Diagnosis and treatment of canine hypothyroidism and thyroiditis (Proceedings)

Causes of hypothyroidism

Hypothyroidism results in decreased production of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) from the thyroid gland. At least 95% of cases of canine hypothyroidism are believed to be due to acquired primary hypothyroidism. Destruction of the thyroid gland can result from lymphocytic thyroiditis, idiopathic thyroid atrophy, or rarely neoplastic invasion. Secondary hypothyroidism (deficiency of TSH) is well described in humans but uncommonly recognized in the dog. Causes of acquired secondary hypothyroidism in the dog include pituitary neoplasia and pituitary malformations such as cystic Rathke's pouch. Tertiary hypothyroidism (deficiency of TRH) has not been documented in dogs.

Signalment

Any breed may develop hypothyroidism, however some breeds such as the golden retriever and the Doberman pinscher have been reported to be at higher risk in several studies. Many other breeds are suspected to have a predisposition for hypothyroidism. Middle aged dogs are at increased risk of hypothyroidism. In one study, mean age at diagnosis was 7.2 years with a range of 0.5 - 15 years. Spayed females and neutered male dogs are at increased risk for developing hypothyroidism compared with sexually intact animals.

Clinical signs

Because thyroid hormones influence the function of many organs, hypothyroidism is considered in the differential diagnosis of a wide range of problems. Clinical signs of hypothyroidism may be nonspecific and insidious in onset, and hypothyroidism is commonly misdiagnosed. Common clinical signs attributable to hypothyroidism include evidence of decreased metabolic rate such as lethargy, mental dullness, weight gain, unwillingness to exercise, and cold intolerance. Dermatologic changes are also common. Manifestations include a dry scaly skin, changes in haircoat quality or color, alopecia, seborrhea (sicca or oleosa), and superficial pyoderma. Hyperkeratosis, hyperpigmentation, comedone formation, hypertrichosis, ceruminous otitis, poor wound healing, increased bruising, and myxedema may also occur. Reproductive failure and neurologic dysfunction are less common manifestations of hypothyroidism.

Diagnosis of hypothyroidism

A clinical suspicion of hypothyroidism should be obtained by evaluation of the signalment, history and physical examination, results of a hemogram, biochemical panel and urinalysis, and measurement of total T4 concentration. Tests that may be utilized to confirm the diagnosis include measurement of free T4 and TSH concentration, provocative thyroid function tests, and response to thyroid hormone supplementation. Choice and interpretation of diagnostic tests is based heavily on the index of suspicion for hypothyroidism.

Clinical Pathology

Clinicopathologic changes that are commonly observed in dogs with hypothyroidism are a normocytic normochromic non-regenerative anemia, fasting hypertriglyceridemia, and hypercholesterolemia.

Basal thyroid hormone concentrations

The two most important thyroid hormones secreted by the thyroid gland are thyroxine (T4) and 3,5,3'triiodothyronine (T3). Thyroxine is the major secretory product of the thyroid gland, while the majority of serum T3 is derived from the extrathyroidal deiodination of T4. Both T3 and T4 are highly protein bound to serum carrier proteins such as thyroid binding globulin, transthyretin, and albumin. Only unbound (free) hormone penetrates cell membranes, binds to receptors and has biological activity. Protein-bound hormone acts as a reservoir and buffer to maintain a steady concentration of free hormone in the plasma despite rapid alterations in release and metabolism of T3 and T4 and changes in plasma protein concentrations. Free T4 is mono-deiodinated within cells to T3, which binds to receptors and induces the cellular effects of thyroid hormone.

