The thyroid gland controls the metabolic rate of the body. When the gland functions insufficiently, a condition known as hypothyroidism occurs. Dogs that are clinically affected may display one or more of the following clinical signs: weakness, lethargy, weight gain to the point of obesity, skin and coat problems, behavioral abnormalities, and infertility. Breed health surveys tell us that hypothyroidism is one of the most common health concerns expressed by breeders.

Canine hypothyroidism is frequently misunderstood, misdiagnosed, and mistreated. Historically, it has been thought that 50 percent of cases of canine hypothyroidism are caused by autoimmune thyroiditis, and the rest are caused by idiopathic hypothyroidism. What the experts now understand is that almost all primary hypothyroidism in dogs is caused by thyroiditis (autoimmune destruction of the thyroid gland), and that this is a genetic disorder. Primary idiopathic hypothyroidism, if it exists at all, is a rare condition. The confusion comes from looking at blood test "snapshots" of hypothyroid dogs, and not understanding the whole "moving picture" of thyroid disease.

Measurable antibodies to the thyroid gland and to thyroid hormones develop in the blood of dogs affected by autoimmune thyroiditis. For months to years, these hormones attack and gradually destroy the normal thyroid gland tissue. It is only after a large portion of the thyroid gland is destroyed that the levels of thyroid hormone in the bloodstream drop. It is at this time that the clinical signs of hypothyroidism mentioned above may appear. Once the thyroid gland is destroyed, the body is no longer stimulated to produce the antithyroid antibodies. The dog is now in end-stage hypothyroidism. Most erroneous diagnoses of primary idiopathic hypothyroidism occur because the blood test is performed at this stage, when the gland is already destroyed and the autoantibodies are gone. Thus, the process that has led to this point is not seen.

In a study by Dr. Raymond Nachreiner and his colleagues Michigan State University, more than 50,000 canine blood samples have been screened for significant levels of autoantibodies to either thyroglobulin (TgAA), thyroid hormone 3 (T3AA), or thyroid hormone 4 (T4AA). Of the blood samples tested, 7.9% tested positive for thyroid autoantibodies. Dogs younger than two years of age tested positive in less than 5 percent of the samples, while the tests were positive between 9 and 11.5 percent of the time for between 2 and 6 years of age. The highest percentage of positive tests occurred at 4 years of age. The peak age for low thyroid hormone levels and no autoantibodies was eight years.

There are metabolic, infectious, endocrinologic, and cancerous illnesses that have no autoimmune components but which can nonetheless cause low thyroid-hormone values. This problem, which occurs less frequently is generally referred to as secondary hypothyroidism. It is not a hereditary thyroid disorder.

There is some controversy as to whether environmental toxins or vaccines cause autoimmune thyroiditis. These act as stresses on a dog's body and could possibly affect the onset or severity of autoimmune thyroiditis. However, Dr. W. Jean Dodds, founder of the animal blood bank Hemopet, states that only dogs that have the genetic potential can develop autoimmune thyroiditis. Therefore, any dog that has significant levels of blood-thyroid autoantibodies is considered genetically affected with hypothyroidism, and to carry a gene (or genes) that cause the disorder. Dr. Dodds also reports that thyroid supplementation may be protective to dogs with thyroid autoantibodies even before their thyroid hormone levels drop.

We now know that measuring autoantibodies is the best available way to diagnose hereditary hypothyroidism. The Orthopedic Foundation for Animals thyroid-registry database states: "As a result of the variable onset of the presence of autoantibodies, periodic testing will be necessary.... Since the majority of affected dogs will have autoantibodies by 4 years of age, annual testing for the first 4 years is recommended. After that, testing every other year should suffice. Any test showing significant levels of thyroid autoantibodies confirms a diagnosis of hereditary hypothyroidism."

Compounding the problem of just who has hereditary hypothyroidism are the myriad of conditions that can respond to thyroid supplementation. The clinical signs of hypothyroidism can appear in dogs that have conditions which are not related to thyroid problems, and these conditions may respond to thyroid supplementation. Just because a dog has a condition that responds to thyroid supplementation, it should not be assumed the dog has hypothyroidism. Unless autoantibodies or low thyroid hormone levels are found, most of these dogs are probably thyroid-normal.

Studies on the mode of inheritance of hereditary hypothyroidism/autoimmune thyroiditis in dogs have been inconclusive to date. What has been established is that some breeds have a much greater likelihood of developing autoimmune thyroiditis than do others, while some breeds have a below-average risk. (see tables). These breeds respectively carry a higher or lower genetic load of hypothyroidism causing genes. As opposed to human autoimmune thyroiditis (Hashimoto's disease), where there is a female to male 10-to -1 ratio, hypothyroidism affects male and female dogs about equally.

Research into hypothyroidism has concentrated on perfecting the diagnostic tests and, in affected dogs, outlining the progression of the disease. There is no active research at this time into the mode of inheritance of canine hereditary hypothyroidism. It is hoped that with more reliable data on which dogs are affected (producing autoantibodies at a young age) and the further development of canine genome screening, we can learn how to better control the disease through selective breeding. At this point, the recommendation that can be offered is the standard one for dealing with polygenic hereditary diseases: Breed normal-testing dogs that come from litters which have mostly tested normal.

Breeds with the highest prevalence (>9% affected) of hypothyroidism (Data from the endocrinology lab at Michigan State University)

English Setter, Dalmatian, Basenji, Rhodesian Ridgeback, Old English Sheepdog, Boxer, Maltese Dog, Chesapeake Bay Retriever, Beagle, Cocker Spaniel, Shetland Sheepdog, Siberian Husky, Border Collie, Husky, Akita, Golden Retriever.

