Diagnosing Hypothyroidism in Dogs

I have a 7-year old spayed Golden Retriever who weighs about 110 lbs. No signs of hypothyroidism except for being overweight with a borderline high serum cholesterol concentrations (256 mg/dl). The serum T4 value was slightly low at 0.9 µg/dl (reference interval, 1.0-4.0 µg/dl).

Is this slightly low serum T4 concentration diagnostic for hypothyroidism? Would you start her on levothyroxine (L-T4) and retest T4 levels in a month?

I'd appreciate your thoughts and recommendations.

My Response: 

I would never base the diagnosis on only a resting serum T4 value alone. We commonly find low values that fluctuate in and out of the reference range in dogs that are clinically normal and never develop hypothyroidism. In addition, most non-thyroidal illness will lower the total T4 values in dogs, and these dogs would not benefit from thyroid hormone supplementation (1). It certainly doesn't sound like your dog is sick or acting ill in any way, so this latter explanation probably doesn't apply here.

For your dog, I'd recommend that your veterinarian collect more sera to do a complete thyroid panel, which should include the following tests (2-4):

• Serum T4 concentration
• Serum T3 concentration
• Serum free T4 by dialysis
• Serum TSH concentration
• Serum levels of thyroglobulin autoantibodies

If you have it available in your area, thyroid scintigraphy (nuclear medicine scan) is actually the best and most accurate way to diagnose hypothyroidism in dogs (4.5).

 References: 

1. Kantrowitz LB, Peterson ME, Melian C, et al. Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin concentrations in dogs with nonthyroidal disease. J Am Vet Med Assoc 2001;219:765-769. 
2. Peterson ME, Melian C, Nichols R. Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and thyrotropin concentrations for diagnosis of hypothyroidism in dogs. J Am Vet Med Assoc 1997;211:1396-1402.  
3. Nachreiner RF, Refsal KR, Graham PA, et al. Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. J Am Vet Med Assoc 2002;220:466-471. 
4. Diaz Espineira MM, Mol JA, Peeters ME, et al. Assessment of thyroid function in dogs with low plasma thyroxine concentration. J Vet Intern Med 2007;21:25-32.  
5. Shiel RE, Pinilla M, McAllister H, et al. Assessment of the value of quantitative thyroid scintigraphy for determination of thyroid function in dogs. J Small Anim Pract 2012;53:278-285. 

Hyperthyroid in Cats: Table of Contents

As you know if you have been following this blog, I've spent much of the last few months writing about issue of hyperthyroidism, the most common endocrine disorder of the cat.

Before I move on to the topics of treatment of this common feline condition, I thought I'd post links to the topics I've covered thus far:

1. Do All Hyperthyroid Cats Have a Thyroid Tumor? Is It Thyroid Cancer?
2. Why Has Hyperthyroidism in Cats Reached Epidemic Levels?
3. Top 10 Signs of Hyperthyroidism in Cats
4. Top 12 Physical Exam Findings in Cats with Hyperthyroidism
5. Diagnosing Hyperthyroidism in Cats: Routine Testing Procedures
6. Diagnosis of Hyperthyroidism in Cats: Serum T4 Concentrations
7. Diagnosis of Hyperthyroidism in Cats: Serum T3 Concentrations
8. Diagnosis of Hyperthyroidism in Cats: Serum Free T4 Concentrations
9. Diagnosis of Hyperthyroidism in Cats: Serum Free T4 (Part 2)
10. Diagnosis of Hyperthyroidism in Cats: Serum Free T3 Concentrations
11. Diagnosis of Hyperthyroidism in Cats: Serum TSH Concentrations
12. Diagnosis of Hyperthyroidism: T3 Suppression Test
13. Diagnosis of Hyperthyroidism: TRH Stimulation Test
14. Diagnosis of Hyperthyroidism: Thyroid Scintigraphy

I'm halfway through with this "book" on feline hyperthyroidism!

Confirming the Diagnosis of Hyperthyroidism in Cats: Thyroid Scintigraphy

Dr. Mark Peterson performing a thyroid scan on one of his hyperthyroid cat patients

Thyroid scintigraphy (thyroid scanning or thyroid imaging) provides valuable information regarding both thyroid anatomy and physiology and can play an integral role in the diagnosis, staging, and management of thyroid disease in cats with suspected hyperthyroidism.

