Monday, August 22, 2011

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.

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