Breeds with the lowest prevalence (<3% affected) of hypothyroidism (Data from the endocrinology lab at Michigan State University)

Chihuahua, Lhasa Apso, Pomeranian, Miniature Pinscher, Cairn Terrier, Basset Hound, Schnauzer, Yorkshire Terrier, Boston Terrier, Norwegian Elkhound, Greyhound, Portuguese Water Dog, Newfoundland, Bichon Frise, Welsh Corgi, Miniature Schnauzer, Cavalier King Charles Spaniel, Flat Coated Retriever.

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Background

Behavioral and psychological changes have been associated with thyroid dysfunction in humans for several hundred years. About two-thirds of human patients with attention deficit-hyperactivity disorder were found to be hypothyroid in a recent study, and supplementing them with thyroxine was largely curative. In animals, hyperthyroid cats tend to be more irritable and show increased vocalization, whereas hypothyroid dogs -- especially those younger dogs with autoimmune thyroiditis -- can display a wide variety of aberrant behaviors.

Although genetic influences on behavioral disorders rarely account for more than half of the phenotypic expression of behavioral differences, inheritance clearly plays an important role. There are multiple genes involved and each can contribute to the overall expression of behavior. While application of newer molecular techniques offers the potential of identifying the DNA marker sequences responsible for behavioral variation, this is especially challenging because behavior is the most complex phenotype. It reflects not only whole body function, but also the body's dynamic changes in response to environmental influences.

For several thousand years now, animals have been bred and selected for their behavior as much as their conformation. This application of behavioural genetics is exemplified by the dramatic differences in behavior and physique among various dog breeds. Today, although dogs (and cats) have a great range of genetic and behavioral variability, a shocking 13 million of them -- 10% of the total pet population -- are being destroyed annually because of behavioral problems.

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Theory

How diminished thyroid function affects behavior is mechanistically unclear. It may relate to the adrenal axis, as some hypothyroid patients have reduced cortisol clearance with chronically elevated circulating cortisol levels. This would mimic a constant state of stress, which could suppress pituitary TSH output and reduce production of thyroid hormones. Chronic stress in humans has been implicated in the pathogenesis of affective disorders such as depression. Major depression has been shown in imaging studies to produce changes in neural activity or volume in areas of the brain which regulate aggressive and other behaviors. Dopamine and serotonin receptors have been clearly demonstrated to be involoved in aggressive pathways in the CNS. Hypothyroid rats have increased turnover of serotonin and dopamine receptors, and an increased sensitivity to ambient neurotransmitter levels, as do mice, rats, and certain types of monkeys. In humans and dogs, mental function is impaired and the animal is likely to respond to stress in a stereotypical rather than a reasoned fashion.

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Current Behavioral Issues

In recent years, clinicians have noted the sudden onset of behavioral changes in dogs around the time of puberty or as young adults. Most of the animals have been purebreds or crossbreeds with an apparent predilection for certain breeds. Neutering these animals usually does not alter the symptoms and the behaviors may even intensify. Many of these dogs belong to certain breeds or dog families susceptible to a variety of immune problems and allergies (e.g. Golden Retriever, Akita, Rottweiler, Doberman Pinscher, English Springer Spaniel, Shetland Sheepdog, and German Shepherd Dog). The clinical signs in these animals, before they show the sudden onset of behavioral aggression, can include minor problems such as inattentiveness, fearfulness, seasonal allergies, skin and coat disorders (e.g. pyoderma, allergic inhalant or ectoparasite dermatitis, alopecia, and intense itching). These may be early subtle signs of thyroid dysfunction, with no other typical signs of thyroid disease being manifested.

The typical history starts out with a quite, well-mannered and sweet-natured puppy or young adult dog. The animal was outgoing, attended training classes for obedience, working, or dog show events, and came from a reputable breeder whose kennel has had no prior history of producing animals with behavioral problems. At the onset of puberty or thereafter, however, sudden changes in personality are observed. Typical signs can be incessant whining, nervousness, schizoid behavior, fear in the presence of strangers, hyperventilating and undue sweating, disorientation, and failure to be attentive (canine cognitive dysfunction). These changes can progress to sudden unprovoked aggressiveness in unfamiliar situations with other animals, people and especially with children.

In adult dogs, moodiness, erratic temperament, periods of hyperactivity, lack of concentration, depression, mental dullness, lethargy, malaise, fearfulness and phobias, anxiety, submissiveness, passivity, compulsiveness, and irritability may be observed. After the episodes, most of the animals behave as though they were coming out of a trance like state, and are unaware of their previous behavior.

Another group of dogs show seizure or seizure-like disorders of sudden onset that can occur at any time from puberty to mid-life. These dogs appear perfectly healthy outwardly, have normal hair coats and energy, but suddenly seizure for no apparent reason. The seizures are often spaced several weeks to months apart, may coincide with the full moon, and can appear in brief clusters. In some cases the animals become aggressive and attack those around them shortly before or after having one of the seizures. The numbers of animals showing these various types of aberrant behavior appear to be increasing in frequency over the last decade.

In dogs with aberrant aggression, a large collaborative study between our group and Dr. Dodman and colleagues at Tufts University School of Veterinary Medicine has shown a favorable response to thyroid replacement therapy within the first week of treatment, whereas it took about three weeks to correct their metabolic deficit. Dramatic reversal of behavior with resumption of previous problems has occurred in some cases if only a single dose is missed. A similar pattern of aggression responsive to thyroid replacement has been reported in a horse.

