Interpreting Tests for Thyroid Disorders [State of the Art Lecture]
World Small Animal Veterinary Association World Congress Proceedings, 2008
Carmel T. Mooney, MVB, Mphil, PhD, DECVIM-CA, MRCVS
University Veterinary Hospital, School of Agriculture, Food Science & Veterinary Medicine
Belfield, Dublin, Ireland

Hypothyroidism is a common endocrine disease in dogs but hyperthyroidism rarely occurs in this species. Hyperthyroidism is common in cats and hypothyroidism rarely occurs. The accurate confirmation of either disorder in practice can be problematic:

 The clinical signs are variable, often subtle, few are pathognomonic and many occur in other more common conditions.

 Many diagnostic tests are available: some are relatively new but none is perfect.

 A myriad non-thyroidal factors, (breed, age, non-thyroidal illness (NTI) and certain drug therapies) can profoundly affect tests of thyroid function.

Consequently, the first step in confirming hypo- or hyperthyroidism is not the investigation of thyroid function per se, but the careful evaluation of the case for supportive features and elimination of non-thyroidal factors that could influence test results. If thyroid testing is subsequently performed, pre-evaluation allows a much more confident interpretation of the results.

Hypothyroidism in Dogs

Aetiology

Hypothyroidism results from inadequate concentrations of the active circulating thyroid hormones thyroxine (T4) and triiodothyronine (T3). The most common cause in adult dogs is acquired thyroid gland disease (primary hypothyroidism) resulting from lymphocytic thyroiditis or idiopathic atrophy, each of which occurs with approximately equal frequency. The underlying cause of lymphocytic thyroiditis is unknown, but it is recognized as a heritable trait. Clinical hypothyroidism only develops once approximately 75% of the thyroid gland is destroyed. Thyroid pathology theoretically can be present for months or years before clinical signs become apparent. The loss of negative feedback control on the pituitary gland is expected to result in an increase in circulating thyrotropin (thyroid stimulating hormone, TSH) concentrations.

Total Thyroxine

Circulating total T4 concentration is invariably decreased in hypothyroid dogs. However, many non-thyroidal factors will also decrease total T4. Certain breeds (sighthounds) have low values. There is an inverse correlation between age and total T4 concentration, with progressively lower values in older dogs. In addition to these normal physiological effects, decreased total T4 is also a common feature in NTI and in dogs treated with various drugs (steroids, potentiated sulphonamides, anti-convulsants, and certain NSAIDs). Therefore demonstration of a total T4 below the reference range does not confirm hypothyroidism, but is a useful method of ruling it out as few hypothyroid dogs have reference range values. However, in approximately 8% of hypothyroid dogs, T4 autoantibodies potentially result in falsely elevated total T4 concentrations. Most of these animals are thyroglobulin autoantibody (TgAA) positive.

Endogenous Thyrotropin (cTSH)

Decreased circulating thyroid hormone concentrations result in reduced negative feedback on the pituitary gland. Circulating cTSH concentration is therefore usually increased in primary hypothyroidism. However, approximately 20-30 % hypothyroid dogs have reference range cTSH values. Although the specificity of cTSH measurement has been reported as relatively high, abnormally elevated values can occur in euthyroid dogs receiving sulphonamide therapy, during the recovery phase of NTI and in compensating hypothyroidism. As a result of this, measurement of cTSH alone has limited value in investigating hypothyroidism.

Free T4

Free T4 is the metabolically active fraction of T4 and its measurement is widely acknowledged to more closely reflect tissue thyroidal status than total T4 determination. Free hormone is less affected by NTI and various drug therapies. However, recently, both glucocorticoids and barbiturate anticonvulsants have been shown to decrease free T4 concentrations in dogs. Certain breeds such as greyhounds have low values. Severe NTI is also known to decrease free T4 concentrations. Measurement of free T4 should be by equilibrium dialysis or ultrafiltration.

