Hypothyroidism

John Cargill MA, MBA, MS and Susan Thorpe Vargas MS, Ph.D. Hypothyroidism is a common and serious genetic problem in purebred dogs.There is virtually no breed of dog unaffected. The scope of the problem cannot be accurately defined because of a lack of complete statistical information; however, it is certain that veterinarians are seeing and treating a lot of thyroid cases. Because of a degree of inheritance associated with hypothyroidism (too little) genetic screening has become a necessity for the conscientious breeder, rather than an option. First, let's get a handle on the thyroid gland; what it is and what it does. Systems Concept Think of the thyroid gland as the crystal that sets the clock speed on your computer. If it produces too much or too little, the body system may malfunction because the various interconnecting subsystems can't interface properly. Together with the pituitary gland, the thyroid gland "calls cadence" for the many interconnected systems of the body, serving much like a combination thermostat, rpm governor, pressure regulator in mechanical systems. Because the thyroid gland plays such a large role in regulation of the body, any disturbances in the thyroid system can cause serious problems in many of the body's other subsystems. The telephone company analogy of thyroid functions is a good one: while the telephone switching central neither originates calls or receives calls, it schedules and directs traffic flow interfacing cable, microwave and satellite transmissions. It matters not how well your individual telephone and telephone lines are working, or how well those of the person to whom you would speak are working, if there is a problem with the telephone central. Built into the body are many selfcompensating properties or control mechanisms. Using the telephone company analogy, if a satellite fails, message traffic may be routed through other systems such as land lines and microwave radio or through other satellites. Each of these systems has a capacity and a rate of throughput, and variable degrees of interface with other systems. Even when the telephone central looses some of its capacity to function, message traffic can be rescheduled to offpeak hours. Similarly, when the thyroid system looses some of its function, other systems and subsystems may function, but at reduced levels of efficiency and operating tempo. In the case of a reduced capacity telephone central operating off of standby generator power, the whole system becomes vulnerable to other insults such as terrorism, floods, electrical storms and computer malfunction. The telephone switching central then has less ability to compensate for these problems and to selfrepair or direct repairs in subsystems in a timely manner. And so it is also with the thyroid system, because, in great part, it influences the immune system of the body. As the immune system becomes depressed or compromised, the whole body system becomes more and more vulnerable to the insults characteristic of every day living, and the body system as a whole becomes less competent to respond to those insults. In fact, if the malfunctions are of a particular type, various subsystems of the body may refuse to recognize other subsystems as "self" and will even attack those other subsystems, much as the security force of a telephone switching central may refuse to allow repairmen in to fix the telephone switching central computers because the computer that contained the approved repair personnel access list had its hard drive crash. Thyroid Gland Now let's get directly to the thyroid gland and examine its properties and functions keeping in mind the above analogies as a framework for understanding. In the dog, the thyroid gland consists of two lobes flanking the trachea (windpipe). It has been established that it secretes at least two related hormones thyroxin (T4) and triiodothyronine (T3). The only difference between the two is that T4 has four iodine atoms attached to it and T3 only has three. Even though the thyroid gland secretes mostly T4 (about 90%), it is T3 that is considered the active form of the hormone.  Conversion of T4 to T3 In a series of complex steps that involve mainly the liver and kidneys, T4 is stripped of an iodine atom and is converted to T3 when needed. Initially, the two forms are released into the blood and are bound to proteins in the plasma (the clear fluid of the blood) . Less than 1% of the T3 and less than 0.1% of T4 remain in the unbound state in the blood. One of the thyroid tests commonly ordered checks for the amount of circulating or 'free' T4 and 'free' T3. The bound thyroid hormone is transported by the blood to their target cells. Only unbound or 'free' hormone is able to enter cells. Once they pass through the cell membrane they bind again to another protein. This attachment process signals a receptor within the cell nucleus and activates the synthesis of various metabolic enzymes. These enzymes are what regulate the body's 'set point' or 'idling speed'. This basal metabolic rate governs the body's rate of oxygen consumption and energy expenditure, which in turn effects heat production. This is why we use up energy keeping warm and why hypothyroid individuals are cold intolerant. Control Mechanism Internal modulation of hormone levels is a complex process in that thyroid hormones are not secreted at a continuous rate, but rather demonstrates the classical physiological example of negative feedback. One can liken negative feedback to a heating thermostat. Once levels of free circulating thyroid hormone have fallen to a certain plasma concentration, thyroid releasing