A sudden onset of behavioral changes in an otherwise healthy young or older animal should alert the client and veterinarian to the possibility of an underlying thyroid imbalance. The age at onset can range widely from 6 months to 15 years; spayed females and neutered males are at increased risk in comparison to sexually intact animals; mid-sized to large breeds are more often involved; and purebreds are much more likely to be affected than mixed breeds. While abnormal behavior can reflect underlying problems of a psychological nature, it also can have a variety of medical causes. Therefore, the medical evaluation should include a complete history, clinical examination and neurological work up, routine laboratory testing of blood counts, blood chemistry and thyroid profiles, urinalysis, fecal exam and x-ray. Additional specific laboratory tests may be indicated based on the specifics involved. If all of these tests prove to be negative, evaluation by a qualified behavioral consultant should be undertaken.

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Diagnostic and Treatment Misunderstandings about Thyroid Disease

Veterinarians commonly are confused about which tests are necessary to accurately diagnose thyroid dysfunction in the dog and cat, as well as another animal species. During case review, many veterinarians contact us about the reference normal ranges provided by their commercial clinical laboratory. Many colleagues assume that these reference ranges are finite and apply to all breeds and breed types [toy and small breeds have higher basal levels, while large or giant breeds and sighthounds have lower basal levels], as well as all ages and physiological circumstances. For example, veterinarians are generally unaware that the printed reference ranges on laboratory reports typically pertain to adults, and not to very young, adolescent, [higher basal levels] or geriatric animals [lower basal levels].

Furthermore, these reference ranges are intended as general guidelines and may not apply to individuals that are athletic, performance animals; under general anesthesia; undergoing sex hormonal change; a pregnant or nursing mother; obese; a patient that is ill or recovering from illness, or taking specific drugs that might influence thyroid function (e.g. corticosteroids, phenobarbital, potentiated sulfonamides, dietary soy and soy phytoestrogens, insulin, narcotic analgesics, salicylates, tricyclic antidepressants, furosemide, phenylbutazone, and o, p1-DDD ). Daily diurnal rhythm fluctuations and the presence of circulating thyroid autoantibodies also changes basal thyroid levels. However, knowledge of these variables that affect thyroid function and circulating levels of thyroid hormones does not preclude their measurement. It is especially frustrating when a veterinarian tells the client that thyroid profiles cannot be measured accurately because the patient is receiving drugs such as corticosteroids or anticonvulsants. As long as the effects of these drugs are taken into account, there is no reason to avoid measuring thyroid function, especially when thyroid dysfunction may be an important underlying component of the patient's clinical problem.

While diagnosing thyroid dysfunction in companion animals can be particularly frustrating, especially when used for wellness screening of potential breeding stock, veterinarians may fail to appreciate that a simple total T4 test is usually nondiagnostic. In fact, the in-office testing of T4 has recently been shown to produce unreliable results in 52% of dogs and 62% of cats, and therefore should not be used even as a general diagnostic screening test. Complete thyroid profiling is the most accurate and correct way to diagnose thyroid dysfunction when coupled with clinical information about the animal. For genetic screening, thyroid testing requires not only thyroglobulin autoantibody (TgAA), but also circulating T3AA and T4AA, because not all dogs with autoimmune thyroiditis have positive TgAA, even though T3AA and/or T4AA are elevated [about 6% false negatives, presumably because the epitopes involved weren't recognized by the TgAA reagent.] Another significant problem is diagnostic over reliance on the canine endogenous TSH test. This test in the dog, unlike the equivalent one in humans, is only ~70% predictive, with a 20-40% discordancy rate (both false positives and false negatives occur).

In the cat, accurately diagnosing hyperthyroidism can be complicated when the animal has concurrent nonthyroidal illness or is very old. In geriatric cats with hyperthyroidism, the T4 can be suppressed to within the upper half of the normal adult reference range, not only because of the cat's age but also because of they commonly have other illnesses. Furthermore, the free T4 assay measured by equilibrium dialysis can provide misleading information, because the assay may be elevated in about a third of cats with pre-existing liver, kidney, and gastrointestinal disease. While some of these cats may also be hyperthyroid, others are clearly euthyroid.

Regarding treatment of thyroid disease, the most common confusion surrounds the expected thyroid values for patients receiving appropriate doses of thyroid supplement thyroid supplement, and whether the therapy should be given once or twice daily. In the dog, Larry supplement is best given twice daily, even though the label directions which of which have been the same for many years indicate once daily dosing. The reason that twice daily dosing is preferred is to match the typical 12-16 hour physiological half-life of thyroxine in the dog. Monitoring of thyroid therapy should be performed at 4-6 hours post dose, and at that time the T4 and free T4 values should be in the upper third to 25% above the laboratory's normal reference range. Rechecking thyroid profiles on animals receiving thyroid supplement is best accomplished by performing the complete profile, and is essential for those animals with autoimmune thyroiditis to determine whether the autoantibodies present are waning. If the client has financial constraints and the case is not thyroiditis, a post-pill T4 and freeT4 will usually suffice. Finally, in the cat treatment with methimazole should be given twice daily or by topical application to the ear, as recently published data indicate that once a day treatment has an unreliable therapeutic effect. When monitoring cats on methimazole, it doesn't matter when the sample is drawn in relation to giving the medication, as the turn over time is long.

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Examples from Case Studies

Aggression

Chip W. - Parsons Jack Russell terrier, 7 year-old neutered male. Mood swings, aggression towards the owners, dry flaky, greasy skin and itching. Seven days after the diagnosis of hypothyroidism the dog's behavior totally changed; he no longer attacks household members and the scratching has significantly diminished.

