Canine hypothyroidism: Shield your patients from overdiagnosis

Photo: Shutterstock.comIn one of his popular endocrinology sessions at CVC Kansas City-now Fetch dvm360-David Bruyette, DVM, DACVIM, said, “There is no question that hypothyroidism is the most overdiagnosed endocrine disorder in the dog.” The true incidence of the disease is unknown, but Dr. Bruyette says it probably is not the most common endocrine disease affecting dogs.

The thyroid-from the Greek thyreoiedes, meaning “shield-shaped”-releases hormones that regulate the metabolic rate in virtually every tissue in the body. And that widespread metabolic influence makes attributing clinical signs to the thyroid gland complicated. Dr. Bruyette says, “A dog that has every sign of hypothyroidism affecting every organ system, that's pretty easy. The problem is that dogs can have just dermatologic, hematologic or neurologic signs. And those signs are not pathognomonic for thyroid disease. There are so many other things that can cause those issues.”

So how do you shield yourself from overdiagnosing hypothyroidism in your canine patients?

Know the basic physiology

As you learned in school, the thyroid gland, the hypothalamus and pituitary gland work in a classic positive-and-negative feedback loop. (Ready for a refresher on the alphabet soup?) The hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH), which in turn stimulates the thyroid gland to release thyroxine (T4) and triiodothyronine (T3). As T3 and T4 concentrations rise in the blood following TSH stimulation, they will inhibit further release of TSH and TRH. The major hormone produced by the thyroid is T4, but T4 is not biologically active and is highly protein bound. A small fraction of T4 is not attached to protein-it is free T4 (fT4). fT4 diffuses inside the cell and is converted to free T3 (fT3). fT3 crosses into the nucleus of the cell and causes all the biologic effects that are ascribed to thyroid hormone. (All coming back to you? Remember fT4-it's going to be your friend.)

As mentioned, most T4 in dogs is bound to a protein called thyroid-binding globulin (TBG) and other proteins. Because T4 is so highly protein bound, many diseases and medications that alter the protein concentrations or that alter the affinity of T4 for those binding proteins can result in falsely low total T4 (TT4) measurements in a dog with normal thyroid function. Dr. Bruyette says that, used alone, TT4 is actually a terrible way to measure thyroid function.

A caveat while we're on this subject: Dogs have only about 15% of the TBG that people do, so T4 concentrations in people are markedly higher than they are in dogs. Because of that, Dr. Bruyette advises sending blood samples for thyroid function tests only to laboratories that analyze canine and feline specimens. Human laboratories are not very accurate at measuring TT4 in the lower range, which are usually the results of greatest interest. So be aware of this if using laboratories that do not specialize in veterinary specimens.

Know the two most common causes

The two most common reasons that dogs develop low TT4 concentrations and clinical signs of hypothyroidism are lymphocytic thyroiditis and idiopathic atrophy. Lymphocytic thyroiditis is an autoimmune disease that causes about 50% of hypothyroidism cases in dogs. It has a strong heritable genetic component; however, there's currently no DNA test for it. Since there's not a DNA-based test, some laboratories will screen for the presence of thyroiditis using TT4, fT4, TSH and antithyroglobulin antibody tests (a dog with thyroiditis produces antithyroglobulin antibodies). If thyroiditis is detected, the dog should probably not be used for breeding. As you may have recognized, this presents a problem. A dog can test normal at 1 or 2 years of age, and then become positive for antithyroglobulin antibody at age 3. By that time, the dog may have already been used for breeding, which means the trait has been transmitted. There is currently no way to test a puppy and predict whether it will eventually develop thyroiditis and then hypothyroidism.

Idiopathic atrophy causes 45% to 50% of hypothyroidism cases in dogs. As the name implies, the cause is unknown. Dogs are born with a normal thyroid and then, between 2 and 5 years of age, the thyroid starts atrophying. There is no suspicion that this is a heritable defect in dogs, and so it is not a concern in breeding animals.

Know this signalment

Most dogs become hypothyroid before the age of 6 years-46% are diagnosed from 1 to 3 years and 29% from 4 to 6 years. This reflects the development of lymphocytic thyroiditis and idiopathic atrophy in those age groups.

Certain breeds are predisposed to the disease:

> Golden retrievers

> Doberman pinschers

> Dachshunds

> Shetland sheepdogs

> Irish setters

> Airedales

> Cocker spaniels

Breeds that are at risk of developing hypothyroidism develop the disease at an earlier age than do other dogs.

Hypothyroidism is more common in females than in males, which is true of all autoimmune endocrine diseases. Spaying and neutering has no effect on prevalence.

Know your thyroid function tests: TT4 vs. TSH vs. fT4

When you order a thyroid function test, you're most likely doing one of two things: confirming a clinical suspicion of hypothyroidism or evaluating a dog for breeding. Dr. Bruyette tells you where to start: “I think everyone agrees you should start screening with a TT4 because the vast majority of dogs you're going to see are normal. Send the sample to a reference lab, because in-house TT4 testing is not very accurate. This is not a STAT test. You can wait for the result.”

Let's talk T4

Free thyroxine is the fraction of T4 unbound to plasma thyroid hormone binding proteins that is proportional to cellular hormone and undergoes conversion to the more biologically active form of thyroid hormone (ie, T3). The pituitary also monitors serum fT4 concentrations as a primary negative feedback signal in determining thyrotropin (TSH) secretion. Results of past studies comparing the accuracy of serum fT4 concentrations versus total T4 concentrations for assessing thyroid gland function have been conflicting, presumably because of differences in the technique used to measure serum fT4 concentration.

