A Diagnostic Dilemma.

AKC Gazette, November, 1995, pp. 67-71.

THE ENIGMATIC NATURE HYPOTHYROIDISM. MAKES IT DIFFICULT TO DISTINGUISH FROM OTHER DISEASES.

By Christine Wilford, DVM, the Veterinary News columnist for the AKC Gazette. She practices veterinary medicine in the Seattle area.

In a survey of parent breed clubs by the AKC, hypothyroidism topped the list of diseases considered to be the most significant problems for breeders. Every group except the Toy Group listed it in the top three. Every year, thousands of dogs are diagnosed with hypothyroidism and most subsequently receive lifelong thyroid supplementation. But many of these dogs do not have the disease. Although hypothyroidism (underactive thyroid) is reportedly the most common endocrine disease in dogs, the actual incidence of canine hypothyroidism remains unknown. Several factors are responsible for the lack of hard numbers. The clinical signs of hypothyroidism resemble many other diseases. Current diagnostic tests have limitations. The presence of any number of diseases or the use of certain medications may alter test results. The vague and insidious nature of hypothyroidism often leads to misdiagnosis and inappropriate treatment.

The thyroid gland is the body's throttle. It controls metabolism - the speed at which the body operates - by secreting hormones into the bloodstream from two lobes located in the neck. Metabolism increases or decreases in response to varying energy demands. Illness and disease cause a normal decline in thyroid function, while increased activity can cause a normal elevation.

Hypothyroidism occurs when thyroid function falls below normal and remains there without an appropriate cause. Hypothyroid animals cannot increase their thyroid function, even when the body demands it.

The exact cause of hypothyroidism is not well understood. Current evidence suggests that, in most cases, an abnormal immune response causes the body to attack and destroy its own thyroid gland as if it were a foreign substance. Why this happens remains a mystery, but evidence gathered from studying Great Danes, Irish Setters and Old English Sheepdogs suggests genetics may play a role.

Debate continues over whether certain breeds are more likely than other breeds or mixed breeds to develop hypothyroidism. Most sources agree that Golden Retrievers, Doberman Pinschers, Irish Setters, Miniature Schnauzers, Dachshunds and Great Danes are at increased risk. Poodles, Boxers, Airedales and Old English Sheepdogs may also be at increased risk. German Shepherds and mixed breeds may actually be at lower risk than the average dog. Regardless of breed, males and females are equally affected by hypothyroidism.

Compensatory Hypothyrodism. A common condition known as compensatory hypothyroidism, or sick euthyroid syndrome (SES), may account for many of the false diagnoses of hypothyroidism. The difference between true hypothyroidism and SES is that in SES, the thyroid gland retains the ability to return to normal function. SES describes the situation in which dogs with normally functioning thyroid glands have decreased thyroid hormone levels with an appropriate cause. Virtually any condition trauma, stress, injury, illness, poor diet can affect thyroid hormone levels and cause SES.

SES is actually a protective mechanism. When the body experiences altered demands and priorities such as illness or stress, the thyroid gland tries to compensate by minimizing energy requirements. Energy is conserved by reducing thyroid hormone secretion. This, in turn, lowers the body's metabolic rate.

Further compounding the problem is that whatever initiates SES may be vague and difficult to identify. Without comprehensive diagnostics and evaluation, low thyroid hormone levels may be the most obvious abnormality, leading to a misdiagnosis of hypothyroidism.

If a dog with SES is misdiagnosed and is supplemented with thyroid hormone, the body's protective mechanism can be negated. As metabolism increases, so do energy requirements, which may detract from the body's other demands. And because the underlying cause of SES is overlooked, another disease persists undiagnosed and untreated.

Dealing with Suspicion. Because impaired thyroid secretion can cause a vast array of signs, hypothyroidism is often suspected in almost all dogs with skin disease, lethargy or reproductive disorders. Once clinical signs lead to suspicion of hypothyroidism, routine laboratory tests, consisting of a complete blood count, serum chemistries and urinalysis, are recommended, if only to rule out other diseases. If no other disease is present, results of routine laboratory tests may be completely normal. Routine tests only provide supportive information; they cannot confirm a diagnosis of hypothyroidism.

One important diagnostic clue is that more than 75 percent of dogs with true hypothyroidism have high cholesterol levels in blood samples drawn after a 12-hour fast. However, other diseases can increase serum cholesterol. Therefore, high cholesterol after a fast supports, a diagnosis of hypothyroidism, but it is not definitive.

Another diagnostic clue is that as many as 40 percent of hypothyroid dogs have anemia - decreased numbers of red blood cells without signs of replenishment. This finding also supports a diagnosis of hypothyroidism, but again, is not definitive. Other causes of anemia should be considered.

Abnormalities in the urinalysis suggest a problem other than hypothyroidism.