Tater N. - Bull Terrier, 3 year-old neutered male. Originally diagnosed with rage syndrome, thyroid tests confirmed autoimmune thyroiditis. He is also deaf, and had been in several homes after developing behavioral problems. His current home is with an animal health technician, where everything was fine for a few months. Then he would suddenly jump up during sleep and roar like a lion. He attacked any person or animal or thing nearby, and then would become fully awake but unaware that anything had happened. After a diagnosis of autoimmune thyroiditis, twice daily thyroid supplement was initiated. Within 6 weeks his abnormal behavior had disappeared to the extent that he is now 90% rage-free.

Bailey A. - Dalmatian, 6 year-old intact female. Unpredictable, aggressive behavior began at age 2 and has continually worsened. She sheds excessively and is extremely lethargic, sleeping most of the day and night. Thyroid testing confirmed end-stage hypothyroidism, and thyroxine supplement for just 10 days resulted in restoration of normal energy pattern, and a calming of her overall demeanor.

Passivity

Daphne O. - Golden retriever, 8 year-old spayed female. Began with anxiety and panic attacks; diagnosed with autoimmune thyroiditis. Before treatment was given, she became very lethargic, nonresponsive, and seemed unaware of her surroundings. Treatment with thyroxine twice daily restored her to normal activity level and behavior almost immediately.

Briar G. - Clumber spaniel, 5 year-old intact female. Acting very fatigued with signs of muscular weakness and massive coat shedding for two months. Not interested in any activity, refused to be touched or interact with other animals, children, or adults in the household. Testing revealed significant hypothyroidism, and treatment with twice daily thyroxine restored her attentiveness, energy level, as sociable behavior.

Phobias

Sherman C. - Cocker spaniel, 6 year-old intact male. This dog becomes easily excited and agitated during thunderstorms and other periods of noise, such as fire crackers. During these episodes he vocalizes, paces constantly, and cannot be touched. Diagnosed with autoimmune thyroiditis, he is now on twice daily thyroxine and once daily melatonin. His temperament is normal and his noise phobia appears to be under control. [This case illustrates the benefit of melatonin either alone or with thyroxine therapy, as needed, in managing phobias.]

Cognitive Disorder

Sally F. - English setter, 4 year-old spayed female. A top-winning obedience and agility dog, she suddenly began to lose concentration and misunderstand routine performance commands, especially during competition events. As the breed at highest risk for autoimmune thyroiditis, the owner requested testing, which confirmed the presence of thyroid autoantibodies and clinical hypothyroidism. Treatment with thyroid supplement twice daily restored her cognitive function within 30 days.

Hazel S. - Bloodhound, 6 year-old spayed female. This experienced search and rescue dog suddenly appeared to lose her concentration and scenting ability. With the exception of minor skin infections, she had produced a healthy litter and had never been ill. Testing revealed significant hypothyroidism, which responded to twice daily replacement with thyroxine and a restoration of her scenting and tracking ability.

Seizure Disorder

Rocky McC. - Golden retriever, 2 year-old intact male. Presented with cluster seizures. Thyroid testing revealed elevated TgAA, although basal thyroid levels were normal. A rabies vaccine had been given one month before the onset of seizures, and the area had been treated with pesticides. He was fed a raw food diet, but the allopathic veterinarian declined to accept him as a patient unless his diet was changed to commercial pet food. A holistic veterinarian was contacted, and he is now taking thyroxine and Pb. He has been seizure-free for 6 months.

Daisy M. - Labrador retriever mix, 5 year-old spayed female. This dog has idiopathic epilepsy under relatively poor control (seizures every 3 weeks). When routine booster vaccinations would normally be given, vaccine antibody titers were measured for parvovirus, distemper virus, and coronavirus. Titer results for parvovirus and distemper were extremely high indicating a very good level of immune memory, but coronavirus titer was poor. Her neurologist insisted on a polyvalent booster vaccination because of the low coronavirus titer and risk of contracting parvovirus disease. Needless to say the client was amazed, because the vaccine titer for parvovirus was very high, and gastrointestinal immunity affords coronavirus protection rather than serum antibody levels. Booster vaccination was not given and another specialist agreed to prescribe thyroxine twice daily, as very low thyroid function was also discovered.

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References

1. Rugg L C. Coping with thyroid disease. AKC Gazette, 120 (7): 48-51, 2003.

2. Nachreiner R F, Refsal K R, Graham P A, Bowman M M. Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. J Am Vet Med Assoc, 220: 466-471, 2002.

3. Bell J S. Hereditary hypothyroidism:understanding the disease process. AKC Gaz, 118(8): 24-27, 2001.

4. Graham P A, et al A 12-month prospective study of 234 thyroglobulin autoantibody positive dogs which had no laboratory evidence of thyroid dysfunction. Proc 19th ACVIM, abst. 105, 2001.

5. Dodds W J. Canine autoimmune thyroiditis:1000 cases. Proc AHVMA, 77-79, 1999.

6. Nachreiner RF, Refsal KR, Graham PA, et al. Prevalence of autoantibodies to thyroglobulin in dogs with nonthyroidal illness. Am J Vet Res 59:951-955, 1998.

7. Scott-Moncrieff JCR, Nelson RW, Bruner JM, et al. Comparison of thyroid-stimulating hormone in healthy dogs, hypothyroid dogs, and euthyroid dogs with concurrent disease. J Am Vet Med Assoc 212:387-391, 1998.