Thyroid scintigraphy is considered the “gold standard” for diagnosing mild hyperthyroidism in cats (1-3, 6,7). It is considered to be the most sensitive diagnostic test available — yes, even better than determination of serum T4, free T4, or TSH for diagnosis of hyperthyroidism.

 In addition, thyroid scanning is an invaluable tool for evaluating the stage and extent of thyroid tumors (adenomas and carcinomas) in hyperthyroid cats (1,4,5,8).

How Thyroid Scintigraphy Works

To perform thyroid scintigraphy, the specialist injects the cat with a small dose of a radioactive tracer subcutaneously. Over the next hour, the cat’s salivary glands and thyroid glands take up the tracer. The radioactive tracer, now in the salivary and thyroid glands, then emits gamma rays (a high energy electromagnetic wave, a bit stronger than an X-ray), which are detected by a gamma camera to form an image.

To perform thyroid imaging, the cats sits normally on the camera (ventral view) or lies on his or her side (lateral view) while the gamma camera acquires the thyroid image (Figure1, above). The scanning process itself generally takes less than a minute and does not require sedation.

To watch video of Dr. Peterson performing a thyroid scan on a cat with hyperthyroidism, click on this link.

Use of Thyroid Scintigraphy as a Diagnostic Test

In normal cats, the thyroid gland appears on thyroid scans as two well-defined, focal (ovoid) areas of radionuclide accumulation in the cranial to middle cervical region. The two thyroid lobes are symmetrical in size and shape and are located side by side (Figure 2).

Figure 2: Thyroid scan of a normal cat.
Notice  the similar uptake of the radionuclide in the thyroid lobes and the salivary glands.

The normal feline thyroid gland will take up about as much of the tracer as the salivary glands do (see Figure 2). On the scan, we expect the thyroid and salivary glands to be equally bright (a 1:1 brightness ratio).  In addition to visual inspection, we can actually calculate the percent thyroidal uptake of the radioactive tracer as well as the exact the thyroid:salivary ratio. Both of these calculations are strongly correlated with circulating thyroid hormone concentrations and provide a extremely sensitive means of diagnosing hyperthyroidism (6,7).

Figure 3: Thyroid scan of a hyperthyroid cat with a single thyroid adenoma.
Notice  the increased uptake of the radionuclide in the thyroid tumor compared with the salivary glands.

Figure 4: Thyroid scan of a hyperthyroid cat with bilateral thyroid adenomas.
Notice  the increased uptake of the radionuclide in both thyroid tumors compared with the salivary glands.

In hyperthyroid cats, thyroid scintigraphy directly visualizes functional thyroid tissue (Figures 3 and 4). Based up the calculated percent tracer uptake or thyroid:salivary ratio, thyroid imaging can diagnose hyperthyroidism before laboratory tests are consistently abnormal. Thyroid scanning can also prevent misdiagnosis of hyperthyroidism in cats with falsely high serum thyroid hormone values.

More Uses for Thyroid Scintigraphy

Thyroid scintigraphy has four more uses in hyperthyroid cats, other than as a diagnostic test. First, it is an excellent method for evaluating the size of ectopic thyroid tissue, which can be located anywhere from base of the tongue to the heart (Figure 5). Second, it can locate large tumors that gravity has pulled into the thoracic cavity. Finally, thyroid scintigraphy also provides valuable information for diagnosing and evaluating cats with thyroid carcinomas (Figure 6).

Figure 5: Thyroid scan of a hyperthyroid cat with ectopic thyroid adenoma located with the chest cavity. Because of its location, this tumor could not be palpated on physical examination.

Figure 6: Thyroid scan of a hyperthyroid cat with a thyroid carcinoma (cancer). Note the extension of tumor beyond the limits of the normal thyroid capsule. This represents regional metastasis characteristic of carcinoma.

Once we locate a hyperthyroid cat's thyroid tumors on the scan, we can then measure the tumor size and calculate tumor volume (3). This is very helpful in individualizing the cat's dose of radioiodine.

Why Isn't Thyroid Scintigraphy Used More Often?

Apart from expense and the licensing needed to handle and administer radioisotopes, few veterinarians have access to the nuclear medicine equipment needed to obtain thyroid images or perform thyroid uptake determinations. Only a few large referral hospitals in the country offer nuclear scintigraphy to do thyroid scanning.

