Diagnosing Hypothyroidism
World Small Animal Veterinary Association World Congress Proceedings, 2013
Carmel T. Mooney, MVB, MPhil, PhD, DECVIM-CA, MRCVS
University College Dublin Veterinary Hospital, UCD, Belfield, Dublin, Ireland

Hypothyroidism is arguably the most commonly diagnosed endocrine disease in dogs. However, its true prevalence is unknown and it probably is overdiagnosed with many dogs receiving unnecessary treatment. The difficulties in accurately confirming the disorder and the tendency towards overdiagnosis occur for a variety of reasons

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

 A wide variety of diagnostic tests are available with variable costs and imperfections.

 A myriad of non-thyroidal factors, including breed and age but particularly non-thyroidal illnesses (NTI) and medications, can profoundly affect tests of thyroid function.

 Hypothyroidism is not a single disease, but rather has many potential causes that progressively result in a decline in thyroid hormone concentrations and the subsequent development of clinical signs.

To accurately interpret results of thyroid function tests, it is necessary to know and understand the factors that influence each test. As such, one of the most important steps in confirming hypothyroidism is not the investigation of thyroid function per se, but careful evaluation of each patient for supportive clinical and clinicopathological features and elimination of non-thyroidal factors including other illnesses, and recent drug therapies that could influence test results. If thyroid testing is subsequently performed, pre-evaluation provides the clinician with much greater confidence in diagnosing or clearly eliminating hypothyroidism.

Aetiology

Hypothyroidism is the clinical syndrome that results from inadequate concentrations of the active circulating thyroid hormones thyroxine (T4) and triiodothyronine (T3). The most commonly recognized cause in adult dogs is irreversible, acquired, thyroid gland disease (primary hypothyroidism) resulting from lymphocytic thyroiditis or idiopathic atrophy, each of which occurs with approximate equal frequency. The loss of negative feedback on the pituitary gland is expected to result in an increase in circulating thyrotropin (thyroid stimulating hormone, TSH) concentrations. Central hypothyroidism, arising because of a defect in the pituitary gland or hypothalamus, is possible, but is of relatively minor importance in the dog.

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. This process may take months to years varying in progression from dog to dog and may not result in hypothyroidism in all cases. Therefore, there are variable periods of time during which there may be significant thyroid pathology and a potentially suboptimal or failing gland, but when clinical hypothyroidism has not yet become apparent. Studies in large numbers of affected dogs suggest a progression through the following stages:

 Silent thyroiditis - tests of thyroid autoimmunity [usually thyroglobulin autoantibody (TgAA)] positive, euthyroid (all thyroid hormones within reference interval)

 Subclinical (compensating) thyroiditis - TgAA positive, euthyroid with reference interval T4 and T3, but with high endogenous cTSH concentration

 Clinical disease - antibody positive, overtly hypothyroid

Over time, tests of thyroid autoimmunity may become negative as thyroid tissue is destroyed and there is a decline in the immune stimulation and response. It has been suggested that idiopathic atrophy may represent the end stage of lymphocytic thyroiditis. This is supported by the prevalence of both forms in certain breeds and the tendency for lymphocytic thyroiditis to be diagnosed at an earlier age.

Total Thyroxine

Circulating total T4 concentration is invariably decreased in dogs with hypothyroidism. However, many non-thyroidal factors will also decrease total T4. Fluctuations occur in healthy dogs, certain breeds have low and subnormal values (particularly sighthounds such as greyhounds, Irish wolfhounds, whippets, salukis), and there is an inverse correlation with age with progressively lower values encountered in older dogs. Decreased total T4 concentration is also a common feature in NTI and in dogs treated with various commonly used drugs (glucocorticoids, potentiated sulphonamides, anti-convulsants, and certain NSAIDs). Therefore, demonstration of a total T4 concentration below the reference interval does not confirm hypothyroidism. On the other hand, it remains a useful method of ruling out hypothyroidism as very few hypothyroid dogs have reference interval values. However, caution is advised as in approximately 8 % of hypothyroid dogs, T4 autoantibodies potentially result in falsely elevated total T4 concentrations. Most of these animals are also TgAA positive.

Endogenous Thyrotropin

Theoretically, circulating cTSH concentration is increased in primary hypothyroidism. However, a proportion of hypothyroid dogs have reference range cTSH values. The cause for this is still somewhat unclear, but possible explanations include random fluctuation, the presence of various isoforms of cTSH some of which may not be measured with current assays, the presence of concurrent disease and central hypothyroidism. Pituitary exhaustion may also play a role, and certainly in experimental cases, there is a marked increase in cTSH within a few months of inducing hypothyroidism followed by a gradual decline over the next few years.

The specificity of cTSH measurement has been reported as relatively high at approximately 80 %. However, 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 poor performance, measurement of cTSH alone has limited value in investigating hypothyroidism.

The high specificity of combined low total T4 and increased cTSH allows a confident diagnosis of hypothyroidism in the majority of cases. A combined total T4 and cTSH measurement is a practical, economic and fairly reliable first-line approach to hypothyroidism, especially if pre-evaluation has been performed. In one study investigating hypothyroidism, veterinarians diagnosed the disorder in over 75 % of dogs using total T4 alone, while that diagnosis was only supported by increased cTSH in approximately 15 % of cases. Thus, combining total T4 with cTSH certainly helps reduce the overdiagnosis of this condition.