8. International Symposium on Canine Hypothyroidism. Can Pract 22 (1) : 4-62, 1997.

9. Panciera DL. Clinical manifestations of canine hypothyroidism. Vet Med 92: 44-49, 1997.

10. 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 211:1396-1402, 1997.

11. Dodds WJ. Autoimmune thyroiditis and polyglandular autoimmunity of purebred dogs. Can Pract 22 (1): 18-19, 1997.

12. Dodds WJ. What's new in thyroid disease ? Proc Am Hol Vet Med Assoc 1997, pp 82-95.

13. Dixon RM, Graham PA, Mooney CT. Serum thyrotropin concentrations: a new diagnostic test for canine hypothyroidism. Vet Rec 138: 594-595, 1996.

14. Dodds WJ. Estimating disease prevalence with health surveys and genetic screening. Adv Vet Sci Comp Med 39: 29-96, 1995.

15. Thacker EL, Refsal KR, Bull RW. Prevalence of autoantibodies to thyroglobulin, thyroxine, or triiodothronine and relationship of autoantibodies and serum concentration of iodothyronines in dogs. Am J Vet Res 53: 449-453, 1992.

16. Cox D. Is Fido acting strange ? It could be his thyroid. Animal Wellness 6(2):14-15, 2004.

17. Beaver BV, Haug LI. Canine behaviors associated with hypothyroidism. J Am An Hosp Assoc, 39: 431-434, 2003.

18. Dodds WJ. Behavioral changes associated with thyroid dysfunction in dogs. Proc Am Hol Vet Med Assoc, 80-82, 1999.

19. Overall KL. Clinical Behavioral Medicine for the Small Animal. St. Louis, Mosby, 1998.

20. Uchida Y, Dodman NH, DeNapoli J, Aronson LP. Characterization and treatment of 20 canine dominance aggression cases. J Vet Med Sci 59:397-399. 1997.

21. Dodman NH, Mertens PA, Aronson, LP. Aggression in two hypothyroid dogs, behavior case of the month. J Am Vet Med Assoc 207:1168-1171, 1995.

22. Hauser P, Zametkin AJ, Martinez, P et al. Attention deficit-hyperactivity disorder in people with generalized resistence to thyroid hormone. N Eng J Med 328:997-1001, 1993.

23. Denicoff KD, Joffe RT, Lakschmanan MC, Robbins J, Rubinow DR. Neuropsychiatric manifestations of altered thyroid state. Am J Psych 147:94-99, 1990.

24. Reinhard DW. Aggressive behavior associated with hypothyroidism. Can Pract 5:69-70, 1978.

25. Beaver BV. Canine aggression. Proc Am An Hosp Assoc 50th annual meeting, 3-4, 1983.

26. Dodds WJ. Apply systemic diagnostic plan to assess aggression: behavior linked to thyroid disease. DVM Mag 23(5):22-23, 1992.

27. Scott-Moncrieff JCR, Guptill-Yoran L. Hypothyroidism. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 5th ed. Philadelphia: WB Saunders, 2000, pp 1419-1429.

28. Beaver BV. Canine behavior: a guide for veterinarians. In: Beaver BV, ed. Philadelphia: WB Saunders, 1999, pp137-199.

29. Ferguson DC. The dog as a model of thyroid physiology. Proc 16th Am Coll Vet Intern Med Forum, 565-567, 1998.

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Bizarre Behavioral Changes? Check your dog for hypothyroidism.

Abnormal behavior in dogs can have a variety of medical causes; it also can reflect underlying problems of a psychological nature.  Your veterinarian follows a systematic diagnostic approach in searching for medical causes when a per exhibits unusual or unacceptable behavior.  As summarized by Landsberg (Canadian Veterinary Journal, 31:225-227, 1990), this includes:

1. a complete patient history;

2. clinical examination and a neurological work-up;

3. routine laboratory testing of complete blood count, blood biochemistry and thyroid profiles, urinalysis, fecal exam and X-ray;

4. additional specific laboratory tests as indicated (e.g., other hormonal tests, bile acids, blood ammonia, glucose tolerance immunologis assays and tests for toxins, fungi and other infections;

5. examination of cerebral spinal fluid; and

6. more specialized neurological examinations such as an electroencephalography and computerized axial tomography scan.

Diagnostic steps 1 through 3 are usually completed first; additional tests such as steps 4 through 6 are performed if indicated.  If these test results prove to be negative, a veterinary behavior consultant or qualified pet behavior therapist should evaluate the dog.

Inheritance has been shown to play an important part in the behavior of both animals and humans; Plomin recently reviewed its role (Science, 248:183-188, 1990).  The genetic influence on behavioral disorders rarely accounts for more than half of the phenotypic expression of behavioral differences.  Each of the multiple genes involved has a small effect on behavior.  Newer techniques in molecular biology should permit the identification of the genetic DNA marker sequences responsible for behavioral variation.

However, behavior is the most complex phenotype because it not only reflects the functioning of the whole organism, but it is dynamic and changes in response to environmental influences.  With respect to animal behavior, applied behavioral genetics first was studied several thousand years ago because animals were bred and selected for their behavior as much as their conformation.  The results can be attested to by the dramatic differences in behavior and physique among various dog breeds.  Today these breeds have a great range of genetic and behavioral variability.

In recent years, many investigators have noted the sudden onset of behavioral changes in dogs around the time of puberty.  Most of the dogs have been purebreds or crossbreds with an apparent predilection for certain breeds (e.g., Golden Retrievers, Shetland Sheepdogs, German Shepherds, Cocker Spaniels, Akitas, Doberman Pinschers and Rottweilers).  Many of these dogs also had begun to show the seasonal effects of allergies to inhalants and ectoparasites such as fleas, followed by the onset of skin and coat disorders, including pyoderma, allergic dermatitis, alopecia and intense itching.