Thyroid-specific tests are necessary to diagnose hypothyroidism, and should be completed before beginning treatment with thyroid supplements. Levels of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) can be measured from blood samples used for routine laboratory tests, but the analysis must be specific for canine thyroid hormones. Analysis at human laboratories yields unreliable results, as do in-house tests at veterinary clinics. Even with these precautions, neither of these tests is by any means definitive.

Because half of all truly hypothyroid dogs maintain normal T3 levels, misdiagnoses will occur if T3 is used as the sole method for diagnosing hypothyroidism. By far the most common and least expensive test is the measurement of T4. This test is known by several names, including basal T4, serum T4, resting T4 and total T4. While slightly more consistent than total T3, total T4 also rarely yields a definitive diagnosis and should only be used as a screening test. Results must be interpreted in light of other clinical and laboratory findings. If the total T4 level is in the mid to high normal range, then hypothyroidism is very unlikely. Low normal or below normal results support a diagnosis of hypothyroidism only in a dog with clinical signs and with other routine laboratory test results that also suggest the problem.

A total T4 result far below normal or near zero strongly suggests true hypothyroidism. Still, more definitive testing is highly recommended before committing a dog to a lifetime of thyroid supplementation and monitoring. Though a popular test, total T4 is a poor method for evaluating thyroid function. It is limited because many uncontrollable factors affect total T4 levels. For example, an older dog is more likely to have lower total T4 than a younger dog. And normal levels tend to be lower in large and giant breeds, higher in smaller breeds. German Shepherds, Cocker Spaniels, Boxers, Beagles, Labrador Retrievers, Alaskan Malamutes and Siberian Huskies may have normally lower total T4 levels. Even ambient temperature can affect a diagnosis - a car ride to the vet's office on a hot summer day may decrease total T4 levels, causing false low results. Other known factors that can have an influence include illnesses, medications, diagnostic agents and stress.

The list of drugs and diagnostic agents that potentially lower total T4 continues to grow. In addition to many antibiotics, it includes glucocorticoids, one of the most common types of medications dispensed. Low total T4 levels are simply unreliable in dogs that are currently taking or have recently taken glucocorticoids such as prednisone or dexamethasone. (While glucocorticoids can decrease total T4, they do not cause clinical signs of hypothyroidism.) Antibiotics containing sulfa, such as Tribrissen, Primor, Bactrim, Septra and many generics, can lead to lower total T4, resulting in misdiagnosis.

Hyperadrenocorticism, or Cushing's disease, is often a diagnosis considered for dogs with symptoms resembling hypothyroidism, and close to 40 percent of dogs with Cushing's disease have low total T4 values. Research indicates that while Cushing's disease may cause a hypothyroid condition, treatment of the Cushing's disease without treating the hypothyroidism not only returns total T4 levels to normal, but also corrects the hypothyroid state.

Even in the absence of these influences, total T4 fluctuates irregularly in a normal dog over the course of a normal day. Attempting to time the blood sample collection in an effort to improve the reliability of the test is also futile. In fact, total T4 levels can vary significantly from hour to hour, especially in dogs with any degree of illness such as skin infections or allergies. Ironically, truly hypothyroid dogs have more stable and less dramatic total T4 fluctuations. (Fortunately for diagnostic considerations, in hypothyroid dogs fluctuations into the normal range are rare and transient.)

To what degree various factors affect total T4 remains unknown. But it is clear that a diagnosis of hypothyroidism based solely on the results of total T4 is seriously flawed. It is subject to tremendous error, which can lead to the inappropriate treatment of many dogs.

Aside from the limitations described, measuring total T, and total T4 neglects to evaluate thyroid function. Because inadequate thyroid function is the distinguishing characteristic of a truly hypothyroid dog, a thyroid function test is imperative for proper diagnosis. There are two main tests of thyroid function: the thyroid releasing hormone (TRH) response and the thyroid stimulating hormone (TSH) response. The TRH is of limited value. An abnormally low response is difficult to identify because a normal response is already very low. Also, 25 percent of healthy dogs have little or no increase in post-TRH total T4 values. Normal dogs release TSH to stimulate thyroid hormone secretion. The TSH response test mimics the body's method for raising thyroid hormone levels. The procedure involves collecting a pre-TSH blood sample, injecting TSH and collecting a post-TSH blood sample several hours later. By knowing the time administered, and the dose, thyroid function can be assessed. The TSH response test is not only more accurate for identifying true hypothyroidism, but is especially useful for differentiating hypothyroidism and sick euthyroid syndrome.

While the advantages of the TSH response test are more accurate assessment of thyroid function and much less risk of misdiagnosis, injectable TSH is not widely marketed and cannot be stored for long periods. Other disadvantages are cost and time. Although prices and protocols vary, a half day to full day at the veterinary hospital and lab fees upward of $80 are typical. However, owners refusing this test based on cost should compare the expense of lifelong thyroid supplementation and monitoring. And if another disease is misdiagnosed as hypothyroidism, inappropriate treatment may not only cost more money, but may cost the dog's life, since it won't receive treatment for the underlying disease.