Table 1. Advantages and disadvantages of various first-line diagnostic tests for hypothyroidism

  

Advantages

Disadvantages

Total T4

Highly sensitive (> 95 %)
Relatively inexpensive
Widely available
Reference values make hypothyroidism unlikely

Poorly specific (~75 %)
Lower in elderly dogs and certain breeds
Decreased by most NTIs
Decreased by many drugs

cTSH

Specificity ~ 80 %

HelpsdifferentiatelowT4of hypothyroidism from other causes

Poorly sensitive (75 %)
Should not be used alone
Increased by certain drugs and NTI recovery

Total T4 & cTSH

Specificity of combined low total T4 and increased cTSH > 90 %
Relatively cheap
Easily available

Low total T4 and normal cTSH does not rule out hypothyroidism

The main diagnostic difficulties associated with total T4 and cTSH measurement arise when total T4 is low but the cTSH value is within reference interval (likely to occur in about 25 % of hypothyroid dogs and a frequent possibility in dogs with NTI etc.). In this situation, if the index of suspicion for hypothyroidism remains high, free T4 and TgAA may both be useful second-line tests. Free hormone analysis should help distinguish genuine hypothyroidism from other causes of decreased total T4 and a positive antibody status confirms thyroid pathology.

Free T4

Free T4 is the metabolically active fraction of T4 and its measurement is widely acknowledged to more closely reflect actual thyroid status than total T4 determination. Free hormone is less affected by NTI and various drug therapies than total T4. However, recently, both glucocorticoids and barbiturate anticonvulsants have been shown to decrease free T4 concentrations in dogs and certain breeds, such as greyhounds, normally 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 are produced during the development of lymphocytic thyroiditis. A sensitive and more importantly specific, commercially available assay for canine TgAA is available and can be used to confirm the presence of thyroid pathology. The principal limitation of TgAA measurement 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 and so cannot be used as a sole diagnostic test. A positive TgAA result is strong evidence of thyroid pathology, but not necessarily hypofunction and a negative result certainly does not rule it out.

Epidemiological analysis of the prevalence of TgAA has shown a peak in dogs up to 4–6 years of age, which subsequently declines, presumably as thyroid tissue becomes destroyed and the antigenic stimulus decreases. Thus, it is of less value diagnostically in older dogs. In addition, it is of highest prevalence in breeds known to be predisposed to hypothyroidism and its measurement is likely to be of greater relevance in these animals.

The ability to reliably measure TgAA has resulted in its use as a marker of thyroid disease in clinically healthy dogs. As there is known to be 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. It must be remembered that not all positive dogs develop hypothyroidism. It has been suggested that of positive euthyroid dogs, 20 % develop thyroid hormone abnormalities suggestive of declining thyroid function and 5 % become overtly hypothyroid within one year.

Table 2. Advantages and disadvantages of various second-line diagnostic tests for hypothyroidism

  

Advantages

Disadvantages

Free T4

Highly specific (> 90 %)
Less affected by NTI and drugs
Unaffected by T4 autoantibodies

Less sensitive (~80 % ) than total T4
More expensive
Can be low in severe NTI and with certain drugs
Less robust during transport than total T4

TgAA

Positive result supports thyroid pathology

Provides no assessment of thyroid function
Negative result does not rule out hypothyroidism

Other Diagnostic Tests

A number of dynamic thyroid function tests have been used in the past. However, with the development of cTSH, free T4 and TgAA assays, these are largely obsolete in the clinical setting.

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

Because of the limited availability of bovine TSH, the TRH response test was often used as an alternative method of assessing thyroid reserve. Hypothyroid dogs fail to demonstrate a response to TRH administration, and a normal response excludes hypothyroidism. However, failure to respond to TRH does not confirm hypothyroidism, as it is a common finding in dogs with NTI and indeed even in healthy dogs and is therefore not recommended.

In humans with primary hypothyroidism, the TSH response to TRH administration is increased while NTI typically blunts the TSH response to TRH. However, in dogs it appears that the cTSH response is limited and this test apparently offers no advantages over the routine basal tests outlined above.

Determination of thyroid size and volume by ultrasound may be a useful test 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 and can reliably differentiate primary hypothyroidism from euthyroidism with low total T4 concentrations, although there can be an overlap in test results particularly in dogs treated with glucocorticoids. It has shown most promise in depicting euthyroidism in breeds with naturally low circulating thyroid hormone concentrations such as greyhounds.

References

1.  Diaz-Espineira MM, Mol JA, van den Ingh TS, van der Vlugt-Meijer RH, Rijnberk A, Kooistra HS. Functional and morphological changes in the adenohypophysis of dogs with induced primary hypothyroidism: loss of TSH hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with transdifferentiation. Domestic Anim Endocrinol. 2008;35:98–111.

2.  Graham PA, Refsal KR, Nachreiner RF. Etiopathologic findings of canine hypothyroidism. Vet Clin North Am Small Anim Pract. 2007;37:617–631.

3.  Mooney CT. Canine hypothyroidism: A review of aetiology and diagnosis. New Zeal Vet J. 2011;59:105–114.

4.  Shiel RE, Sist M, Nachreiner RF, Ehrlich CP, Mooney CT. Assessment of criteria used by veterinary practitioners to diagnose hypothyroidism in sighthounds and investigation of serum thyroid hormone concentrations in healthy Salukis. J Am Vet Med Assoc. 2010;236:302–308.

  

Speaker Information
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Carmel T. Mooney, MVB, MPhil, PhD, DECVIM-CA, MRCVS
University College Dublin Veterinary Hospital, UCD
Belfield, Dublin, Ireland


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