Tuesday, May 22, 2012

Diagnosing Subclinical Hyperthyroidism in Cats

Evaluation of Predictors for the Diagnosis of Hyperthyroidism in Cats

By J. Wakeling, J. Elliott, and H. Syme
Journal of Veterinary Internal Medicine 2011; 25: 1057-1065.

In human patients, measurement of serum thyroid stimulating hormone (TSH) concentration is commonly used as a front-line test of thyroid function (1-3). 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. Therefore, the finding of a suppressed to undetectable serum TSH value in a human patient is considered diagnostic hyperthyroidism, even if serum T4 concentrations remain normal (1-3).

In cats, TSH can be measured using the widely available canine TSH (cTSH) assay (4-7). However, a major problem with the canine TSH assay, being a first generation assay, is that its detection limit (assay sensitivity) is not very good. This can make it difficult to distinguish between low-normal TSH values (found in many normal cats) from suppressed TSH concentrations (expected in hyperthyroid cats).

Despite this limitation, there are two published retrospective studies that suggest that subclinical hyperthyroidism may develop in cats. In one study, TSH concentrations were found to be undetectable in 15 of 16 cats when tested 1 to 3 years before hyperthyroidism was definitively diagnosed (8). In the second study, euthyroid cats that had low serum TSH values (<0.03 ng/ml) had a higher prevalence of adenomatous changes in the thyroid gland than a group of euthyroid cats with higher serum TSH concentrations (9).

The purpose of this study by Wakeling et al (10) was to determine whether or not euthyroid geriatric cats with undetectable TSH concentrations (<0.03 ng/ml) actually have subclinical hyperthyroidism and are at increased risk for subsequently developing overt hyperthyroidism.

Hypothesis of study 
Euthyroid cats with undetectable TSH concentrations have subclinical hyperthyroidism and may subsequently develop overt signs of hyperthyroidism.

Animals studied
104 client-owned geriatric cats (median age, 12.1 years).

In this prospective cohort study, 104 euthyroid, geriatric (>9 years) cats were recruited during routine health checks. Plasma biochemistry was performed at baseline and every 6 months thereafter. Total T4 and TSH concentrations were determined annually.

Short-term follow-up data (within 14 months of recruitment) were used to detect variables at entry that were predictive of the diagnosis of hyperthyroidism, using univariable analysis followed by multi-variable logistic regression analysis. Log rank analysis was used to test the association of initial TSH concentration with diagnosis of hyperthyroidism during the total available follow-up.

Results and Conclusions
In total, 17 of the 104 cats entered into this study were diagnosed with hyperthyroidism —11 cats diagnosed within 14 months that were included in the short-term follow-up data analysis and an additional 6 cats that were diagnosed during the subsequent period of longer follow-up. Median time for follow-up was 26 months (range, 0–54) and the annual incidence of hyperthyroidism developing during the study was 7.4%.

Cats that became hyperthyroid within 14 months had higher serum alkaline phosphatase activity (P = 0.02) and higher prevalence of goiter (P = 0.03) at baseline than the cats that remained euthyroid.

Cats with undetectable TSH at baseline (29/104; 28%) were significantly (P < 0.001) more likely to be diagnosed with hyperthyroidism. However, not all cats with undetectable TSH became hyperthyroid during the study.

My Bottom Line: 
Using cTSH Values as a Diagnostic Test for Feline Hyperthyroidism

This prospective study provides evidence that an undetectable TSH concentration (< 0.03 ng/ml) in euthyroid cats is associated with an increased risk for the subsequent diagnosis of hyperthyroidism. However, it is important to point out that not all cats with low TSH values went on to develop hyperthyroidism.

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 (4), 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 (4).

It is important to remember that the current canine TSH assay only detects approximately 35% of the circulating feline TSH (5,6). 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).

All human TSH assays currently used are second- or even third-generation assays (1-3). 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 (1-3); this much lower detection limit greatly improves their ability to accurately distinguish between normal and even partially suppressed TSH results.

Obviously, a better TSH assay for feline hyperthyroidism is needed— particularly, 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 it can be so difficult to distinguish normal values from the suppressed values expected in cats with hyperthyroidism (11,12). 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 (7).

  1. 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.
  2. Ross DS. Serum thyroid-stimulating hormone measurement for assessment of thyroid function and disease. Endocrinology and Metabolic Clinics of North America 2001; 30:245–264.
  3. Kasagi K, Kousaka T, Misaki T, et al. Comparison of serum thyrotrophin concentrations determined by a third generation assay in patients with various types of overt and subclinical thyrotoxicosis. Clinical Endocrinology 1999; 50:185–189.
  4. 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.
  5. Rayalam S, Eizenstat LD, Davis RR, et al. Expression and purification of feline thyrotropin (fTSH): Immunological detection and bioactivity of heterodimeric and yoked glycoproteins. Domestic Animal Endocrinology 2006; 30:185–202.
  6. 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.
  7. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Canadian Veterinary Journal 2010;51:33-34.
  8. Wakeling J, Elliott J, Syme HS. Does subclinical hyperthyroidism exist in cats? Journal of Veterinary Internal Medicine 2006;20:726 (abstract).
  9. Kirkby R, Scase T, Wakeling J, et al. Adenomatous hyperplasia of the thyroid gland is related to TSH concentration in cats. Journal of Veterinary Internal Medicine 2007;20:1522 (abstract).
  10. Wakeling J, Elliott J, Syme H. Evaluation of predictors for the diagnosis of hyperthyroidism in cats. Journal of Veterinary Internal Medicine 2011;25:1057-1065.
  11. Mooney CT, Peterson ME. Feline hyperthyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;92-110.
  12. Baral RM, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;571-592.

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