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. Clinical 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 or total serum T4 and T3 concentrations decrease.

Clinical signs and clinical pathology changes in hypothyroidism may be non-specific. Where there is clinical suspicion, the first step in diagnosis involves a general biochemistry and haematologic screen and assessment of the Total T4 concentration. Low Total T4 concentrations are seen more frequently now that Total T4 is included in many routine blood screens. A single low basal Total T4 result is not diagnostic as Total T4 can be decreased by a number of chronic disease processes and drugs (the “euthyroid sick” state). Serum Total T4 concentrations fluctuate throughout the day and studies have shown that 50-60% of normal dogs have a T4 below the reference range at some time during the day. Likewise a basal Total T4 in the lower end of the reference range does not rule out hypothyroidism.

To help confirm the diagnosis, measurement of endogenous serum TSH and Free T4 concentrations are recommended. Details of each test are provided below.

Total T4

Total T4 is a measure of all T4 in the circulation and includes protein-bound and free T4. Total T4 may be measured by radioimmunoassay (RIA) or enzyme immunoassay. Gribbles Veterinary Pathology offers an automated enzyme immunoassay for testing Total T4. Both of these tests are validated for use in dogs and cats, and studies show an excellent correlation between these two test methodologies. Furthermore, the enzyme immunoassay has been shown to be less sensitive to interference from autoantibodies. Total T4 by enzyme immunoassay is precise, reliable and should be used as a baseline determination of thyroid status in dogs and cats. As with all endocrine disease, diagnosis may be complicated by concurrent disease and use of medications, including certain antibiotics, corticosteroids and anticonvulsants. As Total T4 predominantly measures protein-bound thyroid hormone, serum concentration may be affected by conditions that impact on the patient’s serum proteins. Interpretation of results should always take clinical history into account and may be aided by combining Total T4 with Free T4 and canine TSH as appropriate.

FreeT4

Free T4 is a measure of metabolically active, unbound thyroid hormone and makes up approximately 1% of the circulating thyroid hormone concentration. Free T4 is the portion of thyroid hormone that enters into cells to perform metabolic functions and exerts a negative feedback on pituitary production of TSH. Although Free T4 is less affected by non-thyroidal illness and autoantibodies than Total T4, it does have limitations, including cost of testing. Free T4 is not commonly used as an initial screening test for thyroid disease, but rather is best used in those patients with discordant clinical signs and Total T4 results, and where there is concern that Total T4 is affected by autoantibodies or concurrent non-thyroidal illness.

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 Total T4 is truly hypothyroid, allowing differentiation of true primary hypothyroidism from “euthyroid sick” syndrome in many, but not all, cases. In most cases, serum TSH will eliminate the need for TSH stimulatory tests. Serum TSH measurements are recommended only after an initial Total T4 result is low or low normal. If the hypothyroidism is secondary and 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 Total T4 measurement. Serum TSH concentrations should not be requested and interpreted alone but need to be interpreted with clinical signs and the concurrent serum Total T4 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 T4 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 Total T4 alone:

  • 0 - 11% of dogs that are actually hypothyroid will have a normal Total T4 concentration (false negatives)
  • 18 - 25% of low Total T4 results will be from normal dogs (euthyroid sick) (false positives)

Using TSH alone:

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

Interpreting T4 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. In these cases, where the clinical signs point to hypothyroidism it is ideal to do a TSH stimulation test; TSH can be difficult to obtain however and this test is not routinely done.
  • 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 lymphocytic thyroiditis 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 clinically 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.

Hypothyroidism in cats

There are few documented cases of naturally occurring hypothyroidism in cats and most cases are iatrogenic following treatment for hyperthyroidism. Hypothyroidism has been reported as a congenital defect in young kittens. Low Total T4 concentrations are seen more frequently now that Total T4 is included in many routine blood screens. In the majority of these cases the low Total T4 will be due to the suppressive effects of other illness (“euthyroid sick”) and not due to hypothyroidism.

Therapeutic Monitoring of Dogs During Thyroxine Treatment

The most important parameter to measure is the clinical response to treatment. Adequate therapy can be associated with T4 concentrations at the high end, or above the reference range.

Monitoring is a useful procedure in dogs under thyroid hormone therapy if:

  • Clinical response to treatment has been poor
  • Possible signs of thyrotoxicosis are present
  • Dosage or product has been changed
  • Other drugs that are known to alter serum T4 concentrations have been administered. The common drugs include corticosteroids, anticonvulsants, nonsteroidal antiinflammatories, some antibiotics and insulin.

Protocol:

  • Continue therapy for two to four weeks before monitoring
  • Take a serum sample (red top tube) just prior to, and 6 hours after administration of levothyroxine regardless of the frequency of dosing
  • Send both samples to the laboratory for measurement of Total T4 concentrations.

To reassess a diagnosis of hypothyroidism via hormone assays in a dog receiving thyroxine supplementation, thyroxine should be discontinued for at least four weeks to let thyroid function return to normal.

While serum TSH concentrations are used in humans to assess the response to treatment, in dogs serum TSH is not considered useful, as high values are found in less than half of under-supplemented dogs and low values cannot be accurately measured.