At the Animal Endocrine Clinic, we routinely perform thyroid scintigraphy on all of our cats in which the diagnosis is not completely clear cut (go to my website for more information).  We believe that thyroid scintigraphy plays an essential role in the diagnosis and management of cats with hyperthyroidism.

References:

1. Broome MR. Thyroid scintigraphy in hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:10-16.
2. Daniel GB, Sharp DS, Nieckarz JA, et al. Quantitative thyroid scintigraphy as a predictor of serum thyroxin concentration in normal and hyperthyroid cats. Veterinary Radiology & Ultrasound 2002;43:374-382.
3. Forrest LJ, Baty CJ, Metcalf M.R, et al, Feline hyperthyroidism: Efficacy of treatment using volumetric analysis for radioiodine dose calculation. Veterinary Radiology & Ultrasound, 1996;37:141-145.
4. Harvey AM, Hibbert A, Barrett EL, et al. Scintigraphic findings in 120 hyperthyroid cats. Journal of Feline Medicine and Surgery 2009;11:96-106.
5. Kintzer PP, Peterson ME. Nuclear medicine of the thyroid gland. Scintigraphy and radioiodine therapy. Veterinary Clinics of North America: Small Animal Practice 1994;24:587-605.
6. Mooney CT, Thoday KL, Nicoll JJ, et al. Qualitative and quantitative thyroid imaging in feline hyperthyroidism using technetium-99m as pertechnetate. Veterinary Radiology & Ultrasound 1992;33,313-320.
7. Nap AM, Pollak YW, van den Brom WE, et al. Quantitative aspects of thyroid scintigraphy with pertechnetate (99m TcO4) in cats. Journal of Veterinary Internal Medicine 1994;8:302-303.
8. Peterson ME, Becker DV. Radionuclide thyroid imaging in 135 cats with hyperthyroidism. Veterinary Radiology 1984;25:23-27.

Confirming the Diagnosis of Hyperthyroidism: Thyrotropin-Releasing Hormone (TRH) Stimulation Test

In my last blog post, I discussed use of dynamic test, the T3 suppression test. Suppression testing can be helpful in confirming the diagnosis when we suspect that a cat has mild hyperthyroidism but serum concentrations of total and free T4 are either normal or borderline.

An alternative dynamic test that can be used to help diagnose cats with mild or occult hyperthyroidism is the thyrotropin-releasing hormone (TRH) stimulation test (1-3). Compared with the T3 suppression test, this test takes the opposite approach — now we are stimulating, rather than suppressing, the secretion of TSH from the pituitary, which in turn, would lead to increased T4 secretion.

Thyrotropin-Releasing Hormone (TSH) Stimulation Test

TRH is the hormone released by the hypothalamus that subsequently stimulates the release of thyrotropin (TSH) from the pituitary gland (4). When administered intravenously to normal cats, TRH causes an prompt increase in TSH secretion and serum T4 concentrations (see Figure 1, left panel).

Figure 1: TRH tests in normal cats (left) & cats with hyperthyroidism (right)

In contrast to the situation in normal cats, administration of large doses of TRH to hyperthyroid cats has little or no effect on TSH or T4 secretion. The reason for this that pituitary TSH secretion has already been completely and chronically suppressed by the higher-than-normal thyroid hormone secretion characteristic of hyperthyroidism (see Figure 1 above, right panel).

Administration of only a single dose of TRH is not enough to stimulate chronically suppressed TSH-secreting cells.

Testing Protocol for the TRH Stimulation Test

To perform the TRH stimulation test in cats, the following protocol is recommended:

1. The veterinarian draws a blood sample for determination of baseline serum concentrations of total T4 (and T3).
2. TRH (Protirelin) is administered to the cat at the dosage of 100 μg/kg, IV.
3. Four hours later, the veterinarian again draws a blood sample for serum T4 (and T3) determinations.

One may ask: but what about measuring TSH? Indeed, that would be a more direct measure and would shorten the testing time from 4 hours to less than an hour (4). However, because use of TSH measurements in cats with thyroid disease have only recently been advocated, studies looking the serum TSH response to TRH have yet to be published in cats.