Techniques for measuring serum fT4 concentrations include standard equilibrium dialysis (SED), radioimmunoassay (RIA), and a combination of both (modified equilibrium dialysis [MED]). Equilibrium dialysis (SED) historically has been considered the gold standard for measurement of the fT4 fraction, with the absolute fT4 concentration being determined as the product of the fT4 fraction and the total T4 concentration. Given the difficulty in using SED in a large laboratory setting, MED is used most often and measurement of the serum fT4 concentration by MED has been shown to be the most accurate means of assessing thyroid gland function in dogs.

Source: Dave Bruyette, DVM, DACVM

Every laboratory provides a normal range, generally 1 to 4 μg/dl. Dr. Bruyette says if the TT4 is greater than 1.5 μg/dl, most dogs can be considered euthyroid. If the result is lower than that, more tests are needed. Many things can cause a low TT4 result. One is the time of day the blood was drawn. Unlike people, dogs (and cats) do not have a diurnal rhythm for T4-their T4 level fluctuates every 20 to 30 minutes. Between 50% and 60% of normal dogs have a TT4 concentration below the reference range at some point during the day. You may have caught your patient at nadir. If the patient looks completely healthy but has a low TT4 lab result, collect a new blood sample on another day and submit it.

There is also an age effect. Puppies have two to three times more T4 in their blood during their first three months of life. After 3 months of age, TT4 concentration becomes consistent. You may see a lot of TT4 results below the reference range in older dogs. Those dogs can look completely healthy, which, Dr. Bruyette says, tells you that TT4 is not a really good test for thyroid function. A low TT4 tells you that an older dog either has some illness lurking or it is receiving a medication that interferes with TT4 measurement. Dr. Bruyette tells this story: “About 15 years ago, our lab suddenly started seeing a lot of low TT4s on a daily basis. A lot of them were from older dogs. We thought there was something catastrophically wrong with the assay. It turned out that this corresponded with the launch of Rimadyl (carprofen). As dogs started taking NSAIDs, we started seeing low TT4s in the lab.”

In a patient receiving an NSAID, you may notice that its TT4 level drops while it's on the drug. The nonsteroidal drug and thyroxine compete for binding sites on proteins in the blood. The NSAID binds with higher affinity, displacing the T4, and the TT4 concentrations drop. You should avoid diagnosing hypothyroidism based on that low TT4 result. If you were to administer thyroid hormone to this dog, the NSAID would be displaced from the proteins, which can increase the drug's side effects. This highlights the fact that you should always have a good drug history when testing thyroid function in a dog.

The breed of dog can also affect the TT4 normal range. Sight hounds (greyhounds, salukis, basenjis) do not have a lot of TGB in their blood, so their TT4 is about 50% of normal. Therefore, you cannot use a typical reference range to diagnose hypothyroidism in these breeds. And, as mentioned, you should never diagnose hypothyroidism based solely on a low TT4 anyway. Dr. Bruyette says, “We're working to get to breed-related normal ranges. To say that TT4 is 1 to 4 μg/dl for all breeds, across all ages, that's crazy. We need to have labs give you a reference range for the breed of the dog.”

The problem with telling a hypothyroid dog from a euthyroid dog with a low TT4 is the effect of nonthyroidal illness or euthyroid sick syndrome. As a patient develops any illness, its TT4 concentrations drop. The sicker the dog and the longer the duration of the illness, the lower the TT4 concentrations will be. According to Dr. Bruyette, TT4 “is a horrible assessment of thyroid function, but it's actually a very good predictor of mortality.” He recommends getting the dog through whatever illness it is experiencing, and then conducting thyroid function tests.

Dr. Bruyette asks, “Because of all the problems with measuring TT4 and because we know that fT4 is really the active hormone, why don't we just measure the free T4 and not worry about the total T4?” In fact, he says, there is one test that always works - fT4 by equilibrium dialysis (fT4 by EqD for short). This test has very high specificity, sensitivity and accuracy. Unfortunately, it is also much more expensive than a TT4 test. Therefore, Dr. Bruyette does not recommend starting with an fT4 test. Instead, he suggests a TT4 test as an initial screening for hypothyroidism. Then, if you still suspect hypothyroidism, confirm your diagnosis with fT4 by EqD.

In human medicine, physicians don't measure T4 or fT4; they simply measure TSH. If a person is euthyroid, the TSH is normal-if hypothyroid, the TSH is high. Unfortunately, the canine TSH assays currently available do not work well. Dr. Bruyette says, “You find that 25% of confirmed hypothyroid dogs do not have a high TSH. The assays only recognize one form of TSH, and there are lots of TSH isoforms in the blood.” Until there is access to a better veterinary assay, TSH concentration cannot be used as a screen. Laboratories often offer combinations of TT4, fT4 and TSH tests, but Dr. Bruyette says these are not especially helpful because of the poor sensitivity of the TSH assay.

Dr. Bruyette says, “If you are super-confused by all of this, what test do you want to run? You want to run fT4 by EqD. That's the one that will give you the right answer most of the time in dogs with nonthyroidal disease and in dogs that are taking medications.”

Editors' note: Want the latest and greatest in the realm of canine hypothyroidism? Check out the supplimentation and monitoring updates here.