Thyroglobulin Autoantibodies

Antibodies against thyroglobulin (TgAA) are produced during the development of lymphocytic thyroiditis. A sensitive and specific assay for canine TgAA is available and can confirm the presence of thyroid pathology. The principal limitation is that not all dogs with hypothyroidism have lymphocytic thyroiditis (it is found in approximately 50 % of hypothyroid dogs) and it provides no detail on thyroid function. Therefore, whilst a positive TgAA result is strong evidence of thyroid disease, a negative result certainly does not rule it out. TgAA peaks in dogs up to 4-6 years of age, and subsequently declines, presumably as thyroid tissue becomes ablated and the antigenic stimulus decreases. TgAA is most prevalent in breeds known to be predisposed to hypothyroidism. It can be used as a marker of thyroid disease in clinically healthy dogs. Since there is a hereditary component to the development of thyroiditis, TgAA measurement is now used by dog breeders to identify predisposed animals prior to breeding, before clinical signs have developed.

Table 1. Features of Total T4, cTSH, Free T4 and TgAAmeasurement.

Total T4:

Advantages:

Inexpensive, sensitive marker for hypothyroidism
Widely available, easily measured

Disadvantages:

Lower in elderly dogs and certain breeds

Decreased by most NTIs

Subnormal at random times during the day

Decreased by certain drugs

Thyrotropin (cTSH):

Advantages:

Helps differentiate primary hypothyroidism from other causes

Disadvantages:

Should not be measured alone

Increased by certain drugs and recovery from NTI

'Normal' in > 20 % hypothyroid dogs

Free T4:

Advantages:

Less affected by NTI and drug therapy than total T4.

Unaffected by T4, autoantibodies

Decreased values more specific for hypothyroidism

Disadvantages:

Must be measured by 'dialysis'--more expensive than total T4

Can be decreased in severe NTI or by certain drugs

Less robust during transport than total T4,

May be low-normal in early hypothyroidism

Thyroglobulin Autoantibodies (TgAA):

Advantages

Positive result is extremely suggestive of thyroid pathology

Disadvantages

Provides no assessment of thyroid functional capacity

 

Negative result does not rule out significant thyroid disease

Combining Basal Analyses

When different tests are used together, the diagnostic limitations of each test are minimised. In combination, the gain from the high sensitivity of total T4 and high specificity of cTSH is maximized: a low total T4 and high cTSH provides for a diagnosis of hypothyroidism in most cases. This is a practical, economic and fairly reliable approach, especially if pre-evaluation has been performed; further diagnostic tests are only warranted in a minority of cases.

The main difficulties associated with total T4 and cTSH measurement arise when total T4 is subnormal but cTSH value is within the reference range. In this situation, if the index of suspicion for hypothyroidism remains high, free T4 and TgAA may be useful next steps. Free T4 should help distinguish genuine hypothyroidism from other causes of decreased total T4 and a positive antibody status confirms thyroid pathology.

TSH Response Test

The bovine TSH response test was once considered the single best test for assessment of thyroidal status. It provides an indication of thyroidal function but more importantly functional reserve capacity. However, bovine TSH is no longer widely available. Human recombinant TSH is available; recent studies have shown that it has equivalent biological activity in dogs and can be used to reliably diagnose hypothyroidism.

TRH Response Test

Because of the limited availability of bovine TSH, the TRH response test was used as an alternative to assess thyroidal reserve. Hypothyroid dogs fail to demonstrate a response to TRH administration: a 'normal' response excludes hypothyroidism. However, with the recent availability of a reliable free T4 assay, both these conclusions can now usually be reached using the tests outlined above. In addition, failure to respond to TRH does not confirm hypothyroidism, as it is a common finding in dogs with NTI and even in healthy dogs. The TRH response test offers no advantages over the basal tests above and is not recommended.

cTSH Response to TRH Administration

In humans with primary hypothyroidism, the TSH response to TRH administration is increased, presumably as a consequence of thyrotrop up-regulation. In contrast, NTI typically blunts the TSH response to TRH. However, the cTSH response seems limited in dogs; this test apparently offers no advantages over the routine basal tests outlined above.

Diagnostic Imaging

Determination of thyroid size and volume by ultrasound may be useful to distinguish between hypothyroid and euthyroid dogs with NTI but is highly operator dependent. Quantitative scintigraphic imaging, if available, provides a useful assessment of thyroid function.

Hyperthyroidism in Cats

Undoubtedly hyperthyroidism is easier to diagnose in cats than hypothyroidism is in dogs.