Total T4 concentration

Total T4 concentration is the most commonly performed static thyroid hormone measurement and is a good initial screening test for canine hypothyroidism. In general a dog with a T4 concentration well within the normal range may be assumed to have normal thyroid function, however a basal T4 concentration below the normal range is not diagnostic for hypothyroidism. In this case the animal may be normal, hypothyroid, or suffering from a non-thyroidal illness with a secondary decrease in the basal T4 concentration (sick euthyroid syndrome). Factors such as time of day, age, breed, and ambient temperature, may affect the total T4 concentration without altering metabolically active free thyroid hormone concentrations. In one study, 50-60% of normal dogs had a low serum total T4 at some time during the day. Estrus, pregnancy, obesity, malnutrition, exogenous glucocorticoids, and drugs such as trimethoprim/sulfamethoxazole, anticonvulsants, salicylates, and phenylbutazone may also change the basal T4 concentration. Systemic illnesses that are particularly likely to decrease basal T4 concentrations include hyperadrenocorticism, diabetes mellitus, hypoadrenocorticism, renal failure, hepatic failure, and infection. Changes in protein binding, decreased conversion of T4 to T3, inhibition of TSH secretion, and inhibition of thyroid hormone synthesis by the thyroid gland are potential mechanisms for decreased total T4 concentrations in sick euthyroid dogs.

Free T4 concentration

Since only the unbound fraction of serum T4 is biologically active, measurement of free T4 has been hypothesized to be useful in differentiating euthyroid dogs from hypothyroid dogs. Despite the usefulness of free T4 assays in humans, most single stage solid phase (analogue) commercial assays for free T4 do not appear to be superior to measurement of total T4 in the dog, probably due to differences in serum binding proteins. A free T4 assay which utilizes an equilibrium dialysis step (direct dialysis) has better accuracy than the analogue methods, and is also more sensitive and specific for diagnosis of hypothyroidism than total T4.

Total T3 concentration

T3 concentrations are less accurate in distinguishing euthyroid from hypothyroid dogs since T3 concentrations fluctuate in and out of the normal range even more than T4 concentrations in euthyroid dogs. Spurious T3 measurements may also occur due to the presence of anti- T3 antibodies that may interfere with commercial assays for T3. Anti- T3 antibodies result in spuriously high values for T3 with most assays.

TSH concentration

Measurement of canine TSH concentration is useful in dogs with a low total T4 concentration, because a low T4 in conjunction with a high TSH is highly specific for diagnosis of hypothyroidism. The main disadvantage of measurement of TSH is the lack of sensitivity for diagnosis of hypothyroidism in the dog. Approximately thirty percent of hypothyroid dogs have a TSH concentration within the reference range. The reasons for this lack of sensitivity are unclear. It has been hypothesized that the current TSH assay may only measure certain isoforms of TSH. Other possibilities include diurnal fluctuation in TSH, effect of concurrent illness or drugs, and pituitary exhaustion.

TSH stimulation test

The TSH stimulation test evaluates the response of the thyroid gland to exogenously administered TSH and is a test of thyroid reserve. It is an accurate test of thyroid function in dogs but its use is limited by the expense and limited availability of TSH. The protocol requires collection of a serum sample for measurement of a basal T4 followed by administration of bovine TSH IV at a dose of 0.1 units/kg, (maximum dose 5 units). A second sample for measurement of T4 is collected 6 hours later. Human recombinant TSH is also now available, although quite expensive. The recommended dose is 75 µg IV with collection of 0 and 4 hour samples. Results are similar to those obtained using the bovine product and this product may be frozen for at least 8 weeks with no loss of potency. Results may reveal a normal response, a blunted response (sick euthyroid syndrome) or no response (hypothyroidism).

TRH stimulation test

In people this test is utilized to evaluate pituitary gland function (change in TSH after TRH administration), however in dogs the test has been used to evaluate thyroid gland function by measurement of change in T4 concentration after TRH administration. Unfortunately the change is not as large as after TSH administration, and some dogs with normal thyroid function have a decreased response to TRH. For this reason the test is of limited clinical utility. Various protocols have been reported with the most commonly used dose being 0.1 mg/kg of TRH administered IV with samples for measurement of T4 collected prior to, and 4-6 hours after TRH administration. Side effects such as salivation, vomiting, urination, defecation, miosis, tachycardia, and tachypnea may be observed. Recent studies have suggested that a lower fixed dose of 100 - 600 µg TRH IV, with samples collected at 0 and 4 hours is as reliable as the higher dose and less likely to result in side effects.