hormone (TRH) is secreted by the hypothalamus. TRH in turn stimulates the release of thyroid stimulating hormone (TSH) from the anterior pituitary which 'turns on' the synthesis of thyroid hormone. Another function of TSH is to maintain the structural integrity of the thyroid gland. Inadequate levels of TSH cause the thyroid gland to atrophy. This is one reason why early diagnosis and intervention of thyroid disorders is so necessary. Once the thyroid gland has atrophied, it cannot recover. Secretion of TSH is 'turned off' when plasma concentrations of thyroid hormone are sufficient and is turned back on again when levels fall once more. Clinical Signs Clinical signs of the disease vary greatly because of the myriad of systems the thyroid hormone impacts. Most owners are alerted to a problem when changes in the dog's coat occur. This is frequently the first symptom of which they become aware. The classical signs include alopecia or hair loss on both sides of the trunk or specifically on the tail, i.e., the 'rat' tail. Hair regrowth is usually slow and may come in dry, dull or differently colored. The skin may also change color and become greasy, strong smelling and thickened. The dog may gain weight easily, becoming lethargic, mentally dull and exercise intolerant. Chronic ear infections have also been noted. Observed also are severe behavior changes and neurological symptoms including unprovoked aggression, head tilt, seizures, ataxia, circling and facial nerve paralysis. Additionally, reproductive functions such as prolonged anestrus and fertility rates may be affected. It is obvious from this list (see Figure 2.) that this is a serious disease and one that needs to be caught early. Causes of Hypothyroidism Two questions are particularly relevant to breeders: What causes canine thyroid disease? Is the incidence of hypothyroidism increasing? Most cases of hypothyroidism are the endstage result of autoimmune thyroiditis. This is a condition where the immune system attacks the tissues of the thyroid gland. The body is able to compensate for this by stimulating the thyroid to secrete greater levels of hormone, but eventually glandular reserves are depleted and the individual is unable to produce enough hormone to sustain clinical health. One of the ways to assess this condition is to look for the presence of antithyroid antibodies, specifically, thyroglobulin autoantibody (TgAA). An improved test for TgAA, made by Oxford BioMedical is now commercially available, and although not as yet a definitive diagnostic test, it is the best available marker for autoimmune thyroiditis at this time. Although it is clear that there is a genetic predisposition for thyroid disorders we would also suggest that there are environmental factors like diet, nutrition, and exposure to chemical toxins, that at the very least will trigger the onset of disease in the genetically susceptible individual. We know that the body's capacity to maintain homeostasis when exposed to changes in it's environment depends in the way it able to detoxify itself. This ability responds in many complex ways to changes in the levels of thyroid hormone. Environmental toxins, nutritional deficiencies and allergies are external factors that can effect our perception of the prevalence of thyroid disease. See Figure 3. Breed Specificity While there may be differences in what should be considered normal thyroid levels by breed of dog, it is all too apparent that there are currently many breeds which are more likely to have low thyroid function. Unfortunately, the list of affected breeds is quite a long list so long that we decided to show it in tabular form in Figure 4. More than 70% of the 140 breeds recognized by the American Kennel Club (AKC) are genetically predisposed to hypothyroidism. This statistic alone is alarming, but to put it into proper context, one has to consider that the most popular breeds are represented, and thus the percentage of individual animals in the AKC registry is very high indeed. Pets Vs Breeding Stock One of the selection criteria for breeding stock is that they should be the animals best suited for perpetuating their breed. Herein lies the rub: what one fancier considers desirable in a given breed, another may consider a fault. What one fancier considers important, another may consider insignificant. But we can all agree that healthy thyroid function deserves serious consideration when it comes to selecting breeding stock. Because of the perception that there is a widespread penetration of hypothyroidism into the overall gene pool of the dog fancy, we can probably all agree that normal thyroid function should be one of the breeding criteria. At a recent symposium held at the University of California Davis , it was decided that there should be two different testing protocols: One protocol for breeding stock and another, much less stringent and less expensive protocol, for the pet population. See Figure 5. Here comes another rub: What constitutes this normal thyroid function? This question may be further refined by: What constitutes normal thyroid function in my breed? Unfortunately, breed specific norms of healthy thyroid function are not well documented; however, normal ranges for dogs in general are known. With the exception of the documented low thyroid levels in Greyhounds, the variances between breeds is not considered to be large; however, we cannot dismiss such variances out of hand. With that said, Figure 6. shows the normal ranges for dogs in general. Testing and Diagnosis Testing for hypothyroidism is an area of much confusion and controversy among clinicians and researchers alike, in