Feline Occult Hyperthyroidism

Profile
Hyperthyroidism is caused by usually bilateral (70%) adenomatous hyperplasia of the thyroid gland. Hyperthyroidism occurs in middle-aged to older (> 6 yr) cats; there is no breed or sex predilection. Hyperthyroid­ism occurs more frequently in indoor cats and those consuming a canned fish-based diet or diets containing liver flavor and giblets. The disease is common in certain coastal areas of the United States as well as in England and Australia, but is uncommon in Japan, France, and South Africa.

HISTORICAL AND PHYSICAL EXAMINATION FINDINGS
Historical findings include weight loss in conjunction with polyphagia, restlessness and increased activity, respiratory distress, weakness, vomiting, diarrhea, unkempt appearance or overgrooming, and such behavioral changes as aggression and inappropriate elimination. The most common physical examination finding is goiter (above image). Other physical examination findings may include tachycardia, panting, hyperthermia, anxiety and overactivity, mydriasis, and long toenails. On rare occasions, cardiac arrhythmia, gallop rhythm, or systolic murmurs may be found on auscultation. Common laboratory findings can include leukocytosis with eosinophilia, erythrocytosis, increased liver enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), and mild azotemia. Low serum cholesterol is an uncommon finding, and urinalysis is often unremarkable.
 

Basic Diagnosis
Hyperthyroidism can be diagnosed in approximately 90% of cats simply by measuring total serum concentrations of T4 (Table). However, this article focuses on the other 10%-those cats with occult hyperthyroidism that have clinical signs suggestive of hyperthyroidism (polyphagia, polydipsia, polyuria, weight loss, goiter) but exhibit normal serum total T4 concentrations at the time of examination. These cats may be challenging to diagnose for three reasons: 1) the hyperthyroidism may be mild or in the early stages, 2) the cat might have another nonthyroid illness that is suppressing total T4 into the normal range, and 3) T4 levels tend to fluctuate (on a daily basis or perhaps even more frequently).

Early or Mild Hyperthyroidism: Repeat the T4
Middle-aged and older hyperthyroid cats that present with weight loss and/or goiter but otherwise seem normal may be difficult to diagnose in the early stages of disease. Resting serum concentrations of both T4 and T3 are above the normal range in most cats with hyperthyroidism; however, some cats with hyperthyroidism (up to 10%) have serum concentrations of T4 that are within the mid- to high-normal range. Because many hyper­thyroid cats with normal serum concentrations of T4 have relatively early hyperthyroidism, it is likely that the thyroid hormone concentrations will eventu­ally increase into the thyro­toxic range if the disorder remains un­treated.

Thyroid hormone concentrations in cats with mild hyperthyroidism may fluctuate into the normal range in some cats, suggesting that a diagnosis of hyperthyroidism cannot be excluded on the basis of the finding of a single normal to high-normal serum T4 or T3 result alone. In cats with clinical signs consis­tent with hyper­thyroidism and in cats with palpable thyroid nodules, more than one serum T4 determination could be required to confirm a diag­nosis. Therefore, the first step should always be to repeat the basal T4 measurement; the second serum T4 determination should be made at least 1 to 2 weeks later. An elevated serum T4 concentration is diagnostic of hyperthyroidism. However, a single serum T4 level in the normal range in a cat with hyperthyroid signs does not rule out the disease.

Because hyperthyroidism has become more common and recognized in its early stages, serum free T4 concentrations have recently been shown to be more diagnostic of early or "occult" hyperthyroidism. If the repeat T4 test is also equivocal, then free T4 is the next test indicated.

Circulating thyroid hormones can either be bound to carrier proteins or free (unbound) in the plasma. Most commercial T4 and T3 assays measure total concentrations, both free and protein-bound. Because only the free fraction of thyroid hormone is available for entry into the cells, free T4 determinations may provide a more consistent assessment of thyroid gland status than total T4 concentrations. The finding of a high free T4 concentration (despite mid- to high-normal levels of T4) in a cat with a consistent history (e.g., weight loss despite good appetite) and physical examination findings (e.g., palpable thyroid nodule) supports the diagnosis of early occult hyperthyroidism. However, measurement of free T4 levels does have the potential for false-positive results (see next section).

Nonthyroid Illness with Suspected Hyperthyroidism: Free T4
In hyperthyroid cats with moderate to severe concurrent nonthyroid illness, such as re­nal disease, diabetes mellitus, systemic neoplasia, primary hepatic disease, or other chronic ill­nesses, normal serum thyroid hormone con­centrations may be found at the time of initial evaluation. Since severe nonthy­roid illness would be expected to decrease serum thyroid hormone concentrations into the low to undetectable range in sick cats without concurrent hyperthyroidism, con­comitant hyperthyroidism should be sus­pected in any middle- to old-aged cat with severe nonthyroid illness and normal serum T4 concentrations, es­pecially if signs of hyperthy­roidism are also present.