Although experts agree that TSH stimulation is the test of choice for the most definitive diagnosis, they disagree about the dose, the route of administration and the best time to collect the second blood sample. They also have different ideas about which results should be considered as falling in the normal range and which indicate hypothyroidism.

Most hypothyroid dogs respond to TSH in a way consistent with most guidelines. A small group of dogs will have discordant results and appear normal by one criteria and hypothyroid by another. For such inconclusive or equivocal results, options include observing for progression of clinical signs or repeating the TSH response test in two to four months. Other alternatives are submitting a free T4 or conducting a therapeutic trial.

Free T4. The latest test available is called the free T4, a measurement of the biologically active form of thyroxine. Besides being a more specific indicator of thyroid function than total T4, free T4 is not subject to the spontaneous fluctuations or drug-induced changes that occur with total T4, making it useful in discriminating between hypothyroid dogs and dogs with low total T4 levels caused by other factors such as illness or medication. Like total T4 and total T3, a blood sample is all that is required for a free T4 measurement. However, how the sample is analyzed determines the reliability of the result.

The most common way of measuring free T4 is by a process called radioimmunoassay. Though a rapid and practical method for laboratories, radioimmunoassay's validity is seriously questioned. In fact, this method received considerable technical criticism from the American Thyroid Association for its use in human medicine. Free T4 analyzed by radioimmunoassay offers no more value than measuring total T4. A more accurate method for measuring free T4 is equilibrium dialysis. In fact, it is considered the gold standard. Unfortunately, this method of testing is not widely available. Samples must be sent to a special laboratory proficient in this time-consuming and technically complex method. Direct dialysis is an alternative method, with results reportedly correlating well with equilibrium dialysis. Because it is more practical to perform and just as accurate, it may eventually become more available. Whether free T4 evaluation by dialysis will replace the TSH response as the test of choice will depend on its accuracy in clinical practice.

A Therapeutic Trial. Under certain circumstances, a therapeutic trial is an option for diagnosing hypothyroidism. When results of thyroid tests are neither clearly within normal limits nor diagnostic of hypothyroidism, supplementation with thyroid hormone may help confirm or exclude a diagnosis. Other indications for a therapeutic trial are if the TSH injection is unavailable or if a free T4 test is not readily accessible.

A therapeutic trial requires administration of a brand-name, synthetic levothyroxine supplement. Generic thyroid supplements, or those of animal origin, do not produce reliable results, and may lead to misdiagnosis in a therapeutic trial. Some dogs may do well on generic products after a diagnosis is confirmed, but a therapeutic trial should be performed with brand-name products only. Initial dosage recommendations vary, but the drug should be administered every 12 hours. If hypothyroidism is confirmed, once-daily treatment can be attempted. (NOTE: Current recommendation [1998] is that the daily supplement be divided and given approximately every 12 hours).

If hypothyroidism is truly present and thyroid supplementation is appropriate, all of the clinical signs and lab work results associated with hypothyroidism can be reversed. Depending on the dog, some changes may be visible within the first week of treatment. Initial improvements include increased mental alertness, activity and appetite. Noticeable improvement of the skin should follow within the first month or six weeks.

Initially, the coat may appear worse if the old coat is shed in large quantities. Several months are required for complete hair regrowth and noticeable reduction in pigmentation. If fertility problems are being linked to hypothyroidism, they are usually the last problems to be resolved. In addition, lab work abnormalities may require several months to clear up.

Even if a completely positive response to therapy is observed, the diagnosis is in no way certain until thyroid supplementation is withdrawn. If clinical signs begin to recur, further thyroid testing should be performed or therapy can be reinitiated. If clinical signs do not recur after discontinuing treatment, hypothyroidism should not be suspected and thyroid supplementation should not be reinitiated.

The take-home message is this: Lifelong thyroid supplementation for a diagnosis of hypothyroidism based on a total T4 and an apparent response to treatment is perhaps the single greatest reason for misdiagnosis and overtreatment. Many diseases may respond to thyroid supplementation in the absence of hypothyroidism. Because a non-thyroid disease seems to improve with thyroid supplementation does not signify a cure, a treatment or, for that matter, even a benefit.
Treatment. Once diagnosis is confirmed, treatment is straightforward: supplement thyroid hormone, 1-thyroxine. Although most experts tend to agree on the dose, there are a few veterinarians recommending unusually high doses and frequency. Higher doses can cause signs of hyperthyroidism (an overactive thyroid), including elevated heart rate, weight loss, increased appetite and nervousness. There is also disagreement over when and how to monitor therapy.

Because of its indefinite symptoms and its resistance to conclusive test results, accurate diagnosis is the critical factor in treating hypothyroidism. While inappropriate supplementation is expensive, a more important concern is the toll taken on a dog that is unnecessarily receiving supplementation - especially when the body decreases thyroid secretion as a protective mechanism.

In the absence of a single superior test, a diagnosis must not be made until a comprehensive history is collected, a thorough physical exam is conducted, blood work and urinalysis are evaluated, and special tests are submitted for thyroid function evaluation.