that affected dogs do not necessarily exhibit clinical signs of the disease. Concurrent nonthyroidal disease can cause lab results to be misleading. The age of the dog needs to be considered too. Concentrations are expected to decrease with age and may actually be above adult 'normal' levels in puppies. Moreover, steroidal drug therapy or the use of sulfa drugs can likewise influence thyroid panel results. Because so many factors can effect thyroid hormone levels, a meaningful diagnosis of thyroid disease must first begin with a thorough initial exam. This would include a history, a physical examination, and routine bloodwork. (Complete blood count, serum biochemistry panel, and urinalysis). If the dog shows clinical signs of the disease, a lab test that shows lower then normal values of T4 combined withelevated levels of TSH is pretty diagnostic for primary hypothyroidism ( previously mentioned factors having been ruled out). (See Figure 7.) IDEXX Laboratories, Diagnostic Products Corporation, Chiron and Nichols Institute Diagnostics manufacture some of the commonly used T3, T4 and TSH tests. It should be noted that while many other manufacturers make such kits, most are not "referenced" or "convertible" for canines. Example: Diagnostic Products Corporation CoatACount Canine T3 and CoatACount Canine T4 are specifically referenced tests for canines. It is most likely that you would be testing an asymptomatic animal if you were considering the dog for your breeding program. Begin testing after the animal has reached sexual maturity and be sure your female is between heats. One year of age is a good place to start. The baseline panel for potential breeding stock would include serum 'free' T4 measured by equilibrium dialysis, existing TSH levels and a test for thyroglobulin autoantibodies. The "cutting edge" test for FT4 is manufactured by Nichols Institute Diagnostics. Do not assume that if these values are normal that you are 'home free' because possible development of thyroid disease has not been precluded. An annual exam and retesting is suggested for all possible breeding animals. Treatment & Dosage Once a diagnosis of hypothyroidism has been made, the normal treatment protocol is the use of a T4 (Lthyroxine) hormone supplement given twice a day. Soloxine" and Synthroid' manufacture some of the more commonly prescribed T4 supplements. Sometimes (very rarely) a dog may have a metabolic disorder that effects the biochemical pathway necessary to convert T4 to T3. In this case a small amount to T3 is also included, but only when used with proper veterinary supervision because T3 can be acutely toxic at the wrong dosage level. In fact, the veterinary T3 supplement is no longer available. What response can you expect from treatment? You should see an increase in activity levels and mental acuity within the first week and some weight loss should be apparent by the end of the fourth week. Skin problems will start to clear up by the end of the sixth week, although shedding will increase sometimes, depending on the stage the dog is in, in its hair growth cycle. Concurrent nonthyroid illness will make modifications of normal treatment conventions necessary. For example, aged dogs or those with diabetes, heart problems or liver or kidney problems would be placed on a lower initial dose which would then be gradually increased. Dogs already on medications and those that have absorption problems effecting the uptake of the drug or how it is metabolized, would have to be very carefully monitored also. Every case must be handled on an individual basis. Response to thyroid therapy varies considerably between animals, and fixing a proper dosage level is more of an art than a science. If your dog is on thyroid replacement therapy, keep careful records and keep your veterinarian informed of changes in attitude, activity levels, appetite, and skin and coat condition. Once in the "ball park", dosage levels are refined through observing the animals responses to treatment. Genetic Screening Required By now, it should be obvious just how serious, deleterious and undesirable thyroid problems can be. Both authors take a hard line approach at this point: If you have not tested your dogs for proper thyroid function, you have no business breeding them. Taking the hard line one step further, to breed hypothyroid or untested dogs is unconscionable, unethical and just plain wrongdoing. Without evil intent to mess up the gene pool of your breed, to conduct such breeding is ignorant, or worse yet, stupid if you have already been informed. Yet, we venture to guess that most breedings are without benefit of screening for thyroid function or other genetically transmittable disease. Please read this paragraph again. There are two camps in the dog fancy: the 'screeners'; and the 'nonscreeners'. After reading about the thyroid system, we hope to have convinced you that it not only makes medical sense to screen for proper thyroid function, but that it also makes economic sense when you attempt to place puppies you have bred. More and more fanciers are becoming aware of hypothyroidism and the problems associated with it, and are starting to advertise not only that they have screened their animals, but also the actual thyroid levels measured. We anticipate this trend will continue to the betterment of the fancy. The authors wish to thank Dr. Ray Nachreiner of the Animal Health Diagnostic Laboratory of Michigan State University for his help in reviewing this article and the valuable discussions of Drs. R. Nachreiner, W.J. Dodds, D.L. Panciera and N.H. Dodman.

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