Thyroid ultrasound

Determination of thyroid gland size and volume by ultrasound may also be a useful adjunctive test for differentiating between hypothyroid and euthyroid dogs. It is important that the study is performed by an experienced operator.

Therapeutic trial

In some cases the most practical approach to confirming the diagnosis of hypothyroidism is a therapeutic trial. This is an acceptable practice providing the following guidelines are followed: Every attempt should be made to rule out non-thyroidal illness prior to starting a therapeutic trial. There is no evidence that thyroid hormone supplementation is beneficial in dogs with sick euthyroid syndrome, and it may be detrimental. Thyroxine supplementation should be initiated at a dose of 20 µg/kg (0.1 mg/10 lbs) q 12 hours. There are very limited studies documenting the comparative efficacy of available thyroxine products in the dog. It is however important to use a product that the clinician is familiar with and that gives a consistent response in their experience. Small differences between product bioavailability are unimportant provided therapeutic monitoring is used to guide the choice of final dose, however it is recommended to use the same product consistently rather than switching brands frequently. Objective criteria should be used to assess response to treatment. If a positive response to treatment occurs, the clinician should be prepared to withdraw therapy to confirm that clinical signs return. This will ensure that dogs with thyroid responsive diseases do not remain on thyroid supplementation for life. Dogs with thyroid responsive diseases are those dogs in which the clinical signs improve due to the nonspecific effects of thyroid hormone or unrelated to therapy. If therapy is unsuccessful, therapeutic monitoring should be performed to identify the cause of treatment failure. Since an incorrect diagnosis is the most common cause of treatment failure, the clinician should be prepared to withdraw therapy and pursue other diagnoses.

Diagnosis of thyroiditis

Anti-Thyroglobulin Antibody

Anti-thyroglobulin antibodies (ATA) are found in 42 to 59% of hypothyroid dogs and are believed to be the result of leakage of thyroglobulin into circulation due to lymphocytic thyroiditis. A commercially available ELISA assay for ATA is a sensitive and specific indicator of thyroiditis, with false positive results occurring in less than 5% of dogs with other endocrine disorders. Because anti-thyroglobulin antibodies are more common in hypothyroid dogs than euthyroid dogs, their presence may be useful in interpretation of other tests of thyroid function. It is important however, to recognize that a positive ATA titer may occur in euthyroid dogs. The proportion of euthyroid dogs with ATA that ultimately develop hypothyroidism is unknown. In one study, approximately 20% of euthyroid dogs with thyroiditis developed some evidence of thyroid dysfunction within one year. A small percentage of dogs (15%) became ATA negative after 12 months. Studies in our laboratory suggest that vaccination may also cause a short term positive result for ATA. Whether other variables such as viral infections can also cause transient thyroiditis is unknown. Measurement of ATA has been advocated for screening breeding stock with the aim of ultimately eliminating heritable forms of thyroiditis. It has yet to be proven that this is an effective approach.