Interpretation of Results of TRH Stimulation Testing

When the TRH stimulation test is performed in normal cats and sick cats without hyperthyroidism (1), there is a consistent rise in serum T4 concentrations (approximately 2-fold rise). In contrast, when the test is performed in cats with hyperthyroidism, even in cats with only slightly high or high-normal resting serum T4 concentrations, there is little, if any, rise in serum T4 values after the administration of TRH (see Figure 2, below).

Figure 2 — Box plots of the serum T4 concentrations before (A) and after (B) TRH stimulation in 31 clinically normal cats, 35 cats with hyperthyroidism, and 15 cats with nonthyroidal disease. The "box" represents the interquartile range from the 25th to 75th percentile (represents the middle one-half of the data). The horizontal bar through the box is the median. The "whiskers" represent the main body of data, which in most cases is equal to the range. Outlying data points are represented by open circles. To convert serum T4 concentrations from nmol/L to µg/dl, divide the given values by 12.87.

Regarding interpretation of the TRH stimulation test results, we found that the relative rise (per cent increase) in serum T4 concentration after administration of TRH was the best (most sensitive) criteria for predicting whether or not cats are hyperthyroid (1). A percent rise in serum T4 of less than 50 per cent is consistent with mild hyperthyroidism, whereas a value of greater than 60 per cent is seen in normal cats; values between 50 and 60 per cent are equivocal or borderline responses.

The serum T3 response to TRH is less helpful in separating normal from hyperthyroid cats, because many normal cats have only a small and inconsistent rise in serum T3 concentrations after TRH administration. Therefore, I do not recommend determining the serum T3 response as part of the TRH stimulation test.

In another study of 36 cats with severe critical illness (5), half of the severely sick cats showed an inadequate T4 response to TRH stimulation test (i.e., a percent rise in serum T4 of less than 50 per cent). Unfortunately, this could create a situation where mild hyperthyroidism is falsely diagnosed in a cat with critical illness.  Although the reason for this is unclear, critical nonthyroidal illness may render pituitary TSH secretion unresponsive to the stimulatory effects of TRH administration.

The bottom line: This test is not meant to differentiate normal and hyperthyroid cats from cats with severe critical illness. I do not recommend doing this test in severely ill cats, inasmuch as the test results may be invalid.

Which is Better: TRH Stimulation Test vs. the T3 Suppression Test?

Advantages of the TRH stimulation test over the T3 suppression test include the shorter time needed to perform the test (4 hours vs. 3 days), and the fact that the TRH stimulation test is not dependent upon the owner's ability to administer oral medication.

The major disadvantage of the TRH stimulation test in cats is that side effects almost invariably occur immediately after administration of the TRH (1, 6-8). These adverse effect include the following:

• Excessive salivation (see Figure 3)
• Vomiting
• Induced defecation
• Rapid breathing (tachypnea); open mouth breathing

Fortunately, all of the adverse side effects are transient and completely resolve by the end of the 4-hour test period. Because of these adverse effects, however, I generally do a T3 suppression test over the TRH stimulation test for dynamic testing of the pituitary-thyroid axis.

Figure 3: Cat showing increased salivation after TRH administration

Our studies show a close relationship between the presence (or absence) of suppressed serum T4 concentrations in response to T3 suppression and stimulated T4 values in response to TRH stimulation. Therefore, although the two tests evaluate the pituitary-thyroid axis in different ways, our findings indicate that the two screening tests provide similar information and can probably be used interchangeably for diagnosing mild hyperthyroidism in cats.

Future Investigations: Serum TSH Response to TRH Stimulation in Cats

In human beings, the TRH stimulation test is generally done by directly evaluating the change in serum TSH concentrations, not indirectly by measuring serum T4  values.  When this is done, the TRH stimulation test is one of the most sensitive tests in detecting early or mild hyperthyroidism in human patients. Again, because TSH production is completely suppressed in hyperthyroid patients, they will not show a rise in serum TSH when TRH is administered, whereas normal individuals will respond with a brisk rise in circulating TSH within 30 minutes of TRH injection. The new, ultra-sensitive human TSH assays have largely eliminated the need for TRH stimulation testing, but it still remains a useful and time-proven test.

