Diagnosis and monitoring of hypothyroidism- general guidelines

Hypothyroidism in dogs

Hypothyroidism is the most common disease condition of the canine thyroid glands. Canine lymphocytic thyroiditis is believed to cause of about 50% of cases of canine hypothyroidism. Hypothyroidism does not occur until a large amount of the thyroid gland is non-functional, and sub clinical lymphocytic thyroiditis is present for some time before clinical signs of hypothyroidism emerge and total serum T4 and T3 concentrations decrease.

Total-T4 (TT4)

Clinical signs and clinical pathology changes in hypothyroidism can be non-specific. Where there is clinical suspicion, the first step in diagnosis involves a general biochemistry and haematologic screen and assessment of the TT4 concentration. A single low basal TT4 result is not diagnostic as TT4 can be decreased by a number of chronic disease processes and drugs (the “sick euthyroid” state). Serum TT4 concentrations fluctuate throughout the day and studies have shown that 50-60% of normal dogs have a TT4 below the reference range at some time during the day. Likewise a basal TT4 in the lower end of the reference range does not rule out the diagnosis. To help confirm the diagnosis, measurement of free-T4 and endogenous serum TSH concentrations are recommended. Details of each test are provided below.

Hypothyroidism in cats

There are few documented cases of naturally acquired hypothyroidism in cats and most cases are iatrogenic following treatment for hyperthyroidism. Hypothyroidism has been reported as a congenital defect in young kittens.

Hypothyroidism in horses

True hypothyroidism is uncommon in horses, with only very occasional reported cases. Nevertheless, single serum TT4 concentrations below the reference range are common. This is usually due to the presence of non-thyroidal illness or medication. In horses in which an initial low serum TT4 concentration is seen, a second TT4 measurement a couple of weeks later after medication has ceased or after recovery from an illness will usually reveal a normal value within the reference range.

Total T4

This is a measure of all T4 in the circulation and includes protein-bound and Free-T4 (FT4). TT4 is generally recognised as the standard screening test used for the determination of baseline thyroid status in dogs and cats. As with all endocrine disease, diagnosis is can be complicated by concurrent disease and use of medications, including certain antibiotics, corticosteroids and anticonvulsants. As TT4 predominantly measures protein-bound thyroid hormone, it may be affected by conditions that impact on the patient’s serum proteins. Thus, interpretation of results should always take clinical history into account and may be aided by combining TT4 with FT4 and canine TSH as appropriate. Awanui Veterinary Pathology offers an automated enzyme immunoassay for testing TT4.

Free-T4

Free-T4 (FT4) is a measure of metabolically active, unbound thyroid hormone and makes up approximately 1% of the circulating thyroid hormone concentration. FT4 is that portion of the thyroid hormone that enters into cells to perform metabolic functions and exerts a negative feedback on pituitary production of TSH. FT4 in dogs and cats is measured at Awanui Veterinary Pathology using a modified equilibrium dialysis method. This entails a preliminary dialysis stage followed by FT4 determination by RIA. Although FT4 by equilibrium dialysis is less affected by non-thyroidal illness and autoantibodies than TT4, it does have limitations, including: it is expensive and labour intensive to perform. FT4 by equilibrium dialysis is not commonly used as an initial screening test for thyroid disease, but rather is best used in those patients whose TT4 results appear not be in keeping with their clinical symptoms and where there is a suspicion that the TT4 concentration is being affected by autoantibodies or concurrent non-thyroidal illness or drug therapy.

Thyroid Stimulating Hormone (TSH) Assay

Hypothyroidism leads to lack of feedback inhibition resulting in increased concentrations of serum TSH. Endogenous serum TSH concentrations are useful in determining if a dog with a low TT4 is truly hypothyroid, i.e. differentiating true primary hypothyroidism from “sick euthyroid” syndrome. Serum TSH measurements are recommended only after an initial TT4 result is low or low normal. If the hypothyroidism is secondary as i.e. as a result of lesions within the pituitary gland or higher in the hypothalamus then TSH secretion will be reduced. In these cases serum TSH concentrations will be below the reference range.

Serum TSH measurement can be done on the same serum sample as the initial serum TT4 measurement. Serum TSH concentrations should not be interpreted alone but need to be interpreted with clinical signs and the concurrent serum TT4 concentration. Depending on the study, 13-38% of hypothyroid dogs may have serum TSH concentrations within the reference range and serum TSH concentrations may be increased above the reference range in 7.6-18% of normal dogs. Where serum TSH and TT4 concentrations are interpreted together there is good diagnostic accuracy. TSH results should be interpreted only in the light of clinical and laboratory evaluation for the presence of non-thyroidal illness.

Test Interpretation

From the two major studies on the diagnosis of hypothyroidism in dogs (Peterson et al 1997, Dixon & Mooney 1999) the following has been found:

Using TT4 alone then

0 – 11% of dogs which are actually hypothyroid will have a normal TT4 concentration (false negatives)
18 – 25% of the low TT4 results will be from normal dogs (sick euthyroid) (false positives)

Using TSH alone then

13 – 24% of dogs which are actually hypothyroid do not have the expected elevation in TSH (false negatives)
7 -18% of the elevated TSH results were from normal dogs (false positives)

Interpreting TT4 and TSH together

Using the two tests together still results in a significant number of true hypothyroid dogs not being diagnosed correctly as 13 -33% of the results in the above studies were false negatives. Interpreting the two tests together results in low numbers (2 – 8%) of false positives. This means that only a low number of normal/sick euthyroid dogs will be diagnosed incorrectly as hypothyroid.

Tests for lymphocytic thyroiditis – thyroglobulin autoantibody test

The best test to diagnose this condition is considered to be the thyroglobulin autoantibody test. All dogs with thyroglobulin autoantibodies are considered to have lymphocytic thyroiditis and this test is both sensitive and specific for the condition. A dog may have antibodies present but may not yet be hypothyroid. It is recommended that dogs with thyroglobulin autoantibodies be monitored regularly for signs of hypothyroidism. Of 171 dogs monitored with thyroglobulin autoantibodes, 20% became hypothyroid in the following year (Graham et al. 2001).

Therapeutic monitoring of TT4 concentrations in dogs during thyroxine treatment

Serum TT4 alone or in combination with TSH should be measured 6-8 weeks after commencing therapy, whenever signs of thyrotoxicosis develops or when there is a poor response to therapy. It should also be checked 2-4 weeks after any dose adjustments are made. Typically sample collection is performed 4 – 6 hours post-pill but pre-pill sampling may be useful when investigating a poor response to therapy in dogs on once daily dosing regimens. It is important that results are interpreted alongside the clinical response as low TT4 concentrations can be seen due to variable drug absorption from the gastrointestinal tract in otherwise well-controlled individuals.

References

Dixon RM, Mooney CT. Evaluation of serum free thyroxine and thyrotropin concentrations in the diagnosis of canine hypothyroidism. J Small Anim Pract. 1999; 40:72-78.
Graham et al. Lymphocytic thyroiditis. Vet Clin North Am. 2001; 31:915-933.
Peterson et al. Measurement of serum total thyroxine, triiodothyronine, free thyroxine and thyrotropin concentrations for the diagnosis of hypothyroidism in dogs. J Am Vet Med Assoc. 1997; 211:1396-1402.