A typical history starts out with a quiet, well-mannered and sweet natured puppy.  The dog is outgoing, has attended puppy training classes to prepare for obedience, working or show events, and comes from a reputable breeder whose kennel has no history of behavioral problems.

However, at the onset of puberty, which varies from seven months to a year in age, sudden major changes in personality are observed.  Typical signs may include incessant whining, nervousness, schizoid behavior, fear in the presence of strangers, hyperventilation, undue sweating, occasional disorientation and failure to be attentive.  These can progress to sudden unprovoked aggressiveness in unfamiliar situations with other animals and with people, especially children.

The owners may attribute the problems to the sex hormonal changes accompanying puberty or just the uncertainties of adolescent development.  Often these animals are neutered, which appears to alleviate the behavioral problems, specifically the aggression, for varying lengths of time.  For a significant proportion of these animals, however, neutering does not alter the symptoms and they intensify progressively to the point that the adult can be described as flaky, unable to handle any kind of stress, frantically circling, hyperventilating and not able to settle down.  Animals used for field work and tracking often fail to follow the scent, whereas those in obedience training may lose the scent articles.  Their powers of concentration are often very short and so dogs that were training very successfully at obedience appear to lag behind in a disinterested fashion.  With all of these changes in behavior, the problem of most concern is unwarranted aggression.  When large breeds are affected it poses a significant hazard to family members, friends and strangers.

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In some cases affected animals do not show aggression but become very shy and fearful to the point that they are social outcasts and do not make acceptable house pets.  These animals clearly are not suitable for show, obedience or working purposes.  Some of these dogs will show extremely submissive behavior, roll over and urinate upon being approached.

The third group of dogs showing aberrant behavior consists of those that experience seizure or seizure-like disorders beginning in puberty and continuing to mid-life.  These are dogs that appear perfectly healthy outwardly and have normal hair coats and energy, but suddenly experience seizures for no apparent reason.  The seizures are often spaced several weeks to months apart, and occasionally they appear in a brief cluster.  In some cases the animals become aggressive and attack those around them shortly before or after having one of these seizure episodes.

The number of dogs showing various types of abnormal behavior in these three classical modes (aggression, extreme shyness or seizure-like activity) has been increasing over the last decade.  Veterinary colleagues have remarked that in recent years some young dogs have become completely unacceptable because of bizarre, sudden behavioral changes.  Consequently, we began to examine these animals by using the stepwise diagnostic approach outlined previously.  The importance of performing complete laboratory profiles in the blood and urine, with specific emphasis on thyroid hormonal function was stressed.

We were surprised to find that in many of the cases studied, significant abnormalities were found in the thyroid profile.  Some cases also had changes in the liver enzyme patterns, specifically with abnormal increases in pre and post meal bile acids and elevated gamma glutamyl transerase levels.  About 10 percent of these young dogs had abnormalities of the liver profile and a few also had changes in renal function.  For the majority, however, the primary abnormality was attributable to abnormal thyroid function.  This thyroid dysfunction would classically express high levels of T3 and T4 autoantibodies with an artifactual, apparent elevation of total T3 level.  It would not be uncommon to find circulating total T3 levels that read as much as 3,000 to 5,000 nanograms per deciliter.  While not all of the affected animals had documented evidence of T3 and T4 autoantibodies, some of these had positive antithyroglobulin antibody tests.  In either event, the diagnosis was confirmed as autoimmune thyroiditis.

The autoimmune thyroid disease present in these patients apparently is inducing some type of physiological change at the cellular lever, which leads to the aberrant behavior.  This supposition can be made with some assurance because treatment of thyroiditis of these dogs with appropriate doses of thyroid replacement hormone given twice daily along with a one-month tapering course of low-dose corticosteroids, has successfully reversed the behavioral problems within four to eight weeks.  Dramatic changes in behavior have been recognized in a few cases as early as after 10 days of therapy.

By contrast, it usually takes five to seven months of thyroid replacement therapy to effect complete disappearance of the circulating antithyroid antibodies.  These dogs should be maintained for life on the appropriate dose of thyroid hormone, which may need to be adjusted periodically.

Another subset of affected dogs consists of those that do not have demonstrable antithyroid antibodies but have baseline thyroid profiles that are clearly abnormal.  In these cases, levels of total T4, total T3, free T4 and free T3 are usually well below the lowest limits of the adult normal ranges or are in the low normal or borderline ranges.  The latter situation is of particular significance in young dogs of nine to 15 months of age.  When these dogs are treated with standard doses of thyroid replacement therapy (0.1 milliliter per 10 pound of body weight, given twice daily) the clinical signs associated with abnormal behavior rapidly resolve.

To date (October 1992) more than 25 animals have been diagnosed as having thyroid imbalance as the major, if not exclusive, cause of their behavioral abnormalities.  Some of these animals have been followed for as long as three years and are still exhibiting abnormal behavior.  Animals on therapy have returned successfully to obedience activities, completed show championships and undertaken active field and tracking work.

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Here are two case studies as examples:

In the first, a four-year-old male Akita, weighing 110 pounds, suddenly attacked his owner and bit her in the face.  The dog had been owned by the same family since early puppyhood and had been a remarkably even tempered, well-behaved and non-aggressive pet with people and other animals.  After seeking the advice of two different veterinary clinicians and a major teaching hospital, the owner was about to give up in despair because no physical abnormalities could be found.