Anti- T3 and T4 Antibodies

Antibodies directed against T3 and T4 also occur in canine thyroiditis, although they are less prevalent than ATA. Anti- T3 antibodies can be identified in approximately 30% of hypothyroid dogs. Anti-T4 antibodies also occur although they are less common (15% hypothyroid dogs). Since some euthyroid dogs also may have anti- T3 or T4 antibodies however, their presence is not diagnostic for hypothyroidism. In the presence of other equivocal results however, the presence of anti-thyroid antibodies increases the likelihood for hypothyroidism. Because T3 and T4 alone are small molecules, these anti-thyroid hormone antibodies probably develop against T3 and T4 containing epitopes of thyroglobulin. There is a higher prevalence of antithyroid antibodies in hypothyroid compared with euthyroid dogs, and antibodies are most prevalent in younger dogs and in breeds with a high prevalence of hypothyroidism. Antibodies directed against T3 and T4 may interfere with hormone assays leading to a spurious increase (most common) or decrease in the measured hormone concentration. In theory these antibodies could also increase a low T4 concentration into the normal or high range and result in a false diagnosis of euthyroidism or hyperthyroidism. Anti-thyroid antibodies do not interfere with response to thyroid supplementation in dogs with hypothyroidism.

Treatment of hypothyroidism

Synthetic thyroid hormone products are preferable to those of animal origin since synthetic products (salts of T3 or T4) are more stable and better standardized for potency. Sodium levothyroxine (synthetic T4) is the initial thyroid supplement of choice. Levothyroxine has a serum half-life of 12 - 16 hours and peak concentrations are achieved at 4 - 12 hours after administration. Recommendations for initiation of therapy are to administer levothyroxine at a dose of 20 µg/kg twice a day. Some dogs will ultimately only require supplementation once a day. Once a clinical response is achieved, a trial with once a day therapy can be instituted. Some authors recommend dosing based on body surface area (0.5 mg/m2). In animals with concurrent heart disease a sudden increase in the basal metabolic rate due to initiation of therapy can lead to cardiac destabilization. These animals should be started on 50% of the recommended starting dose for thyroxine and the dose then adjusted using therapeutic monitoring.

Synthetic triodothyronine administration is only indicated in those few situations when T4 supplementation has failed to achieve a response in a dog with confirmed hypothyroidism. This may occur due to impaired T4 absorption from the gastrointestinal tract. T3 supplementation is not recommended for initial therapy because only serum T3 concentrations are normalized while T4 levels remain low. Dogs receiving T3 supplementation may be more susceptible to iatrogenic thyrotoxicosis since serum T4 concentrations are important in the feedback regulation of the hypothalamic-pituitary-thyroid axis. Combination products which contain both T3 and T4 should be avoided for similar reasons. The plasma half-life of synthetic T3 is 5 - 6 hours so it needs to be administered three times a day. The initial starting dose is 4 - 6 µg/kg q 8 hours.

Response to therapy

Clinical improvement should be observed in 4 - 6 weeks from initiation of therapy although an improvement in the patient's activity level may occur within 1 week. Dermatologic abnormalities may take several months to completely resolve, and initially the appearance of the hair coat may worsen as old hair is shed. Reproductive and clinicopathologic abnormalities are usually the last to resolve.

Poor response to therapy

An absent or inadequate response to therapy may be due to incorrect diagnosis, poor owner compliance, inadequate dose of thyroid supplementation, poor oral absorption of thyroid supplement, or use of thyroid supplements of animal origin. Defective conversion of T4 to T3, and resistance of peripheral tissues to the action of thyroid hormone are theoretical causes of treatment failure that have not been well documented in dogs.

Therapeutic monitoring

Monitoring of serum T4 and/or TSH concentration will allow the clinician to identify the reason for failure to respond to thyroid supplementation and allow individualization of the dose and dosing frequency. Measurement of serum T4 concentrations should be performed after at least one month of therapy. A serum sample is taken prior to, and 4-6 hours after treatment and submitted for measurement of T4 concentrations. Dosage and frequency of thyroid supplementation can then be adjusted appropriately. The pre-pill T4 measurement should be in the normal reference range, and typically the post-pill T4 concentration is slightly above the reference range (up to 6µg/dl is considered acceptable). If it is only possible to collect one sample, a post-pill sample should be collected. The utility of measurement of TSH concentration during therapeutic monitoring is unclear since assay sensitivity does not allow detection of mild hyperthyroidism. Documentation of a TSH in the normal range however would be additional evidence of adequate supplementation.

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