Similar serum TSH responses to TRH have been reported in normal dogs — baseline serum TSH concentrations increase 2- to 3-fold when measured 30 minutes after administration of TRH at doses ranging from 1-10 μg/kg. There are two major advantages of evaluating the TSH response rather than the T4 response to TRH:

1. The test period is shorten from 4 hours to only 15-30 minutes.
2. A much lower dose of TRH is needed, greatly reducing or eliminating the adverse signs commonly seen with the higher doses needed to elicit a serum T4 response.

Measuring the serum TSH response to TRH has not been reported in cats with hyperthyroidism. Obviously, this is an area that needs to be investigated, now that we know that the canine TSH assay can be used to measure circulating TSH in cats.

Because the canine TSH assay is not designed to measure low values, basal TSH measurements are not very useful as a diagnostic test in feline hyperthyroidism (see my previous blog on TSH in cats). However, measuring the response to TRH may turn out to be a extremely useful and sensitive test for this disease.

References:

1. Peterson ME, Broussard JD, Gamble DA: Use of the thyrotropin releasing hormone stimulation test to diagnose mild hyperthyroidism in cats. Journal of Veterinary Internal Medicine 1994;8:279-286.
2. Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:2-9.
3. Peterson ME: Diagnostic testing for feline hyper- and hypothyroidism. Proceedings of the 2011 American College of Veterinary Internal Medicine (ACVIM) Forum, pp. 95-97, 2011.
4. Utiger RD: Tests of thyroregulatory mechanisms. In Ingbar SH and Braverman LE (eds): The Thyroid: A Fundamental and Clinical Text, pp 511-523. Philadelphia, JB Lippincott, 1986.
5. Tomsa K, Glaus TM, Kacl GM, et al. Thyrotropin-releasing hormone stimulation test to assess thyroid function in severely sick cats. Journal of Veterinary Internal Medicine 2001;15:89-93.
6. Holtman JR, Buller AL, Hamosh P, et al: Central respiratory stimulation produced by thyrotropin-releasing hormone in the cat. Peptides 1986;7:207-212.
7. Beleslin DB, Jovanovic-Micic D, Tomic-Beleslin N: Nature of salivation produced by thyrotropin-releasing hormone (TRH). Brain Research Bulletin 1987;18:463-465.
8. Beleslin DB, Jovanovic-Micic D, Samardzic R, et al: Studies of thyrotropin-releasing hormone (TRH)-induced defecation in cats. Pharmacology Biochemistry & Behavior 1987;26:639-641.
9. Yagi K, Ohashi E, Tanabe S, Uzuka Y, Sarashina T. Serum thyrotropin response to TRH administration in six healthy beagle dogs. Veterinary Record 2000;146:706-707.

Confirming the Diagnosis of Hyperthyroidism in Cats: Serum TSH Concentrations

Measuring TSH in Human Patients with Thyroid Disease

In human patients, measurement of circulating thyroid stimulating hormone (TSH; also called thyrotropin) is commonly used as a front-line test of thyroid function. This hormone is secreted by the pituitary gland and, as its name suggests, acts to stimulate the thyroid gland to secrete T4 and T3.

The pituitary gland constantly monitors the circulating levels of T4 and T3, and if it senses the slightest increase in serum thyroid hormone concentrations, it stops producing TSH. In contrast, if the pituitary senses even a slight decrease in circulating T4 and T4 concentrations, it increases the secretion of TSH in an attempt to increase thyroid hormone levels back to normal.

Consequently, the finding of a low to undetectable blood TSH value in a human patient is diagnostic for hyperthyroidism, whereas a high serum TSH concentration is diagnostic for hypothyroidism. When testing human patients, the finding of a normal TSH result excludes both hypo- or hyperthyroidism.

TSH Concentrations as a Diagnostic Test for Cats

A species-specific feline TSH assay has not yet been developed for use in cats, and human TSH assays cannot be used to measure feline TSH. However, assays for measuring canine TSH (cTSH) are widely available, and studies have investigated the use of cTSH measurements as a diagnostic test for cats with suspected thyroid dysfunction — both hyperthyroidism or hypothyroidism (1-3).

However, there are many problems with the use of the cTSH assay, both in dogs as well as in cats.