Aetiology

Hyperthyroidism in cats typically arises because of functional adenomatous hyperplasia (adenoma) of one or both thyroid lobes resulting in increased circulating concentrations of T4 and T3. Thyroid carcinoma is a rare cause of hyperthyroidism in cats. The resultant sustained negative feedback on the pituitary gland is expected to result in a decrease in circulating TSH concentrations.

Total T4

Its measurement is extremely reliable in identifying cats with hyperthyroidism. It is elevated in over 90 % of hyperthyroid cats and is never elevated in euthyroid animals. Approximately 10 % of hyperthyroid cats have values within the reference range as a result of non-specific thyroid hormone fluctuation or the suppressive effects of concurrent NTI. Total T4 fluctuation or suppression is of limited significance if total T4 elevation is marked, but in mildly affected animals a marginally elevated total T4 can descend into the reference range. As NTI has a suppressive effect on total T4 concentrations in euthyroid cats, concurrent hyperthyroidism should always be suspected in severely ill cats with total T4 concentrations in the mid to high reference range. If concurrent NTI is not present and a reference range total T4 value is obtained in an animal with suspected hyperthyroidism, further diagnostic tests should be considered or a T4 measurement should be repeated some weeks later.

Basal Free Thyroxine Concentration

Basal free T4 measurement is a more sensitive diagnostic test: over 98% of affected animals have elevated values. Free T4 must be measured by the more expensive methods of equilibrium dialysis or ultrafiltration. More importantly, free T4 concentrations are elevated in up to 12% of euthyroid cats with NTI. Consequently it is not recommended as a first line diagnostic test for hyperthyroidism. If a total T4 concentration is within the mid to high reference range and there remains a high index of suspicion for hyperthyroidism, free T4 should be measured in the same sample. A high value will confirm hyperthyroidism. By contrast, in euthyroid cats with NTI and high free T4 concentration, total T4 values are usually suppressed to the lower half of the reference range.

Other Diagnostic Tests

In the majority of hyperthyroid cats, identification of concurrent NTI and measurement of total T4 either alone or in combination with free T4 obviates the need for further diagnostic testing. Various other tests such as thyroidal radioactive iodine or technetium uptake or evaluating the response to T3 suppression, or TRH or TSH stimulation, are rarely used today. Preliminary reports suggest that the assay for measuring cTSH concentration is capable of measuring feline TSH and that it may be useful in evaluating early hyperthyroidism. However, caution is advised in its use alone because of its poor sensitivity at the low end of the reference range. Various studies are currently underway evaluating a feline species-specific TSH assay but results are not yet available.

References

1.  Diaz Espineira MM, et al. (2007) Assessment of thyroid function in dogs with low plasma thyroxine concentration Journal of Veterinary Internal Medicine 21, 25-32.

2.  Dixon RM, Mooney CT. (1999) Evaluation of serum free thyroxine and thyrotropin concentrations in the diagnosis of canine hypothyroidism. Journal of Small Animal Practice 40, 72-78.

3.  Graham PA, et al. (2007) Etiopathologic findings of canine hypothyroidism. Veterinary Clinics of North America Small Animal Practice 37, 617-631.

4.  Mooney CT, et al. (1996) Effect of illness not associated with the thyroid gland on serum total and free thyroxine concentrations in cats. Journal of the American Veterinary Medical Association. 208, 2004-8.

5.  Mooney, CT, et al. (2008) Clinical and thyroid hormone abnormalities in dogs with non-thyroidal illness. Journal of Small Animal Practice 49, 11-16

6.  Nachreiner RF, et al. (2002) prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. Journal of the American Veterinary Medical Association 220, 466-71.

7.  Peterson ME, et al. (1997) Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and thyrotropin concentrations for the diagnosis of hypothyroidism in dogs. Journal of the American Veterinary Medical Association 211, 1396-1402.

8.  Peterson ME, et al. (2001) 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. 218, 529-36.

9.  Wakeling J, et al. (2007) Subclinical hyperthyroidism in cats: a spontaneous model of subclinical toxic nodular goiter in humans. Thyroid. 17, 1201-9.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Carmel T. Mooney, MVB, Mphil, PhD, DECVIM-CA, MRCVS
University Veterinary Hospital, School of Agriculture
Food Science & Veterinary Medicine, UCD
Belfield, Dublin, Ireland


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