Free T4 concentrations seem to be much less affected by concurrent nonthyroid illness and may more accurately reflect true thyroid status. Occasionally, however, cats with nonthyroid illness (particularly those with gastrointestinal disease that affects serum binding proteins for T4) that do not have hyperthyroidism have high free T4 concentrations for reasons that are unclear. Therefore, to avoid misdiagnosing hyperthyroidism, free T4 should always be evaluated in conjunction with the total T4 concentration. In general, the combination of a high free T4 value with a low total T4 concentration (< 20 nmol/L or < 2.5 µg/dl) is indicative of nonthyroidal illness, whereas a high free T4 value with a high-normal T4 concentration (>25 nmol/L or >3.0 µg/dl) is suggestive of hyperthyroidism.

Advanced Diagnosis

TESTING FOR OCCULT HYPERTHYROIDISM
Thyroid Hormone (Triiodothyronine) Suppression Test

If a thyroid nodule cannot be palpated or if another illness is known to be present, the diagnosis of hyperthyroidism should be confirmed with T3 suppression or thyroid scintigraphy, which remain the gold standards for diagnosis of occult hyperthyroidism in cats. Inhibition of pituitary TSH secretion by high circulating concentrations of thyroid hormone is a characteristic feature of normal pituitary-thyroid regulation. Administration of T3 decreases TSH secretion in normal cats; this can be detected by a decrease in serum T4 concentrations. In contrast, when thyroid function is autonomous, as in cats with hyperthyroidism, administration of thyroid hormone has little or no effect on thyroid function because TSH secretion has already been chronically suppressed.

To perform the T3 suppression test in cats, draw a blood sample for determination of basal serum concentrations of total T4 and T3 (Table). Centrifuge the blood sample, remove the serum, and keep it refrigerated or frozen. Instruct the owner to administer oral T3 (liothyronine [Cytomel-Jones Medical Industries, St. Louis, MO]) on the following morning at a dosage of 25 µg 3 times daily for 2 days. On the morning of the third day, the owner gives a seventh 25-µg dose of liothyronine and brings the cat to the veterinary clinic within 2 to 4 hours for serum T4 and T3 determinations. When the T3 suppression test is performed in normal cats, there is a marked decrease in serum T4 concentrations after exogenous T3 administration. In contrast, when the test is done in cats with hyperthyroidism-even those with only slightly high or high-normal resting serum T4 levels-minimal if any suppression of serum T4 concentrations is seen. Cats with hyperthyroidism have postliothyronine serum T4 values greater than 20 nmol/L (approximately 1.5 µg/dl), whereas normal cats and cats with nonthyroid disease have T4 values less than 20 nmol/L.

Serum T3 concentrations can be used to monitor owner compliance with giving the drug. If inadequate T4 suppression is found but serum T3 values do not increase after treatment with liothyronine, problems with owner compliance should be suspected and test results should be considered
questionable.

Thyrotropin-Releasing Hormone Stimulation Test
In clinically normal cats, administration of TRH causes increased TSH secretion and serum T4 concentrations, whereas in cats with hyperthyroidism, the TSH and serum T4 response to TRH is blunted or absent. The TRH stimulation test is performed by collecting blood for serum T4 and T3 determinations before and 4 hours after intravenous administration of 0.1 mg/kg TRH (Relefact TRH-Hoechst-Roussel Pharmaceuticals, Somerville, NJ; Thypinone, Abbott Diagnostics-Abbott Park, IL) (Table). Many cats become transiently ill after TRH injection, manifesting vomiting, salivation, urination, and defecation after administration of TRH. Thus, the test is an in-hospital procedure and is less desirable than the T3-suppression test or thyroid scintigraphy. Cats with mild hyperthyroidism show little if any increase in serum T4 values after administration of TRH, whereas a consistent increase of serum T4 concentrations (approximately 2-fold) occurs after TRH administration in both clinically normal cats and those with nonthyroid disease. The relative increase (percentage increase) in serum T4 concentration after administration of TRH is the most sensitive criterion for predicting whether cats are hyperthyroid. An increase in serum T4 less than 50% is consistent with mild hyperthyroidism. Cats with hyperthyroidism have lost the normal pituitary-thyroid axis suppression associated with negative feedback; therefore, there will not be an increase in serum total T4 values after TRH stimulation.

D_X at a glance

What to Do
Diagnosis may be achieved after any given step, precluding the need for succeeding steps.
1. Submit serum sample for total T4 analysis
2. Repeat T4 measurement 1-2 weeks later
3. Submit sample for free T4 analysis (False-positive results sometimes occur for unknown reasons; evaluate in conjunction with total T4 test results, Steps 1 & 2)
4. Conduct T3 suppression test (Owner compliance is a limiting factor.)
5. Perform either:
• TRH stimulation test (Induces transient illness; evaluate patient before use.)
OR
• Thyroid scintigraphy