First Problem: The first issue or problem with the use of the canine TSH assay is that this test, although first developed in 1997 (now 14 years ago), is still a considered "first generation" assay. Overall, this assay is not considered very reliable for the following reasons:

• It has a diagnostic test sensitivity of only 60-75% in canine hypothyroidism, a very common endocrine problem in dog (4-6). Because 25% to 40% of dogs with confirmed hypothyroidism do not have the high serum TSH concentrations (> 0.6 ng/ml) that we expect to find with thyroid failure, it's possible that some isoforms of the TSH hormone are not being detected with this assay.
• In addition to this high incidence of false-negative results, cTSH levels appear to be falsely-high in 10% to 20% of dogs with normal thyroid function (4). Some of these dogs have other nonthyroidal illnesses; however, falsely high serum cTSH values have even been reported in clinically normal dogs that had completely normal total and free T4 concentrations.
• The high prevalence of false-negative and false-positive test results make this assay unreliable to use as a sole diagnostic test for dogs with suspected hypothyroidism.

Second Problem: It is important to remember that the current canine TSH assays only detects approximately 35% of the circulating feline TSH. In other words, the current cTSH assay does not completely cross-react with feline TSH; therefore, the assay is not measuring the total amount of TSH present in the cat's serum.

This poor cross-reactivity of feline TSH in the canine assay explains why the upper limit of the reference range for TSH is so much lower in cats (0.15-0.3 ng/ml) than it is in dogs (0.5-0.6 ng/ml). Again, the cTSH assay is only measuring about a third of the feline TSH present in the circulation.

Third Problem: A major problem with the canine TSH assay, being a first generation assay, is that its detection limit (assay sensitivity) is not very good.  In fact, it's really poor! Therefore, this assay does not perform well when we are trying to measure very low concentrations of TSH.

In cats this issue is again made even worse by the fact that only 35% of the cat's TSH will be detected by the cTSH assay. As a consequence of this poor cross-reactivity, the assay sensitivity, which is already considered poor at 0.03 ng/ml in the dog, equates to only 0.10 ng/ml of TSH in the cat (7).  With such a "high" detection limit, we cannot reliably distinguish a normal TSH concentration from a low or undetectable value in cats with this cTSH assay. In other words, this assay just cannot accurately measure low enough to distinguish between normal and low feline TSH concentrations.

All human TSH assays currently used are second or even third generation assays. Like the cTSH assays, the first generation human TSH assays were also unable to distinguish low-normal from low TSH concentrations. The major advantages of the second to third generation TSH assays is their 10- to 100-fold improvement in assay sensitivity (8); this much lower detection limit greatly improves their ability to accurately distinguish between normal and even partially suppressed TSH results.

Hopefully, we will also be moving on to a second generation of TSH assays for dogs (and cats), which should improve the sensitivity (detection limit) of the assay. This will also help make this a better test for hyperthyroidism, as well as hypothyroidism in cats.

Using TSH Concentrations as a Diagnostic Test for Hyperthyroidism in Cats

Of course, the poor detection limit of the current cTSH assay represents a major issue in cats with hyperthyroidism, where low suppressed values are expected. In one of the best studies of cTSH concentrations in cats (2), all of the hyperthyroid cats tested had cTSH concentrations at or below the limit of detection of the assay (0.03 ng/ml).  However, of the 40 cats without hyperthyroidism tested in that same study, 5 cats also had undetectable levels of TSH, indistinguishable from the values in the hyperthyroid cats (see Figure below).

TSH values in normal cats, hyperthyroid cats, and cats with chronic kidney disease. Notice that  all hyperthyroid cats have very low TSH concentrations. However, there is much overlap between the TSH values in the hyperthyroid cats and the values in the cats without hyperthyroidism. Modified from data in reference 2.

Obviously, a better TSH assay for feline hyperthyroidism is needed— specifically, a feline-specific TSH assay that has adequate sensitivity to reliably distinguish a normal value from a low one. However until better TSH assays for cats are available, caution is advised in over interpreting values in cats since can be so difficult to distinguish normal values from the suppressed values expected in cats with hyperthyroidism. Perhaps the only use for TSH measurements using the cTSH assay would be to exclude hyperthyroidism, i.e., finding a mid- to high-normal value rather than a suppressed value (3).