She was referred to us by an Akita rescue group, as this pattern of behavioral change has been associated with thyroid dysfunction in the breed.  A complete thyroid panel which had not been performed earlier, was suggested and the dog was found to be hypothyroid.  Thyroid therapy was initiated on a twice-daily basis.  The dog's exemplary temperament returned and he has not shown any unusual behavior for more than a year.  An interesting additional complication of the case was a moderately severe thrombocytopenia which also resolved with low doses of alternate-day steroid therapy and thyroid medication.

in the second, a nine month old male Shetland Sheepdog from excellent show-quality bloodlines suddenly became frantic and fearful.  Acting intermittently, as if his vision were impaired he attacked a toddler in the owner' home.  A complete physical examination was given and laboratory testing done; a routine check for T4 was borderline normal.  The dog's abnormal behavior appeared to resolve, but soon reappeared.

After a second attack the dog had a complete thyroid profile done at Michigan State University's Animal Health Diagnostic Laboratory.  The total T4 was 44 nmol/1, total T3 was 0  nmol/1, free T4 was 2pmol/1, free T3 was >20 pmol/1, T4 autoantibody was 18 and T3 autoantibody was 85.  The referring veterinarian did not realize that the results were consistent with autoimmune thyroiditis and the dog was not treated.  Two months later the dog attacked another person and a second thyroid profile was sent to the Michigan State Laboratory.  The second profile showed a total T4 of 29 nmol/1, total T3 of 0 nmol/1, free T4 of 25 pmol/1 free T3 of >20 pmol/1, T4 autoantibody of 48 and T3 autoantibody of 91.  Consultation with our group was made at this point.

The dog had a previous history of facial demodectic mange; because corticosteroids are not recommended with demodecosis, the treatment consisted for a full therapeutic dose of T4 thyroid supplement at 0.1 milligram per 10 pounds and a one-third dose of T3 thyroid supplement at 1 microgram per pound, both given twice daily.  The rationale for treating with both T4 and T3 supplements in this case was to attempt to normalize the thyroid axis as quickly as possible to avoid danger to family members.  At the time of this writing the dog's behavioral aggression has subsided.

For those animals that show occasional seizure disorders, thyroid medication alone usually will suffice.  Anticonvulsant medication is needed along with the thyroid therapy to control cases with more severe seizure clusters.  The anticonvulsants of choice would be phenobarbital or, alternatively, sodium bromide, particularly if the patient has abnormalities of liver function.

Because many of these animals have autoimmune thyroid disease, concomitant medical management includes avoiding environmental factors that can further challenge the immune system.  This means placing the animal on a hypoallergenic "natural" diet preserved with vitamins E and C (e.g., land and rice based lower-protein kibble without added chemical preservatives); avoiding drugs such as the potentiated sulfonamide antibiotics and monthly heartworm preventatives that may adversely affect the immune system in these susceptible dogs; and withholding vaccination boosters until the thyroid function is balanced properly and the behavioral abnormalities are resolved.  If animals are due for annual vaccine boosters during this period, vaccine antibody titers for distemper and parvovirus can be determined.

If your otherwise healthy young or adult dog experiences sudden behavioral changes, you should consult your vet and check for an underlying thyroid imbalance as shown by:

1. The presence of thyroid autoantibodies
2. Low or borderline levels of total T4, total T2 and Free T4 or
3. Failure to triple baseline total T4 levels in response to challenge with thyroid-stimulating hormone.

In our experience, the most predictive thyroid test parameters to identify these cases are 1 and 2, because the thyroid stimulating hormone response test just measures thyroid reserve, which remains adequate in the early stages of thyroid disease.

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In North America, the principal reason for pet euthanasia stems not from disease, but undesirable behavior.  While this abnormal behavior in dogs and cats can have a variety of medical causes, it also can reflect underlying problems of a psychological nature.

Inheritance has been shown to play an important role in the behavior of both animals and humans.  The role of inheritance in behavior was reviewed by Plomin (Science 248:183-188, 1990), who pointed out that the genetic influence on behavioral disorders rarely accounts for more than half of the phenotypic expression of behavioral differences.  Each of the multiple genes involved has a small effect on behavior.  Development and application of newer techniques in molecular biology offers the promise of identifying the DNA marker sequences responsible for behavioral variation.  However, behavior is the most complex phenotype because it reflects not only the functioning of the whole organism but also is dynamic and changes in response to environmental influences.  With respect to animal behavior, applied behavioral genetics was first studied several thousand years ago because animals were bred and selected for their behavior as much as their conformation.  The results can be attested to by the dramatic differences in behavior and physique among various dog breeds.  Today these breeds have a great range of genetic and behavioral variability.

Many investigators in recent years, have noted the sudden onset of behavioral changes in dogs around the time of puberty.  Most of the dogs have been purebreds or crossbreds with an apparent predilection for certain breeds.  For a significant proportion of these animals, neutering does not alter the symptoms and in some cases the behaviors intensify.  The seasonal effects of allergies to inhalants and ectoparasites such as fleas, followed by the onset of skin and coat disorders including pyoderma, allergic dermatitis, alopecia, and intense itching, have also been linked to changes in behavior.

Another interesting association which as been increasing in frequency is the link between thyroid dysfunction and aberrant behavior.  Typical clinical signs include unprovoked aggression towards other animals and/or people, sudden onset of a seizure disorder in adulthood, disorientation, moodiness, erratic temperament, periods of hyperactivity, hypo-attentiveness, depression, fearfulness and phobias, anxiety, submissiveness, passivity, compulsiveness, and irritability.  After the episodes, a majority of the animals were noted to behave as if they were coming out of a trance- like state and were unaware of their previous behavior.

