distinguish normal values from the suppressed values expected in cats with hyperthyroidism. Perhaps the only use for TSH measurements using the cTSH assay would be to exclude hyperthyroidism, i.e., finding a mid- to high-normal value rather than a suppressed value (3).

Using TSH Concentrations as a Diagnostic Test for Hypothyroidism in Cats

At this time, the major use for the current cTSH assay is as a diagnostic test for hypothyroidism, where the low circulating thyroid hormone concentrations sensed by the pituitary gland leads to high serum TSH values. In accord with that, high cTSH values have been reported in cats with naturally occurring hypothyroidism, as well as cats with iatrogenic hypothyroidism, i.e., secondary to methimazole or radioiodine treatment (9).

Normal cats and cats with nonthyroidal illness generally maintain normal values for serum TSH. Therefore, the finding of a low total or free T4 in combination with a high TSH concentration greatly improves the diagnostic sensitivity for hypothyroidism in cats.

References:

1. Greco DS. Diagnosis of congenital and adult-onset hypothyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:40-44
2. Wakeling J, Moore K, Elliott J, et al. Diagnosis of hyperthyroidism in cats with mild chronic kidney disease. Journal of Small Animal Practice 2008;49:287-294.
3. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Canadian Veterinary Journal 2010;51:33-34.
4. Peterson ME, Melian C, Nichols R. Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and thyrotropin concentrations for diagnosis of hypothyroidism in dogs. Journal of the American Veterinary Medical Association 1997;211:1396-1402.
5. Scott-Moncrieff JC, Nelson RW, Bruner JM, et al. Comparison of serum concentrations of thyroid-stimulating hormone in healthy dogs, hypothyroid dogs, and euthyroid dogs with concurrent disease. Journal of the American Veterinary Medical Association 1998;212:387-391.
6. Dixon RM, Mooney CT. Evaluation of serum free thyroxine and thyrotropin concentrations in the diagnosis of canine hypothyroidism. Journal of Small Animal Practice 1999;40:72-78.
7. Ferguson DC, Caaffall Z, Hoenig M. Obesity increases free thyroxine proportionally to nonesterified fatty acid concentrations in adult neutered female cats. Journal of Endocrinology 2007;194:267-273.
8. 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.
9. Baral R, Peterson ME: Thyroid Diseases, In: Little, S. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders, 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 Free T4 (Part 2)

As I discussed in a recent blog post, determining a cat's serum free T4 concentration is a very useful test in confirming the diagnosis of hyperthyroidism, especially when run together with a total T4 concentration (1-6).

Physiology of T4, Total T4, and Free T4 in the Body

Again, what's the difference between total and free T4? When we measure a serum T4 level, we are checking the total amount of T4 hormone circulating in the blood—both the bound and unbound T4 molecules.

More than 99% of T4 hormone in the circulation is “bound,” meaning that it is attached to thyroid-binding proteins in the bloodstream. When bound, this T4-thyroid binding protein complex is too large to enter the body's tissues (Figure 1).

For circulating T4 to do its functions and regulate metabolism, the hormone must first break loose from its binding proteins (i.e., become “free” T4) in order to leave the bloodstream and enter the body’s tissues and cells. Only then can intracellular free T4 be converted to T3 to have its effect on the body’s metabolism (Figure 1).

Serum free T4 represents the tiny fraction (less than 0.1%) of thyroxine hormone that is unbound and therefore is biologically active. It is important to realize that a dynamic equilibrium exists between free and protein-bound T4 that depends on the amount of thyroid-binding proteins in the blood stream, as well as the affinity of the thyroid binding proteins for T4. In other words, a T4 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 T4 portion of the total T4 measured in the blood that can pass into the cells and act on the body’s tissues to influence metabolism (Figure 1).

Figure 1: T4 circulates mostly bound to thyroid binding proteins in the circulation. This bound T4 exists in a dynamic equilibrium with unbound or free T4, which accounts for less than 1% of the total T4 in the circulation. Only the free, nonprotein-bound moiety is able to pass into the body's cells, where it can be converted into T3, the most active thyroid hormone

Measuring Serum T4, T3, and Free T4 in Cats with Mild Hyperthyroidism

When we measure a serum free T4 concentration, we are checking only the free or unbound portion of the T4 hormone circulating in the blood. Since changes in the concentrations (or binding affinity) of the thyroid binding proteins does not affect the free T4 levels, this test is considered a more accurate test of true thyroid activity than determination of serum total T4.

Free T4 is much less likely to be influenced by nonthyroidal illness or drugs. However, the tests biggest advantage appears to be a more sensitive test for diagnosis of early or mild hyperthyroidism.

As might be expected, the free T4 test is a more sensitive diagnostic test for feline hyperthyroidism than is determination of the total T4 concentration.