Using TSH Concentrations as a Diagnostic Test for Hypothyroidism in Cats

At this time, the major use for the current cTSH assay is as a diagnostic test for hypothyroidism, where the low circulating thyroid hormone concentrations sensed by the pituitary gland leads to high serum TSH values. In accord with that, high cTSH values have been reported in cats with naturally occurring hypothyroidism, as well as cats with iatrogenic hypothyroidism, i.e., secondary to methimazole or radioiodine treatment (9).

Normal cats and cats with nonthyroidal illness generally maintain normal values for serum TSH. Therefore, the finding of a low total or free T4 in combination with a high TSH concentration greatly improves the diagnostic sensitivity for hypothyroidism in cats.

References:

1. Greco DS. Diagnosis of congenital and adult-onset hypothyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:40-44
2. Wakeling J, Moore K, Elliott J, et al. Diagnosis of hyperthyroidism in cats with mild chronic kidney disease. Journal of Small Animal Practice 2008;49:287-294.
3. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Canadian Veterinary Journal 2010;51:33-34.
4. Peterson ME, Melian C, Nichols R. Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and thyrotropin concentrations for diagnosis of hypothyroidism in dogs. Journal of the American Veterinary Medical Association 1997;211:1396-1402.
5. Scott-Moncrieff JC, Nelson RW, Bruner JM, et al. Comparison of serum concentrations of thyroid-stimulating hormone in healthy dogs, hypothyroid dogs, and euthyroid dogs with concurrent disease. Journal of the American Veterinary Medical Association 1998;212:387-391.
6. Dixon RM, Mooney CT. Evaluation of serum free thyroxine and thyrotropin concentrations in the diagnosis of canine hypothyroidism. Journal of Small Animal Practice 1999;40:72-78.
7. Ferguson DC, Caaffall Z, Hoenig M. Obesity increases free thyroxine proportionally to nonesterified fatty acid concentrations in adult neutered female cats. Journal of Endocrinology 2007;194:267-273.
8. Dunlap DB. Thyroid Function Tests. In: Walker HK, Hall WD, Hurst JW (eds). Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, 1990.
9. Baral R, Peterson ME: Thyroid Diseases, In: Little, S. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders, in press.

How Do We Confirm a Diagnosis of Hypothyroidism in Dogs?

Because of the vague clinical signs and the absence of specific abnormalities on a routine blood test, the diagnosis should be confirmed through a specific evaluation of the thyroid gland. As always, laboratory results should be interpreted in the light of history and physical examination findings. A thorough clinical examination of the patient, knowledge of the advantages and disadvantages of all available tests and knowledge of the factors that can influence the results, will allow the veterinarian to correctly diagnose the disease.

In dogs with suspected hypothyroidism, the clinical suspicion of the disease is obtained by reviewing the dog’s signalment, history, and clinical features. A general blood screening examination, including a CBC, comprehensive chemical panel, and complete urinalysis are next done to look for changes consistent with hypothyroidism and exclude other problems that mimic hypothyroidism.

If hypothyroidism is still suspected, the diagnosis should be confirmed through a specific evaluation of the thyroid gland function. These tests include measurement of serum concentrations of total and free T4, T3, and TSH. The choice of diagnostic test(s) performed are based heavily on the index of suspicion for hypothyroidism.

In some dogs, it may also be necessary to use thyroid scintigraphy to definitely confirm the condition. However, most veterinary offices do not have the equipment needed to do this thyroid scanning procedure.

Thyroid specific evaluation

Total thyroxine (T4)
This test usually used as the initial thyroid specific screening test. If the results of this test are within normal limits, your veterinarian will usually look for other causes of your dog’s clinical signs. Most dogs with hypothyroidism will have low values for T4 compared with healthy dogs. However, dogs that have other diseases can also have low T4, so false-positive T4 results are commonly observed. Again, that is why general laboratory testing must be done in all dogs with suspected hypothyroidism.

This test measures the total amount of thyroxine (abbreviated T4, because it contains 4 iodine molecules) which is the main hormone produced by the thyroid gland. hormone circulating in the blood, which includes both bound and unbound T4 molecules. More than 99% of T4 hormone is “bound,” meaning that it is attached to proteins in the blood, making the bound T4 too big to pass from the circulation into the tissues. A T4 result by itself is can be misleading, inasmuch as it is affected by anything that changes the amount of binding proteins circulating in the blood, such as occurs with drugs and nonthyroidal illness.

