Thyroxine (T4)

From Cat

Thyroxine (T4) is a prohormone of the biologically active hormone triiodothyronine (T3). Thyroxine is a hormonal product of the feline thyroid gland, produced by follicular cells which utilise iodine as an important mineral element.

Measurement of serum total thyroxine (T4) and triiodothyronine (T3) concentrations is used commonly to assess hyperthyroidism in cats[1]. High basal T4 and T3 concentrations are biochemical landmarks of hyperthyroidism; the finding of high concentrations of T4 or T3 is pathognomonic for this disease, with no false positive results in cats[2][3].

Assay techniques for Thyroid-hormone determination

Assays for measurement of serum total T4 and T3 are readily available, relatively cheap and do not require special sampling techniques. Radioimmunoassay (RIA) is considered the gold standard, but nonisotopic and automated techniques, such as chemiluminescent enzyme immunoassay are becoming increasingly popular[4]. Generally, these nonisotopic methods correlate well with results of RIA analysis; however, each testing methodology is susceptible to sporadic errors that can result in outlying T4 ot T3 values, in addition to technology-specific trends that could produce an overall bias when results from different assay methods are compared.

Semiquantitative assays for total T4 that are suitable for in-hospital testing can also be useful in the diagnosis of hyperthyroidism in cats[5]. Such commercial kits allow practitioners to measure T4 concentrations in-house while a client waits for the results. However, in one study that compared an in-house enzyme-linked immunosorbent assay (ELISA) T4 kit to a commercial RIA in cats, substantial discrepancies in serum T4 concentrations were demonstrated, which led the investigators to conclude that the in-house kit was not accurate for use in cats[6]. Other investigators have, however, confirmed the suitability of ELISA assays for measuring T4 and T3 in quantitatively assessing hyperthyroidism in cats.

Diagnostic sensitivity of thyroid hormone determination

The serum concentrations of total T4 and T3 are highly correlated in hyperthyroid cats, but measurement of total T4 is preferred over T3 because of its better diagnostic sensitivity[7]. More than 30% of hyperthyroid cats have serum total T3 concentrations within the reference range, whereas only 10% of all hyperthyroid cats have normal serum T4 concentrations[8].

Most cats with normal total T3 concentrations have early or mild hyperthyroidism and, accordingly, corresponding serum total T4 concentrations usually are only just above reference ranges. Therefore the normal T3 concentrations likely would increase into the thyrotoxic range in these cats if the disorder were allowed to progress untreated. A possible explanation for normal circulating T3 concentrations in cats with mild hyperthyroidism is that, as thyroid hormone production begins to increase in hyperthyroid cats, a compensatory decrease occurs in peripheral conversion of T4 to the more active T3 (August, 2006). In addition, T3 is located mainly intracellularly, so serum concentrations may not be an accurate reflection of what is present in the body. In any case, measurement of serum T3 concentration alone cannot be strongly recommended as a diagnostic test for hyperthyroidism in cats (Peterson et al, 2001).

Most hyperthyroid cats exhibit persistently high circulating total T4 concentrations, with values up to approximately 20 times the normal range. However, a significant portion of hyperthyroid cats (approximately 10-40%) have serum total T4 concentrations within the reference rage (Broussard et al, 1995). Therefore, hyperthyroidism cannot be excluded based on a single, normal total T4 concentration.

Thyroid hormone levels may also fluctuate over time, and appears to have little clinical significance (August, 2006).

Suppression of T4 due to non-thyroidal disease

In hyperthyroid cats with concurrent diabetes mellitus, systemic neoplasia, primary liver disease and other chronic illness, these diseases tend to suppress T4 levels in the blood, even though the hyperthyroidism is still active as a disease[9]. Therefore, concomitant hyperthyroidism should be suspected in cases with concomitant systemic disease and T4 levels in the high-normal reference range. If after retesting of T4 1-2 weeks shows that the T4 is consistently int eh high-normal range, a free T4 concentration (by dialysis) or provocative testing with a T3-suppression test or thyrotropin-releasing hormone (TRH) stimulation test is recommended[10].

Free thyroid hormone concentrations

Circulating thyroid hormones can be either bound to carrier proteins or free (unbound) in plasma. Most commercial T4 and T3 assays measure total concentrations, both free and protein-bound. Because only the free fraction of thyroid hormones is available for entry into the cells, free T4 determinations should provide a more consistent assessment of thyroid gland status than total T4 concentrations[11]. Also, free T4 concentrations are influence to a lesser degree by factors such as non-thyroidal illness that may falsely lower total T4 concentrations (August, 2006).

Serum free T4 and total T4 concentrations are highly correlated in cats with hyperthyroidism. However, serum free T4 concentrations, as measured by equilibrium dialysis, are more consistently (>98% of cases) elevated in hyperthyroid cats (Peterson et al, 2001). More significantly, serum free T4 concentrations are high in 95% of hyperthyroid cats in which total T4 concentrations are within reference range.

The most important disadvantages of free T4 by dialysis are that the technique is much more expensive than a total T4 determination and is not offered by all commercial laboratories. Measurement of free T4 by dialysis also is subject to more errors than that of total T4 because of sample handling during transport to the laboratory. The most important disadvantage of use of the free T4 determination, however, is the loss of of diagnostic specificity seen occasionally in sick, euthyroid cats.


References

  1. August, JR (2006) Consultations in feline internal medicine. Vol 5. Elsevier Saunders, USA
  2. Peterson, ME et al (1983) Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. J Am Vet Med Assoc 183:103-110
  3. Broussard, JD, Peterson, ME & Fox PR (1995) Changes in clinical and laboratory findings in cats with hyperthyroidism from 1983 to 1993. J Am Vet Med Assoc 206:302-305
  4. Mooney,, CT & Peterson, ME (2004) Feline hyperthyroidism. In Mooney, CT & Peterson, ME (eds): BSAVA Manual of canine and feline endocrinology, ed 3. Gloucester, UK British Small Animal Veterinary Association, pp:95-111
  5. Peterson, ME, de Marco, DL & Sheldon, KM (2003) Total thyroxine testing: Comparison of an in-house test-kit with radioimmuno and chemiluminescent assays. J Vet Int Med 17:396
  6. Lurye, JC, Behrend EN & Kemppainen, RJ (2002) Evaluation of an in-house enzyme-linked immunosorbent assay for quantitative measurement of serum total thyroxine concentrations in dogs and cats. J Am Vet Med Assoc 221:243-249
  7. Feldman, EC & Nelson, RW (2004) Feline hyperthyroidism (thyrotoxicosis). In Canine and feline endocrinology and reproduction, ed 3. Elsevier Science, Philadelphia. pp:152-218
  8. Peterson, ME, Melian, C & Nichols, R (2001) Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with non-thyroidal disease. J Am Vet Med Assoc 218:529-536
  9. Peterson, ME & Gamble, DA (1990) Effect of non-thyroidal illness on serum thyroxine concentrations in cats: 494 cases (1988) J Am Vet Med Assoc 197:1203-1208
  10. Peterson, ME, Graves, TK & Gamble DA (1990) Triiodothyronine (T3) suppression test. An aid in the diagnosis of mild hyperthyroidism in cats. J Vet Intern Med 4:233-238
  11. Ferguson, DC (1995) Free thyroid hormone measurements in the diagnosis of thyroid disease. In Bonagura, JD & Kirk RW, editors: Current veterinary therapy, XII. WB Saunders, Philadelphia. pp:360-364