In our study of 917 hyperthyroid cats (3), we found that determination of serum free T4 was diagnostic in 98.5% of the cases (for more information, see Figure 1 in my last blog post). This ability to confirm hyperthyroidism in cats with the disease was higher than the total T4 concentration, which was diagnostic in 91% of cats or T3, which was diagnostic on only 67%.

However, when we looked at the cats with mild hyperthyroidism in that study (3), the advantage of free T4 over of total T4 or T3 measurements was much more striking (Figure 2).

In that subgroup of 205 cats with mild hyperthyroidism, we found that determination of serum total T4 was diagnostic in 61% of the cases (left panel, yellow boxed data). Use of serum T3 concentrations were of almost no value in cats with mild disease, since they were diagnostic in only 20% of the cases (middle panel, blue boxed data). However, despite the poor test sensitivities of T4 and T3 measurements, determination of free T4 was still diagnostic for hyperthyroidism in 91% of these cats with mild hyperthyroidism (right panel, purple boxed data).

Figure 2: Box plots of serum total T4, T3, and free T4 concentrations in 205 cats with mild hyperthyroidism, defined as a serum T4 less than 5 μg/dl (66 nmol/L). The T-bars represent the main body of data. The box represents the interquartile range (25th percentile to 75th percentile or middle half of the data). The horizontal bar in the box is the median or 50% percentile. Outlying data points are represented by open circles. The green shaded area represents the reference interval (normal range). From reference 3.

Disadvantages of Free T4 as a Diagnostic Test

Although the free T4 is a very sensitive diagnostic, the main problem with free T4 assays is that the test is less specific than the total T4 value. In other words, many cats suffering from other illnesses NOT associated with hyperthyroidism can have false-positive results with the free T4 test (for more information, see this blog post).

In contrast, cats with nonthyroidal illness will never have high total T4 values. Rather, the will have corresponding total T4 values in the low-normal or subnormal range. For this reason, the total T4 test remains the diagnostic test of choice for cats with suspected hyperthyroidism because we almost never see false-positive results with the total T4 test. Measurement of free T4 alone can never be used to make a reliable diagnosis because of the chance that the result is not accurate.

However, in cats in which hyperthyroidism is suspected based on clinical features (e.g., weight loss despite a good appetite, palpable thyroid tumor), the finding of a high free T4 concentration can be considered diagnostic. This is especially true when the total T4 values are in the upper half of the reference range (see Figure 2: left panel, yellow boxed data) and all other diseases have been excluded. 

If the corresponding total T4 is in the lower half of the reference range, however, nonthyroidal disease is very likely. In our study (3), all 5 of the cats that had total T4 concentrations in the low-normal range had severe concurrent illnesses (see Figure 2: left panel, yellow boxed data).

References:

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

Obesity Growing Among Dogs and Cats

Obesity rates are rising among pets and more than half of cats and dogs are overweight or obese according to Association for Pet Obesity Prevention.

Obesity Facts and Risks 

• 54% of Dogs and Cats in the United States are Overweight 
• 21% of US Dogs and Cats are Overtly Obese 
• 55.6% of US Dogs are Overweight 
• 20% of US Dogs are Overtly Obese 
• 54% of US Cats are Overweight
• 22% of US Cats are Overtly Obese

All of this data is taken from a 2010 study reported by theAssociation for Pet Obesity Prevention - click here to view the 2010 Pet Obesity Study.

Just as obesity does in humans, extra pounds can lead to adverse health conditions in animals. The most common side effects of obesity seen in dogs and cats include the following concurrent problems.

Primary Risks of Excess Weight in Pets

• Diabetes mellitus
• Insulin resistance and the metabolic syndrome
• High blood pressure
• Heart and respiratory diseases
• Osteoarthitis and other joint problems
• Kidney Disease
• Many Forms of Cancer
• Decreased life expectancy (up to 2.5 years)

Veterinarians advise owners looking help their pets trim down to replace traditional treats with healthier choices. It's also a good idea to switch to a lower-calorie diet, and add more exercise. To learn more, I'd strongly recommend that you go to the Association for Pet Obesity Prevention website.

Taking Your Cat to the Veterinarian: Lessening the Stress of Vet Visits for You and Your Cat

The American Association of Feline Practitioners and the International Society of Feline Medicine have released an important handout for cat owners, entitled "Getting Your Cat to the Veterinarian: Reducing the Stress of Veterinary Visits for You and Your Cat."

This handout discusses the following topics that will help make veterinary visits easier for you and your cat:

• Understanding your Cat’s Behavior
• Helping Your Cat Become Comfortable with the Carrier
• Getting an Unwilling Cat into the Carrier
• Coming Home – Keeping the Peace in a Multi-Cat Household
• What Type of Carriers are Best?

To see and print this handout, click here.

For my related posts on this topic, click here.