Certain kinds of drugs (e.g. sulfa antibiotics, anti-inflammatory, anti-depressant and anti-seizure medication) can cause artificially lowered thyroid levels so it is important to make sure we account for these before making a diagnosis.

In addition, although normal T4 reference levels of healthy adult dogs tend to be similar for most breeds, they do vary depending on age and breed. Puppies, for example, display higher T4 levels than adult dogs, because their bodies need extra hormones as they undergo the maturation process. Compared to the adult dog “normal range,” the optimal thyroid levels for puppies are normally in the high-normal to slightly high range. Conversely, the basal metabolism of geriatric dogs is usually slowing, so optimal T4 levels are likely to be closer to midrange or even slightly lower. Similarly, giant breed dogs have lower basal T4 levels, and Sight hounds as a group have the lowest T4 levels of all the breed categories.

Free T4
Serum free T4 represents the tiny fraction (< 0.1%) of total T4 that is unbound and therefore is biologically active and able to enter the tissues. Since protein levels in the blood do not (or only minimally) affect free T4, it is considered a more accurate test of true thyroid activity than the total T4. Free T4 is much less likely to be influenced by nonthyroidal illness or drugs.

Both total T4 and free T4 are lowered in almost all dogs of hypothyroidism. While most endocrinologists favor the equilibrium dialysis method for measuring free T4, newer technologies offer alternative and accurate assays that are faster and less costly.

Overall, this is a more sensitive indicator of hypothyroidism. Some dogs that are not truly hypothyroid may have a low total T4 but a normal free T4.

Total T3
Measuring serum T3 alone is not considered an accurate method of diagnosing hypothyroidism, as this hormone reflects tissue thyroid activity and is often influenced by concurrent nonthyroidal illness. It is, however, useful as part of a thyroid profile or health screening panel.

Thyroid stimulating hormone (TSH)
Production of thyroid hormones is regulated by the pituitary gland, through a hormone called thyroid-stimulating hormone (TSH). A feedback loop exists between the body and the pituitary gland, with TSH production by the pituitary going up when the body needs thyroid hormone and turning off when thyroid hormone levels are high.

Therefore, dogs with primary hypothyroidism are expected to have high serum TSH concentrations. Unfortunately, the current TSH test used in dogs is associated with a high incidence of false-negative or false-positive results.

Result for serum TSH must be evaluated together with serum T4 (and free T4) concentrations. Finding a low T4, low free T4, and a high TSH concentration is diagnostic for canine hypothyroidism. On the other hand, finding a high TSH level together with normal values for T4 or free T4 does not confirm hypothyroidism and is best ignored (at least for the time being).

Thyroglobulin autoantibody levels
High titers of thyroglobulin autoantibodies are present in the serum of dogs with autoimmune thyroiditis, which is the heritable form of hypothyroidism. Performing this test is especially important in screening breeding stock for autoimmune thyroiditis, as dogs testing positive for thyroglobulin autoantibodies should not be bred.

This is not in any way a stand-alone test for hypothyroidism and evaluation of additional tests is necessary to determine whether a dog is hypothyroid.

Thyroid Scintigraphy (Scanning)
Thyroid scintigraphy provides valuable information regarding both thyroid anatomy and physiology and can play an integral role in the diagnosis of thyroid disease in dogs or cats. Although rarely used to diagnose hypothyroidism, is now clear that thyroid imaging is also the best way to confirm the diagnosis of that common disorder. At the Animal Endocrine Clinic, we have the equipment needed to perform thyroid scintigraphy and we readily use this in the diagnosis of dogs and cats with thyroid disease. For more information about thyroid scans, please visit our Nuclear Imaging Facebook page.

In normal dogs, the thyroid gland appears on thyroid scans as two well-defined, focal (ovoid) areas of uptake in the cranial to middle cervical region. The two thyroid lobes are symmetrical in size and shape and are located side by side. Activity in the normal thyroid closely approximates activity in the salivary glands, with an expected “brightness” ratio of 1:1.

In dogs with hypothyroidism, thyroid scanning typically reveals decreased or even absent thyroid uptake (thyroid gland is not at all visible on the scan). In contrast, dogs that have falsely low serum thyroid hormone concentrations secondary to illness or drug therapy have a normal thyroid image.