Hypothyroidism by Mike Herrtage: Part 2

Thyroid function tests

Serum total T4 and free T4

Baseline serum T4 concentration using a validated assay is more accurate than serum T3 in assessing the status of thyroid gland function and is recommended for initial evaluation of the thyroid gland.  Random fluctuations in serum T4 concentrations occur, but a true circadian rhythm has not been identified.

Serum T4 concentrations can be affected by breed, age, illness and drug administration.  Certain breeds particularly the sight hounds have lower serum T4 concentrations than other breeds and this is important when interpreting results from Greyhounds or Afghan Hounds.  Serum T4 concentrations tend to be higher in young growing puppies and lower in old dogs when compared to normal adult concentrations.  Concurrent illness can suppress serum thyroid hormone concentrations (sick euthyroid syndrome).  The degree of suppression is dependent on the severity of the illness or catabolic state rather than the specific disorder.  Various drugs can alter thyroid hormone metabolism and serum binding particularly glucocorticoids, anticonvulsants, non-steroidal anti-inflammatory drugs, frusemide and anaesthetic agents.

Serum free T4 concentrations measure metabolically active T4 and should not be influenced by the effects of serum binding.  However measurement of serum free T4 by most assays has not proved to be any more reliable than total T4 concentrations in the diagnosis of hypothyroidism.

A low baseline serum T4 concentration with a history and clinical signs compatible with hypothyroidism may be sufficient evidence to warrant a therapeutic trial.  In one study, the predictive value of a positive test result was 0.75 and of a negative test result was 0.87 using T4 concentrations to diagnose hypothyroidism.  Serum T4 concentrations in the low normal or non-diagnostic range should have further tests performed such as a canine TSH concentration and/or a TSH or TRH stimulation test if the index of suspicion is still high for hypothyroidism.

Serum T4 concentrations in the normal range are unlikely to be associated with hypothyroidism.  However antibodies to thyroid hormone can cause discordance between measured thyroid hormone concentrations and clinical status of the dog.  Depending on their concentration, binding affinity and the assay method employed, thyroid antibodies can result in either falsely elevated or falsely low thyroid hormone concentrations.  Autoantibodies to T4 and T3 can be measured in these cases.

Serum total T3 and free T3

Baseline serum T3 concentrations are less accurate for predicting hypothyroidism than serum T4.  Random fluctuations in serum T3 concentrations are greater than with serum T4 and have a greater tendency to be misleading with respect to the status of thyroid gland function.  Possible explanations for this discrepancy include the normal thyroid gland’s preference for secreting T4, the intracellular formation and location of most T3, the preferential secretion of T3 compared to T4 as thyroid function progressively fails and the development of anti-T3 antibodies.  The diagnostic value of serum T3 concentrations in hypothyroidism is therefore inferior to serum T4.

TSH stimulation test

The administration of exogenous TSH to measure thyroid secretory reserve is the most definitive method available for the diagnosis of hypothyroidism.  The use of this test is limited by the expense of the TSH injection and its inconsistent availability. Bovine TSH is no longer available, but human recombinant TSH is.

Peak serum T4 responses are decreased by non-thyroidal illness and drug administration in the same way as basal T4 concentrations.  Thyroid function testing is thus best performed after resolution of non-thyroidal illness and, if possible, with the patient off all mediation.

TRH stimulation test

TRH is readily available and less expensive than TSH.  However the T4 response to TRH is less predictable and peak concentrations tend to be lower than with TSH stimulation.  Increasing the dose of TRH increases the duration but not the magnitude of the T4 response.  TRH administration may cause cholinergic signs such as salivation, vomiting and defaecation.  Responses are also affected by non-thyroidal illness and drug administration.

Reverse T3 (rT3)

The measurement of serum rT3 concentration can be useful in identifying cases with significant non-thyroidal illness and should be reserved for those cases with discordant or equivocal T4 concentrations.  If the serum rT3 concentration is high in a dog with low or low-normal T4, hypothyroidism is unlikely to be the cause of the animal’s clinical signs.

Endogenous canine TSH (c-TSH)

A reliable assay for canine TSH would be a valuable aid to diagnosis particularly in primary hypothyroidism where the concentrations should be high.  In one study, it was concluded that cTSH measurements were a useful additional diagnostic test to serum T4 concentrations in the diagnosis of cases of suspected hypothyroidism, but that the sensitivity of the test was insufficient to obviate the need for a dynamic test (TSH or TRH stimulation test) to confirm the diagnosis in some cases of hypothyroidism.

Thyroid biopsy

Although not commonly performed, the histological examination of a thyroid gland biopsy provides an accurate method of differentiating between primary and secondary hypothyroidism.  In primary hypothyroidism, there is loss of thyroid follicles resulting from either lymphocytic thyroiditis or thyroid atrophy.  In secondary hypothyroidism, the thyroid follicles become distended with colloid and the follicular epithelial cells are flattened.  Testing thyroid function is still required to make a diagnosis of hypothyroidism, since the degree of histological change does not always relate to reduced hormone production and release.

Treatment

Thyroid hormone replacement is required for the treatment of hypothyroidism.  Synthetic forms of T4 and T3 are available.  Sodium levothyroxine (L-thyroxine) is the treatment of choice because it most closely resembles the preferential secretion of T4 by the normal thyroid gland.  Synthetic T4 is readily deiodinated to T3 in peripheral tissues and therefore does not by-pass the normal cellular regulatory processes that control the production of the more potent T3 in those tissues.

An initial replacement dose of L-thyroxine is 20 to 40 micrograms/kg daily in divided doses.  Although it has been suggested that once daily dosing is sufficient in many cases, the author has documented several cases where once daily administration has failed to maintain adequate serum concentrations throughout the day with a consequent failure of the clinical signs to resolve fully.  Poor absorption and a short half-life for T4 explain why dogs require higher doses and more frequent administration than human patients with hypothyroidism.

Therapy should always be continued for a minimum of three months.  Improved activity and mental alertness is usually seen within two weeks, but skin and hair coat changes may take up to 6 months to resolve.  Improved left ventricular function demonstrated by echocardiography and increased amplitude of the P and R waves on ECG is detectable within two months.

The effect of treatment can be monitored by measurement of post-pill serum T4 concentrations.  Sampling 4 to 6 hours after dosing will give a peak serum T4 concentration and a sample taken just prior to dosing will give the lowest serum T4 concentration.  The dose and frequency of administration should be adjusted to maintain the serum T4 concentration within the normal range throughout the day.  Underdosage may lead to treatment failure and overdosage can lead to iatrogenic hyperthyroidism.  Replacement therapy is required for life.

Cases of congenital hypothyroidism should be treated as early as possible to achieve normal growth and development.  The dose may require adjustment as the patient grows and gets older.

L-triiodothyronine must be administered every 8 hours at a dose of 4 to 6 micrograms/kg.  The disadvantages of this drug are its short half-life, expense and difficulty in monitoring.  Treatment with synthetic T3 is rarely justified.

Possible causes for cases failing to respond to replacement therapy include misdiagnosis, inadequate dose or frequency of administration, poor gastrointestinal absorption and peripheral tissue resistance.