A similar association between behavioral and psychologic changes and thyroid dysfunction has been recognized in humans since the 19th century, and more recently has been noticed in cats with hyperthyroidism.  In a recent human study, 66% of patients with attention deficit-hyperactivity disorder were found to be hypothyroid, and supplementing their thyroid levels was largely curative.

The mechanism whereby diminished thyroid function affects behavior is unclear.  Hypothyroid patients have reduced cortisol clearance, and the constantly elevated levels or circulating cortisol mimic the condition of an animal in a constant state of stress, as well as suppressed TSH output and production of thyroid hormones.  In humans and seemingly in dogs, mental function is impaired and the animal is likely to respond to stress in a stereotypical rather than a reasoned fashion.  Chronic stress in humans has been implicated in the pathogenesis of affective disorders such as depression.  Major depression has been shown in imaging studies to produce changes in neural activity or volume in areas of the brain which regulate aggressive and other behaviors.  Dopamine and serotonin receptors have been clearly demonstrated to be involved in aggressive pathways in the CNS.  Hypothyroid rats have increased turnover of serotonin and dopamine receptors, and an increased sensitivity to ambient neurotransmitter levels.  In dogs with aberrant aggression, a large collaborative study at Tufts University has shown a favorable response to thyroid replacement therapy within the first week of treatment, whereas it took about three weeks to correct their metabolic deficit.  Dramatic reversal of behavior with resumption of previous problems has occurred in some cases if only a single dose is missed.  A similar pattern of aggression responsive to thyroid replacement has been reported in a horse.

Tables 1 and 2 summarize results of complete thyroid diagnostic profiling on 634 canine cases of aberrant behavior, compiled by the authors in collaboration with Drs. Nicholas Dodman, and Jean DeNapoli of Tufts University School of Veterinary Medicine, North Grafton, MA.

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Table 1. Canine Aberrant Behavior *

* Mean Age, 3.7 years (Range 0.5-12 years).  Median Age, 2.5 years. 

Table 2. Most Commonly Represented Breeds with

Thyroid Dysfunction and Aberrant Behavior*

* Some dogs had more than 1 abnormal behavior.
Numerator = Thyroid Dysfunction.  Denominator = Aberrant behavior

*Ninety percent (568 dogs) were purebreds and 10% were mixed breeds.

*There was no sex predilection found in this case cohort, whether or not the animals were intact or neutered.

*63% had thyroid dysfunction as judged by finding 3 or more abnormal results on the comprehensive thyroid profile

*The major categories of aberrant behavior were:  aggression (40% of cases), seizures (30%), fearfulness (9%), and hyperactivity (7%); some dogs exhibited more than 1 of these behaviors.

*Thyroid dysfunction was found in 62% of the aggressive dogs, 77% of seizuring dogs, 47% of fearful dogs, and 31% of hyperactive dogs.

*Outcomes of treatment intervention with standard twice daily doses of thyroid replacement were evaluated in 95 cases.  Of these, 58 dogs had greater than 50% improvement in their behavior as judged by a predefined 6-point subjective scale (34 were improved >75%), and another 23 dogs had >25 but <50% improvement.  Only 10 dogs experienced no appreciable change, and 2 dogs had a worsening of their behavior.  When compared to 20 cases of dominance aggression treated with conventional behavioral or other habit modification over the same time period, only 11 dogs improved >25% and of the remaining 9 cases, 3 failed to improve and 3 were euthanized or placed in another home.  These initial results are so promising that complete thyroid diagnostic profiling and treatment with thyroid supplement, where indicated, is warranted for all cases presenting with aberrant behavior.

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References

1. Baverman LE, Utiger RD (eds). Werner and Ingbar's The Thyroid:  A Fundamental and Clinical Text, 7th ed.  Philadelphia, Lippincott-Raven, 1996.

2. Cameron DL, Crocker AD.  The hypothyroid rat as a model of increased sensitivity to dopamine receptor agonists.  Pharm Biochem Behav 37:627-632, 1990

3. Denicoff KD, Joffe RT, Lakschmanan MC, Robbins J, Rubinow DR.  Neuropsychiatric manifestations of altered thyroid state. Am J Psych 147:94-99, 1990

4. Dewey CW, Shelton GD, Bailey, CS.  Neuromuscular dysfunction in five dogs with acquired myasthenia gravis and presumptive hypothyroidism.  Prog Vet Neurol 6:117-123, 1995.

5. Dodds, WJ. Estimating disease prevalence with health surveys and genetic screening.  Adv Vet Sci Comp Med 39: 29-96, 1995.

6. Dodds WJ.  What's new in thyroid disease?  Proc AM Hol Vet Med Assoc 1997; pp 82-95.

7. Dodman NH, Mertens PA, Aronson, LP.  Aggression in two hypothyroid dogs, behavior case of the month J Am Vet Med Assoc 207:1168-1171, 1995.

8. Happ GM.  Thyroiditis - A model canine autoimmune disease.  Adv Vet Sci Comp Med 39: 97-139, 1995.

9. Hauser P, Zametkin AJ, Martinez, P et al.  Attention deficit-hyperactivity disorder in people with generalized resistence to thyroid hormone.  N Eng J Med 328:997-1001, 1993.

10. Henley WN Chen X, Klettner C. Bullush LL, Notestine MA. Hypothyroidism increases serotonin turnover and sympathetic activity in the adult rat.  Can J Physiol Parmacol 69:205-210, 1991.